MAT2A inhibitors

Abstract

The present invention discloses a MAT2A inhibitor, and specifically, relates to a compound or a pharmaceutically acceptable salt thereof as shown in Formula I. The definitions of each substituent are as described in the specification, and the present invention also provides a preparation method thereof.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a MAT2A inhibitor and a preparation method thereof. Background Art

[0002] Methionine adenyltransferase (MAT), also known as S-adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP and is considered to be the rate-limiting step of the methionine cycle. In the liver, the methionine cycle has an additional function, mainly to quickly remove excess methionine in the blood after a high methionine or high protein diet, and finally transport it to other organs through homocysteine, cysteine, cystathionine, and glutathione. MTAP (methylthioadenosine phosphorylase) is an enzyme widely expressed in normal tissues that catalyzes the conversion of MTA to adenine and 5-methylthioribose-1-phosphate. Adenine is recycled to generate adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Due to this salvage pathway, MTA can be used as a source of alternative purines when de novo purine synthesis is blocked, such as L-alanosine antimetabolites.

[0003] There are three different isoforms of MAT: α (or MATI), β (or MATIII), and γ (or MATII). MATI and MATIII are liver-specific and encode the same gene, MAT1A, which is a marker of liver differentiation or mature phenotype. MATII encodes another completely different gene, MAT2A. A third gene, MAT2B, encodes the regulatory subunit of MAT2A. MAT1A is specifically expressed in adult liver, while MAT2A is widely distributed. MAT1A is a marker of high differentiation of hepatocytes, which stops expressing in hepatocellular carcinoma (HCC) and decreases in patients with liver disease. This switch between MAT1A / MAT2A is conducive to the rapid growth of liver cancer cells.

[0004] In HCC, MAT1A downregulation and MAT2A upregulation occur, which is called the MAT1A:MAT2A switch. This switch is accompanied by the upregulation of MAT2B, resulting in a decrease in SAM content, which provides a growth advantage for liver cancer cells. The SAM level of MAT1A-expressing cells is much higher than that of MAT2A-expressing cells. Studies have found that hypomethylation of the MAT2A promoter and histone acetylation cause upregulation of MAT2A expression. Because MAT2A plays a crucial role in promoting the growth of liver cancer cells, it is a target for anti-tumor therapy. Recent studies have shown that silencing using small interfering RNA can significantly inhibit the growth of liver cancer cells and induce cell apoptosis.

[0005] Some MTAP-deficient cancer cells are particularly sensitive to MAT2A inhibition. Many human and mouse malignant tumor cells lack MTAP activity. MTAP deficiency is not only found in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma. Therefore, finding effective MAT2A inhibitors is an important direction for the current development of tumor-targeted drugs. Summary of the invention

[0006] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in:

[0009] Selected from

[0010] R 1 is selected from phenyl, 5-8 membered heterocyclic group, 5-6 membered cycloalkenyl group, C1-C3 alkyl group, C1-C3 alkanoyl group, NR a R b , C2-C4 alkynyl or C5-C7 cycloalkyl, wherein the 5-8 membered heterocyclic group is optionally substituted by methyl or halogen, and the C1-C3 alkyl is optionally substituted by phenyl or pyrrolidinyl;

[0011] R a is H or C1-C3 alkyl;

[0012] R b for C1-C3 alkyl or C3-C5 cycloalkyl;

[0013] R 2 is H, C1-C3 alkyl or NH2, wherein the NH2 may be substituted by pyridyl;

[0014] R 3 is a phenyl group optionally substituted by a C1-C3 alkoxy group;

[0015] R 4 Selected from H;

[0016] or R 4 , Together with the atoms to which they are attached, they form a six-membered nitrogen-containing heterocyclic ring;

[0017] X is a bond, O, -NR c, methylene, ethylene, vinylene or ethynylene, wherein the methylene group is optionally replaced by R 7 replace;

[0018] R 7 is selected from C1-C4 alkyl, hydroxy, MeO, C3-C5 cycloalkyl or ethynyl, wherein the C1-C4 alkyl is optionally substituted by halogen or C1-C3 alkoxy;

[0019] R c is a C1-C3 alkyl group;

[0020] R 5 is selected from phenyl or 5-12 membered heteroaryl, wherein the group is optionally substituted by one or more R 8 replace;

[0021] R 8 is selected from C1-C4 alkyl, hydroxy, halogen, benzyloxy, NH2, C1-C5 alkoxy, pyrrolidinyl, =O, C3-C5 cycloalkyl or ethynyl; wherein the C1-C4 alkyl is optionally substituted with halogen or methoxy, and the NH2 is optionally substituted with methyl, Acetyl or C1-C3 alkyl optionally substituted by MeO or cyclopropyl, the C1-C5 alkoxy optionally substituted by halogen, MeO or cyclopropyl;

[0022] or R 5 The ring carbon atoms on R 2 Together with the atoms to which they are attached, they form a 7-10 membered ring.

[0023] In some embodiments, for

[0024] In some embodiments, R 1 NR a R b , phenyl, isopropyl, methyl, acetyl, ethynyl, The Optionally substituted with methyl or fluorine, said methyl or isopropyl optionally substituted with phenyl or replace.

[0025] In some embodiments, R a It is hydrogen or methyl.

[0026] In some embodiments, R a is hydrogen or ethyl; in some typical embodiments, R a H is preferred.

[0027] In some embodiments, R b for ethyl or cyclopentyl; in some typical embodiments, R b Best

[0028] In some embodiments, R 1 Selected from:

[0029]

[0030] In some typical embodiments, R 1 Selected from

[0031] In some more typical embodiments, R 1 Selected from

[0032] In some embodiments, R 4 Selected from hydrogen or R 4 , Together with the atoms they are attached to form:

[0033]

[0034] In some typical embodiments, R 4 Selected from hydrogen.

[0035] In some embodiments, R 2 It is hydrogen, methyl or NH2 substituted by pyridyl.

[0036] In some typical embodiments, R 2 Methyl or

[0037] In some more typical embodiments, R 2 It is methyl.

[0038] In some embodiments, R 3 It is a phenyl group substituted by a methoxy group.

[0039] In some typical embodiments, R 3 It is 4-methoxyphenyl.

[0040] In some embodiments, X is selected from a bond, O, -NMe, methylene, ethylene, ethynylene, or vinylene; wherein the methylene is optionally replaced by R 7 replace.

[0041] In some more typical embodiments, X is selected from a bond or a methylene group, wherein the methylene group is optionally replaced by R 7 replace.

[0042] In some embodiments, R 7 Selected from methyl, ethyl, isopropyl, n-butyl, cyclopropyl, hydroxy, OMe, ethynyl, methoxyethyl, CF2HCH2, CF3CH2 or CF3.

[0043] In some embodiments, R 7 Selected from methyl, ethyl, isopropyl or OMe.

[0044] In some more typical embodiments, R 7 Selected from methyl or ethyl.

[0045] In some typical embodiments, R 7 Selected from methyl.

[0046] In some embodiments, R 5 Selected from phenyl, pyridyl, wherein the group is optionally replaced by one or more R 8 replace.

[0047] In some embodiments, R 5 Selected from phenyl, wherein the group is optionally replaced by one or more R 8 replace.

[0048] In some typical embodiments, R 5 Selected from phenyl, wherein the group is optionally replaced by one or more R 8 replace.

[0049] In some more typical embodiments, R 5 Selected from phenyl, wherein the group is optionally replaced by one or more R 8 replace.

[0050] In some of the most typical embodiments, R 5 is selected from phenyl, wherein the group is optionally substituted by one or more R 8 replace.

[0051] In some embodiments, R 8 is selected from OMe, NH2, methyl, fluorine, Br, benzyloxy, =O, ethynyl, methoxyethoxy, cyclopropylmethoxy, isopropoxy, CF3CH2O, cyclopropyl, hydroxyl or wherein the NH2 is optionally substituted by acetyl or methyl.

[0052] In some embodiments, R 8 is selected from OMe, methyl, fluorine, NH2 or hydroxy; wherein the NH2 is substituted by methyl.

[0053] In some typical embodiments, R 8 Selected from OMe, NHCH3, NCH3CH3 or hydroxyl.

[0054] In some more typical embodiments, R 8 Selected from OMe, NHCH3 or NCH3CH3.

[0055] In some embodiments, R 5 Selected from:

[0056]

[0057]

[0058]

[0059] In some embodiments, X is a bond and R 5 The ring carbon atoms on R 2 Together with the atoms they are attached to form:

[0060]

[0061] In some embodiments, the compound of formula I has a structure as shown in formula II,

[0062]

[0063] Among them, R 1 , R 2 , R 3 The definition of is as defined in the compound of formula I.

[0064] In some embodiments, R 1 It is phenyl.

[0065] In some embodiments, R 2 It is methyl.

[0066] In some embodiments, R 3 for

[0067] In some embodiments, the compound of the aforementioned formula I has a structure as shown in formula III,

[0068]

[0069] Among them, R 1 , R 3 The definition of is as defined in the compound of formula I.

[0070] In some embodiments, R 1 It is phenyl.

[0071] In some embodiments, R 3 for

[0072] In another aspect, the present invention provides a compound represented by formula IV or a pharmaceutically acceptable salt thereof,

[0073]

[0074] Among them, R 1 It is phenyl or a nitrogen-containing heterocycle.

[0075] In some embodiments, R 1 Phenyl or

[0076] In another aspect, the present invention provides a compound represented by formula V or a pharmaceutically acceptable salt thereof,

[0077]

[0078] Among them, X, R 1 , R 2 , R 4 , R 5 The definition of is as defined in the compound of formula I.

[0079] In some embodiments, X is a bond.

[0080] In some embodiments, R 1 It is phenyl.

[0081] In some embodiments, R 2 For hydrogen.

[0082] In some embodiments, R 4 For hydrogen.

[0083] In some embodiments, R 5 for

[0084] In another aspect, the present invention provides a compound represented by Formula VI or a pharmaceutically acceptable salt thereof,

[0085]

[0086] Among them, R 5 , R 7 The definition of is as defined in the compound of formula I.

[0087] In some specific embodiments, the present invention provides the following compounds or pharmaceutically acceptable salts thereof,

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 3.9 min. The chromatographic conditions are as follows:

[0095] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0096] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 3.5 min. The chromatographic conditions were as follows:

[0097] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0098] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 4.1 min. The chromatographic conditions were as follows:

[0099] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0100] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 3.9 min. The chromatographic conditions are as follows:

[0101] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0102] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 4.9 min. The chromatographic conditions were as follows:

[0103] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0104] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 4.0 min. The chromatographic conditions were as follows:

[0105] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0106] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 5.0 min. The chromatographic conditions were as follows:

[0107] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0108] In some specific embodiments, the compound The isomers were analyzed by SFC analysis chromatographic conditions with a retention time of 5.8 min. The chromatographic conditions are as follows:

[0109] Chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0110] In another aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0112] The pharmaceutical composition of the present invention can be administered by any applicable route or method, for example, by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of Formula I, II, III, IV, V or VI compound is from about 0.001 mg to 20 mg / Kg body weight / day, preferably from 0.01 mg to 10 mg / Kg body weight / day.

[0113] For oral administration, the pharmaceutical composition of the present invention is generally provided in the form of tablets, capsules or solutions. Tablets may contain the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, a diluent, a disintegrant, a binder, a lubricant, a colorant or a preservative. Capsules include hard capsules and soft capsules.

[0114] For parenteral administration, the pharmaceutical composition of the present invention can be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided in a sterile aqueous solution or suspension or lyophilized powder, and the appropriate pH and isotonicity are adjusted.

[0115] In another aspect, the present invention also provides the use of a compound of formula I, II, III, IV, V or VI in the preparation of a medicament for preventing and / or treating a disease or disease state mediated by methionine adenosyltransferase (MAT).

[0116] On the other hand, the present invention also provides a method for preventing and / or treating a disease or disease state mediated by methionine adenosyltransferase (MAT), which comprises administering a compound of formula I, II, III, IV, V or VI of the present invention or a pharmaceutical composition of the present invention to an individual in need thereof.

[0117] On the other hand, the present invention also provides a compound of formula I, II, III, IV, V or VI of the present invention or a pharmaceutical composition of the present invention for preventing and / or treating a disease or disease state mediated by methionine adenosyltransferase (MAT). Examples of diseases or disease states mediated by methionine adenosyltransferase (MAT) include, but are not limited to, cancer, such as pancreatic cancer and bladder cancer. DETAILED DESCRIPTION

[0118] Related definitions

[0119] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0120] The "compounds" described in the present invention include all stereoisomers and tautomers.

[0121] The compounds of the present invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise indicated, the "compounds" of the present invention refer to any one stereoisomer or a mixture of two or more stereoisomers. Stereoisomers include, but are not limited to, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in an optically pure form or in the form of a mixture of two or more stereoisomers. The optically pure form can be separated from a mixture of two or more stereoisomers, or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present invention.

[0122] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0123] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring of said event or circumstance.

[0124] Numerical ranges herein refer to individual integers in a given range. For example, "C1-C5" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, or 5 carbon atoms, "C2-C4" means that the group can have 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms, and "C5-C7" means that the group can have 5 carbon atoms, 6 carbon atoms, or 7 carbon atoms.

[0125] The term "substituted" or "substituted" means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, as long as the valence state of the specific atom or group is normal and the substituted compound is stable. When the substituent is =0, it means that two hydrogen atoms are replaced. When multiple hydrogen atoms are replaced by substituents, each substituent is independent of each other and can be the same substituent or different substituents. Unless otherwise specified, the type and number of substituents can be any on the basis of chemical realization.

[0126] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including a linear or branched saturated hydrocarbon group, the hydrocarbon group having the indicated number of carbon atoms. For example, "C1-C4 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl and C4 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. It can be divalent, such as methylene, ethylene.

[0127] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including a straight or branched unsaturated hydrocarbon group having the indicated number of carbon atoms. For example, "C2-C4 alkynyl" includes ethynyl, propynyl, butynyl.

[0128] The term "alkoxy" refers to a group having an -O-alkyl structure, wherein the alkyl group is a linear or branched saturated monovalent hydrocarbon group, such as "C1-C3 alkoxy" including -OCH3, -OC2H5, -OC2H4CH3 and -OCH(CH3)2.

[0129] The term "alkanoyl" refers to a group having a RC(=O)-structure, wherein R is H or a saturated aliphatic hydrocarbon group, including a linear or branched saturated monovalent hydrocarbon group. For example, "C1-C3 alkanoyl" includes C1 alkanoyl, C2 alkanoyl, and C3 alkanoyl. Suitable alkanoyl groups include formyl, acetyl, n-propionyl, and isopropionyl.

[0130] The term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0131] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system without heteroatoms and double bonds. For example, "C3-C5 cycloalkyl" includes cyclopropyl, cyclobutyl and cyclopentyl; "C5-C7 cycloalkyl" includes cyclopentyl, cyclohexyl and cycloheptyl.

[0132] The term "cycloalkenyl" refers to a monocyclic unsaturated hydrocarbon system containing one carbon-carbon double bond and no heteroatoms, such as "5-6 membered cycloalkenyl" including cyclopentenyl and cyclohexenyl.

[0133] The term "membered" refers to the number of backbone atoms that make up the ring. For example, "5-8 membered" means that the number of backbone atoms that make up the ring is 5, 6, 7, or 8. Thus, for example, cyclopentane, cyclopentene, thiophene, and pyrrole are five-membered rings, pyridine, piperidine, piperazine, cyclohexane, cyclohexene, and benzene are six-membered rings, and cycloheptane is a seven-membered ring.

[0134] The term "5-12 membered heteroaryl" refers to a monovalent aromatic group containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur, and including a monocyclic or fused ring system of 5-12 atoms (at least one of the fused ring systems is aromatic). Examples of 5-12 membered heteroaryl groups include, but are not limited to, pyridyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thienyl, imidazolyl, pyrimidinyl, furanyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, imidazopyridinyl, benzofuranyl, pyridazinyl, isoindolyl,

[0135] The term "5-8 membered heterocycle" refers to a 5-8 membered saturated monocyclic ring having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur or oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Examples include, but are not limited to, pyrrolidinyl, piperidinyl or morpholinyl ring groups.

[0136] The term "nitrogen-containing heterocycle" refers to a 6- to 8-membered monocyclic ring containing a nitrogen atom, and the rest of the ring except the nitrogen atom are carbon atoms.

[0137] A single wave line in Refers to the chemical bond connection. When the connection position is uncertain, it means that the connection site is located at any carbon atom on the single ring. When the connection position is uncertain, it means that the connection site is limited to Any atom on the single ring where the valence permits. For example, It means that the connection site is located only on any atom of the benzene ring in the bicyclic ring and must meet the requirements of atomic valence bonds.

[0138] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without adverse biological effects, such as acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).

[0139] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0140] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or pharmaceutical agent to achieve the desired effect.

[0141] The term "pharmaceutically acceptable carrier" refers to those carriers that have no significant irritation to the body and do not impair the biological activity and performance of the active compound. It includes but is not limited to any diluent, disintegrant, binder, glidant, wetting agent approved by the State Food and Drug Administration for use in humans or animals.

[0142] The abbreviations used in the claims and the specification have the following meanings:

[0143] M:mol / L

[0144] mM:mmol / L

[0145] nM: nmol / L

[0146] DMSO: dimethyl sulfoxide;

[0147] 1 H NMR: nuclear magnetic resonance

[0148] LCMS: Liquid chromatography-mass spectrometry

[0149] SFC: Supercritical Fluid Chromatography

[0150] h: hour;

[0151] min: minutes;

[0152] THF: Tetrahydrofuran

[0153] EA: Ethyl acetate

[0154] EDTA: Ethylenediaminetetraacetic acid

[0155] BPS: Brominated polystyrene

[0156] TCL: Thin Layer Chromatography

[0157] ATP: Adenosine triphosphate

[0158] MAT2A: methionine adenosyltransferase 2A

[0159] The preparation method of compound of the present invention is described in more detail below, but these specific preparation methods do not constitute any restriction to the scope of the present invention. In addition, reaction conditions such as reactant, solvent, alkali, the amount of compound used, reaction temperature, reaction time etc. are not limited to the following examples.

[0160] The SFC conditions of the present invention are as follows:

[0161] SFC analysis chromatographic conditions: instrument: waters UPCC; chromatographic column: Daicel Chiralcel AD, 2.1×150mm ID, 3μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); gradient: B phase 5%-40% (volume ratio), time 0-8min; flow rate: 1ml / min; column temperature: 40℃.

[0162] SFC preparative chromatography conditions: instrument: SFC200; chromatographic column: Daicel Chiralcel AD, 250×30 mm I.D., 5 μm; mobile phase: A is CO2, B is ethanol (0.1% ammonia water); A:B=60:40 (volume ratio); flow rate: 50 ml / min; column temperature: 38°C.

[0163] Example 1 3-(4-methoxyphenyl)-2-methyl-7,8-diphenylpyrazolo[1,5-a][1,3,5]triazine-4(3H)-one

[0164]

[0165] a) Preparation of 3-oxo-2,3-diphenylpropionitrile

[0166] Dissolve benzyl cyanide (25 g) and methyl benzoate (30.5 g) in anhydrous tetrahydrofuran (200 mL), add sodium hydride (60%, 17 g) in batches under ice bath, stir and react at room temperature overnight under nitrogen protection. After the reaction is complete, neutralize with 2M dilute hydrochloric acid, separate the liquids, extract the aqueous phase with 200 mL of ethyl acetate, concentrate the organic phase to dryness, slurry with 150 mL of low-boiling petroleum ether, filter with suction, and dry the filter cake in vacuum to obtain 47.8 g of the title compound.

[0167] LCMS m / z=222.1[M+1] +

[0168] b) Preparation of 3,4-diphenyl-1H-pyrazole-5-amine

[0169] 3-Oxo-2,3-diphenylpropionitrile (47.8 g) was dissolved in anhydrous ethanol (200 mL) and glacial acetic acid (48 mL), 80% hydrazine hydrate (33.8 g) was added, and the mixture was heated to 80°C and stirred to react overnight. After the reaction was complete, the mixture was concentrated to dryness, and the pH was adjusted to 7-8 with a saturated sodium carbonate aqueous solution. The reaction solution was extracted with 300 mL of ethyl acetate, and the organic phase was concentrated to dryness, and slurried with a mixed solvent of 100 mL of low-boiling point petroleum ether and 100 mL of tert-butyl methyl ether, and filtered with suction. The filter cake was dried under vacuum to obtain 29.57 g of the title compound.

[0170] LCMS m / z=236.2[M+1] +

[0171] c) Preparation of ethyl N-(3,4-diphenyl-1H-pyrazol-5-yl)imidoyl acetate

[0172] 3,4-Diphenyl-1H-pyrazol-5-amine (400 mg), triethyl orthoacetate (607 mg) and acetic acid (2 drops) were added to acetonitrile (20 ml), heated under reflux and stirred for 7 hours, and then stirred at 60°C overnight. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: ethyl acetate / n-hexane = 1 / 2 (V / V)) to obtain the title compound (410 mg).

[0173] d) Preparation of 3-(4-methoxyphenyl)-2-methyl-7,8-diphenylpyrazolo[1,5-a][1,3,5]triazine-4(3H)-one

[0174] Add N-(3,4-diphenyl-1H-pyrazol-5-yl) ethyl iminoyl acetate (200 mg) to tetrahydrofuran (10 ml) and stir, cool to 0°C, then add triethylamine (265 mg) and 4-methoxyphenyl isocyanate (122 mg), stir at room temperature for 2 hours, then heat to reflux for 16 hours. After the reaction is complete, the reaction solution is concentrated to obtain a crude product, and the title compound (44.5 mg) is prepared from the liquid phase.

[0175] 1 H NMR (400MHz, DMSO-d6) δ7.51 (dd, J=10.3, 6.3Hz, 4H), 7.46–7.28 (m, 8H), 7.13 (d, J=8.8Hz, 2H), 3.85 (s, 3H), 2.08 (s, 3H).

[0176] LCMS m / z=409.1[M+1] +

[0177] Example 2 3-(4-methoxyphenyl)-7,8-diphenylpyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-one

[0178]

[0179] Add 3,4-diphenyl-1H-pyrazole-5-amine (200 mg) to water (4.25 ml) and stir, cool to 0-5°C, add hydrochloric acid solution (0.85 ml, 4M), then dissolve sodium nitrite (59 mg) in water (1.7 ml), slowly drop it into the reaction solution, and after the dropwise addition is complete, the reaction solution is stirred at 0-5°C for 45 minutes. Add dichloromethane (12.75 ml) to the reaction solution, then adjust the pH to 7-8 with saturated sodium carbonate solution, add 4-methoxyphenyl isocyanate (127 mg), after the addition is complete, stir the reaction at 0-5°C for 2 hours, and then stir the reaction at room temperature overnight. After the reaction is complete, the reaction solution is separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, and concentrated to obtain a crude product, which is purified by column chromatography (mobile phase: dichloromethane) to obtain the title compound (137 mg).

[0180] 1 H NMR (400MHz, DMSO-d6) δ7.59 (ddt, J=9.6, 4.8, 3.0Hz, 4H), 7.53–7.39 (m, 8H), 7.19–7.13 (m, 2H), 3.86 (s, 3H).

[0181] LCMS m / z=396.1[M+1] +

[0182] Example 3 6-(4-methoxyphenoxy)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0183]

[0184] a) Preparation of methyl 2-(4-methoxyphenoxy)-3-oxobutanoate

[0185] Sodium hydride (483 mg) was added to N, N-dimethylformamide (18 ml) and stirred. 4-methoxyphenol (1.00 g) was added and stirred at room temperature for 0.5 hours. Then methyl 2-chloroacetoacetate (1.72 g) was slowly added dropwise. After the addition was complete, the mixture was heated to 85°C and stirred for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated citric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution in sequence. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain the title compound (115 mg).

[0186] b) Preparation of 6-(4-methoxyphenoxy)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0187] Add 2-(4-methoxyphenoxy)-3-oxobutyric acid methyl ester (200 mg) and 5-phenyl-4-(1-piperidinyl)-1H-pyrazol-3-amine (202 mg) to acetic acid (10 ml), heat to 100° C. and stir to react for 5 hours. After the reaction is completed, the reaction solution is concentrated to obtain a crude product, which is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate=1 / 2 (V / V)) to obtain the title compound (915 mg).

[0188] 1 H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.11(d,J=7.2Hz,2H),7.49– 7.34(m,3H),6.87(dd,J=21.1,9.0Hz,4H),3.70(s,3H),3.09(s,4H),2.29(s,3H),1.61(d,J=32.8Hz,6H).

[0189] LCMS m / z=431.2[M+1] +

[0190] Example 4 6-(3-methoxyphenoxy)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0191]

[0192] The preparation method of Example 3 is referred to for preparation, except that 4-methoxyphenol in step a) is replaced by 3-methoxyphenol.

[0193] 1 H NMR (400MHz, DMSO-d6) δ11.50 (s, 1H), 8.12 (d, J = 7.6Hz, 2H), 7.49 (t, J=7.5Hz,2H),7.44–7.36(m,1H),7.20(t,J=8.2Hz,1H),6.73–6.38(m,3H),3.76(s,3H),3.11(s,4H),2.33(s,3H),1.64(d,J=32.6Hz,6H).

[0194] LCMS m / z=431.2[M+1] +

[0195] Example 5 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-3-oxy)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0196]

[0197] The preparation method is described in Example 3, except that 4-methoxyphenol in step a) is replaced by 3-hydroxypyridine.

[0198] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.43(d,J=2.5Hz,1H),8.26(d,J=4.5Hz,1H),8.08(d,J=7.6Hz,2H),7.44(dt,J=27.0,7.2Hz,4H),7.33(dd, J=8.4,4.6Hz,1H),3.07(s,4H),2.37(s,3H),1.62(d,J=33.0Hz,6H).

[0199] LCMS m / z=402.2[M+1] +

[0200] Example 6 3-Isopropyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0201]

[0202] a) Preparation of methyl 2-(4-methoxyphenyl)-3-oxobutanoate

[0203] Under nitrogen protection, add lithium diisopropylamide 2M tetrahydrofuran solution (96mL) in batches to a solution of 4-methoxyphenylacetic acid methyl ester (30g) in anhydrous tetrahydrofuran (180mL) in a -80℃ cold trap, and keep the temperature to react for 1.5h. Add acetyl chloride (12.5mL) dropwise, react for 1h, transfer to room temperature and stir overnight. After the reaction is completed, add 300mL of saturated ammonium chloride aqueous solution to quench the reaction, extract the reaction solution with 300mL of ethyl acetate, and concentrate the organic phase to remove the solvent to obtain 43.4g of the title compound.

[0204] 1 H NMR (400MHz, DMSO-d6) δ7.28–7.21(m,2H),6.97–6.92(m,2H),5.07(s,1H),3.75(s,3H),3.60(s,3H),2.11(s,3H).

[0205] b) Preparation of 6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0206] Dissolve methyl 2-(4-methoxyphenyl)-3-oxobutanoate (42 g) and 5-phenyl-3-aminopyrazole (18.8 g) in dioxane (200 mL) and glacial acetic acid (40 mL), and heat to 100°C under nitrogen protection for reflux reaction for 3.5 h. After the reaction is complete, cool, filter, wash the filter cake with ethyl acetate, and vacuum dry the filter cake to obtain 19.52 g of the title compound.

[0207] 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.06–7.93(m,2H),7.49(t,J= 7.3Hz,2H),7.45–7.38(m,1H),7.31–7.20(m,2H),7.00(dd,J=9.2,2.4Hz,2H),6.60(s,1H),3.81(s,3H),2.19(s,3H).

[0208] LCMS m / z=332.1[M+1] +

[0209] c) Preparation of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0210] Dissolve 6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (10.0 g) in anhydrous N,N-dimethylformamide (100 mL), add potassium carbonate (10.4 g), add 2-(trimethylsilyl)ethoxymethyl chloride (9.1 mL) dropwise under ice bath, and stir at room temperature overnight under nitrogen protection. After the reaction is completed, add 200 mL of water to quench, extract the reaction solution with 200 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)) to obtain 7.6 g of the title compound.

[0211] LCMS m / z=462.2[M+1] +

[0212] d) Preparation of 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0213] Dissolve 6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (7.6g) in dichloromethane (120mL), add N-bromosuccinimide (3.51g) in batches, and stir at room temperature for 5h. After the reaction is completed, add 200mL of water and stir, separate the liquids, extract once with 100mL of dichloromethane, and combine the organic phases and concentrate to dryness. After adding 50mL of ethyl acetate to dissolve, add 250mL of petroleum ether to slurry overnight, filter, and vacuum dry the filter cake to obtain 7.9g of the title compound.

[0214] LCMS m / z=540.2[M+1] +

[0215] e) Preparation of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1-propen-2-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0216] 3-Bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (350 mg), isopropenylboronic acid pinacol ester (184 mg), di(tri-tert-butylphosphine)palladium (17 mg) and potassium carbonate (446 mg) were dissolved in dioxane (15 mL) and water (3 mL), heated to 85°C and stirred overnight under nitrogen protection. After the reaction was completed, 60 mL of water and 30 mL of ethyl acetate were added, the insoluble matter was filtered off, the liquid was separated, the aqueous phase was extracted once with 30 mL of ethyl acetate, the organic phases were combined and concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol=20 / 1 (V / V)) to obtain 320 mg of the title compound.

[0217] LCMS m / z=502.2[M+1] +

[0218] f) Preparation of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1-propen-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0219] Dissolve 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1-propene-2-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (80 mg) in dichloromethane (1.5 mL), add trifluoroacetic acid (3.5 mL), stir at room temperature and react overnight. The reaction solution was concentrated to dryness, and 5 mL of ammonia water was added and stirred at room temperature for 6 h. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with 20 mL of ethyl acetate. The organic phase was concentrated to dryness to obtain 56 mg of the title compound.

[0220] LCMS m / z=372.1[M+1] +

[0221] g) Preparation of 3-isopropyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0222] Dissolve 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1-propene-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (154 mg) in methanol (15 mL), add palladium hydroxide (29 mg), replace with hydrogen, and stir at room temperature for 6 hours. After the reaction is completed, filter with suction, wash the filter cake with 5 mL of methanol, and concentrate the filtrate to dryness to obtain a crude product, which is purified by preparative liquid chromatography to obtain 68 mg of the title compound.

[0223] 1 H NMR (400MHz, DMSO-d6) δ7.80–7.70(m,2H),7.48–7.41(m,2H),7.41– 7.33(m,3H),7.25(t,J=7.4Hz,2H),7.17(dd,J=10.4,7.0Hz,3H),7.07(d, J=8.7Hz,2H),4.30(s,2H),3.83(s,3H),2.29(s,3H).

[0224] LCMS m / z=374.2[M+1] +

[0225] Example 7 3-Acetyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0226]

[0227] a) Preparation of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0228] 3-Bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (300 mg), bistriphenylphosphine palladium dichloride (39 mg), triphenylphosphine (29 mg), cuprous iodide (11 mg) were dissolved in triethylamine (6 mL) and anhydrous tetrahydrofuran (6 mL), and trimethylsilylacetylene (0.39 mL) was added after nitrogen replacement, and the mixture was heated to 90°C for 3 h under nitrogen protection. After the reaction was completed, the insoluble matter was filtered off, and 20 mL of water was added to quench, the reaction solution was extracted with 20 mL of ethyl acetate, the organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 99 mg of the title compound.

[0229] LCMS m / z=558.2[M+1] +

[0230] b) Preparation of 3-ethynyl-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0231] Dissolve 6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (75 mg) in methanol (4 mL), add potassium carbonate (2 mL), and react at room temperature for 1 h. After the reaction is completed, concentrate to dryness, add 10 mL of water and 10 mL of dichloromethane for extraction, and concentrate the organic phase to dryness to obtain 65 mg of the title compound.

[0232] LCMS m / z=486.2[M+1] +

[0233] c) Preparation of 3-acetyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0234] Dissolve 3-ethynyl-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (65 mg) in dichloromethane (1.5 mL), add trifluoroacetic acid (3 mL), and stir at room temperature to react overnight. After the reaction is completed, concentrate to dryness, dissolve in methanol (1 mL), add ammonia water (3 mL), and stir at room temperature for 4 hours. After the reaction is completed, add 20 mL of water, extract with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by preparative liquid phase to obtain 10 mg of the title compound.

[0235] 1 H NMR (400MHz, DMSO-d6) δ11.83 (s, 1H), 7.63 (dd, J = 6.5, 3.0Hz, 2H), 7.52 (d,J=2.4Hz,3H),7.23(d,J=8.7Hz,2H),6.99(d,J=8.7Hz,2H),3.80(s,3H),2.29(s,3H),2.10(s,3H).

[0236] LCMS m / z=374.1[M+1] +

[0237] Example 8 3-ethynyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0238]

[0239] a) Preparation of 3-ethynyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0240] Dissolve 3-ethynyl-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (65 mg) in anhydrous THF (6 mL), add tetrabutylammonium fluoride 1M tetrahydrofuran solution (0.93 mL) and ethylenediamine (200 mg), and heat to 67°C under nitrogen protection for 5 hours. After the reaction is completed, concentrate to dryness, and purify the crude product by preparative liquid phase to obtain 5.06 mg of the title compound.

[0241] 1 H NMR (400MHz, DMSO-d6) δ8.23–8.07 (m, 2H), 7.52 (t, J = 7.2Hz, 2H), 7.46 (t,J=7.2Hz,1H),7.23(d,J=8.4Hz,2H),6.99(d,J=8.4Hz,2H),4.53(s,1H),3.80(s,3H),2.21(s,3H).

[0242] LCMS m / z=356.2[M+1] +

[0243] Example 9 3-(Bicyclo[3.1.0]hex-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0244]

[0245] a) Preparation of 3-(cyclopentyl-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0246] 3-Bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (650 mg), cyclopenten-1-ylboronic acid pinacol ester (466 mg), bis(triphenylphosphine)palladium dichloride (84 mg) and cesium carbonate (782 mg) were dissolved in dioxane (20 mL) and water (4 mL), and heated to 85°C under nitrogen protection and stirred for 5 hours. After the reaction was completed, 40 mL of water was added to quench, and the reaction solution was extracted with 40 mL of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 40 / 1 (V / V)) to obtain 668 mg of the title compound.

[0247] LCMS m / z=528.2[M+1] +

[0248] b) Preparation of 3-(cyclopentyl-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(3H)-one

[0249] Dissolve 3-(cyclopentyl-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (668 mg) in dichloromethane (10 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 5 h. After the reaction, concentrate to dryness, dissolve in methanol (2 mL), add ammonia water (6 mL), and stir at room temperature for 4 h. After the reaction, add 2M dilute hydrochloric acid to neutralize, extract the reaction solution with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: dichloromethane / methanol=20 / 1 (V / V)) to obtain 395 mg of the title compound.

[0250] LCMS m / z=398.2[M+1] +

[0251] c) Preparation of 3-(bicyclo[3.1.0]hex-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0252] Dissolve 3-(cyclopent-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (342 mg) in anhydrous dichloromethane (12 mL). Add diethylzinc (3.5 mL) and diiodomethane (0.28 mL) in an ice bath and under nitrogen protection, and stir at room temperature to react overnight. After the reaction is completed, add 3 mL of 2M dilute hydrochloric acid to quench, then add 20 mL of water, extract the reaction solution with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by preparative liquid phase to obtain 25 mg of the title compound.

[0253] 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),7.76(d,J=7.2Hz,2H),7.49(t,J=7.4Hz,2H),7.42(t,J=7.3Hz,1H),7.22(d,J=8.6Hz,2H),6.98(d,J=8.7 Hz,2H),3.80(s,3H),2.26(s,3H),2.20(dd,J=12.1,8.1Hz,1H),2.12–1.9 9(m,1H),1.92(q,J=11.6Hz,1H),1.72(td,J=12.2,11.1,6.8Hz,2H),1.42– 1.28(m,1H),1.17(dt,J=7.9,3.7Hz,1H),0.88(t,J=4.3Hz,1H),0.46(dd,J=7.9,4.8Hz,1H)

[0254] LCMS m / z=412.1[M+1] +

[0255] Example 10 3-Benzyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0256]

[0257] a) Preparation of 7-chloro-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde

[0258] Under nitrogen protection, phosphorus oxychloride (8.43 mL) was added to anhydrous N, N-dimethylformamide (60 mL) in an ice bath, stirred for 0.5 h, then stirred at room temperature for 1 h, and a suspension (20 mL) of 6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (5 g) in anhydrous N, N-dimethylformamide was added, stirred for 0.5 h, and then heated to 60°C for 3 h. After the reaction was completed, 100 mL of ice water was added to quench the reaction, the pH was adjusted to neutral with a saturated sodium bicarbonate solution, extracted with 120 mL of ethyl acetate, filtered, the organic phase was concentrated to dryness, combined with the insoluble matter, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 1.84 g of the title compound.

[0259] LCMS m / z=378.0[M+1] +

[0260] b) Preparation of N'-(((7-chloro-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)-4-methylbenzenesulfonylhydrazide

[0261] Dissolve 4-methylbenzenesulfonyl hydrazide (246 mg) in methanol (15 mL), heat to 60°C, add 7-chloro-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (500 mg), heat to 70°C, stir and react for 2.5 hours. After the reaction is complete, filter and wash the filter cake with 20 mL of petroleum ether, and dry the filter cake in vacuum to obtain 500 mg of the title compound.

[0262] LCMS m / z=546.1[M+1] +

[0263] c) Preparation of 3-benzyl-7-chloro-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine

[0264] (E)-N'-(((7-chloro-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)-4-methylbenzenesulfonylhydrazide (270 mg), phenylboronic acid (91 mg) and potassium carbonate (102 mg) were dissolved in anhydrous dioxane (6 mL), heated to 100°C under nitrogen protection and stirred for 3 h. After the reaction was completed, 20 mL of water was added to quench, the reaction solution was extracted with 20 mL of ethyl acetate, the organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1 (V / V)) to obtain 44 mg of the title compound.

[0265] LCMS m / z=440.2[M+1] +

[0266] d) Preparation of 3-benzyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0267] 3-Benzyl-7-chloro-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine (44 mg) was dissolved in methanol (1 mL), and 5% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was heated to 70°C and stirred for 16 h. After the reaction was completed, the mixture was neutralized with 2M dilute hydrochloric acid, extracted with 20 mL of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by preparative liquid phase to obtain 13 mg of the title compound.

[0268] 1 H NMR (400MHz, DMSO-d6) δ7.80–7.70(m,2H),7.48–7.41(m,2H),7.41– 7.33(m,3H),7.25(t,J=7.4Hz,2H),7.17(dd,J=10.4,7.0Hz,3H),7.07(d, J=8.7Hz,2H),4.30(s,2H),3.83(s,3H),2.29(s,3H).

[0269] LCMS m / z=422.2[M+1] +

[0270] Example 11 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0271]

[0272] a) Preparation of 7-chloro-6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]pyrimidine

[0273] 7-Chloro-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-3-carboxaldehyde (25 mg), tetrahydropyrrole (100 mg) and sodium triacetoxyborohydride (700 mg) were dissolved in anhydrous dichloromethane (10 mL), and stirred at room temperature under nitrogen protection overnight. After the reaction was completed, 20 mL of water was added to quench, and the reaction solution was extracted with 20 mL of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 166 mg of the title compound.

[0274] LCMS m / z=433.1[M+1] +

[0275] b) Preparation of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0276] 7-Chloro-6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]pyrimidine (166 mg) was dissolved in tetrahydrofuran (1 mL), 5% aqueous sodium hydroxide solution (8 mL) was added, and the mixture was heated to 80°C and stirred for 2 days. After the reaction was completed, the mixture was neutralized with 2M dilute hydrochloric acid, extracted with 20 mL of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by preparative liquid phase to obtain 11 mg of the title compound.

[0277] 1 H NMR (400MHz, DMSO-d6) δ8.27 (s, 1H), 7.98 (d, J = 7.4Hz, 2H), 7.48 (t, J =7.4Hz,2H),7.41(t,J=7.2Hz,1H),7.23(d,J=8.5Hz,2H),6.98(d,J=8.5H z,2H),3.82(s,2H),3.80(s,3H),2.60(br,4H),2.21(s,3H),1.71(br,4H).

[0278] LCMS m / z=415.2[M+1] +

[0279] Example 12 N-(6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)cyclopropylcarboxamide

[0280]

[0281] a) Preparation of 6-(4-methoxyphenyl)-5-methyl-3-nitro-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0282] Dissolve 6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (3.26 g) and copper nitrate dihydrate (1.67 g) in acetic anhydride (40 mL) and glacial acetic acid (30 mL), and stir overnight at room temperature. After the reaction is completed, concentrate to dryness, add saturated sodium bicarbonate solution to adjust the pH to neutral, extract with 200 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: dichloromethane / methanol=40 / 1 (V / V)) to obtain 1.77 g of the title compound.

[0283] 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),7.86–7.75(m,2H),7.54–7.40 (m,3H),7.24(d,J=8.7Hz,2H),6.98(d,J=8.7Hz,2H),3.85(s,3H),2.42(s,3H).

[0284] LCMS m / z=377.2[M+1] +

[0285] b) Preparation of 6-(4-methoxyphenyl)-5-methyl-3-nitro-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0286] Dissolve 6-(4-methoxyphenyl)-5-methyl-3-nitro-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (1.88g) in anhydrous N,N-dimethylformamide (30mL), add 60% sodium hydride (440mg) under ice bath, stir at room temperature for 1h under nitrogen protection, then add 2-(trimethylsilyl)ethoxymethyl chloride (1.67g) dropwise, stir at room temperature overnight. After the reaction is completed, add 50ml of water to quench, extract the reaction solution with 50ml of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 650mg of the title compound.

[0287] LCMS m / z=505.0[M-1] -

[0288] c) Preparation of 3-amino-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0289] Dissolve 6-(4-methoxyphenyl)-5-methyl-3-nitro-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (650 mg) in methanol (15 mL) and tetrahydrofuran (15 mL), add zinc powder (447 mg) and ammonium chloride (738 mg), and stir in a sealed container at room temperature for 4 h. After the reaction is completed, filter and concentrate the filtrate to dryness. Purify the crude product by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 320 mg of the title compound.

[0290] LCMS m / z=477.2[M+1] +

[0291] d) Preparation of N-6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)cyclopropylcarboxamide

[0292] 3-Amino-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (48 mg) was dissolved in anhydrous tetrahydrofuran (5 mL), potassium carbonate (42 mg) and cyclopropylcarbonyl chloride (17 mg) were added, and the mixture was stirred at room temperature for 3 h under nitrogen protection. After the reaction was completed, 20 ml of water was added to quench the reaction, and the reaction solution was extracted with 20 ml of ethyl acetate. The organic phase was concentrated to dryness to obtain 80 mg of a crude green solid.

[0293] LCMS m / z=545.3[M+1] +

[0294] e) Preparation of N-(6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)cyclopropylcarboxamide

[0295] Dissolve N-6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)cyclopropylcarboxamide (80 mg) in dichloromethane (1.5 mL), add trifluoroacetic acid (3 mL), and stir at room temperature to react overnight. The next day, the reaction solution was concentrated to dryness, methanol (1 mL) and ammonia water (3 mL) were added, and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, it was neutralized with 2M dilute hydrochloric acid, extracted with 15 mL of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 18 mg of the title compound.

[0296] 1 H NMR (400MHz, DMSO-d6) δ12.06 (s, 1H), 9.61 (s, 1H), 7.83 (d, J = 7.1Hz, 2H), 7.48 (t, J = 7.3Hz, 2H), 7.43 (t, J = 7.1Hz, 1H), 7.24 (d, J = 8.6Hz, 2H), 6.99(d,J=8.7Hz,2H),3.80(s,3H),2.19(s,3H),1.92–1.78(m,1H),0.83(d,J=5.9Hz,4H).

[0297] LCMS m / z=415.1[M+1] +

[0298] Example 13 N-(6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-N-methylcyclopropylcarboxamide

[0299]

[0300] a) Preparation of N-6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-N-methylcyclopropylcarboxamide

[0301] N-6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)cyclopropylcarboxamide (88 mg) was dissolved in anhydrous N,N-dimethylformamide (5 mL), cesium carbonate (208 mg) and iodomethane (69 mg) were added, and the mixture was stirred at room temperature under nitrogen protection for 6 h. After the reaction was completed, 20 mL of water was added to quench the reaction, and the reaction solution was extracted with 20 mL of ethyl acetate, and the organic phase was concentrated to dryness to obtain 110 mg of the title compound.

[0302] LCMS m / z=559.3[M+1] +

[0303] b) Preparation of N-(6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-N-methylcyclopropylcarboxamide

[0304] Dissolve N-6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)-N-methylcyclopropylcarboxamide (110 mg) in dichloromethane (2 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 2 h. The next day, the reaction solution was concentrated to dryness, methanol (1 mL) and ammonia water (3 mL) were added, and the reaction was stirred at room temperature overnight. After the reaction was completed, it was neutralized with 2M dilute hydrochloric acid, extracted with 15 mL of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by preparative liquid phase to obtain 16 mg of the title compound.

[0305] 1H NMR (400MHz, DMSO-d6) δ12.52 (s, 1H), 7.77 (d, J = 7.2Hz, 2H), 7.51 (t, J=7.3Hz,2H),7.47–7.42(m,1H),7.25(d,J=8.5Hz,2H),7.00(d,J=8.6Hz, 2H),3.80(s,3H),3.16(s,3H),2.21(s,3H),1.69–1.51(m,1H),0.86–0.78 (m,1H),0.67–0.46(m,2H),0.44–0.36(m,1H).

[0306] LCMS m / z=429.2[M+1] +

[0307] Example 14 3-(Cyclopropylamino)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0308] a) Preparation of 3-amino-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0309] Dissolve 6-(4-methoxyphenyl)-5-methyl-3-nitro-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (1.0 g) in methanol (40 mL) and tetrahydrofuran (30 mL), add zinc powder (1.04 g) and ammonium chloride (1.7 g), and stir at room temperature overnight. After the reaction is complete, add 4 g of 200-300 mesh silica gel sand, and purify by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 1.13 g of the title compound.

[0310] LCMS m / z=347.1[M+1] +

[0311] b) Preparation of 3-(cyclopropylamino)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0312] 3-Amino-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (50 mg) was dissolved in anhydrous acetonitrile (3 mL), cyclopropanone (25 mg) and boron trifluoride etherate (82 mg) were added, and the mixture was heated to 60°C under nitrogen protection for 4 h. The reaction solution was cooled to room temperature, sodium borohydride (55 mg) and anhydrous methanol (5 mL) were added, and the mixture was stirred at room temperature for 4 h. After the reaction was completed, 5 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was filtered with suction. The filter cake was washed with 10 mL of tetrahydrofuran, 10 mL of water was added to the filtrate, and the mixture was extracted with 15 mL of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by preparative liquid phase to obtain 7.6 mg of the title compound.

[0313] 1 H NMR(400MHz,DMSO-d6)δ8.14(d,J=7.3Hz,2H),7.46(t,J=7.5Hz,2H), 7.38(t,J=7.3Hz,1H),7.23(d,J=8.8Hz,2H),6.98(d,J=8.8Hz,2H),3.80(s ,3H),3.74(s,1H),2.22(s,3H),1.70–1.61(m,2H),1.61–1.52(s,2H),1.45 –1.36(s,4H).

[0314] LCMS m / z=415.2[M+1] +

[0315] Example 15 4-(4-methoxyphenyl)-5-methyl-1-phenyl-7,8-dihydro-3H,6H-2,2a,5a,8-tetraazaacenaphthylene-3-one

[0316]

[0317] a) Preparation of 2-chloro-N-(6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)acetamide

[0318] Dissolve 3-amino-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (250 mg) in anhydrous N,N-dimethylformamide (8 mL), add chloroacetyl chloride (122 mg) and triethylamine (220 mg), and stir at room temperature under nitrogen protection overnight. After the reaction is completed, add 20 mL of water to quench, extract the reaction solution with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain 150 mg of the title compound.

[0319] LCMS m / z=423.1[M+1] +

[0320] b) Preparation of 3-((2-chloroethyl)amino)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0321] Dissolve 2-chloro-N-(6-(4-methoxyphenyl)-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-yl)acetamide (59 mg) in anhydrous tetrahydrofuran (6 mL), add 1M borane tetrahydrofuran solution (1.4 mL), and stir at room temperature under nitrogen protection overnight. After the reaction is completed, add 10 mL of water to quench, extract the reaction solution with 10 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: dichloromethane / methanol=20 / 1 (V / V)) to obtain 22 mg of the title compound.

[0322] LCMS m / z=409.1[M+1] +

[0323] c) Preparation of 4-(4-methoxyphenyl)-5-methyl-1-phenyl-7,8-dihydro-3H,6H-2,2a,5a,8-tetraazaacenaphthylene-3-one

[0324] 3-((2-chloroethyl)amino)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (22 mg) was dissolved in anhydrous tetrahydrofuran (3.5 mL), cooled to -35°C under nitrogen protection, added with 2M tetrahydrofuran solution of lithium diisopropylamide (0.13 mL), heated to 50°C and reacted for 8 h. After the reaction, 10 mL of saturated ammonium chloride solution was added to quench, the reaction solution was extracted with 10 mL of ethyl acetate, the organic phase was concentrated to dryness, and the crude product was purified by preparative liquid phase to obtain 1.35 mg of the title compound.

[0325] 1 H NMR (400MHz, DMSO-d6) δ8.23–7.93 (m, 2H), 7.43 (t, J = 7.3Hz, 2H), 7.36 (q,J=7.5,6.5Hz,1H),7.20(d,J=8.1Hz,2H),6.96(d,J=8.6Hz,2H),4.01(t,J=4.6Hz,2H),3.84(s,3H),3.63(t,J=4.6Hz,2H),2.21(s,3H).

[0326] LCMS m / z=373.2[M+1] +

[0327] Example 16 3-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0328]

[0329] a) Preparation of 2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)acetonitrile

[0330] To the reaction bottle was added 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (800 mg), acetonitrile (20 ml), and potassium carbonate (1.35 g) in sequence, and stirred at room temperature for 0.5 h. Then bromoacetonitrile (322 mg) was added and stirred at 70 °C for 8 h. The reaction was completed when LCMS detected that the reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to obtain the title compound, which was directly used as the feed for the next step.

[0331] b) Preparation of 2-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-3-oxo-3-phenylpropionitrile

[0332] 2-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)acetonitrile (385 mg), tetrahydrofuran (15 ml), and methyl benzoate (398 mg) were added to the reaction bottle in sequence. The reaction system was cooled to -5°C to 0°C and sodium bis(trimethylsilyl)amide (536 mg) was added dropwise to control the internal temperature between -5°C and 0°C. The reaction was completed after 4 hours. Ethyl acetate (30 ml) was added to the reaction system to dilute it, and then an aqueous solution of ammonium chloride (30 ml) was added and stirred for 5 minutes. The organic phase was collected and the aqueous phase was back-extracted twice with ethyl acetate (30 ml). The organic phases were combined and washed once with saturated brine (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and sanded, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to obtain about 470 mg of the title compound.

[0333] c) Preparation of 4-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-3-phenyl-1H-pyrazole-5-amine

[0334] 2-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-3-oxo-3-phenylpropionitrile (420 mg), ethanol (8 ml), acetic acid (1.6 ml), hydrazine hydrate (160 mg, 85%) were added to the reaction bottle in sequence, and the reaction was carried out at 85°C for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure until there was no droplet. 30 ml of ethyl acetate was added, and then sodium bicarbonate aqueous solution (10%) was added to adjust the pH to 7-8. The mixture was stirred for 5 minutes, and the liquid was separated and extracted. The aqueous phase was back-extracted with ethyl acetate (30 ml) twice, and the organic phases were combined and washed once with saturated brine (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain about 350 mg of the title compound. It was directly used as the feed for the next step.

[0335] d) Preparation of 3-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0336] 4-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-3-phenyl-1H-pyrazol-5-amine (350 mg), methyl 2-(4-methoxyphenyl)-3-oxobutanoate (366 mg) and glacial acetic acid (5 ml) were added to the reaction system in sequence, heated to 100°C, reacted for 4 hours, the solvent in the reaction system was concentrated to dryness, an appropriate amount of ethyl acetate was added to slurry, filtered and dried to obtain about 177 mg of the title compound.

[0337] 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 8.04 (dd, J = 16.2, 7.7Hz, 2H), 7.49 –7.32(m,3H),7.23(d,J=8.6Hz,2H),6.99(d,J=8.7Hz,2H),3.80(s,3H),3.73(d,J=8.2Hz,2H),3.33(s,2H),2.52(d,J=11.7Hz,2H),2.24(s,3H).

[0338] LCMS m / z=449.2[M+1] +

[0339] Example 17 3-(6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0340]

[0341] Prepare by referring to the preparation method of Example 16, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride.

[0342] 1 H NMR (400MHz, CDCl3) δ7.84 (s, 2H), 7.35 (d, J = 29.5Hz, 4H), 6.96 (s, 3H), 3.83(s,3H),3.43(s,2H),3.14(s,2H),2.29(s,3H),1.05(s,3H),0.88(s,3H), 0.05(d,J=17.6Hz,2H).

[0343] LCMS m / z=441.2[M+1] +

[0344] Example 18 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(5-azaspiro[2.4]hept-5-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0345]

[0346] The preparation method was referred to Example 16, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) was replaced with 5-azaspiro[2.4]heptane hydrochloride.

[0347] 1 H NMR (400MHz, DMSO-d6) δ7.44 (s, 5H), 7.20 (d, J = 7.3Hz, 2H), 6.95 (s, 2H), 3.79(s,3H),2.16(s,3H),1.92(s,2H),1.46(s,2H),0.85(d,J=6.9Hz,13H),0.60(s,3H).

[0348] LCMS m / z=427.3[M+1] +

[0349] Example 19 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(5-azaspiro[2.5]octyl-5-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0350]

[0351] The preparation method is described in Example 16, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced with 5-azaspiro[2.5]octane hydrochloride.

[0352] 1 H NMR (400MHz, DMSO-d6) δ11.32 (s, 1H), 8.29 (d, J = 7.4Hz, 2H), 7.46 (t, J=7.5Hz,2H),7.39(t,J=7.2Hz,1H),7.23(d,J=8.5Hz,2H),6.99(d,J=8.6Hz,2H),3.80(s,3H) ,3.23–3.10(m,2H),2.88(s,2H),2.26(s,3H),1.77(s,2H),1.47(d,J=5.2Hz,2H),0.37(s,4H).

[0353] LCMS m / z=441.3[M+1] +

[0354] Example 20 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(6-azaspiro[2.5]oct-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0355]

[0356] The preparation method is described in Example 16, except that the 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by 6-azaspiro[2.5]octane hydrochloride.

[0357] 1 H NMR (400MHz, DMSO-d6) δ11.36 (s, 1H), 8.13 (d, J = 7.3Hz, 2H), 7.47 (t, J=7.5Hz,2H),7.40(d,J=7.2Hz,1H),7.22(d,J=8.4Hz,2H),6.98(d,J=8.4 Hz,2H),3.80(s,3H),3.14(s,4H),2.24(s,3H),1.49(s,4H),0.36(s,4H).

[0358] LCMS m / z=441.3[M+1] +

[0359] Example 21 3-(Hexahydrocyclopentyl[c]pyrrol-2(1H)-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0360]

[0361] Prepare by referring to the preparation method of Example 16, except that the 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by octahydrocyclopenta[c]pyrrole hydrochloride.

[0362] 1 H NMR (400MHz, DMSO-d6) δ11.45 (s, 1H), 8.04 (d, J = 7.1Hz, 2H), 7.42 (dt, J=21.0,7.1Hz,3H),7.22(d,J=8.5Hz,2H),6.99(d,J=8.6Hz,2H),3.80(s,3 H),3.46(t,J=7.2Hz,2H),2.76(d,J=8.3Hz,2H),2.69(s,2H),2.24(s,3H), 1.95–1.70(m,3H),1.46(s,3H).

[0363] LCMS m / z=439.3[M-1] +

[0364] Example 22 3-(3-Azabicyclo[3.1.0]hex-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0365]

[0366] Prepare by referring to the preparation method of Example 16, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by 3-azabicyclo[3.1.0]hexane hydrochloride.

[0367] 1 H NMR (400MHz, DMSO-d6) δ7.96 (d, J = 7.4Hz, 2H), 7.42 (t, J = 7.5Hz, 2H), 7.34(t,J=7.1Hz,1H),7.20(d,J=8.5Hz,2H),6.95(d,J=8.5Hz,2H),3.79(s,3H),3.61(d,J=7.6Hz,2H),2.97(d,J=7.9Hz,2H),2.19(d,J=20.9Hz, 3H),1.91(s,1H),1.54(s,2H),0.79(d,J=3.6Hz,1H),0.53(d,J=3.6Hz,1H).

[0368] LCMS m / z=413.2[M+1]+

[0369] Example 23 3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0370]

[0371] The preparation method is referred to Example 16, except that the 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.

[0372] 1 H NMR (400MHz, DMSO-d6) δ11.67 (s, 1H), 8.05 (d, J = 7.1Hz, 2H), 7.50 (t, J=7.3Hz,2H),7.43(dd,J=8.5,6.0Hz,1H),7.22(d,J=8.7Hz,2H),6.99(d,J=8.7Hz,2H),4.34(s,2H),3.80(s,3H),3.61(d,J=9.1Hz,2H),2.57(d,J =10.3Hz,2H),2.25(s,3H),1.98(t,J=6.0Hz,2H),1.91–1.78(m,2H).

[0373] LCMS m / z=443.2[M+1] +

[0374] Example 24 3-((1R, 4R)-2-oxo-5-azabicyclo[2.2.1]hept-5-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0375]

[0376] Prepare by referring to the preparation method of Example 16, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride.

[0377] 1H NMR (400MHz, DMSO-d6) δ8.24–8.06(m,1H),7.97(s,1H),7.43(dt,J=30.1,15.4Hz,3H),7.22(d,J=8.6Hz,2H),6.97(d,J=8.7Hz,2H),4.57(d,J =23.0Hz,1H),3.93(s,2H),3.82(d,J=15.4Hz,1H),3.79(d,J=4.0Hz,3H),3.60(s,3H),2.20(s,1H),2.12(d,J=39.7Hz,3H),1.82–1.60(m,1H).

[0378] LCMS m / z=429.2[M+1] +

[0379] Example 25 3-((1S, 4S)-2-oxo-5-azabicyclo[2.2.1]hept-5-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0380]

[0381] Prepare by referring to the preparation method of Example 16, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride.

[0382] 1 H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 7.86 (d, J = 7.0Hz, 2H), 7.46 (dq, J=14.3,7.0Hz,3H),7.23(d,J=8.5Hz,2H),6.99(d,J=8.6Hz,2H),4.56(s,1H),3.87(t,J=9.6Hz,1H),3.81(s,4H),3.59(d,J=6.6Hz,1H),3.37(d,J =8.1Hz,1H),3.21(d,J=9.2Hz,1H),2.25(s,3H),1.97–1.87(m,1H),1.75 (d,J=9.6Hz,1H).

[0383] LCMS m / z=429.2[M+1] +

[0384] Example 26 3-(2-oxa-5-azabicyclo[2.2.2]octyl-5-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0385]

[0386] The preparation method is described in Example 16, except that the 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced with 2-oxa-5-azabicyclo[2.2.2]octane oxalate.

[0387] 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 8.01 (d, J = 7.2Hz, 2H), 7.48 (t, J=7.3Hz,2H),7.42(t,J=7.2Hz,1H),7.23(d,J=8.7Hz,2H),6.99(d,J=8.7Hz,2H),4.12(s,1H),3.79(d,J=8.9Hz,3H),3.74(d,J=8.3Hz,2H),3.44 (dd,J=31.2,20.5Hz,2H),2.85(s,1H),2.22(d,J=26.5Hz,3H),2.08–1.92 (m,2H),1.92–1.70(m,2H).

[0388] LCMS m / z=443.2[M+1] +

[0389] Example 27 3-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0390]

[0391] The preparation method is described in Example 16, except that the 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced with 6-oxa-3-azabicyclo[3.1.1]heptane p-toluenesulfonate.

[0392] 1H NMR (400MHz, DMSO-d6) δ11.79 (s, 1H), 7.95 (dd, J = 20.9, 14.0Hz, 2H), 7.59 –7.33(m,3H),7.25(d,J=8.7Hz,2H),7.00(d,J=8.7Hz,2H),4.59(d,J=6.3 Hz,2H),3.81(s,3H),3.69(d,J=10.5Hz,2H),3.14(d,J=10.6Hz,2H),3.11 –2.98(m,1H),2.60–2.52(m,1H),2.33–2.13(m,3H).

[0393] LCMS m / z=429.2[M+1] +

[0394] Example 28 3-(3-oxa-8-azabicyclo[3.2.1]octyl-8-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0395]

[0396] The preparation method is referred to Example 16, except that the 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced with 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride.

[0397] 1 H NMR (400MHz, DMSO-d6) δ10.58 (s, 1H), 7.83 (d, J = 7.1Hz, 2H), 7.44 (tt, J=19.4,9.6Hz,3H),7.21(t,J=9.5Hz,2H),6.96(t,J=12.7Hz,2H),3.89–3.75(m,5H),3.60(s,2H),3.42(t,J=12.8Hz,2H),2.24(d,J=12.9Hz,3H), 1.75(d,J=6.9Hz,2H),1.54(s,2H).

[0398] LCMS m / z=443.1[M+1] +

[0399] Example 29 3-(Diethylamino)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0400]

[0401] Prepare by referring to the preparation method of Example 16, except that 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride in step a) is replaced by diethylamine hydrochloride.

[0402] 1 H NMR (400MHz, DMSO-d6) δ11.51 (s, 1H), 8.10 (d, J = 7.2Hz, 2H), 7.45 (t, J =7.4Hz,2H),7.38(t,J=7.2Hz,1H),7.24(d,J=8.4Hz,2H),6.98(d,J=8.4H z,2H),3.80(s,3H),3.09(q,J=7.2Hz,4H),2.23(s,3H),0.94(t,J=7.2Hz, 6H).

[0403] LCMS m / z=403.3[M+1] +

[0404] Example 30 6-((4-methoxyphenyl)methylamino)-5-methyl-2-phenyl-3-(piperidin-1yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0405]

[0406] a) Preparation of 2-(piperidin-1-yl)acetonitrile

[0407] Add piperidine (20 g) and bromoacetonitrile (33.8 g), acetonitrile (200 ml) and potassium carbonate (97.4 g) into a 1 L single-necked bottle in sequence, stir at room temperature overnight, filter, and concentrate the filtrate under reduced pressure until there is no droplet to obtain the title compound, which is directly used as the feed for the next step.

[0408] b) Preparation of 3-oxo-3-phenyl-2-(piperidin-1-yl)propionitrile

[0409] 2-(Piperidin-1-yl)acetonitrile (20 g) was dissolved in tetrahydrofuran (200 ml) and added to a 1L three-necked flask, followed by the addition of methyl benzoate (26.3 g), nitrogen replacement protection, the reaction system was cooled to -5°C to 0°C, sodium bis(trimethylsilyl)amide (35.4 g) was added dropwise, and the internal temperature was controlled between -5°C and 0°C, stirred at room temperature overnight, ethyl acetate (100 ml) was added to the reaction system for dilution, and then an aqueous solution of ammonium chloride (100 ml) was added for stirring, extraction and separation were performed, the organic phase was collected, the aqueous phase was back-extracted twice with ethyl acetate (100 ml), the organic phases were combined, washed once with saturated brine (100 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until there was no droplet, and crystallized with ethyl acetate / petroleum ether to obtain about 12 g of the title compound.

[0410] c) Preparation of 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine

[0411] 3-Oxo-3-phenyl-2-(piperidin-1-yl)propionitrile (6 g), ethanol (120 ml), and acetic acid (24 ml) were added to a 500 ml single-mouth bottle in sequence, and hydrazine hydrate (2.6 g, 85%) was added. The mixture was heated to 85°C and reacted for 7 h. The reaction system was cooled to room temperature and concentrated under reduced pressure until there was no droplet. 100 ml of ethyl acetate was added, and then a 10% aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. The mixture was stirred for 5 minutes and separated by extraction. The aqueous phase was back-extracted twice with ethyl acetate (100 ml*2). The organic phases were combined and washed once with saturated brine (100 ml). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol=10 / 1 (V / V)) to obtain 6 g of the title compound.

[0412] d) Preparation of ethyl 2-((4-methoxyphenyl)(methyl)amino)-3-oxobutanoate

[0413] 4-Methoxy-N-methylaniline (500 mg) and ethyl 2-diazo-3-oxobutanoate (740 mg) were sequentially added into a 100 ml single-necked bottle, and chloroform (20 ml) was added. The mixture was heated to reflux. After 3 h, the reaction was completed. The reaction mixture was made into sand and separated by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 650 mg of the title compound.

[0414] e) Preparation of 6-((4-methoxyphenyl)(methyl)amino)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0415] Ethyl 2-((4-methoxyphenyl)(methyl)amino)-3-oxobutanoate (200 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (146 mg) were added to a 50 ml single-mouth bottle in sequence, and glacial acetic acid (5 ml) was added and heated to 100° C. After 3 h, the reaction was completed. The solvent in the reaction system was concentrated under reduced pressure until there was no droplet, and ethyl acetate (30 ml) was added to dilute it. The pH was adjusted to 7-8 with 10% sodium bicarbonate aqueous solution, and the extraction was carried out. The aqueous phase was back-extracted twice with ethyl acetate (30 ml*2), and the organic phases were combined, washed once with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until there was no droplet, and purified by column chromatography (mobile phase: dichloromethane / methanol=10 / 1 (V / V)) to obtain 11 mg of the target compound.

[0416] 1H NMR (400MHz, DMSO-d6) δ11.40 (s, 1H), 8.07 (d, J = 7.4Hz, 2H), 7.46 (t, J=7.3Hz,2H),7.42–7.32(m,1H),6.76(d,J=8.7Hz,2H),6.56(d,J=8.8Hz ,2H),3.66(s,3H),3.09(s,4H),3.07(s,3H),2.30(s,3H),1.63(d,J=20.5 Hz,4H),1.58(s,2H).

[0417] LCMS m / z=444.2[M+1] +

[0418] Example 31 6-(2-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0419]

[0420] a) Preparation of ethyl 2-(2-methoxybenzyl)-3-oxobutanoate

[0421] 1-(Chloromethyl)-2-methoxybenzene (1g) and ethyl acetoacetate (831mg) were added to a 100ml single-mouth bottle in sequence, N,N-dimethylformamide (15ml) was added, and potassium carbonate (882mg) was added. The mixture was stirred at room temperature overnight. Water (30ml) was added to the system, and ethyl acetate (30ml) was added. The mixture was stirred for 5 minutes, and the mixture was separated and extracted. The aqueous phase was back-extracted twice with ethyl acetate (30ml*2). The organic phases were combined, washed once with saturated brine (30ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to make sand. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to obtain 1g of the title compound.

[0422] b) Preparation of 6-(2-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0423] Ethyl 2-(2-methoxybenzyl)-3-oxobutanoate (110 mgl) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (85 mg) were added to a 50 ml single-necked bottle, glacial acetic acid (3 ml) was added, and the mixture was heated to 100°C. After 3 h, the reaction was completed. The solvent in the reaction system was concentrated under reduced pressure until there was no droplet, and ethyl acetate was used for slurrying to obtain 15 mg of the title compound.

[0424] 1H NMR (400MHz, DMSO-d6) 11.25 (s, 1H), 8.11 (d, J = 7.4Hz, 2H), 7.47 (t, J = 7.4Hz, 2H), 7.39 (t, J = 7.2Hz, 1H), 7.18 (t, J = 7.4Hz, 1H), 6.97 (dd, J = 14.8, 7.7Hz, 2H), 6.81 (t, J = 7.3Hz, 1H), 3.86 (s, 3H), 3.78 (s, 2H), 3.07 (s, 4H), 2.36 (d, J = 10.9Hz, 3H), 1.63 (d, J = 20.7Hz, 4H), 1.58 (s, 2H).

[0425] LCMS m / z=429.1[M+1] +

[0426] Example 32 6-(((2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methyl]-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0427]

[0428] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxane.

[0429] 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.18–8.01(m,2H),7.46(t,J= 7.4Hz,2H),7.42–7.35(m,1H),6.75–6.65(m,3H),4.18(d,J=4.1Hz,4H),3 .74(s,2H),3.04(d,J=5.2Hz,4H),2.40(s,3H),1.64(s,4H),1.57(s,2H).

[0430] LCMS m / z=457.2[M+1] +

[0431] Example 33 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(quinoline-6-methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0432]

[0433] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 6-(bromomethyl)quinoline.

[0434] 1 H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 8.82 (dd, J = 4.2, 1.6Hz, 1H), 8.30 (d,J=8.3Hz,1H),8.14–8.08(m,2H),7.94(d,J=8.7Hz,1H),7.76(s,1H),7 .70(dd,J=8.7,1.9Hz,1H),7.54–7.43(m,3H),7.39(t,J=7.3Hz,1H),4.09 (d,J=10.3Hz,2H),3.05(d,J=5.2Hz,4H),2.45(s,3H),1.65(s,4H),1.57(d,J=4.0Hz,2H).

[0435] LCMS m / z=450.2[M+1] +

[0436] Example 34 6-(3-Fluoro-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0437]

[0438] The preparation method is referred to Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 3-fluoro-4-methoxybenzyl bromide.

[0439] 1 H NMR (400MHz, DMSO-d6) δ7.98(br,2H),7.39(br,3H),7.01(d,J=9.2Hz, 1H),6.83(t,J=8.3Hz,2H),3.90(s,2H),3.83(s,3H),2.38(br,3H),1.64(br, 6H).

[0440] LCMS m / z=447.2[M+1] +

[0441] Example 35 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-ylmethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0442]

[0443] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 4-bromomethylpyridine.

[0444] 1 H NMR (400MHz, DMSO-d6) δ11.30 (br, 1H), 8.43 (d, J = 4.4Hz, 2H), 8.10 (d, J=7.4Hz,2H),7.46(t,J=7.4Hz,2H),7.39(t,J=7.2Hz,1H),7.25(d,J=5.0H z,2H),3.89(s,2H),3.05(br,4H),2.41(s,3H),1.64(br,4H),1.57(br,2H).

[0445] LCMS m / z=440.2[M+1] +

[0446] Example 36 6-((5-methoxypyridin-2-yl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0447]

[0448] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 2-bromomethyl-5-methoxypyridine.

[0449] 1 H NMR (400MHz, DMSO-d6) δ11.20 (s, 1H), 8.15 (d, J = 2.8Hz, 1H), 8.10 (d, J = 7.2Hz, 2H), 7.46 (t, J = 7.4Hz, 2H), 7.39 (t, J = 7.3Hz, 1H), 7.29 (dd, J = 8.6, 2.9Hz,1H),7.22(d,J=8.6Hz,1H),3.93(s,2H),3.77(s,3H),3.05(br,4H),2.46(s,3H),1.64(br,4H),1.57(br,2H).

[0450] LCMS m / z=430.2[M+1] +

[0451] Example 37 5-methyl-2-phenyl-3-(1-piperidinyl)-6-(4-(trifluoromethoxy)benzyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0452]

[0453] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 4-trifluoromethoxybenzyl bromide.

[0454] 1 H NMR (400MHz, DMSO-d6) δ11.25 (s, 1H), 8.09 (d, J = 7.4Hz, 2H), 7.46 (t, J=7.5Hz,2H),7.38(m,3H),7.25(d,J=8.2Hz,2H),3.89(s,2H),3.03(d,J=4.9Hz,4H),2.42(s,3H),1.60(d,J=28.8Hz,6H).

[0455] LCMS m / z=483.2[M+1] + .

[0456] Example 38 6-(3,4-dimethoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0457]

[0458] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 3,4-dimethoxybenzyl chloride.

[0459] 1 H NMR (400MHz, DMSO-d6) δ11.18 (s, 1H), 8.11 (d, J = 7.2Hz, 2H), 7.46 (t, J=7.5Hz,2H),7.38(t,J=7.3Hz,1H),6.90(d,J=1.7Hz,1H),6.82(d,J=8.2Hz,1H),6.70(dd,J=8.2,1.6H z,1H),3.79(s,2H),3.72(s,3H),3.69(s,3H),3.04(m,4H),2.41(s,3H),1.64(s,4H),1.59–1.52(m,2H).

[0460] LCMS m / z=459.2[M+1] + .

[0461] Example 39 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0462]

[0463] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 4-methoxybenzyl chloride.

[0464] 1 H NMR (400MHz, DMSO-d6) δ11.18 (s, 1H), 8.10 (d, J = 7.4Hz, 2H), 7.46 (t, J=7.5Hz,2H),7.40(d,J=7.3Hz,1H),7.16(d,J=8.5Hz,2H),6.82(d,J=8.5 Hz,2H),3.79(s,2H),3.70(s,3H),3.04(d,J=4.8Hz,4H),2.40(s,3H),1.60 (d,J=28.7Hz,6H).

[0465] LCMS m / z=429.2[M+1] +

[0466] Example 40 6-(3-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0467]

[0468] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 3-methoxybenzyl chloride.

[0469] 1 H NMR (400MHz, DMSO-d6) δ11.21 (s, 1H), 8.11 (d, J = 7.6Hz, 2H), 7.47 (t, J=7.5Hz,2H),7.40(t,J=7.3Hz,1H),7.18(t,J=7.8Hz,1H),6.81(d,J=8.3Hz,2H),6.75(d,J=7.8Hz,1H),3.84(s,2H),3.72(s,3H),3.05(d,J=4.7 Hz, 4H), 2.41 (s, 3H), 1.61 (d, J = 28.5Hz, 6H).

[0470] LCMS m / z=429.1[M+1] +

[0471] Example 41 5-methyl-6-((5-methylisoxazol-3-yl)methyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0472]

[0473] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced by 3-bromomethyl-5-methylisoxazole.

[0474] 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),8.10(d,J=7.6Hz,2H),7.47(t,J=7.5Hz,2H),7.41(d,J=7.2Hz,1H),6.06(s,1H),3.82(s,2H),3.04(d,J =4.9Hz,4H),2.44(s,3H),2.32(s,3H),1.61(d,J=28.9Hz,6H).

[0475] LCMS m / z=404.2[M+1] +

[0476] Example 42 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0477]

[0478] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 3-bromomethylpyridine.

[0479] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.52(s,1H),8.38(d,J=4.3Hz, 1H),8.10(d,J=7.6Hz,2H),7.63(d,J=7.8Hz,1H),7.46(t,J=7.5Hz,2H), 7.38(t,J=7.4Hz,1H),7.28(dd,J=7.7,4.7Hz,1H),3.87(s,2H),3.05(s,4H),2.44(s,3H),1.60(d,J=29.1Hz,6H).

[0480] LCMS m / z=400.2[M+1] +

[0481] Example 43 5-methyl-6-(oxazol-2-ylmethyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0482]

[0483] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 2-bromomethyloxazole.

[0484] 1 H NMR (400MHz, DMSO-d6) δ11.53 (s, 1H), 8.12 (d, J = 7.4Hz, 2H), 7.96 (s, 1H),7.45(t,J=7.5Hz,2H),7.37(t,J=7.3Hz,1H),7.06(s,1H),4.01(s,2H),3.08(s,4H),2.42(s,3H),1.60(d,J=29.2Hz,6H).

[0485] LCMS m / z=390.1[M+1] +

[0486] Example 44 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(3,4,5-trimethoxybenzyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0487]

[0488] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 3,4,5-trimethoxybenzyl chloride.

[0489] 1 H NMR (400MHz, DMSO-d6) δ11.21 (s, 1H), 8.11 (d, J = 7.5Hz, 2H), 7.46 (t, J=7.4Hz,2H),7.38(t,J=7.2Hz,1H),6.58(s,2H),3.80(s,2H),3.72(s,6H),3.61(s,3H),3.05(s,4H),2.44(s,3H),1.60(d,J=28.5Hz,6H).

[0490] LCMS m / z=489.2[M+1] +

[0491] Example 45 6-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0492]

[0493] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 5-chloromethyl-3-methoxymethyl-1,2,4-oxadiazole.

[0494] 1 H NMR (400MHz, DMSO-d6) δ11.44 (s, 1H), 8.11 (s, 2H), 7.43 (d, J = 26.1Hz, 3H),4.48(s,2H),4.20(s,2H),3.31(s,3H),3.08(s,4H),2.50–2.49(m,3H),1.60(d,J=31.0Hz,6H).

[0495] LCMS m / z=435.2[M+1] +

[0496] Example 46 6-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolin[1,5-a]pyrimidin-7(4H)-one

[0497]

[0498] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole.

[0499] 1 H NMR (400MHz, DMSO-d6) δ11.27 (s, 1H), 8.11 (d, J = 7.4Hz, 2H), 7.46 (dd, J=9.7,5.2Hz,2H),7.38(t,J=7.1Hz,1H),7.31–7.25(m,2H),7.10(d,J=8 .4Hz,1H),3.89(s,2H),3.06(s,4H),2.41(s,3H),1.60(d,J=29.0Hz,6H).

[0500] LCMS m / z=479.1[M+1] +

[0501] Example 47 5-methyl-6-((1-methyl-1H-benzo[d]imidazol-6-yl)methyl)-2-phenyl-3-(piperidin-1-yl)pyrazole

[0502] [1,5-a]Pyrimidin-7(4H)-one

[0503]

[0504] a) Preparation of 6-(chloromethyl)-1-methyl-1H-benzo[d]imidazole

[0505] Add 410 mg of 1-methyl-1H-benzo[d]imidazol-6-yl)methanol to 30 ml of phosphorus oxychloride, heat to 100°C and stir for 3.5 hours. After the reaction is complete, concentrate the reaction solution to obtain the crude product of the title compound. The theoretical yield is 456 mg and then used for the next reaction.

[0506] b) Preparation of ethyl 2-((1-methyl-1H-benzo[d]imidazol-6-yl)methyl)-3-oxobutanoate

[0507] 6-(Chloromethyl)-1-methyl-1H-benzo[d]imidazole (456 mg), ethyl acetoacetate (657 mg) and potassium carbonate (872 mg) were added to N,N-dimethylformamide (20 ml) and stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (128 mg).

[0508] c) 5-methyl-6-((1-methyl-1H-benzo[d]imidazol-6-yl)methyl)-2-phenyl-3-(piperidin-1-yl)pyrazole

[0509] Preparation of [1,5-a]pyrimidin-7(4H)-one

[0510] 5-phenyl-4-(1-piperidinyl)-1H-pyrazol-3-amine (113 mg) and ethyl 2-((1-methyl-1H-benzo[d]imidazol-6-yl)methyl)-3-oxobutanoate (128 mg) were added to acetic acid (8 ml), heated to 100°C and stirred for 4 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the title compound (39 mg) was prepared by liquid phase.

[0511] 1H NMR (400MHz, DMSO-d6) δ11.18(s,1H),8.12(d,J=7.2Hz,2H),8.08(s,1H),7.52(d,J=8.3Hz,1H),7.46(t,J=7.4Hz,2H),7.42–7.35(m,2H),7.12 (dd,J=8.4,1.3Hz,1H),4.01(s,2H),3.79(s,3H),3.05(d,J=5.1Hz,4H),2.42(s,3H),1.60(d,J=29.7Hz,6H).

[0512] LCMS m / z=453.2[M+1] +

[0513] Example 48 6-(Benzofuran-5-ylmethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0514]

[0515] a) 5-Bromomethylbenzofuran

[0516] 5-Methylbenzofuran (700 mg), N-bromosuccinimide (943 mg) and benzoyl peroxide (103 mg) were added to carbon tetrachloride (21 ml), replaced with nitrogen, heated to 77°C and stirred for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted twice with dichloromethane, concentrated to obtain a crude product, and purified by column chromatography (mobile phase: petroleum ether) to obtain the title compound (780 mg).

[0517] b) Ethyl 2-(Benzofuran-5-ylmethyl)-3-oxobutanoate

[0518] 5-Bromomethylbenzofuran (780 mg), ethyl acetoacetate (529 mg) and potassium carbonate (536 mg) were added to N,N-dimethylformamide (15 ml) and stirred at room temperature for overnight reaction. After the reaction was completed, the reaction solution was poured into water, extracted twice with ethyl acetate, concentrated to obtain a crude product, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain the title compound (589 mg).

[0519] c) 6-(Benzofuran-5-ylmethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0520] Ethyl 2-(benzofuran-5-ylmethyl)-3-oxobutanoate (200 mg), 5-phenyl-4-(1-piperidinyl)-1H-pyrazol-3-amine (186 mg) and trifluoroacetic acid (403 mg) were added to ethanol (6 ml), heated to 80° C. and stirred for 3.5 hours. After the reaction was completed, the reaction solution was allowed to stand overnight. Solids precipitated in the reaction solution, which was filtered, and the filter cake was washed with ethyl acetate and dried to obtain the title compound (60 mg).

[0521] 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.15–8.07(m,2H),7.92(d,J=2.2Hz,1H),7.46(t,J=8.0Hz,4H),7.40(dt,J=9.5,4.3Hz,1H),7.23(dd,J =8.5,1.7Hz,1H),6.88(dd,J=2.2,0.9Hz,1H),3.96(s,2H),3.10–2.97(m,4H),2.42(s,3H),1.69–1.50(m,6H).

[0522] LCMS m / z=439.2[M+1] +

[0523] Example 49 N-(2-hydroxy-5-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)phenyl)acetamide

[0524]

[0525] The preparation method is described in Example 48, except that 5-methylbenzofuran in step a) is replaced by 2,5-dimethylbenzoxazole.

[0526] 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),9.51(s,1H),9.42(s,1H),8.17– 8.06(m,2H),7.54–7.33(m,4H),6.85(dd,J=8.3,1.9Hz,1H),6.75(d,J=8.2 Hz,1H),3.74(s,2H),3.04(d,J=5.2Hz,4H),2.39(s,3H),2.06(s,3H),1.60 (d,J=29.0Hz,6H).

[0527] LCMS m / z=472.2[M+1] +

[0528] Example 50 5-methyl-6-((2-methylbenzo[d]oxazol-5-yl)methyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0529]

[0530] N-(2-hydroxy-5-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)phenyl)acetamide (130 mg) and p-toluenesulfonic acid monohydrate (26 mg) were added to toluene (10 ml), and the mixture was heated, stirred and refluxed for 6 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the title compound (16.5 mg) was prepared from the liquid phase.

[0531] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.11(d,J=7.3Hz,2H),7.51(d,J =7.8Hz,2H),7.46(t,J=7.5Hz,2H),7.38(t,J=7.3Hz,1H),7.24(d,J=9.5H z,1H),3.97(s,2H),3.05(s,4H),2.57(s,3H),2.41(s,3H),1.60(d,J=29.4 Hz,6H).

[0532] LCMS m / z=454.2[M+1] +

[0533] Example 51 6-(4-Hydroxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0534]

[0535] 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg) was added to dichloromethane (24 ml) and stirred. The mixture was protected by nitrogen and cooled to -60°C. Boron tribromide (1.68 ml, 1.0 M dichloromethane solution) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was cooled to -5°C and methanol was added dropwise to quench the reaction. Water was added to separate the mixture. The aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The title compound (48 mg) was obtained by preparative liquid phase purification.

[0536] 1H NMR (400MHz, DMSO-d6) δ11.16 (s, 1H), 9.12 (s, 1H), 8.10 (d, J = 7.4Hz, 2H), 7.46 (t, J = 7.5Hz, 2H), 7.39 (d, J = 7.3Hz, 1H), 7.03 (d, J = 8.4Hz, 2H), 6.64(d,J=8.4Hz,2H),3.74(s,2H),3.04(d,J=5.0Hz,4H),2.39(s,3H),1.60(d,J=28.6Hz,6H).

[0537] LCMS m / z=415.2[M+1] +

[0538] Example 52 / 53 (R)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0539]

[0540] a) Preparation of 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0541] 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.34 g) and potassium carbonate (864 mg) were added to N,N-dimethylformamide (135 ml) and stirred, and 2-(trimethylsilyl)ethoxymethyl chloride (1.04 g) was added, and nitrogen was protected and stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain the title compound (1.37 g).

[0542] b) Preparation of 6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0543] 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (600mg) was dissolved in tetrahydrofuran (30ml) and stirred. The mixture was replaced with nitrogen and cooled to -65°C. n-butyllithium (2.01ml, 1.6M) was added dropwise. Then iodomethane (1.52g) was dissolved in tetrahydrofuran (3ml) and added dropwise to the reaction solution. After the addition was completed, the reaction solution was stirred at -65°C for 1 hour. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (247mg).

[0544] c) Preparation of (R)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0545] 6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (50 mg) was added to N,N-dimethylformamide (15 ml), and then sodium hydride (24 mg, 60%) was added. The mixture was heated to 60°C and stirred for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined and concentrated to obtain a crude product. The racemic compound (10.5 mg) was obtained by preparative liquid phase purification, and a pair of enantiomers was obtained by SFC separation.

[0546] The first compound obtained by SFC separation is numbered as Example 52, which is analyzed by SFC analysis chromatographic conditions, RT = 3.1min, and the structural confirmation data are:

[0547] 1 H NMR (400MHz, DMSO-d6) δ11.04 (s, 1H), 8.17–8.04 (m, 2H), 7.45 (t, J = 7.4 Hz,2H),7.38(dd,J=8.5,6.1Hz,1H),7.24(d,J=8.6Hz,2H),6.83(d,J=8.7 Hz,2H),4.37(q,J=7.1Hz,1H),3.71(s,3H),3.03(d,J=5.2Hz,4H),2.36(s, 3H),1.73–1.42(m,9H).

[0548] LCMS m / z=443.2[M+1] +

[0549] The second compound obtained by SFC separation is numbered as Example 53, which is analyzed by SFC analysis chromatographic conditions, RT = 3.9 min, structural confirmation data:

[0550] 1H NMR (400MHz, DMSO-d6) δ11.04 (s, 1H), 8.09 (d, J = 7.2Hz, 2H), 7.45 (t, J =7.4Hz,2H),7.38(t,J=7.3Hz,1H),7.24(d,J=8.6Hz,2H),6.83(d,J=8.7H z,2H),4.37(q,J=7.0Hz,1H),3.71(s,3H),3.03(d,J=5.1Hz,4H),2.36(s, 3H),1.75–1.42(m,9H).

[0551] LCMS m / z=443.2[M+1] +

[0552] Example 54 / 55 (R)-6-(1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0553]

[0554] Prepare by referring to the preparation method of Example 52 / 53, except that the methyl iodide in step b) is replaced by ethyl iodide.

[0555] The first compound obtained by SFC separation is numbered as Example 54, which is analyzed by SFC analysis chromatographic conditions, RT = 3.0min, and the structural confirmation data are:

[0556] 1H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.13–8.12(d,J=7.3Hz,2H),7.45 (t,J=7.5Hz,2H),7.37(t,J=7.3Hz,1H),7.31(d,J=8.6Hz,2H),6.81(d, J=8.7Hz,2H),4.05–3.92(m,1H),3.70(s,3H),3.02(d,J=4.9Hz,4H),2.45( s,3H),2.29(dt,J=15.6,7.4Hz,1H),2.14(td,J=13.8,6.9Hz,1H),1.59(d, J=27.3Hz,6H),0.87(t,J=7.3Hz,3H).

[0557] LCMS m / z=457.4[M+1] +

[0558] The second compound obtained by SFC separation is numbered as Example 55, which is analyzed by SFC analysis chromatographic conditions, RT = 3.5min, and the structural confirmation data are:

[0559] 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.09–8.07(m,2H),7.45(t,J= 7.5Hz,2H),7.37(t,J=7.3Hz,1H),7.31(d,J=8.7Hz,2H),6.81(d,J=8.7Hz ,2H),4.06–3.91(m,1H),3.70(s,3H),3.02(d,J=5.1Hz,4H),2.45(s,3H), 2.29(dt,J=16.2,7.3Hz,1H),2.20–2.05(m,1H),1.59(d,J=27.4Hz,6H),0.87(t,J=7.3Hz,3H).

[0560] LCMS m / z=457.4[M+1] +

[0561] Example 56 6-(4-(2-methoxyethoxy)benzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0562]

[0563] a) Preparation of (4-(2-methoxyethoxy)phenyl)methanol

[0564] Add p-hydroxybenzyl alcohol (1 g), 2-bromoethyl methyl ether (1.34 g), acetonitrile (10 ml), and cesium carbonate (5.25 g) to the reaction bottle in sequence, stir at room temperature for overnight, add 50 ml of water to quench the reaction, extract the reaction solution with 50 ml of ethyl acetate, and concentrate the organic phase to dryness to obtain 640 mg of the title compound.

[0565] b) Preparation of 1-(bromomethyl)-4-(2-methoxyethoxy)benzene

[0566] To the reaction flask was added (4-(2-methoxyethoxy)phenyl)methanol (0.64 g), dichloromethane (10 mL), and trimethylsilyl bromide (0.67 ml) in sequence, and the mixture was reacted at room temperature for 15 minutes. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)) to give 440 mg of the title compound.

[0567] c) Preparation of 6-(4-(2-methoxyethoxy)benzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0568] Prepare by referring to the preparation method of Example 31, replacing 1-(chloromethyl)-2-methoxybenzene in step a) with 1-(bromomethyl)-4-(2-methoxyethoxy)benzene, and replacing 2-(2-methoxybenzyl)-3-oxobutanoic acid ethyl ester in step b) with 2-(4-(2-methoxyethoxy)benzyl)-3-oxobutanoic acid ethyl ester to obtain the title compound.

[0569] 1 H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.13–8.08(m,2H),7.46(t,J= 7.5Hz,2H),7.38(t,J=7.3Hz,1H),7.14(d,J=8.6Hz,2H),6.83(d,J=8.6Hz ,2H),4.04–3.99(m,2H),3.78(s,2H),3.65–3.60(m,2H),3.28(s,3H),3.03 (d,J=5.1Hz,4H),2.40(s,3H),1.63(s,4H),1.59–1.51(m,2H).

[0570] LCMS m / z=473.3[M+1] + .

[0571] Example 57 6-(4-(Cyclopropylmethoxy)benzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0572]

[0573] Prepare by referring to the preparation method of Example 56, except that 2-bromoethyl methyl ether in step a) is replaced by bromomethylcyclopropane.

[0574] 1 H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.13–8.06(m,2H),7.46(t,J= 7.4Hz,2H),7.42–7.35(m,1H),7.13(d,J=8.6Hz,2H),6.80(d,J=8.7Hz,2 H),3.81–3.70(m,4H),3.07–2.99(m,4H),2.39(s,3H),1.70–1.50(m,6H), 1.22–1.13(m,1H),0.58–0.51(m,2H),0.31–0.23(m,2H).

[0575] LCMS m / z=469.2[M+1] +

[0576] Example 58 6-(4-isopropoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0577]

[0578] Prepare by referring to the preparation method of Example 56, except that 2-bromoethyl methyl ether in step a) is replaced by 2-bromopropane.

[0579] 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 8.10 (d, J = 6.9Hz, 2H), 7.43 (dd, J=26.3,4.5Hz,3H),7.12(d,J=6.9Hz,2H),6.89–6.72(m,2H),4.52(dq,J =12.0,6.2Hz,1H),3.78(d,J=5.4Hz,2H),3.32(s,3H),3.04(q,J=5.7,5.2 Hz, 4H), 1.61 (d, J = 30.4Hz, 6H), 1.22 (t, J = 5.5Hz, 6H).

[0580] LCMS m / z=457.3[M+1] + .

[0581] Example 59 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(4-(2,2,2-trifluoroethoxy)benzyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine

[0582]

[0583] a) Preparation of 4-(2,2,2-trifluoroethoxy)benzaldehyde

[0584] To the reaction flask, p-hydroxybenzaldehyde (1 g), 2,2,2-trifluoroethyl p-toluenesulfonate (3.12 g), N,N-dimethylformamide (30 ml), cesium carbonate (5.34 g, heated to 100 ° C for 12 h. After the reaction is completed, 100 ml of water is added to quench, the reaction solution is extracted with 100 ml of ethyl acetate, the organic phase is concentrated to dryness, and the crude product is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 1.17 g of the title compound.

[0585] b) Preparation of 4-(2,2,2-trifluoroethoxy)benzyl alcohol

[0586] 4-(2,2,2-trifluoroethoxy)benzaldehyde (0.45 g) and methanol (10 ml) were added to the reaction bottle in sequence, and the nitrogen atmosphere was replaced. Sodium borohydride (0.17 g) was added under ice bath, and the reaction was carried out at 0°C for 1 hour. After the reaction, the reaction solution was dripped into 100 ml of ice water, extracted with ethyl acetate (100 ml*2), dried, and the organic phase was concentrated to dryness to obtain 0.40 g of the title compound.

[0587] c) Preparation of 1-(chloromethyl)-4-(2,2,2-trifluoroethoxy)benzene

[0588] 4-(2,2,2-trifluoroethoxy)benzyl alcohol (0.4 g, 1.94 mmol), dichloromethane (10 mL), and thionyl chloride (0.7 ml) were added to the reaction flask in sequence and reacted at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated to dryness to obtain 0.52 g of the title compound.

[0589] d) 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(4-(2,2,2-trifluoroethoxy)benzyl)-4,7-dihydropyrazolo[2 ...

[0590] Preparation of [1,5-a]pyrimidine

[0591] Prepare by referring to the preparation method of Example 31, replace 1-(chloromethyl)-2-methoxybenzene in step a) with 1-(chloromethyl)-4-(2,2,2-trifluoroethoxy)benzene, and replace 2-(2-methoxybenzyl)-3-oxobutyric acid ethyl ester in step b) with 3-oxo-2-(4-(2,2,2-trifluoroethoxy)benzyl)butyric acid ethyl ester to obtain the title compound.

[0592] 1 H NMR (400MHz, DMSO-d6) δ11.19 (s, 1H), 8.10 (d, J = 7.2Hz, 2H), 7.46 (t, J=7.4Hz,2H),7.38(t,J=7.3Hz,1H),7.20(d,J=8.6Hz,2H),6.95(d,J=8.7Hz,2H),4.6 9(q,J=8.9Hz,2H),3.81(s,2H),3.03(d,J=5.1Hz,4H),2.40(s,3H),1.68–1.51(m,6H).

[0593] LCMS m / z=497[M+1] + .

[0594] Example 60 6-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0595]

[0596] a) Preparation of 6-(hydroxymethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0597] Add 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid methyl ester (5 g) and tetrahydrofuran (250 mL) to the reaction bottle in sequence, cool to 0°C under nitrogen, add lithium aluminum hydride (1.83 g), react at -40°C for 3 hours, add 500 ml of saturated sodium sulfite aqueous solution to quench the reaction, extract the reaction solution with 800 ml of ethyl acetate, concentrate the organic phase to dryness, and slurry the crude product to obtain 2.71 g of the title compound.

[0598] b) Preparation of 6-(chloromethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0599] Prepare by referring to the preparation method of Example 59, except that 4-(2,2,2-trifluoroethoxy)benzyl alcohol in step c) is replaced by 6-(hydroxymethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one.

[0600] c) Preparation of 6-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0601] Prepare by referring to the preparation method of Example 31, replacing 1-(chloromethyl)-2-methoxybenzene in step a) with 6-(chloromethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one, and replacing 2-(2-methoxybenzyl)-3-oxobutanoic acid ethyl ester in step b) with 3-oxo-2-(((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl))methyl)butanoic acid ethyl ester to obtain the title compound.

[0602] 1 H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.50(s,1H),8.14–8.06(m,2H), 7.46(t,J=7.4Hz,2H),7.42–7.36(m,1H),6.87–6.80(m,2H),6.79(d,J=2.3Hz,1 H),4.49(s,2H),3.78(s,2H),3.10–3.00(m,4H),2.39(s,3H),1.69–1.52(m,6H).

[0603] LCMS m / z=490[M+1] + .

[0604] Example 61 4-methyl-6-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0605]

[0606] a) Preparation of 6-(hydroxymethyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0607] 6-(Hydroxymethyl)-2H-benzo[b][1,4]oxazine-3(4H)-one (1g), cesium carbonate (3.64g), N,N-dimethylformamide (50mL), iodomethane (0.42ml) were added to the reaction bottle in sequence and reacted at room temperature for 1.5 hours. After the reaction was completed, 300ml of water was added to quench the reaction, and the reaction solution was extracted with 300ml of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 80 / 1 (V / V)) to obtain 830mg of the title compound.

[0608] b) Preparation of 6-(chloromethyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0609] Prepare by referring to the preparation method of Example 59, except that 4-(2,2,2-trifluoroethoxy)benzyl alcohol in step c) is replaced by 6-(hydroxymethyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one.

[0610] c) Preparation of 6-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0611] Prepare by referring to the preparation method of Example 31, replacing 1-(chloromethyl)-2-methoxybenzene in step a) with 6-(chloromethyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, and replacing 2-(2-methoxybenzyl)-3-oxobutanoic acid ethyl ester in step b) with 2-((4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-3-oxobutanoic acid ethyl ester to obtain the title compound.

[0612] 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.14–8.06(m,2H),7.46(t,J= 7.4Hz,2H),7.42–7.36(m,1H),7.11(d,J=1.5Hz,1H),6.90–6.82(m,2H),4 .58(s,2H),3.85(s,2H),3.26(s,3H),3.07–3.00(m,4H),2.44(s,3H),1.70 –1.50(m,6H).

[0613] LCMS m / z=484[M+1] + .

[0614] Example 62 6-((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0615]

[0616] To the reaction flask, 6-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (34 mg) and tetrahydrofuran (3 ml) were added sequentially. Under nitrogen protection, borane-tetrahydrofuran complex (0.36 mL, 1 M tetrahydrofuran solution) was added dropwise under ice bath. The mixture was stirred at room temperature for 48 hours. After completion of the reaction, 5 ml of methanol was added dropwise to quench the reaction. The mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography to obtain 30 mg of the title compound.

[0617] 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.13–8.08(m,2H),7.49–7.43 (m,2H),7.41–7.36(m,1H),6.51(d,J=8.1Hz,1H),6.40(d,J=2.0Hz,1H), 6.34(dd,J=8.1,2.0Hz,1H),5.64(s,1H),4.08–3.99(m,2H),3.67(s,2H), 3.24–3.18(m,2H),3.08–3.00(m,4H),2.37(s,3H),1.69–1.51(m,6H).

[0618] LCMS m / z=456[M+1] + .

[0619] Example 63 5-methyl-6-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0620]

[0621] Prepare by referring to the preparation method of Example 62, except that 6-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one is replaced with 4-methyl-6-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one.

[0622] 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.13–8.07(m,2H),7.46(t,J= 7.4Hz,2H),7.42–7.35(m,1H),6.64(d,J=1.8Hz,1H),6.52(d,J=8.0Hz,1H ),6.38(dd,J=8.1,1.9Hz,1H),4.19–4.13(m,2H),3.73(s,2H),3.21–3.16 (m,2H),3.08–3.00(m,4H),2.79(s,3H),2.41(s,3H),1.68–1.51(m,6H).

[0623] LCMS m / z=470[M+1] + .

[0624] Example 64 6-(3-bromo-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0625]

[0626] a) Preparation of 2-bromo-4-(bromomethyl)-1-methoxybenzene

[0627] Dissolve 3-bromo-4-methoxytoluene (15.0 g) in carbon tetrachloride (180 mL), add azobisisobutyronitrile (180 mg) and N-bromosuccinimide (13.95 g), and heat to reflux for 6 h under nitrogen protection. After the reaction is completed, concentrate to dryness, add 100 mL of water and 100 mL of dichloromethane for separation, extract the aqueous phase with 100 mL of dichloromethane once, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate = 15 / 1 (V / V)) to obtain 17.98 g of the title compound.

[0628] 1H NMR (400MHz, CDCl3) δ7.59 (d, J=2.2Hz, 1H), 7.30 (dd, J=8.4, 2.2Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 4.43 (s, 2H), 3.89 (s, 3H).

[0629] b) Preparation of ethyl 2-(3-bromo-4-methoxybenzyl)-3-oxobutanoate

[0630] Under nitrogen protection, sodium hydride (1.26 g) was suspended in anhydrous tetrahydrofuran (80 mL), and a solution of ethyl acetoacetate (3.97 mL) in anhydrous tetrahydrofuran (10 mL) was added under ice bath, and the mixture was stirred at room temperature for 0.5 h, and then a solution of 2-bromo-4-(bromomethyl)-1-methoxybenzene (8.0 g) in anhydrous tetrahydrofuran (20 mL) was added, and the mixture was heated to reflux for 8 h, and the mixture was reacted overnight at room temperature. After the reaction was completed, 60 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with 100 mL of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 5.5 g of the title compound.

[0631] LCMS m / z=351.0[M+Na] +

[0632] c) Preparation of 6-(3-bromo-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0633] Dissolve 2-(3-bromo-4-methoxybenzyl)-3-oxobutanoic acid ethyl ester (163 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (60 mg) in glacial acetic acid (5 mL), heat to 106°C and reflux for 4 hours. After the reaction is completed, concentrate to dryness, neutralize with saturated sodium bicarbonate aqueous solution, extract the reaction solution with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by preparative liquid phase to obtain 65 mg of the title compound.

[0634] 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.14–8.07(m,2H),7.50–7.42(m, 3H),7.42–7.36(m,1H),7.22(dd,J=8.5,2.1Hz,1H),7.00(d,J=8.5Hz,1H), 3.80(s,2H),3.79(s,3H),3.09–3.00(m,4H),2.40(s,3H),1.64(s,4H),1.59 –1.51(m,2H).

[0635] LCMS m / z=506.9[M+1] +

[0636] Example 65 6-(4-methoxy-3-methylbenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0637]

[0638] a) Preparation of ethyl 2-(4-methoxy-3-methylbenzyl)-3-oxobutanoate

[0639] Ethyl 2-(3-bromo-4-methoxybenzyl)-3-oxobutanoate (300 mg), methylboronic acid (109 mg), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (65 mg) and cesium carbonate (740 mg) were dissolved in dioxane (15 mL) and water (3 mL), and heated to reflux for 3.5 h under nitrogen protection. After the reaction was completed, 20 mL of water was added to quench the reaction, and the reaction solution was extracted with 20 mL of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 180 mg of the title compound.

[0640] LCMS m / z=287.2[M+Na] +

[0641] b) Preparation of 6-(4-methoxy-3-methylbenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0642] Dissolve 2-(4-methoxy-3-methylbenzyl)-3-oxobutanoic acid ethyl ester (224 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (147 mg) in glacial acetic acid (10 mL), heat to 106°C and reflux for 4 hours. After the reaction is completed, concentrate to dryness, neutralize with saturated sodium bicarbonate aqueous solution, extract the reaction solution with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by preparative liquid phase to obtain 25 mg of the title compound.

[0643] 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),8.15–8.06(m,2H),7.46(t,J=7.3Hz,2H),7.38(t,J=7.3Hz,1H),7.04–6.97(m,2H),6.83–6.76(m,1H),3.76 (s,2H),3.72(s,3H),3.10–3.00(m,4H),2.38(s,3H),2.09(s,3H),1.63(s,4H),1.56(s,2H).

[0644] LCMS m / z=443.2[M+1] +

[0645] Example 66 6-(3-cyclopropyl-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0646]

[0647] Prepare by referring to the preparation method of Example 65, except that the methylboric acid in step a) is replaced by cyclopropylboric acid.

[0648] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),8.11(d,J=7.2Hz,2H),7.46(t,J=7.2Hz,2H),7.38(t,J=7.2Hz,1H),6.94(dd,J=8.4,2.1Hz,1H),6.80(d, J=8.4Hz,1H),6.77(d,J=2.1Hz,1H),3.74(s,3H),3.74(s,2H),3.09–3.00( m,4H),2.37(s,3H),2.09–2.00(m,1H),1.63(s,4H),1.59–1.50(m,2H),0.89 –0.82(m,2H),0.60–0.53(m,2H).

[0649] LCMS m / z=469.0[M+1] +

[0650] Example 67 6-(4-methoxy-3-(pyrrolidin-1-yl)benzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0651]

[0652] a) Preparation of ethyl 2-(4-methoxy-3-(pyrrolidin-1-yl)benzyl)-3-oxobutanoate

[0653] Dissolve 2-(3-bromo-4-methoxybenzyl)-3-oxobutanoic acid ethyl ester (300 mg), tetrahydropyrrole (194 mg), tris(dibenzylideneacetone)dipalladium (0) (41 mg) and 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (43 mg) in dioxane (15 mL), add 1M tetrahydrofuran solution of sodium tert-butoxide (1.46 mL), and heat to 80° C. under nitrogen protection for 6 h. After the reaction is completed, 20 mL of water is added to quench the reaction, and the reaction solution is extracted with 20 mL of ethyl acetate. The organic phase is concentrated to dryness, and the crude product is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 180 mg of the title compound.

[0654] LCMS m / z=320.1[M+1] +

[0655] b) Preparation of 6-(4-methoxy-3-(pyrrolidin-1-yl)benzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0656] Dissolve 2-(4-methoxy-3-(pyrrolidin-1-yl)benzyl)-3-oxobutanoic acid ethyl ester (126 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (68 mg) in glacial acetic acid (5 mL), heat to 106°C and reflux for 6 h. After the reaction is completed, concentrate to dryness, neutralize with saturated sodium bicarbonate aqueous solution, extract the reaction solution with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by preparative liquid phase to obtain 11 mg of the title compound.

[0657] 1 H NMR(400MHz, DMSO-d6)δ8.12(d,J=7.4Hz,2H),7.45(t,J=7.5Hz,2H), 7.37(t,J=7.3Hz,1H),6.74(d,J=8.4Hz,1H),6.65(s,1H),6.55(d,J=8.0H z,1H),3.74(s,2H),3.68(s,3H),3.18(t,J=6.1Hz,4H),3.05(s,4H),2.39 (s,3H),1.82(t,J=6.2Hz,4H),1.63(s,4H),1.56(s,2H).

[0658] LCMS m / z=498.3[M+1] +

[0659] Example 68 6-(3-ethynyl-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0660]

[0661] a) Preparation of ethyl 2-(4-methoxy-3-((trimethylsilyl)ethynyl)benzyl)-3-oxobutanoate

[0662] Dissolve 2-(3-bromo-4-methoxybenzyl)-3-oxobutanoic acid ethyl ester (400 mg), bis(triphenylphosphine)palladium dichloride (43 mg) and cuprous iodide (12 mg) in triethylamine (8 mL), add trimethylsilyl acetylene (0.51 mL) under nitrogen protection, and heat to 60°C for 4 h. After the reaction is completed, filter out the insoluble matter, extract the filter cake with 10 mL of ethyl acetate, and concentrate the filtrate to dryness to obtain 660 mg of the title compound.

[0663] LCMS m / z=369.0[M+Na] +

[0664] b) Preparation of methyl 2-(3-ethynyl-4-methoxybenzyl)-3-oxobutanoate

[0665] Dissolve ethyl 2-(4-methoxy-3-((trimethylsilyl)ethynyl)benzyl)-3-oxobutanoate (422 mg) and cesium carbonate (20 mg) in methanol (15 mL), and stir at room temperature to react overnight. After the reaction is completed, the reaction solution is concentrated to make sand, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 134 mg of the title compound.

[0666] LCMS m / z=283.0[M+Na] +

[0667] c) Preparation of 6-(3-ethynyl-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0668] Dissolve methyl 2-(3-ethynyl-4-methoxybenzyl)-3-oxobutanoate (134 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (90 mg) in glacial acetic acid (5 mL), heat to 106°C and reflux for 6 h. After the reaction is completed, concentrate to dryness, neutralize with saturated sodium bicarbonate aqueous solution, extract the reaction solution with 20 mL of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by preparative liquid phase to obtain 13 mg of the title compound.

[0669] 1H NMR (400MHz, DMSO-d6) δ11.25 (s, 1H), 8.11 (d, J = 7.2Hz, 2H), 7.46 (t, J =7.2Hz,2H),7.38(t,J=6.8Hz,1H),7.25(d,J=8.7Hz,2H),6.94(d,J=8.4Hz ,2H),4.16(s,1H),3.77(s,5H),3.05(s,4H),2.39(s,3H),1.63(s,4H),1.56 (s,2H).

[0670] LCMS m / z=453.3[M+1] +

[0671] Example 69 / 70 (S)-6-(1-(2,3-dihydrobenzofuran-5-yl)ethyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-6-(1-(2,3-dihydrobenzofuran-5-yl)ethyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0672]

[0673] a) Preparation of ethyl 2-((2,3-dihydrobenzofuran-5-yl)methylene)-3-oxobutanoate

[0674] Under ice bath, titanium tetrachloride (8.9 mL) was slowly added to anhydrous tetrahydrofuran (50 mL) under nitrogen protection, and then carbon tetrachloride (7.8 mL) and ethyl acetoacetate (5.3 g) were added. After stirring in ice bath for 1 h, a solution of 2,3-dihydrobenzofuran-5-carboxaldehyde (6 g) in anhydrous tetrahydrofuran (10 mL) was added. After continuing to stir in ice bath for 1 h, a solution of pyridine (13 mL) in anhydrous tetrahydrofuran (10 mL) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, 100 mL of water was added to quench, and the reaction solution was extracted with 100 mL of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to obtain 640 mg and 1.85 g of the cis and trans isomers of the title compound.

[0675] LCMS m / z=261.1[M+1] +

[0676] b) Preparation of ethyl 2-acetyl-3-(2,3-dihydrobenzofuran-5-yl)butanoate

[0677] Under nitrogen protection, cuprous iodide (2.19 g) was suspended in anhydrous tetrahydrofuran (25 mL), cooled to -40 °C and stirred. Methyl lithium 1.3 M tetrahydrofuran solution (16.6 mL) was added dropwise, and after the addition was complete, the mixture was transferred to an ice bath and stirred for 1 h, and then cooled to -78 °C. A solution of ethyl 2-((2,3-dihydrobenzofuran-5-yl)methylene)-3-oxobutanoate (2 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at -78 °C for 1 h. After the reaction was completed, 50 mL of saturated ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with 50 mL of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to obtain 1.66 g of the title compound.

[0678] LCMS m / z=299.0[M+Na] +

[0679] c) Preparation of (S)-6-(1-(2,3-dihydrobenzofuran-5-yl)ethyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-6-(1-(2,3-dihydrobenzofuran-5-yl)ethyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0680] Ethyl 2-acetyl-3-(2,3-dihydrobenzofuran-5-yl)butanoate (100 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazole-5-amine (73 mg) were dissolved in 2-methyltetrahydrofuran (6 mL), and a 1M dichloromethane solution of titanium tetrachloride (0.3 mL) was added under nitrogen protection, and the mixture was heated to 85°C and refluxed for 8 h. After the reaction was completed, 20 mL of water was added to quench the reaction, and the reaction solution was extracted with 20 mL of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by preparative liquid phase to obtain 57 mg of a racemic compound. SFC separation gave a pair of enantiomers of 22.1 mg and 21.7 mg.

[0681] The first compound obtained by SFC separation is numbered as Example 69, which is analyzed by SFC analysis chromatographic conditions, RT = 3.2min, and the structural confirmation data are:

[0682] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.19–8.01(m,2H),7.45(t,J=7.4Hz,2H),7.38(dd,J=8.4,6.2Hz,1H),7.20(s,1H),7.11–6.97(m,1H),6.64 (d,J=8.2Hz,1H),4.46(t,J=8.7Hz,2H),4.34(q,J=7.0Hz,1H),3.12(t, J=8.6Hz,2H),3.08–2.98(m,4H),2.37(s,3H),1.62(d,J=7.2Hz,7H),1.57(s,2H).

[0683] LCMS m / z=455.1[M+1] +

[0684] The second compound obtained by SFC separation is numbered as Example 70, which is analyzed by SFC analysis chromatographic conditions, RT = 4.1min, structural confirmation data:

[0685] 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 8.14–8.02 (m, 2H), 7.45 (t, J = 7.4 Hz,2H),7.38(t,J=7.3Hz,1H),7.20(s,1H),7.08–6.98(m,1H),6.64(d,J =8.2Hz,1H),4.46(t,J=8.7Hz,2H),4.34(d,J=21.2Hz,1H),3.12(t,J=8.7 Hz,2H),3.03(d,J=5.1Hz,4H),2.37(s,3H),1.62(d,J=7.2Hz,7H),1.59– 1.51(m,2H).

[0686] LCMS m / z=455.1[M+1] +

[0687] Example 71 / 72 (S)-5-methyl-6-(1-(3-methylbenzo[d]isoxazol-5-yl)ethyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-5-methyl-6-(1-(3-methylbenzo[d]isoxazol-5-yl)ethyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0688]

[0689] The preparation method of Example 69 / 70 was used to prepare the compound, except that the 2,3-dihydrobenzofuran-5-carboxaldehyde in step a) was replaced by 3-methylbenzo[d]isoxazole-5-carboxaldehyde.

[0690] The first compound obtained by SFC separation is numbered as Example 71, which is analyzed by SFC analysis chromatographic conditions, RT = 3.5min, and the structural confirmation data are:

[0691] 1 H NMR (400MHz, DMSO-d6) δ8.07 (d, J=7.2Hz, 2H), 7.80 (s, 1H), 7.62–7.53 (m,2H),7.45(t,J=7.5Hz,2H),7.37(t,J=7.3Hz,1H),4.53(q,J=7.0Hz,1H ),3.03(d,J=5.2Hz,4H),2.56(s,3H),2.44(s,3H),1.73(d,J=7.1Hz,3H), 1.68–1.60(m,4H),1.60–1.52(m,2H).

[0692] LCMS m / z=468.1[M+1] +

[0693] The second compound obtained by SFC separation is numbered as Example 72, which is analyzed by SFC analysis chromatographic conditions, RT = 3.9 min, structural confirmation data:

[0694] 1 H NMR (400MHz, DMSO-d6) δ8.12–8.02(m,2H),7.80(s,1H),7.64–7.52(m,2H),7.45(t,J=7.4Hz,2H),7.37(t,J=7.3Hz,1H),4.53(q,J=7.0Hz,1H), 3.03(d,J=5.1Hz,4H),2.56(s,4H),2.44(s,3H),1.73(d,J=7.2Hz,3H),1.64(s,4H),1.60–1.51(m,2H).

[0695] LCMS m / z=468.1[M+1] +

[0696] Example 73 / 74 (R)-5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(1-(quinoxalin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(1-(quinoxalin-6-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0697]

[0698] The preparation method is described in Example 69 / 70, except that the 2,3-dihydrobenzofuran-5-carboxaldehyde in step a) is replaced by quinoxaline-6-carboxaldehyde; and the methyl lithium in step b) is replaced by methyl magnesium bromide.

[0699] The first compound obtained by SFC separation is numbered as Example 73, which is analyzed by SFC analysis chromatographic conditions, RT = 4.2min, structural confirmation data:

[0700] 1 H NMR (400MHz, DMSO-d6) δ11.19 (s, 1H), 8.92 (d, J = 1.8Hz, 1H), 8.88 (d, J=1.8Hz,1H),8.08(d,J=7.2Hz,2H),8.03(s,1H),7.98(d,J=8.7Hz,1H),7.81(dd,J=8.8,1.9Hz,1H),7.44(t,J=7.4Hz,2H),7.36(t,J=7.3Hz,1H), 4.64(d,J=7.0Hz,1H),3.05(d,J=4.9Hz,4H),2.46(s,3H),1.80(d,J=7.1Hz,3H),1.60(d,J=29.0Hz,6H).

[0701] LCMS m / z=465.2[M+1] +

[0702] The second compound obtained by SFC separation is numbered as Example 74, which is analyzed by SFC analysis chromatographic conditions, RT = 4.9 min, structural confirmation data:

[0703] 1H NMR (400MHz, DMSO-d6) δ11.18 (s, 1H), 8.92 (d, J = 1.6Hz, 1H), 8.88 (d, J=1.6Hz,1H),8.08(d,J=7.3Hz,2H),8.03(s,1H),7.98(d,J=8.7Hz,1H),7.81(d,J=8.7Hz,1H),7.44(t,J=7.4Hz,2H),7.37(t,J=7.3Hz,1H),4.64 (d, J=7.0Hz, 1H), 3.06 (s, 4H), 2.47 (s, 3H), 1.80 (d, J=7.0Hz, 3H), 1.60 (d, J=28.5Hz, 6H).

[0704] LCMS m / z=465.2[M+1] +

[0705] Example 75 6-(1-(2-methoxyquinolin-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0706]

[0707] The preparation method of Example 69 / 70 is referred to, except that the 2,3-dihydrobenzofuran-5-carboxaldehyde in step a) is replaced by 2-methoxyquinoline-6-carboxaldehyde.

[0708] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.21(d,J=8.9Hz,1H),8.08(d,J=7.3Hz,2H),7.83(s,1H),7.68(d,J=8.6Hz,1H),7.61(dd,J=8.7,1.6Hz, 1H),7.45(t,J=7.5Hz,2H),7.37(t,J=7.1Hz,1H),6.97(d,J=8.8Hz,1H),4 .59(q,J=6.3Hz,1H),3.96(s,3H),3.05(s,4H),2.39(s,3H),1.74(d,J=7.1 Hz,3H),1.64(s,4H),1.56(s,2H).

[0709] LCMS m / z=494.2[M+1] +

[0710] Example 76 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(1-(4-(pyrrolidin-1-yl)phenyl)ethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0711]

[0712] The preparation method is described in Example 69 / 70, except that the 2,3-dihydrobenzofuran-5-carboxaldehyde in step a) is replaced by 4-(1-pyrrolinyl)benzaldehyde; and the methyllithium in step b) is replaced by methylmagnesium bromide.

[0713] 1 H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 8.09 (d, J = 7.6Hz, 2H), 7.45 (t, J=7.5Hz,2H),7.37(t,J=7.3Hz,1H),7.11(d,J=8.3Hz,2H),6.45(d,J=8.4 Hz,2H),4.37(q,J=6.6Hz,1H),3.16(s,4H),3.03(s,4H),2.31(s,3H),1.92 (s,4H),1.70–1.48(m,10H).

[0714] LCMS m / z=482.2[M+1] + .

[0715] Example 77 6-(3-Benzyloxy-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0716]

[0717] a) Preparation of (3-benzyloxy-4-methoxyphenyl)methanol

[0718] Add 5-hydroxymethyl-2-methoxyphenol (20 g) into a 1L single-mouth bottle, add acetonitrile (200 ml), then add potassium carbonate (35.9 g), stir for 0.5 h, then add benzyl bromide (22.2 g), heat and reflux for 4 h, filter, and concentrate the filtrate under reduced pressure until there is no droplet. Add petroleum ether for crystallization to obtain 31.7 g of the title compound.

[0719] b) Preparation of 2-benzyloxy-4-bromomethyl-1-methoxybenzene

[0720] Add (3-benzyloxy-4-methoxyphenyl)methanol (20 g) into a 1 L single-mouth bottle, add chloroform (400 ml), add trimethylsilyl bromide (18.8 g), stir at room temperature for 15 minutes, concentrate under reduced pressure to evaporate the solvent, add ethyl acetate / petroleum ether = 1 / 3 to slurry, filter and obtain 24 g of the title compound.

[0721] c) Preparation of ethyl 2-(3-benzyloxy-4-methoxybenzyl)-3-oxobutanoate

[0722] Ethyl acetoacetate (6.4 g) was dissolved in N,N-dimethylformamide (150 ml), potassium carbonate (6.8 g) was added, and the mixture was stirred at room temperature for 15 minutes. 2-Benzyloxy-4-bromomethyl-1-methoxybenzene (15 g) was added to the reaction system in batches, and the mixture was stirred at room temperature overnight. Ethyl acetate (80 ml) was added to the reaction system, followed by water (80 ml), and the mixture was extracted and separated. The aqueous phase was back-extracted twice with ethyl acetate, the organic phases were combined, washed once with saturated brine (80 ml), dried over anhydrous sodium sulfate, filtered, sanded, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 8 g of the title compound.

[0723] d) Preparation of 6-(3-benzyloxy-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0724] Add ethyl 2-(3-benzyloxy-4-methoxybenzyl)-3-oxobutanoate (3 g) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (2.45 g) into a 250 ml single-necked bottle, add anhydrous ethanol (75 ml) and trifluoroacetic acid (3.6 ml), heat to 100° C., react for 18 h, concentrate under reduced pressure until there is no droplet, make sand, and separate by column chromatography (mobile phase: dichloromethane / methanol=80 / 1 (V / V)) to obtain 3 g of the title compound.

[0725] 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.13(t,J=9.5Hz,2H),7.46(t,J=7.4Hz,2H),7.39(t,J=7.2Hz,3H),7.34–7.24(m,3H),6.93(d,J=1.7 Hz,1H),6.85(d,J=8.3Hz,1H),6.75(dd,J=8.2,1.7Hz,1H),5.03(s,2H),3.7 6(s,2H),3.70(d,J=12.5Hz,3H),3.05(d,J=5.1Hz,4H),2.32(s,3H),1.65(s, 4H),1.57(s,2H).

[0726] LCMS m / z=535.3[M-1] +

[0727] Example 78 6-(3-Hydroxy-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0728]

[0729] Add 6-(3-benzyloxy-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (30 mg) to a 50 ml single-mouth bottle, add anhydrous methanol (3 ml), palladium / carbon (30 mg), replace with hydrogen, stir overnight to react. Filter the palladium carbon, evaporate the filtrate to dryness, and obtain 11 mg of the title compound.

[0730] 1 H NMR (400MHz, DMSO-d6) δ11.20 (s, 1H), 8.74 (s, 1H), 8.17 (d, J = 7.0Hz, 2H), 7.43 (t, J = 7.5Hz, 2H), 7.35 (d, J = 7.2Hz, 1H), 6.77 (d, J = 8.3Hz, 1H), 6.63(dd,J=18.4,5.0Hz,2H),3.72(s,2H),3.69(s,3H),3.09(s,4H),2.34– 2.21(m,3H),1.63(s,4H),1.54(s,2H).

[0731] LCMS m / z=445.2[M-1] +

[0732] Example 79 6-(3-isopropoxy-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0733]

[0734] Add 6-(3-hydroxy-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg) into a sealed tube, add MeCN (5 ml), then add bromopropane (83 mg), add cesium carbonate (440 mg) and heat to 55°C. React for 8 h, filter, sand the filtrate, and purify by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 (V / V)) to obtain 34 mg of the target compound.

[0735] 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.13–8.07(m,2H),7.46(t,J= 7.4Hz,2H),7.43–7.36(m,1H),6.89(d,J=1.9Hz,1H),6.83(d,J=8.3Hz,1H),6.73(dd,J=8.3,1.9Hz,1H),4.46(hept,J=6.0Hz,1H),3.77(s,2H),3.69 (s,3H),3.10–2.96(m,4H),2.41(s,3H),1.64(s,4H),1.53(d,J=30.1Hz,2H),1.23(s,3H),1.22(s,3H).

[0736] LCMS m / z=487.3[M-1] +

[0737] Example 80 6-(4-methoxy-3-(2-methoxyethoxy)benzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0738]

[0739] Prepare by referring to the preparation method of Example 79, except that the bromopropane in step a) is replaced with 1-bromo-2-methoxyethane.

[0740] 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.16–8.03(m,2H),7.46(t,J= 7.4Hz,2H),7.38(t,J=7.3Hz,1H),6.90(d,J=1.8Hz,1H),6.83(d,J=8.3Hz,1H),6.73(dd,J=8.2,1.8Hz,1H),4.07–3.97(m,2H),3.78(s,2H),3.70 (s,3H),3.62(dd,J=5.3,3.9Hz,2H),3.28(s,3H),3.03(d,J=5.2Hz,3H),2.42(d,J=16.0Hz,3H),1.63(s,4H),1.56(s,2H).

[0741] LCMS m / z=403.3[M-1] +

[0742] Example 81 6-(1-(3-hydroxy-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0743]

[0744] a) Preparation of 6-(3-(benzyloxy)-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0745] 6-(3-(Benzyloxy)-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (3 g) was added to a single-mouth bottle, and N,N-dimethylformamide (30 ml) was added, followed by potassium carbonate (1.55 g) and 2-(trimethylsilyl)ethoxymethyl chloride (1.87 g). The mixture was replaced with nitrogen and stirred overnight at room temperature. Ethyl acetate (30 ml) was added, and then an appropriate amount of water was added to quench the reaction. The mixture was separated and extracted. The aqueous phase was back-extracted with ethyl acetate twice, and the organic phase was washed with saturated brine (30 ml) twice, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, sanded, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 2.8 g of the title compound.

[0746] b) Preparation of 6-(1-(3-(benzyloxy)-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0747] 6-(3-(Benzyloxy)-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (500 mg) was added to a 100 ml three-necked flask. Under nitrogen protection, ultra-dry tetrahydrofuran (10 ml) was added. The dry ice ethanol was cooled to -70 °C. N-butyl lithium (242 mg) was slowly added dropwise. After the addition was completed, the mixture was stirred for 0.5 min. h, iodomethane (1.07 g) was diluted with tetrahydrofuran to 2 ml, and added dropwise to the reaction system. After the addition was completed, stirring was continued for 0.5 h, water was added to quench the reaction, and ethyl acetate (30 ml) was added. The liquids were extracted and separated. The aqueous phase was back-extracted with ethyl acetate twice. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. Sand was made and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 110 mg of the title compound.

[0748] c) Preparation of 6-(1-(3-(benzyloxy)-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0749] 6-(1-(3-(Benzyloxy)-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (110 mg) was added to a 50 ml single-mouth bottle, replaced with nitrogen for protection, N,N-dimethylformamide (4 ml) was added, and then sodium hydride (15.6 mg) was added. The mixture was heated to 60°C and reacted for 4 h. An appropriate amount of water was added to quench the reaction, and ethyl acetate (30 ml) was added. The mixture was separated and extracted, washed with water and back-extracted with ethyl acetate twice, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, sanded, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 31 mg of the title compound.

[0750] d) Preparation of 6-(1-(3-hydroxy-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0751] Add 6-(1-(3-(Benzyloxy)-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (31 mg) to a single-necked bottle, add methanol (3 ml), add palladium / carbon (10%, 20 mg), replace with hydrogen, stir overnight at room temperature, filter, evaporate the filtrate to dryness, and purify to obtain 5 mg of the title compound.

[0752] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J=6.7Hz, 2H), 7.37 (t, J=6.8Hz, 3H), 6.94 –6.82(m,2H),6.75(d,J=8.3Hz,1H),4.65(d,J=7.0Hz,1H),3.85(s,3H),3.64(s,1H),3.02–2.90(m,4H),2.21(d,J=9.1Hz,3H),1.36(d,J=5.6Hz, 3H), 1.32 (d, J=6.9Hz, 2H), 0.93–0.80 (m, 4H).

[0753] LCMS m / z=459.2[M-1] +

[0754] Example 82 / 83 (R)-6-(1-(1-,2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(1-,2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0755]

[0756] a) Preparation of 6-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl]-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0757] 6-(((2,3-Dihydrobenzo[b][1,4]dioxane-6-yl)methyl]-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (280 mg) was dissolved in N,N-dimethylformamide (15 ml), 2-(trimethylsilyl)ethoxymethyl chloride (205 mg) was added, and the mixture was stirred at room temperature overnight under nitrogen protection. Ethyl acetate (30 ml) and water (30 ml) were added to the reaction system, and the mixture was extracted and separated. The aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, sand-made, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 280 mg of the title compound.

[0758] b) Preparation of 6-(1-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0759] 6-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl]-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (220 mg) was added to a 100 ml three-necked flask. Under nitrogen protection, ultra-dry tetrahydrofuran (15 ml) was added. Dry ice ethanol was cooled to -70°C, and n-butyl lithium (72 mg) was slowly added dropwise. After the addition was completed, the mixture was stirred for 0.5 h. Iodomethane (532 mg) was diluted with tetrahydrofuran and added dropwise to the reaction system. After the addition was completed, the mixture was stirred for 0.5 h. 5 ml of water was added to quench the reaction. Ethyl acetate (30 ml) was added and the mixture was extracted. The aqueous phase was back-extracted with ethyl acetate twice. The combined organic phases were washed once with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, sanded, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give 140 mg of the title compound.

[0760] c) Preparation of (R)-6-(1-(1-,2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(1-,2,3-dihydrobenzo[b][1,4]dioxan-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0761] 6-(1-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (140 mg) was added to a 50 ml single-mouth bottle, nitrogen replacement protection was added, N, N-dimethylformamide (5 ml) was added, and then sodium hydride (34 mg) was added, heated at 80°C for 7 h, and an appropriate amount of water was added to quench the reaction, and ethyl acetate (30 ml) was added, and the mixture was separated and extracted. The organic phase was washed with water and back-extracted with ethyl acetate twice, and the organic phase was washed once with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, sanded, and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 (V / V)) to obtain 63 mg of the racemic compound, which was purified by SFC The isomers were separated into two pairs.

[0762] The first compound obtained by SFC separation is numbered as Example 82, which is analyzed by SFC analysis chromatographic conditions, RT = 4.0min, and the structural confirmation data are:

[0763] 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.13–8.03(m,2H),7.45(t,J= 7.4Hz,2H),7.38(t,J=7.3Hz,1H),6.84–6.69(m,3H),4.27(dt,J=20.4,10.2 Hz,1H),4.19(s,4H),3.03(d,J=5.2Hz,4H),2.37(s,3H),1.71–1.49(m,9H).

[0764] The second compound obtained by SFC separation is numbered as Example 83, which is analyzed by SFC analysis chromatographic conditions, RT = 4.7min, structural confirmation data:

[0765] 1 H NMR (400MHz, DMSO) δ11.04 (s, 1H), 8.09 (d, J = 7.1Hz, 2H), 7.45 (t, J =7.4Hz,2H),7.38(t,J=7.3Hz,1H),6.84–6.69(m,3H),4.29(d,J=7.1Hz, 1H), 4.19 (s, 4H), 3.03 (d, J = 5.3Hz, 4H), 2.37 (s, 3H), 1.70–1.47 (m, 9H).

[0766] Example 84 / 85 (R)-6-(1-(3,4-dimethoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(3,4-dimethoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0767]

[0768] Prepare with reference to the preparation method of Example 82 / 83, except that the 6-(((2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methyl]-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one in step a) is replaced with 6-(3,4-dimethoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

[0769] The first compound obtained by SFC separation is numbered as Example 84, which is analyzed by SFC analysis chromatographic conditions, RT = 4.0min, and the structural confirmation data are:

[0770] 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.13–8.04(m,2H),7.46(t,J= 7.4Hz,2H),7.38(t,J=7.3Hz,1H),6.94(s,1H),6.84(s,2H),4.39(q,J=6. 9Hz,1H),3.71(d,J=4.2Hz,6H),3.03(d,J=5.3Hz,4H),2.38–2.31(m,3H), 1.69–1.53(m,9H).

[0771] LCMS m / z=473.38[M+1] +

[0772] The second compound obtained by SFC separation is numbered as Example 85, which is analyzed by SFC analysis chromatographic conditions, RT = 4.3min, structural confirmation data:

[0773] 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.12–8.05(m,2H),7.45(t,J= 7.4Hz,2H),7.41–7.35(m,1H),6.95(s,1H),6.84(s,2H),4.39(q,J=7.1Hz ,1H),3.71(d,J=4.2Hz,6H),3.03(d,J=5.2Hz,4H),2.34(d,J=9.0Hz,3H), 1.68–1.50(m,9H).

[0774] LCMS m / z=473.38[M+1] +

[0775] Example 86 N-(2-methoxy-5-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)phenyl)-N-methylacetamide

[0776]

[0777] a) Preparation of N-(2-methoxy-5-methylphenyl)acetamide

[0778] Add 2-methoxy-5-methylaniline (20 g) into a 250 ml single-mouth bottle, add acetic acid (35 g), then add acetic anhydride (17.9 g), stir at room temperature for 4 h, add ethyl acetate (100 ml) to the reaction system to dilute, then add saturated sodium bicarbonate to neutralize, separate and extract, back-extract the aqueous phase with ethyl acetate twice, wash the organic phase with saturated sodium bicarbonate and saturated sodium chloride aqueous solution once each, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure until there is no droplet to obtain 16 g of the title compound.

[0779] b) Preparation of N-(2-methoxy-5-methylphenyl)-N-methylacetamide

[0780] Add N-(2-methoxy-5-methylphenyl)acetamide (10g) to a 1L single-mouth bottle, add N,N-dimethylformamide (40ml), add iodomethane (11.88g), add sodium hydride (2.68g) under N2 protection, stir at room temperature overnight, add ethyl acetate (100ml) to the reaction system to dilute, then add water (100ml), separate and extract, back-extract the aqueous phase with ethyl acetate twice, wash the organic phase with saturated brine twice, dry over anhydrous sodium sulfate, filter, sand, concentrate under reduced pressure to evaporate the solvent, sand, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 30 / 1 (V / V)). 16g of the title compound was obtained.

[0781] c) Preparation of N-(5-(bromomethyl)-2-methoxyphenyl)-N-methylacetamide

[0782] Dissolve N-(2-methoxy-5-methylphenyl)-N-methylacetamide (5 g) in carbon tetrachloride (100 ml), add N-bromosuccinimide (9.21 g), then add benzoyl peroxide (627 mg), heat to 85°C and react for 5 h, filter out insoluble matter, make sand, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 30 / 1 (V / V)) to obtain 3.37 g of the title compound.

[0783] d) Preparation of N-(2-methoxy-5-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)phenyl)-N-methylacetamide

[0784] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with N-(5-(bromomethyl)-2-methoxyphenyl)-N-methylacetamide.

[0785] 1H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.10(d,J=7.1Hz,2H),7.47(t,J=7.4Hz,2H),7.39(t,J=7.3Hz,1H),7.20(dd,J=15.7,5.3Hz,2H),7.04(d, J=8.5Hz,1H),3.82(s,2H),3.78(s,3H),3.05(d,J=5.4Hz,4H),3.00(s,3H),2.41(s,3H),1.65(s,7H),1.57(s,2H).

[0786] LCMS m / z=500.3[M-1] +

[0787] Example 87 6-(4-methoxy-3-(methylamino)benzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0788]

[0789] Add N-(2-methoxy-5-((5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)methyl)phenyl)-N-methylacetamide (50 mg) into a 50 ml single-necked bottle, dissolve with 10% hydrochloric acid (5 ml), add a little ethylene glycol to assist dissolution, heat to 100°C, react for 18 h, add ethyl acetate to extract twice, discard the organic phase, neutralize the aqueous phase with saturated NaHCO3, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure until there is no droplet, and purify to obtain 33 mg of the title compound.

[0790] 1 H NMR (400MHz, DMSO-d6) δ11.14 (s, 1H), 8.11 (d, J = 7.2Hz, 2H), 7.45 (q, J=7.1Hz,2H),7.39(t,J=7.3Hz,1H),6.64(d,J=8.1Hz,1H),6.46–6.41(m,1H),6.35(d,J=8.0Hz,1H),5.02–4.78(m,2H),3.74(d,J=2.4Hz,3H), 3.71(s,3H),3.04(d,J=5.0Hz,4H),2.70(d,J=5.2Hz,1H),2.40(s,3H),1.64(s,4H),1.57(s,2H).

[0791] LCMS m / z=458.0[M-1]+

[0792] Example 88 6-(3-(Dimethylamino)-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0793]

[0794] a) Preparation of methyl 3-(dimethylamino)-4-methoxybenzoate

[0795] Add methyl 3-amino-4-methoxybenzoate (5 g) into a 250 ml single-mouth bottle, add tetrahydrofuran (200 ml), then add potassium carbonate (7.63 g), stir at room temperature for 0.5 h, then add iodomethane (11.75 g), stir overnight, filter out insoluble matter, make sand, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 30 / 1 (V / V)) to obtain 1.3 g of the title compound.

[0796] b) Preparation of (3-(dimethylamino)-4-methoxyphenyl)methanol

[0797] Add methyl 3-(dimethylamino)-4-methoxybenzoate (330 mg) into a 100 ml three-necked flask, add tetrahydrofuran (10 ml), add lithium aluminum tetrahydride under N2 protection in an ice bath, remove the ice bath and stir at low temperature for 1 hour, add the reaction system into 10% aqueous sodium sulfite solution, add ethyl acetate, separate the liquids and extract, back-extract the aqueous phase twice with ethyl acetate, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to evaporate the solvent to obtain 270 mg of a colorless oil, which is directly used as a feed for the next step.

[0798] c) Preparation of 5-(chloromethyl)-2-methoxy-N,N-dimethylaniline

[0799] Dissolve (3-(Dimethylamino)-4-methoxyphenyl)methanol (270 mg) in dichloromethane (20 ml) under N2 protection, add thionyl chloride (0.3 ml) under ice bath, remove the ice bath, stir at room temperature for 2 h, evaporate the solvent and use it directly as feed for the next step.

[0800] d) Preparation of 6-(3-(dimethylamino)-4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0801] Prepare by referring to the preparation method of Example 31, except that 1-(chloromethyl)-2-methoxybenzene in step a) is replaced with 5-(chloromethyl)-2-methoxy-N,N-dimethylaniline.

[0802] 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.14–8.06(m,2H),7.50–7.41 (m,2H),7.39(t,J=7.3Hz,1H),6.83(d,J=1.8Hz,1H),6.77(d,J=8.3Hz,1H),6.70(dd,J=8.2,1.8Hz,1H),3.76(s,2H),3.72(s,3H),3.04(d,J=5.2 Hz,4H),2.66(s,6H),2.42(s,3H),1.64(s,4H),1.57(s,2H).

[0803] LCMS m / z=470.1[M+1] +

[0804] Example 89 / 90 (R)-6-(1-(4-methoxy-3-(methylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(4-methoxy-3-(methylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0805]

[0806] a) Preparation of ethyl 2-(4-methoxy-3-nitrobenzylidene)-3-oxobutanoate

[0807] Dissolve 4-methoxy-3-nitrobenzaldehyde (5 g) in isopropanol (150 ml), add ethyl acetoacetate (3.59 g), then add piperidine (3.75 ml) and acetic acid (3.75 ml), react at room temperature overnight with stirring, and filter to obtain 7.57 g of the target compound.

[0808] b) Preparation of ethyl 2-acetyl-3-(4-methoxy-3-nitrophenyl)butyrate

[0809] Cuprous iodide (5.84 g) was added to a three-necked flask, and ultra-dry THF was added under nitrogen protection. Methyl lithium (1.26 g, 57.28 mmol) was added dropwise under a dry ice bath, and the mixture was stirred for 1 h. Ethyl 2-(4-methoxy-3-nitrobenzylidene)-3-oxobutanoate (6 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was added dropwise to the reaction system, and the mixture was stirred for 1 h. Saturated aqueous ammonium chloride solution was added to the reaction system for quenching, and ethyl acetate was added, and the mixture was separated and extracted. The aqueous phase was back-extracted twice with ethyl acetate, the organic phases were combined, and the mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and sanded. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 4.5 g of the title compound.

[0810] c) Preparation of 6-(1-(4-methoxy-3-nitrophenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0811] Ethyl 2-acetyl-3-(4-methoxy-3-nitrophenyl)butyrate (4 g) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazole-5-amine (3.13 g) were added to a reaction bottle, 4-methyltetrahydrofuran was added to dissolve, titanium tetrachloride (2.45 g) was added under nitrogen protection, heated to 85° C., reacted for 8 h, added an appropriate amount of water to quench, and then added ethyl acetate, separated and extracted, the aqueous phase was back-extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, sand was made, and purified by column chromatography (mobile phase: dichloromethane / methanol=10 / 1 (V / V)) to obtain 1.3 g of the title compound.

[0812] d) Preparation of 6-(1-(4-(methoxy-3-nitrophenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0813] 6-(1-(4-methoxy-3-nitrophenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (600 mg) was dissolved in N,N-dimethylformamide (10 ml). Sodium hydride (98.4 mg) was added under nitrogen protection, and then 2-(trimethylsilyl)ethoxymethyl chloride (307.8 mg) was added. The mixture was stirred overnight, and aqueous ammonium chloride solution was added, followed by ethyl acetate. The mixture was separated and extracted. The aqueous phase was back-extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and sand was prepared. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 400 mg of the title compound.

[0814] e) Preparation of 6-(1-(3-(3-amino-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0815] 6-(1-(4-(methoxy-3-nitrophenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg) was added to ethanol (5 ml), and under nitrogen protection, ammonium formate (204 mg) was added, and then Pd / C (30 mg) was added. The mixture was heated to 85°C and stirred for 3 h. The insoluble matter in the reaction system was filtered through diatomaceous earth, and sand was made. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 90 mg of the title compound.

[0816] f) Preparation of 6-(1-(4-(methoxy-3-(methylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyridin-7(4H)-one

[0817] 6-(1-(3-(3-amino-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg) was dissolved in N,N-dimethylformamide (8 ml), potassium carbonate (56.4 mg) was added, and then iodomethane (57.9 mg / l) was added, and the mixture was stirred overnight. Water was added to dilute the mixture, and ethyl acetate was added to separate the extractions. The mixture was washed with water and stripped with EA twice, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified to obtain 73 mg of the title compound.

[0818] g) Preparation of (R)-6-(1-(4-methoxy-3-(methylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-6-(1-(4-methoxy-3-(methylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0819] 6-(1-(4-(methoxy-3-(methylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyridine-7(4H)-one (100 mg) was dissolved in N,N-dimethylformamide (5 ml), sodium hydride (13.3 mg) was added, nitrogen was protected, and the reaction was heated at 60° for 6 h. An aqueous ammonium chloride solution was added to the reaction system, ethyl acetate was added, the mixture was separated and extracted, dried over anhydrous sodium sulfate, filtered, evaporated, and purified to obtain 50 mg of a racemic compound, which was separated by SFC to obtain a pair of enantiomers.

[0820] The first compound obtained by SFC separation is numbered as Example 89, which is analyzed by SFC analysis chromatographic conditions, RT=5.0min, and the structural confirmation data are as follows:

[0821] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.15–7.94(m,2H),7.45(t,J=7.4Hz,2H),7.38(t,J=7.3Hz,1H),6.67(d,J=8.1Hz,1H),6.52–6.44(m, 2H),4.87(d,J=5.2Hz,1H),4.40(q,J=7.2Hz,1H),3.72(s,3H),3.03(d,J =5.2Hz,4H),2.67(d,J=5.1Hz,3H),2.34–2.24(m,3H),1.60(q,J=10.4Hz, 9H).

[0822] LCMS m / z=472.28[M+1] +

[0823] The second compound obtained by SFC separation is numbered as Example 90, which is analyzed by SFC analysis chromatographic conditions, RT = 6.2min, structural confirmation data:

[0824] 1H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 8.10 (d, J = 7.2Hz, 2H), 7.45 (t, J=7.4Hz,2H),7.38(t,J=7.3Hz,1H),6.67(d,J=8.1Hz,1H),6.56–6.37(m ,2H),4.87(d,J=5.2Hz,1H),4.47–4.33(m,1H),3.72(s,3H),3.04(s,4H), 2.67(d,J=5.1Hz,3H),2.31(s,3H),1.60(dd,J=17.8,10.5Hz,9H).

[0825] LCMS m / z=472.28[M+1] +

[0826] Example 91 N-(2-methoxy-5-(1-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)ethyl)phenyl)acetamide

[0827]

[0828] Prepare by referring to the preparation method of Example 89 / 90, except that methyl iodide in step f) is replaced by acetic anhydride.

[0829] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.05(s,1H),8.09(d,J=7.4Hz, 2H),7.87(s,1H),7.45(t,J=7.5Hz,2H),7.38(t,J=7.3Hz,1H),7.03(d,J =8.2Hz,1H),6.92(d,J=8.5Hz,1H),4.39(d,J=7.1Hz,1H),3.78(s,3H),3.05(s,4H),2.35(s,3H),2.01(d,J=18.1Hz,3H),1.75–1.43(m,9H).

[0830] LCMS m / z=500.27[M+1] +

[0831] Example 92 6-(1-(3-(((cyclopropylmethyl)amino)-4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0832]

[0833] Prepare by referring to the preparation method of Example 89 / 90, except that the iodomethane in step f) is replaced with (bromomethyl)cyclopropane.

[0834] 1 H NMR (400MHz, DMSO-d6) δ11.45 (s, 1H), 8.15 (s, 2H), 7.43 (d, J = 7.5Hz, 2H),7.36(s,1H),6.68(d,J=8.2Hz,1H),6.57–6.47(m,2H),4.58(s,1H),4 .41(s,1H),3.74(s,3H),3.11(s,4H),2.87(s,2H),2.64(d,J=30.6Hz,1H), 2.33(s,3H),1.59(d,J=7.3Hz,9H),0.52–0.33(m,2H),0.17(t,J=8.8Hz, 2H).

[0835] LCMS m / z=510.36[M+1] +

[0836] Example 93 6-(1-(4-methoxy-3-((2-methoxyethyl)amino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0837]

[0838] Prepare by referring to the preparation method of Example 89 / 90, except that the iodomethane in step f) is replaced with 1-bromo-2-methoxyethane.

[0839] 1 H NMR (400MHz, DMSO-d6) δ11.58–10.92(m,1H),8.14(s,2H),7.43(d,J=6.9Hz,2H),7.37(s,1H),6.69(d,J=8.1Hz,1H),6.60–6.50(m,2H),4.61(s, 1H),4.42(s,1H),3.73(d,J=4.9Hz,3H),3.48(t,J=5.3Hz,2H),3.23(s,3H ),3.15(d,J=5.8Hz,2H),3.09(s,4H),2.33(s,3H),1.59(d,J=7.3Hz,9H).

[0840] HPLC: 89.91%

[0841] LCMS m / z=514.15[M+1]+

[0842] Example 94 6-(3,3-difluoro-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0843]

[0844] a) Preparation of 6-(3,3-difluoro-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0845] 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (300 mg) was dissolved in tetrahydrofuran (5 ml), and the temperature was lowered to -80°C under nitrogen protection. n-Butyl lithium (103.2 mg) was added dropwise, and 1,1-difluoro-2-iodoethane (1.03 g) was diluted and slowly added dropwise to the reaction system. The mixture was stirred for 30 minutes, and an aqueous ammonium chloride solution was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified to obtain 80 mg of the title compound.

[0846] b) Preparation of 6-(3,3-difluoro-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0847] Dissolve 6-(3,3-difluoro-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (40 mg) in trifluoroacetic acid (2 ml), heat to 60°C, react for 3 h, evaporate the solvent, add saturated sodium bicarbonate to neutralize, extract with ethyl acetate, dry over sodium sulfate, and purify to obtain 5 mg of the title compound.

[0848] 1H NMR (400MHz, DMSO-d6) δ8.34 (s, 2H), 7.40 (dd, J = 101.9, 70.0Hz, 5H), 6.77 (d,J=97.4Hz,2H),5.32(t,J=4.9Hz,1H),4.33(s,1H),3.62(s,3H),3.60(s, 1H),2.99(s,4H),2.64(d,J=21.0Hz,3H),2.00(dd,J=14.9,6.9Hz,2H),1.52 (d,J=33.2Hz,4H).

[0849] Example 95 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(3,3,3-trifluoro-1-(4-methoxyphenyl)propyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0850]

[0851] The preparation method of Example 94 was used to prepare the compound, except that 1,1-difluoro-2-iodoethane in step a) was replaced with 1,1,1-trifluoro-2-iodoethane.

[0852] 1 H NMR (400MHz, DMSO-d6) δ11.12–10.84 (m, 1H), 8.04 (d, J = 7.1Hz, 2H), 7.53–7.35(m,5H),6.69(d,J=8.6Hz,2H),3.63(s,3H),3.35(d,J=3.7Hz, 1H), 2.91 (s, 3H), 2.74 (s, 2H), 2.00 (dd, J = 15.0, 6.9Hz, 3H), 1.52 (s, 7H).

[0853] Example 96 6-(3-methoxy-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0854]

[0855] a) Preparation of 6-(3-methoxy-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0856] 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.3 g) and tetrahydrofuran (5 mL) were added to the reaction bottle in sequence. Under nitrogen protection, the temperature was lowered to -78°C, n-butyl lithium (0.84 ml, 1.6 M tetrahydrofuran solution) was added, stirred for 30 minutes, and 1-iodo-2-methoxyethane (0.5 g) was added. The reaction was allowed to react at -78°C for 1 hour. After the reaction was completed, 30 ml of saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with 30 ml of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to obtain 64 mg of the title compound.

[0857] b) Preparation of 6-(3-methoxy-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0858] 6-(3-methoxy-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (64 mg) and N,N-dimethylformamide (3 ml) were added to the reaction bottle in sequence. Sodium hydride (16.6 mg, 60%) was added under nitrogen protection, and the mixture was heated to 60°C for 6 hours. After the reaction was completed, 30 ml of saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with 30 ml of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 50 / 1 (V / V)) to obtain 6 mg of the title compound.

[0859] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.10–8.04(m,2H),7.44(t,J=7.4Hz,2H),7.37(t,J=7.3Hz,1H),7.32(d,J=8.7Hz,2H),6.81(d,J=8.7 Hz,2H),4.14(dd,J=9.1,5.8Hz,1H),3.70(s,3H),3.26(ddd,J=15.3,10.9, 6.2Hz,2H),3.21(s,3H),3.03(t,J=4.6Hz,4H),2.58(ddd,J=14.1,10.0,5.2 Hz,1H),2.36–2.25(m,1H),1.68–1.50(m,6H).

[0860] LCMS m / z=487.2[M+1]+ .

[0861] Example 97 6-(1-(4-methoxyphenyl)pentyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0862]

[0863] a) Preparation of 6-(3-methoxy-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0864] 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.3 g) and tetrahydrofuran (5 mL) were added to the reaction bottle in sequence. Under nitrogen protection, the temperature was lowered to -78°C, and n-butyl lithium (0.84 ml, 1.6 M tetrahydrofuran solution) was added. The reaction was stirred for 1 hour. After the reaction was completed, 30 ml of saturated ammonium chloride aqueous solution was added to quench, and the reaction solution was extracted with 30 ml of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to obtain 160 mg of the title compound.

[0865] b) Preparation of 6-(1-(4-methoxyphenyl)pentyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0866] Prepare with reference to the preparation method of Example 96, except that 6-(3-methoxy-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one in step b) is replaced with 6-(3-methoxy-1-(4-methoxyphenyl)propyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

[0867] 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 8.08 (d, J = 7.4Hz, 2H), 7.45 (t, J=7.4Hz,2H),7.37(t,J=7.3Hz,1H),7.31(d,J=8.5Hz,2H),6.81(d,J=8.6Hz,2H),4.13–4.00(m,1H),3.69(s,3H),3.03(s,4H),2.44(s,3H),2.29 (s,1H),2.07(td,J=12.8,5.7Hz,1H),1.59(d,J=27.1Hz,6H),1.28(ddt,J =35.1,14.8,6.7Hz,4H),0.85(t,J=7.1Hz,3H).

[0868] LCMS m / z=485.3[M+1] + .

[0869] Example 98 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0870]

[0871] Cuprous iodide (34.1 mg) and 1-(trifluoromethyl)-1,2-benzidoyl-3(1H)-one (424 mg) were added to a three-necked flask under nitrogen protection. 6-(4-methoxybenzyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (500 mg) was dissolved in N,N-dimethylformamide (10 ml) and added to the reaction system. The mixture was heated to 90°C and stirred for 1 h. Ethyl acetate was added to the reaction system for dilution. Saturated brine was added, the mixture was separated and extracted, and the mixture was dried over anhydrous sodium sulfate. Purification gave 6 mg of the target compound.

[0872] 1 H NMR (400MHz, DMSO-d6) δ12.03–10.67 (m, 1H), 8.12 (d, J = 7.6Hz, 2H), 7.57 –7.41(m,5H),7.37(t,J=7.1Hz,1H),7.14(d,J=8.4Hz,1H),3.85(s,1H),3.83(s,3H),3.06(s,4H),2.38(s,3H),1.63(s,4H),1.55(s,2H).

[0873] LCMS m / z=497.13[M+1] +

[0874] Example 99 6-(1-(4-methoxyphenyl)prop-2-yn-1-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0875]

[0876] a) Preparation of ethyl-2-(4-methoxybenzylidene)-3-oxobutyrate

[0877] 4-Methoxybenzaldehyde (5.00 g), ethyl acetoacetate (4.78 g), piperidine (156 mg) and acetic acid (110 mg) were added to ethanol (100 ml) and stirred at room temperature for overnight reaction. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (7.34 g).

[0878] b) Preparation of ethyl 2-acetyl-3-(4-methoxyphenyl)pent-4-ynoate

[0879] Cuprous chloride (80 mg) was added to tetrahydrofuran (20 ml) and stirred. The mixture was replaced with nitrogen and cooled to -5°C. Ethylene magnesium bromide (26.58 ml, 0.5 M) was added dropwise. The mixture was stirred at -5 to 0°C for 10 minutes. Ethyl-2-(4-methoxybenzylidene)-3-oxobutyrate (1.00 gl) was dissolved in tetrahydrofuran (5 ml) and added dropwise to the reaction solution. The mixture was stirred at -5 to 0°C for 1 hour. After the reaction was completed, 1N hydrochloric acid solution was added dropwise to the reaction solution to quench the mixture. The mixture was extracted twice with ethyl acetate. The organic phases were combined, washed twice with saturated sodium chloride solution, and concentrated to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (550 mg).

[0880] c) Preparation of 6-(1-(4-methoxyphenyl)prop-2-yn-1-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0881] 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (330 mg), ethyl 2-acetyl-3-(4-methoxyphenyl)pent-4-ynoate (560 mg) and titanium tetrachloride (1.36 ml, 1.0 M) were added to 2-methyltetrahydrofuran (25 ml), heated to 80° C. and stirred for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, concentrated to obtain a crude product, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (166 mg).

[0882] 1 H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.15–8.08(m,2H),7.47(t,J= 7.4Hz,2H),7.44–7.37(m,1H),7.33(d,J=8.4Hz,2H),6.90(d,J=8.8Hz,2H),5.71(d,J=2.2Hz,1H),3.73(s,3H),3.38(d,J=2.7Hz,1H),3.04(t,J =4.8Hz,4H),2.31(s,3H),1.60(d,J=29.2Hz,6H).

[0883] LCMS m / z=453.2[M+1] +

[0884] Example 100 6-(1-(4-methoxyphenyl)-2-methylpropyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazol[1,5-a]pyrimidin-7(4H)-one

[0885]

[0886] Prepare by referring to the preparation method of Example 99, except that the ethynylmagnesium bromide in step b) is replaced by isopropylmagnesium chloride.

[0887] 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 8.12 (d, J = 7.5Hz, 2H), 7.44 (dd, J=16.3,8.0Hz,3H),7.40–7.24(m,2H),6.78(d,J=8.5Hz,2H),3.68(s,3H), 3.62(s,1H),3.04(s,4H),2.33(s,3H),1.57(d,J=26.9Hz,7H),0.83(dd,J= 23.0,6.2Hz,6H).

[0888] LCMS m / z=471.3[M+1]+

[0889] Example 101 6-(Cyclopropyl(4-methoxyphenyl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0890]

[0891] Prepare by referring to the preparation method of Example 99, except that the ethynylmagnesium bromide in step b) is replaced by cyclopropylmagnesium bromide.

[0892] 1 H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 8.09 (d, J = 7.3Hz, 2H), 7.45 (t, J=7.5Hz,2H),7.37(dd,J=15.2,7.9Hz,3H),6.90–6.77(m,2H),3.71(s,3H), 3.04(d,J=5.0Hz,4H),2.33(s,3H),2.18(s,1H),1.60(d,J=28.6Hz,6H),1.23 (s,1H),0.74(s,1H),0.41(tt,J=8.8,4.3Hz,1H),0.30(td,J=8.9,4.6Hz,1H),0.25–0.15(m,1H).

[0893] LCMS m / z=469.2[M+1] +

[0894] Example 102 6-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0895]

[0896] Preparation of 2,2-Dimethylbenzo[d][1,3]dioxol-5-acetaldehyde

[0897] 3,4-dihydroxybenzaldehyde (20.00g) and acetone (10.09g) were added to toluene (120ml), nitrogen was protected, and the temperature was cooled to 0°C in an ice-salt bath. Phosphorus pentachloride (12.06g) was added to the reaction solution in 6 portions, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane twice, the organic phases were combined, washed with NaCl solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (2.98g).

[0898] b) Preparation of 6-(1-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0899] Prepare by referring to the preparation method of Example 99, except that the 4-methoxybenzaldehyde in step a) is replaced by 2,2-dimethylbenzo[d][1,3]dioxole-5-acetaldehyde; and the ethynylmagnesium bromide in step b) is replaced by methylmagnesium chloride.

[0900] 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.14–8.02(m,2H),7.45(t,J= 7.4Hz,2H),7.38(dd,J=8.4,6.2Hz,1H),6.83(d,J=1.3Hz,1H),6.75(d,J=8.2Hz,1H),6.69(d,J=8.0Hz,1H),4.28(q,J=6.9Hz,1H),3.03(d,J=5.2 Hz,4H),2.41(s,3H),1.71–1.48(m,15H).

[0901] LCMS m / z=485.2[M+1] +

[0902] Example 103 6-(1-(Imidazol[1,2-a]pyrazin-2-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazol[1,5-a]pyrimidin-7(4H)-one

[0903]

[0904] a) Preparation of 2-(dichloromethyl)imidazole[1,2-a]pyrazine

[0905] Add pyrazine-2-amine (5.00g) to ethylene glycol dimethyl ether (50ml) and stir. Dissolve 1,1,3-trichloroacetone (10.61g) in ethylene glycol dimethyl ether (10ml) and add dropwise to the reaction solution. Stir and react at room temperature overnight. Dissolve 1,1,3-trichloroacetone (4.77g) in ethylene glycol dimethyl ether (5ml) and add to the reaction solution. Continue stirring and reacting at room temperature for 24 hours. After the reaction is completed, slowly pour the reaction solution into tetrahydrofuran (400ml) under stirring, filter, add the filter cake to ethanol (40ml), heat to reflux and react for 6 hours. Dilute the reaction solution with water, extract 6 times with tetrahydrofuran / ethyl acetate = 1:1, and concentrate to obtain the title compound (2.5g).

[0906] b) Preparation of imidazo[1,2-a]pyrazine-2-acetaldehyde

[0907] 2-(Dichloromethyl)imidazole[1,2-a]pyrazine (2.5 g) and calcium carbonate were added to water (12.5 ml) and heated under reflux for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and extracted 4 times with tetrahydrofuran / ethyl acetate = 1:1 and concentrated to obtain the title compound (1.59 g).

[0908] c) Preparation of 6-(1-(imidazo[1,2-a]pyrazin-2-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0909] Prepare by referring to the preparation method of Example 99, except that the 4-methoxybenzaldehyde in step a) is replaced by imidazole [1,2-a] pyrazine-2-acetaldehyde; and the ethynyl magnesium bromide in step b) is replaced by methyl magnesium bromide.

[0910] 1 H NMR (400MHz, MeOD-d4) δ8.82 (s, 1H), 8.44 (s, 1H), 7.99 (d, J = 6.6Hz, 3H),7.83(d,J=4.4Hz,1H),7.39(s,3H),4.62(d,J=7.0Hz,1H),3.13–2.91(m,4H),2.52(s,3H),1.84(d,J=6.9Hz,3H),1.74–1.51(m,6H).

[0911] LCMS m / z=454.2[M+1] +

[0912] Example 104 6-(1-(Imidazol[1,2-a]pyridin-6-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazol[1,5-a]pyrimidin-7(4H)-one

[0913]

[0914] a) Preparation of ethyl 2-acetyl-3-(imidazo[1,2-a]pyridin-6-yl)butanoate

[0915] Prepare by referring to steps a) and b) of the preparation method of Example 99, except that the 4-methoxybenzaldehyde in step a) is replaced by imidazole [1,2-a] pyridine-6-acetaldehyde; and the ethynyl magnesium bromide in step b) is replaced by methyl magnesium bromide.

[0916] b) Preparation of 6-(1-(imidazole [1,2-a] pyridin-6-yl) ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl) pyrazol [1,5-a] pyrimidin-7 (4H) -one

[0917] Ethyl 2-acetyl-3-(imidazole [1,2-a] pyridin-6-yl) butyrate (192 mg), 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (170 mg) and trifluoroacetic acid (368 mg) were added to ethanol (9 ml), heated to 80° C. and stirred for 9 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the crude product was subjected to TLC (dichloromethane / methanol=10 / 1 (V / V)) to obtain the title compound (55 mg).

[0918] 1 H NMR (400MHz, DMSO-d6) δ11.26 (s, 1H), 8.48 (s, 1H), 8.08 (d, J = 7.3Hz, 2H),7.92(s,1H),7.52(s,1H),7.48–7.34(m,4H),7.17(d,J=9.2Hz,1H),4.38 (d,J=6.8Hz,1H),3.06(s,4H),2.50–2.47(m,3H),1.69(d,J=7.1Hz,3H),1.61(d,J=26.5Hz,6H).

[0919] LCMS m / z=453.2[M+1] +

[0920] Example 105 6-(1-(2,4-dimethoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0921]

[0922] Prepare by referring to the preparation method of embodiment 99, except that the 4-methoxybenzaldehyde in step a) is replaced by 2,4-dimethoxybenzaldehyde; and the ethynylmagnesium bromide in step b) is replaced by methylmagnesium bromide.

[0923] LCMS m / z=473.2[M+1] +

[0924] Example 106 6-(1-(4-(dimethylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0925]

[0926] a) Preparation of ethyl 2-acetyl-3-(4-(dimethylamino)phenyl)butyrate

[0927] Refer to steps a) and b) of the preparation method of embodiment 99, except that the 4-methoxybenzaldehyde in step a) is replaced by 4-(dimethylamino)benzaldehyde; and the ethynylmagnesium bromide in step b) is replaced by methylmagnesium bromide.

[0928] b) Preparation of 6-(1-(4-(dimethylamino)phenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0929] Ethyl 2-acetyl-3-(4-(dimethylamino)phenyl)butanoate (500 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (436 mg) were dissolved in 2-methyltetrahydrofuran (40 ml). Titanium tetrachloride (683.8 mg) was added dropwise under nitrogen protection. The mixture was heated to 85° C. and stirred for 4 h. Water was added to the reaction system to quench the reaction. Ethyl acetate was then added and the mixture was separated and extracted. The aqueous phase was back-extracted twice with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Purification afforded 7 mg of the title compound.

[0930] 1 H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 8.09 (d, J = 7.2Hz, 2H), 7.45 (t, J=7.5Hz,2H),7.38(t,J=7.3Hz,1H),7.14(d,J=8.6Hz,2H),6.65(d,J=8.7Hz,2H),4.36(d,J=7.2Hz,1H),3.03(d,J=5.1Hz,4H),2.83(s,6H),2.33 (s,3H),1.60(dd,J=17.3,10.0Hz,9H).

[0931] LCMS m / z=456.26[M+1] +

[0932] Example 107 / 108 (R)-3-(Cyclohex-1-en-1-yl)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-3-(Cyclohex-1-en-1-yl)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0933]

[0934] a) Preparation of ethyl-2-(4-methoxybenzylidene)-3-oxobutyrate

[0935] 4-Methoxybenzaldehyde (5.00 g), ethyl acetoacetate (4.78 g), piperidine (156 mg) and acetic acid (110 mg) were added to ethanol (100 ml) and stirred at room temperature for overnight reaction. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (7.34 g).

[0936] b) Preparation of ethyl 2-acetyl-3-(4-methoxyphenyl)butyrate

[0937] Cuprous iodide (1.92 g) was added to tetrahydrofuran (30 ml) and stirred. The mixture was replaced with nitrogen and cooled to 0°C. Methyl lithium (7.75 ml, 1.3 M) was added dropwise. The mixture was stirred at 0°C for 1 hour. The mixture was cooled to -78°C. Ethyl-2-(4-methoxybenzylidene)-3-oxobutyrate (1.00 g) was dissolved in THF (5 ml) and added dropwise to the reaction solution. The mixture was stirred at -78°C for 1 hour. After the reaction was completed, a saturated ammonium chloride solution was added dropwise to quench the mixture. The mixture was diluted with water and extracted twice with ethyl acetate. The mixture was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain the title compound (840 mg).

[0938] c) Preparation of (R)-3-(cyclohex-1-en-1-yl)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one and (S)-3-(cyclohex-1-en-1-yl)-6-(1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0939] 4-(Cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine (290 mg), ethyl 2-acetyl-3-(4-methoxyphenyl) butyrate (480 mg) and titanium tetrachloride (2.1 ml, 1.0 M) were added to 2-methyltetrahydrofuran (30 ml), heated to 80° C. and stirred for 4 hours, titanium tetrachloride (1.58 ml, 1.0 M) was added to the reaction solution, and the reaction was continued at 80° C. for 14 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate 3 times, and concentrated to obtain a crude product, and purified by column chromatography (mobile phase: tetrahydrofuran / dichloromethane = 1 / 9 (V / V)) to obtain a racemic compound (113 mg), which was separated by SFC to obtain a pair of enantiomers.

[0940] The first compound obtained by SFC separation is numbered as Example 107, which is analyzed by SFC analysis chromatographic conditions, RT = 5.5min, and the structural confirmation data are:

[0941] 1 H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 7.73 (d, J = 7.1Hz, 2H), 7.45 (t, J=7.3Hz,2H),7.38(t,J=7.3Hz,1H),7.24(d,J=8.6Hz,2H),6.83(d,J=8.7Hz,2H),5.79(s,1H),4.37(dd,J=14.1,6.8Hz,1H),3.71(s,3H),2.33(s, 3H), 2.18 (s, 2H), 2.02 (s, 2H), 1.67 (s, 4H), 1.63 (d, J = 7.2Hz, 3H).

[0942] LCMS m / z=440.4[M+1] +

[0943] The second compound obtained by SFC separation is numbered as Example 108, which is analyzed by SFC analysis chromatographic conditions, RT = 5.8min, structural confirmation data:

[0944] 1 H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 7.73 (d, J = 7.1Hz, 2H), 7.45 (t, J=7.3Hz,2H),7.38(t,J=7.3Hz,1H),7.24(d,J=8.6Hz,2H),6.84(d,J=8.7Hz,2H),5.79(s,1H),4.38(dd,J=14.1,6.9Hz,1H),3.71(s,3H),2.33(s, 3H), 2.18 (s, 2H), 2.01 (s, 2H), 1.67 (s, 4H), 1.63 (d, J = 7.2Hz, 3H).

[0945] LCMS m / z=440.4[M+1] +

[0946] Example 109 1-(5-methoxybenzo[d]oxazol-2-yl)-3,4-diphenyl-1H-pyrazol-5-amine

[0947]

[0948] 3,4-Diphenyl-1H-pyrazol-5-amine (500 mg), 2-chloro-5-methoxybenzo[d]oxazole (332 mg) and potassium carbonate (1.13 g) were added to N,N-dimethylformamide (20 ml) and stirred at room temperature for overnight reaction. After the reaction was completed, the reaction solution was diluted with water, extracted twice with ethyl acetate, concentrated to obtain a crude product, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (210 mg).

[0949] 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=8.9Hz,1H),7.47–7.27(m,9H),7.26 –7.19(m,2H),6.97(dd,J=8.9,2.5Hz,1H),6.77(s,2H),3.83(s,3H).

[0950] LCMS m / z=383.1[M+1] +

[0951] Example 110 1-(5-methoxybenzo[d]oxazol-2-yl)-3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine

[0952]

[0953] The preparation method of Example 109 was used to prepare the product, except that 3,4-diphenyl-1H-pyrazole-5-amine in step a) was replaced with 3-phenyl-4-(piperidin-1-yl)-1H-pyrazole-5-amine.

[0954] 1 H NMR(400MHz,DMSO-d6)δ8.09(d,J=1.5Hz,1H),8.07(d,J=1.1Hz,1H), 7.69(d,J=8.9Hz,1H),7.49–7.42(m,2H),7.39(ddd,J=7.3,3.6,1.4Hz,1H), 7.32(d,J=2.5Hz,1H),6.95(dd,J=8.9,2.6Hz,1H),6.53(s,2H),3.83(s,3H), 3.07–2.91(m,4H),1.65–1.48(m,6H).

[0955] LCMS m / z=390.1[M+1] +

[0956] Example 111 3-(Bicyclo[4.1.0]heptane-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0957]

[0958] a) Preparation of 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0959] 4-(Cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (500 mg), ethyl 2-(4-methoxyphenyl)-3-oxobutanoate (494 mg) and trifluoroacetic acid (1.10 g) were added to ethanol (10 ml), heated to 80° C. and stirred for 6 hours. After the reaction was completed, the mixture was allowed to stand at room temperature overnight, solid precipitated, filtered, and the filter cake was washed with ethyl acetate and dried to obtain the title compound (120 mg).

[0960] b) Preparation of 3-(bicyclo[4.1.0]heptane-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

[0961] 3-(Cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg) was added to dichloromethane (5 ml), and the mixture was cooled to 0°C under nitrogen protection. Diethylzinc (0.97 ml, 1.0 M) was added dropwise, and then diiodomethane (260 mg) was added. The reaction mixture was stirred at 0°C for 1 hour, and then stirred at room temperature overnight. The reaction mixture was cooled to 0°C, and diethylzinc (2.43 ml, 1.0 M) was added dropwise, and diiodomethane (651 mg) was added. The mixture was stirred at 0°C for 1 hour, and then stirred at room temperature overnight. After the reaction was completed, the reaction mixture was cooled to 0°C, quenched with saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, and concentrated to obtain a crude product, which was then subjected to TLC (dichloromethane / methanol = 10 / 1) to obtain the title compound (60 mg).

[0962] 1H NMR (400MHz, DMSO-d6) δ11.49(s,1H),7.89–7.79(m,2H),7.51(t,J=7.4Hz,2H),7.45(d,J=7.3Hz,1H),7.27–7.17(m,2H),7.05–6.93(m,2H), 3.80(s,3H),2.39–2.31(m,1H),2.26(s,3H),1.95–1.79(m,2H),1.66–1.5 6(m,1H),1.56–1.46(m,1H),1.41(d,J=8.9Hz,1H),1.36(s,1H),1.33(d,J =7.7Hz,1H),1.23(s,1H),0.80(d,J=2.8Hz,1H),0.72(d,J=5.0Hz,1H).

[0963] LCMS m / z=426.1[M+1] +

[0964] Example 112 (E)-6-(3-methoxyphenylvinyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0965]

[0966] a) Preparation of 5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0967] 5-phenyl-4-(1-piperidinyl)-1H-pyrazol-3-amine (10.00 g) and ethyl acetoacetate (10.74 g) were added to acetic acid (10 ml) and stirred, and heated under reflux for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with water and 0°C methanol and dried to obtain the title compound (8.47 g).

[0968] b) Preparation of 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0969] 5-Methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (8.45 g) was added to N,N-dimethylformamide (80 ml) and stirred. The mixture was replaced with nitrogen and cooled to 0°C. Sodium hydride (2.19 g, 60%) was added in batches. After the addition was completed, the mixture was stirred at 0°C for 1 hour. 2-(trimethylsilyl)ethoxymethyl chloride (5.48 g) was added and then stirred at room temperature overnight. After the reaction was completed, a saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate for 3 times. The organic phases were combined, washed once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 20 / 1 (V / V)) to obtain the title compound (3.95 g).

[0970] c) Preparation of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0971] 5-Methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (3.00 g) was added to dichloromethane (60 ml) and stirred, and then triethylamine (831 mg) and N-bromosuccinimide (1.58 g) were added in sequence and stirred at room temperature overnight; N-bromosuccinimide (487 mg) was added and the reaction was continued with stirring for 1.5 hours; N-bromosuccinimide (487 mg) was added again and the reaction was continued with stirring for 1 hour. After the reaction was completed, the reaction solution was washed with water and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4 / 1 (V / V)) to obtain the title compound (2.75 g).

[0972] d) Preparation of 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylpyrazolopyrazolo[1,5-a]pyrimidin-7(4H)-one

[0973] 6-Bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazol[1,5-a]pyrimidin-7(4H)-one (960 mg), vinylboronic acid pinacol ester (343 mg), potassium phosphate (1.18 g) and bis(tri-tert-butylphosphine)palladium(0) (95 mg) were added to 1,4-dioxane / water (38.4 ml / 9.6 ml), replaced with nitrogen for protection, heated to 60°C and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain the title compound (244 mg).

[0974] e) Preparation of (E)-6-(3-methoxyphenylvinyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-(2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0975] 5-Methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylpyrazolpyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg), 3-iodoanisole (131 mg), triethylamine (87 mg) and bis(tri-tert-butylphosphine)palladium(0) (44 mg) were added to toluene (20 ml), replaced with nitrogen for protection, heated to 80° C. and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain the title compound (89 mg).

[0976] f) Preparation of (E)-6-(3-methoxyphenylvinyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0977] (E)-6-(3-methoxyphenylvinyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-(2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (82 mg) was added to N,N-dimethylformamide (15 ml), and then sodium hydride (24 mg) was added, and the mixture was heated to 60°C and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate 3 times, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 2 (V / V)) to obtain the title compound (39.6 mg).

[0978] 1H NMR (400MHz, DMSO-d6) δ11.54 (s, 1H), 8.12 (t, J = 6.5Hz, 2H), 7.68 (d, J=16.0Hz,1H),7.47(t,J=7.4Hz,2H),7.40(t,J=7.2Hz,1H),7.27(t,J=7.8Hz,1H),7.17–6.99(m,3H),6.81(d,J=7.9Hz,1H),3.80(s,3H),3.07(s, 4H), 2.65 (s, 3H), 1.61 (d, J = 30.4Hz, 6H).

[0979] LCMS m / z=441.2[M+1] +

[0980] Example 113 (E)-6-(2-methoxyphenylvinyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0981]

[0982] Prepare by referring to the preparation method of Example 112, except that 3-iodoanisole in step e) is replaced by o-iodoanisole.

[0983] 1 H NMR (400MHz, DMSO-d6) δ11.43 (s, 1H), 8.12 (d, J = 7.4Hz, 2H), 7.97 (d, J=16.3Hz,1H),7.63(d,J=7.2Hz,1H),7.48(t,J=7.5Hz,2H),7.40(t,J=7.3Hz,1H),7.23(t,J=7.6Hz,1H),7.08–6.91(m,3H),3.84(s,3H),3.07(s, 4H), 2.64 (s, 3H), 1.62 (d, J = 29.9Hz, 6H).

[0984] LCMS m / z=441.2[M+1] +

[0985] Example 114 (E)-6-(4-methoxyphenylvinyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0986]

[0987] Prepare by referring to the preparation method of Example 112, except that 3-iodoanisole in step c) is replaced by 4-iodoanisole.

[0988] 1 H NMR (400MHz, DMSO-d6) δ11.44 (s, 1H), 8.12 (t, J = 6.8Hz, 2H), 7.63 (d, J=16.1Hz,1H),7.47(dd,J=8.0,6.9Hz,4H),7.40(t,J=7.3Hz,1H),6.92(dd ,J=12.4,7.2Hz,3H),3.77(s,3H),3.06(d,J=4.9Hz,4H),2.64(s,3H),1.61 (d,J=29.8Hz,6H).

[0989] LCMS m / z=441.2[M+1] +

[0990] Example 115 (E)-5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(2-(pyridin-3-yl)vinyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0991]

[0992] a) Preparation of (E)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyridine

[0993] 3-iodopyridine (820 mg), vinylboronic acid pinacol ester (800 mg), palladium acetate (90 mg), triphenylphosphine (210 mg), triethylamine (820 mg) and toluene (80 ml) were added to a two-necked flask, and a condenser was added to replace the nitrogen and refluxed for 5 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 460 mg of the title compound.

[0994] b) Preparation of (E)-5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(2-(pyridin-3-yl)vinyl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0995] (E)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)pyridine (360 mg), 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (700 mg), potassium phosphate (850 mg), di(tri-tert-butylphosphine)palladium (66 mg), 1,4-dioxane (28 ml) and water (7 ml) were added to a two-necked flask in sequence, and a condenser was added to replace the nitrogen atmosphere. The mixture was heated to 60°C and stirred for reaction for 5 hours. After the reaction, the reaction solution was diluted with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 283 mg of the title compound.

[0996] c) Preparation of (E)-5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(2-(pyridin-3-yl)vinyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[0997] (E)-5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(2-(pyridin-3-yl)vinyl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (190 mg), sodium hydride (100 mg) and N,N-dimethylformamide (20 ml) were added to a two-necked flask in sequence, and the atmosphere was replaced with nitrogen and stirred at 60°C for 4 h. After the reaction, saturated aqueous ammonium chloride solution (5 mL) was added, followed by ethyl acetate (100 mL), and the mixture was washed with saturated brine (50 mL×3) and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol=20 / 1 (V / V)) to obtain 71 mg of the title compound.

[0998] 1 H NMR (400MHz, Methanol-d4) δ8.65 (s, 1H), 8.37 (d, J = 4.8Hz, 1H), 8.06 (d, J=7.5Hz,3H),7.83(d,J=16.1Hz,1H),7.50–7.33(m,4H),7.25(d,J=16.2H z,1H),3.08(t,J=5.3Hz,4H),2.71(s,3H),1.71(s,4H),1.60(d,J=7.8Hz, 2H).

[0999] LCMS m / z=412[M+1] +

[1000] Example 116 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(2-(pyridin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1001]

[1002] (E)-5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(2-(pyridin-3-yl)vinyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (36 mg), palladium / carbon (30 mg) and methanol (3 ml) were added to a two-necked flask, replaced with hydrogen and stirred overnight at room temperature. After the reaction was completed, the solid was filtered out with filter paper and rinsed twice with methanol, the organic phase was collected and concentrated to dryness, and 7 mg of the title compound was obtained by slurrying with ethyl acetate and petroleum ether.

[1003] 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.46–8.38(m,2H),8.14–8.06 (m,2H),7.66(dt,J=7.8,2.0Hz,1H),7.50–7.43(m,2H),7.42–7.37(m,1H),7 .32(dd,J=7.7,4.8Hz,1H),3.03(d,J=5.7Hz,3H),2.76(s,4H),2.25(s,3H), 1.59(d,J=30.0Hz,6H).

[1004] LCMS m / z=414.1[M+1] +

[1005] Example 117 6-(1-(4-methoxy-1H-indol-1-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1006]

[1007] a) Preparation of ethyl 2-acetylbut-2-enoate

[1008] Take a 500mL three-necked flask, blow dry with a hair dryer and plug it, add anhydrous tetrahydrofuran (100mL) after nitrogen replacement, and place it in an ice-water bath and stir for 10 minutes. Then add titanium tetrachloride (3.3mL) and continue stirring for 5 minutes, then add pyridine (6.5mL) and ethyl acetoacetate (2.6mL), and finally add acetaldehyde (2.3mL), and continue stirring in an ice-water bath for 1h. After the reaction is completed, add water (150mL), extract with ethyl acetate (50ml×3), collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate the organic phase to dryness. The crude product is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain 2.2g of the title compound.

[1009] b) Preparation of ethyl 2-acetyl-3-(4-methoxy-1H-indol-1-yl)butyrate

[1010] 4-Methoxyindole (471 mg) and potassium tert-butoxide (395 mg) were added to a two-necked flask and replaced with nitrogen. Ethyl 2-acetylbut-2-enoate (500 mg) was dissolved in anhydrous acetonitrile (20 mL) and added to the flask, and stirred overnight at room temperature. After the reaction was completed, the solid was filtered out with filter paper, rinsed twice with ethyl acetate, and the organic phase was collected and concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain 362 mg of the title compound.

[1011] c) Preparation of 6-(1-(4-methoxy-1H-indol-1-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1012] 2-Acetyl-3-(4-methoxy-1H-indol-1-yl)butyric acid ethyl ester (134 mg), 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (107 mg) and 2-methyltetrahydrofuran (8 mL) were added to the reaction bottle in sequence, and a condenser and a balloon were installed. After nitrogen replacement, titanium tetrachloride (0.22 mL, 1M dichloromethane solution) was added and reacted at 80°C for 8 h. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 ml × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and then concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 26 mg of the title compound.

[1013] 1H NMR (400MHz, Methanol-d4) δ7.99 (s, 2H), 7.42 (d, J = 42.5Hz, 4H), 7.06 –6.77(m,2H),6.48(d,J=7.9Hz,2H),6.01(s,1H),3.88(s,3H),2.98(d,J=6.1Hz,4H),2.18(d,J=5.7Hz,3H),1.95(s,3H),1.57(d,J=45.3Hz,6H).

[1014] LCMS m / z=482.1[M+1] +

[1015] Example 118 6-(2-(4-methoxyphenyl)propan-2-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1016]

[1017] a) Preparation of ethyl 2-acetyl-3-methylbut-2-enoate

[1018] Prepare by referring to the preparation method of Example 117, except that the acetaldehyde in step a) is replaced by acetone.

[1019] b) Preparation of ethyl 2-acetyl-3-(4-methoxyphenyl)-3-methylbutyrate

[1020] Cuprous iodide (167 mg) was added to a two-necked flask, and a rubber stopper was added to replace nitrogen. Anhydrous tetrahydrofuran (7 mL) was added, and then p-methoxyphenyl magnesium chloride (7 mL, 1M tetrahydrofuran solution) was added, and the mixture was reacted at 0°C for 30 minutes. Ethyl 2-acetyl-3-methylbut-2-enoate (600 mg) was dissolved in tetrahydrofuran (1 mL) and added to the flask, and the mixture was stirred in an ice bath and naturally warmed to room temperature and reacted overnight. After the reaction was completed, a saturated aqueous solution of ammonium chloride (20 mL) was added and stirred for 30 minutes, and the mixture was extracted with ethyl acetate (20 ml × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and then concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain 836 mg of the title compound.

[1021] c) Preparation of 6-(2-(4-methoxyphenyl)propan-2-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1022] 2-Acetyl-3-(4-methoxyphenyl)-3-methylbutyric acid ethyl ester (1.19 g), 3-phenyl-4-(piperidin-1-yl)-1H-pyrazole-5-amine (0.945 g) and 2-methyltetrahydrofuran (55 mL) were added to the flask in sequence, and a condenser and a balloon were installed. After nitrogen replacement, titanium tetrachloride (1.9 mL, 1M dichloromethane solution) was added and refluxed at 80°C for 7 h. After the reaction was completed, the solvent was dried by spin drying and 10 mg of the title compound was obtained by preparative liquid separation.

[1023] 1 H NMR(400MHz,DMSO-d6)δ8.16(d,J=7.7Hz,2H),7.51(t,J=7.5Hz,2H), 7.44(d,J=7.3Hz,1H),7.27(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),3.79(s,3H),3.09(s,4H),2.00(s,3H),1.79(s,6H),1.64(d,J=29.4Hz,6H).

[1024] LCMS m / z=457.24[M+1] +

[1025] Example 119 6-(Methoxy(4-methoxyphenyl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1026]

[1027] a) Preparation of 6-(hydroxy(4-methoxyphenyl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1028] 5-Methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (438.3 mg) was added to the flask, and after nitrogen replacement, anhydrous tetrahydrofuran (10 mL) was added, and the mixture was stirred in a dry ice acetone bath for 15 minutes. Then, n-butyl lithium (0.75 mL, 1.6 M tetrahydrofuran solution) was added, and the mixture was stirred in a dry ice acetone bath for 1 hour. p-Anisaldehyde (163.3 mg) was dissolved in anhydrous tetrahydrofuran (1 mL) and added to the flask, and the reaction was continued in a dry ice acetone bath for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 ml×3). The organic phase was collected and dried over anhydrous sodium sulfate, concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give 230 mg of the title compound.

[1029] b) Preparation of 6-(methoxy(4-methoxyphenyl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1030] Sodium hydride (20 mg, 60%) and 6-(hydroxy(4-methoxyphenyl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (112 mg) were added to the flask in sequence and replaced with nitrogen. Iodomethane (60 mg) was dissolved in anhydrous tetrahydrofuran (5 mL) and added to the flask and stirred overnight at room temperature. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to quench. The mixture was extracted with ethyl acetate (10 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and then concentrated to dryness. The crude product was purified by TLC separation (developing solvent: dichloromethane / methanol = 20 / 1 (V / V)) and slurried with ethyl acetate and petroleum ether to obtain 10 mg of the title compound.

[1031] 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.11(d,J=7.9Hz,2H),7.47(t,J=7.4Hz,2H),7.40(d,J=7.4Hz,1H),7.25(d,J=8.6Hz,2H),6.91–6.84 (m,2H),5.96(s,1H),3.72(d,J=1.6Hz,3H),3.05(s,4H),2.23(s,3H),1.59(d,J=30.7Hz,6H).

[1032] LCMS m / z=457.27[M-1]-

[1033] Example 120 6-(1-hydroxy-1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1034]

[1035] a) Preparation of 6-(1-hydroxy-1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1036] 5-Methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (500 mg) was added to a two-necked flask. After nitrogen replacement, anhydrous tetrahydrofuran (11.5 mL) was added and stirred in a dry ice acetone bath for 15 minutes. Then n-butyl lithium (1.78 mL, 1.6 M tetrahydrofuran solution) was added and stirred in a dry ice acetone bath for 0.5 h. p-Methoxyacetophenone (343 mg) was dissolved in anhydrous tetrahydrofuran (0.5 mL) and added to the reaction solution, and the reaction was continued for 1 h. After the reaction was completed, saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to give 183 mg of the title compound.

[1037] b) Preparation of 6-(methoxy(4-methoxyphenyl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1038] 6-(1-hydroxy-1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (183 mg) was added to a two-necked bottle, and after nitrogen replacement, tetrabutylammonium fluoride (3.1 mL, 1 tetrahydrofuran solution) and 2-methyltetrahydrofuran (15 mL) were added, and the reaction was stirred at 80°C for 1 hour. After the reaction was completed, the organic phase was concentrated to dryness, separated by TLC (developing solvent: dichloromethane / methanol = 20 / 1 (V / V)) and purified to obtain a crude product, which was slurried with ethyl acetate and petroleum ether to obtain 15 mg of the title compound.

[1039] 1H NMR (400MHz, DMSO-d6) δ10.72 (s, 1H), 8.08 (d, J = 7.6Hz, 2H), 7.42 (dt, J=21.2,7.3Hz,5H),6.86(d,J=8.4Hz,2H),5.93(s,1H),3.70(s,3H),3.23–3.05(m,4H),2.95(s,3H),1.65–1.50(m,9H).

[1040] LCMS m / z=459.22[M+1] +

[1041] Example 121 6-(1-methoxy-1-(4-methoxyphenyl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1042]

[1043] 6-(Methoxy(4-methoxyphenyl)methyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (23 mg) and dichloromethane (1.5 mL) were added to a flask and stirred in an ice-water bath for 20 minutes. Diethylaminosulfur trifluoride (17 mg) was dissolved in dichloromethane (0.5 mL) and added dropwise to the reaction solution. Methanol (10 mL) was added after two hours of reaction and stirring was continued for 1 hour. After the reaction was completed, the organic phase was concentrated to dryness and purified by TLC separation (developing solvent: dichloromethane / methanol = 20 / 1 (V / V)) to obtain a crude product, which was slurried with ethyl acetate and petroleum ether to obtain 1.5 mg of the title compound.

[1044] 1 H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.10 (d, J = 7.6Hz, 2H), 7.49–7.30 (m,5H),6.93(d,J=8.3Hz,2H),5.42(s,1H),3.74(s,3H),3.08(m,7H),2.93(s,3H),1.61(d,J=12.9Hz,9H).

[1045] LCMS m / z=473[M+1] +

[1046] Example 122 6-((3-methoxyphenyl)ethynyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1047]

[1048] a) Preparation of 6-(((3-methoxyphenyl)ethynyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1049] 6-Bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (104 mg), 3-alkynylanisole (54 mg), bis(acetonitrile)palladium(II) chloride (10.4 mg), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (38.1 mg), cesium carbonate (195.5 mg) and anhydrous acetonitrile (2 mL) were added to a reaction bottle in sequence, replaced with nitrogen, and reacted at 60° C. for 3 h. After the reaction was completed, the solid residue was filtered off, the organic phase was concentrated, and separated by TLC (developing solvent: petroleum ether / ethyl acetate=10 / 1 (V / V)) to obtain 50 mg of the title compound.

[1050] b) Preparation of 6-((3-methoxyphenyl)ethynyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1051] 6-(((3-methoxyphenyl)ethynyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (50 mg) was added to a single-necked bottle, and after nitrogen replacement, tetra-n-butylammonium fluoride (0.9 mL, 1 M tetrahydrofuran solution) and 2-methyltetrahydrofuran (3 mL) were added, and the mixture was reacted at 80°C for 2 h. After the reaction was completed, 5 mg of the title compound was isolated by preparative liquid separation.

[1052] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.13(s,2H),7.48–7.26(m,4H), 7.08–6.87(m,3H),3.80(s,3H),3.09(s,4H),1.59(d,J=33.8Hz,6H).

[1053] LCMS m / z=439.1[M+1] +

[1054] Example 123 6-(((2-methoxyphenyl)ethynyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1055]

[1056] Prepare by referring to the preparation method of Example 122, except that 3-alkynylanisole in step a) is replaced by 2-alkynylanisole.

[1057] 1 H NMR (400MHz, DMSO-d6) δ8.22–8.10(m,2H),7.50–7.25(m,5H),7.05(d, J=8.3Hz,1H),6.95(t,J=7.5Hz,1H),3.85(s,3H),3.11(s,4H),1.59(d,J =33.0Hz,6H).

[1058] LCMS m / z=439.1[M+1] +

[1059] Example 124 7-(4-methoxyphenyl)-2,3-diphenylimidazo[1,2-b]pyridazin-8(5H)-one

[1060]

[1061] a) Preparation of 4-bromo-6-chloro-5-(4-methoxyphenyl)pyridazin-3-amine

[1062] 6-Chloro-5-(4-methoxyphenyl)pyridazin-3-amine (900 mg) was added to a 100 ml three-necked flask, methanol (22.5 ml) was added, and then sodium bicarbonate (850 mg) was added. Nitrogen was replaced for protection, the temperature was lowered to 0°C, liquid bromine (793 mg) was diluted in methanol (9 ml), and added dropwise to the reaction system. The reaction was completed after 3 h. The solvent of the reaction system was evaporated to dryness and concentrated under reduced pressure until there was no droplet. Dichloromethane (30 ml) was added to dilute, and then saturated brine (30 ml) was added to wash twice, separated and extracted, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until there was no droplet, slurried with petroleum ether (10 ml), and filtered to obtain 1.1 g of the title compound.

[1063] b) Preparation of 8-bromo-6-chloro-7-(4-methoxyphenyl)-2,3-diphenylimidazo[1,2-b]pyridazine

[1064] Add 6-bromo-5-(4-methoxyphenyl)pyridazin-3-amine (700 mg) and 2-bromo-1,2-diphenylacetophenone (735 mg) into a 100 ml single-necked bottle, add ethanol (15 ml), heat to 90 ° C, react for 4 days, concentrate the reaction system under reduced pressure, make sand, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 6 / 1 (V / V)) to obtain 400 mg of the title compound.

[1065] c) Preparation of 8-(benzyloxy)-6-chloro-7-(4-methoxyphenyl)-2,3-diphenylimidazo[1,2-b]pyridazine

[1066] Sodium hydride (19.6 mg) and benzyl alcohol (66 mg) were added to a 50 ml three-necked flask, and tetrahydrofuran (20 ml) was added. The mixture was protected by nitrogen and cooled to 0°C. The mixture was stirred for 0.5 h. 8-Bromo-6-chloro-7-(4-methoxyphenyl)-2,3-diphenylimidazo[1,2-b]pyridazine (200 mg) was dissolved in tetrahydrofuran (5 ml) and added dropwise to the reaction system. The mixture was stirred overnight at room temperature. Ethyl acetate (20 ml) was added to the reaction system for dilution. Saturated brine (20 ml) was added and the mixture was stirred for 5 minutes. The mixture was extracted and separated. The aqueous phase was back-extracted twice with ethyl acetate (20 ml). The organic phases were combined and washed once with saturated brine (20 ml). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 6 / 1 (V / V)) to obtain 80 mg of the title compound.

[1067] d) Preparation of 7-(4-methoxyphenyl)-2,3-diphenylimidazo[1,2-b]pyridazin-8(5H)-one

[1068] Add 8-(Benzyloxy)-6-chloro-7-(4-methoxyphenyl)-2,3-diphenylimidazo[1,2-b]pyridazine (80 mg) into a 100 ml single-necked bottle, add methanol (20 ml), then add 10% palladium carbon, replace with hydrogen for protection, heat at 40°C, react for 4 days, filter the insoluble matter, evaporate the filtrate to dryness, and prepare 6 mg of the title compound.

[1069] 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.08(s,1H),7.84(s,2H),7.55(s, 2H),7.53–7.31(m,6H),7.24(s,2H),6.94(d,J=7.0Hz,2H),3.77(s,3H),2.08–1.93(m,1H).

[1070] LCMS m / z=394.2[M+1] +

[1071] Example 125 6-(1-(1-(5-methoxy-1-methyl-1H-indol-2-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1072]

[1073] a) Preparation of (5-methoxy-1H-indol-2-yl)methanol

[1074] Add methyl 5-methoxy-1H-indole-2-carboxylate (5 g) into a 250 ml single-mouth bottle, add tetrahydrofuran (100 ml) under nitrogen protection, add lithium aluminum tetrahydride (1.66 g) three times under ice bath, stir at room temperature for 3 h, add sodium sulfate solution in ice water to the reaction system, then add ethyl acetate (150 ml) to dilute, separate and extract, back-extract the aqueous phase with ethyl acetate twice, wash the organic phase with saturated sodium chloride aqueous solution twice each, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure until there is no droplet to obtain 3.3 g of the title compound.

[1075] b) Preparation of 5-methoxy-1H-indole-2-carbaldehyde

[1076] Add (5-methoxy-1H-indol-2-yl)methanol (3.3 g) to dimethyl sulfoxide (20 ml), add 2-iodoacylbenzoic acid (6.26 g), stir at room temperature overnight, add ethyl acetate (100 ml) to the reaction system to dilute, then add water (100 ml), filter out insoluble matter, separate the liquids and extract, back-extract the aqueous phase twice with ethyl acetate, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, filter, make sand, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)), 3.1 g of the title compound.

[1077] c) Preparation of 5-methoxy-1-methyl-1H-indole-2-carbaldehyde

[1078] 5-Methoxy-1H-indole-2-carbaldehyde (500 mg) was dissolved in N,N-dimethylformamide (24 ml). Sodium hydride (170 mg) was added under nitrogen protection in an ice bath, and then iodomethane (486 mg) was added. The mixture was stirred at room temperature for 2 h. Ethyl acetate (30 ml) was added to the reaction system, and then aqueous ammonium chloride solution was added to quench the reaction. The mixture was separated and extracted. The aqueous phase was back-extracted twice with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 200 mg of the title compound.

[1079] d) Preparation of ethyl 2-(((5-methoxy-1-methyl-1H-indol-2-yl)methylene)-3-oxobutanoate

[1080] Dissolve 5-methoxy-1-methyl-1H-indole-2-carbaldehyde (200 mg) in isopropanol (8 ml), add ethyl acetoacetate (138 mg), then add piperidine (0.15 ml) and acetic acid (0.15 ml), react at room temperature with stirring overnight, and filter to obtain 220 mg of the title compound.

[1081] e) Ethyl 2-acetyl-3-(5-methoxy-1-methyl-1H-indol-2-yl)butanoate

[1082] Cuprous iodide (208 mg) was added to a three-necked flask, and ultra-dry tetrahydrofuran was added under nitrogen protection. The temperature was lowered to -80°C, and methyl lithium (44.92 mg) was added dropwise. The mixture was stirred for 1 h. Ethyl 2-(((5-methoxy-1-methyl-1H-indol-2-yl)methylene)-3-oxobutanoate (220 mg) was dissolved in tetrahydrofuran (8 ml), and the mixture was added dropwise to the reaction system. The mixture was stirred for 0.5 h under a dry ice bath. Saturated ammonium chloride was added to the reaction system to quench the mixture, and ethyl acetate was added. The mixture was separated and extracted. The aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined and washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and sanded. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 200 mg of the title compound.

[1083] f) Preparation of 6-(1-(1-(5-methoxy-1-methyl-1H-indol-2-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1084] Add ethyl 2-acetyl-3-(5-methoxy-1-methyl-1H-indol-2-yl)butanoate (200 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazole-5-amine (152.7 mg) into a sealed tube, add diphenyl ether to dissolve, heat to 200°, react for 8 h, make sand out of the reaction solution, and purify by column chromatography to obtain 6 mg of the title compound.

[1085] 1 H NMR(400MHz,DMSO-d6)δ8.13(d,J=7.5Hz,2H),7.46(t,J=7.5Hz,2H), 7.37(dd,J=12.5,7.8Hz,2H),6.88(d,J=1.6Hz,1H),6.64(dd,J=8.5,2.1H z,1H),6.36(s,1H),4.83(d,J=7.4Hz,1H),3.77(s,3H),3.41(d,J=11.6Hz, 3H), 3.04 (s, 4H), 2.16 (d, J = 14.1Hz, 3H), 1.61 (d, J = 7.0Hz, 3H), 1.54 (s, 6H).

[1086] LCMS m / z=498.1[M+1] +

[1087] Example 126 6-(1-(1-(5-methoxybenzofuran-2-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1088]

[1089] a) Preparation of 2-(2,2-methoxyethoxy)-5-methoxybenzaldehyde

[1090] Add 2-hydroxy-5-methoxybenzaldehyde (10 g) into a 250 ml single-mouth bottle, add potassium carbonate (9.63 g), add N, N-dimethylformamide (70 ml), add 2-bromo-1,1-diethoxyethane (13.73 g) dropwise, heat at 150 ° C and stir for 6 hours, add ethyl acetate (100 ml) to the reaction system to dilute, then add saturated sodium bicarbonate to neutralize, separate and extract, the aqueous phase is back-extracted twice with ethyl acetate, the organic phase is washed once with saturated sodium bicarbonate and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure until there is no droplet to obtain the title compound.

[1091] b) Preparation of 5-methoxybenzofuran-2-carboxaldehyde

[1092] Add 2-(2,2-methoxyethoxy)-5-methoxybenzaldehyde (5 g) into a 100 ml single-mouth bottle, add acetic acid (10 ml), heat to 140°C, evaporate the reaction solvent, add 100 ml of ethyl acetate to the reaction system for dilution, then add 100 ml of water, separate and extract, back-extract the aqueous phase twice with ethyl acetate, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, filter, sand-make, and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain the title compound.

[1093] c) Preparation of ethyl 2-(((5-methoxybenzofuran-2-yl)methylene)-3-oxobutanoate

[1094] Dissolve 5-methoxybenzofuran-2-carbaldehyde (300 mg) in isopropanol (10 ml), add ethyl acetoacetate (222 mg), piperidine (0.21 ml) and acetic acid (0.21 ml), react at room temperature with stirring overnight, and filter to obtain 320 mg of the title compound.

[1095] d) Preparation of ethyl 2-acetyl-3-(5-methoxybenzofuran-2-yl)butanoate

[1096] Cuprous iodide (297 mg) was added to a three-necked flask, and ultra-dry tetrahydrofuran was added under nitrogen protection. Methyl lithium was added dropwise under the temperature lowered to -80°C, and the mixture was stirred for 1 h. Ethyl 2-(((5-methoxybenzofuran-2-yl)methylene)-3-oxobutanoate (300 mg) was dissolved in tetrahydrofuran (0.5 ml), and the mixture was added dropwise to the reaction system. The mixture was heated to an ice bath and stirred for 2 h. Saturated ammonium chloride was added to the reaction system for quenching, and ethyl acetate was added. The mixture was separated and extracted. The aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined and washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and sanded. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 102 mg of the title compound.

[1097] e) Preparation of 6-(1-(1-(5-methoxybenzofuran-2-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1098] 6-(1-(1-(5-methoxybenzofuran-2-yl)ethyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (90 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (71.6 mg) were added to a reaction bottle, 2-methyltetrahydrofuran was added to dissolve, titanium tetrachloride (84.1 mg) was added under nitrogen protection, heated to 85°C and reacted for 8 h, an appropriate amount of water was added to quench, ethyl acetate was added, the mixture was separated and extracted, the aqueous phase was back-extracted with ethyl acetate twice, the mixture was dried over anhydrous sodium sulfate, the solvent was filtered and evaporated, and purification was performed to obtain 13 mg of the title compound.

[1099] 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 8.11 (s, 2H), 7.43 (d, J = 7.2Hz, 2H),7.32(d,J=9.0Hz,2H),7.05(s,1H),6.76(d,J=9.0Hz,1H),6.59(s,1H) ,4.59(s,1H),3.76(s,3H),3.08(s,4H),2.34(d,J=9.3Hz,3H),1.34(s,3H), 1.25(d,J=9.3Hz,6H).

[1100] LCMS m / z=483[M+1] +

[1101] Example 127 6-(1-(4-methoxyphenyl)ethyl)-2-phenyl-3-(piperidin-1-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1102]

[1103] a) Preparation of ethyl 2-cyano-3-(4-methoxyphenyl)acrylate

[1104] Add p-anisaldehyde (35 g), ethyl 2-cyanoacetate (29.1 g) and piperidine (26.2 g) into the reaction bottle in sequence, stir at room temperature for 2 days, evaporate the reaction solvent, add isopropanol to slurry, and filter to obtain 39 g of the title compound.

[1105] b) Preparation of ethyl 2-cyano-3-(4-methoxyphenyl)butyrate

[1106] Cuprous iodide (1.15 g) was added to a three-necked flask, and tetrahydrofuran (80 ml) was added under nitrogen protection. The temperature was lowered to -20°C, and methylmagnesium bromide (9.1 g) was added dropwise. The stirring was continued for 0.5 h. Ethyl 2-cyano-3-(4-methoxyphenyl)acrylate was diluted in tetrahydrofuran, added dropwise to the reaction system, and the temperature was raised. The mixture was stirred at room temperature for 3 h, and an aqueous ammonium chloride solution was added to quench the reaction. Ethyl acetate was added, and the mixture was separated and extracted. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and sanded. The mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 6.8 g of the title compound.

[1107] c) Preparation of 5-amino-6-(1-(4-methoxyphenyl)ethyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1108] Ethyl 2-cyano-3-(4-methoxyphenyl)butanoate (500 mg) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (489 mg) were dissolved in diphenyl ether in sequence, heated to 140° C. for reaction for 2 days, the reaction solution was sanded and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 180 mg of the title compound.

[1109] d) Preparation of 6-(1-(4-methoxyphenyl)ethyl)-2-phenyl-3-(piperidin-1-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one

[1110] 5-Amino-6-(1-(4-methoxyphenyl)ethyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg), palladium acetate (13.5 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (7.3 mg) and 2-bromopyridine (21.3 mg) were added to a two-necked bottle in sequence, 1,4-dioxane was added, the mixture was heated to 120°C and stirred for 7 h, ethyl acetate was added to dilute, saturated brine was added, the mixture was separated and extracted, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified to obtain 1.6 mg of the title compound.

[1111] LCMS m / z=519.4[M-1] +

[1112] Example 128 3-Methoxy-10-phenyl-9-(piperidin-1-yl)-5,6,7,8-tetrahydro-13H-benzo[3,4]cyclohepta[1,2-d]pyrazolo[1,5-a]pyrimidin-13-one

[1113]

[1114] a) Preparation of 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene

[1115] Add methyl triphenylphosphonium bromide (12.16 g) and tetrahydrofuran (50 ml) to the reaction bottle in sequence, cool to -20°C under nitrogen protection, add lithium bistrimethylsilylamide (43 ml, 1M tetrahydrofuran solution), stir and react for 1 hour, then add 6-methoxy-1-tetralinone (5 g), stir and react at room temperature for 12 hours. After the reaction is completed, add 300 ml of saturated ammonium chloride aqueous solution to quench, extract the reaction solution with 500 ml of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 2.8 g of the title compound.

[1116] b) Preparation of 2-methoxy-5,7,8,9-tetrahydro-6H-benzo[7]cyclopenten-6-one

[1117] Add iodobenzene (2.69 g), p-toluenesulfonic acid (2.51 g), dichloromethane (12 ml), hexafluoroisopropanol (2 ml), and m-chloroperbenzoic acid (2.28 g) to the reaction bottle in sequence, react at room temperature for 30 minutes, cool the reaction solution to 0°C, dissolve 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (2 g) in a mixed solvent of methanol (10 ml) and water (1 ml), dropwise add the above reaction solution, and stir at 0°C for 1 hour. After the reaction is complete, add 50 ml of saturated sodium bicarbonate aqueous solution to quench, extract the reaction solution with 100 ml of ethyl acetate, concentrate the organic phase to dryness, and purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 1.5 g of the title compound.

[1118] c) Preparation of methyl 2-methoxy-6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]cyclopentyl 5-carboxylate

[1119] Sodium hydride (0.79 g, 60%), dimethyl carbonate (10 ml), 2-methoxy-5,7,8,9-tetrahydro-6H-benzo[7]cyclopentene-6-one (1.25 g) were added to the reaction bottle in sequence, and the mixture was heated to 90°C for 1 hour under nitrogen protection. After the reaction was completed, 50 ml of saturated aqueous ammonium chloride solution was added to quench the reaction solution, and the reaction solution was extracted with 100 ml of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 0.56 g of the title compound.

[1120] d) Preparation of 3-methoxy-10-phenyl-9-(piperidin-1-yl)-5,6,7,8-tetrahydro-13H-benzo[3,4]cyclohepta[1,2-d]pyrazolo[1,5-a]pyrimidin-13-one

[1121] Prepare by referring to the preparation method of Example 31, except that 2-(2-methoxybenzyl)-3-oxobutanoic acid ethyl ester in step b) is replaced by 2-methoxy-6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]cyclopentyl 5-carboxylic acid methyl ester.

[1122] 1 H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.10(m,2H),7.53–7.36(m,4H), 6.92–6.86(m,2H),3.79(s,3H),3.08(s,4H),2.58(s,2H),2.24(s,4H),1.72 –1.51(m,6H).

[1123] LCMS m / z=441.1[M+1] + .

[1124] Bioactivity test MAT2A enzymatic test method

[1125] 1. Experimental Procedure

[1126] a) First, prepare 5×MAT2A Assay Buffer (250 mM Tris-HCl, pH 8.0; 250 mM KCl; 75 mM MgCl2; 0.025% BSA; 0.05% Brij35; 1.5 mM EDTA), and partially dilute to 1× for later use;

[1127] b) Preparation and addition of MAT2A enzyme (BPS, 71401): MAT2A enzyme was prepared to 3.674 ng / μL (1.67×, final concentration 2.20 ng / μL) with 1×MAT2A Assay Buffer. Using a BioTek (MultiFlo FX) automatic dispenser, 15 μL of 1.67×MAT2A enzyme solution was added to the compound test wells and negative control wells, respectively. At the same time, 15 μL of 1×MAT2A Assay Buffer was added to the blank control wells.

[1128] c) Compound preparation and addition: Use DMSO to dilute the test compound from 10mM stock solution to 100μM, and dilute the positive drug AGI-24512 under the same conditions. Use Tecan compound titrator (D300e) to automatically spray into each well according to the preset concentration gradient. The amount of sprayed volume is negligible. The concentration gradient starts at 1μM, 1 / 2log dilution, and a total of 8 gradients are set. Centrifuge at 2500rpm for 30s and incubate at 25℃ for 30min;

[1129] d) ATP preparation: dilute 10 mM ATP (Sigma, A7699) to 700 μM using 1×MAT2A Assay Buffer;

[1130] e) Preparation and addition of substrate and ATP mixed solution: 5×MAT2A Assay Buffer, 3μL / well; 750μM L-Methionine (Adamas, 01100469), 2.5μL / well; 700μM ATP, 2.5μL / well; ddH2O, 2μL / well. Prepare the total amount of the required mixed solution according to the number of test wells, and add 10μL to each well using the BioTek (MultiFlo FX) automatic dispenser; centrifuge at 2500rpm for 30s, and react at 25℃ for 150min;

[1131] f) Addition of Biomol Green detection reagent: 50 μL Biomol Green (Enzo, BML-AK111) was added to each well using a BioTek (MultiFlo FX) automatic dispenser, centrifuged at 2500 rpm for 30 s, and incubated at 25°C for 20 min;

[1132] g) After the reaction, the OD was read using a Perkin Elmer (Envision 2105) multi-function plate reader. 620 value.

[1133] 2. Data Analysis

[1134] The inhibition rate calculation formula is as follows:

[1135]

[1136] in,

[1137] ODsample: OD620 value of the sample well;

[1138] ODmin: represents the mean OD620 value of blank control wells without enzyme and test compound;

[1139] ODmax: represents the mean OD620 value of negative control wells with enzyme and no compound.

[1140] GraphPad Prism 5 software was then used to fit the dose-effect curve using log (inhibitor) vs. response-Variable slope to obtain the IC50 value of the compound's inhibition of the MAT2A enzyme.

[1141] 3. Experimental results:

[1142] The experimental results of the compounds of the present invention are shown in the following table:

[1143]

[1144]

[1145]

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof, in: for R 1 Selected from NR a R b , R a is H; R b for R 2 is a C1-C3 alkyl group; R 4 Selected from H; X is methylene or R 7 substituted methylene; R 7 is selected from C1-C4 alkyl, hydroxy, MeO, C3-C5 cycloalkyl, ethynyl or C1-C4 alkyl substituted by halogen; R 5 Selected from phenyl, pyridyl, or one or more R 8 Substituted phenyl, pyridyl, R 8 is selected from OMe, NH2, methyl, fluorine, Br, =O, ethynyl, methoxyethoxy, cyclopropylmethoxy, isopropoxy, cyclopropyl, hydroxy, NH2 substituted by acetyl or NH2 substituted by methyl; or R 5 The ring carbon atoms on R 2 Together with the atoms to which they are attached, they form a 7-10 membered ring.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from 4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 2 It is methyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: X is selected from methylene or R 7 substituted methylene; R 7 Selected from methyl, ethyl, isopropyl, n-butyl, cyclopropyl, hydroxy, OMe, ethynyl, CF2HCH2, CF3CH2 or CF3.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized in that: R 7 Selected from methyl, ethyl, isopropyl or OMe.

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized in that: R 7 Selected from methyl or ethyl.

9. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized in that: R 7 Selected from methyl.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 5 Selected from phenyl, or one or more R 8 Substituted phenyl, 11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, characterized in that: R 5 Selected from phenyl, or one or more R 8 Substituted phenyl, 12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, characterized in that: R 5 Selected from phenyl, or one or more R 8 Substituted phenyl, 13. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, characterized in that: R 5 Selected from phenyl, or one or more R 8 Substituted phenyl, 14. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, characterized in that: R 5 Selected from phenyl or one or more R 8 Substituted phenyl.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 8 is selected from OMe, methyl, fluorine, NH2 or hydroxy; wherein the NH2 is substituted by methyl.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, characterized in that: R 8 Selected from OMe, NHCH3, NCH3CH3 or hydroxyl.

17. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, characterized in that: R 8 Selected from OMe, NHCH3 or NCH3CH3.

18. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, characterized in that: R 5 Selected from:

19. A compound represented by formula VI or a pharmaceutically acceptable salt thereof, in, R 5 , R 7 The definition of is as defined in the compound of formula I.

20. The following compound or a pharmaceutically acceptable salt thereof, 21. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

23. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 21 or 22 in the preparation of a medicament for preventing and / or treating pancreatic cancer or bladder cancer mediated by methionine adenosyltransferase.

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