Heterocyclic compound, preparation method and application thereof, and pharmaceutical composition for preventing and treating tumors

Abstract

The invention belongs to the technical field of chemical medicines, and particularly relates to a heterocyclic compound, a preparation method and application thereof, and a pharmaceutical composition for preventing and treating tumors. The heterocyclic compound provided by the invention has obviously improved activity, can selectively inhibit the activity of RET, overcomes the drug resistance problem of the existing RET inhibitor, has good pharmacokinetic property and better solubility, reduces the treatment cost of patients, and increases the new drug accessibility of the patients. The invention also provides application of the heterocyclic compound in the scheme or the heterocyclic compound obtained by the preparation method in the scheme in preparation of RET inhibitors, tumor prevention drugs or tumor treatment drugs. The compound provided by the invention can effectively inhibit the growth of various tumor cells, especially has an inhibiting effect on RET kinase, and selectively inhibits RET lung cancer cells.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical medicine, and particularly relates to a heterocyclic compound, a preparation method, an application thereof, and a pharmaceutical composition for preventing and treating tumors. Background Art

[0002] Molecular targeted therapy of tumors is based on key molecules closely related to tumor growth, and selectively kills tumor cells by chemical or biological means. It has high specificity, strong selectivity, and relatively mild toxic and side effects; when used in combination, it can enhance the efficacy of traditional chemotherapy and radiotherapy and reduce postoperative recurrence.

[0003] The rearranged during transfection gene (RET gene) is an oncogene, and gene abnormalities such as point mutations, gene fusions, and overexpressions of the RET gene are closely related to the occurrence, development, and poor prognosis of various tumors. RET gene point mutations are common in medullary thyroid carcinoma (MTC), while RET gene fusion mutations often occur in tumors such as lung cancer, papillary thyroid carcinoma, and esophageal cancer. RET gene point mutations and gene fusions lead to ligand-independent autophosphorylation of RET kinase, which in turn mediates tumorigenesis and development, and become important driving factors for tumors such as medullary thyroid carcinoma and non-small cell lung cancer, and have been identified as reliable tumor treatment targets.

[0004] In recent years, breakthroughs have been made in the research and development of selective RET inhibitors. Eli Lilly and Company has developed selpercatinib (LOXO-292, 2020 / 5), and Blueprint Medicines has developed pralsetinib (BLU-667, 2020 / 7). Two RET-selective small molecule inhibitors have been approved for marketing. Although the two selective RET inhibitors have achieved certain clinical efficacy, their activities need to be improved, and patients quickly develop drug resistance after using the two selective RET inhibitors. Summary of the Invention

[0005] The purpose of the present invention is to provide a heterocyclic compound, a preparation method, an application thereof, and a pharmaceutical composition for preventing and treating tumors. The heterocyclic compound provided by the present invention has significantly improved activity and can overcome the drug resistance problem of existing RET inhibitors.

[0006] In order to achieve the above purpose, the present invention provides the following technical solutions:

[0007] The present invention provides a heterocyclic compound, including one of 2-aminopyrazolopyrimidinone compounds or their prodrugs, pharmaceutically acceptable salts, prodrugs of pharmaceutically acceptable salts, stereoisomers and prodrugs of stereoisomers. The structure of the 2-aminopyrazolopyrimidinone compound is shown in Formula I:

[0008]

[0009] In Formula I, X is CH or N; W is CH or N; L is a group of Formula A, a group of Formula B, a group of Formula C, C5-C10 monocyclic alkyl, substituted C5-C10 monocyclic alkyl, C5-C10 bridged cycloalkyl, substituted C5-C10 bridged cycloalkyl, C5-C10 fused cycloalkyl or substituted C5-C10 fused cycloalkyl;

[0010] -(CH2) n NH-group of Formula A;

[0011] In Formula A, n is 1-8, and -CH2- is connected to X; in Formula B and Formula C, n is 0, 1, 2 or 3;

[0012] R1 is H, C1-C3 alkyl, substituted C1-C3 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, group of Formula H, group of Formula J, group of Formula K or group of Formula M;

[0013]

[0014] In Formula H, Formula J, Formula K and Formula M, n is 0, 1 or 2; A1, A2, A3, A4 and A5 are independently: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C6 fluoroalkyl, substituted C1-C6 fluoroalkyl, C1-C6 heteroatom-containing alkyl, substituted C1-C6 heteroatom-containing alkyl, -NO2, -CN, -COOH, -CONH2, a group of Formula N, a 5-membered heterocyclic group containing one or more nitrogen atoms, a substituted 5-membered heterocyclic group containing one or more nitrogen atoms, a 6-membered heterocyclic group containing one or more nitrogen atoms, a substituted 6-membered heterocyclic group containing one or more nitrogen atoms, a 5- to 12-membered saturated carbocyclic ring is formed between any two adjacent substitution sites, a 5- to 12-membered saturated heterocyclic ring containing 1 to 3 heteroatoms is formed between any two adjacent substitution sites, or an ester, amide, sulfone, sulfoxide or urea formed from C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C6 fluoroalkyl, substituted C1-C6 fluoroalkyl, C1-C6 heteroatom-containing alkyl, substituted C1-C6 heteroatom-containing alkyl, -NO2, -CN, -COOH, -CONH2, a group of Formula N, a 5-membered heterocyclic group containing one or more nitrogen atoms, a substituted 5-membered heterocyclic group containing one or more nitrogen atoms, a 6-membered heterocyclic group containing one or more nitrogen atoms, a substituted 6-membered heterocyclic group containing one or more nitrogen atoms;

[0015]

[0016] In Formula N, R4 and R5 are independently C1-C5 alkyl, substituted C1-C5 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, a 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring containing 1 to 3 heteroatoms formed by cyclization of R4 and R5, or a substituted 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring containing 1 to 3 heteroatoms formed by cyclization of R4 and R5;

[0017] R2 is H, C1-C4 alkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, a group of Formula D, a group of Formula E, a group of Formula F or a group of Formula G;

[0018] (CH2) n Y is a group of Formula G;

[0019] In Formulas D to F, R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclopentyl or cyclohexyl; in Formula G, n is 0 to 6, and Y is halogen, hydroxy, amino, (N-methyl)amino or (N,N-dimethyl)amino.

[0020] Preferably, in L, the C5-C10 monocyclic alkyl group is one or more of cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl; the substituted C5-C10 monocyclic alkyl group is one or more of 2-methylcyclopentane, 3-methylcyclopentane, 2-methylcyclohexane and 3-methylcyclohexane.

[0021] Preferably, in R1, the C1-C3 alkyl group is methyl, ethyl, n-propyl or isopropyl; the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the substituted C3-C6 cycloalkyl group is methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl or 2-ethyl-cyclopentyl.

[0022] Preferably, in A1, A2, A3, A4 and A5, the halogen includes one or more of fluorine, chlorine, bromine and iodine; the C1-C6 alkyl group includes one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl; the C3-C6 cycloalkyl group includes one or more of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the substituted C3-C6 cycloalkyl group includes one or more of methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl and 2-ethyl-cyclopentyl; the C1-C4 alkoxy group includes one or more of methoxy, ethoxy, propoxy and butoxy; the substituted C1-C4 alkoxy group includes one or more of N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-acetylpiperazinyl)ethoxy, 2-morpholinoethoxy, 2-thiomorpholinoethoxy, 2-piperidinoethoxy and 2-pyrrolidinylethoxy; the C1-C6 fluoroalkyl group includes one or more of trifluoromethyl, difluoromethyl and fluoromethyl; the C1-C6 heteroatom-containing alkyl group includes one or more of pyrrolidinyl, R-pyridyl, S-pyridyl, R-piperidyl and S-piperidyl; the 5-membered heterocyclic group containing more than 1 nitrogen atom includes one or more of pyrrolidinyl, group 1-1, group 1-2, group 1-3, group 1-4, group 1-5, group 1-6, group 1-7, group 1-8, group 1-9, group 1-10, group 1-11, group 1-12, group 1-13 and group 1-14.

[0023]

[0024] The substituted 5-membered heterocyclic group containing one or more nitrogen atoms has 1 to 3 substituents; the substituted 5-membered heterocyclic group containing one or more nitrogen atoms includes one or both of 3-N,N-dimethylpyrrolidinyl and 1-methylimidazolyl; the 6-membered heterocyclic group containing one or more nitrogen atoms can be one or more of the group of formula 2-1, the group of formula 2-2, the group of formula 2-3, the group of formula 2-4, morpholinyl, thiomorpholinyl, and piperidinyl;

[0025]

[0026] The substituted 6-membered heterocyclic group containing one or more nitrogen atoms has 1 to 3 substituents; the substituted 6-membered heterocyclic group containing one or more nitrogen atoms includes one or more of N-methylpiperazinyl, 4-N,N-dimethylpiperidinyl, 4-acetylpiperazinyl, 1-methyl-4-(piperazin-4-substituted)piperidinyl, 4-(4-methylpiperazin-1-substituted)methyl, 1-methylpiperidin-4-ylamine, 4-piperazin-2-one, and 1-methyl-4-piperazin-2-one; any two adjacent substitution sites form a 5- to 12-membered saturated carbocyclic ring including one or both of 3-methylhexahydropyrimidinyl and 3-dimethylimidazolidinyl; any two adjacent substitution sites form a 5- to 12-membered saturated heterocyclic ring containing 1 to 3 heteroatoms including one or more of thiomorpholinyl and tetrahydrothiazolyl.

[0027] Preferably, among R4 and R5, the C1-C5 alkyl group includes one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and pentyl; the C3-C6 cycloalkyl group includes one or more of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the substituted C3-C6 cycloalkyl group includes one or more of methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, and 2-ethyl-cyclopentyl; the 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring formed by cyclization of R4 and R5 containing 1 to 3 heteroatoms includes imidazolyl, indolyl, isopyrazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, pyrazolyl, thienyl, triazolyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidinone, 2-pyrrolidone, triazolyl, 1,4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisopyrazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydropyrazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuryl, tetrahydrothienyl, or its N-oxide.

[0028] Preferably, the structure of the heterocyclic compound is shown in Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII:

[0029]

[0030] Preferably, the heterocyclic compound is (R)-2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-ethyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclohexyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(p-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclopropyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclopentyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclobutyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(2-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,[2,3-d]Pyrimidin-7(8H)-one, (R)-2-((1-(2-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(4-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(o-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(m-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-3-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-4-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-2-((1-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-2-((1-(2-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or (R)-2-((1-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one.,

[0031] The present invention also provides a method for preparing the heterocyclic compound described in the above solution, including the following steps:

[0032] Mix compound A and compound B and carry out a first coupling reaction and a first substitution reaction in sequence to obtain compound C; carry out a reduction reaction on the compound C to obtain compound D; or, mix compound J and compound K to carry out a second coupling reaction to obtain compound D;

[0033] Mix compound E and compound F to carry out a second substitution reaction to obtain compound G; mix the compound G and trans-crotonic acid and carry out a Heck coupling reaction and a ring-closing reaction in sequence to obtain compound H;

[0034] Mix the compound D and compound H, carry out a third substitution reaction, then deprotect and carry out a nucleophilic substitution reaction with acyl chloride to obtain the 2-aminopyrazolopyrimidinone compound;

[0035] Saltify the 2-aminopyrazolopyrimidinone compound to obtain a pharmaceutically acceptable salt of the 2-aminopyrazolopyrimidinone compound;

[0036] Carry out isomer transformation on the 2-aminopyrazolopyrimidinone compound to obtain a stereoisomer of the 2-aminopyrazolopyrimidinone compound;

[0037] The structures of the compounds A, D-H, J-K are as shown in formulas A, D-H, J-K, and the compound B includes one or more of the compound of formula B and halogenated benzene; the compound C includes one or more of the compound of formula C, aminopyrazole, and cycloalkylpyrazole;

[0038]

[0039] The present invention also provides the use of the heterocyclic compound described in the above solution or the heterocyclic compound obtained by the preparation method described in the above solution in the preparation of RET inhibitors, drugs for preventing tumor recurrence, drugs for preventing tumors, or drugs for treating tumors.

[0040] The present invention also provides a pharmaceutical composition for preventing and treating tumors, including an active ingredient, and the active ingredient includes the heterocyclic compound described in the above solution or the heterocyclic compound obtained by the preparation method described in the above solution.

[0041] The present invention provides a heterocyclic compound. The heterocyclic compound provided by the present invention has significantly improved activity, can bind to the orthosteric site (ATP binding pocket) of the RET mutant protein, form hydrogen bonds with Asp892 and Ala707, thereby being able to selectively inhibit the activity of RET, overcome the drug resistance problem of existing RET inhibitors, has a group with better solubility, enabling it to have good pharmacokinetic properties, better solubility, reducing the treatment cost of patients, and increasing the accessibility of new drugs for patients.

[0042] The present invention also provides a preparation method of the heterocyclic compound described in the above solution. The preparation method provided by the present invention has simple steps, good safety, convenient operation, good feasibility and stability, and is suitable for industrial production.

[0043] The present invention also provides the use of the heterocyclic compound described in the above solution or the heterocyclic compound obtained by the preparation method described in the above solution in the preparation of RET inhibitors, drugs for preventing tumor recurrence, drugs for preventing tumors or drugs for treating tumors. The compound provided by the present invention can effectively inhibit the growth of various tumor cells, especially has an inhibitory effect on RET kinase, and selectively inhibits RET lung cancer cells.

[0044] The present invention also provides a pharmaceutical composition for preventing and treating tumors, including an active ingredient, and the active ingredient includes the heterocyclic compound described in the above solution or the heterocyclic compound obtained by the preparation method described in the above solution. The heterocyclic compound provided by the present invention can be used to prepare anti-tumor drugs and can overcome the drug resistance problems induced by existing drugs (such as Gefitinib, Erlotinib, Selpercatinib (LOXO-292), Pralsetinib (BLU-667), especially Selpercatinib and Pralsetinib). The heterocyclic compound provided by the present invention can also be used to prevent the postoperative recurrence of various tumors, further consolidate the treatment, prolong the survival period of tumor patients, improve their quality of life, and inhibit tumor deterioration. Detailed implementation manners

[0045] The present invention provides a heterocyclic compound, including one of 2-aminopyrazolopyrimidinone compounds or their prodrugs, pharmaceutically acceptable salts, prodrugs of pharmaceutically acceptable salts, stereoisomers and prodrugs of stereoisomers. The structure of the 2-aminopyrazolopyrimidinone compound is shown in Formula I:

[0046]

[0047] In Formula I, X is CH or N; W is CH or N; L is a group of Formula A, a group of Formula B, a group of Formula C, C5-C10 monocyclic alkyl, substituted C5-C10 monocyclic alkyl, C5-C10 bridged cycloalkyl, substituted C5-C10 bridged cycloalkyl, C5-C10 fused cycloalkyl or substituted C5-C10 fused cycloalkyl;

[0048] -(CH2) n NH-group of Formula A;

[0049] In Formula A, n is 1-8, and -CH2- is connected to X; in Formula B and Formula C, n is 0, 1, 2 or 3;

[0050] R1 is H, C1-C3 alkyl, substituted C1-C3 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, group of Formula H, group of Formula J, group of Formula K or group of Formula M;

[0051]

[0052] In Formula H, Formula J, Formula K and Formula M, n is 0, 1 or 2, and A1, A2, A3, A4 and A5 are independently: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C6 fluoroalkyl, substituted C1-C6 fluoroalkyl, C1-C6 heteroatom-containing alkyl, substituted C1-C6 heteroatom-containing alkyl, -NO2, -CN, -COOH, -CONH2, group of Formula N, 5-membered heterocyclic group containing one or more nitrogen atoms, substituted 5-membered heterocyclic group containing one or more nitrogen atoms, 6-membered heterocyclic group containing one or more nitrogen atoms, substituted 6-membered heterocyclic group containing one or more nitrogen atoms, a 5-12 membered saturated carbocyclic ring is formed between any two adjacent substitution sites, a 5-12 membered saturated heterocyclic ring containing 1-3 heteroatoms is formed between any two adjacent substitution sites, or an ester, amide, sulfone, sulfoxide or urea formed by C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C6 fluoroalkyl, substituted C1-C6 fluoroalkyl, C1-C6 heteroatom-containing alkyl, substituted C1-C6 heteroatom-containing alkyl, -NO2, -CN, -COOH, -CONH2, group of Formula N, 5-membered heterocyclic group containing one or more nitrogen atoms, substituted 5-membered heterocyclic group containing one or more nitrogen atoms, 6-membered heterocyclic group containing one or more nitrogen atoms, substituted 6-membered heterocyclic group containing one or more nitrogen atoms;

[0053]

[0054] In formula N, R4 and R5 are independently C1-C5 alkyl, substituted C1-C5 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, a 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring containing 1 to 3 heteroatoms formed by cyclization of R4 and R5, or a substituted 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring containing 1 to 3 heteroatoms formed by cyclization of R4 and R5;

[0055] R2 is H, C1-C4 alkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, a group of formula D, a group of formula E, a group of formula F or a group of formula G;

[0056] (CH2) n Y is a group of formula G;

[0057] In formulas D to F, R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclopentyl or cyclohexyl; in formula G, n is 0 to 6, and Y is halogen, hydroxy, amino, (N-methyl)amino or (N,N-dimethyl)amino.

[0058] In the present invention, in L, the C5-C10 monocyclic alkyl group may be one or more of cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl; the substituted C5-C10 monocyclic alkyl group may be one or more of 2-methylcyclopentane, 3-methylcyclopentane, 2-methylcyclohexane and 3-methylcyclohexane.

[0059] In the present invention, L (L is connected to X at the upper end and L is connected to R I at the lower end) may specifically be:

[0060]

[0061] More specifically, it may be:

[0062]

[0063] Even more specifically, it may be:

[0064]

[0065] In the present invention, in R1, the C1-C3 alkyl group may be methyl, ethyl, n-propyl or isopropyl; the C3-C6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the substituted C3-C6 cycloalkyl group may be methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl or 2-ethyl-cyclopentyl.

[0066] In the present invention, among A1, A2, A3, A4 and A5, the halogen may include one or more of fluorine, chlorine, bromine and iodine, and more preferably fluorine.

[0067] In the present invention, among A1, A2, A3, A4 and A5, the C1-C6 alkyl group may include one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl, and more preferably may be methyl; the C1-C6 alkyl group may be a C1-C3 alkyl group.

[0068] In the present invention, among A1, A2, A3, A4 and A5, the C3-C6 cycloalkyl group may include one or more of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0069] In the present invention, among A1, A2, A3, A4 and A5, the substituted C3-C6 cycloalkyl group may include one or more of methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl and 2-ethyl-cyclopentyl.

[0070] In the present invention, among A1, A2, A3, A4 and A5, the C1-C4 alkoxy group may include one or more of methoxy, ethoxy, propoxy and butoxy.

[0071] In the present invention, among A1, A2, A3, A4 and A5, the substituted C1-C4 alkoxy group may include one or more of N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-acetylpiperazinyl)ethoxy, 2-morpholinoethoxy, 2-thiomorpholinoethoxy, 2-piperidinoethoxy and 2-pyrrolidinylethoxy.

[0072] In the present invention, among A1, A2, A3, A4 and A5, the C1-C6 fluoroalkyl group may include one or more of trifluoromethyl, difluoromethyl and fluoromethyl.

[0073] In the present invention, among A1, A2, A3, A4 and A5, the C1-C6 heteroatom-containing alkyl group may include one or more of pyrrolidinyl, R-pyridyl, S-pyridyl, R-piperidyl and S-piperidyl.

[0074] In the present invention, among A1, A2, A3, A4 and A5, the 5-membered heterocyclic group containing one or more nitrogen atoms may include one or more of pyrrolidinyl, group of formula 1-1, group of formula 1-2, group of formula 1-3, group of formula 1-4, group of formula 1-5, group of formula 1-6, group of formula 1-7, group of formula 1-8, group of formula 1-9, group of formula 1-10, group of formula 1-11, group of formula 1-12, group of formula 1-13 and group of formula 1-14;

[0075]

[0076] In the present invention, among A1, A2, A3, A4 and A5, the substituted 5-membered heterocyclic group containing one or more nitrogen atoms may have 1 to 3 substituents; the substituted 5-membered heterocyclic group containing one or more nitrogen atoms may include one or both of 3-N,N-dimethylpyrrolidinyl and 1-methylimidazolyl.

[0077] In the present invention, among A1, A2, A3, A4 and A5, the 6-membered heterocyclic group containing one or more nitrogen atoms may be one or more of the group of formula 2-1, the group of formula 2-2, the group of formula 2-3, the group of formula 2-4, morpholinyl, thiomorpholinyl and piperidinyl;

[0078]

[0079]

[0080] In the present invention, among A1, A2, A3, A4 and A5, the substituted 6-membered heterocyclic group containing one or more nitrogen atoms may have 1 to 3 substituents; the substituted 6-membered heterocyclic group containing one or more nitrogen atoms may include one or more of N-methylpiperazinyl, 4-N,N-dimethylpiperidinyl, 4-acetylpiperazinyl, 1-methyl-4-(piperazin-4-yl)piperidinyl, 4-(4-methylpiperazin-1-yl)methyl, 1-methylpiperidin-4-ylamino, 4-piperazin-2-oneyl and 1-methyl-4-piperazin-2-oneyl.

[0081] In the present invention, among A1, A2, A3, A4 and A5, the 5- to 12-membered saturated carbocyclic ring formed between any two adjacent substitution sites may include one or both of 3-methylhexahydropyrimidinyl and 3-dimethylimidazolidinyl.

[0082] In the present invention, among A1, A2, A3, A4 and A5, the 5- to 12-membered saturated heterocyclic ring containing 1 to 3 heteroatoms formed between any two adjacent substitution sites may include one or more of thiomorpholinyl and tetrahydrothiazolyl.

[0083] In the present invention, among R4 and R5, the C1-C5 alkyl group may include one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and pentyl.

[0084] In the present invention, among R4 and R5, the C3-C6 cycloalkyl group may include one or more of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0085] In the present invention, among R4 and R5, the substituted C3-C6 cycloalkyl group may include one or more of methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl and 2-ethyl-cyclopentyl.

[0086] In the present invention, among R4 and R5, the 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring formed by cyclization of R4 and R5 and containing 1 to 3 heteroatoms may include imidazolyl, indolyl, isopyrazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, pyrazolyl, thienyl, triazolyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidinone, 2-pyrrolidone, triazolyl, 1,4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisopyrazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydropyrazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuryl, tetrahydrothienyl or their N-oxides.

[0087] In the present invention, the substituents of the substituted 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring containing 1 to 3 heteroatoms can be achieved through carbon atoms or heteroatoms.

[0088] In the present invention, among R2, the C1-C4 alkyl may include one or several of methyl, ethyl, propyl and butyl; the C1-C4 alkoxy may include one or several of methoxy, ethoxy, propoxy and butoxy.

[0089] In the present invention, among Y in R2, the halogen may include one or several of fluorine, chlorine, bromine and iodine.

[0090] In the present invention, R2 may specifically be a group of formula D, a group of formula E or a group of formula F, and more specifically a group of formula D.

[0091] In the present invention, the structure of the heterocyclic compound may be as shown in formula II or formula III:

[0092]

[0093] Specifically, it may be as shown in formula IV or formula V:

[0094]

[0095] More specifically, it may be as shown in formula VI or formula VII:

[0096]

[0097] In a specific embodiment of the present invention, the heterocyclic compound may be (R)-2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-ethyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclohexyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(p-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclopropyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclopentyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclobutyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(2-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,[2,3-d]Pyrimidin-7(8H)-one, (R)-2-((1-(2-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(4-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(o-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(m-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-3-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-4-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-2-((1-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-2-((1-(2-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one or (R)-2-((1-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one.,

[0098] In the present invention, in the heterocyclic compounds, when any substituent group (such as R1) appears more than once in any substance, its definition for each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituent groups are allowed as long as such combinations render the heterocyclic compounds stable. The line from a substituent group into the ring system indicates that the indicated bond can be connected to any ring atom capable of being substituted. If the ring system is polycyclic, it means that this bond is only connected to any appropriate carbon atom of the adjacent ring. It is to be understood that those of ordinary skill in the art can select the substituent groups and substitution patterns of the heterocyclic compounds of the present invention to provide compounds that are chemically stable and can be easily synthesized from starting materials that are readily available by conventional techniques in the art and the methods proposed in the present invention. If a substituent group itself is substituted by more than one group, it should be understood that these groups can be on the same carbon atom or different carbon atoms as long as the structure is stable.

[0099] In the present invention, the "alkyl" and "alkylene" mean branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. The "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms.

[0100] In the present invention, the prodrug refers to a substance that can be converted in vivo into the structure of the heterocyclic compounds of the present invention and their pharmaceutically acceptable salts.

[0101] Since under physiological conditions, the deprotonated acidic moiety in a compound such as a carboxyl group can be anionic, and this carried charge can then be balanced and offset by an internally cationic protonated or alkylated basic moiety such as a quaternary nitrogen atom, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0102] The present invention also provides a method for preparing the heterocyclic compounds described in the above scheme, including the following steps:

[0103] Mix compound A and compound B and sequentially carry out a first coupling reaction and a first substitution reaction to obtain compound C; carry out a reduction reaction on the compound C to obtain compound D; alternatively, mix compound J and compound K to carry out a second coupling reaction to obtain compound D;

[0104] Mix compound E and compound F to carry out a second substitution reaction to obtain compound G; mix the compound G with trans-crotonic acid and sequentially carry out a Heck coupling reaction and a ring-closing reaction to obtain compound H;

[0105] Mix the compound D and the compound H, carry out the third substitution reaction, then deprotect and carry out a nucleophilic substitution reaction with an acyl chloride to obtain the 2-aminopyrazolopyrimidinone compound;

[0106] Saltify the 2-aminopyrazolopyrimidinone compound to obtain a pharmaceutically acceptable salt of the 2-aminopyrazolopyrimidinone compound;

[0107] Carry out isomer transformation on the 2-aminopyrazolopyrimidinone compound to obtain a stereoisomer of the 2-aminopyrazolopyrimidinone compound;

[0108] The structures of the compounds A, D-H, J-K are as shown in formulas A, D-H, J-K. The compound B includes one or more of the compound of formula B and a halogenated benzene; the compound C includes one or more of the compound of formula C, an aminopyrazole and a cycloalkylpyrazole;

[0109]

[0110] In the present invention, the compound A and the compound B are mixed and successively carried out a first coupling reaction and a first substitution reaction to obtain the compound C. In the present invention, the halogenated benzene may include one or more of iodobenzene, fluoroiodobenzene, chloroiodobenzene, cyanoiodobenzene, hydroxyiodobenzene, methyliodobenzene, methoxyiodobenzene and trifluoromethyl iodobenzene; the fluoroiodobenzene may include one or two of 2-fluoroiodobenzene and 4-fluoroiodobenzene; the chloroiodobenzene may include one or more of 2-chloroiodobenzene, 3-chloroiodobenzene and 4-chloroiodobenzene; the cyanoiodobenzene may include one or more of 2-cyanoiodobenzene, 3-cyanoiodobenzene and 4-cyanoiodobenzene; the hydroxyiodobenzene may include one or more of 2-hydroxyiodobenzene, 3-hydroxyiodobenzene and 4-hydroxyiodobenzene; the methyliodobenzene may include one or more of 2-methyliodobenzene and 4-methyliodobenzene; the methoxyiodobenzene may include one or more of 2-methoxyiodobenzene, 3-methoxyiodobenzene and 4-methoxyiodobenzene; the trifluoromethyl iodobenzene may include one or more of 2-trifluoromethyl iodobenzene, 3-trifluoromethyl iodobenzene and 4-trifluoromethyl iodobenzene.

[0111] In the present invention, the molar ratio of the compound A to the compound B may be 0.9-1.8:1, specifically may be 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1 or 1.8:1.

[0112] In the present invention, the temperature of the first coupling reaction can be 20 to 35 °C, specifically 20 °C, 25 °C, 30 °C or 35 °C, and the heat preservation reaction time can be 10 to 14 h, specifically 10 h, 11 h, 12 h, 13 h or 14 h; the first coupling reaction can be carried out in a protective atmosphere; the protective atmosphere can be an inert gas; the inert gas can be argon; the first coupling reaction can be carried out in the presence of a catalyst, a ligand and an organic solvent; the catalyst can include one or more of azo compounds and metal salts; the azo compound can be di-tert-butyl azodicarboxylate; the metal salt can include one or more of Cs2CO3 and CuBr; the ligand can be phosphine; the phosphine can be triphenylphosphine; the organic solvent can include one or more of furan solvents and amide solvents; the furan solvent can be tetrahydrofuran; the amide solvent can be N,N-dimethylformamide; the molar ratio of compound A to the ligand can be 1:1; the molar ratio of compound A to the catalyst can be 1.2:1.3 to 2, specifically 1.2:1.3, 1.2:1.5, 1.2:1.7, 1.2:1.9 or 1.2:2; the molar ratio of compound A to the organic solvent can be 0.06 to 0.25:1, specifically 0.06:1, 0.08:1, 0.1:1, 0.12:1, 0.15:1, 0.17:1, 0.2:1, 0.22:1 or 0.25:1.

[0113] In the present invention, the temperature of the first substitution reaction can be 110 to 130 °C, specifically 110 °C, 120 °C or 130 °C, and the heat preservation reaction time can be 10 to 14 h, specifically 10 h, 11 h, 12 h, 13 h or 14 h; the first substitution reaction can be carried out under stirring conditions; the first substitution reaction can be carried out in the presence of a catalyst and an organic solvent; the catalyst can include one or more of azo compounds and metal salts; the azo compound can be di-tert-butyl azodicarboxylate; the metal salt can include one or more of Cs2CO3 and CuBr; the organic solvent can include one or more of furan solvents and amide solvents; the furan solvent can be tetrahydrofuran; the amide solvent can be N,N-dimethylformamide; the molar ratio of compound A to the catalyst can be 0.1 to 0.2:1, specifically 0.1:1, 0.12:1, 0.14:1, 0.16:1, 0.18:1 or 0.2:1; the molar ratio of compound A to the organic solvent can be 0.06 to 1.5:1, specifically 0.06:1, 0.08:1, 0.1:1, 0.5:1, 0.7:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1.

[0114] In the present invention, after the first substitution reaction, the obtained product may further be subjected to extraction, drying of the organic phase, and purification in sequence; the extraction reagent may be dichloromethane and water; the drying may be carried out by drying with anhydrous Na2SO4 and filtering and rotary evaporation in sequence; the purification may be column chromatography; the column chromatography may be SiO2 column chromatography; the SiO2 column chromatography may be gradient elution with petroleum ether / ethyl acetate (PE / EA); the volume ratio of PE / EA may be 5 to 10:1, specifically 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1.

[0115] After obtaining compound C, the present invention subjects compound C to a reduction reaction to obtain compound D. In the present invention, the aminopyrazole may include one or more of N-methyl-3-aminopyrazole, N-ethyl-3-aminopyrazole, and 3-aminopyrazole; the cycloalkylpyrazole may include one or more of 1-cyclohexyl-1H-pyrazol-3-amine, 1-cyclopropyl-1H-pyrazol-3-amine, 1-cyclopentyl-1H-pyrazol-3-amine, and 1-cyclobutyl-1H-pyrazol-3-amine.

[0116] In the present invention, the temperature of the reduction reaction may be room temperature, and the heat preservation reaction time may be 20 to 120 min, specifically 20 min, 30 min, 50 min, 70 min, 90 min, or 120 min; the reduction reaction may be carried out in the presence of a catalyst, an alcohol, and a reducing gas; the catalyst may be a palladium catalyst; the palladium catalyst may be Pd / C; the alcohol may be methanol; the reducing gas may be hydrogen; the molar ratio of compound A to the catalyst may be 5 to 11:1, specifically 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or 11:1; the molar ratio of compound A and the alcohol may be 0.03 to 0.2:1, specifically 0.03:1, 0.05:1, 0.07:1, 0.2:1, 0.13:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, or 0.2:1; the introducing device of the reducing gas may be a hydrogen balloon.

[0117] Alternatively, the present invention mixes compound J and compound K to carry out a second coupling reaction to obtain compound D. In the present invention, the molar ratio of compound J to compound K may be 0.7 to 1.3:1, specifically 0.7:1, 0.9:1, 1.1:1, 1.15:1, 1.27:1.06, 1.25:1, or 1.3:1.

[0118] In the present invention, the temperature of the second coupling reaction can be 105 to 130 °C, specifically 105 °C, 110 °C, 115 °C, 120 °C, 125 °C or 130 °C, and the holding reaction time can be 10 to 18 h, specifically 10 h, 12 h, 14 h, 16 h or 18 h; the second coupling reaction can be carried out in a protective atmosphere; the protective atmosphere can be an inert gas; the inert gas can be argon; the second coupling reaction can be carried out under the conditions of a catalyst and an organic solvent; the catalyst can include one or several of alkali metal hydroxides and metal oxides; the alkali metal hydroxide can be potassium hydroxide; the metal oxide can be copper oxide; the copper oxide can be Cu2O; the organic solvent can be a sulfone solvent; the sulfone solvent can be dimethyl sulfoxide (DMSO); the molar ratio of compound J to the catalyst can be 0.1 to 0.5:1, specifically 0.1:1, 0.2:1, 0.3:1, 0.4:1 or 0.5:1; the molar ratio of compound J to the organic solvent can be 0.03 to 1.5:1, specifically 0.03:1, 0.05:1, 0.1:1, 0.3:1, 0.5:1, 0.75:1, 1:1, 1.3:1 or 1.5:1.

[0119] In the present invention, after the second coupling reaction, it may further include successively subjecting the obtained product to extraction, drying of the organic phase and purification; the extraction reagent can be dichloromethane and saturated ammonium chloride; the drying can be successively carried out by drying with anhydrous Na2SO4 and filtering and rotary evaporation; the purification can be column chromatography; the column chromatography can be SiO2 column chromatography; the SiO2 column chromatography can be gradient elution with petroleum ether / ethyl acetate (PE / EA); the volume ratio of PE / EA can be 5 to 10:1, specifically 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1.

[0120] In the present invention, compound E and compound F are mixed to carry out a second substitution reaction to obtain compound G. In the present invention, the molar ratio of compound E to compound F can be 1.0 to 1.5:1, specifically 1:1, 1:1.05, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1.

[0121] In the present invention, the temperature of the second substitution reaction can be -10 to 10 °C, specifically -10 °C, -5 °C, 0 °C, 5 °C or 10 °C, and the holding reaction time can be 3 to 5 h, specifically 3 h, 4 h or 5 h; the second substitution reaction can be carried out in the presence of a catalyst and a nitrile solvent; the catalyst can be a base; the base can be K2CO3; the nitrile solvent can be acetonitrile; the molar ratio of compound E to the catalyst can be 1.1:2 to 3.5, specifically 1.1:2, 1.1:2.2, 1.1:2.5, 1.1:2.7, 1.1:3, 1.1:3.2 or 1.1:3.5; the molar ratio of compound E to the nitrile solvent can be 0.01 to 0.40:1, specifically 0.01:1, 0.02:1, 0.05:1, 0.07:1, 0.1:1, 0.2:1 or 0.4:1.

[0122] In the present invention, after the second substitution reaction, it may further include successively subjecting the obtained product to extraction, drying of the organic phase and purification; the extraction reagent can be dichloromethane and water; the drying can be successively carried out with anhydrous Na2SO4 drying and filtration and rotary evaporation; the purification can be column chromatography; the column chromatography can be SiO2 column chromatography; the SiO2 column chromatography can be gradient elution with petroleum ether / ethyl acetate (PE / EA); the volume ratio of PE / EA can be 5 to 10:1, specifically 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1.

[0123] In the present invention, compound G and trans-crotonic acid are mixed and successively subjected to a Heck coupling reaction and a ring-closure reaction to obtain compound H. In the present invention, the molar ratio of compound G to trans-crotonic acid can be 1:3.5 to 7, specifically 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5 or 1:7.

[0124] In the present invention, the temperature of the Heck coupling reaction can be 75 to 85 °C, specifically 75 °C, 77 °C, 80 °C, 83 °C or 85 °C, and the holding reaction time is 14 to 24 h, specifically 14 h, 15 h, 16 h, 17 h, 18 h, 20 h, 22 h or 24 h; the Heck coupling reaction can be carried out in a protective atmosphere; the protective atmosphere can be an inert gas or N2; the inert gas can be argon; the Heck coupling reaction can be carried out in the presence of a catalyst, a ligand and a furan solvent; the catalyst can include one or more of a palladium catalyst and an amine; the palladium catalyst can be bis(benzyl cyanide)palladium dichloride; the amine can be N,N-diisopropylethylamine (DIPEA); the ligand can be a phosphine; the phosphine can be tris(o-tolyl)phosphine; the furan solvent can be tetrahydrofuran; the molar ratio of compound G to the catalyst can be 1:0.04 to 10, specifically 1:0.04, 1:0.08, 1:0.1, 1:0.5, 1:1, 1:5 or 1:10; the molar ratio of compound G to the ligand can be 1:0.04 to 0.08, specifically 1:0.04, 1:0.05, 1:0.06, 1:0.07 or 1:0.08; the molar ratio of compound G to the furan solvent can be 0.02 to 0.75:1, specifically 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.3:1, 0.45:1, 0.55:1, 0.60:1, 0.65:1, 0.70:1 or 0.75:1.

[0125] In the present invention, the temperature of the ring-closing reaction can be 85 to 100 °C, specifically 85 °C, 90 °C, 95 °C or 100 °C, and the holding reaction time can be 20 to 28 h, specifically 20 h, 22 h, 24 h, 26 h or 28 h; the ring-closing reaction can be carried out in the presence of acetic anhydride; the molar ratio of compound G to acetic anhydride can be 0.3 to 2:1, specifically 0.3:1, 0.4:1, 0.5:1, 0.7:1, 0.9:1, 1.1:1, 1.3:1, 1.5:1, 1.7:1, 1.9:1 or 2:1.

[0126] In the present invention, after the ring-closing reaction, it may further include sequentially cooling the obtained reaction system, removing the solvent, washing, drying, filtering, concentrating under reduced pressure and purifying; the final temperature of the cooling can be room temperature; the removal of the solvent can be rotary evaporation under reduced pressure; the washing can be sequentially washing with dichloromethane (DCM), HCl and saturated brine; the drying can be drying with anhydrous Na2SO4, and the drying time can be 30 min; the purification can be column chromatography.

[0127] After obtaining the compound D and the compound H, the present invention mixes the compound D and the compound H to carry out a third substitution reaction, followed by deprotection and a nucleophilic substitution reaction with an acyl chloride to obtain the 2-aminopyrazolopyrimidinone compound. In the present invention, the molar ratio of the compound D to the compound H can be 1.1 to 1.5:1, specifically 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1.

[0128] In the present invention, the temperature of the third substitution reaction can be 105 to 125 °C, specifically 105 °C, 110 °C, 115 °C, 120 °C or 125 °C, and the heat preservation reaction time can be 10 to 18 h, specifically 10 h, 11 h, 12 h, 13 h, 14 h, 16 h or 18 h; the third substitution reaction can be carried out in the presence of a catalyst and an alcohol solvent; the catalyst can be an acid; the acid can be trifluoroacetic acid (TFA); the alcohol solvent can be a C1-C8 alcohol; the C1-C8 alcohol can be butanol; the butanol can be sec-butanol; the molar ratio of the compound D to the alcohol solvent can be 1:1.1 to 45, specifically 1:1.1, 1:3, 1:5, 1:7, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40 or 1:45; the molar ratio of the compound D to the catalyst can be 1.2:1.1 to 1.8, specifically 1.2:1.1, 1.2:1.2, 1.2:1.3, 1.2:1.4, 1.2:1.5, 1.2:1.6, 1.2:1.7 or 1.2:1.8.

[0129] In the present invention, after the third substitution reaction, it may further include successively cooling, extracting, combining the organic phases, washing, drying and purifying the obtained reaction system; the final temperature of the cooling can be room temperature; the extraction can be adding the cooled reaction solution into a 10 wt% aqueous NaHCO3 solution and extracting with dichloromethane; the number of extraction times can be more than 2 times; the washing reagent can be saturated brine; the number of washing times can be more than 2 times; the drying can be drying with anhydrous Na2SO4; the purification can be column chromatography.

[0130] In the present invention, the deprotection can be carried out in the presence of a catalyst and a substituted hydrocarbon solvent; the catalyst can be an acid; the acid can be trifluoroacetic acid (TFA); the substituted hydrocarbon solvent can be a substituted methane; the substituted methane can be dichloromethane (DCM); the molar ratio of the compound D to the catalyst can be 0.04 to 3:1, specifically 0.04:1, 0.1:1, 0.3:1, 0.5:1, 1:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1 or 3:1; the molar ratio of the compound D to the substituted hydrocarbon solvent can be 0.1 to 0.5:1, specifically 0.10:1, 0.15:1, 0.20:1, 0.25:1, 0.30:1, 0.35:1, 0.40:1, 0.45:1 or 0.50:1.

[0131] In the present invention, after the deprotection, it may further include adjusting the pH value of the obtained reaction system to 9, extraction, washing, drying and concentration in sequence; the reagent for pH adjustment can be saturated aqueous NaHCO3 solution; the extraction may include: extracting the reaction system after pH adjustment with dichloromethane (DCM) (denoted as extraction A) and then extracting with 10 wt% aqueous NaHCO3 solution (denoted as extraction B); the number of times of extraction A can be more than 2 times; the number of times of extraction B can be more than 2 times; the reagent for washing can be saturated brine; the number of times of washing can be more than 2 times; the drying can be drying with anhydrous Na2SO4.

[0132] In the present invention, the acyl chloride can include one or more of formyl chloride, acetyl chloride, propionyl chloride, benzoyl chloride, oxalyl chloride, chloroacetyl chloride and trichloroacetyl chloride.

[0133] In the present invention, the molar ratio of the compound D to the acyl chloride can be 2 to 10:1, specifically 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1.

[0134] In the present invention, the temperature of the nucleophilic substitution reaction can be -10 to 10 °C, specifically -10 °C, -5 °C, 0 °C, 5 °C or 10 °C, and the holding reaction time can be 15 to 60 min, specifically 15 min, 20 min, 30 min, 40 min, 50 min or 60 min; the nucleophilic substitution reaction can be carried out in the presence of a catalyst and a substituted hydrocarbon solvent; the catalyst can be a base; the base can be triethylamine (Et3N); the substituted hydrocarbon solvent can be a substituted methane; the substituted methane can be dichloromethane (DCM); the molar ratio of compound D to the catalyst can be 1.2 to 2:1, specifically 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.8:1 or 2:1; the molar ratio of compound D to the substituted hydrocarbon solvent can be 0.5 to 2:1, specifically 0.5:1, 0.7:1, 0.9:1, 1:1, 1.2:1, 1.5:1, 1.7:1 or 2:1.

[0135] In the present invention, after the nucleophilic substitution reaction, it may further include pouring the obtained reaction system into an aqueous NaHCO3 solution for extraction, combining the organic phases, washing, drying and purification in sequence; the concentration of the aqueous NaHCO3 solution can be 10 wt%; the extraction reagent can be dichloromethane (DCM); the number of extractions can be more than 2 times; the washing reagent can be saturated brine; the number of washings can be more than 2 times; the drying can be drying with anhydrous Na2SO4; the purification can be column chromatography.

[0136] In the present invention, the 2-aminopyrazolopyrimidinone compound is salted to obtain a pharmaceutically acceptable salt of the 2-aminopyrazolopyrimidinone compound. In the present invention, the salting can include reacting with an acid to obtain a non-toxic salt or reacting with a base to obtain a non-toxic salt. The pharmaceutically acceptable salts of the present invention include non-toxic salts formed by reacting the basic compounds of the present invention with acids and non-toxic salts formed by reacting the acidic compounds of the present invention with bases.

[0137] In the present invention, the acid can include one or more of inorganic acids and organic acids; the inorganic acids can include one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; the organic acids can include one or more of acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid and trifluoroacetic acid.

[0138] In the present invention, the base may include one or more of inorganic bases and organic bases; the inorganic base may include one or more of aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts and zinc salts, and more preferably may be one or more of ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts; the organic base may include one or more of primary amines, secondary amines, tertiary amines and substituted amines; the substituted amine may include one or more of natural substituted amines, cyclic amines and basic ion exchange resins; the natural substituted amine may include one or more of arginine, betaine, choline, diethylamine, 2 - diethylaminoethanol, 2 - dimethylaminoethanol, aminoethanol, procaine, isopropylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, lysine, ethanolamine and ethylenediamine; the cyclic amine may include one or more of caffeine, N,N'-dibenzylethylenediamine, N - ethylmorpholine, N - ethylpiperidine, glucosamine, aminoglucose, histidine, hydroxocobalamin, methylglucosamine, morpholine, piperazine, piperidine, piperidine, purine and theobromine; the basic ion exchange resin may be a polyamine resin.

[0139] In the present invention, the 2 - aminopyrazolopyrimidinone compound is subjected to isomer transformation to obtain the stereoisomer of the 2 - aminopyrazolopyrimidinone compound.

[0140] In the present invention, the method of isomer transformation may adopt a conventional method and will not be elaborated herein.

[0141] The present invention also provides the use of the heterocyclic compound described in the above - mentioned solution or the heterocyclic compound obtained by the preparation method described in the above - mentioned solution in the preparation of RET inhibitors, drugs for preventing tumor recurrence, drugs for preventing tumors or drugs for treating tumors.

[0142] In the present invention, the tumors involved in the drugs for preventing tumors or treating tumors may be malignant tumors with RET gene fusion, and specifically may include one or more of histiocytic lymphoma, non - small cell lung cancer, malignant melanoma, multiple myeloma, small cell lung cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, B - lymphoma, prostate cancer, kidney cancer, liver cancer, lung cancer, laryngeal cancer, skin cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, nasopharyngeal cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer and leukemia, and more specifically may be non - small cell lung cancer.

[0143] The present invention also provides a pharmaceutical composition for preventing and treating tumors, including an active ingredient, and the active ingredient includes the heterocyclic compound described in the above - mentioned solution or the heterocyclic compound obtained by the preparation method described in the above - mentioned solution.

[0144] In the present invention, the pharmaceutical composition may further include a combination therapy; the active ingredient of the combination therapy may include, but is not limited to, an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxin / cytostatic agent, an anti-proliferative agent, a protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protein kinase inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a cell proliferation and survival signal inhibitor, a drug that interferes with cell cycle checkpoints and an apoptosis inducer, a cytotoxic drug, a tyrosine protein inhibitor, an EGFR inhibitor, a VEGFR inhibitor, a serine / threonine protein inhibitor, a Bcr-Abl inhibitor, a c-Kit inhibitor, a Met inhibitor, a Raf inhibitor, a MEK inhibitor, an MMP inhibitor, a topoisomerase inhibitor, a histone deacetylase inhibitor, a proteasome inhibitor, a CDK inhibitor, a Bcl-2 family protein inhibitor, an MDM2 family protein inhibitor, an IAP family protein inhibitor, a STAT family protein inhibitor, a PI3K inhibitor, an AKT inhibitor, an integrin blocker, an interferon, interleukin-12, a COX-2 inhibitor, the human tumor suppressor gene p53, a p53 activator, a VEGF antibody, and an EGF antibody, or one or more of them.

[0145] In the present invention, the combined medications may include, but are not limited to, aldesleukin, alendronic acid, interferon, atrinotec, allopurinol, allopurinol sodium, palonosetron hydrochloride, altretamine, aminoglutethimide, amifostine, amrubicin, aclarubicin, anastrozole, dolasetron, darbepoetin alfa (aranesp), arglabin, arsenic trioxide, arimidex, 5-azacytidine, azathioprine, bacillus calmette-guerin or tice bacillus calmette-guerin, betahistine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromodeoxyuridine, bortezomib, busulfan, calcitonin, alemtuzumab injection, capecitabine, carboplatin, casodex, cefesone, cimaleukin, daunorubicin, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, 166Ho-chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, epoetin beta, iproplatin, levamisole tablets, estradiol preparation, 17-β-estradiol, estramustine phosphate sodium, ethinyl estradiol, amifostine, etidronic acid, neupogen, finasteride, ferrestra, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestane, 1-β-D-arabinofuranosylcytosine-5'-stearoyl phosphate, fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imatinib mesylate, carmustine wafer capsule, goserelin, granisetron hydrochloride, histrelin, mithramycin, hydrocortisone, erythro-hydroxy-nonyl adenine, hydroxyurea, iodine-131 tositumomab, idarubicin, ifosfamide, interferon alpha, interferon-α2, interferon α-2A, interferon α-2B, interferon α-n1, interferon α-n3, interferon beta, interferon gamma-la, interleukin-2, intron A, gefitinib, irinotecan, camptosar, lentinan sulfate, letrozole, leucovorin, leuprorelin, leuprorelin acetate, levamisole, calcium levoleucovorin, levothyroxine sodium, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, liposomal doxorubicin citrate, nedaplatin, pegfilgrastim, oprelvekin,Filgrastim (Neupogen), nilutamide, tamoxifen, Uckuline (NSC-631570), recombinant human interleukin 1-β, octreotide, ondansetron hydrochloride, prednisolone oral solution, oxaliplatin, paclitaxel, sodium prednisolone phosphate preparation, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, prednimustine, stipropranolone, prednisone, Premarin, procarbazine, recombinant human erythropoietin, raltitrexed, Rebif, rhenium-186 etidronate, Rituxan, Redoxon-A, romurtide, pilocarpine hydrochloride tablets, octreotide, sargramostim, semustine, sizofiran, sobuzoxane, methylprednisolone sodium succinate, pafuramidine, stem cell therapy, streptozocin, strontium-89 chloride, levothyroxine sodium, tamoxifen, tamsulosin, tasosnamine, tastolactone, Taxotere, tixocarbazin, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, methotrexate tablets, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, verulizine, dexrazoxane, zindostatin stimalamer, Zofran, paclitaxel protein-stabilized preparation, acolbifene, interferon γ-1b, afatinib (Affinitak), aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, sorafenib (BAY43-9006), Avastin, temsirolimus (CCI-779), lenalidomide (CDC-501), Celebrex, cetuximab, clinacanthus nutans, cyproterone acetate, decitabine, doxorubicin-MTC, doxylamine (dSLIM), dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 multiple myeloma (holmium-166 DOTMP), ibandronic acid, interferon γ, intron-PEG, ixabepilone, keyhole limpet hemocyanin, carboxyamidotriazole (L-651582), lanreotide, lasofoxifene, Libra, lonafamib, miproxifene, minocarbate, dofequidar fumarate (MS-209), mifamurtide (liposomal MTP-PE), nafarelin, nemorubicin, nevadensin, nolatrexed, olimersen, vincristine (onco-TCS), osidem, paclitaxel polyglutamate, sodium perfluorooctanesulfonate, uridine triacetate (PN-401), vaccine adjuvant (QS-21), quazepam, R-1549, raloxifene, batroxobin,One or more of 13-cis retinoic acid, satraplatin, calcitriol, T-138067, tarceva, docetaxel, thymosin α1, tipifarnib, tirapazamine, glutathione analogue prodrug (TLK-286), toremifene, trans-hydroxy loxoprofen (trans MID-lo7R), fosaprepitant, vapreotide, vatalanib, verteporfin, vinflunine, zaltoprofen (Z-100) and zoledronic acid.

[0146] The heterocyclic compounds of the present invention can be used in combination with known drugs for treating or improving similar conditions. When administered in combination, the original administration method and dosage of the drugs remain unchanged, while the heterocyclic compounds of the present invention are taken simultaneously or subsequently. When the heterocyclic compounds of the present invention are taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the heterocyclic compounds of the present invention. The combination of drugs also includes taking the heterocyclic compounds of the present invention and one or more other known drugs over an overlapping time period. When the heterocyclic compounds of the present invention are combined with one or more other drugs, the dosage of the heterocyclic compounds of the present invention or the known drugs may be lower than the dosage when they are used alone.

[0147] To further illustrate the present invention, the following examples are used to describe the solutions of the present invention in detail, but they should not be construed as limiting the scope of protection of the present invention.

[0148] In the following examples of the present invention, the preparation route of the heterocyclic compounds is as follows:

[0149]

[0150] Example 1

[0151] In this example, (R)-2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, is denoted as Compound 660206:

[0152] Step a: At room temperature, 3-amino-1H-pyrazole (Compound 1) (500 mg, 6.02 mmol) was added to 13 mL of DMSO, followed by the addition of Cu2O (86 mg, 0.602 mmol), KOH (678 mg, 12.04 mmol), and 3-fluoroiodobenzene (Compound 2) (2.174 g, 8.428 mmol). The mixed system was purged with Ar three times, and then heated to 120 °C and stirred for 12 h. The reaction was monitored by TLC. After the raw materials were completely reacted, the mixture was extracted with dichloromethane and saturated ammonium chloride. The organic phase was taken, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. Column chromatography separation (SiO2, gradient elution with PE / EA, volume ratio 10 - 5:1) was performed to obtain 610 mg of a brown solid product (Compound 3) with a yield of 57.22%.

[0153] Step b: At room temperature, 2,4-dichloro-5-bromopyrimidine (Compound 4) (15.124 g, 66.37 mmol), R-1-N-Boc-3-aminopiperidine (Compound 5) (13.034 g, 60.56 mmol), and K2CO3 (16.739 g, 121.1 mmol) were added to 183 mL of MeCN. The mixed system was continuously stirred at room temperature, and the reaction was monitored by TLC. After the raw materials were completely reacted, the mixture was extracted with dichloromethane and water. The organic phase was taken, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. Column chromatography separation (SiO2, gradient elution with PE / EA, volume ratio 10:1 - 5:1) was performed to obtain 23.382 g of an oily compound (Compound 6) with a yield of 95%. The chemical name of Compound 6 is tert-butyl (R)-3-((5-bromo-2-chloropyrimidin-4-yl)amino)piperidine-1-carboxylate, and its English name is tert-butyl (R)-3-((5-bromo-2-chloropyrimidin-4-yl)amino)piperidine-1-carboxylate.

[0154] Characterization results: 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.17 (s, 1H), 4.04 (s, 1H), 3.91 (s, 1H), 3.82 (s, 1H), 3.71 - 3.62 (m, 1H), 3.00 (s, 1H), 2.86 (s, 1H), 1.99 (s, 1H), 1.83 (s, 1H), 1.66 (s, 1H), 1.37 (s, 9H).

[0155] MS (ESI) m / z 391.04582 [M+H] + 。

[0156] Step c: At room temperature, add tert-butyl (R)-3-((5-bromo-2-chloropyrimidin-4-yl)amino)piperidine-1-carboxylate (Compound 6) (12.686 g, 31.2 mmol) and trans-crotonic acid (13.430 g, 156 mmol) into THF (120 mL), then slowly add DIPEA (51 mL) into the system. The system is purged with Ar three times, and then dichloro(diphenylacetonitrile)palladium(II) (0.599 g, 1.56 mmol) and tris(o-tolyl)phosphine (0.475 g, 1.56 mmol) are added into the mixed system. The system is purged with Ar three times again, heated to 80 °C and stirred for 24 h. Then add Ac2O (7.5 mL) into the system, continue to heat to 90 °C and stir for 24 h. Stop heating. When the temperature of the system drops to room temperature, remove part of the solvent by rotary evaporation under reduced pressure. Then add DCM (120 mL) into the system, wash the organic phase with HCl (1 M, 230 mL), and then wash it once with saturated brine (230 mL). Collect the organic phase, dry it with anhydrous Na2SO4 for 30 min, filter, concentrate under reduced pressure, and perform column chromatography to obtain 4.436 g of a white solid (Compound 7) with a yield of 36.1%. The chemical name is tert-butyl (R)-3-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate, and its English name is tert-butyl (R)-3-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate.

[0157] Characterization results: 1 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 6.61 (s, 1H), 5.17 (s, 1H), 3.90 (dd, J = 62.1 - 23.9 Hz, 4H), 2.66 (s, 2H), 2.45 (s, 3H), 1.76 (d, J = 39.6 Hz, 2H), 1.48 (s, 1H), 1.41 (s, 9H).

[0158] MS (ESI) m / z 379.14587 [M+H] + 。

[0159] Step d: Add tert-butyl (R)-3-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate (Compound 7) (417 mg, 1.06 mmol) into a sealed bottle containing 5 mL of sec-butanol. Then add 1-(3-fluorophenyl)-1H-pyrazol-3-amine (Compound 3) (225 mg, 1.27 mmol) and TFA (0.09 mL, 1.166 mmol) successively. Heat the mixture to 110 °C and stir for 18 h. Cool it to room temperature, pour it into 10% aqueous NaHCO3 solution, extract with dichloromethane twice, combine the organic phases, wash with saturated brine twice, dry over anhydrous Na2SO4, and perform column chromatography to obtain 88 mg of a light yellow solid with a yield of 16%. The chemical name is tert-butyl (R)-3-(2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate, and the English name is tert-butyl (R)-3-(2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate.

[0160] Characterization results: 1 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 7.61 (d, J = 57.2 Hz, 1H), 7.10 (s, 1H), 6.27 (s, 1H), 5.47 (s, 1H), 3.91 (s, 2H), 3.16 (s, 4H), 2.38 (d, J = 2.9 Hz, 3H), 1.90 (s, 1H), 1.76 (s, 2H), 1.36 (s, 9H).

[0161] HRMS (ESI) m / z 520.23942 [M+H] + 。

[0162] Step e: Dissolve tert-butyl (R)-3-(2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl) (Compound 8) (200 mg, 0.385 mmol) in DCM (6.8 mL), then add TFA (2.3 mL), and react at room temperature for 0.5 h. After the reaction, adjust the pH to 9 with saturated aqueous NaHCO3, extract with DCM twice, then extract with 10 wt% aqueous NaHCO3 twice, wash with saturated brine twice, dry over anhydrous Na2SO4, concentrate and proceed to the next step; dissolve the concentrated compound in anhydrous DCM, add triethylamine (0.2 mL, 0.716 mmol) under an ice bath at 0 °C, slowly dropwise add propionyl chloride (0.03 mL, 0.43 mmol), after the reaction, pour it into 10 wt% aqueous NaHCO3, extract with dichloromethane twice, combine the organic phases, wash with saturated brine twice, dry over anhydrous Na2SO4, and perform column chromatography to obtain 68 mg of white solid Compound 660206 with a yield of 37.2%.

[0163] Characterization results: 1 1H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.09 (s, 1H), 8.13 (s, 1H), 7.58 (s, 1H), 7.48 (s, 2H), 7.20 (s, 1H), 6.84 (s, 1H), 5.78 (s, 1H), 4.83 (s, 1H), 4.47 (s, 1H), 4.30 (s, 1H), 3.66 (s, 1H), 2.97 (s, 3H), 2.60 (s, 3H), 2.32 (s, 1H), 2.19 (s, 1H), 2.01 (s, 1H), 1.48 (s, 3H).

[0164] HRMS (ESI) m / z 476.22175 [M+H] + .

[0165] Example 2

[0166] In this example, (R)-2-((1-(3-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-2-((1-(3-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660208, and the structure is as follows:

[0167]

[0168] The preparation method of this example is the same as that of Example 1, except that: compound 3 is replaced by compound 12.

[0169] The preparation method of compound 12 described in this example is as follows:

[0170] Step g: Dissolve 3-nitro-1H-pyrazole (compound 9) (1 g, 8.84 mmol) in DMF (10 mL) at room temperature, and then add Cs2CO3 (4.32 g, 13.26 mmol), CuBr (152 mg, 1.06 mmol) and 3-iodophenol (compound 10, 2.023 g, 9.19 mmol). After the mixture is subjected to an Ar2 coupling reaction for 14 h, it is heated to 120 °C and stirred for 14 h. After the reaction is completed, it is extracted with dichloromethane and water. The organic phase is taken, dried over anhydrous Na2SO4, then filtered and concentrated by rotary evaporation, and separated by column chromatography to obtain 834 mg of gray compound 11 with a yield of 46%.

[0171] Characterization results: 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.47 (d, J = 19.6 Hz, 1H), 7.23 - 6.95 (m, 3H), 6.83 (s, 1H), 6.58 (d, J = 9.6 Hz, 1H).

[0172] MS (ESI) m / z 206.18 [M + H] + 。

[0173] Step h: Add Pd / C (86 mg, 0.812 mmol) to a solution of 3-(3-nitro-1H-pyrazol-1-yl)phenol (compound 11) (834 mg, 4.06 mmol) in MeOH (10 mL) at room temperature. The mixture is degassed in vacuo and purged with H2 several times. The reaction mixture is stirred at room temperature for 2 h under an H2 (30 psi) atmosphere. The mixture is filtered and the filtrate is concentrated to obtain 459 mg of light gray compound 12 with a yield of 64%.

[0174] Characterization results: 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.47 (d, J = 19.6 Hz, 1H), 7.23 - 6.95 (m, 3H), 6.83 (s, 1H), 6.58 (d, J = 9.6 Hz, 1H), 5.97 (s, 2H).

[0175] MS(ESI) m / z 176.39 [M+H] + 。

[0176] Characterization results of compound 660208: 1 H NMR (400 MHz, Trifluoroacetic acid-d) δ 8.97 (s, 1H), 7.89 (s, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 6.83 (s, 1H), 6.58 (s, 1H), 6.33 (s, 1H), 5.51 (s, 1H), 4.59 (s, 1H), 4.23 (s, 1H), 4.04 (s, 1H), 3.40 (s, 3H), 2.72 (s, 3H), 2.35 (s, 1H), 1.94 (s, 1H), 1.72 (s, 1H), 1.22 (s, 3H).

[0177] HRMS(ESI) m / z 474.22573 [M+H] + 。

[0178] Example 3

[0179] In this example, (R)-2-((1-(3-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-2-((1-(3-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as compound 660207, and the structure is as follows:

[0180]

[0181] The preparation method of this example is the same as that of Example 1, except that: compound 2 was replaced with commercially available 3-methoxyphenyl iodide.

[0182] Characterization results: 1HNMR(400MHz,Trifluoroacetic acid-d)δ9.02(s,1H),7.96(s,1H),7.56(s,1H),7.38(s,1H),7.16(s,1H),6.94(s,1H),6.63(s,1H),6.39(s,H),5.52(s,1H),4.61(s,1H),4.26(s,1H),4.10(s,1H),3.91(s,3H),3.44(s,1H),2.74(s,3H),2.39(s,3H),2.11(s,1H),1.95(s,1H),1.76(s,1H),1.26(s,3H).

[0183] HRMS(ESI)m / z488.24133[M+H] + 。

[0184] Example 4

[0185] In this example, (R)-5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660210, and the structure is as follows:

[0186]

[0187] The preparation method of this example is the same as that of Example 1, except that: Compound 3 was replaced with commercially available N-methyl-3-aminopyrazole.

[0188] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ9.00(s,1H),7.76(s,1H),6.64(s,1H),5.48(s,1H),4.62(s,1H),4.15(s,1H),4.07(s,1H),3.97(s,3H),3.39(s,1H),2.71(s,3H),2.41(s,3H),2.12(s,1H),1.98(s,1H),1.73(s,1H),1.24(s,3H),1.14(s,2H).

[0189] HRMS(ESI) m / z 396.21506 [M+H] + 。

[0190] Example 5

[0191] In this example, (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared. Its English name is (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660213, and its structure is as follows:

[0192]

[0193] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available iodobenzene.

[0194] Characterization results: 1 H NMR(400MHz, Trifluoroacetic acid-d) δ 8.80(s, 1H), 7.84(s, 1H), 7.38 - 7.24(m, 5H), 6.54(s, 1H), 5.49(s, 1H), 4.56(s, 1H), 4.17(s, 1H), 4.02(s, 1H), 3.35(s, 1H), 2.67(s, 3H), 2.30(s, 3H), 2.03(s, 1H), 1.90(s, 1H), 1.66(s, 1H), 1.18(s, 3H).

[0195] HRMS(ESI) m / z 458.2314 [M+H] + 。

[0196] Example 6

[0197] In this example, (R)-2-((1-ethyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared. Its English name is (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660216, and its structure is as follows:

[0198]

[0199] The preparation method of this example is the same as that of Example 1, except that compound 3 is replaced with commercially available N-ethyl-3-aminopyrazole.

[0200] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ8.91(s,1H),7.74(s,1H),6.55(s,1H),5.35(s,1H),4.52(s,1H),4.21(s,2H),4.08(s,1H),3.98(s,1H),3.31(s,1H),2.59(s,3H),2.31(s,3H),2.00(s,1H),1.85(s,1H),1.61(s,1H),1.38(s,3H),1.13(s,3H).

[0201] HRMS(ESI)m / z410.23108[M+H] + .

[0202] Example 7

[0203] This example prepared (R)-2-((1-(3-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(3-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as compound 660217, and the structure is as follows:

[0204]

[0205] The preparation method of this example is the same as that of Example 1, except that compound 2 is replaced with commercially available 3-chloroiodobenzene.

[0206] Characterization results: 1HNMR(400MHz,Trifluoroacetic acid-d)δ8.83(s,1H),7.86(s,1H),7.49(s,1H),7.31 - 7.22(m,3H),6.58(s,1H),6.35(s,1H),5.52(s,1H),4.56(s,1H),4.19(s,1H),4.03(s,1H),3.41(s,1H),2.71(s,3H),2.33(s,3H),2.07(s,1H),1.91(s,1H),1.75(s,1H),1.22(s,3H).

[0207] HRMS(ESI)m / z492.19261[M + H] + 。

[0208] Example 8

[0209] In this example, (R)-2-((1-cyclohexyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-2-((1-cyclohexyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660223, and the structure is as follows:

[0210]

[0211] The preparation method of this example is the same as that of Example 1, except that: Compound 3 was replaced with the synthesized 1-cyclohexyl-1H-pyrazol-3-amine;

[0212] The preparation method of the said 1-cyclohexyl-1H-pyrazol-3-amine is the same as that of Compound 12 in Example 2, except that: Compound 10 was replaced with cyclohexanol.

[0213] Characterization results: 11H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.45 (s, 1H), 8.50 (s, 1H), 7.01 (s, 1H), 5.66 (s, 1H), 5.04 (s, 1H), 4.90 (s, 1H), 4.37 (s, 2H), 3.70 (s, 1H), 2.98 (s, 3H), 2.77 (s, 3H), 2.42 (s, 3H), 2.23 (s, 3H), 2.17 (s, 2H), 2.07 (s, 2H), 1.93 (s, 1H), 1.78 (s, 3H), 1.55 (s, 3H), 1.49 (s, 2H).

[0214] HRMS (ESI) m / z 464.2785 [M+H] + 。

[0215] Example 9

[0216] In this example, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(p-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(p-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660224, and the structure is as follows:

[0217]

[0218] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available 4-methyl iodobenzene.

[0219] Characterization results: 1 1H NMR (400 MHz, Trifluoroacetic acid-d) δ 8.87 (s, 1H), 7.88 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.61 (s, 2H), 5.51 (s, 1H), 4.60 (s, 1H), 4.24 (s, 1H), 4.06 (s, 1H), 3.45 (s, 1H), 2.69 (s, 3H), 2.37 (s, 3H), 2.27 (s, 3H), 2.10 (s, 1H), 1.97 (s, 1H), 1.76 (s, 1H), 1.23 (s, 4H).

[0220] HRMS(ESI) m / z 472.24695 [M+H] + 。

[0221] Example 10

[0222] In this example, (R)-2-((1-cyclopropyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-2-((1-cyclopropyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660226, and the structure is as follows:

[0223]

[0224] The preparation method of this example is the same as that of Example 1, except that: Compound 3 was replaced with the synthesized 1-cyclopropyl-1H-pyrazol-3-amine;

[0225] The preparation method of the said 1-cyclopropyl-1H-pyrazol-3-amine is the same as that of Compound 12 in Example 2, except that: Compound 10 was replaced with cyclopropanol.

[0226] Characterization results: 1 H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.39 (s, 1H), 8.21 (s, 1H), 7.04 (s, 2H), 5.84 (s, 1H), 4.98 (s, 1H), 4.59 (s, 1H), 4.47 (s, 1H), 4.01 (s, 1H), 3.83 (s, 1H), 3.10 (s, 3H), 2.81 (s, 3H), 2.51 (s, 1H), 2.36 (s, 1H), 2.11 (s, 1H), 1.63 (s, 3H), 1.55 (s, 5H).

[0227] HRMS(ESI) m / z 422.23065 [M+H] + 。

[0228] Example 11

[0229] In this example, (R)-2-((1-cyclopentyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared. Its English name is (R)-2-((1-cyclopentyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as compound 660227, and its structure is as follows:

[0230]

[0231] The preparation method of this example is the same as that of Example 1, except that: compound 3 is replaced with the synthesized 1-cyclopentyl-1H-pyrazol-3-amine;

[0232] The preparation method of the 1-cyclopentyl-1H-pyrazol-3-amine is the same as that of compound 12 in Example 2, except that: compound 10 is replaced with cyclopentanol.

[0233] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.43(s,1H),8.31(s,1H),7.08(s,1H),5.87(s,1H),5.21(s,1H),5.03(s,1H),4.60(s,1H),4.49(s,1H),3.82(s,1H),3.13(s,3H),2.84(s,3H),2.68(s,2H),2.53(d,J=9.0Hz,1H),2.35(s,3H),2.20(s,5H),1.66(s,3H).

[0234] HRMS(ESI)m / z450.26300[M+H] + 。

[0235] Example 12

[0236] In this example, (R)-2-((1-cyclobutyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-cyclobutyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, is denoted as compound 660228, and its structure is as follows:

[0237]

[0238] The preparation method of this example is the same as that of Example 1, except that: compound 3 is replaced with the synthesized 1-cyclobutyl-1H-pyrazol-3-amine;

[0239] The preparation method of the said 1-cyclobutyl-1H-pyrazol-3-amine is the same as that of compound 12 in Example 2, except that: compound 10 is replaced with cyclobutanol.

[0240] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.39(s,1H),8.29(s,1H),7.04(s,1H),5.87(s,1H),5.28(s,1H),4.99(s,1H),4.52(d,J=65.4Hz,2H),3.80(s,1H),3.55(s,1H),3.10(s,3H),2.93(s,2H),2.80(s,5H),2.51(s,1H),2.31(s,3H),2.09(s,1H),1.63(s,4H).

[0241] HRMS(ESI)m / z 436.24689[M+H] + .

[0242] Example 13

[0243] In this example, (R)-2-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, is denoted as Compound 660229, and its structure is as follows:

[0244]

[0245] The preparation method of this example is the same as that of Example 1, except that: Compound 2 is replaced with commercially available 4-chloroiodobenzene.

[0246] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.36(s,1H),8.38(s,1H),7.92(s,2H),7.88(s,2H),7.13(s,1H),6.91(s,1H),6.08(s,1H),5.14(s,1),4.76(s,1H),4.59(s,1H),3.96(s,1H),3.65(s,1H),3.26(s,3H),2.89(s,3H),2.64(s,1H),2.48(s,1H),2.30(s,1H),1.78(s,3H).

[0247] HRMS(ESI)m / z492.19205[M+H] + 。

[0248] Example 14

[0249] In this example, (R)-2-((1-(2-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(2-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one), is denoted as Compound 660230, and its structure is as follows:

[0250]

[0251] The preparation method of this example is the same as that of Example 1, except that compound 2 is replaced with commercially available 2-chloroiodobenzene.

[0252] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.30(s,1H),8.34(s,1H),7.88(s,2H),7.83(s,2H),7.76(q,J=7.4,6.1Hz,1H),7.05(s,1H),5.98(s,1H),5.05(s,1H),4.71(s,1H),4.50(s,1H),3.90(s,1H),3.52(s,1H),3.17(s,3H),2.81(s,3H),2.57(s,1H),2.41(s,1H),2.17(s,1H),1.69(s,3H).

[0253] HRMS(ESI)m / z492.19224[M+H] + .

[0254] Example 15

[0255] This example prepared (R)-2-((1-(2-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(2-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as compound 660234, and the structure is as follows:

[0256]

[0257] The preparation method of this example is the same as that of Example 1, except that compound 2 is replaced with commercially available 2-fluoroiodobenzene.

[0258] Characterization results: 11H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.31 (s, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 7.64 (s, 2H), 7.08 (s, 1H), 6.02 (s, 1H), 5.09 (s, 1H), 4.73 (s, 1H), 4.55 (s, 1H), 3.92 (s, 1H), 3.56 (s, 1H), 3.21 (s, 3H), 2.84 (s, 3H), 2.58 (s, 1H), 2.45 (s, 1H), 2.23 (s, 1H), 1.73 (s, 3H).

[0259] HRMS (ESI) m / z 476.22183 [M+H] + 。

[0260] Example 16

[0261] In this example, (R)-2-((1-(4-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared. Its English name is (R)-2-((1-(4-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660235, and the structure is as follows:

[0262]

[0263] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available 4-fluoroiodobenzene.

[0264] Characterization results: 1 1H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.28 (s, 1H), 8.28 (s, 1H), 7.89 (s, 2H), 7.51 (s, 2H), 7.06 (s, 1H), 6.01 (s, 1H), 5.07 (s, 1H), 4.70 (s, 1H), 4.52 (s, 1H), 3.90 (s, 1H), 3.57 (s, 1H), 3.19 (s, 3H), 2.82 (s, 3H), 2.76 (s, 1H), 2.56 (s, 1H), 2.40 (s, 1H), 2.20 (s, 1H), 1.71 (s, 3H).

[0265] HRMS(ESI) m / z 476.22236 [M+H] + 。

[0266] Example 17

[0267] In this example, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(o-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(o-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660237, and the structure is as follows:

[0268]

[0269] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available 2-methyl iodobenzene.

[0270] Characterization results: 1 H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.28 (s, 1H), 8.18 (s, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 7.67 (s, 2H), 7.05 (s, 1H), 5.97 (s, 1H), 5.05 (s, 1H), 4.68 (s, 1H), 4.53 (s, 1H), 3.87 (s, 1H), 3.16 (s, 3H), 2.80 (s, 3H), 2.53 (s, 4H), 2.46 (s, 2H), 2.20 (s, 1H), 1.69 (s, 4H).

[0271] HRMS(ESI) m / z 472.24646 [M+H] + 。

[0272] Example 18

[0273] In this example, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(m-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(m-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as compound 660238, has the following structure:

[0274]

[0275] The preparation method of this example is the same as that of Example 1, except that: compound 2 is replaced with commercially available 3-methyl iodobenzene.

[0276] Characterization results: 1 H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.34 (s, 1H), 8.38 (s, 1H), 7.73 (s, 3H), 7.65 (s, 1H), 7.09 (s, 1H), 6.05 (s, 1H), 5.07 (s, 1H), 4.71 (s, 1H), 4.56 (s, 1H), 3.91 (s, 1H), 3.20 (s, 3H), 2.85 (s, 3H), 2.77 (s, 3H), 2.57 (s, 1H), 2.42 (s, 1H), 2.21 (s, 1H), 1.72 (s, 4H), 1.15 (s, 2H).

[0277] HRMS (ESI) m / z 472.24656 [M+H] + .

[0278] Example 19

[0279] In this example, (R)-2-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as compound 660239, has the following structure:

[0280]

[0281] The preparation method of this example is the same as that of Example 1, except that: compound 3 is replaced by 3-aminopyrazole.

[0282] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.50(s,1H),8.50(s,1H),7.15(s,1H),6.04(s,1H),5.12(s,1H),4.58(s,2H),3.90(s,1H),3.20(s,3H),2.93(s,3H),2.81(s,1H),2.61(s,1H),2.44(s,1H),2.20(s,1H),1.94(s,1H),1.74(s,4H).

[0283] HRMS(ESI)m / z 382.19952[M+H] + 。

[0284] Example 20

[0285] In this example, (R)-3-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile was prepared. Its English name is (R)-3-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, denoted as compound 660240. The structure is as follows:

[0286]

[0287] The preparation method of this example is the same as that of Example 1, except that: compound 2 is replaced by commercially available 3-cyanoiodobenzene.

[0288] Characterization results: 11H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.33 (s, 1H), 8.46 (s, 2H), 8.32 (s, 1H), 8.09 (s, 2H), 7.09 (s, 1H), 6.91 (s, 1H), 6.00 (s, 1H), 5.09 (s, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 3.91 (s, 1H), 3.74 - 3.51 (m, 1H), 3.23 (s, 3H), 2.84 (s, 3H), 2.59 (s, 1H), 2.44 (s, 1H), 2.25 (s, 1H), 1.73 (s, 3H).

[0289] HRMS (ESI) m / z 483.22629 [M + H] + 。

[0290] Example 21

[0291] In this example, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660241, and the structure is as follows:

[0292]

[0293] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available 3-iodobenzotrifluoride.

[0294] Characterization results: 1 1H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.35 (s, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.05 (s, 2H), 7.12 (s, 1H), 6.05 (s, 1H), 5.13 (s, 1H), 4.77 (s, 1H), 4.60 (s, 1H), 3.94 (s, 1H), 3.25 (s, 3H), 2.87 (s, 3H), 2.58 (s, 1H), 2.46 (s, 1H), 2.28 (s, 1H), 1.93 (s, 1H), 1.78 (s, 4H).

[0295] HRMS(ESI) m / z 526.21919 [M+H] + 。

[0296] Example 22

[0297] In this example, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared. Its English name is (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660264, and its structure is as follows:

[0298]

[0299] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available 4-(trifluoromethyl)phenyl iodide.

[0300] Characterization results: 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.83 (s, 1H), 8.60 (s, 1H), 8.00 (s, 2H), 7.83 (d, J = 8.4 Hz, 2H), 6.89 (s, 1H), 6.22 (s, 1H), 5.35 (s, 1H), 4.36 (s, 1H), 3.75 (s, 1H), 2.99 (s, 1H), 2.37 (s, 4H), 2.22 (s, 2H), 1.71 (s, 2H), 1.43 (s, 2H), 0.95 (d, J = 48.5 Hz, 3H).

[0301] HRMS(ESI) m / z 526.21887 [M+H] + 。

[0302] Example 23

[0303] In this example, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, is denoted as Compound 660265, and its structure is as follows:

[0304]

[0305] The preparation method of this example is the same as that of Example 1, except that: Compound 2 is replaced with commercially available 2-iodobenzotrifluoride.

[0306] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ9.20(s,1H),8.25(s,1H),8.20 - 7.99(m,3H),7.91(s,1H),7.08(s,1H),6.90(s,1H),6.02(s,1H),5.10(s,1H),4.73(s,1H),4.58(s,1H),3.92(s,1H),3.57(s,1H),3.23(s,3H),2.83(s,3H),2.59(s,1H),2.43(s,1H),2.26(s,1H),1.74(s,3H).

[0307] HRMS(ESI)m / z 526.21944[M+H] + .

[0308] Example 24

[0309] In this example, (R)-4-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, with the English name (R)-4-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, is denoted as Compound 660270, and its structure is as follows:

[0310]

[0311] The preparation method of this example is the same as that of Example 1, except that compound 2 is replaced with commercially available 4-cyanoiodobenzene.

[0312] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.53(s,1H),8.69(s,1H),8.41(s,4H),7.28(s,1H),7.11(s,1H),6.22(s,1H),5.27(s,1H),4.88(s,1H),4.73(s,1H),4.10(s,1H),3.79(s,1H),3.40(s,3H),3.03(s,3H),2.76(s,1H),2.63(s,1H),2.42(s,1H),1.91(s,3H).

[0313] HRMS(ESI)m / z483.22671[M+H] + 。

[0314] Example 25

[0315] This example prepared (R)-2-((1-(2-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(2-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as compound 660271, and the structure is as follows:

[0316]

[0317] The preparation method of this example is the same as that of Example 1, except that compound 2 is replaced with commercially available 2-methoxyiodobenzene.

[0318] Characterization results: 11H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.52 (s, 1H), 8.61 (s, 1H), 7.98 (d, J = 30.9 Hz, 2H), 7.69 (s, 2H), 7.21 (s, 2H), 6.10 (s, 1H), 5.19 (s, 1H), 4.83 (s, 1H), 4.67 (s, 1H), 4.41 (s, 3H), 3.75 (s, 3H), 3.42 (s, 1H), 3.29 (s, 1H), 2.98 (s, 3H), 2.69 (s, 1H), 2.54 (s, 1H), 2.33 (s, 1H), 1.84 (s, 3H).

[0319] HRMS (ESI) m / z 488.24243 [M+H] + 。

[0320] Example 26

[0321] In this example, (R)-2-((1-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one was prepared, with the English name (R)-2-((1-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, denoted as Compound 660272, and the structure is as follows:

[0322]

[0323] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available 4-methoxyphenyl iodide.

[0324] Characterization results: 1 1H NMR (400 MHz, Trifluoroacetic acid-d) δ 9.42 (s, 1H), 8.41 (s, 1H), 8.01 (s, 2H), 7.62 (s, 2H), 7.18 (s, 1H), 7.01 (s, 1H), 6.12 (s, 1H), 5.20 (s, 1H), 4.82 (s, 1H), 4.67 (s, 1H), 4.44 (s, 3H), 4.03 (s, 1H), 3.32 (s, 3H), 2.94 (s, 3H), 2.68 (s, 1H), 2.55 (s, 1H), 2.35 (s, 1H), 1.82 (s, 3H).

[0325] HRMS(ESI) m / z 488.24260 [M+H] + 。

[0326] Example 27

[0327] In this example, (R)-2-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile was prepared. Its English name is (R)-2-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, denoted as Compound 660273, and its structure is as follows:

[0328]

[0329] The preparation method of this example is the same as that of Example 1, except that: Compound 2 was replaced with commercially available 2-cyanoiodobenzene.

[0330] Characterization results: 1 HNMR(400MHz, Trifluoroacetic acid-d) δ 9.37(s, 1H), 8.59(s, 1H), 8.37(s, 1H), 8.30(s, 1H), 8.14(s, 1H), 8.01(s, 1H), 7.20(s, 1H), 7.04(s, 1H), 6.12(s, 1H), 5.17(s, 1H), 4.82(s, 1H), 4.66(s, 1H), 4.02(s, 1H), 3.73(s, 1H), 3.32(s, 3H), 2.97(s, 3H), 2.68(s, 1H), 2.54(s, 1H), 2.35(s, 1H), 1.83(s, 3H).

[0331] HRMS(ESI) m / z 483.22734 [M+H] + 。

[0332] Example 28

[0333] In this example, (R)-2-((1-(2-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(2-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, is denoted as compound 660274, and its structure is as follows:

[0334]

[0335] The preparation method of this example is the same as that of Example 1, except that: compound 2 is replaced with commercially available 2-hydroxyiodobenzene.

[0336] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.39(s,1H),8.48(s,1H),7.80(s,2H),7.51(s,2H),7.12(s,2H),6.02(s,1H),5.09(s,1H),4.74(s,1H),4.54(s,1H),3.87(s,1H),3.19(s,3H),2.88(s,3H),2.56(s,1H),2.44(s,1H),2.23(s,1H),1.70(s,3H).

[0337] HRMS(ESI)m / z474.22711[M+H] + .

[0338] Example 29

[0339] In this example, (R)-2-((1-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, with the English name (R)-2-((1-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, is denoted as compound 660275, and its structure is as follows:

[0340]

[0341] The preparation method of this example is the same as that of Example 1, except that compound 2 is replaced with commercially available 4-hydroxyiodobenzene.

[0342] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ9.37(s,1H),8.34(s,1H),7.89(s,2H),7.50(s,2H),7.13(s,1H),6.93(s,1H),6.06(s,1H),5.12(s,1H),4.77(s,1H),4.61(s,1H),3.96(s,1H),3.25(s,3H),2.89(s,3H),2.62(s,1H),2.47(s,1H),2.28(s,1H),1.77(s,3H).

[0343] HRMS(ESI)m / z 496.209[M+Na] + 。

[0344] Test Example 1

[0345] The compounds prepared in Examples 1 to 29 were tested for their cell growth inhibitory effects. According to the test results, the half inhibitory concentration (IC 50 ) values were calculated, and the results are shown in Table 1.

[0346] Table 1 Half inhibitory concentrations of the compounds in Examples 1 to 29

[0347]

[0348] As can be seen from Table 1, the compounds of the present invention can significantly inhibit the proliferation of Ba / F3-CCDC6-RET V804M and Ba / F3-CCDC6-RET G810C cells, and the inhibition rate is positively correlated with the drug concentration.

[0349] Test Example 2

[0350] The compounds prepared in Examples 1 to 29 were tested for solubility. The test method was the observation method. The results showed that the compounds of the present invention could dissolve well in DMSO and had good solubility.

[0351] As can be seen from the above examples, the compounds provided by the present invention can selectively inhibit the activity of RET, have inhibitory activity against mutant RET, and have good pharmacokinetic properties.

[0352] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. Other embodiments can also be obtained based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A heterocyclic compound, characterized in that, It includes one of 2-aminopyrazolopyrimidinone compounds or their prodrugs, pharmaceutically acceptable salts, prodrugs of pharmaceutically acceptable salts, stereoisomers and prodrugs of stereoisomers. The structure of the 2-aminopyrazolopyrimidinone compound is shown in Formula I: In Formula I, X is CH or N; W is CH or N; L is a group of Formula A, a group of Formula B, a group of Formula C, C5-C10 monocyclic alkyl, substituted C5-C10 monocyclic alkyl, C5-C10 bridged cycloalkyl, substituted C5-C10 bridged cycloalkyl, C5-C10 fused cycloalkyl or substituted C5-C10 fused cycloalkyl; -(CH2) n NH - formula A; In Formula A, n is 1-8, and -CH2- is connected to X; in Formula B and Formula C, n is 0, 1, 2 or 3; R1 is H, C1-C3 alkyl, substituted C1-C3 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, a group of Formula H, a group of Formula J, a group of Formula K or a group of Formula M; In Formula H, Formula J, Formula K and Formula M, n is 0, 1 or 2, and A1, A2, A3, A4 and A5 are independently: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C6 fluoroalkyl, substituted C1-C6 fluoroalkyl, C1-C6 heteroatom-containing alkyl, substituted C1-C6 heteroatom-containing alkyl, -NO2, -CN, -COOH, -CONH2, a group of Formula N, a 5-membered heterocyclic group containing one or more nitrogen atoms, a substituted 5-membered heterocyclic group containing one or more nitrogen atoms, a 6-membered heterocyclic group containing one or more nitrogen atoms, a substituted 6-membered heterocyclic group containing one or more nitrogen atoms, a 5-12-membered saturated carbon ring is formed between any two adjacent substitution sites, a 5-12-membered saturated heterocyclic ring containing 1-3 heteroatoms is formed between any two adjacent substitution sites, or an ester, amide, sulfone, sulfoxide or urea formed by C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C6 fluoroalkyl, substituted C1-C6 fluoroalkyl, C1-C6 heteroatom-containing alkyl, substituted C1-C6 heteroatom-containing alkyl, -NO2, -CN, -COOH, -CONH2, a group of Formula N, a 5-membered heterocyclic group containing one or more nitrogen atoms, a substituted 5-membered heterocyclic group containing one or more nitrogen atoms, a 6-membered heterocyclic group containing one or more nitrogen atoms, a substituted 6-membered heterocyclic group containing one or more nitrogen atoms; In Formula N, R4 and R5 are independently C1-C5 alkyl, substituted C1-C5 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, a 4-8-membered saturated heterocyclic or aromatic heterocyclic ring containing 1-3 heteroatoms formed by cyclization of R4 and R5, or a substituted 4-8-membered saturated heterocyclic or aromatic heterocyclic ring containing 1-3 heteroatoms formed by cyclization of R4 and R5; R2 is H, C1-C4 alkyl, C1-C4 alkoxy, substituted C1-C4 alkoxy, a group of Formula D, a group of Formula E, a group of Formula F or a group of Formula G; (CH2) n Y-type G; In Formulas D to F, R3 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclopentyl or cyclohexyl; in Formula G, n is 0 to 6, and Y is halogen, hydroxy, amino, (N-methyl)amino or (N,N-dimethyl)amino.

2. The heterocyclic compound according to claim 1, characterized in that In L, the C5-C10 monocyclic alkyl group is one or more of cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl; the substituted C5-C10 monocyclic alkyl group is one or more of 2-methylcyclopentane, 3-methylcyclopentane, 2-methylcyclohexane and 3-methylcyclohexane.

3. The heterocyclic compound according to claim 1, wherein In R1, the C1-C3 alkyl group is methyl, ethyl, n-propyl or isopropyl; the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the substituted C3-C6 cycloalkyl group is methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl or 2-ethyl-cyclopentyl.

4. The heterocyclic compound according to claim 1 or 3, characterized in that, In A1, A2, A3, A4 and A5, the halogen includes one or more of fluorine, chlorine, bromine and iodine; the C1-C6 alkyl group includes one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl; the C3-C6 cycloalkyl group includes one or more of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the substituted C3-C6 cycloalkyl group includes one or more of methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl and 2-ethyl-cyclopentyl; the C1-C4 alkoxy group includes one or more of methoxy, ethoxy, propoxy and butoxy; the substituted C1-C4 alkoxy group includes one or more of N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-acetylpiperazinyl)ethoxy, 2-morpholinoethoxy, 2-thiomorpholinoethoxy, 2-piperidinoethoxy and 2-pyrrolidinylethoxy; the C1-C6 fluoroalkyl group includes one or more of trifluoromethyl, difluoromethyl and fluoromethyl; the C1-C6 heteroatom-containing alkyl group includes one or more of pyrrolidinyl, R-pyridyl, S-pyridyl, R-piperidyl and S-piperidyl; the 5-membered heterocyclic group containing more than 1 nitrogen atom includes one or more of pyrrolidinyl, Formula 1-1 group, Formula 1-2 group, Formula 1-3 group, Formula 1-4 group, Formula 1-5 group, Formula 1-6 group, Formula 1-7 group, Formula 1-8 group, Formula 1-9 group, Formula 1-10 group, Formula 1-11 group, Formula 1-12 group, Formula 1-13 group and Formula 1-14 group; The substituted 5-membered heterocyclic group containing more than 1 nitrogen atom has 1 to 3 substituents; the substituted 5-membered heterocyclic group containing more than 1 nitrogen atom includes one or two of 3-N,N-dimethylpyrrolidinyl and 1-methylimidazolyl; the 6-membered heterocyclic group containing more than 1 nitrogen atom can be one or more of Formula 2-1 group, Formula 2-2 group, Formula 2-3 group, Formula 2-4 group, morpholino, thiomorpholino and piperidyl; The substituted 6-membered heterocyclic group containing one or more nitrogen atoms has 1 to 3 substituents; the substituted 6-membered heterocyclic group containing one or more nitrogen atoms includes one or more of N-methylpiperazinyl, 4-N,N-dimethylpiperidinyl, 4-acetylpiperazinyl, 1-methyl-4-(piperazine-4-substituted)piperidinyl, 4-(4-methylpiperazine-1-substituted)methyl, 1-methylpiperidin-4-ylamine, 4-piperazin-2-one group and 1-methyl-4-piperazin-2-one group; the saturated carbocyclic ring formed between any two adjacent substitution sites is a 5- to 12-membered saturated carbocyclic ring including one or two of 3-methylhexahydropyrimidinyl and 3-dimethylimidazolidinyl; the saturated heterocyclic ring containing 1 to 3 heteroatoms formed between any two adjacent substitution sites is a 5- to 12-membered saturated heterocyclic ring including one or more of thiomorpholinyl and tetrahydrothiazolyl.

5. The heterocyclic compound according to claim 1 or 3, characterized in that, Among R4 and R5, the C1-C5 alkyl group includes one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and pentyl; the C3-C6 cycloalkyl group includes one or more of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the substituted C3-C6 cycloalkyl group includes one or more of methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, and 2-ethyl-cyclopentyl; the 4- to 8-membered saturated heterocyclic or aromatic heterocyclic ring formed by the cyclization of R4 and R5 and containing 1 to 3 heteroatoms includes imidazolyl, indolyl, isopyrazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, pyrazolyl, thienyl, triazolyl, 1-pyrrolidone, 2- piperidone, 2-pyrimidinone, 2-pyrrolidone, triazolyl, 1,4-dioxanyl, pyrrolidinyl, dihydro imidazolyl, dihydroisoxazolyl, dihydroisopyrazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydropyrazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuryl, tetrahydrothienyl, or their N-oxides.

6. The heterocyclic compound according to claim 1, characterized in that, The structures of the heterocyclic compounds are shown in Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII:

7. The heterocyclic compound according to claim 1 or 2, characterized in that, The heterocyclic compounds are (R)-2-((1-(3-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-ethyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(3-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclohexyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(p-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclopropyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclopentyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-cyclobutyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(2-chlorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,[2,3-d]Pyrimidin-7(8H)-one, (R)-2-((1-(2-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1-(4-fluorophenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(o-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(m-tolyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-3-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-4-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-2-((1-(4-methoxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, (R)-2-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-2-((1-(2-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]Pyrimidin-7(8H)-one or (R)-2-((1-(4-hydroxyphenyl)-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one., 8. A method for preparing the heterocyclic compound according to any one of claims 1 to 7, characterized in that, Comprising the following steps: Mix compound A and compound B and successively carry out a first coupling reaction and a first substitution reaction to obtain compound C; carry out a reduction reaction on the compound C to obtain compound D; Alternatively, mix compound J and compound K to carry out a second coupling reaction to obtain compound D; Mix compound E and compound F to carry out a second substitution reaction to obtain compound G; mix the compound G and trans-crotonic acid and successively carry out a Heck coupling reaction and a ring-closing reaction to obtain compound H; Mix the compound D and compound H, carry out a third substitution reaction, then deprotect and carry out a nucleophilic substitution reaction with an acyl chloride to obtain the 2-aminopyrazolopyrimidinone compound; Saltify the 2-aminopyrazolopyrimidinone compound to obtain a pharmaceutically acceptable salt of the 2-aminopyrazolopyrimidinone compound; Carry out isomer transformation on the 2-aminopyrazolopyrimidinone compound to obtain a stereoisomer of the 2-aminopyrazolopyrimidinone compound; The structures of the compounds A, D-H, J-K are shown in Formula A, D-H, J-K, the compound B includes one or more of the compound of Formula B and a halogenated benzene; the compound C includes one or more of the compound of Formula C, an aminopyrazole and a cycloalkylpyrazole; 9. Use of the heterocyclic compound according to any one of claims 1 to 7 or the heterocyclic compound obtained by the preparation method according to claim 8 in the preparation of a RET inhibitor, a drug for preventing tumor recurrence, a drug for preventing tumors or a drug for treating tumors.

10. A pharmaceutical composition for preventing and treating tumors, characterized in that, Comprising an active ingredient, the active ingredient includes the heterocyclic compound according to any one of claims 1 to 7 or the heterocyclic compound obtained by the preparation method according to claim 8.

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