A heterocyclic compound, a preparation method and application thereof, and a pharmaceutical composition for preventing and treating tumors

Abstract

This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a heterocyclic compound, its preparation method, application, and pharmaceutical composition for preventing and treating tumors. The heterocyclic compound provided by this invention exhibits significantly enhanced activity, selectively inhibiting RET activity, overcoming the drug resistance problem of existing RET inhibitors, possessing good pharmacokinetic properties, better solubility, reducing treatment costs for patients, and increasing patients' access to new drugs. This invention also provides the application of the heterocyclic compound described above or the heterocyclic compound prepared by the method described above in the preparation of RET inhibitors, tumor prevention drugs, or tumor treatment drugs. The compound provided by this invention can effectively inhibit the growth of various tumor cells, especially inhibiting RET kinase and selectively inhibiting RET lung cancer cells.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to a heterocyclic compound, its preparation method, application, and a pharmaceutical composition for preventing and treating tumors. Background Technology

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

[0003] The RET gene, a transfection rearrangement gene, is an oncogene. Abnormalities such as point mutations, gene fusions, and overexpression are closely related to the occurrence, development, and poor prognosis of various tumors. RET gene point mutations are commonly found in medullary thyroid carcinoma (MTC), while RET gene fusion mutations frequently occur in lung cancer, papillary thyroid carcinoma, esophageal cancer, and other tumors. RET gene point mutations and gene fusions lead to ligand-independent autophosphorylation of RET kinase, thereby mediating tumorigenesis and development. RET kinase has become an important driver of tumors such as medullary thyroid carcinoma and non-small cell lung cancer, and has been identified as a reliable target for tumor therapy.

[0004] In recent years, significant progress has been made in the development of selective RET inhibitors. Lilly developed serpercatinib (LOXO-292, 2020 / 5), and Blueprint Medicines developed pralsetinib (BLU-667, 2020 / 7), both of which have been approved for marketing. Although these two selective RET inhibitors have achieved some clinical efficacy, their activity needs improvement, and patients have rapidly developed resistance after using them. Summary of the Invention

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

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention provides a heterocyclic compound comprising one of a 2-aminopyrazolidinepyridone compound or a prodrug thereof, a pharmaceutically acceptable salt, a prodrug of a pharmaceutically acceptable salt, a stereoisomer, and a prodrug of a stereoisomer, wherein the structure of the 2-aminopyrazolidinepyridone 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, Formula B, Formula C, C5-C10 monocyclic alkyl, substituted C5-C10 monocyclic alkyl, C5-C10 bridged cyclic alkyl, substituted C5-C10 bridged cyclic alkyl, C5-C10 fused cyclic alkyl, or substituted C5-C10 fused cyclic alkyl.

[0010] -(CH2) n NH-form A;

[0011] In formula A, n is 1 to 8, and -CH2- is connected to X; in formulas B and 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, H group, J group, K group or M group;

[0013]

[0014] In formulas H, J, K, and 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, N-group, 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, or a group formed between any two adjacent substitution sites. The following are esters, amides, sulfones, sulfoxides, or ureas formed between any two adjacent substitution sites: 5- to 12-membered saturated carbon rings; 5- to 12-membered saturated heterocycles containing 1 to 3 heteroatoms formed between any two adjacent substitution sites; or C1- to C6 alkyl groups, substituted C1- to C6 alkyl groups, C3- to C6 cycloalkyl groups, substituted C3- to C6 cycloalkyl groups, C1- to C4 alkoxy groups, substituted C1- to C4 alkoxy groups, C1- to C6 fluoroalkyl groups, substituted C1- to C6 fluoroalkyl groups, C1- to C6 heteroatom-containing alkyl groups, substituted C1- to C6 heteroatom-containing alkyl groups, -NO2, -CN, -COOH, -CONH2, N-groups, 5-membered heterocyclic groups containing 1 or more nitrogen atoms, substituted 5-membered heterocyclic groups containing 1 or more nitrogen atoms, 6-membered heterocyclic groups containing 1 or more nitrogen atoms, and substituted 6-membered heterocyclic groups containing 1 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, 4-8 membered saturated heterocycles or aromatic heterocycles containing 1-3 heteroatoms formed by the cyclization of R4 and R5, and substituted 4-8 membered saturated heterocycles or aromatic heterocycles containing 1-3 heteroatoms formed by the cyclization of R4 and R5.

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

[0018] (CH2) n Y-type 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, hydroxyl, amino, (N-methyl)amino, or (N,N-dimethyl)amino.

[0020] Preferably, in L, the C5-C10 monocycloalkyl group is one or more of cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl; and the substituted C5-C10 monocycloalkyl 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; and 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 N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-ethyl-... The C1-C6 fluorinated alkyl group includes one or more of the following: acylpiperazinylethoxy, 2-morpholinylethoxy, 2-thiophenolinylethoxy, 2-piperidinylethoxy, and 2-tetrahydropyrrolylethoxy; the C1-C6 fluorinated alkyl group includes one or more of the following: trifluoromethyl, difluoromethyl, and monofluoromethyl; the C1-C6 heteroatom-containing alkyl group includes one or more of the following: pyrrolyl, R-pyridyl, S-pyridyl, R-piperidinyl, and S-piperidinyl; the 5-membered heterocyclic group containing one or more nitrogen atoms includes one or more of the following: tetrahydropyrrolyl, formula 1-1, formula 1-2, formula 1-3, formula 1-4, formula 1-5, formula 1-6, formula 1-7, formula 1-8, formula 1-9, formula 1-10, formula 1-11, formula 1-12, formula 1-13, and formula 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 two of 3-N,N-dimethyltetrahydropyrrole and 1-methylimidazolyl; the 6-membered heterocyclic group containing one or more nitrogen atoms can be one or more of the following: Formula 2-1 group, Formula 2-2 group, Formula 2-3 group, Formula 2-4 group, morpholino, thiophenolino, 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-amino, 4-piperazin-2-one, and 1-methyl-4-piperazin-2-one; the 5- to 12-membered saturated carbon ring formed between any two adjacent substitution sites includes one or two of 3-methylhexahydropyrimidinyl and 3-dimethylimidazolyl; the 5- to 12-membered saturated heterocycle containing one to three heteroatoms formed between any two adjacent substitution sites includes one or more of thiomorpholinyl and tetrahydrothiazolyl.

[0027] Preferably, in 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 4-8 membered saturated heterocycle or aromatic heterocycle containing 1-3 heteroatoms formed by the cyclization of R4 and R5 includes imidazole, indolyl, isopyrazolyl, isoxazolyl, oxadiazolyl, ox ... 1-N-yl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, quinoxalinyl, tetrazolyl, thiadiazolyl, pyrazolyl, thiopheneyl, triazolyl, 1-pyrrolidone, 2-piperidinone, 2-pyrimidinone, 2-pyrrolidone, triazolyl, 1,4-dioxane, pyrroloyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisopyrazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrroloyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydropyrazolyl, dihydrothiopheneyl, dihydrotriazolyl, dihydroazacyclobutane, tetrahydrofuranyl, tetrahydrothiopheneyl or their N-oxides.

[0028] Preferably, the structure of the heterocyclic compound is as 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)pyrimido[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(p-tolyl)-1H-pyrazol-3-yl)amino)pyridyl[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)pyridinyl[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-(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[2,3-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)pyridyl[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl (R)-8-(1-propionylpiperidin-3-yl)-2-((1-(m-tolyl)-1H-pyrazol-3-yl)amino)pyridyl[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrimido[2,3-d]pyrimidin-7(8H)-one, (R)-3-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyridin[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(3-(trifluoromethyl) (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-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-pyrazole-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-dihydropyridine [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 above, comprising the following steps:

[0032] Compound A and compound B are mixed and subjected to a first coupling reaction and a first substitution reaction in sequence to obtain compound C; compound C is then subjected to a reduction reaction to obtain compound D; or, compound J and compound K are mixed and subjected to a second coupling reaction to obtain compound D.

[0033] Compound E was mixed with compound F and subjected to a second substitution reaction to obtain compound G; compound G was then mixed with trans-crotonic acid and subjected to Heck coupling and ring-closing reactions in sequence to obtain compound H;

[0034] After mixing compound D and compound H and carrying out a third substitution reaction, the compound was deprotected and then carried out a nucleophilic substitution reaction with an acyl chloride to obtain the 2-aminopyrazolepyrimidine pyridinone compound.

[0035] The 2-aminopyrazolidinepyridone compound is salted to obtain a pharmaceutically acceptable salt of the 2-aminopyrazolidinepyridone compound;

[0036] The 2-aminopyrazolidinepyridone compound was subjected to isomerization to obtain the stereoisomer of the 2-aminopyrazolidinepyridone compound;

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

[0038]

[0039] The present invention also provides the use of the heterocyclic compounds described in the above-described schemes or the heterocyclic compounds obtained by the preparation methods described in the above-described schemes 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, comprising an active ingredient, said active ingredient comprising the heterocyclic compound described in the above-described scheme or the heterocyclic compound obtained by the preparation method described in the above-described scheme.

[0041] This invention provides a heterocyclic compound. The heterocyclic compound provided by this invention exhibits significantly enhanced activity, can bind to the orthomeric site (ATP-binding pocket) of RET mutant proteins, and forms hydrogen bonds with 892Asp and Ala707, thereby selectively inhibiting RET activity. This overcomes the drug resistance problem of existing RET inhibitors, possesses groups with better solubility, resulting in improved pharmacokinetic properties, reduced treatment costs for patients, and increased access to new drugs.

[0042] This invention also provides a method for preparing the heterocyclic compounds described above. The preparation method provided by this invention is simple in steps, safe, easy to operate, feasible, and stable, and is suitable for industrial production.

[0043] This invention also provides the application of the heterocyclic compounds described in the above-described schemes or the heterocyclic compounds prepared by the above-described schemes in the preparation of RET inhibitors, drugs for preventing tumor recurrence, drugs for preventing tumors, or drugs for treating tumors. The compounds provided by this invention can effectively inhibit the growth of various tumor cells, especially inhibiting RET kinase and selectively inhibiting RET lung cancer cells.

[0044] This invention also provides a pharmaceutical composition for the prevention and treatment of tumors, comprising an active ingredient, said active ingredient comprising the heterocyclic compound described in the above-described scheme or a heterocyclic compound obtained by the preparation method described in the above-described scheme. The heterocyclic compound provided by this invention can be used to prepare antitumor drugs and can overcome the drug resistance problems induced by existing drugs (such as gefitinib, erlotinib, serpercatinib (LOXO-292), and pralsetinib (BLU-667), especially serpercatinib and pralsetinib). The heterocyclic compound provided by this invention can also be used to prevent postoperative recurrence of various tumors, further consolidate treatment, prolong the survival of cancer patients, improve their quality of life, and inhibit tumor progression. Detailed Implementation

[0045] This invention provides a heterocyclic compound comprising one of a 2-aminopyrazolidinepyridone compound or a prodrug thereof, a pharmaceutically acceptable salt, a prodrug of a pharmaceutically acceptable salt, a stereoisomer, and a prodrug of a stereoisomer, wherein the structure of the 2-aminopyrazolidinepyridone 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, Formula B, Formula C, C5-C10 monocyclic alkyl, substituted C5-C10 monocyclic alkyl, C5-C10 bridged cyclic alkyl, substituted C5-C10 bridged cyclic alkyl, C5-C10 fused cyclic alkyl, or substituted C5-C10 fused cyclic alkyl.

[0048] -(CH2) n NH-form A;

[0049] In formula A, n is 1 to 8, and -CH2- is connected to X; in formulas B and 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, H group, J group, K group or M group;

[0051]

[0052] In formulas H, J, K, and 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, N-group, 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, or a group formed between any two adjacent substitution sites. The following are esters, amides, sulfones, sulfoxides, or ureas formed between any two adjacent substitution sites: 5- to 12-membered saturated carbon rings; 5- to 12-membered saturated heterocycles containing 1 to 3 heteroatoms formed between any two adjacent substitution sites; or C1- to C6 alkyl groups, substituted C1- to C6 alkyl groups, C3- to C6 cycloalkyl groups, substituted C3- to C6 cycloalkyl groups, C1- to C4 alkoxy groups, substituted C1- to C4 alkoxy groups, C1- to C6 fluoroalkyl groups, substituted C1- to C6 fluoroalkyl groups, C1- to C6 heteroatom-containing alkyl groups, substituted C1- to C6 heteroatom-containing alkyl groups, -NO2, -CN, -COOH, -CONH2, N-groups, 5-membered heterocyclic groups containing 1 or more nitrogen atoms, substituted 5-membered heterocyclic groups containing 1 or more nitrogen atoms, 6-membered heterocyclic groups containing 1 or more nitrogen atoms, and substituted 6-membered heterocyclic groups containing 1 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, 4-8 membered saturated heterocycles or aromatic heterocycles containing 1-3 heteroatoms formed by the cyclization of R4 and R5, and substituted 4-8 membered saturated heterocycles or aromatic heterocycles containing 1-3 heteroatoms formed by the cyclization of R4 and R5.

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

[0056] (CH2) n Y-type 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, hydroxyl, amino, (N-methyl)amino, or (N,N-dimethyl)amino.

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

[0059] In this invention, the upper end of L is connected to X, and the lower end of L is connected to R. I The connection can specifically be:

[0060]

[0061] More specifically:

[0062]

[0063] To be more specific, it can be:

[0064]

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

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

[0067] In this invention, in A1, A2, A3, A4 and A5, the C1 to 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 may be methyl; the C1 to C6 alkyl group may be C1 to C3 alkyl group.

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

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

[0070] In this invention, in A1, A2, A3, A4 and A5, the C1 to C4 alkoxy groups may include one or more of methoxy, ethoxy, propoxy and butoxy groups.

[0071] In this invention, the substituted C1-C4 alkoxy group in A1, A2, A3, A4, and A5 may include one or more of N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy, 2-(N-methylpiperazinyl)ethoxy, 2-(N-acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 2-thiophenolinylethoxy, 2-piperidinylethoxy, and 2-tetrahydropyrroleylethoxy.

[0072] In this invention, among A1, A2, A3, A4 and A5, the C1 to C6 fluoroalkyl groups may include one or more of trifluoromethyl, difluoromethyl and monofluoromethyl.

[0073] In this invention, in A1, A2, A3, A4 and A5, the C1 to C6 heteroatom-containing alkyl groups may include one or more of pyrrolidinyl, R-pyridyl, S-pyridyl, R-piperidinyl and S-piperidinyl.

[0074] In this 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 the following: tetrahydropyrrole group, 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;

[0075]

[0076] In this 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 two of 3-N,N-dimethyltetrahydropyrrole and 1-methylimidazolyl.

[0077] In this invention, in A1, A2, A3, A4 and A5, the 6-membered heterocyclic group containing one or more nitrogen atoms can be one or more of the following: Formula 2-1 group, Formula 2-2 group, Formula 2-3 group, Formula 2-4 group, morpholino, thiophenolino and piperidinyl.

[0078]

[0079]

[0080] In this invention, in 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-substituted)piperidinyl, 4-(4-methylpiperazin-1-substituted)methyl, 1-methylpiperidin-4-amino, 4-piperazin-2-one, and 1-methyl-4-piperazin-2-one.

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

[0082] In this invention, the 5- to 12-membered saturated heterocycle containing 1 to 3 heteroatoms formed between any two adjacent substitution sites in A1, A2, A3, A4, and A5 may include one or more of thiomorpholino and tetrahydrothiazolyl groups.

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

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

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

[0086] In this invention, R4 and R5, the 4-8 membered saturated heterocycle or aromatic heterocycle containing 1-3 heteroatoms formed by the cyclization of R4 and R5, may include imidazole, indolyl, isopyrazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinoxolinyl, tetrazolyl, thiadiazolyl, pyrazolyl, thiophene, triazolyl, 1-pyrrolidone, 2 -piperidinone, 2-pyrimidinone, 2-pyrrolidone, triazolyl, 1,4-dioxyl, pyrrolyl, dihydroimidazolyl, dihydroisooxazolyl, dihydroisopyrazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrroleyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydropyrazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazacyclobutane, tetrahydrofuranyl, tetrahydrothiophenyl or its N-oxide.

[0087] In this invention, the substituents of the substituted 4-8 membered saturated heterocycles or aromatic heterocycles containing 1-3 heteroatoms can be implemented by carbon atoms or heteroatoms.

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

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

[0090] In this invention, R2 can specifically be a group of formula D, a group of formula E, or a group of formula F, and more specifically, it can be a group of formula D.

[0091] In this invention, the structure of the heterocyclic compound can be as shown in Formula II or Formula III:

[0092]

[0093] Specifically, it can be shown in Equation IV or Equation V:

[0094]

[0095] More specifically, it can be shown in Equation VI or Equation VII:

[0096]

[0097] In specific embodiments 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)pyridyl[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-pyrimidin ...1-cyclopentyl-1H-pyrimidin-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3- (R)-2-((1-cyclobutyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyridinyl[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-(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[2,3-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)pyridyl[2,3-d]pyrimidin-7(8H)-one, (R)-5-methyl (R)-8-(1-propionylpiperidin-3-yl)-2-((1-(m-tolyl)-1H-pyrazol-3-yl)amino)pyridyl[2,3-d]pyrimidin-7(8H)-one, (R)-2-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrimido[2,3-d]pyrimidin-7(8H)-one, (R)-3-(3-((5-methyl-7-oxo-8-(1-propionylpiperidin-3-yl)-7,8-dihydropyridin[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)benzonitrile, (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(3-(trifluoromethyl) (R)-5-methyl-8-(1-propionylpiperidin-3-yl)-2-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-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-pyrazole-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-dihydropyridine [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 this invention, in the heterocyclic compounds, when any substituent (e.g., R1) appears more than once in any substance, the definition of each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituents are permitted, provided that such combinations stabilize the heterocyclic compound. The line drawn from the substituent into the ring system indicates that the bond can be attached to any substituted ring atom. If the ring system is polycyclic, it means that such a bond is attached only to any suitable carbon atom of a neighboring ring. It is to be understood that those skilled in the art can choose the substituents and substitution patterns of the heterocyclic compounds of this invention to provide chemically stable compounds that can be easily synthesized from readily available starting materials using conventional techniques and the methods proposed in this invention. If a substituent is itself replaced 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 this invention, "alkyl" and "alkylene" refer to saturated aliphatic hydrocarbon groups, including branched and straight-chain groups having a specific number of carbon atoms. "Cycloalkyl" refers to monocyclic saturated aliphatic hydrocarbon groups having a specific number of carbon atoms.

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

[0101] Since the deprotonated acidic portion of the compound, such as the carboxyl group, can be anionic under physiological conditions, and this charge can then be balanced by the protonated or alkylated basic portion, such as the tetravalent nitrogen atom, which carries a cation, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.

[0102] The present invention also provides a method for preparing the heterocyclic compound described above, comprising the following steps:

[0103] Compound A and compound B are mixed and subjected to a first coupling reaction and a first substitution reaction in sequence to obtain compound C; compound C is then subjected to a reduction reaction to obtain compound D; or, compound J and compound K are mixed and subjected to a second coupling reaction to obtain compound D.

[0104] Compound E was mixed with compound F and subjected to a second substitution reaction to obtain compound G; compound G was then mixed with trans-crotonic acid and subjected to Heck coupling and ring-closing reactions in sequence to obtain compound H;

[0105] After mixing compound D and compound H and carrying out a third substitution reaction, the compound was deprotected and then carried out a nucleophilic substitution reaction with an acyl chloride to obtain the 2-aminopyrazolepyrimidine pyridinone compound.

[0106] The 2-aminopyrazolidinepyridone compound is salted to obtain a pharmaceutically acceptable salt of the 2-aminopyrazolidinepyridone compound;

[0107] The 2-aminopyrazolidinepyridone compound was subjected to isomerization to obtain the stereoisomer of the 2-aminopyrazolidinepyridone compound;

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

[0109]

[0110] In this invention, compound A and compound B are mixed and subjected to a first coupling reaction and a first substitution reaction in sequence to obtain compound C. In this invention, the halogenated benzene may include one or more of iodobenzene, fluoroiodobenzene, chloroiodobenzene, cyanoiodobenzene, hydroxyiodobenzene, methyliodobenzene, methoxyiodobenzene, and trifluoromethyliodobenzene; 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; and the trifluoromethyliodobenzene may include one or more of 2-trifluoromethyliodobenzene, 3-trifluoromethyliodobenzene, and 4-trifluoromethyliodobenzene.

[0111] In this invention, the molar ratio of compound A to compound B can be 0.9 to 1.8:1, specifically 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 this invention, the temperature of the first coupling reaction can be 20–35°C, specifically 20°C, 25°C, 30°C, or 35°C, and the reaction time can be 10–14 hours, specifically 10 hours, 11 hours, 12 hours, 13 hours, or 14 hours. The first coupling reaction can be carried out in a protective atmosphere, which can be an inert gas, specifically 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 an azo compound and a metal salt. The azo compound can be di-tert-butyl azodicarbonate. The metal salt can include one or more of Cs₂CO₃ and CuBr. The ligand can be phosphine. Triphenylphosphine; the organic solvent may include one or more of furan solvents and amide solvents; the furan solvent may be tetrahydrofuran; the amide solvent may be N,N-dimethylformamide; the molar ratio of compound A to the ligand may be 1:1; the molar ratio of compound A to the catalyst may 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 may 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 this invention, the temperature of the first substitution reaction can be 110–130°C, specifically 110°C, 120°C, or 130°C, and the reaction time can be 10–14 hours, specifically 10 hours, 11 hours, 12 hours, 13 hours, or 14 hours. 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 an azo compound and a metal salt. The azo compound can be di-tert-butyl azodicarbonate. The metal salt can include one or more of Cs₂CO₃ and CuBr. The organic solvent can include furans. The solvent is one or more of a solvent and an amide solvent; the furan solvent may be tetrahydrofuran; the amide solvent may be N,N-dimethylformamide; the molar ratio of compound A to the catalyst may 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 may 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 this invention, the first substitution reaction may further include sequential extraction, organic phase drying, and purification of the obtained product; the extraction reagent may be dichloromethane and water; the drying may be sequential drying with anhydrous Na2SO4 and filtration; the purification may be column chromatography; the column chromatography may be SiO2 column chromatography; the SiO2 column chromatography may be petroleum ether / ethyl acetate (PE / EA) gradient elution; 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 reduces compound C 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-pyrazole-3-amine, 1-cyclopropyl-1H-pyrazole-3-amine, 1-cyclopentyl-1H-pyrazole-3-amine, and 1-cyclobutyl-1H-pyrazole-3-amine.

[0116] In this invention, the reduction reaction temperature can be room temperature, and the holding time can be 20–120 min, specifically 20 min, 30 min, 50 min, 70 min, 90 min, or 120 min; the reduction reaction can be carried out in the presence of a catalyst, an alcohol, and a reducing gas; the catalyst can be a palladium catalyst; the palladium catalyst can be Pd / C; the alcohol can be methanol; the reducing gas can be hydrogen; the molar ratio of compound A to the catalyst... The ratio can 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 to alcohol can 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 reducing gas introduction device can be a hydrogen balloon.

[0117] Alternatively, in this invention, compound J and compound K are mixed to undergo a second coupling reaction to obtain compound D. In this invention, the molar ratio of compound J to compound K can 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 this invention, the temperature of the second coupling reaction can be 105–130°C, specifically 105°C, 110°C, 115°C, 120°C, 125°C, or 130°C, and the holding time can be 10–18 hours, specifically 10 hours, 12 hours, 14 hours, 16 hours, or 18 hours; 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 conditions of a catalyst and an organic solvent; the catalyst can include one or more of alkali metal hydroxides and metal oxides; the alkali metal hydroxide can be hydrogen... Potassium oxide; 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 this invention, the second coupling reaction may further include sequential extraction, organic phase drying, and purification of the obtained product; the extraction reagent may be dichloromethane and saturated ammonium chloride; the drying may be sequential drying with anhydrous Na2SO4 and filtration; the purification may be column chromatography; the column chromatography may be SiO2 column chromatography; the SiO2 column chromatography may be petroleum ether / ethyl acetate (PE / EA) gradient elution; 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.

[0120] In this invention, compound E and compound F are mixed to undergo a second substitution reaction to obtain compound G. In this 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 this 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 time can be 3 to 5 hours, specifically 3 hours, 4 hours, or 5 hours. 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 this invention, the second substitution reaction may further include sequential extraction, organic phase drying, and purification of the obtained product; the extraction reagent may be dichloromethane and water; the drying may be sequential drying with anhydrous Na2SO4 and filtration; the purification may be column chromatography; the column chromatography may be SiO2 column chromatography; the SiO2 column chromatography may be petroleum ether / ethyl acetate (PE / EA) gradient elution; 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.

[0123] In this invention, compound G is mixed with trans-crotonic acid and subjected to Heck coupling and ring-closing reactions sequentially to obtain compound H. In this 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 this invention, the temperature of the Heck coupling reaction can be 75–85°C, specifically 75°C, 77°C, 80°C, 83°C, or 85°C, and the reaction time is 14–24 hours, specifically 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 20 hours, 22 hours, or 24 hours. The Heck coupling reaction can be carried out in a protective atmosphere, which 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 palladium dichloride dibenzylcyanide. The amine can be N,N-diisopropylethylamine (DIPEA). The ligand can be phosphine. The phosphine can be tri(ortho)phosphine. The compound is a methylphenylphosphine; 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 this invention, the temperature of the ring-closure reaction can be 85–100°C, specifically 85°C, 90°C, 95°C, or 100°C, and the holding time can be 20–28 h, specifically 20 h, 22 h, 24 h, 26 h, or 28 h; the ring-closure reaction can be carried out in the presence of acetic anhydride; the molar ratio of compound G to acetic anhydride can be 0.3–2:1, 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 this invention, after the closed-loop reaction, the resulting reaction system may be subjected to sequential cooling, solvent removal, washing, drying, filtration, vacuum concentration, and purification; the final cooling temperature may be room temperature; the solvent removal may be vacuum rotary evaporation; the washing may be sequential washing with dichloromethane (DCM), HCl, and saturated brine; the drying may be drying with anhydrous Na2SO4 for 30 min; and the purification may be column chromatography.

[0127] After obtaining compounds D and H, the present invention mixes compounds D and H and performs a third substitution reaction, followed by deprotection and nucleophilic substitution reaction with an acyl chloride to obtain the 2-aminopyrazolidinepyridone compound. In the present invention, the molar ratio of compounds D and 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 this invention, the temperature of the third substitution reaction can be 105–125°C, specifically 105°C, 110°C, 115°C, 120°C, or 125°C, and the reaction time can be 10–18 hours, specifically 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, or 18 hours. 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; and the butanol... The solvent can be sec-butanol; the molar ratio of 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 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 this invention, the third substitution reaction may further include sequentially cooling, extracting, combining organic phases, washing, drying, and purifying the resulting reaction system; the final cooling temperature may be room temperature; the extraction may involve adding the cooled reaction solution to a 10 wt% NaHCO3 aqueous solution and extracting with dichloromethane; the number of extractions may be two or more; the washing reagent may be saturated saline solution; the number of washings may be two or more; the drying may be anhydrous Na2SO4; and the purification may be column chromatography.

[0130] In this 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 substituted methane; the substituted methane can be dichloromethane (DCM); the molar ratio of 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 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 this invention, the process after deprotection may further include sequentially adjusting the pH of the resulting reaction system to 9, extraction, washing, drying, and concentration; the pH adjustment reagent may be a saturated NaHCO3 aqueous solution; the extraction may include: extracting the pH-adjusted reaction system with dichloromethane (DCM) (denoted as extraction A) and then extracting it with a 10wt% NaHCO3 aqueous solution (denoted as extraction B); the number of extractions A may be more than two; the number of extractions B may be more than two; the washing reagent may be saturated saline solution; the number of washings may be more than two; the drying may be drying with anhydrous Na2SO4.

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

[0133] In this invention, the molar ratio of compound D to 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 this 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 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 substitution... The 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 this invention, the nucleophilic substitution reaction may further include sequentially pouring the resulting reaction system into an aqueous NaHCO3 solution for extraction, combining the organic phases, washing, drying, and purification; the concentration of the NaHCO3 aqueous solution may be 10 wt%; the extraction reagent may be dichloromethane (DCM); the extraction may be performed more than twice; the washing reagent may be saturated saline solution; the washing may be performed more than twice; the drying may be performed using anhydrous Na2SO4; and the purification may be performed using column chromatography.

[0136] This invention involves the salt formation of the 2-aminopyrazolidinepyridone compounds to obtain pharmaceutically acceptable salts of these compounds. In this invention, the salt formation may include reaction with an acid to obtain a non-toxic salt or reaction with a base to obtain a non-toxic salt. The pharmaceutically acceptable salts of this invention include non-toxic salts formed by reacting the basic compound of this invention with an acid, and non-toxic salts formed by reacting the acidic compound of this invention with a base.

[0137] In this invention, the acid may include one or more of inorganic acids and organic acids; the inorganic acid may include one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid; the organic acid may 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, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, and trifluoroacetic acid.

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

[0139] The present invention involves isomerization of the 2-aminopyrazole pyrimidine pyridone compound to obtain stereoisomers of the 2-aminopyrazole pyrimidine pyridone compound.

[0140] In this invention, the method for isomer transformation can be a conventional method, and will not be described in detail here.

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

[0142] In this invention, the tumor involved in the tumor prevention drug or tumor treatment drug can be a malignant tumor with RET gene fusion, specifically including one or more of the following: 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 carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, and leukemia, more specifically non-small cell lung cancer.

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

[0144] In this invention, the pharmaceutical composition may further include combination therapy; the active ingredients of the combination therapy may include, but are not limited to, estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins / cell inhibitors, antiproliferative agents, proteotransferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors. The following are listed as inhibitors: Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon, interleukin-12, COX-2 inhibitors, human tumor suppressor gene p53, p53 activators, VEGF antibodies, and EGF antibodies, or one or more of these.

[0145] In this invention, the combined medication may include, but is not limited to, alephrine, alendronate, interferon, atrazonoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglucopyranoside, amifostine, amrubicin, benzoyl dimethicone, anatozol, dolasetron, aranesp, agrabin, arsenic trioxide, anoxin, 5-azacytidine, azathioprine, BCG or TICE BCG, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotin, bleomycin sulfate, bromouridine, bortezomib, busulfan, calcitonin, alectozumab injection, capecitabine, carboplatin, ceftazidime, and cephalosporin. Cefesone, simvastatin, daunorubicin, chlorambucil, cisplatin, cladribine, clodronate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposomes, dexamethasone, dexamethasone phosphate, estradiol valerate, diethylstilbestrol, desmopressin, dilatozone, diethylstilbestrol, fluconazole, docetaxel, deoxyfluorouridine, doxorubicin, dronabinol, 166-chitosan complex, eligard, raburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, etoposide, levamisole tablets, estradiol preparations, 17-β-estradiol, estradiol sodium phosphate, ethinylestradiol, amifostine. Hydroxyphosphate, Vanbex, Etoposide, Fazodazole, Tamoxifen preparations, Filgrasting, Finasteride, Feraxilate, Fluorouracil, Fluconazole, Fludarabine, 5-Fluorodeoxyuridine monophosphate, 5-Fluorouracil, Flumethasone, Flutamide, Formestan, 1-β-D-arasulofuranylcytidine-5'-stearoyl phosphate, Formustine, Fulvestrant, Gamma globulin, Gemcitabine, Gemtuzumab, Imatinib Mesylate, Carmustine rice paper capsules, Goserelin, Granisilone Hydrochloride, Histamine Relin, Hemifentanil, Hydrocortisone, Erythro-hydroxynonyladenine, Hydroxyurea, Tetane-Isbemumab, Idarubicin, Ifosfamide, Interferon α, Interferon-α2, Interferon α-2A, Interferon α-2B, Steroids Interferon α-n1, Interferon α-n3, Interferon β, Interferon γ-la, Interleukin-2, Intron A, Iressa, Irinotecan, Keterene, Lentinan sulfate, Letrozole, Levofloxacin, Levofloxacin acetate, Levotetraimidazole, Levolecithin calcium salt, Levothyroxine sodium, Levothyroxine sodium preparations, Lomustine, Clonidamine, Drowanediol, Nitrogen mustard, Mecobalamin, Medroxyprogesterone acetate, Medroxyprogesterone acetate, Melphalan, Esterified estrogen, 6-Mercaptopurine, Mesna, Methotrexate, Methylaminolevulinate, Mitofosine, Minocycline, Mitomycin C, Mitotane, Mitoxantrone, Tralocysteine, Doxorubicin citrate liposomes, Nedaplatin, Pegylated filgrastim, Opirimicarb interleukinFilgrastim (neupogen), Nilumet, Tamoxifen, Ukrin (NSC-631570), Recombinant Human Interleukin-1-β, Octreotide, Odanciron Hydrochloride, Dehydrocortisone Oral Solution, Oxaliplatin, Paclitaxel, Prednisone Sodium Phosphate, Pegaspargase, Pegasys, Pentostatin, Streptomycin, Pilucarpine Hydrochloride, Pirarubicin, Plucamycin, Porphyrom sodium, Prednimustine, Steprednisolone, Prednisone, Premarin, Procarbazine, Recombinant Human Erythropoietin, Raltitrexed, Lipiridone, Rhenium-186 Etidronate, Rituximab, Redoxon-A, Romotide, Pilocarpine Hydrochloride Tablets, Octreotide, Samoxifen, Semustine, Cizonan, Sobuzosen, Methylprednisolone Sodium, Paphosic Acid Stem cell therapy, streptozoline, strontium-89 chloride, levothyroxine sodium, tamoxifen, tansulosin, tastolactone, dosoteri, tecithin, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyroid-stimulating hormone, teludromic acid, topotecan, toremifene, tosimomab, trastuzumab, tresorcinol, tretinoin, methotrexate tablets, trimethylmelamine, trimethoprim, triptorelin acetate, triptorelin dinaphthylnaphthyl acid, urofluidin, uridine, pentorubicin, vestrulinone, vinblastine, vincristine, vinblastine, vinorelbine, velurazine, dextromethorphan, fentostatin, styraxine, paclitaxel protein stabilizers, azithromycin (aco) lbifene), interferon r-lb, afatinib (affinitak), aminopterin, azoxifen, aspirin (asoprisnil), atametane, atrasentan, sorafenib (BAY43-9006), Avastin, tesimolimus (CCI-779), lenalidomide (CDC-501), celecoxib, cetuximab, cristatin, cyproterone acetate, decitabine, doxorubicin-MTC, doxylamine (dSLIM), dutasteride, edotecarin, efornithine, ixenogamma, fenvitamin A, histamine dihydrochloride, histamine relin hydrogel implant, holmium-166 multiple myeloma (holmium-166DOTMP) Ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole hemocyanin, carboxytriazole (L-651582), lanafamib, lasoxifene, libra, lonafamib, miprexifen, minotropium fumarate, dofequidil fumarate (MS-209), mivaminopeptide (liposome MTP-PE), nafarelin, nemorubicin, neovastatin, noratropide, olimolsen, vincristine (onco-TCS), osimerin, paclitaxel polyglutamate, sodium pamoate, uridine triacetate (PN-401), vaccine adjuvant (QS-21), quasi-yen, R-1549, raloxifene, leopard frog enzyme,One or more of the following: 13-cis-retinoic acid, saplatin, ciocalcitriol, T-138067, tarceva, docosahexaenoic acid paclitaxel, thymosin alpha 1, tipifanab, terazamine, glutathione analog prodrug (TLK-286), toremifene, trans-hydroxyloxoprofen (trans-MID-lo7R), vasoporta, vaporat, vatalanib, verteporfen, vinflunine, zaltopibuprofen (Z-100), and zoledronic acid.

[0146] The heterocyclic compounds of this invention can be used in combination with known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage remain unchanged, while the heterocyclic compound of this invention is taken simultaneously or subsequently. When the heterocyclic compound of this invention is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the heterocyclic compound of this invention is preferred. Drug combination also includes taking the heterocyclic compound of this invention with one or more other known drugs during overlapping time periods. When the heterocyclic compound of this invention is used in combination with one or more other drugs, the dosage of the heterocyclic compound of this invention or the known drug may be lower than the dosage when they are taken alone.

[0147] To further illustrate the present invention, the following detailed description of the embodiments is provided in conjunction with the present invention, but these descriptions should not be construed as limiting the scope of protection of the present invention.

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

[0149]

[0150] Example 1

[0151] This embodiment prepared (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, designated 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 Cu2O (86 mg, 0.602 mmol), KOH (678 mg, 12.04 mmol), and 3-fluoroiodobenzene (compound 2) (2.174 g, 8.428 mmol). The mixture was further substituted with Ar three times. The mixture was heated to 120 °C and stirred for 12 h. The reaction was monitored by TLC. After the reactants were completely reacted, the mixture was extracted with dichloromethane and saturated ammonium chloride. The organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The mixture was then separated by column chromatography (SiO2, PE / EA gradient elution, volume ratio 10–5:1) to obtain 610 mg of brown solid product (compound 3), with a yield of 57.22%.

[0153] Step b: 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 at room temperature. The mixture was stirred at room temperature, and the reaction was monitored by TLC. After the reactants had reacted completely, the mixture was extracted with dichloromethane and water. The organic phase was collected, dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The resulting solution was then subjected to column chromatography. Separation was performed using SiO2, PE / EA gradient elution, volume ratio 10:1 to 5:1, yielding 23.382 g of an oily compound (compound 6) with a yield of 95%. The chemical name is tert-butyl(R)-3-((5-bromo-2-chloropyrimidin-4-yl)amino)piperidine-1-carboxylate.

[0154] Characterization results: 1 H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.17(s,1H),4.04(s,1H),3.91(s,1H),3.82(s,1H),3.7 1-3.62(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, 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) were added to THF (120 mL), and then DIPEA (51 mL) was slowly added to the system. The system was replaced with Ar three times. Then, palladium dichloride diphenylacetonitrile (0.599 g, 1.56 mmol) and tris(o-methylphenyl)phosphine (0.475 g, 1.56 mmol) were added to the mixture, and the system was replaced with Ar three times again. The system was heated to 80 °C and stirred for 24 h. Then Ac2O (7.5 mL) was added to the system, and the system was heated to 90 °C and stirred for 24 h. Heating was stopped, and the system temperature was allowed to drop to room temperature. Part of the solvent was removed by rotary evaporation under reduced pressure. Then, DCM (120 mL) was added to the system, and the organic phase was washed with HCl (1 M, 230 mL). The organic phase was then washed once with saturated brine (230 mL). The organic phase was collected, dried with anhydrous Na2SO4 for 30 min, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain 4.436 g of white solid (compound 7), with a yield of 36.1%. Its chemical 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 HNMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 6.61 (s, 1H), 5.17 (s, 1H), 3.90 (dd, J = 62.1-23. 9Hz, 4H), 2.66 (s, 2H), 2.45 (s, 3H), 1.76 (d, J = 39.6Hz, 2H), 1.48 (s, 1H), 1.41 (s, 9H).

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

[0159] Step d: tert-butyl(R)-3-(2-chloro-5-methyl-7-oxopyridyl[2,3-d]pyrimidin-8(7H)-yl)piperidin-1-carboxylic acid ester (compound 7) (417 mg, 1.06 mmol) was added to a sealed flask containing 5 mL of sec-butanol, followed by the addition of 1-(3-fluorophenyl)-1H-pyrazole-3-amine (compound 3) (225 mg, 1.27 mmol) and TFA (0.09 mL, 1.166 mmol). The mixture was heated to 110 °C and stirred for 18 h. Cool to room temperature, pour into 10% NaHCO3 aqueous solution, extract twice with dichloromethane, combine organic phases, wash twice with saturated brine, dry with anhydrous Na2SO4, and perform column chromatography to give 88 mg of a pale 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.

[0160] Characterization results: 1 HNMR (400MHz, DMSO-d6) δ10.71(s,1H),8.85(s,1H),8.54(s,1H),7.61(d,J=57.2Hz,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=2.9Hz,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 is complete, adjust the pH to 9 with saturated NaHCO3 aqueous solution, extract twice with DCM, and then extract twice with 10 wt% NaHCO3 aqueous solution. Wash twice with brine, dry in anhydrous Na2SO4, concentrate, and proceed to the next step; dissolve the concentrated compound in anhydrous DCM, add triethylamine (0.2 mL, 0.716 mmol) in an ice bath at 0°C, slowly add propionyl chloride (0.03 mL, 0.43 mmol), after the reaction is complete, pour into 10 wt% NaHCO3 aqueous solution, extract twice with dichloromethane, combine the organic phases, wash twice with saturated brine, dry in anhydrous Na2SO4, and perform column chromatography to give 68 mg of white solid compound 660206, with a yield of 37.2%.

[0163] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.09(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 / z476.22175[M+H] + .

[0165] Example 2

[0166] In this embodiment, (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 its structure is as follows:

[0167]

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

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

[0170] Step g: 3-Nitro-1H-pyrazole (compound 9) (1 g, 8.84 mmol) was dissolved in DMF (10 mL) at room temperature, followed by the addition of Cs₂CO₃ (4.32 g, 13.26 mmol), CuBr (152 mg, 1.06 mmol), and 3-iodophenol (compound 10, 2.023 g, 9.19 mmol). The mixture was coupled with Ar₂ for 14 h, then heated to 120 °C and stirred for 14 h. After the reaction was complete, the mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. Column chromatography was used to separate the organic phase into 834 mg of gray compound 11, with a yield of 46%.

[0171] Characterization results: 1 H NMR (400MHz, DMSO-d6) δ8.97 (s, 1H), 8.47 (d, J = 19.6Hz, 1H), 7.23-6.95 (m, 3H), 6.83 (s, 1H), 6.58 (d, J = 9.6Hz, 1H).

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

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

[0174] Characterization results: 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.47(d,J=19.6Hz,1H),7.23-6.95(m,3H),6.83(s,1H),6.58(d,J=9.6Hz,1H),5.97(s,2H).

[0175] MS(ESI) m / z 176.39 [M+H] + .

[0176] Characterization results of compound 660208: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ8.97(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 / z474.22573[M+H] + .

[0178] Example 3

[0179] In this embodiment, (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, designated as compound 660207, and its structure is as follows:

[0180]

[0181] The preparation method of this embodiment is the same as that of Example 1, except that compound 2 is replaced with commercially available 3-methoxyiodobenzene.

[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 embodiment, (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, designated as compound 660210, and its structure is as follows:

[0186]

[0187] The preparation method of this embodiment is the same as that of Example 1, except that compound 3 is 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 embodiment, (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, with the English name (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, designated as compound 660213, and its structure is as follows:

[0192]

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

[0194] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ8.80(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 embodiment, (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, with the English name (R)-5-methyl-2-((1-phenyl-1H-pyrazol-3-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, designated as compound 660216, and its structure is as follows:

[0198]

[0199] The preparation method of this embodiment 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] In this embodiment, (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 was prepared, 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, designated as compound 660217, and its structure is as follows:

[0204]

[0205] The preparation method of this embodiment 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 embodiment, (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, designated as compound 660223, and its structure is as follows:

[0210]

[0211] The preparation method of this embodiment is the same as that of Example 1, except that compound 3 is replaced with the synthesized 1-cyclohexyl-1H-pyrazole-3-amine.

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

[0213] Characterization results: 1H NMR(400MHz,Trifluoroacetic acid-d)δ9.45(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] This embodiment prepared (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, 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, designated as compound 660224, and its structure is as follows:

[0217]

[0218] The preparation method of this embodiment is the same as that of Example 1, except that compound 2 is replaced with commercially available 4-methyliodobenzene.

[0219] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ8.87(s,1H),7.88(s,1H),7.30(d,J=8.3Hz,2H),7.21(d,J=8.2Hz,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 / z472.24695[M+H] + .

[0221] Example 10

[0222] In this embodiment, (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, designated as compound 660226, and its structure is as follows:

[0223]

[0224] The preparation method of this embodiment is the same as that of Example 1, except that compound 3 is replaced with the synthesized 1-cyclopropyl-1H-pyrazole-3-amine.

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

[0226] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ9.39(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 embodiment, (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, with the English name (R)-2-((1-cyclopentyl-1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, designated as compound 660227, and its structure is as follows:

[0230]

[0231] The preparation method of this embodiment is the same as that of Example 1, except that compound 3 is replaced with the synthesized 1-cyclopentyl-1H-pyrazole-3-amine.

[0232] The preparation method of the 1-cyclopentyl-1H-pyrazole-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 / z 450.26300 [M+H] + .

[0235] Example 12

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

[0237]

[0238] The preparation method of this embodiment is the same as that of Example 1, except that compound 3 is replaced with the synthesized 1-cyclobutyl-1H-pyrazole-3-amine.

[0239] The preparation method of 1-cyclobutyl-1H-pyrazole-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 embodiment, (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 was prepared, 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, designated as compound 660229, and its structure is as follows:

[0244]

[0245] The preparation method of this embodiment 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 embodiment, (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 was prepared, 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), designated as compound 660230, and its structure is as follows:

[0250]

[0251] The preparation method of this embodiment 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] In this embodiment, (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 was prepared, 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, designated as compound 660234, and its structure is as follows:

[0256]

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

[0258] Characterization results: 1H NMR(400MHz,Trifluoroacetic acid-d)δ9.31(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 embodiment, (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, with the English name (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, designated as compound 660235, and its structure is as follows:

[0262]

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

[0264] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.28(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 / z476.22236[M+H] + .

[0266] Example 17

[0267] This embodiment prepared (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, 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, designated as compound 660237, and its structure is as follows:

[0268]

[0269] The preparation method of this embodiment is the same as that of Example 1, except that compound 2 is replaced with commercially available 2-methyliodobenzene.

[0270] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ9.28(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] This embodiment prepared (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, designated as compound 660238, and its structure is as follows:

[0274]

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

[0276] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ9.34(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 embodiment, (R)-2-((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-((1H-pyrazol-3-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one, designated as compound 660239, and its structure is as follows:

[0280]

[0281] The preparation method of this embodiment is the same as that of Example 1, except that compound 3 is replaced with 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] This embodiment prepared (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, with the English name (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, designated as compound 660240, and its structure is as follows:

[0286]

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

[0288] Characterization results: 1H NMR(400MHz,Trifluoroacetic acid-d)δ9.33(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] This embodiment prepared (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, 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, designated as compound 660241, and its structure is as follows:

[0292]

[0293] The preparation method of this embodiment is the same as that of Example 1, except that compound 2 is replaced with commercially available 3-trifluoromethyliodobenzene.

[0294] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.35(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 embodiment, (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, with the English name (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, designated as compound 660264, and its structure is as follows:

[0298]

[0299] The preparation method of this embodiment is the same as that of Example 1, except that compound 2 is replaced with commercially available 4-trifluoromethyliodobenzene.

[0300] Characterization results: 1 H NMR((400MHz,DMSO-d6)δ10.64(s,1H),8.83(s,1H),8.60(s,1H),8.00(s,2H),7.83(d,J=8.4Hz,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=48.5Hz,3H).

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

[0302] Example 23

[0303] In this embodiment, (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 was prepared, 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, designated as compound 660265, and its structure is as follows:

[0304]

[0305] The preparation method of this embodiment is the same as that of Example 1, except that compound 2 is replaced with commercially available 2-trifluoromethyliodobenzene.

[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] This embodiment prepared (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, designated as compound 660270, and its structure is as follows:

[0310]

[0311] The preparation method of this embodiment 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] In this embodiment, (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 was prepared, 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, designated as compound 660271, and its structure is as follows:

[0316]

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

[0318] Characterization results: 1H NMR(400MHz,Trifluoroacetic acid-d)δ9.52(s,1H),8.61(s,1H),7.98(d,J=30.9Hz,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 embodiment, (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, designated as compound 660272, and its structure is as follows:

[0322]

[0323] The preparation method of this embodiment is the same as that of Example 1, except that compound 2 is replaced with commercially available 4-methoxyiodobenzene.

[0324] Characterization results: 1 H NMR(400MHz,Trifluoroacetic acid-d)δ9.42(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] This embodiment prepared (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, with the English name (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, designated as compound 660273, and its structure is as follows:

[0328]

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

[0330] Characterization results: 1 HNMR(400MHz,Trifluoroacetic acid-d)δ9.37(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 / z483.22734[M+H] + .

[0332] Example 28

[0333] In this embodiment, (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 was prepared, 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, designated as compound 660274, and its structure is as follows:

[0334]

[0335] The preparation method of this embodiment 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 embodiment, (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 was prepared, 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, designated as compound 660275, and its structure is as follows:

[0340]

[0341] The preparation method of this embodiment 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 1-29 were tested for their inhibitory effects on cell growth, and the half-maximal inhibitory concentration (IC50) was calculated based on the test results. 50 The values ​​are shown in Table 1.

[0346] Table 1. Half-maximal inhibitory concentrations of compounds in Examples 1-29

[0347]

[0348] As shown in Table 1, the compounds of this invention can significantly inhibit Ba / F3-CCDC6-RET. V804M and Ba / F3-CCDC6-RET G810C Cell proliferation inhibition rate is positively correlated with drug concentration.

[0349] Test Example 2

[0350] The compounds prepared in Examples 1-29 were subjected to solubility tests by observation. The results showed that the compounds of the present invention are well soluble in DMSO, exhibiting good solubility.

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

[0352] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A heterocyclic compound, characterized in that, Compounds with the following structures or pharmaceutically acceptable salts thereof: 。 2. The use of the heterocyclic compound of claim 1 in the preparation of RET inhibitors.

3. The use of the heterocyclic compound of claim 1 in the preparation of a drug for preventing tumor recurrence.

4. The use of the heterocyclic compound of claim 1 in the preparation of antitumor drugs or antitumor drugs.

5. A pharmaceutical composition for preventing and treating tumors, characterized in that, It includes an active ingredient, which includes the heterocyclic compound of claim 1.

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