Tetrahydropteridinone derivatives as Plk1 kinase selective covalent inhibitors

Abstract

The invention discloses a tetrahydropteridinone derivative as a Plk1 kinase selective covalent inhibitor, the derivative is shown as a general formula (I), and the definition of substituent groups is shown in the specification. According to the present invention, the high Plk1 inhibition activity is maintained while the selectivity on the same family kinase is improved so as to improve the Plk1 kinase targeting property, such that the effect of the drug on other targets is reduced while the drug effect is performed at the action site, and the occurrence of adverse reaction events is reduced. Meanwhile, compared with a reported Plk1 kinase inhibitor, the Plk1 inhibitor provided by the invention has different binding mechanisms, and forms a covalent bond with Plk1. The new mechanism can effectively overcome the drug resistance of the existing Plk1 inhibitor caused by target binding site mutation. Meanwhile, the compound has the advantages of higher selectivity, longer drug effect duration and the like. # imgabs0 #

Description

Technical Field

[0001] This article relates to medicinal chemistry techniques, in particular tetrahydropteridinone derivatives as selective covalent inhibitors of Plk1 kinase. Background Art

[0002] Plk1 mainly plays a role in promoting tumorigenesis in various tumors, and can also inhibit tumorigenesis under special circumstances. Currently, many Plk1 small molecule inhibitors have entered the clinical trial stage, but no Plk1 inhibitors are currently on the market. Given the important role of Plk1 in cell cycle, cell proliferation, apoptosis inhibition and promotion of epithelial-mesenchymal transition, Plk1 is a potential target for cancer treatment. By comparing the Plk1 content in cancer tissues and normal tissues, it was found that the expression of Plk1 in cancer tissues was significantly increased, and the expression of Plk1 in advanced cancer tissues was further increased, indicating that Plk1 may be related to cancer progression. Plk1 can inhibit the activity of tumor suppressors. Plk1 and the tumor suppressor p53 regulate each other, and Plk1 can induce the degradation of p53 through various methods. Plk1 can also affect nuclear localization by phosphorylating PTEN, activate the PI3K / AKT pathway, drive cell proliferation and glycolysis, and this pathway has been shown to be more important in some cancer cells. Plk1 can also stabilize oncogenes. Plk1 can phosphorylate and degrade the E3 ligase FBW7, thereby preventing MYC family proteins from being ubiquitinated and degraded. In addition, studies have found that Plk1 is involved in the resistance of several chemotherapeutic drugs, including doxorubicin, gemcitabine, paclitaxel, androgen signaling inhibitors, and metformin, which is related to the DNA damage repair function of Plk1, and also means that Plk1 inhibitors may have better efficacy when combined with other anticancer drugs. Because Plk1 has the function of spindle assembly and nuclear chromosome stability, Plk1 inhibition can lead to chromosomal abnormalities and tumorigenesis in some cases. Plk1 can act as a tumor suppressor in these cases. A study showed that Plk1 overexpression can hinder KRAS or HER2-induced breast tumors, and Plk1 overexpression was found to mean higher survival rates in patients with certain types of breast cancer. Similarly, high Plk1 levels can improve the survival rate of colorectal cancer carrying specific APC mutations.

[0003] In recent years, a variety of highly effective small molecule inhibitors of Plk1 have been developed, most of which have shown excellent anti-tumor activity in cells and have been tested in clinical trials. Currently, Rigosertib and BI 6727 are in clinical phase III, NMS-1286937 is in clinical phase II, CYC140 is in clinical phase I, and BI 2536, GSK461364 and TAK-960 have stopped clinical trials due to effectiveness reasons. So far, no small molecule inhibitor targeting Plk1 has been marketed. Plk1 consists of two domains, the kinase domain (KD) and the polo box domain (PBD), which provide a structural basis for the development of small molecule inhibitors of Plk1. In recent years, researchers have developed many new small molecule Plk1 inhibitors, including KD inhibitors and PBD inhibitors. These inhibitors bind to the KD or PBD of Plk1 and have high potency, high selectivity and good PK. After correcting the problems of each compound, these small molecules in preclinical studies will have great potential to become clinical candidates. Summary of the invention

[0004] The present application provides a novel tetrahydropteridinone derivative, which can irreversibly bind to Plk1.

[0005] The present application provides a novel tetrahydropteridinone derivative, wherein the derivative is represented by the general formula (I), or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0006]

[0007] R1 and R2 are each independently selected from hydrogen and C1-C6 alkyl;

[0008] R3 is -YW; Y is a single bond (or absent), C1-C6 alkylene, C1-C6 alkyleneamino, C3-C8 cycloalkylene, C3-C8 cycloalkyleneamino or C2-C8 heterocycloalkylene; W is a covalent warhead selected from and cyano, where R a is hydrogen or halogen, or R a With R b Form a single bond, R c and R b Each independently selected from hydrogen, C1-C4 alkyl, C1-C8 heteroalkyl and C2-C 12 Heterocycloalkyl, R d is a halogenated C1-C6 alkyl or acetonitrile group; or, -YW is an oxo C3-C8 cycloalkyl or an oxa C5-C 12 Spirocycloalkyl;

[0009] R4 is hydrogen or C1-C6 alkyl;

[0010] R5 is halogen, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxy;

[0011] R6 is hydrogen or halogen;

[0012] R7 is hydrogen or -C(O)-NR e R f Here, R e and R f Each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl and C2-C 12 Heterocycloalkyl, and the C1-C6 alkyl, the C3-C8 cycloalkyl or the C2-C 12 The heterocycloalkyl group is optionally substituted with a group of Group A;

[0013] R8 is hydrogen, halogen or in,

[0014] L1 and L2 are each independently selected from a single bond (or absent) and C1-C4 alkylene optionally substituted by a group of Group A;

[0015] R 13 is hydrogen or a C1-C4 alkyl group optionally substituted by a group of Group A, or R 13 With R 10 connected and together with the groups to which they are attached form a C2-C 11 Azacycloalkyl, or R 13 With R 12 connected and together with the groups to which they are attached form a C2-C 11 Azacycloalkyl;

[0016] R9 and R 10 Each is independently selected from hydrogen, halogen, C1-C4 alkyl optionally substituted by a group of Group A, nitro, hydroxyl and C1-C4 alkoxy optionally substituted by a group of Group A;

[0017] R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, and C1-C4 alkanoyl optionally substituted by a group of Group A;

[0018] Group A groups are hydroxyl, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C6-C 12 Aryl-substituted C1-C6 alkyl, halogenated C1-C6 alkoxy or C6-C 12 Aryl.

[0019] On the other hand, the present application provides a method for preparing the novel tetrahydropteridinone derivatives.

[0020] The third aspect of the present application provides a pharmaceutical composition, which comprises the compound of general formula (I) described in the present application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier excipient or diluent.

[0021] In a fourth aspect, the present application provides a compound of the general formula (I) described in the present application, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or its pharmaceutical composition, for use as a medicine or for use as a medicine for treating or preventing diseases caused by excessive proliferation of malignant tumor cells.

[0022] In a fifth aspect, the present application provides the use of the compound of general formula (I) described in the present application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preparing drugs for treating or preventing diseases caused by excessive proliferation of malignant tumor cells.

[0023] The sixth aspect of the present application provides a method for treating or preventing diseases caused by excessive proliferation of malignant tumor cells, the method comprising administering the compound of general formula (I) described in the present application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically acceptable salts, or the pharmaceutical composition to a subject in need thereof.

[0024] In an embodiment of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0025]

[0026] R1 and R2 are each independently selected from hydrogen and C1-C6 alkyl; preferably, R1 is hydrogen and R2 is C1-C6 alkyl; here, the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl, etc.;

[0027] R3 is -YW; Y is a single bond (or absent), C1-C6 alkylene, C1-C6 alkyleneamino, C3-C8 cycloalkylene, C3-C8 cycloalkyleneamino or C2-C8 heterocycloalkylene; W is a covalent warhead selected from and cyano, where R a is hydrogen or halogen, or R a With R b Form a single bond, R c and R b Each independently selected from hydrogen, C1-C4 alkyl, C1-C8 heteroalkyl and C2-C 12 Heterocycloalkyl, R d is a halogenated C1-C6 alkyl or acetonitrile group; or, -YW is an oxo C3-C8 cycloalkyl or an oxa C5-C 12 Spirocycloalkyl; preferably, Y is a single bond (or absent), methylene, ethylene, propylene, butylene, pentylene, hexylene, ethyleneamino, propyleneamino, butyleneamino, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutyleneamino, cyclopentyleneamino, cyclohexyleneamino, azetidinyl, pyrrolidinylene or piperidinylene, W is a covalent warhead selected from and cyano, where R a is hydrogen or halogen, or R a With R b Form a single bond, R c and R b Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-C4 alkoxy C1-C4 alkyl, mono-C1-C4 alkylamino C1-C4 alkyl, di-C1-C4 alkylamino C1-C4 alkyl, and C2-C 12 Heterocycloalkyl, wherein the C2-C 12 Heterocycloalkyl is an unsubstituted C2-C 12 Heterocycloalkyl or substituted C2-C 12 Heterocycloalkyl may be selected from oxirane, oxetanyl, dioxolanyl, dithiacyclopentyl, dioxanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisoquinolyl, octahydroisoquinolyl, decahydroisoquinolyl, tetrahydroquinolyl, octahydroquinolyl, tetrahydroimidazolinyl, pyrazolidinyl, pyrrolidinyl, pyrrolidinone, piperidinyl, piperidone, piperazinyl, piperazinone, N-methylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, N-methylpiperazinyl, N-benzylpiperazinyl, N-acetylpiperazinyl, N-methylsulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, imidazolidinyl, tetrahydroimidazolonyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, quinuclidinyl or nortropine, or a ring thereof which is benzo-fused, such as benzopyrrolidinyl, benzomorpholinyl, etc.; R dis selected from the following groups substituted by one or more of fluorine, chlorine, bromine and iodine, or acetonitrile: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl; or, -YW is oxocyclobutyl, oxocyclopentyl, oxocyclohexyl, oxocycloheptyl, oxocyclooctyl, 1-oxaspiro[2,4]heptyl, 1-oxaspiro[2,5]octyl or 1-oxaspiro[2,6]nonyl, etc.;

[0028] R4 is hydrogen or C1-C6 alkyl; preferably, R4 is C1-C6 alkyl; here, the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl, etc.;

[0029] R5 is halogen, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxyl; preferably, R5 is unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxyl; here, the halogen is fluorine, chlorine, bromine or iodine; the unsubstituted C1-C6 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy The halogenated C1-C6 alkoxy group refers to alkyl substituted with fluorine, chlorine, bromine or iodine at any position, including but not limited to trifluoromethoxy, difluoromethoxy and monofluoromethoxy; the hydroxy-substituted C1-C6 alkoxy group refers to alkyl substituted with hydroxy at any position, including but not limited to hydroxymethoxy, hydroxyethoxy, hydroxy-n-propoxy, hydroxy-isopropoxy, hydroxy-n-butoxy, hydroxy-isobutoxy, hydroxy-sec-butoxy, hydroxy-tert-butoxy, hydroxy-n-pentoxy or hydroxy-n-hexoxy;

[0030] R6 is hydrogen or halogen; here, the halogen is chlorine, bromine, iodine or fluorine;

[0031] R7 is hydrogen or -C(O)-NR e R f Here, R e and R f Each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl and C2-C 12 Heterocycloalkyl, and the C1-C6 alkyl, the C3-C8 cycloalkyl or the C2-C 12 The heterocycloalkyl group is optionally substituted with a group of Group A; preferably, R e is hydrogen, and R fis hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxiranyl, oxetanyl, dioxolanyl, dithiacyclopentanyl, dioxanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisoquinolyl, octahydroisoquinolyl, decahydroisoquinolyl, tetrahydroquinolyl, octahydroquinolyl, tetrahydroimidazolonyl, pyrazolidinyl, pyrrolidinyl, pyrrolidinyl, alkyl, pyrrolidinyl, piperidinyl, piperidonyl, piperazinyl, piperazinonyl, N-methylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, N-methylpiperazinyl, N-benzylpiperazinyl, N-acetylpiperazinyl, N-methylsulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, imidazolidinyl, tetrahydroimidazolone, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, quinuclidinyl or nortropine;

[0032] R8 is hydrogen, fluorine, chlorine, bromine, iodine, or in,

[0033] L1 and L2 are each independently selected from a single bond (or absent) and a C1-C4 alkylene group optionally substituted by a group of Group A; Here, the C1-C4 alkylene group is -CH2-, -CH2-CH2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-;

[0034] R 13 is hydrogen or a C1-C4 alkyl group optionally substituted by a group of Group A, or R 13 With R 10 connected and together with the groups to which they are attached form a C2-C 11 Azacycloalkyl, or R 13 With R 12 connected and together with the groups to which they are attached form a C2-C 11 Here, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the C2-C 11 The aziridine group is aziridine, azetidinyl, pyrazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, tetrahydroimidazolinyl, morpholinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl, etc.;

[0035] R9 and R 10Each is independently selected from hydrogen, halogen, C1-C4 alkyl optionally substituted by a group of Group A, nitro, hydroxyl and C1-C4 alkoxy optionally substituted by a group of Group A; Here, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Here, the C1-C4 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

[0036] R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, and C1-C4 alkanoyl optionally substituted by a group of Group A; wherein the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl; and the C1-C4 alkanoyl is formyl, acetyl, propionyl or butyryl, etc.;

[0037] The A group is hydrogen, hydroxyl, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C6-C 12 Aryl-substituted C1-C6 alkyl (e.g., benzyl), halogenated C1-C6 alkoxy or C6-C 12 Aryl.

[0038] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), wherein:

[0039] R5 is halogen, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxy;

[0040] R6 is hydrogen or halogen; here, the halogen is chlorine, bromine, iodine or fluorine;

[0041] R7 is -C(O)-NR e R f ;

[0042] R8 is hydrogen, fluorine, chlorine, bromine or iodine.

[0043] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), wherein:

[0044] R5 is halogen, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxy;

[0045] R6 is hydrogen or halogen; here, the halogen is chlorine, bromine, iodine or fluorine;

[0046] R7 is hydrogen;

[0047] R8 is

[0048] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R1 is hydrogen and R2 is ethyl, and the carbon atom to which R1 and R2 are attached is in R configuration.

[0049] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R3 is -YW; Y is a single bond (or absent), methylene, ethylene, propylene, butylene, pentylene, hexylene, ethyleneamino, propyleneamino, butyleneamino, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutyleneamino, cyclopentyleneamino, cyclohexyleneamino, azetidinyl, pyrrolidinylene or piperidinylene, W is a covalent warhead selected from and cyano, where R a is hydrogen or halogen (such as chlorine or fluorine), or R a With R b Form a single bond, R c and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and dimethylaminomethyl, R d is monochloromethyl, dichloromethyl, propynyl or acetonitrile; or, -YW is oxocyclobutyl, oxocyclopentyl, oxocyclohexyl, oxocycloheptyl, oxocyclooctyl, 1-oxaspiro[2,4]heptyl, 1-oxaspiro[2,5]octyl or 1-oxaspiro[2,6]nonyl.

[0050] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R3 is one of the following groups:

[0051]

[0052] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, preferably, R4 is methyl.

[0053] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R1 is hydrogen and R2 is ethyl, and the carbon atom to which R1 and R2 are attached is in R configuration; and R4 is methyl.

[0054] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R1 is hydrogen and R2 is ethyl, and the carbon atom to which R1 and R2 are attached is in R configuration;

[0055] R3 is -YW; Y is a single bond (or absent), methylene, ethylene, propylene, butylene, pentylene, hexylene, ethyleneamino, propyleneamino, butyleneamino, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutyleneamino, cyclopentyleneamino, cyclohexyleneamino, azetidinyl, pyrrolidinylene or piperidinylene, W is a covalent warhead selected from and cyano, where R a is hydrogen or halogen, or R a With R b Form a single bond, R c and R b are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and dimethylaminomethyl, R d is monochloromethyl, dichloromethyl or acetonitrile; or, -YW is oxocyclobutyl, oxocyclopentyl, oxocyclohexyl, oxocycloheptyl, oxocyclooctyl, 1-oxaspiro[2,4]heptyl, 1-oxaspiro[2,5]octyl or 1-oxaspiro[2,6]nonyl; and

[0056] R4 is methyl.

[0057] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R1 is hydrogen and R2 is ethyl, and the carbon atom to which R1 and R2 are attached is in R configuration;

[0058] R3 is one of the following groups:

[0059]

[0060] and

[0061] R4 is methyl.

[0062] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, hydroxymethoxy, hydroxyethoxy, hydroxy-n-propoxy, hydroxyisopropoxy, hydroxy-n-butoxy, hydroxyisobutoxy, hydroxy-sec-butoxy or hydroxy-tert-butoxy, preferably, R5 is methoxy, trifluoromethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy or 2-hydroxypropoxy.

[0063] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R6 is hydrogen, chlorine, bromine, fluorine or iodine, preferably, R6 is hydrogen, chlorine or fluorine.

[0064] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R1 is hydrogen and R2 is ethyl, and the carbon atom to which R1 and R2 are attached is in R configuration; R4 is methyl; R5 is methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy or 2-hydroxypropoxy; R6 is hydrogen, chlorine or fluorine.

[0065] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in the general formula (I), wherein R1 is hydrogen and R2 is ethyl, and the carbon atom to which R1 and R2 are attached is in R configuration; and R3 is one of the following groups:

[0066]

[0067] R4 is methyl; R5 is methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy or 2-hydroxypropoxy; R6 is hydrogen, chlorine or fluorine.

[0068] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), wherein: for

[0069] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), wherein: for

[0070] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), wherein: Medium R 13 is hydrogen, L1 is a single bond, -CH2- or -CH2-CH2-; L2 is a single bond, -CH2- or -CH2-CH2-; R9 and R 10 All are hydrogen; R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, and C1-C4 alkanoyl optionally substituted by a group of Group A; preferably, R 13 is hydrogen, L1 is -CH2-; L2 is -CH2-; R9 and R 10 All are hydrogen; R 11 is hydrogen, and R 12 is methyl or ethyl; more preferably, R 13is hydrogen, L1 is -CH2-; L2 is -CH2-; R9 and R 10 All are hydrogen; R 11 is hydrogen, and R 12 It is ethyl.

[0071] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), wherein: For R 11 (R 12 )N- pyrrolidinyl or R optionally substituted by a group A 11 (R 12 )N-piperidinyl optionally substituted by a group of Group A, R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, and C1-C4 alkanoyl optionally substituted by a group of Group A; preferably, R 11 (R 12 )N-pyrrolidinyl or R 11 (R 12 )N-piperidinyl, R 11 and R 12 Each is independently selected from hydrogen and tert-butyloxycarbonyl; more preferably, 4-aminopiperidine or 4-tert-butyloxycarbonyl-aminopiperidine.

[0072] In some embodiments of the first aspect, the present application provides a novel tetrahydropteridinone derivative as shown in general formula (I), wherein: 4-R 12 - piperazinyl optionally substituted by a group of Group A, R 12 is hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, or C1-C4 alkanoyl optionally substituted by a group of Group A; preferably, 4-R 12 -piperazinyl, R 12 is hydrogen, methyl, ethyl or tert-butyloxycarbonyl.

[0073] In some embodiments of the first aspect, the present application provides the following compounds, or pharmaceutically acceptable salts thereof:

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] In the embodiment of the present application, the compound provided by the present application is obtained in the form of a free form or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and characteristics of the compound of the present application, and does not generally refer to a salt that is biologically or otherwise undesirable. In many cases, due to the presence of an amino and / or carboxyl group or a group similar thereto, the compound of the present application can form an acid salt and / or a base salt.

[0083] The compounds of the present application can form pharmaceutically acceptable acid addition salts with inorganic acids and organic acids. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. The organic acids include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[0084] In some embodiments of the present application, the present application provides the following forms of the novel tetrahydropteridinone derivatives: acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucuronate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, hydroxyethyl The invention can be in the form of hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester, hydroxyethyl ester,

[0085] The novel tetrahydropteridinone derivatives provided in the present application include compounds having formula (I), compounds having subformulas thereof and exemplary compounds, pharmaceutically acceptable salts thereof, and all stereoisomers (including diastereomers and enantiomers), tautomers, and isotope-labeled compounds (including deuterium substitutions), and solvates or hydrates thereof.

[0086] The present application includes all possible stereoisomers, including racemic mixtures, diastereomeric mixtures and optically pure forms.Optically active (R)- and (S)-stereoisomers may be prepared by chiral synthesis or using chiral reagents, or resolved using conventional techniques.

[0087] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present application can exist in a racemic or enantiomerically enriched form, for example, (R)-, (S)-, or (R, S)-configuration. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess of (R)- or (S)-configuration.

[0088] In an embodiment of the second aspect, the present application provides a preparation method of a novel tetrahydropteridinone derivative as shown in general formula (I) and an intermediate compound or a pharmaceutically acceptable salt thereof, wherein the preparation method comprises:

[0089]

[0090] The compound of formula (II) is coupled with the compound of formula (III) to obtain a novel tetrahydropteridinone derivative as shown in the general formula (I). The definitions of the substituents in formula (II) and formula (III) are the same as those in formula (I). In formula (III), X is chlorine, bromine or iodine.

[0091] In some embodiments of the second aspect, the coupling reaction uses an anhydrous polar aprotic solvent, in the presence of a Pd metal catalyst such as palladium acetate, palladium trifluoroacetate, tri(dibenzylideneacetone) dipalladium or bis(dibenzylideneacetone) palladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl and the like are added, and the aromatic amine represented by formula (II) and the aromatic halide represented by formula (III) are metal coupled under an inert gas atmosphere under alkaline conditions of 80°C-150°C, and the reaction time is 12-24 hours to obtain the product; optionally, the coupling reaction further includes the step of removing the hydroxyl or amino protecting group, for example, a hydrolysis reaction is carried out under alkaline conditions to obtain the product.

[0092] In some embodiments of the second aspect, the anhydrous polar aprotic solvent is 1,4-dioxane, acetonitrile or N,N-dimethylformamide; the Pd metal catalyst is palladium acetate, palladium trifluoroacetate, tris(dibenzylideneacetone)dipalladium or bis(dibenzylideneacetone)palladium; the ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl or dicyclohexyl[3,6- dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine; the inert gas is argon or nitrogen; the alkaline conditions are provided by inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate; the coupling reaction temperature is 80°C-150°C; the coupling reaction time is 12-24 hours; the molar ratio of the compound to the metal Pd catalyst, the ligand and the base is 1:0.02-0.1:0.2-1:1.5-2.

[0093] In some embodiments of the second aspect, the alkaline conditions of the deprotection reaction are provided by potassium carbonate; the hydrolysis reaction solvent is a mixed solvent of any one of methanol, ethanol or isopropanol and water; the hydrolysis reaction temperature is 25°C-60°C; the hydrolysis reaction time is 4-12 hours; the molar ratio of the compound to the base is 1:2-5; and the mixing ratio between the alcohol solvent and water is 5:3.

[0094] In some embodiments of the second aspect, the present application provides an intermediate compound as shown in the general formula (IV), or a pharmaceutically acceptable salt thereof, which can be used for a novel tetrahydropteridinone derivative as shown in the general formula (I):

[0095]

[0096] wherein the substituents R1, R2 and R4 to R8 are defined as R1, R2 and R4 to R8 in the general formula (I); 14 It is -YW, where Y is defined the same as Y in R3 in the general formula (I), and W is specified to be hydrogen or a protecting group (eg, an amino protecting group).

[0097] In some embodiments of the second aspect, the present application provides intermediate compounds or pharmaceutically acceptable salts thereof, including but not limited to:

[0098]

[0099]

[0100] In the third aspect of the present application, the present application provides a pharmaceutical composition, which comprises a therapeutically effective amount of the above-mentioned novel tetrahydropteridinone derivative, or its tautomer, geometric isomer, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier excipient or diluent.

[0101] In the embodiment of the third aspect, the pharmaceutical composition of the present application can be formulated for specific administration routes, such as oral administration, parenteral administration (such as by injection, instillation, transdermal or topical administration) and rectal administration. Topical administration also includes suction or intranasal administration. The pharmaceutical composition of the present application can be made into solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid form (including but not limited to solutions, suspensions or emulsions). Tablets can add film coatings or enteric coatings according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following excipients: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silicon dioxide, talc, magnesium or calcium stearate, and / or polyethylene glycol; c) binders, such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavorings and sweeteners. Those skilled in the art can refer to, for example, Remington The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press 2013.

[0102] The fourth aspect of the present application provides a compound of the general formula (I) described in the present application, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicine.

[0103] In an embodiment of the fourth aspect, the drug may be used as a Plk1 kinase selective inhibitor. In some embodiments, the drug is used as a drug for treating or preventing diseases caused by excessive proliferation of malignant tumor cells.

[0104] In a fifth aspect, the present application provides the use of the compound of general formula (I) described in the present application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preparing drugs for treating or preventing diseases caused by excessive proliferation of malignant tumor cells.

[0105] The sixth aspect of the present application provides a method for treating or preventing diseases caused by excessive proliferation of malignant tumor cells, the method comprising administering the compound of general formula (I) described in the present application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically acceptable salts, or the pharmaceutical composition to a subject in need thereof.

[0106] In the embodiments of the present application, the malignant tumor cell proliferation diseases include: colorectal adenocarcinoma, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, epidermal cell carcinoma, esophageal cancer, thyroid cancer, acute leukemia, chronic myeloid leukemia, gastrointestinal cancer, liver cancer, lymphoma, myeloma, head and neck tumors, etc.

[0107] The novel tetrahydropteridinone derivative provided by the present application has a simple synthesis method, and shows a strong kinase inhibitory activity against Plk1 kinase in the kinase activity test results, and has good selectivity for Plk2 and Plk3 kinases in the same kinase family, thereby improving its targeting to Plk1 kinase, so that it can exert its drug effect at the site of action while reducing the impact of the drug on other targets and reducing the occurrence of adverse events. The Plk1 inhibitors of the present application have different binding mechanisms, that is, they form a covalent bond with Plk1, while traditional Plk1 inhibitors do not form a covalent bond with Plk1. This new mechanism can effectively overcome the drug resistance caused by mutations in the target binding site of existing Plk1 inhibitors. At the same time, this type of compound has the advantages of higher selectivity and longer duration of drug effect.

[0108] Other features and advantages of the present application will be described in the following description, and part of them will become apparent from the description, or will be understood by implementing the present application. Other advantages of the present application can be realized and obtained by the schemes described in the description.

[0109] the term

[0110] As used herein, the term "subject" refers to mammals, primates (e.g., humans (male or female)), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0111] As used herein, the term "treatment" or "treating" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the progression of the disease or at least one clinical symptom thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including physical parameters or biomarkers that may not be discernible by the subject.

[0112] As used herein, the term "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0113] As used herein, a subject is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from the treatment.

[0114] As used herein, the term "therapeutically effective amount" of a compound of the present application refers to the amount of the compound of the present application that will induce a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). BRIEF DESCRIPTION OF THE DRAWINGS

[0115] The accompanying drawings are used to provide an understanding of the technical solution of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present application and do not constitute a limitation on the technical solution of the present application.

[0116] Figure 1 The therapeutic effect of compound 7 of the present application on a non-small cell lung cancer (A549) transplanted tumor mouse model, Figure 1 A in the middle shows the weight changes of mice; Figure 1 Middle B shows the change in A549 tumor volume; Figure 1 Center C is the A549 tumor weight. DETAILED DESCRIPTION

[0117] The technical solutions in the embodiments of the present application are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

[0118] In all embodiments of the present application, the structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) and mass spectrometry (MS). 1 The HNMR spectrum was measured using a nuclear magnetic resonance instrument (600 MHz, Agilent Technologies, USA, VNMRS600). The chemical shift is expressed in ppm, using tetramethylsilane as the internal standard (0.00 ppm). The measurement solvents were deuterated chloroform and deuterated dimethyl sulfoxide. 1 H NMR notation: S = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0119] The mass spectrum was measured using an LC / MS instrument (ACQUITY UPLC LCT Premier XE, Waters, USA), and the ionization method could be ESI or APCI.

[0120] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm. Column chromatography uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0121] Kinases and cancer cell IC 50 The determination was carried out using NovoStar microplate reader (BMG, Germany).

[0122] The starting materials of this application were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., Aladdin Reagent Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sinopharm Group Chemical Reagent Co., Ltd. and other companies.

[0123] Nitrogen atmosphere means that the reaction device is connected to a balloon with a volume of about 1L, and the gas in the original reaction device is replaced with nitrogen more than three times.

[0124] abbreviation

[0125] BOC: tert-butyloxycarbonyl; PE: petroleum ether; EA: ethyl acetate; HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; ATP: adenosine triphosphate; MOPS: 3-(N-morpholino)propanesulfonic acid; EDTA: ethylenediaminetetraacetic acid; DTT: dithiothreitol.

[0126] Example 1

[0127] The synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 1) is as follows:

[0128]

[0129] (1) Synthesis of intermediate (R)-2-aminobutyric acid methyl ester (intermediate 1b)

[0130] Step I: Dissolve the commercially available raw material 1a (8 g, 77.58 mmol) in 100 mL of methanol, slowly add dichlorothionyl (12 mL, 165.22 mmol) to the system at 0°C using a constant pressure separatory funnel, remove the ice bath and constant pressure separatory funnel after the addition of dichlorothionyl is complete, stir at room temperature for 15 minutes, and then place in a 60°C oil bath for reflux reaction for 2 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, add petroleum ether (50 mL×3) for washing, and filter to obtain a pure white solid, which is dried overnight in vacuum to obtain intermediate 1b (7.9 g, pure white solid, yield 87%).

[0131] (2) Synthesis of intermediate (R)-2-(1-tert-butyloxycarbonyl-4-piperidinyl)-aminobutyric acid methyl ester (Intermediate 1c)

[0132] Step II: Dissolve the intermediate 1b (7.9 g, 67.49 mmol) in 70 mL of dichloromethane, adjust the reaction system to weak acidity (pH = 5-6) with triethylamine at 0 ° C, then add N-tert-butyloxycarbonyl-4-piperidone (13.5 mL, 67.75 mmol) and 4.5 g of sodium acetate in batches, remove the ice bath after the reaction system is stable and does not release heat, stir and react at room temperature for 2 hours, finally add sodium triacetoxyborohydride (28.7 g, 135.4 mmol) in batches to the system, stir and react at room temperature for 16 hours, and monitor the reaction by fumigating the thin layer chromatography plate in an iodine cylinder to observe the changes in the raw material point and the product point at any time. After the raw material reaction is completed, pour the reaction solution into 100 ml of water to quench and stir, and a large number of bubbles are observed. Saturated sodium bicarbonate solution was added dropwise to adjust the pH of the solution to 7-8, extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a silica gel column (dichloromethane: methanol = 20:1) to obtain intermediate 1c (19.5 g, light brown oil, yield 96%).

[0133] (3) Synthesis of Intermediate (R)-tert-butyl 4-((2-chloro-5-nitropyrimidin-4-yl)(1-methoxy-1-oxobutan-2-yl)amino)piperidine-1-carboxylate (Intermediate 1d)

[0134] Step III: Under ice bath conditions, take intermediate 1c (19.5 g, 64.91 mmol) and dissolve it in 40 mL of anhydrous acetonitrile, then add potassium carbonate (11.20 g, 81.04 mmol) and 8.0 g of anhydrous sodium sulfate to the reaction system and stir, finally add 2,4-dichloro-5-nitropyrimidine (12.6 g, 64.96 mmol) in anhydrous acetonitrile, and reflux in an oil bath at 60°C for 12 h. After the reaction is completed by monitoring the reaction on a thin layer chromatography plate, stop the reaction, remove the salt in the reaction system by suction filtration, and then extract with ethyl acetate and water (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure, and finally obtain intermediate 1d (12.5 g, yellow solid, yield 42%) by column chromatography (petroleum ether: ethyl acetate = 5:1).

[0135] (4) Synthesis of Intermediate (R)-4-(2-chloro-7-ethyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1e)

[0136] Step IV: Dissolve the intermediate 1d (12.5 g, 27.30 mmol) in 30 mL of methanol, add ammonium chloride (8.03 g, 150 mmol), and stir. Soak zinc powder (10.0 g, 153 mmol) in 1 mol / L hydrochloric acid for 1 minute to activate it, pour out the hydrochloric acid, wash with methanol, and add the reaction solution under ice bath. Remove the ice bath and react at room temperature for 12 hours. After the reaction is completed by monitoring the thin layer chromatography plate, remove the excess zinc powder and ammonium chloride by suction, wash the filter cake with methanol, combine the filtrate, concentrate under reduced pressure, and chromatograph on a silica gel column (dichloromethane: methanol = 20: 1) to obtain the intermediate 1e (2.7 g, light yellow solid, yield 25%).

[0137] (5) Synthesis of Intermediate (R)-4-(2-chloro-7-ethyl-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1f)

[0138] Step V: Dissolve the intermediate 1e (2.7 g, 6.83 mmol) in 10 ml of acetonitrile, add potassium carbonate (1.05 g, 7.5 mmol), and drop iodomethane (470 μL, 5.6 mmol) at room temperature. After the addition, raise the temperature to 50 degrees and react for 4 hours. After the reaction is completed, add 50 mL of saturated brine and ethyl acetate (50 mL × 3) to extract, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and chromatograph on a silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain the intermediate 1f (2.3 g, light yellow solid, yield 82%).

[0139] (6) Synthesis of intermediate 3-methoxy-N-methyl-4-nitrobenzamide (intermediate 1h)

[0140] Step VI: Dissolve the commercially available raw materials 3-methoxy-4-nitrobenzoic acid, i.e., 1 g (1 g, 5.07 mmol) and methylamine (0.16 g, 5.14 mmol) in 5 mL of dichloromethane, add N,N-diisopropylethylamine (0.4 mL, 6.78 mmol) and HBTU (2.5 g, 6.60 mmol) under stirring at 0°C, and react for 1 h. After the reaction of the raw materials is completed, the mixture is extracted with water and dichloromethane (50 mL×3) and the organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain the intermediate 1h (0.80 g, white solid, yield 75%).

[0141] (7) Synthesis of Intermediate 4-amino-3-methoxy-N-methylbenzamide (Intermediate 1i)

[0142] Step VII: 1h (0.80 g, 3.80 mmol) was dissolved in 15 mL of methanol, 5% palladium / carbon catalyst (1 mol%) was added, hydrogen was replaced and stirred overnight. After the reaction was completed, the catalyst was removed by filtration, the solid was re-dissolved in 30 mL of dichloromethane, washed with saturated brine (30 mL×3), the organic layer was dried, and concentrated under reduced pressure to obtain intermediate 1i (0.63 g, light yellow solid, yield 92%).

[0143] (8) Synthesis of Intermediate (R)-tert-butyl 4-(7-ethyl-2-((2-methoxy-4-(methylcarbamoyl)phenyl)amino)-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)piperidine-1-carboxylate (Intermediate 1j)

[0144] Step VIII: Dissolve 1i (0.63 g, 3.00 mmol) in anhydrous 1,4-dioxane in an eggplant-shaped bottle, and add intermediate 1f (1.48 g, 3.60 mmol), cesium carbonate (1.95 g, 6.00 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (0.35 g, 0.6 mmol) to the eggplant-shaped bottle in sequence. Put a balloon filled with nitrogen on the mouth of the eggplant-shaped bottle, and use a vacuum pump to replace the nitrogen several times until no bubbles emerge in the system. At this time, quickly add tri(dibenzylideneacetone)dipalladium (0.27 g, 0.3 mmol), continue to use a vacuum pump to repeatedly replace the nitrogen for about one hour, and finally place the system completely under nitrogen protection and react in an oil bath at 110°C for 16 hours. After the reaction solution was cooled to room temperature, it was filtered and washed with ethyl acetate. The filtrate was collected and extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 1j (0.75 g, light yellow solid, yield 59%) was obtained by column chromatography (ethyl acetate: methanol = 10:1).

[0145] (9) Synthesis of Intermediate (R)-4-((7-ethyl-5-methyl-6-oxo-8-(piperidin-4-yl)-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-methylbenzamide (Intermediate 1k)

[0146] Step IX: Dissolve 1j (750 mg, 1.35 mmol) in 5 mL of dichloromethane, add 1 mL of trifluoroacetic acid dropwise to the reaction system under ice bath conditions, remove the ice bath after the reaction system is stable, and stir the reaction at room temperature for 12 hours. After the reaction is completed, concentrate under reduced pressure to remove the volatile liquid, and finally obtain the intermediate 1k (0.55 g, light yellow solid, yield 67%) by column chromatography (ethyl acetate: methanol = 5:1).

[0147] (10) Synthesis of the target product (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 1)

[0148] Step X: 1k (550 mg, 1.21 mmol) was dissolved in 8 mL of dichloromethane under ice bath conditions, N, N-diisopropylethylamine (0.069 mL, 1.82 mmol) was added dropwise to the reaction system, and then acryloyl chloride (0.04 mL, 1.21 mmol) was added dropwise to the reaction system, and the reaction was stirred for 2 h under ice bath. After the reaction was completed, the volatile liquid was removed by concentration under reduced pressure, and finally compound 1 (279 mg, light yellow solid, yield 45%) was obtained by column chromatography (ethyl acetate: methanol = 8: 1); 1HNMR (600MHz, DMSO-d6) δ (ppm): 8.39 (t, J = 7.7Hz, 3H), 8.27 (d, J = 4.6Hz, 3H), 7.84 (s, 3H), 7.64 (s, 3H), 7.46 (d, J = 7.0Hz, 6H), 6 .85(ddd,J=16.4,10.3,5.9Hz,3H),6.14(d,J=16.6Hz,3H),5.69(dd,J=10.5,2.2Hz,3H),4.63(d,J=10.1Hz,3H),4.41(d,J=11.2 Hz,3H),4.31-4.17(m,6H),4.02(q,J=7.1Hz,1H),3.92(s,9H),3.23(s,9H),3.18(dd,J=27.3,13.5Hz,3H),2.78(d,J=4.4Hz,9H) ,2.76-2.70(m,3H),2.13(d,J=11.3Hz,3H),2.00-1.94(m,3H),1.81-1.58(m,13H),0.72(t,J=7.3Hz,9H); HRMS(ESI):m / z,(M+H) + , measured value 508.2691.

[0149] Example 2

[0150] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 2)

[0151]

[0152] Referring to the preparation of compound 1, ethylamine was used instead of methylamine according to the same feed ratio to obtain the title compound 2 (158 mg, white solid, yield 48%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.39 (t, J = 9.4Hz, 1H), 8.36-8.28 (m, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 7.47 (d, J = 7.5Hz, 2H), 6.86 (ddd, J =16.5,10.2,6.2Hz,1H),6.14(d,J=16.7Hz,1H),5.69(dd,J=10.5,2.0Hz,1H),4.64(t,J=11.9Hz,1H),4.40(d,J=12.2Hz,1H),4.32-4 .17(m,2H),3.92(s,3H),3.29(dt,J=13.7,7.1Hz,2H),3.24(s,3H),3.18(dd,J=27.7,13.9Hz,1H),2.74(dd,J=22.7,10.9Hz,1H),2.1 3(d,J=11.6Hz,1H),1.98(s,1H),1.82-1.68(m,3H),1.63(m,1H),1.13(t,J=7.2Hz,3H),0.73(t,J=7.3Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 522.2841.

[0153] Example 3

[0154] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-propylbenzamide (Compound 3)

[0155]

[0156] Referring to the preparation of compound 1, methylamine was replaced with n-propylamine according to the same feed ratio to obtain the title compound 3 (265 mg, light yellow solid, yield 53%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.39 (s, 1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.48 (d, J = 8.1Hz, 2H), 6.84 (dd, J = 16.6, 10.6H z,1H),6.13(dd,J=16.7,1.9Hz,1H),5.69(dd,J=10.5,2.3Hz,1H),4.64(s,1H),4.41(d,J=8.9Hz,1H),4.31-4.14(m,2H),3.93(s, 3H),3.24(s,3H),3.24-3.20(m,2H),3.20-3.12(m,1H),2.75(d,J=7.3Hz,1H),2.12(d,J=11.7Hz,1H),2.00(d,J=16.8Hz,1H),1.7 6(dd,J=8.6,5.2Hz,3H),1.68-1.59(m,1H),1.58-1.51(m,2H),0.90(t,J=7.4Hz,3H),0.74(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value: 536.3001.

[0157] Example 4

[0158] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-butyl-3-methoxybenzamide (Compound 4)

[0159]

[0160] Referring to the preparation of compound 1, the title compound 4 (165 mg, white solid, yield 29%) was obtained by replacing methylamine with compound n-butylamine according to the same feed ratio; 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.38 (s, 1H), 8.22 (s, 1H), 7.85 (s, 1H), 7.63 (s, 1H), 7.48 (d, J = 8.5Hz, 2H), 6.84 (dd, J = 16.4, 10.6Hz, 1 H),6.13(dd,J=16.7,1.7Hz,1H),5.68(dd,J=10.5,2.2Hz,1H),4.64(s,1H),4.40(d,J=7.6Hz,1H),4.31-4.16(m,2H),3.93(s,3H),3. 30-3.25(m,3H),3.24(s,3H),3.16(t,J=20.2Hz,1H),2.75(d,J=8.4Hz,1H),2.11(t,J=12.9Hz,1H),1.98(s,1H),1.76(dd,J=8.6,5.0 Hz,3H),1.68-1.59(m,1H),1.55-1.48(m,2H),1.38-1.29(m,2H),0.91(t,J=7.4Hz,3H),0.74(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 550.3153.

[0161] Example 5

[0162] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-isobutyl-3-methoxybenzamide (Compound 5)

[0163]

[0164] Referring to the preparation of compound 1, isobutylamine was used instead of methylamine according to the same feed ratio to obtain the title compound 5 (257 mg, light yellow solid, yield 48%); 1H NMR(600MHz,DMSO-d6)δ(ppm):8.44-8.35(m,1H),8.35-8.27(m,1H),7.86(s,1H),7.64(s,1H),7.49(s,2H),6.91-6.82(m ,1H),6.13(d,J=16.7Hz,1H),5.69(d,J=10.4Hz,1H),4.63(t,J=11.9Hz,1H),4.41(d,J=12.9Hz,1H),4.24(dd,J=36.3,15 .1Hz,2H),3.93(s,3H),3.23(d,J=9.6Hz,3H),3.21-3.13(m,1H),3.08(t,J=6.3Hz,2H),2.79-2.70(m,1H),2.16-2.09(m, 1H), 1.99 (q, J=15.5Hz, 1H), 1.89-1.58 (m, 5H), 0.87 (dd, J=20.1, 5.7Hz, 6H), 0.73 (t, J=7.0Hz, 3H); HRMS (ESI): m / z, (M+H) + , measured value 550.3163.

[0165] Example 6

[0166] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (Compound 6)

[0167]

[0168] Referring to the preparation of compound 1, cyclopropylamine was used instead of methylamine according to the same feed ratio to obtain the title compound 6 (185 mg, white solid, yield 29%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.41-8.32 (m, 1H), 8.31-8.22 (m, 1H), 7.85 (s, 1H), 7.64 (s, 1H), 7.44 (d, J = 6.5Hz, 2H), 6.86 (ddd, J = 16.4, 10.4, 5.3Hz,1H),6.17-6.09(m,1H),5.69(dd,J=10.6,2.6Hz,1H),4.63(t,J=13.4Hz,1H),4.39(d,J=14.7Hz,1H),4.32-4.17(m,2H),3.92(d,J=1.0H z,3H),3.24(s,3H),3.18(q,J=13.9Hz,1H),2.81(tq,J=7.6,3.9Hz,1H),2.74(q,J=12.1Hz,1H),2.11(d,J=12.1Hz,1H),2.05-1.94(m,1H),1.8 1-1.70(m,3H),1.63(dt,J=14.3,7.3Hz,1H),0.73(q,J=5.8,4.2Hz,3H),0.69(dt,J=6.9,3.3Hz,2H),0.58-0.55(m,2H); HRMS(ESI):m / z,(M+H) + , measured value 534.2835.

[0169] Example 7

[0170] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-2-fluoro-5-methoxybenzamide (Compound 7)

[0171]

[0172] Referring to the preparation of compound 6, 2-fluoro-5-methoxy-4-nitrobenzoic acid was used to replace the raw material 3-methoxy-4-nitrobenzoic acid according to the same feed ratio to obtain the title compound 7 (189 mg, white solid, yield 48%); 1H NMR(600MHz,DMSO-d6)δ(ppm):8.32(dd,J=13.7,6.8Hz,1H),8.02(t,J=3.8Hz,1H),7.90(s,1H),7.73(s,1H),7.18(d,J=6.7Hz,1H),6.85(dd,J=16 .7,10.5Hz,1H),6.12(dd,J=16.7,2.5Hz,1H),5.69(d,J=10.4Hz,1H),4. 62(s,1H),4.46(s,1H),4.29(d,J=9.3Hz,1H),4.22(s,1H),3.90(s,3H),3 .25(s,3H),3.16(t,J=13.0Hz,1H),2.81(tq,J=7.9,4.1Hz,1H),2.75-2. 69(m,1H),2.12(dt,J=12.4,3.1Hz,1H),2.05-1.91(m,1H),1.76(tq,J=10 .7,3.3Hz,3H),1.63(dp,J=14.9,7.4Hz,1H),0.74(t,J=7.4Hz,3H),0.68( td,J=7.0,4.7Hz,2H),0.56(dt,J=6.9,4.3Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 552.2705.

[0173] Example 8

[0174] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-3-(trifluoromethoxy)benzamide (Compound 8)

[0175]

[0176] Referring to the preparation of compound 6, the compound 4-nitro-3-trifluoromethoxybenzoic acid was used to replace the raw material 3-methoxy-4-nitrobenzoic acid according to the same feed ratio to obtain the title compound 8 (190 mg, light yellow solid, yield 50%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.50-8.42 (m, 2H), 8.27 (dd, J = 14.4, 8.7Hz, 1H), 7.84 (d, J = 2.4Hz, 1H), 7.80 (t, J = 8.3Hz, 2H), 6.8 1(dt,J=16.6,10.2Hz,1H),6.10(dd,J=16.8,3.0Hz,1H),5.67(dd,J=8.3,5.3Hz,1H),4.60(d,J=12.8Hz,1H),4.35-4.23(m,2H),4 .18(t,J=12.1Hz,1H),3.09(dt,J=50.7,12.7Hz,1H),2.82(tq,J=7.6,3.9Hz,1H),2.66(dt,J=41.7,12.1Hz,1H),2.09-1.95(m,2H ),1.76(ddt,J=22.3,11.7,3.5Hz,3H),1.63(dp,J=14.7,7.6Hz,1H),0.76-0.68(m,5H),0.60-0.54(m,2H); HRMS(ESI):m / z,(M+H) + , measured value 588.2513.

[0177] Example 9

[0178] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 9)

[0179]

[0180] Referring to the preparation of compound 1, the compound 4-amino-1-methylpiperidine was used to replace methylamine according to the same feed ratio to obtain the title compound 9 (437 mg, yellow solid, yield 41%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.38 (dd, J=14.7, 8.8Hz, 1H), 8.06 (dd, J=14.9 ,7.8Hz,1H),7.86(s,1H),7.64(d,J=8.4Hz,1H),7.47(s,2H),6.86(ddd,J=16. 1,10.3,5.3Hz,1H),6.13(d,J=16.6Hz,1H),5.69(d,J=11.6Hz,1H),4.61(q,J =20.6,16.9Hz,1H),4.43-4.32(m,1H),4.31-4.24(m,1H),4.23-4.17(m,1H),3 .93(s,3H),3.77-3.68(m,1H),3.24(s,3H),3.16(q,J=15.1,13.0Hz,1H),2.7 7(d,J=11.3Hz,2H),2.16(s,3H),2.11(d,J=11.7Hz,1H),2.04(d,J=3.0Hz,1H) ,1.99(s,1H),1.92(t,J=11.1Hz,2H),1.79-1.72(m,4H),1.67-1.55(m,4H),0. 84(ddd,J=13.1,9.8,6.6Hz,1H),0.73(t,J=7.2Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 591.3315.

[0181] Example 10

[0182]

[0183] Synthesis of (R)-tert-butyl 4-(7-ethyl-2-((2-methoxy-4-(1-methylpiperidin-4-yl)carbamoyl)phenyl)amino)-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)piperidine-1-carboxylate (Compound 10)

[0184] Referring to the preparation of compound 9, the title compound 10 (155 mg, white solid, yield 41%) was obtained by synthesizing to step VIII according to the same feed ratio; HRMS (ESI): m / z, (M+H) + , the measured value is 637.3853.

[0185] Embodiment 11

[0186] Synthesis of (R)-4-((7-ethyl-5-methyl-6-oxo-8-(piperidin-4-yl)-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 11)

[0187]

[0188] Referring to the preparation of compound 9, the title compound 11 (256 mg, white solid, yield 49%) was obtained by synthesizing to step IX according to the same feed ratio.

[0189] Example 12

[0190] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-3-(trifluoromethoxy)benzamide (Compound 12)

[0191]

[0192] Referring to the preparation of compound 9, 4-nitro-3-trifluoromethoxybenzoic acid was used instead of 3-methoxy-4-nitrobenzoic acid according to the same feed ratio to obtain the title compound 12 (179 mg, light yellow solid, yield 48%); 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.59-8.54 (m, 1H), 8.47 (d, J = 6.2Hz, 1H), 8.30 (td, J = 17.5, 16.2, 8.7Hz, 1H), 7.95-7.90 (m, 1H), 7.86 (dd, J = 16 .2,4.3Hz,2H),6.81(td,J=15.5,10.2Hz,1H),6.12-6.05(m,1H),5.70- 5.63(m,1H),4.59(d,J=13.0Hz,1H),4.34-4.24(m,2H),4.18(t,J=17.4 Hz,1H),4.01(q,J=7.6Hz,1H),3.24(s,3H),3.18-3.11(m,1H),3.04-2.94(m,2H),2.64(s,3H),2.05(d,J=12.3Hz,1H),1.96(q,J=6.7Hz,4H), 1.81-1.70(m,3H),1.63(dt,J=13.8,7.2Hz,1H),1.30-1.18(m,3H),0.85(dt,J=14.6,7.3Hz,1H),0.73(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H)+ , measured value 645.3087.

[0193] Example 13

[0194] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-2,5-dimethoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 13)

[0195]

[0196] Referring to the preparation of compound 9, 2,5-dimethoxy-4-nitrobenzoic acid was used instead of 3-methoxy-4-nitrobenzoic acid to obtain the title compound 13 (186 mg, white solid, yield 39%) according to the same feed ratio; 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.39 (s, 1H), 7.98 (d, J = 7.4Hz, 1H), 7.90 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 6.83 (dd, J = 16.7, 10.5Hz, 1H), 6.12 (dd ,J=16.7,2.5Hz,1H),5.69(d,J=10.5Hz,1H),4.57(s,1H),4.45(tt,J=12 .2,4.0Hz,1H),4.26(q,J=8.4,7.3Hz,1H),4.16(d,J=13.7Hz,1H),3.91( s,3H),3.86(s,3H),3.25(s,3H),3.17-3.09(m,2H),2.94(s,2H),2.69(q ,J=13.0Hz,1H),2.42(s,3H),2.03(d,J=12.1Hz,2H),1.92(dd,J=15.6,5 .1Hz,2H),1.75-1.65(m,4H),1.62(dd,J=14.6,7.3Hz,1H),0.84(dtd,J=12.5,7.9,7.3,4.7Hz,1H),0.75(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 621.3483.

[0197] Embodiment 14

[0198] Synthesis of (R)-4-((8-(4-acrylamidocyclohexyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 14)

[0199]

[0200] Referring to the preparation of compound 9, 4-N-Boc-aminocyclohexanone was used in step II to replace the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 14 (178 mg, light yellow solid, yield 48%); 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.45 (dd, J=11.1, 7.3Hz, 2H), 8.18-8.05 (m, 3H), 7.86 (d, J= 2.4Hz,1H),7.85-7.81(m,1H),7.69-7.62(m,2H),7.48(tt,J=4.4,2.2Hz,2H),6.43(dd,J= 17.1,10.2Hz,1H),6.24(dd,J=17.1,10.2Hz,1H),6.12(ddd,J=17.2,7.4,2.4Hz,1H),5.60 (td,J=9.6,2.3Hz,1H),4.36(dd,J=7.8,3.6Hz,1H),4.31(td,J=9.3,5.8Hz,2H),4.08(dd,J =8.1,4.1Hz,1H),3.94(s,3H),3.25(s,3H),3.24(d,J=2.9Hz,2H),2.78(d,J=11.0Hz,3H), 2.16(s,3H),2.11-2.03(m,2H),1.93(dd,J=12.9,10.3Hz,3H),1.89(s,1H),1.84(d,J=7.0H z,1H),1.77(q,J=3.3,2.8Hz,2H),1.74(s,2H),1.70(td,J=11.1,9.4,5.6Hz,3H),1.60(dd d,J=12.1,9.1,3.4Hz,2H),1.14(t,J=7.2Hz,2H),0.80-0.75(m,3H); HRMS(ESI):m / z,(M+H) + , measured value 605.3559.

[0201] Embodiment 15

[0202] Synthesis of (R)-4-((8-(1-(2-butynoyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 15)

[0203]

[0204] Referring to the preparation of compound 9, 2-butynoyl chloride was used in step X to replace the raw material acryloyl chloride according to the same feed ratio to obtain the title compound 15 (155 mg, white solid, yield 54%); 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.33(dd,J=8.2,5.6Hz,1H),8.09-8.01(m,1H),7.84(d,J=2.2Hz,1 H),7.64(s,1H),7.46(dd,J=8.9,1.6Hz,2H),4.49-4.27(m,3H),3.92(s,3H),3.24-3.19(m,5H),2 .87-2.71(m,3H),2.22(s,3H),2.01(d,J=2.6Hz,3H),1.88(d,J=1.3Hz,2H),1.82-1.68(m,5H),1. 61(dd,J=14.0,7.8Hz,3H),1.38-1.21(m,3H),0.72(td,J=7.4,2.1Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 603.3383.

[0205] Example 16

[0206] Synthesis of (R)-4-((8-(1-(2-butynoyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (Compound 16)

[0207]

[0208] Referring to the preparation of compound 6, 2-butynoyl chloride was used instead of acryloyl chloride according to the same feed ratio to obtain the title compound 16 (375 mg, white solid, yield 56%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.33 (dd, J=8.3, 1.2Hz, 1H), 8.26 (dd, J=5.5, 3.9Hz, 1H), 7.84 (d, J=1.2 Hz,1H),7.64(s,1H),7.45-7.41(m,2H),4.50-4.34(m,3H),4.28-4.24(m,1H),3.90(s,3H),3.22(s,3H ),2.82-2.72(m,2H),2.01(d,J=2.8Hz,3H),1.97(s,1H),1.93-1.87(m,1H),1.79-1.57(m,4H),1.15(t ,J=7.1Hz,1H),0.70(dtd,J=15.2,7.3,2.5Hz,5H),0.55(tt,J=4.5,1.9Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 546.2829.

[0209] Embodiment 17

[0210] Synthesis of (R)-4-((8-(1-(2-butynoyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-3(trifluoromethoxy)benzamide (Compound 17)

[0211]

[0212] Referring to the preparation of compound 8, 2-butynoyl chloride was used instead of acryloyl chloride according to the same feed ratio to obtain the title compound 17 (136 mg, white solid, yield 34%); 1H NMR(600MHz, DMSO-d6)δ(ppm):8.50(d,J=8.1Hz,1H),8.45(t,J=3.8Hz,1H),8.26(ddd,J=10.3,8.6,2.1Hz,1H),7.87-7.83(m,1H), 7.80(tt,J=6.0,1.8Hz,2H),4.46(t,J=11.7Hz,1H),4.37(s,1H),4.28(dd,J=7.7,3.5Hz,2H),3.20(t,J=12.9Hz,3H),3.12(t,J=13 .2Hz,1H),2.82(tp,J=7.8,3.9Hz,1H),2.69(dt,J=46.9,13.1Hz,1H),2.07(d,J=12.7Hz,1H),2.02(d,J=1.2Hz,3H),1.86-1.80(m, 1H),1.79-1.68(m,3H),1.63(ddd,J=14.5,12.3,7.1Hz,1H),0.75-0.68(m,5H),0.58(tt,J=6.7,2.4Hz,2H); HRMS(ESI):m / z,(M+H) + , the measured value is 600.2539.

[0213] Embodiment 18

[0214] Synthesis of 4-((7R)-8-(1-acryloylpyrrolidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (Compound 18)

[0215]

[0216] Referring to the preparation of compound 6, 1-tert-butyloxycarbonyl-3-pyrrolidone was used in step II instead of the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 18 (535 mg, white solid, yield 66%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.34-8.20 (m, 2H), 7.89 (d, J = 11.0Hz, 1H), 7. 77-7.67(m,1H),7.39(ddd,J=25.7,11.9,5.0Hz,2H),6.67-6.47(m,1H),6.2 1-6.09(m,1H),5.75-5.58(m,1H),4.64-4.52(m,1H),4.26(dtt,J=25.7,8.1 ,3.7Hz,1H),4.02(t,J=8.6Hz,1H),3.91(s,3H),3.85(dt,J=12.5,8.1Hz,1H ),3.78(dd,J=16.8,8.3Hz,1H),3.70(dtd,J=9.0,6.4,5.9,3.4Hz,1H),3.60 (tt,J=12.2,4.7Hz,1H),2.80(qd,J=6.4,3.1Hz,1H),2.28-2.10(m,1H),1.8 1-1.59(m,3H),1.17(t,J=7.1Hz,1H),0.76(dt,J=18.9,7.4Hz,3H),0.70(dq ,J=5.7,3.6,2.7Hz,2H),0.56(dp,J=6.8,4.1Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 520.2825.

[0217] Embodiment 19

[0218] Synthesis of N-cyclopropyl-4-(((7R)-7-ethyl-5-methyl-6-oxo-8-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxybenzamide (Compound 19)

[0219]

[0220] Referring to the preparation of compound 18, the title compound 19 (165 mg, light yellow solid, yield 38%) was obtained by synthesizing to step IX according to the same feed ratio; HRMS (ESI): m / z, (M+H) + , measured value 466.2504.

[0221] Embodiment 20

[0222] Synthesis of 4-((7R)-7-ethyl-5-methyl-6-oxo-8-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 20)

[0223]

[0224] Referring to the preparation of compound 9, 1-tert-butyloxycarbonyl-3-pyrrolidone was used as the raw material instead of N-tert-butyloxycarbonyl-4-piperidone in step II according to the same feed ratio, and the title compound 20 (150 mg, white solid, yield 35%) was obtained in step IX; 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.46-8.32 (m, 1H), 8.10 (d, J = 8.2Hz, 1H), 7.90-7.81 (m, 1H), 7.69-7. 58(m,1H),7.52-7.43(m,2H),4.43(s,1H),4.30-4.20(m,1H),3.93(s,3H),3.76-3.67(m,1H),3.03(d t,J=45.8,11.3Hz,2H),2.89(dd,J=11.0,6.1Hz,1H),2.78(dd,J=9.2,5.8Hz,3H),2.16(s,3H),1.92( td,J=11.8,2.4Hz,3H),1.80-1.71(m,3H),1.39(s,2H),0.75(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 523.3139.

[0225] Embodiment 21

[0226] Synthesis of 4-((7R)-8-(1-acryloylpyrrolidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 21)

[0227]

[0228] Referring to the preparation of compound 9, the title compound 21 (150 mg, white solid, yield 35%) was obtained by replacing N-tert-butyloxycarbonyl-4-piperidone with 1-tert-butyloxycarbonyl-3-pyrrolidone in step II according to the same feed ratio; 1HNMR(600MHz,DMSO-d6)δ(ppm):8.28(ddd,J=32.0,8.4,4.7Hz,1H),8.05(dd,J=20.1,7.8Hz,1H),7.92-7.87(m,1H),7.70(d,J=27.0Hz,1H),7.47- 7.36(m,2H),6.69-6.54(m,1H),6.17(ddd,J=16.7,12.1,2.4Hz,1H),5.7 3-5.61(m,1H),4.58(dq,J=16.1,7.6Hz,1H),4.26(ddd,J=29.2,7.6,3.5H z,1H),4.02(dd,J=10.1,8.0Hz,1H),3.92(dd,J=2.5,1.1Hz,3H),3.78-3 .66(m,2H),3.61(qd,J=10.1,8.7,6.6Hz,2H),3.25(s,3H),2.79(d,J=11. 0Hz,2H),2.18(d,J=1.2Hz,3H),1.99-1.93(m,2H),1.90(s,1H),1.80-1.7 1(m,3H),1.69-1.54(m,3H),0.75(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 577.3242.

[0229] Embodiment 22

[0230] Synthesis of 4-((7R)-8-(1-(2-butynoyl)pyrrolidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 22)

[0231]

[0232] Referring to the preparation of compound 21, 2-butynoyl chloride was used instead of acryloyl chloride to obtain the title compound 22 (150 mg, white solid, yield 35%) according to the same feed ratio; 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.27 (ddd, J=8.5, 4.4, 2.5Hz, 1H), 8.11 (dd, J=16.7, 7.7Hz, 1H), 7.89 (dd, J=2.7 ,1.1Hz,1H),7.70(d,J=28.1Hz,1H),7.50-7.42(m,2H),4.54(h,J=7.2,6.4Hz,1H),4.27(td,J=7.8,3.5Hz,1H) ,3.93(d,J=1.1Hz,3H),3.88-3.74(m,3H),3.63-3.54(m,2H),2.86(d,J=11.1Hz,2H),2.24(s,2H),2.06(s,3H) ,1.94(s,1H),1.79-1.73(m,3H),1.70-1.59(m,3H),1.39(s,1H),0.74(q,J=7.6Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 589.3241.

[0233] Embodiment 23

[0234] Synthesis of (R)-4-((8-(1-(2-butynoyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 23)

[0235]

[0236] Referring to the preparation of compound 2, 2-butynoyl chloride was used instead of acryloyl chloride at the same feed ratio to obtain the title compound 23 (163 mg, yellow solid, yield 38%); 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.40 (d, J = 8.7Hz, 1H), 8.38-8.32 (m, 1H), 7.88 (s, 1H), 7.68 (s, 1 H),7.53-7.48(m,2H),4.57-4.38(m,3H),4.33-4.27(m,1H),3.95(s,3H),3.33-3.28(m,2H),3.2 6(s,3H),2.85-2.74(m,1H),2.24-2.13(m,1H),2.05(d,J=2.4Hz,3H),1.88-1.72(m,3H),1.72-1 .56(m,2H),1.15(t,J=7.2Hz,3H),0.89-0.81(m,1H),0.75(t,J=7.4,3H).HRMS(ESI):m / z,(M+H) + , measured value 534.2833.

[0237] Embodiment 24

[0238] Synthesis of (R)-4-((8-(4-(2-butynylamido)cyclohexyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 24)

[0239]

[0240] Referring to the preparation of compound 23, 4-N-Boc-aminocyclohexanone was used in step II to replace the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 24 (123 mg, light yellow solid, yield 30%); 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.48-8.41(m,1H),8.41-8.29(m,1H),7.90-7.82(m,1 H),7.68(s,1H),7.65-7.52(m,1H),7.50(s,1H),4.30(d,J=8.1Hz,1H),4.12(s,1H),3 .96(s,3H),3.73(s,1H),3.34-3.28(m,2H),3.25(s,3H),2.16-1.59(m,10H),1.52-1. 33(m,2H),1.24(s,1H),1.20-1.12(m,3H),0.75(t,J=7.7,3H).HRMS(ESI):m / z,(M+H) + , measured value 548.2996.

[0241] Embodiment 25

[0242] Synthesis of (R)-4-((8-(1-(2-butynyl)piperidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 25)

[0243]

[0244] Referring to the preparation of compound 23, N-tert-butyloxycarbonyl-3-piperidone was used in step II to replace the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 25 (138 mg, light yellow solid, yield 33%); 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.54-8.22(m,2H),7.97-7.64(m,2H),7.53-7.43(m,2H),4. 42-4.18(m,2H),4.08(s,1H),3.95(d,J=7.8Hz,3H),3.30(t,J=6.6Hz,2H),3.27(q,J=2.4,1 .8Hz,3H),3.09(q,J=11.5,10.3Hz,1H),2.33-1.92(m,2H),1.85(t,J=9.9Hz,5H),1.61-1.2 0(m,2H),1.14(t,J=7.2,3H),0.89-0.83(m,1H),0.79(t,7.6Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 534.2839.

[0245] Embodiment 26

[0246] Synthesis of (R)-4-((8-(1-(2-butynyl)pyrrolidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 26)

[0247]

[0248] Referring to the preparation of compound 23, 1-tert-butyloxycarbonyl-3-pyrrolidone was used in step II to replace the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 26 (143 mg, light yellow solid, yield 34%); 1HNMR(400MHz,DMSO-d6)δ(ppm):8.38-8.23(m,2H),7.96-7.88(m,1H),7.76(d,J=14.1Hz,1 H),7.53-7.42(m,2H),4.77-4.44(m,1H),4.36-4.20(m,1H),4.14-3.50(m,7H),3.33-3.28 (m,2H),3.27(s,3H),2.30-2.11(m,1H),2.07(d,J=4.4Hz,1H),1.99-1.90(m,1H),1.85-1. 59(m,2H),1.25(s,1H),1.15(t,J=7.2Hz,3H),0.77(t,J=7.2Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 520.2681.

[0249] Embodiment 27

[0250] Synthesis of (R)-4-((8-(3-(2-butynylamido)cyclobutyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 27)

[0251]

[0252] Referring to the preparation of compound 23, tert-butyl 3-oxocyclobutylcarbamate was used in step II to replace the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 27 (127 mg, light yellow solid, yield 32%); 1 HNMR(400MHz,DMSO-d6)δ(ppm):8.53-8.42(m,1H),8.40-8.32(m,1H),7.90(d,J=6.2Hz,1H),7.62 (s,1H),7.54-7.46(m,2H),5.44-5.27(m,1H),4.39-4.00(m,3H),3.95(s,3H),3.34-3.25(m,5H),2 .96-2.59(m,2H),2.46(d,J=6.5Hz,1H),2.30-2.08(m,1H),1.99(d,J=16.8Hz,2H),1.77-1.47(m,1 H),1.25(s,1H),1.15(t,J=7.2,3H),0.91-0.81(m,1H),0.76(t,J=6.6,3H).HRMS(ESI):m / z,(M+H) + , measured value 520.2680.

[0253] Embodiment 28

[0254] Synthesis of (R)-4-((8-(1-(2-butynyl)azetidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 28)

[0255]

[0256] Referring to the preparation of compound 23, 1-Boc-3-azetidinone was used in step II to replace the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 28 (110 mg, light yellow solid, yield 30%); 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.40-8.32 (m, 2H), 7.94 (s, 1H), 7.76 (d, J = 7.3Hz, 1H) ,7.55-7.47(m,2H),4.62-4.43(m,2H),4.38-4.24(m,3H),4.17-4.03(m,1H),3.95(s ,3H),3.31(d,J=6.6Hz,2H),3.28(s,3H),2.01(d,J=5.9Hz,3H),1.79-1.61(m,1H),1 .61-1.52(m,1H),1.14(t,J=7.2Hz,3H),0.74(t,J=7.3Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 506.2523.

[0257] Embodiment 29

[0258] Synthesis of (R)-4-((8-(1-(2-chloroacetyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 29)

[0259]

[0260] Referring to the preparation of compound 23, chloroacetyl chloride was used to replace the raw material 2-butynoyl chloride according to the same feed ratio to obtain the title compound 29 (159 mg, yellow solid, yield 38%); 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.45-8.31 (m, 2H), 7.88 (d, J = 1.7Hz, 1H), 7.71 (s, 1H),7.53-7.47(m,2H),4.60-4.37(m,4H),4.35-4.23(m,1H),4.07-3.92(m,4H), 3.34-3.25(m,6H),2.85-2.66(m,1H),2.16-2.07(m,1H),2.00-1.86(m,1H),1.85 -1.60(m,4H),1.15(t,J=7.2Hz,3H),0.76(t,J=7.4Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 544.2447.

[0261] Embodiment 30

[0262] Synthesis of (R)-4-((8-(1-(2,2-dichloroacetyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 30)

[0263]

[0264] Referring to the preparation of compound 23, dichloroacetyl chloride was used to replace the raw material 2-butynoyl chloride according to the same feed ratio to obtain the title compound 30 (210 mg, yellow solid, yield 44%); 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.47-8.31 (m, 1H), 7.88 (d, J = 4.2Hz, 1H), 7.76 (s, 1H), 7.59-7.42 (m, 2H ),7.34(d,J=2.4Hz,1H),4.60-4.08(m,3H),3.95(s,2H),3.81-3.72(m,1H),3.44-3.28(m,5H),3.22(d ,J=1.9Hz,1H),2.34-1.88(m,2H),1.87-1.76(m,2H),1.74-1.57(m,2H),1.41(s,1H),1.25(s,1H),1.1 3(t,J=7.2Hz,3H),0.91-0.79(m,1H),0.79-0.73(m,2H),0.69(t,J=7.5Hz,1H).HRMS(ESI):m / z,(M+H) + , measured value 578.2057.

[0265] Embodiment 31

[0266] Synthesis of (R)-4-((8-(1-cyanopiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 31)

[0267]

[0268] Referring to the preparation of compound 23, cyanogen bromide was used to replace the raw material 2-butynoyl chloride according to the same feed ratio to obtain the title compound 31 (263 mg, yellow solid, yield 51%); 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.40 (d, J = 8.7Hz, 1H), 8.36 (d, J = 6.8Hz, 1H), 7.87 (s, 1H), 7 .69(s,1H),7.52-7.47(m,2H),4.60(t,J=10.9Hz,1H),4.47-4.36(m,1H),4.32-4.26(m,1H ),3.95(s,3H),3.34-3.28(m,2H),3.26(s,3H),2.64(t,J=13.2Hz,1H),2.07(d,J=1.7Hz,4 H),1.91-1.61(m,4H),1.15(t,J=7.2Hz,3H),0.76(t,J=7.4Hz,3H).HRMS(ESI):m / z,(M+H) + , the measured value is 493.2676.

[0269] Embodiment 32

[0270] Synthesis of (R)-4-((8-(1-(2-butynyl)azetidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-2-fluoro-5-methoxybenzamide (Compound 32)

[0271]

[0272] Referring to the preparation of compound 28, 2-fluoro-5-methoxy-4-nitrobenzoic acid was used to replace the raw material 3-methoxy-4-nitrobenzoic acid according to the same feed ratio to obtain the title compound 32 (89 mg, white solid, yield 24%); 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.41-8.33 (m, 1H), 8.06-7.96 (m, 2H), 7.77 (d, J= 24.3Hz,1H),7.26(d,J=3.5Hz,1H),4.55(d,J=11.7Hz,2H),4.41-4.29(m,3H),3. 93(s,3H),3.31-3.25(m,5H),2.01(d,J=3.6Hz,2H),1.75(s,1H),1.61(s,1H),1. 22-1.16(m,2H),1.12(t,J=7.2Hz,3H),0.77-0.70(m,3H).HRMS(ESI):m / z,(M+H) + , measured value 524.2423.

[0273] Embodiment 33

[0274] Synthesis of (R)-4-((8-(1-(2-butynoyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-2-fluoro-5-methoxybenzamide (Compound 33)

[0275]

[0276] Referring to the preparation of compound 23, 2-fluoro-5-methoxy-4-nitrobenzoic acid was used instead of 3-methoxy-4-nitrobenzoic acid according to the same feed ratio to obtain the title compound 33 (93 mg, white solid, yield 25%); 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.35 (d, J = 13.7Hz, 1H), 8.05-7.98 (m, 1H), 7.93 (s, 1H), 7.80 (s, 1H), 7. 27(d,J=6.8Hz,1H),4.50(d,J=12.6Hz,2H),4.43(d,J=11.7Hz,1H),4.34-4.28(m,1H),3.93(s,3H),3. 32-3.28(m,2H),3.27(s,3H),2.85-2.73(m,1H),2.23-2.10(m,1H),2.05(s,3H),1.87-1.70(m,3H),1. 71-1.58(m,2H),1.13(t,J=7.1Hz,3H),0.90-0.81(m,1H),0.76(t,J=6.9Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 552.2742.

[0277] Embodiment 34

[0278] The synthesis of 4-((8-(2-(2-butynylamido)ethyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 34) is as follows:

[0279]

[0280] (1) Synthesis of intermediate 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)butyric acid methyl ester (Intermediate 34b)

[0281] Step I: 8 ml of N-tert-butyloxycarbonyl-1,2-ethylenediamine (50 mmol) and 7.7 ml of triethylamine (55 mmol) were dissolved in 30 ml of toluene. 6.5 ml of methyl 2-bromobutyrate (50 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was heated under reflux for 7 hours, then cooled to room temperature and stirred at room temperature for 3 days, and then tested by TLC. After the reaction was completed, 100 ml of ethyl acetate was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and chromatographed on a silica gel column (CH2Cl2 / MeOH=20 / 1) to obtain intermediate 34b (12.5 g, yellow oil, yield 96%).

[0282] (2) Synthesis of Intermediate 2-((2-((tert-butoxycarbonyl)amino)ethyl)(2-chloro-5-nitropyrimidin-4-yl)amino)butanoic acid methyl ester (Intermediate 34c)

[0283] Step II: Dissolve 12.5 g of compound 34b in 40 ml of anhydrous acetonitrile, add potassium carbonate (8.3 g, 60 mmol) and 5.0 g of anhydrous sodium sulfate and stir, and dropwise add anhydrous acetonitrile solution of 2,4-dichloro-5-nitropyrimidine (7.8 g, 48 mmol) at room temperature, and the reaction solution changes from yellow to orange. After the addition is complete, heat to 60 degrees, react for 12 hours, and the reaction solution changes to dark red brown to black. After the reaction is completed by TLC monitoring, add 200 ml of ethyl acetate, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, and obtain compound 34c (8.4 g, yellow solid, yield 42%) after silica gel column chromatography (PE / EA=5 / 1).

[0284] (3) Synthesis of Intermediate (tert-butyl (2-(2-chloro-7-ethyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)ethyl)carbamate (Intermediate 34d)

[0285] Step III: Dissolve 8.4 g of compound 34c in 30 ml of methanol, add 8.0 g of ammonium chloride (150 mmol), and stir. Soak 10.0 g of zinc powder (153 mmol) in 1 M hydrochloric acid for 1 minute to activate, pour out the hydrochloric acid, wash with methanol, and add the reaction solution under ice bath. Remove the ice bath, react at room temperature for 12 hours, and the reaction solution changes from yellow to gray-green suspension. After the reaction is completed, the excess zinc and ammonium chloride are removed by suction filtration, the filter cake is washed with methanol, the filtrate is combined, and after silica gel column chromatography (CH2Cl2 / MeOH=20 / 1), compound 34d (1.8 g, yellow solid, yield 25%) is obtained.

[0286] (4) Synthesis of Intermediate (tert-butyl (2-(2-chloro-7-ethyl-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)ethyl)carbamate (Intermediate 34e)

[0287] Step IV: Dissolve 1.8 g of compound 34d in 10 ml of acetonitrile, add 0.8 g of potassium carbonate (5.5 mmol), and dropwise add 350 μl of iodomethane (5.6 mmol) at room temperature. After the addition, raise the temperature to 50 degrees, react for 4 hours, and monitor by TLC. After the reaction, add 60 ml of ethyl acetate, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, and chromatograph on a silica gel column (PE / EA=2 / 1) to obtain compound 34e (1.0 g, yellow solid, yield 54%).

[0288] (5) Synthesis of Intermediate (tert-butyl (2-(7-ethyl-2-((4-(ethylcarbamoyl)-2-methoxyphenyl)amino)-5-methyl-6-oxy-6,7-dihydropteridin-8(5H)-yl)ethyl)carbamate (Intermediate 34f)

[0289] Step V: Take 111 mg of compound 34e and 4-amino-N-ethyl-3-methoxybenzamide (58 mg, 0.3 mmol) in a 25 ml round-bottom flask, add 5 ml of anhydrous 1,4-dioxane to fully dissolve. Then add 10 mg of Pd2(dba)3 (0.01 mmol), 12 mg of Xantphos (0.02 mmol) and 160 mg of cesium carbonate (0.5 mmol), immediately add a condenser and protect with argon. The reaction solution is heated to 110 degrees for 12 hours and monitored by TLC. After the reaction is completed, 20 ml of ethyl acetate is added and washed with water three times. The organic layer is dried over anhydrous sodium sulfate and chromatographed on a silica gel column (CH2Cl2 / MeOH=20 / 1) to obtain compound 34f (65 mg, yellow solid, yield 41%).

[0290] (6) Synthesis of Intermediate 4-((8-(2-aminoethyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Intermediate 34 g)

[0291] Step VI: Dissolve 65 mg of compound 34f in 2 ml of ethyl acetate, add 4 ml of hydrochloric acid in ethyl acetate, and stir at room temperature for 2 hours. After the reaction, spin dry the reaction solution, add 10 ml of water, and adjust the pH to 8-9 with saturated sodium bicarbonate. Extract three times with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, spin off the solvent to obtain a yellow solid, which can be used directly in the next step.

[0292] (7) Synthesis of the target product 4-((8-(2-(2-butynylamido)ethyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 34)

[0293] Step VII: The product of the previous step was dissolved in 2 ml of dichloromethane, 140 μl of triethylamine (1 mmol) was added, and 50 μl of 2-butynoyl chloride (0.6 mmol) was added dropwise under ice bath, and the reaction was carried out for 4 hours, and the reaction progress was monitored by TLC. After the reaction was completed, 20 ml of water was added to quench the reaction, and the dichloromethane was extracted. The organic layer was dried over anhydrous sodium sulfate, and after silica gel column chromatography (CH2Cl2 / MeOH=20 / 1), compound 34 (7 mg, yellow solid, yield 11%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.49-8.41(m,1H),8.39-8.32(m,1H),7.83(s,1H),7.6 2(s,1H),7.55-7.46(m,2H),4.29(s,1H),4.21-4.07(m,1H),3.96(s,3H),3.69-3.60(m ,1H),3.52-3.42(m,1H),3.33-3.29(m,2H),3.29(s,3H),3.24-3.13(m,1H),1.93(s,2 H),1.88-1.75(m,2H),1.18-1.05(m,5H),0.73(t,J=7.4Hz,3H).HRMS(ESI):m / z,(M+H) + , the measured value is 494.2523.

[0294] Embodiment 35

[0295] Synthesis of 4-((8-(3-(2-butynylamido)propyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-3-methoxybenzamide (Compound 35)

[0296]

[0297] Referring to the preparation of compound 34, N-tert-butyloxycarbonyl-1,3-propylenediamine was used to replace the raw material N-tert-butyloxycarbonyl-1,2-ethylenediamine according to the same feed ratio to obtain the title compound 35 (6 mg, yellow solid, yield 10%); 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.50-8.42(m,1H),8.39-8.31(m,1H),7.82(s,1H), 7.63(s,1H),7.54-7.47(m,2H),4.36-4.29(m,1H),4.05-3.96(m,1H),3.96(s,3H), 3.68-3.61(m,1H),3.35-3.28(m,2H),3.26(s,3H),3.20-3.13(m,2H),1.94(s,2H), 1.85-1.76(m,3H),1.18-1.05(m,6H),0.74(t,J=7.4Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 508.2681.

[0298] Embodiment 36

[0299] Synthesis of 4-((8-(2-(2-butynylamino)ethyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-2-fluoro-5-methoxybenzamide (Compound 36)

[0300]

[0301] Referring to the preparation of compound 34, 2-fluoro-5-methoxy-4-nitrobenzoic acid was used to replace the raw material 3-methoxy-4-nitrobenzoic acid according to the same feed ratio to obtain the title compound 36 (7 mg, yellow solid, yield 10%); 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.43-8.37 (m, 1H), 8.05-8.00 (m, 1H), 7.88 (d, J = 1.0Hz, 1H), 7.7 3(s,1H),7.26(d,J=6.8Hz,1H),5.30-5.20(m,1H),4.32-4.27(m,1H),4.19-4.09(m,1H),3.94(s ,3H),3.33-3.29(m,2H),3.27(s,3H),3.14-3.06(m,1H),1.92(s,1H),1.87-1.74(m,2H),1.25(s ,1H),1.19(t,J=7.3Hz,2H),1.13(t,J=7.2Hz,4H),0.74(t,J=7.4Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 512.2422.

[0302] Embodiment 37

[0303] Synthesis of 4-((8-(3-(2-butynylamino)propyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-ethyl-2-fluoro-5-methoxybenzamide (Compound 37)

[0304]

[0305] Referring to the preparation of compound 35, 2-fluoro-5-methoxy-4-nitrobenzoic acid was used to replace the raw material 3-methoxy-4-nitrobenzoic acid according to the same feed ratio to obtain the title compound 37 (17 mg, yellow solid, yield 26%); 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.41 (dd, J = 13.9, 7.4Hz, 1H), 8.01 (p, J = 5.4Hz, 1H), 7.86 (d, J = 1.1Hz, 1H), 7.72 (s ,1H),7.26(d,J=6.8Hz,1H),5.29(d,J=6.5,1H),4.39-4.32(dt,J=6.4,3.4Hz,1H),4.06-3.96(m,1H),3.93(d,J=1 .5Hz,3H),3.32(d,J=6.9Hz,1H),3.30(d,J=1.6Hz,1H),3.28(d,J=4.3Hz,3H),3.14(dt,J=21.4,6.9Hz,3H),1.95 (s,2H),1.92-1.69(m,4H),1.18(d,J=7.3Hz,1H),1.13(t,J=7.2Hz,3H),0.79-0.71(m,3H).HRMS(ESI):m / z,(M+H) + , measured value 526.2585.

[0306] Embodiment 38

[0307] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-3-(2-hydroxyethoxy)benzamide (Compound 38), the reaction route is as follows:

[0308]

[0309] (1) Synthesis of intermediate N-cyclopropyl-3-hydroxy-4-nitrobenzamide (Intermediate 38b)

[0310] Step I: Dissolve 38a (1.6 g, 8.74 mmol) in a small amount of DMF solvent under ice bath conditions, weigh an appropriate amount of condensing agent HBTU (5.30 g, 13.98 mmol) into a reaction bottle, then add triethylamine (2.19 mL, 17.48 mmol) as a basic catalyst, remove the ice bath after the reaction system is stable, add cyclopropylamine (1.08 mL, 10.49 mmol), and stir at room temperature to react overnight. Monitor the progress of the reaction by TLC, and stop the reaction when the raw materials are consumed. The reaction solution is extracted with ethyl acetate and water (100 mL × 3), the organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally column chromatography (ethyl acetate: methanol = 10: 1) is used to obtain intermediate 38b (1.36 g, yellow solid, yield 75%).

[0311] (2) Synthesis of Intermediate N-cyclopropyl-3-(2-hydroxyethoxy)-4-nitrobenzamide (Intermediate 38c)

[0312] Step II: Dissolve 38b (1.36 g, 6.12 mmol) in an appropriate amount of 2-bromoethanol, add potassium hydroxide (1.03 g, 18.26 mmol) as a basic catalyst, and stir at 45°C for about 2 hours. Monitor the progress of the reaction by TLC, and stop the reaction when the raw materials are consumed. Extract the reaction solution with ethyl acetate and water (100 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate.

[0313] The residue was concentrated under reduced pressure and finally purified by column chromatography (ethyl acetate:methanol=8:1) to give intermediate 38c (1.14 g, brown oil, yield 72%).

[0314] (3) Synthesis of Intermediate 4-amino-N-cyclopropyl-3-(2-hydroxyethoxy)benzamide (Intermediate 38d)

[0315] Step III: 38c (1.14 g, 4.28 mmol) was dissolved in a mixture of ethanol and water (volume ratio of 2:1) as a solvent, ammonium chloride (0.69 g, 12.84 mmol) was added, and reduced iron powder (1.20 g, 21.40 mmol) was slowly added. The mixture was refluxed and stirred at 60°C for 2 hours. After the reaction was completed, diatomaceous earth was used for suction filtration, and the filtrate was collected. The filtrate was extracted with ethyl acetate and water (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, the intermediate 38d (0.58 g, yellow solid, yield 52%) was obtained by column chromatography (ethyl acetate: methanol = 7:1).

[0316] (4) Synthesis of Intermediate (R)-4-(2-((4-(cyclopropylcarbamoyl)-2-(2-hydroxyethoxy)phenyl)amino)-7-ethyl-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 38e)

[0317] Step IV: 38d (0.58 g, 2.45 mmol) was dissolved in anhydrous 1,4-dioxane in an eggplant-shaped bottle, and intermediate 1f (0.87 g, 2.94 mmol), cesium carbonate (1.60 g, 4.90 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.28 g, 0.44 mmol) were added to the eggplant-shaped bottle in sequence. A balloon filled with nitrogen was placed on the mouth of the eggplant-shaped bottle, and the nitrogen was replaced several times with a vacuum pump until no bubbles emerged in the system. At this time, tri(dibenzylideneacetone)dipalladium (0.23 g, 0.25 mmol) was quickly added, and the nitrogen was repeatedly replaced with a vacuum pump for about one hour. Finally, the system was completely placed under nitrogen protection and reacted in an oil bath at 110°C for 18 hours. After the reaction solution was cooled to room temperature, it was filtered and washed with ethyl acetate. The filtrate was collected and extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 38e (0.66 g, yellow solid, yield 57%) was obtained by column chromatography (ethyl acetate: methanol = 10:1).

[0318] (5) Synthesis of Intermediate (R)-N-cyclopropyl-4-((7-ethyl-5-methyl-6-oxo-8-(piperidin-4-yl)-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-(2-hydroxyethoxy)benzamide (Intermediate 38f)

[0319] Step V: 38e (660 mg, 1.08 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise to the reaction system under ice bath conditions. After the reaction system was stable, the ice bath was removed and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the volatile liquid was removed by vacuum concentration, and finally the intermediate 38f (0.45 g, light yellow solid, yield 69%) was obtained by column chromatography (ethyl acetate: methanol = 5:1).

[0320] (6) Synthesis of the target product (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-3-(2-hydroxyethoxy)benzamide (Compound 38)

[0321] Step VI: 38f (450 mg, 0.90 mmol) was dissolved in 8 ml of dichloromethane under ice bath conditions, N, N-diisopropylethylamine (0.128 mL, 2.70 mmol) was added dropwise to the reaction system, and then acryloyl chloride (0.03 mL, 0.90 mmol) was added dropwise to the reaction system, and the reaction was stirred for 2 h under ice bath. After the reaction was completed, the volatile liquid was removed by concentration under reduced pressure, and finally compound 38 (279 mg, light yellow solid, yield 45%) was obtained by column chromatography (ethyl acetate: methanol = 6:1); 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.37(dd,J=12.0,8.6Hz,1H),8.25(dd,J=14.6,4.0Hz,1H),8.12(s,1H),7.86(s,1H),7.45(d,J=8.0Hz,2H),6.85 (dt,J=16.7,10.1Hz,1H),6.13(d,J=16.6Hz,1H),5.69(dd,J=10.4,2.4Hz,1H),5.20(t,J=5.9Hz,1H),4.65(t,J=13.5Hz,1H),4.39(q,J=11.6Hz, 1H),4.31-4.18(m,2H),4.09(t,J=4.7Hz,2H),3.78(q,J=5.0,4.6Hz,2H ),3.17(dt,J=24.1,12.9Hz,1H),2.84-2.68(m,2H),2.15(d,J=12.0Hz,1 H),1.82-1.73(m,3H),1.64(td,J=15.6,14.5,8.4Hz,2H),0.73(t,J=7.5Hz,3H),0.71-0.67(m,2H),0.56(p,J=4.5Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 564.2955.

[0322] Embodiment 39

[0323] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-(2-hydroxyethoxy)-N-(1-methylpiperidin-4-yl)benzamide (Compound 39)

[0324]

[0325] Referring to the preparation of compound 38, the compound 4-amino-1-methylpiperidine was used to replace cyclopropylamine according to the same feed ratio to obtain the title compound 39 (335 mg, yellow solid, yield 43%); 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.37 (dd, J = 14.0, 8.7Hz, 1H), 8.12 (s, 1H), 8.05 (dt, J = 15.3, 6.6Hz, 1H), 7.86 (d, J = 2.9Hz, 1H), 7.47 (d, J = 4.1Hz, 2H), 6.85(dt,J=16.6,10.1Hz,1H),6.12(dd,J=16.8,5.0Hz,1H),5.69(dd,J=10 .7,2.3Hz,1H),4.63(d,J=13.4Hz,1H),4.44-4.33(m,2H),4.31-4.18(m,2H ),4.11(t,J=4.6Hz,2H),3.78(t,J=4.7Hz,2H),3.72(d,J=7.5Hz,2H),3.2 5(s,3H),2.80-2.75(m,2H),2.16(s,3H),2.04(d,J=4.8Hz,1H),1.96-1.90 (m,2H),1.81(s,3H),1.76(t,J=11.3Hz,3H),1.60(dtt,J=28.2,12.0,5.7H z,3H),1.16(t,J=7.2Hz,1H),0.73(t,J=7.6Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 621.3525.

[0326] Embodiment 40

[0327] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-2-fluoro-5-(3-hydroxypropoxy)benzamide (Compound 40)

[0328]

[0329] With reference to the preparation of compound 38, the raw material 4-nitro-3-hydroxybenzoic acid was replaced with the compound 2-fluoro-4-nitro-5-hydroxybenzoic acid according to the same feed ratio, and the raw material 2-bromoethanol was replaced with the compound 3-bromo-1-propanol to obtain the title compound 40 (155 mg, white solid, yield 47%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.30 (dd, J=13.8, 5.8Hz, 1H), 8.01 (t, J=3.8Hz, 1H),7.89(s,1H),7.77(s,1H),7.20(d,J=6.7Hz,1H),6.84(dd,J=16.7,10.5Hz ,1H),6.12(dd,J=16.7,2.5Hz,1H),5.69(dd,J=10.5,2.5Hz,1H),4.63(t,J=5. 3Hz,2H),4.40(d,J=11.9Hz,1H),4.31(d,J=9.7Hz,1H),4.26-4.20(m,1H),4.17 (t,J=6.3Hz,2H),3.61(q,J=5.7Hz,2H),3.15(t,J=13.7Hz,1H),2.81(tq,J=7. 8,4.1Hz,1H),2.72(q,J=11.9Hz,1H),2.17-2.10(m,1H),1.95-1.89(m,3H),1.7 8(dq,J=14.2,3.4Hz,3H),1.64(dt,J=14.5,7.5Hz,1H),0.74(t,J=7.5Hz,3H), 0.68(td,J=7.0,4.6Hz,2H),0.56(dt,J=7.0,4.5Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 596.2959.

[0330] Embodiment 41

[0331] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-2-fluoro-5-(3-hydroxypropoxy)-N-(1-methylpiperidin-4-yl)benzamide (Compound 41)

[0332]

[0333] Referring to the preparation of compound 40, the compound 4-amino-1-methylpiperidine was used to replace cyclopropylamine according to the same feed ratio to obtain the title compound 41 (200 mg, white solid, yield 36%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.30 (dd, J=13.6, 6.4Hz, 1H), 7.89 (s, 1H), 7.83-7.75 (m, 2H), 7.19 (d, J=6.8Hz, 1H), 6.84 (dd, J=16.7, 10.5Hz, 1H), 6.11 (dd, J = 16.7, 2.4Hz, 1H), 5.69 (d, J = 10.6Hz, 1H), 4.64 (d, J = 13.0Hz, 2H), 4.39 (d, J = 12.3Hz, 2H), 4.29 (d, J = 8.9Hz, 1H), 4.22 (t, J = 7. 1Hz,1H),4.16(t,J=6.2Hz,2H),3.70(dt,J=7.7,4.1Hz,1H),3.61(t,J=6.2Hz,2H),3.25(s,3H),3.16(s,2H),2.76-2.68(m,3H),2.14(s,3H), 1.97-1.91(m,4H),1.80-1.73(m,4H),1.65(tt,J=14.6,6.9Hz,2H),1.55(qd,J=11.9,3.7Hz,2H),0.74(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 553.3550.

[0334] Embodiment 42

[0335] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-2-fluoro-5-(2-hydroxyethoxy)-N-(1-methylpiperidin-4-yl)benzamide (Compound 42)

[0336]

[0337] Referring to the preparation of compound 41, the raw material 3-bromo-1-propanol was replaced by compound 2-bromoethanol according to the same feed ratio to obtain the title compound 42 (158 mg, light yellow solid, yield 34%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.40-8.30 (m, 2H), 8.03 (s, 1H), 7.91 (s, 1H), 7.20 (d, J = 6.8Hz, 1H), 6.84 (dd, J = 16.7, 10.5Hz, 1H), 6.11 (dd, J = 16.7 ,2.4Hz,1H),5.69(d,J=10.5Hz,1H),5.26(s,1H),4.64(s,1H),4.48(s,1 H),4.33-4.20(m,2H),4.07(t,J=4.6Hz,2H),3.90(s,1H),3.75(t,J=4.5H z,2H),3.26(s,3H),3.19-3.07(m,4H),2.73(q,J=16.0,14.6Hz,2H),2.1 6(d,J=12.4Hz,1H),1.99(s,1H),1.94-1.88(m,3H),1.77(dtt,J=10.9,7. 2,3.6Hz,4H),1.64(tt,J=14.5,7.7Hz,2H),1.25(dt,J=18.2,5.9Hz,1H), 1.17(td,J=7.3,4.3Hz,1H),0.74(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 639.3387.

[0338] Embodiment 43

[0339] Synthesis of (R)-4-((8-(1-acryloylpiperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-2-fluoro-5-(2-hydroxyethoxy)benzamide (Compound 43)

[0340]

[0341] Referring to the preparation of compound 42, cyclopropylamine was used to replace 4-amino-1-methylpiperidine according to the same feed ratio to obtain the title compound 43 (186 mg, white solid, yield 39%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.31 (d, J = 13.0Hz, 2H), 8.01 (t, J = 3.8Hz, 1H), 7.90 (s, 1H), 7.19 (d, J = 6.8Hz, 1H), 6.84 (dd, J = 16.7, 10.5Hz, 1H), 6.11 (d d,J=16.7,2.5Hz,1H),5.68(dd,J=10.4,2.4Hz,1H),5.25(s,1H),4.63(s,1H ),4.48(d,J=11.8Hz,1H),4.29(tt,J=8.0,3.2Hz,1H),4.22(s,1H),4.06(t, J=4.6Hz,2H),3.75(t,J=4.6Hz,2H),3.15(t,J=12.9Hz,1H),2.81(tq,J=7.9 ,4.1Hz,1H),2.72(q,J=13.4Hz,1H),2.15(d,J=12.0Hz,1H),1.76(dqd,J=14 .9,7.4,3.4Hz,3H),1.64(tq,J=14.5,7.5Hz,2H),0.74(t,J=7.4Hz,3H),0.6 8(td,J=7.0,4.7Hz,2H),0.55(dt,J=7.0,4.3Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 582.2811.

[0342] Embodiment 44

[0343] Synthesis of 4-((7R)-7-ethyl-5-methyl-6-oxo-8-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropteridin-2-yl)amino)-2-fluoro-5-(2-hydroxyethoxy)-N-(1-methylpiperidin-4-yl)benzamide (Compound 44)

[0344]

[0345] Referring to the preparation of compound 42, the raw material N-tert-butyloxycarbonyl-4-piperidone was replaced with compound 1-tert-butyloxycarbonyl-3-pyrrolidone according to the same feed ratio, and the title compound 44 (165 mg, light yellow solid, yield 38%) was obtained by reaction step V; 1H NMR(600MHz,DMSO-d6)δ(ppm):8.52-8.20(m,2H),7.88(d,J=2.9Hz,1H),7.80(dd,J=7.8,3.9Hz,1H),7.20-7.09(m,1H),4 .45-4.20(m,2H),4.10-3.92(m,2H),3.81-3.71(m,2H),3.67(ddd,J=15.7,9.5,4.3Hz,2H),3.55(s,1H),3.23(s,3H),3.0 7(dd,J=23.9,11.0Hz,2H),2.93(s,1H),2.70(d,J=11.0Hz,2H),2.13(s,3H),2.03-1.88(m,3H),1.75(ddt,J=16.5,12.9, 3.8Hz,3H),1.69-1.58(m,2H),1.53(qd,J=11.8,3.7Hz,2H),1.29-1.15(m,1H),0.77-0.68(m,3H); HRMS(ESI):m / z,(M+H) + , measured value 571.3153.

[0346] Embodiment 45

[0347] Synthesis of 4-((7R)-8-(1-acryloylpyrrolidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-2-fluoro-5-(2-hydroxyethoxy)-N-(1-methylpiperidin-4-yl)benzamide (Compound 45)

[0348]

[0349] Referring to the preparation of compound 44, the title compound 45 (150 mg, white solid, yield 35%) was obtained by following the same feed ratio and continuing to connect the acryloyl chloride warhead in step VI; 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.36-8.17 (m, 2H), 7.98-7.89 (m, 2H), 7.22-7.12 (m, 1H), 6.66-6.52 (m, 1H), 6.13 (ddd, J=18.9, 16.7, 2.4 Hz,1H),5.75-5.59(m,1H),4.68-4.56(m,1H),4.25(ddd,J=38.7,7.7,3.6Hz,1H),4.04(dddd,J=17.6,10.2,6.4,4.5Hz,3H),3.88-3.78 (m,2H),3.76-3.67(m,3H),3.66-3.55(m,2H),3.53-3.44(m,1H),3.41-3.31(m,2H),3.02(s,2H),2.64-2.50(m,2H),2.45-2.35(m,3H), 2.31-2.14(m,1H),1.87(d,J=20.7Hz,2H),1.80-1.59(m,4H),1.38-1.18(m,1H),0.74(qd,J=8.7,7.5,3.1Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 525.3252.

[0350] Embodiment 46

[0351] The synthesis of (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 46) is as follows:

[0352]

[0353] (1) Synthesis of Intermediate 4-bromo-1-methoxy-2-nitrobenzene (Intermediate 46b)

[0354] Step I: 46a (1.6 g, 7.34 mmol) was dissolved in an appropriate amount of acetone, and then anhydrous potassium carbonate (3.04 g, 22.02 mmol) and iodomethane (0.52 mL, 8.07 mmol) were added, and the mixture was refluxed in an oil bath at 60°C for 4.5 h. The reaction progress was monitored by TLC, and the reaction was stopped after the raw materials were consumed. The reaction solution was extracted with ethyl acetate and water (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 46b (1.46 g, yellow solid, yield 86%) was obtained by column chromatography (petroleum ether: ethyl acetate = 2:1).

[0355] (2) Synthesis of Intermediate 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine (Intermediate 46c)

[0356] Step II: In an eggplant-shaped bottle, 46b (1.46 g, 6.29 mmol) was dissolved in 10 mL of anhydrous 1,4-dioxane. Methylpiperazine (0.71 mL, 6.35 mmol), cesium carbonate (3.08 g, 9.44 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.82 g, 3.15 mmol) were added to the bottle in sequence. A balloon filled with nitrogen was placed on the mouth of the eggplant-shaped bottle. The nitrogen was pumped out several times with a vacuum pump until no bubbles emerged in the system. At this time, tri(dibenzylideneacetone)dipalladium (0.58 g, 0.63 mmol) was quickly added. The nitrogen was repeatedly pumped out with a vacuum pump for about one hour. Finally, the system was completely placed under nitrogen protection and reacted in an oil bath at 110°C for 18 h. After the reaction solution was cooled to room temperature, it was filtered and washed with ethyl acetate. The filtrate was collected and extracted with water and ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 46c (1.14 g, brown oil, yield 72%) was obtained by column chromatography (ethyl acetate: methanol = 10:1).

[0357] (3) Synthesis of Intermediate 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (Intermediate 46d)

[0358] Step III: 46c (1.14 g, 4.54 mmol) was dissolved in a mixture of ethanol and water (volume ratio of 2:1) as a solvent, ammonium chloride (0.73 g, 13.62 mmol) was added, and reduced iron powder (1.27 g, 20.35 mmol) was slowly added, and the mixture was refluxed and stirred at 60°C for 2 hours. After the reaction was completed, diatomaceous earth was used for suction filtration, and the filtrate was collected. The filtrate was extracted with ethyl acetate and water (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, the intermediate 46d (0.49 g, yellow solid, yield 49%) was obtained by column chromatography (ethyl acetate: methanol = 8:1).

[0359] (4) Synthesis of Intermediate (R)-4-(7-ethyl-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 46e)

[0360] Step IV: In an eggplant-shaped bottle, 46d (0.49 g, 2.21 mmol) was dissolved in anhydrous 1,4-dioxane, and intermediate 1f (0.78 g, 2.65 mmol), cesium carbonate (1.08 g, 3.32 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.25 g, 0.44 mmol) were added to the eggplant-shaped bottle in sequence. A balloon filled with nitrogen was placed on the mouth of the eggplant-shaped bottle, and the nitrogen was replaced several times with a vacuum pump until no bubbles emerged in the system. At this time, tri(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol) was quickly added, and the nitrogen was repeatedly replaced with a vacuum pump for about one hour. Finally, the system was completely placed under nitrogen protection and reacted in an oil bath at 140°C for 15 hours. After the reaction solution was cooled to room temperature, it was filtered and washed with ethyl acetate. The filtrate was collected and extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 46e (0.56 g, yellow solid, yield 52%) was obtained by column chromatography (ethyl acetate: methanol = 10:1).

[0361] (5) Synthesis of Intermediate (R)-7-ethyl-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(piperidin-4-yl)-7,8-dihydropteridin-6(5H)-one (Intermediate 46f)

[0362] Step V: 46e (777 mg, 1.27 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise to the reaction system under ice bath conditions. After the reaction system was stable, the ice bath was removed and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the volatile liquid was removed by vacuum concentration, and finally the intermediate 46f (0.45 g, light yellow solid, yield 67%) was obtained by column chromatography (ethyl acetate: methanol = 5:1).

[0363] (6) Synthesis of the target product (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 46)

[0364] Step VI: 46f (450 mg, 0.90 mmol) was dissolved in 8 mL of dichloromethane under ice bath conditions, N, N-diisopropylethylamine (0.128 mL, 2.70 mmol) was added dropwise to the reaction system, and then acryloyl chloride (0.03 mL, 0.90 mmol) was added dropwise to the reaction system, and the reaction was stirred for 2 h under ice bath. After the reaction was completed, the volatile liquid was removed by concentration under reduced pressure, and finally compound 46 (279 mg, light yellow solid, yield 45%) was obtained by column chromatography (ethyl acetate: methanol = 8: 1);1 HNMR(600MHz,DMSO-d6)δ(ppm):7.97(d,J=2.8Hz,1H),7.83(s,1H),7.42(s,1H),6.88-6.80(m,2H),6.48(dd,J=8.8,2.9Hz, 1H),6.11(dd,J=16.7,2.5Hz,1H),5.68(d,J=10.4Hz,1H),4.57(t,J=16.6Hz,1H),4.46-4.38(m,1H),4.26-4.11(m,3H),3.7 9(s,3H),3.23(s,3H),2.99(ddd,J=31.3,12.1,6.4Hz,4H),2.72(q,J=14.2Hz,1H),2.42(d,J=4.8Hz,4H),2.18(s,3H),2.05 -1.92(m,2H),1.71(tdd,J=13.2,8.5,4.4Hz,3H),1.60(dq,J=14.5,7.5Hz,1H),0.73(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 549.3264.

[0365] Embodiment 47

[0366] Synthesis of (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((5-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 47)

[0367]

[0368] Referring to the preparation of compound 46, ethylpiperazine was used instead of methylpiperazine according to the same feed ratio to obtain the title compound 47 (124 mg, white solid, yield 46%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.98 (s, 1H), 7.84 (s, 1H), 7.43 (s, 1H), 6.89-6.77 (m, 2H), 6.48 (dd, J = 8.8, 2.8Hz, 1H), 6.11 (dd, J = 16.7, 2.4 Hz,1H),5.68(d,J=10.3Hz,1H),4.61-4.53(m,1H),4.44(t,J=11.5Hz,1H),4.22(dd,J=13.8,7.0Hz,1H),4.16(s,1H),3.79(s,3H),3.23(s,3 H),3.16(dd,J=29.7,15.6Hz,1H),3.00(d,J=23.5Hz,4H),2.72(dt,J=23.2,12.2Hz,1H),2.46(s,4H),2.32(q,J=7.1Hz,2H),2.06-1.99(m, 1H),1.74-1.69(m,3H),1.59(dt,J=14.4,7.4Hz,1H),1.27-1.20(m,1H),1.00(t,J=7.2Hz,3H),0.74(t,J=7.2Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 563.3455.

[0369] Embodiment 48

[0370] Synthesis of (R)-8-(1-(2-butynoyl)piperidin-4-yl)-7-ethyl-2-((2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 48)

[0371]

[0372] Referring to the preparation of compound 46, 2-butynoyl chloride was used instead of acryloyl chloride according to the same feed ratio to obtain the title compound 48 (475 mg, light yellow solid, yield 52%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.92 (s, 1H), 7.81 (d, J = 1.1Hz, 1H), 7.44 (d, J = 2.0Hz, 1H), 6.84 (dd, J = 8.8, 2.7Hz, 1 H),6.48(ddd,J=8.8,2.9,1.3Hz,1H),4.45-4.31(m,3H),4.21(dt,J=7.7,3.7Hz,1H),3.77(d,J=2.6Hz,3H),3.21(s ,4H),3.00(d,J=27.5Hz,4H),2.79-2.67(m,2H),2.23(s,3H),2.01(d,J=4.4Hz,4H),1.89(s,1H),1.82(dt,J=12.3 ,6.1Hz,1H),1.77-1.65(m,3H),1.63-1.53(m,2H),1.21(s,1H),0.71(td,J=7.4,2.1Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 561.3303.

[0373] Embodiment 49

[0374] Synthesis of (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((5-(4-ethylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 49)

[0375]

[0376] Referring to the preparation of compound 47, the compound 3-nitro-4-trifluoromethoxybromobenzene was used to replace the raw material 4-bromo-2-nitrophenol according to the same feed ratio to obtain the title compound 49 (463 mg, white solid, yield 49%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.10 (s, 1H), 7.78 (s, 1H), 7.44 (s, 1H), 7.14 (dt, J = 9.0, 1.6Hz, 1H), 6.79 (dd, J = 16.7, 10.5Hz, 1H), 6.64 (dd, J=9.1,2.9Hz,1H),6.09(dd,J=16.7,2.5Hz,1H),5.66(d,J=10.5Hz,1H),4.52(dd,J=28.1,13.1Hz,1H),4.22(d,J=14.7Hz,2H),4.10(t,J=16 .5Hz,1H),3.12(dp,J=17.2,6.6,5.6Hz,4H),3.05-2.94(m,1H),2.60(t,J=12.5Hz,1H),2.47(t,J=5.1Hz,4H),2.34(q,J=7.2Hz,2H),1.91(d d,J=42.0,12.7Hz,2H),1.75-1.65(m,3H),1.59(dt,J=14.5,7.4Hz,1H),1.01(t,J=7.1Hz,3H),0.72(t,J=7.5Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 617.3192.

[0377] Embodiment 50

[0378] Synthesis of (R)-N-(4-(7-ethyl-2-((5-(4-ethylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)cyclohexyl)acrylamide (Compound 50)

[0379]

[0380] Referring to the preparation of compound 49, the compound 4-N-tert-butyloxycarbonyl-aminocyclohexanone was used to replace the raw material N-tert-butyloxycarbonyl-4-piperidone according to the same feed ratio to obtain the title compound 50 (231 mg, light yellow solid, yield 38%); 1HNMR(600MHz,DMSO-d6)δ(ppm):8.08(d,J=10.0Hz,1H),7.97(d,J=7.8Hz,1H),7.75( s,1H),7.42(d,J=2.9Hz,1H),7.16(t,J=9.0Hz,1H),6.66(td,J=8.4,3.0Hz,1H),6.4 3(dd,J=17.1,10.2Hz,1H),6.21(dd,J=17.1,10.1Hz,1H),6.08(ddd,J=16.8,13.7,2 .3Hz,1H),5.96(dd,J=17.3,10.0Hz,1H),5.57(ddd,J=16.6,10.1,2.3Hz,1H),4.33( dd,J=8.1,3.6Hz,1H),4.25-4.19(m,1H),4.04-3.95(m,1H),3.64-3.58(m,1H),3.22 (d,J=11.2Hz,3H),3.12(q,J=5.0,4.4Hz,4H),2.35(q,J=7.4Hz,2H),2.03-1.94(m,1 H),1.92-1.82(m,2H),1.80-1.70(m,3H),1.64-1.56(m,2H),1.23(dq,J=12.3,8.9,7 .5Hz,3H),1.02(q,J=7.4Hz,3H),0.75(dt,J=17.5,7.5Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 631.3346.

[0381] Embodiment 51

[0382] The synthesis of (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 51) is as follows:

[0383]

[0384] (1) Synthesis of Intermediate 2-(4-bromo-2-nitrophenoxy)ethane-1-ol (Intermediate 51a)

[0385] Step I: Weigh the raw material 4-bromo-2-nitrophenol (1.6 g, 7.34 mmol) into a thick-walled pressure bottle and dissolve it in a small amount of DMF solvent, add 2-bromoethanol (1.11 mL, 18.13 mmol) to the reaction system, then add N,N-diisopropylethylamine (5.75 mL, 33.03 mmol) dropwise to the reaction system, and stir the reaction at 120°C for 3 h. After the reaction is completed, extract with water and ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and finally obtain intermediate 51a (1.6 g, orange-yellow solid, yield 85%) by column chromatography (petroleum ether: ethyl acetate = 6:1).

[0386] (2) Synthesis of Intermediate 2-(4-bromo-2-nitrophenoxy)ethyl acetate (Intermediate 51b)

[0387] Step II: 51a (1.6 g, 6.15 mmol) was dissolved in dichloromethane, and 4-dimethylaminopyridine (1.2 g, 9.84 mmol) and acetic anhydride (0.615 mL, 3.47 mmol) were added to the reaction system under ice bath conditions. After the system was stable, the ice bath was removed and the reaction was stirred at room temperature for 5 h. After the reaction was completed, the volatile solvent in the system was dried by spin drying, and the mixture was extracted with water and ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally column chromatography (petroleum ether: ethyl acetate = 8:1) was used to obtain intermediate 51b (1.7 g, yellow-green oil, yield 91%).

[0388] (3) Synthesis of Intermediate 2-(4-(4-methylpiperazin-1-yl)-2-nitrophenoxy)ethyl acetate (Intermediate 51c)

[0389] Step III: Dissolve 51b (1.7 g, 5.59 mmol) in 10 mL of anhydrous 1,4-dioxane in an eggplant-shaped bottle, add 1-methylpiperazine (0.63 mL, 5.65 mmol), cesium carbonate (2.73 g, 8.385 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.65 g, 1.12 mmol) to the eggplant-shaped bottle in sequence, put a balloon filled with nitrogen on the mouth of the eggplant-shaped bottle, and use a vacuum pump to replace the nitrogen several times until no bubbles emerge in the system. At this time, quickly add tri(dibenzylideneacetone)dipalladium (0.51 g, 0.559 mmol), continue to use a vacuum pump to repeatedly replace the nitrogen for about one hour, and finally place the system completely under nitrogen protection and react in an oil bath at 110°C for 18 hours. After the reaction solution was cooled to room temperature, it was filtered and washed with ethyl acetate. The filtrate was collected and extracted with water and ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 51c (1.46 g, brown oil, yield 81%) was obtained by column chromatography (ethyl acetate: methanol = 10:1).

[0390] (4) Synthesis of Intermediate 2-(2-amino-4-(4-methylpiperazin-1-yl)phenoxy)ethyl acetate (Intermediate 51d)

[0391] Step IV: 51c (1.46 g, 4.98 mmol) was dissolved in a mixture of ethanol and water (volume ratio of 2:1) as a solvent, ammonium chloride (0.8 g, 14.94 mmol) was added, and reduced iron powder (1.39 g, 24.9 mmol) was slowly added, and the mixture was refluxed and stirred at 60°C for 2 hours. After the reaction was completed, diatomaceous earth was used for suction filtration, and the filtrate was collected. The filtrate was extracted with ethyl acetate and water (100 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 51d (0.73 g, brown-yellow solid, yield 55%) was obtained by column chromatography (ethyl acetate: methanol = 8:1).

[0392] (5) Synthesis of Intermediate (R)-4-(2-((2-acetoxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-7-ethyl-5-methyl-6-oxo-6,7-dihydropteridin-8(5H)-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 51e)

[0393] Step V: Dissolve 51d (0.73 g, 2.48 mmol) in anhydrous 1,4-dioxane in an eggplant-shaped bottle, and add intermediate 1f (0.88 g, 2.98 mmol), cesium carbonate (1.21 g, 3.72 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.29 g, 0.5 mmol) to the eggplant-shaped bottle in sequence. Put a balloon filled with nitrogen on the mouth of the eggplant-shaped bottle, and use a vacuum pump to replace the nitrogen several times until no bubbles emerge in the system. At this time, quickly add tri(dibenzylideneacetone)dipalladium (0.23 g, 0.25 mmol), continue to use a vacuum pump to repeatedly replace the nitrogen for about one hour, and finally place the system completely under nitrogen protection and react in an oil bath at 110°C for 16 hours. After the reaction solution was cooled to room temperature, it was filtered and washed with ethyl acetate. The filtrate was collected and extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, intermediate 51e (0.9 g, brown solid, yield 61%) was obtained by column chromatography (ethyl acetate: methanol = 10:1).

[0394] (6) Synthesis of Intermediate (R)-2-(2-((7-ethyl-5-methyl-6-oxo-8-(piperidin-4-yl)-5,6,7,8-tetrahydropteridin-2-yl)amino)-4-(4-methylpiperazin-1-yl)phenoxy)ethyl acetate (Intermediate 51f)

[0395] Step VI: 51e (0.9 g, 1.59 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise to the reaction system under ice bath conditions. After the reaction system was stable, the ice bath was removed and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the volatile liquid was removed by vacuum concentration, and finally the intermediate 51f (0.65 g, light yellow solid, yield 67%) was obtained by column chromatography (ethyl acetate: methanol = 5:1).

[0396] (7) Synthesis of Intermediate (R)-7-ethyl-2-((2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(4-piperidinyl)-7,8-dihydropteridin-6(5H)-one (Intermediate 51 g)

[0397] Step VII: 51f (0.65 g, 1.24 mmol) was dissolved in a mixture of methanol and water (volume ratio of 5:3) as a solvent, and then potassium carbonate (0.53 g, 3.72 mmol) was added to the reaction system and stirred at room temperature for 5 hours. After the reaction was completed, the volatile solvent was removed by concentration under reduced pressure, and the intermediate 51g (0.61 g, white solid, yield 77%) was obtained by column chromatography (ethyl acetate: methanol = 4:1).

[0398] (8) Synthesis of the target product (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 51)

[0399] Step VIII: Dissolve 51g (0.61g, 1.16mmol) in 8mL of dichloromethane under ice bath conditions, first add N,N-diisopropylethylamine (0.165mL, 3.48mmol) dropwise to the reaction system, then add acryloyl chloride (0.13mL, 1.16mmol) dropwise to the reaction system, and stir the reaction for 2h under ice bath. After the reaction is completed, concentrate under reduced pressure to remove volatile liquids, and finally obtain compound 51 (315mg, white solid, yield 68%) by column chromatography (ethyl acetate: methanol = 8:1); 1 HNMR(600MHz,DMSO-d6)δ(ppm):7.99(d,J=2.8Hz,1H),7.90(s,1H),7.84(s,1H),6.88-6.80(m,2H),6.45(dd,J=8.6,2.6Hz,1H),6.11(d,J=16.6 Hz,1H),5.70-5.65(m,1H),5.09(d,J=5.5Hz,1H),4.58(dd,J=28.2,13.1 Hz,1H),4.47(t,J=12.4Hz,1H),4.26-4.12(m,2H),3.95(tq,J=10.0,5.0 ,4.6Hz,2H),3.70(t,J=4.5Hz,2H),3.24(s,3H),3.16(q,J=12.6,11.0Hz ,1H),3.06-2.93(m,4H),2.73(dt,J=23.6,12.5Hz,1H),2.45-2.38(m,4H ),2.18(s,3H),2.06(dq,J=15.5,10.5,7.6Hz,1H),1.76-1.65(m,3H),1.59(dt,J=14.4,7.3Hz,2H),0.73(q,J=6.5Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 579.3307.

[0400] Embodiment 52

[0401] Synthesis of (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((5-(4-ethylpiperazin-1-yl)-2-(2-hydroxyethoxy)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 52)

[0402]

[0403] Referring to the preparation of compound 51, ethylpiperazine was used instead of methylpiperazine according to the same feed ratio to obtain the title compound 52 (274 mg, off-white solid, yield 56%); 1 H NMR (600MHz, CDCl3) δ (ppm): 8.16 (d, J = 39.4Hz, 1H), 7.68 (d, J = 4.2Hz, 1H), 7.59 (d, J = 51.2Hz, 1H), 6.85 (d, J = 8.7Hz, 1H), 6.62 (dd, J = 16.8, 10.6Hz, 1H ),6.51(t,J=9.3Hz,1H),6.34(dd,J=16.8,5.6Hz,1H),5.74(d,J=10.6Hz,1 H),4.83(t,J=15.0Hz,1H),4.36(s,1H),4.12(td,J=34.2,32.2,22.0Hz,4H ),3.97(s,2H),3.31(s,3H),3.29-3.22(m,1H),3.22-3.12(m,4H),2.82(t, J=12.7Hz,1H),2.74(t,J=13.1Hz,1H),2.60(t,J=5.1Hz,3H),2.47(q,J=7. 3Hz,2H),2.10(d,J=13.7Hz,1H),1.85(dd,J=44.4,23.9Hz,3H),1.26(s,1H ),1.12(t,J=7.2Hz,3H),0.85(p,J=8.0,7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 593.3576.

[0404] Embodiment 53

[0405] Synthesis of (R)-7-ethyl-2-((2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(4-piperidinyl)-7,8-dihydropteridin-6(5H)-one (Compound 53)

[0406]

[0407] Referring to the preparation of compound 51, the title compound 53 (610 mg, light yellow solid, yield 77%) was obtained according to the same feed ratio and the reaction was carried out to step VII; HRMS (ESI): m / z, (M+H) + , measured value 525.3202.

[0408] Embodiment 54

[0409] Synthesis of (R)-7-ethyl-2-((5-(4-ethylpiperazin-1-yl)-2-(2-hydroxyethoxy)phenyl)amino)-5-methyl-8-(piperidin-4-yl)-7,8-dihydropteridin-6(5H)-one (Compound 54)

[0410]

[0411] Referring to the preparation of compound 53, ethylpiperazine was used instead of methylpiperazine according to the same feed ratio to obtain the title compound 54 (437 mg, yellow solid, yield 41%); 1 H NMR (600MHz, DMSO-d6) δ (ppm): 8.15 (s, 1H), 7.78 (d, J = 17.2Hz, 1H), 7.76 (s, 1H), 6.84 (s, 1H), 6.42 (s, 1H), 4. 21(s,1H),4.12(s,2H),3.93(s,3H),3.79(s,2H),3.70(s,1H),3.23(s,3H),3.16(s,3H),3.06-2.97(m,4H),2. 58(d,J=36.8Hz,2H),2.35(dd,J=14.3,7.1Hz,2H),2.25(s,1H),1.97(d,J=16.6Hz,1H),1.77(s,2H),1.65(d, J=25.5Hz,2H),1.40(dd,J=33.9,24.8Hz,2H),1.04-0.98(m,3H),0.74(t,J=7.0Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 539.2703.

[0412] Embodiment 55

[0413] Synthesis of (7R)-2-((3-chloro-2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-7-ethyl-5-methyl-8-(pyrrolidin-3-yl)-7,8-dihydropteridin-6(5H)-one (Compound 55)

[0414]

[0415] With reference to the preparation of compound 53, 4-bromo-2-chloro-6-nitrophenol was used instead of 4-bromo-2-nitrophenol according to the same feed ratio, and 1-tert-butoxycarbonyl-3-pyrrolidone was used instead of the raw material N-tert-butoxycarbonyl-4-piperidone to obtain the title compound 55 (155 mg, white solid, yield 43%);1 H NMR (600MHz, CDCl3) δ (ppm): 9.11 (s, 1H), 8.19 (d, J = 2.9Hz, 1H), 7.70 (s, 1H), 6.47 (d, J = 2.9Hz, 1H), 4.31 (ddd, J = 10.8, 5.1, 2 .1Hz,1H),4.16(dd,J=6.7,3.4Hz,1H),3.97(ddd,J=10.9,7.2,2.3Hz,1H),3.92-3.81(m,3H),3.61-3.52(m,2H),3.47(s,3H) ,3.31(s,3H),3.21(s,1H),3.00(td,J=10.2,7.3Hz,1H),2.66(p,J=8.5Hz,1H),2.57(t,J=5.0Hz,4H),2.34(s,3H),2.17(s,1 H),2.07-1.96(m,2H),1.78(dp,J=14.4,7.3Hz,1H),1.42(s,1H),1.32-1.21(m,1H),0.87-0.80(m,3H); HRMS(ESI):m / z,(M+H) + , measured value 545.2739.

[0416] Embodiment 56

[0417] Synthesis of (7R)-8-(1-acryloylpyrrolidin-3-yl)-2-((3-chloro-2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 56)

[0418]

[0419] Referring to the preparation of compound 55, the title compound 56 (256 mg, white solid, yield 47%) was obtained by following the same feed ratio and continuing to connect the acryloyl chloride warhead in step VIII; 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.70 (d, J = 29.3Hz, 1H), 8.12-8.08 (m, 1H), 7.90 (s, 1H),6.60(ddd,J=16.7,14.0,10.3Hz,1H),6.50(dd,J=6.6,2.9Hz,1H),6.15(ddd, J=20.7,16.7,2.4Hz,1H),5.67(ddd,J=40.2,10.3,2.5Hz,1H),5.39(s,1H),4.70( s,1H),4.23(ddd,J=36.7,8.0,3.7Hz,1H),4.00-3.95(m,1H),3.94-3.85(m,2H),3. 79(td,J=9.8,9.0,3.6Hz,1H),3.65(td,J=8.6,4.1Hz,2H),3.60-3.53(m,1H),3.4 6(dd,J=12.2,8.0Hz,1H),3.05(d,J=5.0Hz,4H),2.43-2.37(m,5H),2.35-2.27(m,1 H),2.22-2.14(m,4H),1.72(dddq,J=18.1,11.0,7.5,3.6Hz,1H),1.60(dtd,J=14. 5,7.5,4.2Hz,1H),1.39(s,1H),0.76(td,J=7.4,5.3Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 599.2834.

[0420] Embodiment 57

[0421] Synthesis of (7R)-7-ethyl-2-((3-fluoro-2-(3-hydroxypropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(pyrrolidin-3-yl)-7,8-dihydropteridin-6(5H)-one (Compound 57)

[0422]

[0423] With reference to the preparation of compound 55, 4-bromo-2-fluoro-6-nitrophenol was used instead of 4-bromo-2-nitrophenol according to the same feed ratio, and 3-bromo-1-propanol was used instead of 2-bromoethanol to obtain the title compound 57 (178 mg, light yellow solid, yield 48%); 1H NMR (600MHz, CDCl3) δ (ppm): 8.40 (s, 1H), 8.06 (dd, J = 2.9, 1.4Hz, 1H), 7.70 (s, 1H), 6.26 (dd, J = 13.7, 2.9Hz, 1H), 4.21 (ddd, J = 9. 5,5.9,3.8Hz,1H),4.16(dd,J=6.8,3.4Hz,1H),4.07(td,J=8.8,3.3Hz,1H),3.97-3.84(m,3H),3.47-3.43(m,1H),3.32(s,3H),3. 21-3.15(m,4H),3.01(ddd,J=10.8,8.7,6.9Hz,1H),2.67-2.61(m,1H),2.57(t,J=5.0Hz,3H),2.35(s,3H),2.17(s,2H),2.01(dd dd,J=21.1,17.4,14.1,9.4Hz,5H),1.80(dp,J=14.5,7.3Hz,2H),1.33-1.23(m,1H),0.85(t,J=7.5Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 543.3200.

[0424] Embodiment 58

[0425] Synthesis of (7R)-8-(1-acryloylpyrrolidin-3-yl)-7-ethyl-2-((3-fluoro-2-(3-hydroxypropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 58)

[0426]

[0427] Referring to the preparation of compound 57, the title compound 58 (186 mg, white solid, yield 39%) was obtained by following the same feed ratio and continuing to connect the acryloyl chloride warhead in step VIII; 1H NMR (600MHz, CDCl3) δ (ppm): 7.98-7.91 (m, 1H), 7.75-7.65 (m, 2H), 6.51-6.36 (m, 2H), 6.29-6.24 (m, 1H), 5.73 (ddd, J = 42.0, 9.1, 3.1Hz, 1H) ,4.68-4.32(m,1H),4.22(dt,J=7.8,3.8Hz,1H),4.20-4.13(m,1H),4 .13-4.07(m,1H),4.07-3.96(m,1H),3.91-3.80(m,2H),3.65(td,J=9. 6,7.0Hz,1H),3.59-3.52(m,1H),3.48(s,3H),3.33(d,J=1.2Hz,3H),3.16(dt,J=14.9,5.1Hz,4H),2.56(td,J=5.2,2.7Hz,4H),2.35-2.33( m,3H),2.05-1.96(m,3H),1.89(dd,J=29.6,15.1Hz,1H),1.69(ddt,J=18.2,14.6,7.4Hz,1H),0.86(t,J=7.5Hz,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 597.3306.

[0428] Embodiment 59

[0429] Synthesis of (7R)-7-ethyl-2-((3-fluoro-2-((2S)-2-hydroxypropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(pyrrolidin-3-yl)-7,8-dihydropteridin-6(5H)-one (Compound 59)

[0430]

[0431] Referring to the preparation of compound 57, the compound (S)-1-bromo-2-propanol was used to replace the raw material 2-bromoethanol according to the same feed ratio to obtain the title compound 59 (178 mg, light yellow solid, yield 48%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.01-8.39 (m, 1H), 8.19-7.90 (m, 1H), 7.83 (d, J = 18.5Hz, 1H), 6.38-6.29(m,1H),4.28(d,J=26.9Hz,2H),4.06-3.81(m,2H),3.66-3.47(m,2H),3.26-3.14(m ,5H),3.07(dt,J=6.5,3.5Hz,5H),2.43(t,J=5.0Hz,4H),2.20(d,J=17.6Hz,4H),1.61(d,J=2 .4Hz,2H),1.28-1.16(m,4H),1.14-1.07(m,2H),0.74(q,J=7.3Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 543.3197.

[0432] Embodiment 60

[0433] Synthesis of (2S)-1-(2-((7R)-8-(1-acryloylpyrrolidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-6-fluoro-4-(4-methylpiperazin-1-yl)phenoxy)propan-2-yl acetate (Compound 60)

[0434]

[0435] Referring to the preparation of compound 59, step VII was omitted and the acryloyl chloride warhead was connected in step VIII according to the same feed ratio to obtain the title compound 60 (155 mg, white solid, yield 54%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.63-8.46 (m, 1H), 7.90-7.86 (m, 1H), 6.64-6.54 (m, 1H), 6.36 (dd, J = 10.9, 9.3Hz, 1H), 6.1 5(ddq,J=19.3,16.7,2.2Hz,1H),5.72-5.61(m,1H),4.66(dq,J=23.3,7.8Hz,1H),4.23(dtd,J=31.0,8.8,8.4,4.1Hz,1H) ,3.93-3.78(m,3H),3.70-3.44(m,6H),3.26-3.19(m,4H),3.04(h,J=3.3Hz,4H),2.40(q,J=4.8Hz,4H),2.19(dd,J=9.2,3 .5Hz,3H),1.78-1.62(m,2H),1.55(s,2H),1.24-1.17(m,2H),1.12-1.06(m,2H),0.79-0.72(m,3H); HRMS(ESI):m / z,(M+H) + , the measured value is 639.3402.

[0436] Embodiment 61

[0437] Synthesis of (2S)-1-(2-((7R)-8-(1-(2-butynoyl)pyrrolidin-3-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-6-fluoro-4-(4-methylpiperazin-1-yl)phenoxy)propan-2-yl acetate (Compound 61)

[0438]

[0439] Referring to the preparation of compound 60, 2-butynoyl chloride was used instead of acryloyl chloride according to the same feed ratio to obtain the title compound 61 (375 mg, white solid, yield 56%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.88 (t, J = 2.7Hz, 1H), 7.75-7.63 (m, 2H), 6.43 (dd, J = 14.3, 2.8Hz, 1H), 5.09-4.98 (m, 1H), 4.75-4. 55(m,2H),4.25(ddd,J=11.0,7.1,3.5Hz,2H),4.16-4.07(m,1H),3.99(tq,J=7.6,4.8,4.1Hz,2H),3.83-3.65(m,3H),3.51(s,1H) ,3.25(s,3H),3.05(p,J=4.9Hz,3H),2.41(q,J=4.7Hz,4H),2.20(d,J=5.2Hz,4H),2.03(d,J=2.1Hz,2H),2.00(d,J=1.5Hz,1H),1. 94(d,J=3.7Hz,1H),1.71(d,J=18.4Hz,2H),1.24(ddd,J=8.6,6.4,2.6Hz,4H),0.76(td,J=7.4,4.3Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 651.3407.

[0440] Embodiment 62

[0441] Synthesis of (7R)-8-(1-acryloylpyrrolidin-3-yl)-7-ethyl-2-((3-fluoro-2-((S)-2-hydroxypropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 62)

[0442]

[0443] Referring to the preparation of compound 59, the title compound 62 (136 mg, white solid, yield 34%) was obtained by following the same feed ratio and continuing to connect the acryloyl chloride warhead in step VIII; 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.70-8.61 (m, 1H), 8.55-8.47 (m, 1H), 7.91-7.81 (m, 2H), 6.66-6.55 (m, 1H), 6.37 (ddt, J=12.6 ,6.6,3.2Hz,1H),6.15(ddq,J=19.4,16.8,2.3Hz,1H),5.73-5.62(m,1H),4.68(ddq,J=22.1,16.0,8.2,7.3Hz,1H),4.27-4.17 (m,1H),3.93-3.76(m,3H),3.70-3.46(m,5H),3.04(dt,J=9.3,4.6Hz,3H),2.40(t,J=4.9Hz,4H),2.18(d,J=3.1Hz,3H),1.64- 1.56(m,2H),1.22(ddt,J=16.5,10.4,6.0Hz,3H),1.11-1.06(m,2H),0.76(dq,J=11.7,6.4,4.9Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 597.3305.

[0444] Embodiment 63

[0445] Synthesis of (7R)-8-(1-(2-butynoyl)pyrrolidin-3-yl)-7-ethyl-2-((3-fluoro-2-((S)-2-hydroxypropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 63)

[0446]

[0447] Referring to the preparation of compound 62, 2-butynoyl chloride was used instead of acryloyl chloride according to the same feed ratio to obtain the title compound 63 (535 mg, white solid, yield 66%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.64-8.46 (m, 1H), 7.91-7.79 (m, 2H), 6.38 (ddt, J=14.1, 6.0, 2.6Hz, 1H), 5.36-5.17 (m, 1H) ,4.70-4.50(m,1H),4.23(dtd,J=16.5,8.7,8.1,3.4Hz,1H),4.08-3.98(m,1H),3.95-3.75(m,3H),3.74-3.47(m,3H),3.42 (dd,J=17.6,9.1Hz,1H),3.25(s,3H),3.05(t,J=5.1Hz,3H),2.42(t,J=4.9Hz,3H),2.20(d,J=4.2Hz,4H),2.03(s,1H),1.9 8-1.92(m,1H),1.78-1.57(m,2H),1.34-1.18(m,3H),1.11(td,J=4.3,2.1Hz,2H),0.82-0.73(m,3H); HRMS(ESI):m / z,(M+H) + , measured value 609.3305.

[0448] Embodiment 64

[0449] Synthesis of (R)-4-((8-(1-(2-butynoyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-2-fluoro-5-methoxybenzamide (Compound 64)

[0450]

[0451] Referring to the preparation of compound 7, 2-butynoyl chloride was used instead of acryloyl chloride to obtain the title compound 64 (413 mg, white solid, yield 43%) according to the same feed ratio; 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.29 (dd, J=13.4, 3.0Hz, 1H), 8.06 (d, J=7.7Hz, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.18 ( d,J=6.6Hz,1H),4.51-4.45(m,2H),4.44-4.38(m,1H),4.30(dd,J=7.9,3.3Hz,1H),3.91(s,3H),3.24(s,4H),3.09( dt,J=7.1,3.5Hz,1H),2.84-2.78(m,1H),2.78-2.72(m,1H),2.14(dd,J=34.0,12.1Hz,1H),2.03(d,J=2.0Hz,3H),1 .81-1.71(m,3H),1.66-1.60(m,1H),0.75-0.72(m,3H),0.71-0.66(m,2H),0.58-0.54(m,2H); HRMS(ESI):m / z,(M+H) + , measured value 564.2729.

[0452] Embodiment 65

[0453] (R)-N-cyclopropyl-4-((7-ethyl-8-(1-(2-fluoroacryloyl)piperidin-4-yl)-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-2-fluoro-5-methoxybenzamide (Compound 65)

[0454] Referring to the preparation of compound 64, 2-fluoroacrylic acid was used to replace the raw material 2-butynoyl chloride according to the same feed ratio, and HATU equivalent to 2 equivalents of the raw material in this step was added to obtain the title compound 65 (662 mg, white solid, yield 61%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.32 (d, J = 13.3Hz, 1H), 8.05 (d, J = 4.4Hz, 1H), 7.91 (d, J = 2.0Hz, 1H), 7.75 (s, 1H) ,7.18(d,J=6.5Hz,1H),5.33-5.24(m,2H),5.17(d,J=4.0Hz,1H),4.51-4.42(m,2H),4.32(dd,J=7.8,3.4Hz,1H) ,4.02(s,1H),3.90(s,3H),3.25(s,3H),2.89-2.78(m,2H),2.13(d,J=12.2Hz,2H),1.81-1.71(m,3H),1.63(dt, J=14.6,7.4Hz,1H),0.74(t,J=7.4Hz,3H),0.70-0.66(m,2H),0.55(q,J=3.8,3.1Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 570.2637.

[0455] Embodiment 66

[0456] (R,E)-N-cyclopropyl-4-((8-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-2-fluoro-5-methoxybenzamide (Compound 66)

[0457]

[0458] Referring to the preparation of compound 65, trans-4-dimethylaminocrotonic acid was used to replace the raw material 2-fluoroacrylic acid according to the same feed ratio to obtain the title compound 66 (433 mg, light yellow solid, yield 52%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.32 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.17 (d, J = 6.5Hz, 1H), 6.66 (d, J = 15.2Hz, 1H ),6.63-6.57(m,1H),4.62(s,1H),4.46(d,J=15.0Hz,1H),4.29(s,1H),4.20(s,1H),3.90(s,3H),3.24(s,3H),3.15(t,J=13.2Hz ,1H),3.07(d,J=5.9Hz,2H),2.83-2.79(m,1H),2.71(d,J=16.2Hz,1H),2.18(s,6H),2.12(d,J=12.0Hz,1H),1.97(s,1H),1.79-1 .71(m,3H),1.62(d,J=15.0Hz,1H),0.73(t,J=7.4Hz,3H),0.70-0.66(m,2H),0.55(dt,J=6.9,4.4Hz,2H); HRMS(ESI):m / z,(M+H) + , measured value 609.3317.

[0459] Embodiment 67

[0460] (R)-4-((8-(1-(2-cyanoacetyl)piperidin-4-yl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-cyclopropyl-2-fluoro-5-methoxybenzamide (Compound 67)

[0461]

[0462] Referring to the preparation of compound 65-+, cyanoacetic acid was used to replace the raw material 2-fluoroacrylic acid according to the same feed ratio to obtain the title compound 67 (326 mg, white solid, yield 39%); 1H NMR(600MHz,DMSO-d6)δ(ppm):8.35-8.29(m,1H),8.06-7.99(m,1H),7.92-7.89(m,1H),7.75(s,1H),7.18(d, J=6.6Hz,1H),4.53-4.45(m,2H),4.36(t,J=5.0Hz,1H),4.08(s,2H),3.91(s,3H),3.47-3.42(m,1H),3.25(s,3 H),3.16(t,J=13.0Hz,1H),2.84-2.79(m,1H),2.72(d,J=12.4Hz,1H),2.14-2.03(m,2H),1.78-1.70(m,2H),1. 65(dt,J=14.5,8.3Hz,2H),0.74(t,J=7.4Hz,3H),0.71-0.66(m,2H),0.58-0.54(m,2H); HRMS(ESI):m / z,(M+H) + , measured value 565.2686.

[0463] Embodiment 68

[0464] (R)-7-ethyl-2-((3-fluoro-2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-(2-fluoroacryloyl)piperidin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 68)

[0465]

[0466] With reference to the preparation of compound 51, 4-bromo-2-fluoro-6-nitrophenol was used to replace 4-bromo-2-nitrophenol, 2-fluoroacrylic acid was used to replace acryloyl chloride, and HATU equivalent to 2 equivalents of the raw material in this step was added to obtain the title compound 68 (274 mg, light yellow solid, yield 39%). 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.47 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 6.38 (dd, J=13.9, 2.8Hz, 1H), 5.29 (d, J=4.0Hz, 1H), 5.25 (dd, J= 14.8,4.0Hz,2H),5.15(d,J=4.0Hz,1H),4.47-4.36(m,2H),4.27(dd,J=7.8,3.4Hz,1H),4.05-4.00(m,1H),4.00-3.95(m,1H),3.94-3. 89(m,1H),3.65(s,2H),3.24(s,3H),3.14-3.05(m,5H),2.83(s,1H),2.69(s,1H),2.27(s,3H),2.15-2.11(m,1H),2.03(s,1H),1.99(s ,1H),1.91(s,1H),1.77(t,J=3.1Hz,1H),1.76-1.68(m,2H),1.62(dt,J=14.5,7.4Hz,1H),0.74(t,J=7.4Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 615.3216.

[0467] Embodiment 69

[0468] (R)-8-(1-(2-butynyl)piperidin-4-yl)-7-ethyl-2-((3-fluoro-2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 69)

[0469]

[0470] Referring to the preparation of compound 68, 2-butynoic acid was used instead of 2-fluoroacrylic acid according to the same feed ratio to obtain the title compound 69 (255 mg, yellow solid, yield 35%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.47 (s, 1H), 7.93 (s, 1H), 7.85 (d, J = 1.8Hz, 1H), 6.41-6.35 (m, 1H), 5.25 (t, J = 4.9Hz, 1H), 4.48 -4.44(m,1H),4.44-4.39(m,2H),4.38-4.34(m,1H),4.25(dd,J=7.4,3.6Hz,1H),4.00-3.96(m,1H),3.94-3.90(m,1H),3.65(s ,2H),3.24(s,3H),3.20(dt,J=13.4,3.0Hz,1H),3.11-3.04(m,4H),2.77-2.70(m,1H),2.44(t,J=5.1Hz,4H),2.22(d,J=1.4Hz ,3H),2.18-2.13(m,1H),2.03(d,J=2.2Hz,3H),1.79-1.70(m,2H),1.66-1.54(m,2H),0.75-0.71(m,3H); HRMS(ESI):m / z,(M+H) + , measured value 609.3309.

[0471] Embodiment 70

[0472] (R)-8-(1-acryloylpiperidin-4-yl)-7-ethyl-2-((3-fluoro-2-(2-hydroxyethoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 70)

[0473]

[0474] Referring to the preparation of compound 69, the compound acrylic acid was used to replace 2-butynoic acid according to the same feed ratio to obtain the title compound 70 (186 mg, light yellow oil, yield 27%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 8.49 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 6.47 (dd, J = 13.7, 2.8Hz, 1H), 5.27 (d, J = 5.8Hz ,1H),4.51(t,J=15.0Hz,1H),4.38-4.30(m,1H),4.24(dt,J=8.0,4.0Hz,1H),4.01-3.86(m,4H),3.65(q,J=4.7Hz,2H ),3.24(s,3H),3.13(s,1H),3.11(d,J=5.3Hz,2H),3.09(s,2H),3.08(s,2H),3.05(d,J=14.6Hz,2H),2.67(s,3H),2. 58(t,J=12.5Hz,1H),2.03(s,4H),1.80-1.72(m,2H),1.67-1.61(m,2H),0.74(t,J=7.4Hz,3H); HRMS(ESI):m / z,(M+H) + , measured value 597.3308.

[0475] Embodiment 71

[0476] (R)-8-(1-(2-butynyl)piperidin-4-yl)-7-ethyl-2-((2-(3-hydroxypropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 71)

[0477]

[0478] With reference to the preparation of compound 69, 4-bromo-2-nitrophenol was used instead of 4-bromo-2-fluoro-6-nitrophenol, and 3-bromopropanol was used instead of 2-bromoethanol to obtain the title compound 71 (398 mg, light yellow solid, yield 47%) according to the same feed ratio; 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.96 (s, 1H), 7.83 (d, J = 1.7Hz, 1H), 7.48 (s, 1H), 6.87 (dd, J = 8.8, 1.8Hz, 1H), 6.49-6.44 (m, 1H), 4.56 (t, J = 5.2Hz,1H),4.49-4.41(m,1H),4.40-4.32(m,2H),4.25(dt,J=7.2,3.2Hz,1H),4.04(dd,J=7.2,4.6Hz,2H),3.59(dt,J=6.2,3.1Hz,2H),3.2 4(s,3H),3.02(q,J=6.2,5.4Hz,2H),2.97(q,J=6.2,5.6Hz,2H),2.80-2.70(m,1H),2.69(s,1H),2.43(d,J=5.1Hz,4H),2.20(d,J=1.9Hz,3H ),2.11-2.06(m,1H),2.04-1.97(m,4H),1.91-1.85(m,2H),1.80-1.70(m,3H),1.65-1.59(m,1H),0.76-0.70(m,3H).HRMS(ESI):m / z,(M+H) + , measured value 605.3558.

[0479] Embodiment 72

[0480] (R)-7-ethyl-8-(1-(2-fluoroacryloyl)piperidin-4-yl)-2-((2-(3-hydroxypropoxy)-5-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (Compound 72)

[0481]

[0482] Referring to the preparation of compound 71, 2-fluoroacrylic acid was used instead of 2-butynoic acid according to the same feed ratio to obtain the title compound 72 (133 mg, light yellow solid, yield 26%); 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.98 (d, J = 2.9Hz, 1H), 7.84 (s, 1H), 7.48 (s, 1H) ,6.86(d,J=8.8Hz,1H),6.46(dd,J=8.8,2.9Hz,1H),5.31-5.21(m,2H),5.14(d ,J=3.9Hz,1H),4.57(s,1H),4.45-4.36(m,2H),4.26(dd,J=7.8,3.5Hz,1H),4. 04(td,J=6.3,2.4Hz,3H),3.58(t,J=6.1Hz,2H),3.24(s,3H),3.02(q,J=5.7,5 .0Hz,2H),2.97(dt,J=11.0,5.0Hz,2H),2.84(s,1H),2.44(t,J=5.1Hz,4H),2. 20(s,3H),2.07(dt,J=12.5,2.9Hz,1H),1.99(td,J=13.7,12.6,6.7Hz,1H),1. 88(dt,J=12.4,6.6Hz,2H),1.79-1.77(m,1H),1.74(ddt,J=15.0,7.5,3.7Hz,2 H),1.63(dq,J=14.5,7.4Hz,1H),0.74(t,J=7.5Hz,3H).HRMS(ESI):m / z,(M+H) + , measured value 611.3456.

[0483] Biological evaluation test case

[0484] Test Example 1: Determination of the inhibitory activity of the compounds of the present application on Plks kinase

[0485] Transphosphorylation assays were used to determine the inhibitory activity of putative kinase inhibitors and the potency of selected compounds. 33 In the presence of ATP tracer P-γ-ATP, specific peptide or protein substrates are transphosphorylated by their specific serine-threonine or tyrosine kinases in the presence of their own optimal buffer and cofactors.

[0486] The principle of the activity test method is as follows: This experiment uses the transphosphorylation assay to determine the inhibitory activity of Plk1 kinase inhibitors. The specific working principle is to 33 The ATP labeled with P-γ-ATP transphosphorylates a specific protein substrate under the action of specific Plk1 kinase. When the phosphorylation reaction is completed, the different fluorescence absorption intensities of unlabeled ATP and radioactive ATP are detected by an enzyme reader to evaluate their activity.

[0487] The specific operations are:

[0488] (1) Prepare hPlk1, hPlk2 and hPlk3 kinase buffers by adding hPlk1, hPlk2 and hPlk3 to 8 mM MOPS pH 7.0, 0.2 mM EDTA, 20 mM DTT, 1.25 mg / mL casein, 10 mM magnesium acetate and [γ- 33 P-ATP] and diluted in a buffer solution for later use;

[0489] (2) All compounds (0.5 mg) were dissolved and diluted with DMSO to 9 concentration gradients, namely 0.001 μM, 0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM, and 10 μM;

[0490] (3) The prepared compound solution was added to a 96-well plate and replicated once, and then the previously prepared kinase buffer was added. The buffer was used as a blank group. The reaction was marked by the addition of the MgATP mixture. After incubation at room temperature for about 40 minutes, 5 μL of 3% phosphoric acid solution was added to terminate the reaction. Then 10 μL of the reaction solution was dropped onto a P30 filter pad, washed three times with 75 mM phosphoric acid within five minutes, and washed once with methanol before drying and scintillation counting. The fluorescence intensity absorption value was detected by an enzyme reader, and the inhibition rate was calculated by scintillation counting;

[0491] (4) Draw the inhibition curve and calculate the IC by analyzing the inhibition curve. 50 The results are shown in Table 1.

[0492] Table 1: IC values ​​of small molecule inhibitors of this application on human hPlks enzyme 50 (nM) value

[0493]

[0494]

[0495]

[0496] The compounds of the present application have inhibitory activity against Plk1 kinase, and the selectivity of some compounds within the P1k family has been greatly improved.

[0497] Test Example 2: Inhibitory effect of the compounds of the present application on tumor cells

[0498] According to the results of the kinase test, the compounds of the present application were subjected to MTT assay in the following human non-small cell lung cancer cell line A549, human non-small cell lung cancer cell line H460 and human lung adenocarcinoma cell line PC-9 cell lines.

[0499] The MTT assay is a method for detecting cell survival and growth, and is widely used in the detection of bioactive factors, large-scale anti-tumor drug screening, cytotoxicity tests, and tumor radiosensitivity assays.

[0500] Principle: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) is a yellow dye. Succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple formazan crystals and deposit them in cells, while dead cells do not have this function. The formazan in cells is dissolved by DMSO and its light absorption value is measured at a wavelength of 490nm using an enzyme-linked immunosorbent assay, which can indirectly reflect the number of living cells.

[0501] The experiment includes the following steps:

[0502] (1) Plate the cells using a 96-well plate. The cell density in each well should be controlled at 4000-5000 cells per well, with a volume of 100 μl per well.

[0503] (2) Incubate at 37°C with 5% CO2. After the cells adhere to the wall for 4 to 6 hours, add drugs in a concentration gradient (only use the middle 60 wells).

[0504] (3) Incubate at 37°C with 5% CO2 for 16-48 hours and observe under an inverted microscope.

[0505] (4) Add 20 μl of MTT solution (5 mg / ml, i.e., 0.5% MTT) to each well and continue culturing for 4 h.

[0506] (5) Terminate the culture and pour out the liquid in the wells at once.

[0507] (6) Add 150 μl of dimethyl sulfoxide to each well and shake at low speed on a shaker for 10 min to fully dissolve the crystals. Measure the absorbance of each well at OD 490 nm using an enzyme-linked immunosorbent assay. Data processing was completed using GraphPad Prism 8.0.

[0508]

[0509] The experimental results show that the compounds of the present application have inhibitory activity against human non-small cell lung cancer cell line A549, human non-small cell lung cancer cell line H460 and human lung adenocarcinoma cell line PC-9 cell lines.

[0510] Test Example 3: Study on the therapeutic effect of compound 7 on a non-small cell lung cancer (A549) transplanted tumor mouse model

[0511] 18-20g BALB / c nude mice were randomly divided into 4 groups, 4 mice in each group, and kept in SPF animal culture room at a constant temperature of 23℃. A549 cells were expanded and cultured. After digestion, centrifugation and washing, 2×105 A549 cells were evenly dispersed in 200μL (100μL matrix gel and 100μL DMEM culture medium) suspension. 200μL of cell suspension was subcutaneously injected into the right armpit of each nude mouse with a 1mL medical syringe. After about two weeks of feeding, the volume of the transplanted tumor in the armpit was measured with a vernier caliper. When the tumor volume reached 100mm, oral administration was started. Grouping method: divided into blank control group (Vehicle), compound 24 (10mg / kg) group, compound 7 (10mg / kg) group, compound 7 (20mg / kg) group, BI2536 (10mg / kg) group. The mice in the control group were gavaged with 30% PEG-400 aqueous solution once and gavage twice a week; the compound 24 (10 mg / kg) group, the compound 7 (10 mg / kg) group, and the compound 7 (20 mg / kg) group were gavaged twice a week; the BI2536 (10 mg / kg) group was intraperitoneally injected twice a week; the administration was continued for 21 days. The tumor volume and the weight of the nude mice were measured every two days. After 21 days of administration, the animals were anesthetized with 10% chloral hydrate, and the animals were killed by dislocation of the neck after sampling. The nude mice were killed, the tumors were removed, the tumor weight was weighed, and then fixed with 4% paraformaldehyde.

[0512] Statistics and processing of data: The results were described by mean standard deviation (X±SD), and individual data were directly listed. When the sample size was less than 3, no statistical comparison was performed on the data of this group. The quantitative indicators were first tested for variance homogeneity using the LEVENE test. When the variance was homogeneous (P>0.05), one-way analysis of variance (ANOVA) was used for statistical testing; when the variance was unequal (P≤0.05), the Kruskal-Wallis H rank sum test (KW method) was used for statistical analysis. When the one-way ANOVA showed that the difference was statistically significant (P≤0.05), the Dunnett's t test (Dunnett method) was used to compare the differences between the groups; when the one-way ANOVA showed that the difference was not statistically significant (P>0.05), the statistical analysis ended. When the Kruskal-Wallis H rank sum test showed a statistically significant difference (P ≤ 0.05), the Mann-Whitney U test (MW method) was used to compare the differences between the groups; when the Kruskal-Wallis H rank sum test showed no statistically significant difference (P> 0.05), the statistical analysis was terminated. All tests were two-sided tests with a p value of 0.05. All analyses were performed by gender. GraphPad Prism version 8 data acquisition system was used for statistical analysis.

[0513] Test Example 4: Metabolic properties of compounds 7 and 24 in mice

[0514] The metabolic properties of the compounds in mice were detected by ICR mice. ICR male mice weighing 20-22g were selected, with 3 mice in each group. Compounds 7 and 24 were administered by gavage (10 mg / kg) and tail vein injection (1 mg / kg), respectively. The compounds were dissolved in 5% DMSO, 10% Solutol HS-15, and 85% hydroxypropyl-β-cyclodextrin 10.5% solution. Then blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, 20 μL each time, and 200 μL 0.1% FA ACN:MeOH was added; after mixing for 10 minutes, centrifuged at 14000 rpm for 10 minutes; 100 μL of the supernatant was diluted with 200 μL 0.1% FA 25% MeOH; after mixing evenly, 0.3 μL was taken for LC-MS / MS detection. Liquid phase conditions: ACQUITY-BEH-C18 column (2.1*50 mm, 1.7 μm), mobile phase A: acetonitrile / water 95:5 (v / v) containing 0.1% FA; mobile phase B: water / acetonitrile 95:5 (v / v) containing 0.1% FA, 2 mM ammonium acetate; mass spectrometry conditions: GS1:40; GS2:70; evaporator temperature: 400°C; ionization spray voltage: 2000 V. The blood drug concentration curve was drawn based on the data, and the pharmacokinetic parameters were calculated.

[0515]

[0516]

[0517] Although the embodiments of the present application have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present application, and that the scope of the present application is defined by the appended claims and their equivalents.

Claims

1. A novel tetrahydropteridinone derivative, as shown in the general formula (I), or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof: R1 and R2 are each independently selected from hydrogen and C1-C6 alkyl; R3 is -YW; Y is a single bond (or absent), C1-C6 alkylene, C1-C6 alkyleneamino, C3-C8 cycloalkylene, C3-C8 cycloalkyleneamino or C2-C8 heterocycloalkylene; W is a covalent warhead selected from and cyano, among which R a is hydrogen or halogen, or R a With R b Form a single bond, R c and R b Each independently selected from hydrogen, C1-C4 alkyl, C1-C8 heteroalkyl and C2-C 12 Heterocycloalkyl, R d is a halogenated C1-C6 alkyl or acetonitrile group; or, -YW is an oxo C3-C8 cycloalkyl or an oxa C5-C 12 Spirocycloalkyl; R4 is hydrogen or C1-C6 alkyl; R5 is halogen, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxy; R6 is hydrogen or halogen; R7 is hydrogen or -C(O)-NR e R f Here, R e and R f Each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl and C2-C 12 Heterocycloalkyl, and the C1-C6 alkyl, the C3-C8 cycloalkyl or the C2-C 12 The heterocycloalkyl group is optionally substituted with a group of Group A; R8 is hydrogen, halogen or in, L1 and L2 are each independently selected from a single bond (or absent) and C1-C4 alkylene optionally substituted by a group of Group A; R 13 is hydrogen or a C1-C4 alkyl group optionally substituted by a group of Group A, or R 13 With R 10 connected and together with the groups to which they are attached form a C2-C 11 Azacycloalkyl, or R 13 With R 12 connected and together with the groups to which they are attached form a C2-C 11 Azacycloalkyl; R9 and R 10 Each is independently selected from hydrogen, halogen, C1-C4 alkyl optionally substituted by a group of Group A, nitro, hydroxyl and C1-C4 alkoxy optionally substituted by a group of Group A; R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, and C1-C4 alkanoyl optionally substituted by a group of Group A; Group A groups are hydroxyl, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C6-C 12 Aryl-substituted C1-C6 alkyl, halogenated C1-C6 alkoxy or C6-C 12 Aryl.

2. The derivative according to claim 1, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R5 is halogen, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxy; R6 is hydrogen or halogen; here, the halogen is chlorine, bromine, iodine or fluorine; R7 is -C(O)-NR e R f ; R8 is hydrogen, fluorine, chlorine, bromine or iodine.

3. The derivative according to claim 1, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R5 is halogen, unsubstituted C1-C6 alkoxy, halogenated C1-C6 alkoxy or C1-C6 alkoxy substituted by hydroxy; R6 is hydrogen or halogen; here, the halogen is chlorine, bromine, iodine or fluorine; R7 is hydrogen; R8 is 4. The derivative according to any one of claims 1 to 3, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen and R2 is C1-C6 alkyl, preferably, R1 is hydrogen and R2 is ethyl, and the carbon atom to which R1 and R2 are attached is in R configuration.

5. The derivative according to any one of claims 1 to 4, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, preferably, R4 is methyl.

6. The derivative according to any one of claims 1 to 5, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R5 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, hydroxymethoxy, hydroxyethoxy, hydroxy-n-propoxy, hydroxyisopropoxy, hydroxy-n-butoxy, hydroxyisobutoxy, hydroxy-sec-butoxy or hydroxy-tert-butoxy, preferably, R5 is methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy or 2-hydroxypropoxy.

7. The derivative according to any one of claims 1 to 6, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R6 is hydrogen, chlorine, bromine, fluorine or iodine, preferably, R6 is hydrogen, chlorine or fluorine.

8. The derivative according to any one of claims 1 to 7, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R3 is -YW; Y is a single bond (or absent), methylene, ethylene, propylene, butylene, pentylene, hexylene, ethyleneamino, propyleneamino, butyleneamino, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutyleneamino, cyclopentyleneamino, cyclohexyleneamino, azetidinyl, pyrrolidinylene or piperidinylene, W is a covalent warhead selected from and cyano, where R a is hydrogen or halogen, or R a With R b Form a single bond, R c and R b Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C1-C4 alkoxy C1-C4 alkyl, mono-C1-C4 alkylamino C1-C4 alkyl, di-C1-C4 alkylamino C1-C4 alkyl, and C2-C 12 Heterocycloalkyl, wherein the C2-C 12 The heterocycloalkyl group is oxirane, oxetanyl, dioxolanyl, dithiacyclopentyl, dioxanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisoquinolyl, octahydroisoquinolyl, decahydroisoquinolyl, tetrahydroquinolyl, octahydroquinolyl, tetrahydroimidazolinyl, pyrazolidinyl, pyrrolidinyl, pyrrolidinone, piperidinyl, piperidone, piperazinyl, piperazinone, N-methylpyrrolidinyl, 2- R is hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, N-methylpiperazinyl, N-benzylpiperazinyl, N-acetylpiperazinyl, N-methylsulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, imidazolidinyl, tetrahydroimidazolonyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, quinuclidinyl or nortropine, or a ring thereof which is benzo-fused, such as benzopyrrolidinyl, benzomorpholinyl, etc.; R d is selected from the following groups substituted by one or more of fluorine, chlorine, bromine and iodine, or acetonitrile: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl; or, -YW is oxocyclobutyl, oxocyclopentyl, oxocyclohexyl, oxocycloheptyl, oxocyclooctyl, 1-oxaspiro[2,4]heptyl, 1-oxaspiro[2,5]octyl or 1-oxaspiro[2,6]nonanyl.

9. The derivative according to claim 8, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R3 is one of the following groups:

10. The derivative according to any one of claims 1 to 9, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Medium R 13 is hydrogen, L1 is a single bond, -CH2- or -CH2-CH2-; L2 is a single bond, -CH2- or -CH2-CH2-; R9 and R 10 All are hydrogen; R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, and C1-C4 alkanoyl optionally substituted by a group of Group A; preferably, R 13 is hydrogen, L1 is -CH2-; L2 is -CH2-; R9 and R 10 All are hydrogen; R 11 is hydrogen, and R 12 is methyl or ethyl; more preferably, R 13 is hydrogen, L1 is -CH2-; L2 is -CH2-; R9 and R 10 All are hydrogen; R 11 is hydrogen, and R 12 is ethyl; or 4-R 12 - piperazinyl optionally substituted by a group of Group A, R 12 is hydrogen, C1-C6 alkyl optionally substituted by a group of Group A, or C1-C4 alkanoyl optionally substituted by a group of Group A; preferably, 4-R 12 -piperazinyl, R 12 is hydrogen, methyl, ethyl or tert-butyloxycarbonyl.

11. A compound, or a pharmaceutically acceptable salt thereof, selected from one of the following:

12. A method for preparing the derivative according to claim 1, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, the method comprising: The compound of formula (II) is coupled with the compound of formula (III) to obtain a novel tetrahydropteridinone derivative as shown in the general formula (I). The definitions of the substituents in formula (II) and formula (III) are the same as those in formula (I). In formula (III), X is chlorine, bromine or iodine.

13. A pharmaceutical composition comprising a therapeutically effective amount of the derivative according to any one of claims 1 to 11, or its tautomer, geometric isomer, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier excipient or diluent.

14. Use of the derivative according to any one of claims 1 to 11, or its tautomer, geometric isomer, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 as a selective inhibitor of Plk1 kinase, preferably, in the preparation of a medicament for treating or preventing diseases caused by excessive proliferation of malignant tumor cells.

15. The use according to claim 14, wherein: The diseases caused by excessive proliferation of malignant tumor cells include: colorectal adenocarcinoma, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, epidermal cell cancer, esophageal cancer, thyroid cancer, acute leukemia, chronic myeloid leukemia, digestive tract cancer, liver cancer, lymphoma, myeloma, head and neck tumors, etc.

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