4-indolinyl substituted pyridino [3, 2-d] pyrimidine compound and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to 4-indoline substituted pyridine [3, 2-d] pyrimidine compounds and application thereof in preparation of Mnk inhibitors and medicines for treating and / or preventing various cancers, metabolic diseases, inflammatory diseases, autoimmune diseases and viral diseases. The invention relates to a 4-indolinyl substituted pyrido [3, 2-d] pyrimidine compound, which is a compound as shown in a general formula I, an isomer and pharmaceutically acceptable salts, hydrates, solvates and metabolites thereof: # imgabs0 #. The active compound provided by the invention can be used as a unique anti-cancer drug, or can be combined with one or more other anti-tumor drugs for use. The combined treatment is realized by simultaneously, sequentially or separately administering each treatment component.

Description

Technical field:

[0001] The present invention belongs to the field of medical technology, and specifically relates to 4-indoline substituted pyridine [3,2-d] pyrimidine compounds and their use in preparing Mnk inhibitors and drugs for treating and / or preventing various cancers, metabolic, inflammatory, autoimmune and viral diseases. Background technology:

[0002] MAP kinase-interacting kinase or MAPkinase signal-integrating kinase (Mnk) is a serine / threonine kinase belonging to the Ca 2+ / calmodulin-dependent kinase family, located downstream of the MAPK signaling pathway responsible for regulating cell survival and proliferation. Mnk kinase is the only known kinase that regulates the phosphorylation of eukaryotic initiation factor 4E (eIF4E): Mnk can phosphorylate eIF4E at eIF4E Ser209, thereby regulating the cap-dependent translation initiation process. It has been reported in the literature that Mnk overactivation marked by overexpression of p-eIF4E has been found in a variety of tumor cells, such as breast cancer, colon cancer, bladder cancer, lung cancer, and blood cancer. In addition to eIF4E, Mnk's downstream substrates include hnRNPA1, PSF, and cPLA2. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) plays an important role in regulating mRNA metabolism. Mnk can respond to T cell activation by phosphorylating hnRNPA1. Studies have shown that overactivated hnRNPA1 has been found in solid tumors such as colorectal cancer, non-small cell lung cancer, and multiple myeloma. In addition, Mnk can participate in the synthesis of TNFα by phosphorylating hnRNPA1. Therefore, inhibiting Mnk can inhibit the release of TNFα and IL-6, and thus be used to treat inflammatory diseases. Polypyrimidine tract binding protein-associated splicing factor (PSF) is a nucleic acid protein that participates in the transcription and processing of RNA. Buxade et al. demonstrated that in cells, Mnk can phosphorylate PSF at Ser8 and Ser283, thereby enhancing the binding of PSF to TNFαmRNA, thereby participating in the synthesis of TNFα. Cytoplasmic phospholipase A2 (cPLA2) plays an important role in the production of eicosanoids, and thus participates in the immune response and inflammatory response. Mnk1 can promote the production of eicosanoids by phosphorylating cPLA2 at Ser727 and activating it. Therefore, in addition to tumor diseases, Mnk is also an effective target for the treatment of autoimmune diseases and inflammatory diseases.

[0003] In addition to regulating downstream signaling pathways, Mnk can also promote tumor cell survival by mediating drug resistance and tumor cell immune escape. At present, overactivation of Mnk kinase and eIF4E has been found in a variety of drug-resistant cells. Studies have shown that after treating AML cells with the mTOR inhibitor rapamycin, Mnk kinase is overactivated through a negative feedback mechanism, and the levels of eIF4E and p-eIF4E are significantly increased. The combination of the Mnk inhibitor cercosporamide and rapamycin can significantly improve the anti-proliferative effect on AML cells. Zhang et al. found that the levels of eIF4E and p-eIF4E were significantly increased in anlotinib-resistant non-small cell lung cancer cell lines. The combination of anlotinib and the Mnk inhibitor cercosporamide can improve the anti-proliferative activity of anlotinib in vitro, and the combination in vivo can also improve the anti-tumor effect of anlotinib. In addition, Mnk can also mediate the resistance of tumor cells to a variety of chemotherapeutic drugs, and the combination of Mnk inhibitors with it can increase the sensitivity of tumor cells to the corresponding chemotherapeutic drugs. In the mouse A549 xenograft tumor model, the combination of the Mnk inhibitor Bay1143269 and docetaxel can significantly improve the in vivo anti-tumor activity of docetaxel. In the PDX model of non-small cell lung cancer, the combination of Bay1143269 and pemetrexed can significantly improve the in vivo anti-tumor effect of pemetrexed. In addition to mediating the expression of a variety of tumorigenic proteins, Mnk-eIF4E can also regulate the expression of immune checkpoint-related proteins (PD-1, TIM3 and LAG3). Therefore, inhibiting the activity of Mnk kinase can downregulate the level of checkpoint-related proteins in immune cells, thereby restoring the recognition of tumor cells by immune cells. Summary of the invention:

[0004] The technical problem solved by the present invention is to provide 4-indoline substituted pyridine [3,2-d] pyrimidine compounds and their use as Mnk inhibitors in preventing and / or treating cancer, metabolic, inflammatory, autoimmune and viral diseases.

[0005] To achieve the above purpose, the present invention adopts the following technical solution:

[0006] A 4-indolyl-substituted pyrido[3,2-d]pyrimidine compound, wherein the compound is a compound represented by general formula I, an isomer thereof, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof:

[0007]

[0008] in,

[0009] R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C2-4-6-yl, unsubstituted or substituted by at least one of the following groups which may be the same or different: 10 Alkyl, CONR9R 10 and SO2NR9R 10 , the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkoxy; R2, R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine oxide, C2-C 10 alkenyl, unsubstituted or substituted by at least one of the following groups which are the same or different 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12 ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl;

[0010] Y is

[0011] The left side of Y is connected to the pyridopyrimidine mother nucleus;

[0012] R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, Hydroxyl C2-C 10 Alkyl, amino C2-C 10 Alkyl, C1-C4 alkoxy C1-C4 alkyl, unsubstituted or substituted with at least one of the same or different halogen, amino, oxygen, C1-C 10 Alkyl-substituted C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C4-C8 heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CSNR9R 10 、-CH2CONR9R 10 、-SO2NR9R 10 、-OCONR9R 10 、-NHCONHR9R 10 ;

[0013] R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, carbamoyl, dimethylphosphine, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Haloalkyl, CF3SO2-, CHF2SO2-, CH3SO2-, CH3SO2NH-;

[0014] R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, haloalkyl (C1-C 10 )、C3-C 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

[0015] Preferably, the compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof, wherein:

[0016] R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C8 alkyl which is unsubstituted or substituted by at least one of the following groups which may be the same or different, CONR9R 10 and SO2NR9R 10 , the following groups are halogen, hydroxy, amino, cyano, C1-C4 alkoxy;

[0017] R2 and R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl;

[0018] Y is The left side of Y is connected to the pyridopyrimidine mother nucleus;

[0019] R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 C2-C8 alkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C8 alkoxy which is unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CSNR9R 10 、-CH2CONR9R 10 、-SO2NR9R 10 、-OCONR9R 10 、-NHCONHR9R 10 ;

[0020] R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, carbamoyl, dimethylphosphine, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Haloalkyl;

[0021] R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

[0022] More preferably, the compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof.

[0023] R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C8 alkyl which is unsubstituted or substituted by at least one of the following groups which may be the same or different, the following groups being halogen, hydroxyl, amino, cyano, C1-C4 alkoxy;

[0024] R2 and R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12 ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl;

[0025] Y is The left side of Y is connected to the pyridopyrimidine mother nucleus;

[0026] R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 C2-C8 alkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C8 alkoxy which is unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CH2CONR9R 10 、-OCONR9R 10 、-NHCONHR9R 10 ;

[0027] R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Haloalkyl;

[0028] R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

[0029] Still more preferably, the compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof,

[0030] R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl;

[0031] R2 and R3 may be the same or different and are independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12 ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl; Y is The left side of Y is connected to the pyridopyrimidine mother nucleus;

[0032] R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 C2-C8 alkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C8 alkoxy which is unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CH2CONR9R 10 ;

[0033] R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, C1-C 10 Alkyl, C1-C 10 Haloalkyl;

[0034] R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C 10Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

[0035] More preferably, the compound is the following compound, isomer and pharmaceutically acceptable salt, hydrate, solvate, metabolite thereof,

[0036]

[0037]

[0038]

[0039] A pharmaceutical composition comprises the compound, isomers and pharmaceutically acceptable salts, hydrates, solvates and metabolites thereof.

[0040] The present invention includes a pharmaceutical composition comprising a 4-indoline substituted pyrido[3,2-d]pyrimidine compound of general formula I and a pharmaceutically acceptable excipient thereof. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and / or carrier that can be used in the pharmaceutical field. The present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0041] The pharmaceutical combination of the present invention can be formulated into several dosage forms, which contain some excipients commonly used in the pharmaceutical field, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions, or injectable dry powders, which can be used immediately by adding injection water before injection); topical preparations (such as ointments or solutions).

[0042] The carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for local preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically), and if some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0043] An application of the compound or the composition, and application of the compound or the composition in the preparation of drugs for treating and / or preventing various cancer diseases or autoimmune diseases with abnormal expression of Mnk or Pim.

[0044] The cancer is breast cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, liver cancer, bladder cancer, uterine cancer, pancreatic cancer, ovarian cancer, lymphoma, ovarian cancer, skin cancer or blood cancer.

[0045] The autoimmune disease is septic shock or acute organ damage.

[0046] The active compounds of the present invention can be used as the sole anticancer drug or in combination with one or more other antitumor drugs. Combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially or separately. Specific implementation method:

[0047] The embodiments are intended to illustrate rather than limit the scope of the present invention. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0048] The NMR spectra of the compounds were measured using a Bruker ARX-600 NMR spectrometer in DMSO-d6 with TMS as the internal standard, and the high-resolution mass spectra were measured using a Bruker micro-TOF-Q.

[0049] Example 1: Preparation of (3-(4-(5-fluoro-3,3-dimethylindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(piperazine-1-yl)methanone

[0050] Step A: Preparation of tert-butyl 5-fluoro-2-oxoindoline-1-carboxylate (1)

[0051]

[0052] 5-Fluoroindole-2-one (2.0 g, 13.24 mmol), di-tert-butyl dicarbonate (2.89 g, 13.24 mmol) and sodium bicarbonate (1.67 g, 19.86 mmol) were placed in a 100 mL eggplant-shaped bottle, 30 mL tetrahydrofuran was added to dissolve, and the reaction was carried out at 50 ° C. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane, extracted three times with saturated sodium bicarbonate aqueous solution, and the organic phase was dried. The organic phase was evaporated to dryness to obtain a crude product, which was purified by column chromatography (P:E=25:1) to obtain 1.9 g of a white solid with a yield of 57.2%.

[0053] Step B: Preparation of tert-butyl 5-fluoro-3,3-dimethyl-2-oxoindoline-1-carboxylate (2)

[0054]

[0055] 1 (400 mg, 1.59 mmol) and iodomethane (1130 mg, 7.96 mmol) were placed in a 50 mL eggplant-shaped bottle, and dry tetrahydrofuran was added to dissolve. The temperature of the reaction solution was lowered to below 0°C, and sodium hydride (84 mg, 3.5 mmol) was added in batches. After the addition was completed, the reaction was transferred to room temperature. After TLC monitoring of the reaction was complete, ice water was added to the reaction solution to quench, the water layer was extracted three times with ethyl acetate, the organic phases were combined, extracted once with saturated brine, and the organic phase was dried. The organic phase was evaporated to dryness to obtain a crude product, which was purified by column chromatography to obtain a colorless oily product of 300 mg in a yield of 67.6%. Intermediates 2b and 2c were prepared according to the method of 2a

[0056] Step C: Preparation of 5-fluoro-3,3-dimethylindolin-2-one (3)

[0057]

[0058] 2a (300 mg, 1.08 mmol) was placed in a 50 mL eggplant-shaped bottle, and 10 mL of dichloromethane was added to dissolve. The reaction bottle was placed in a cold trap and cooled to -20 ° C. 2.5 mL of trifluoroacetic acid was slowly added to the reaction bottle. After the reaction was completed by TLC monitoring, a saturated sodium bicarbonate aqueous solution was added to the reaction bottle to quench the reaction, and the organic phase and the aqueous phase were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined, extracted once with saturated brine, dried, and evaporated to obtain the product as a white solid of 184 mg, with a yield of 95%.

[0059] Intermediates 3b and 3c were prepared according to the method of 3a.

[0060] Step D: Preparation of 5-fluoro-3,3-dimethylindoline (4)

[0061]

[0062] 3a (184 mg, 1.03 mmol) was placed in a 25 mL eggplant-shaped bottle and 10 mL of tetrahydrofuran was added to dissolve. Lithium aluminum hydride was slowly added at room temperature to obtain 2.1 mL of tetrahydrofuran solution (1 mol / L). After the addition was completed, the mixture was refluxed for reaction. TLC monitored the reaction to be complete. Ice water was slowly added to the reaction solution to quench. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and extracted once with saturated brine, dried, and evaporated to obtain the product as a colorless oil (136 mg) with a yield of 80%.

[0063] Intermediates 4b and 4c were prepared according to the method of 4a.

[0064] Step E: Preparation of 6-chloro-4-(5-fluoro-3,3-dimethylindolin-1-yl)pyrido[3,2-d]pyrimidine (5)

[0065] 4,6-Dichloropyrido[3,2-d]pyrimidine (150 mg, 0.75 mmol), 4a (184 mg, 0.83 mmol) and triethylamine (114 mg, 1.13 mmol) were placed in a 25 mL eggplant-shaped bottle, 15 mL of isopropanol was added to dissolve, and the mixture was reacted at 50° C. After the reaction was completed by TLC monitoring, the product was filtered to obtain 190 mg of a yellow solid with a yield of 77.2%.

[0066] Intermediates 5b and 5c were prepared according to the method of 5a.

[0067] Step F: 3-(4-(5-Fluoro-3,3-dimethylindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)benzoic acid (6)

[0068]

[0069] 5a (150 mg, 0.46 mmol, m-carboxyphenylboronic acid (92 mg, 0.55 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (Pd(dppf)Cl2, 17 mg, 0.023 mmol) and potassium carbonate (95 mg, 0.69 mmol) were placed in a 50 mL two-necked bottle, 12 mL of 1,4-dioxane and 3 mL of water were added to dissolve, and refluxed under nitrogen protection. After the reaction was completed as monitored by TLC, 15 mL of ice water was added to the reaction bottle to dilute the reaction solution, and the pH was adjusted to 6 with 10% HCl aqueous solution. A large amount of solid precipitated, and the product was filtered to obtain 130 mg of yellow solid with a yield of 68.3%.

[0070] Intermediates 6b and 6c were prepared according to the method of 6a.

[0071] Steps G, H: Preparation of (3-(4-(5-fluoro-3,3-dimethylindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(piperazin-1-yl)methanone (Example 1)

[0072]

[0073] 6a (130 mg, 0.31 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 141 mg, 0.37 mmol), 4-dimethylaminopyridine (DMAP, 45 mg, 0.37 mmol) and N,N-diisopropylethylamine (DIPEA, 60 mg, 0.47 mmol) were placed in a 25 mL eggplant-shaped bottle, and 10 mL of tetrahydrofuran was added to dissolve. After the reaction was completed by TLC monitoring, tert-butyl piperazine-1-carboxylate (69 mg, 0.37 mmol) was added to the reaction bottle and reacted at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane, extracted with 10% HCl aqueous solution, water, saturated sodium bicarbonate aqueous solution, water and saturated saline, dried, evaporated to dryness to obtain a yellow oily substance, which was placed in a 100 mL eggplant-shaped bottle, dissolved in 20 mL dichloromethane, and 5 mL trifluoroacetic acid was added at room temperature to react at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, the residue was dissolved in water, the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted 5 times with dichloromethane: methanol = 10:1, the organic phases were combined, dried, evaporated to dryness to obtain a crude product, and the product was purified by column chromatography (dichloromethane: methanol = 20:1) to obtain 70 mg of a yellow solid, with a two-part yield of 46.8%. mp: 145.1-146.7℃. 1 H-NMR (600MHz, DMSO-d6) δ8.70 (s, 1H), 8.54 (d, J = 8.7Hz, 1H), 8.46 (dd, J = 9.0 ,4.9Hz,1H),8.28(dd,J=8.5,4.1Hz,2H),8.21(s,1H),7.66(t,J=7.7Hz,1H), 7.53(d,J=7.5Hz,1H),7.28(dd,J=8.4,2.8Hz,1H),7.09(td,J=9.0,2.8Hz,1H ), 4.86 (s, 2H), 3.44 (d, J = 205.0Hz, 2H), 2.72 (d, J = 76.8Hz, 4H), 1.39 (s, 6H). 13 C-NMR (151MHz, DMSO) δ168.60,159.69,158.10,157.27,154.30,153.08,146.66,144.36,138.80,137.98,137.06,136.81,132.68,129 .35,128.14,127.73,125.34,124.96,119.55,113.20,109.68,68.27,48.48,45.85,45.21,42.64,40.42,27.65.HRMS(ESI,m / z)calcd forC 28 H27 FN6O[M+H] + ,483.2303;found,483.2304.

[0074] Example 2: Preparation of (S)-(3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(3-methylpiperazin-1-yl)methanone Using 6a and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester as starting materials, 63 mg of yellow solid was obtained according to the preparation method of Example 1, with a yield of 41.0%. mp: 94.1-95.0℃. 1 H-NMR(600MHz,DMSO-d6)δ8.70(s,1H),8.54(d,J=8.9Hz,1H),8.28(t,J=7.7Hz,2H) ,8.21(s,1H),7.66(t,J=7.7Hz,1H),7.52(d,J=7.5Hz,1H),7.28(dd,J=8.4,2.8Hz, 1H),7.10(dd,J=9.0,2.8Hz,1H),4.86(s,2H),4.38(s,1H),3.49(d,J=15.3Hz,1H), 3.08(s,1H),2.97(s,1H),2.79(s,1H),2.67(s,3H),1.38(s,7H),0.87-0.80(m,3H). 13 C-NMR(151MHz,DMSO-d6)δ168.58,159.74,158.14,157.30,154.34,153.10,14 6.69,144.34,138.85,138.03,137.16,136.86,132.72,129.38,128.15,127.7 8,125.41,124.99,119.54,113.25,109.73,68.37,54.23,50.78,50.20,48.56 ,47.91,46.16,44.69,40.44,30.96,27.68,22.06,13.97.HRMS(ESI,m / z)calcd for C 29 H 29 FN6O[M+H] + ,497.2460;found,497.2461.

[0075] Example 3: Preparation of (3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone Using 6a and tert-butyl 4-methylpiperazine-1-carboxylate as starting materials, a yellow solid of 78 mg was obtained according to the preparation method of Example 1 with a yield of 50.7%. mp: 110.1-111.8°C. 1 H-NMR (600MHz, DMSO) δ8.71 (s, 1H), 8.55 (d, J = 8.9 Hz, 1H), 8.47 (dd, J = 8.9, 4.9 Hz,1H),8.29(t,J=6.5Hz,2H),8.22(s,1H),7.66(t,J=7.7Hz,1H),7.53(d,J=7 .6Hz,1H),7.29(dd,J=8.4,2.8Hz,1H),7.10(td,J=9.0,2.8Hz,1H),4.87(s,2H ),3.68(s,2H),3.39(s,2H),2.33(d,J=76.6Hz,4H),2.19(s,3H),1.39(s,6H). 13 C-NMR (151MHz, DMSO) δ168.65,159.70,158.10,157.28,154.32,153.08,146.67,144.36,138.82,138.04,136.91,136.84,132.71,129.38 ,128.13,127.86,125.38,125.00,119.51,113.22,109.70,68.33,54.80,54.19,47.15,45.58,41.42,40.43,27.73.HRMS(ESI,m / z)calcd for C 29 H 29 FN6O[M+H] + ,497.2460;found,497.2471.

[0076] Example 4: Preparation of (S)-(3-aminopiperidin-1-yl)(3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)methanone Using 6a and (S)-piperidin-3-ylcarbamic acid tert-butyl ester as starting materials, 62 mg of yellow solid was obtained according to the preparation method of Example 1, with a yield of 40.3%. mp: 105.2-106.7℃. 1H-NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.55(d,J=8.8Hz,1H),8.47(s,1H),8.31-8.26(m,2H ),8.22(s,1H),7.66(t,J=7.7Hz,1H),7.53(d,J=7.6Hz,1H),7.28(dd,J=8.4,2.8Hz,1H),7. 10(td,J=9.0,2.8Hz,1H),4.87(s,2H),4.39(s,1H),3.55(d,J=53.5Hz,1H),3.04(s,1H),2. 96-2.86(m,1H),2.80(s,1H),2.66(s,1H),1.82(d,J=69.9Hz,2H),1.62(s,1H),1.39(s,6H). 13 C-NMR (151MHz, DMSO-d6) δ168.90,159.74,158.14,157.32,154.34,153. 15,146.69,144.40,138.84,138.00,137.27,136.85,132.72,129.37,128 .10,127.77,125.34,125.00,119.54,113.09,109.72,68.36,47.32,41.7 0,40.45,32.61,31.87,29.01,27.64,23.99,23.02.HRMS(ESI,m / z)calcd for C 29 H 29 FN6O[M+H] + ,497.2460;found,497.2478.

[0077] Example 5: Preparation of (R)-(3-aminopiperidin-1-yl)(3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)methanone Using 6a and (R)-piperidin-3-ylcarbamic acid tert-butyl ester as starting materials, a yellow solid of 48 mg was obtained according to the preparation method of Example 1, with a yield of 31.2%. mp: 135.6-136.7℃. 1H-NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.55(d,J=8.8Hz,1H),8.46(s,1H),8.31-8.26(m,2H),8.2 2(s,1H),7.66(t,J=7.7Hz,1H),7.53(d,J=7.6Hz,1H),7.29(dd,J=8.4,2.8Hz,1H),7.10(td,J=9. 0,2.8Hz,1H),4.87(s,3H),4.30(d,J=107.2Hz,1H),3.55(d,J=59.9Hz,1H),3.03(s,1H),2.85(d, J=74.2Hz,1H),2.67(s,1H),1.88(s,1H),1.69(d,J=87.9Hz,1H),1.54-1.42(m,1H),1.39(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.90,159.74,158.14,157.33,154.35,153.18 ,146.70,144.36,138.84,138.01,137.26,136.86,132.74,129.37,128. 11,127.77,125.32,125.01,119.54,113.10,109.57,68.34,47.20,42.2 6,40.45,32.52,32.13,29.02,27.64,23.99,22.09.HRMS(ESI,m / z)calcd for C 29 H 29 FN6O[M+H] + ,497.2460;found,497.2466.

[0078] Example 6: Preparation of (R)-(3-(4-(5-fluoro-3,3-dimethylindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(3-hydroxypyrrolidin-1-yl)methanone

[0079] 6a (130 mg, 0.31 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 141 mg, 0.37 mmol), 4-dimethylaminopyridine (DMAP, 45 mg, 0.37 mmol) and N,N-diisopropylethylamine (DIPEA, 60 mg, 0.47 mmol) were placed in a 25 mL eggplant-shaped bottle, and 10 mL of tetrahydrofuran was added to dissolve. After the reaction was completed by TLC monitoring, (R)-pyrrolidin-3-ol (33 mg, 0.37 mmol) was added to the reaction bottle and reacted at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane, extracted with 10% HCl aqueous solution, water, saturated sodium bicarbonate aqueous solution, water and saturated brine respectively, dried, evaporated to dryness to obtain a yellow oil, which was purified by column chromatography (dichloromethane: methanol = 50: 1) to obtain a yellow solid product of 63 mg, with a yield of 42.1%. mp: 57.1-58.2℃. 1 H-NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.55(dd,J=8.8,5.5Hz,2H),8.46(dt,J=9.4,4.8Hz,2H),8.35(d,J= 5.2Hz, 3H), 8.29 (ddd, J=16.0, 7.8, 3.2Hz, 5H), 7.69-7.63 (m, 5H), 7.28 (dd, J=8.4, 2.8Hz, 3H), 7.10 (td, J= 8.9,2.8Hz,3H),4.99(dd,J=53.1,3.3Hz,3H),4.87(s,5H),4.30(d,J=69.3Hz,2H),3.67-3.59(m,4H),3.58 -3.45(m,2H),3.42(d,J=12.7Hz,1H),3.25(d,J=11.0Hz,2H),2.01-1.89(m,1H),1.87(s,1H),1.39(s,6H). 13 C-NMR(151MHz,DMSO-d6)δ168.29,159.73,158.14,156.90,154.32,153.13, 146.67,144.47,138.84,137.95,137.76,136.83,132.72,129.22,128.46,12 8.18,125.73,125.07,119.55,113.06,109.55,69.36,68.37,68.03,57.22,5 4.39,47.03,44.16,40.45,34.43,32.25,27.73,27.62.HRMS(ESI,m / z)calcd for C28 H 26 FN5O2[M+H] + ,484.2143;found,484.2155.

[0080] Example 7: Preparation of (S)-(3-(4-(5-fluoro-3,3-dimethylindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(3-hydroxypyrrolidin-1-yl)methanone Using 6a and (S)-pyrrolidin-3-ol as starting materials, a yellow solid of 55 mg was obtained according to the preparation method of Example 6 with a yield of 36.7%. mp: 110.7-111.7°C. 1 H-NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.55(dd,J=8.9,5.5Hz,1H),8.46(dt,J=9.4,4.9Hz,1H),8.35(d ,J=5.1Hz,1H),8.29(ddd,J=16.4,7.7,3.1Hz,1H),7.69-7.64(m,5H),7.28(dd,J=8.4,2.8Hz,1H),7.10 (td,J=8.9,2.8Hz,1H),4.99(dd,J=53.0,3.4Hz,1H),4.87(s,2H),4.30(d,J=63.6Hz,1H),3.68-3.60(m ,2H),3.59-3.45(m,1H),3.42(d,J=12.9Hz,1H),3.25(d,J=11.3Hz,1H),1.99-1.79(m,2H),1.39(s,6H). 13 C-NMR(151MHz,DMSO-d6)δ168.29,159.73,158.13,157.30,154.32,153.24,14 6.67,144.42,138.83,137.95,137.89,137.76,136.83,132.72,129.22,128.46 ,128.18,125.73,125.08,119.55,113.21,109.71,69.36,68.37,68.03,57.22 ,54.39,47.03,44.16,40.45,34.43,32.25,27.73,27.56.HRMS(ESI,m / z)calcd for C 28 H 26 FN5O2[M+H] + ,484.2143;found,484.2170.

[0081] Example 8: Preparation of (3-(4-(5-fluoro-3,3-dimethylindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(morpholinyl)methanone Using 6a and morpholine as starting materials, the preparation method of Example 6 was used to obtain 72 mg of a yellow solid with a yield of 48.1%. mp: 207.1-208.0°C. 1 H-NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.54(d,J=8.8Hz,1H),8.45(dd,J=8.9,4.8Hz,1H),8.24(s,1H),7.67(t,J=7.7Hz,1H),7 .56(d,J=7.7Hz,1H),7.28(dd,J=8.4,2.8Hz,1H),7.09(td,J=9.0,2.8Hz,1H),4.86(s,2H),3.62(d,J=74.4Hz,6H),1.39(s,6H). 13 C-NMR (151MHz, DMSO) δ168.73,159.71,158.11,157.30,154.30,153.08,146.62,144.36,138.80,138.04,136.79,136.52,132. 69,129.39,128.29,127.97,125.52,125.03,119.51,113.05,109.53,68.30,66.14,47.83,40.45,27.62.HRMS(ESI,m / z)calcd for C 28 H 26 FN5O2[M+H] + ,484.2143;found,484.2145.

[0082] Example 9: Preparation of (S)-(3-aminopyrrolidin-1-yl)(3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)methanone Using 6a and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester as starting materials, 56 mg of yellow solid was obtained according to the preparation method of Example 1, with a yield of 37.6%. mp: 110.1-111.7℃. 1H-NMR (600MHz, DMSO-d6) δ8.72(s,1H),8.70(s,1H),8.57(d,J=8.9Hz,1H),8.52-8.48(m,1H),8.42(d,J=7.8Hz,1H ),8.36(d,J=7.8Hz,1H),8.31(d,J=8.8Hz,1H),7.99(d,J=9.3Hz,1H),7.68(t,J=7.7Hz,1H),7.28(dd,J=8.4,2.8Hz ,1H),7.11(td,J=9.0,2.9Hz,1H),4.93(s,2H),3.98-3.89(m,1H),3.10(dd,J=11.9,4.2Hz,1H),2.91(dd,J=12.8,4 .0Hz,1H),1.91(d,J=10.2Hz,1H),1.73-1.68(m,1H),1.53(dd,J=16.3,6.8Hz,2H),1.41(s,6H),1.27-1.20(m,1H). 13 C-NMR(151MHz,DMSO-d6)δ168.10,159.74,158.14,157.31,154.35,153.25 ,146.68,144.47,138.84,137.94,137.68,136.87,132.74,129.23,128.47 ,128.26,125.70,125.07,119.56,113.08,109.56,68.34,56.12,52.69,50 .96,49.31,47.12,44.36,40.46,33.21,31.52,27.70.HRMS(ESI,m / z)calcd for C 28 H 27 FN6O[M+H] + ,483.2303;found,483.2335.

[0083] Example 10

[0084] Example 11: Preparation of (R)-3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-N-(piperidin-3-yl)benzamide Using 6a and (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester as starting materials, a yellow solid of 80 mg was obtained according to the preparation method of Example 1, with a yield of 52.0%. mp: 126.1-126.7°C. 1H-NMR (600MHz, DMSO-d6) δ8.72(s,1H),8.70(s,1H),8.57(d,J=8.9Hz,1H),8.50(dd,J=8.9,4.9Hz,1H),8.42(d,J=7.8Hz, 1H),8.36(d,J=7.8Hz,1H),8.31(d,J=8.8Hz,1H),7.99(d,J=9.3Hz,1H),7.68(t,J=7.7Hz,1H),7.28(dd,J=8.4,2.8Hz,1H) ,7.11(td,J=9.0,2.8Hz,1H),4.93(s,2H),3.94(qd,J=9.9,4.3Hz,1H),3.10(dd,J=12.0,4.3Hz,1H),2.91(dd,J=12.7,4. 0Hz,1H),1.91(d,J=10.2Hz,1H),1.73-1.68(m,1H),1.55-1.47(m,2H),1.41(s,6H),1.39-1.27(m,1H),1.27-1.20(m,1H). 13 C-NMR (151MHz, DMSO-d6) δ165.56,159.75,158.15,157.29,154.34,153. 31,146.69,144.54,138.84,137.93,136.83,135.52,132.74,129.52,129 .13,128.78,125.91,125.01,119.61,113.25,109.74,68.35,49.55,47.0 0,45.69,44.61,41.32,30.05,27.76,24.97,10.63.HRMS(ESI,m / z)calcd forC 29 H 29 FN6O[M+H] + ,497.2490;found,497.2461.

[0085] Example 12: Preparation of (S)-3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-N-(piperidin-3-yl)benzamide Using 6a and (S)-3-aminopiperidine-1-carboxylic acid tert-butyl ester as starting materials, a yellow solid of 72 mg was obtained according to the preparation method of Example 1 with a yield of 46.8%. mp: 121.1-121.9°C. 1H-NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.70(s,1H),8.56(d,J=8.9Hz,1H),8.50(dd,J=8.9,4.9Hz,1H),8.43(d,J=7.8Hz ,1H),8.36(dt,J=7.8,1.5Hz,1H),8.31(d,J=8.8Hz,1H),7.99(dt,J=7.7,1.3Hz,1H),7.68(t,J=7.7Hz,1H),7.28(dd,J= 8.4,2.8Hz,1H),7.11(td,J=8.9,2.8Hz,1H),4.93(s,2H),3.94(dp,J=14.0,4.5,4.0Hz,1H),3.12-3.07(m,1H),2.91(dd ,J=12.6,4.1Hz,1H),1.94-1.88(m,2H),1.70(dq,J=10.7,3.5Hz,1H),1.56-1.48(m,2H),1.40(s,7H),0.87-0.82(m,3H). 13 C-NMR(151MHz,DMSO-d6)δ165.58,159.75,158.15,157.29,154.34,153.31,14 6.69,144.49,138.84,137.93,136.83,135.47,132.74,129.54,129.14,128.7 8,125.93,125.01,119.61,113.10,109.58,68.35,65.03,49.67,46.05,44.85 ,40.48,29.88,27.76,23.97,22.06,18.65,13.97,13.55.HRMS(ESI,m / z)calcd for C 29 H 29 FN6O[M+H] + ,497.2490;found,497.2446.

[0086] Example 13: Preparation of (3-(4-(5-fluoro-3,3-dimethylindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(4-hydroxypiperidin-1-yl)methanone Using 6a and piperidin-4-ol as starting materials, 54 mg of yellow solid was obtained according to the preparation method of Example 6. The yield was 35.0%. mp: 210.1-211.7℃. 1H-NMR (600MHz, DMSO-d6) δ8.70(s,1H),8.54(d,J=8.8Hz,1H),8.46(dd,J=8.9,4.9Hz,1H),8.28(dd,J=8.6,3. 8Hz,2H),8.21(d,J=1.9Hz,1H),7.65(t,J=7.7Hz,1H),7.52(dt,J=7.6,1.4Hz,1H),7.28(dd,J=8.5,2.8Hz,1H ),7.09(td,J=9.0,2.8Hz,1H),4.86(s,2H),4.81(d,J=3.8Hz,1H),4.06(s,1H),3.75(tq,J=8.0,3.8Hz,1H),3 .56(s,1H),3.30-3.15(m,2H),1.75(d,J=84.1Hz,2H),1.48(d,J=11.3Hz,1H),1.38(s,6H),1.35-1.28(m,1H). 13 C-NMR(151MHz,DMSO-d6)δ168.66,159.72,158.13,157.29,154.32,153.11,146.68,144.34,138.83,138.00,137.32,136.8 3,132.71,129.37,127.73,125.19,119.58,113.07,109.71,68.36,65.39,44.76,40.44,33.71,27.20.HRMS(ESI,m / z)calcd for C 29 H 28 FN5O2[M+H] + ,498.2300;found,498.2302.

[0087] Example 14: Preparation of (3-(4-(5'-fluorospiro[cyclopentane-1,3'-indoline]-1'-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(piperazin-1-yl)methanone Using 6b and tert-butyl piperazine-1-carboxylate as starting materials, a yellow solid of 76 mg was obtained according to the preparation method of Example 1 with a yield of 48.3%. mp: 206.1-206.9°C. 1H-NMR (600MHz, DMSO-d6) δ8.72(s,1H),8.61(dd,J=8.9,4.9Hz,1H),8.55(d,J=8.8Hz,1H ),8.29(d,J=2.0Hz,1H),8.27(d,J=2.6Hz,1H),8.20(t,J=1.8Hz,1H),7.65(t,J=7.7Hz, 1H),7.51(s,1H),7.28(dd,J=8.5,2.8Hz,1H),7.10(td,J=9.0,2.8Hz,1H),4.96(s,2H), 3.61(s,2H),3.32(s,2H),2.80(s,2H),2.65(s,2H),1.91(q,J=6.4Hz,6H),1.78(s,2H). 13 C-NMR (151MHz, DMSO-d6) δ168.60,159.82,158.22,156.90,154.29,152.92,146.70,142.54,139.80,138.16,137.23,136.84,132. 82,129.25,127.99,125.21,119.54,113.16,109.81,67.80,51.48,48.36,45.80,44.77,42.46,40.06,24.17.HRMS(ESI,m / z)calcd forC 30 H 30 FN6O[M+H] + ,509.2460;found,509.2469.

[0088] Example 15: Preparation of (3-(4-(5'-fluorospiro[cyclohexane-1,3'-indoline]-1'-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(piperazin-1-yl)methanone Using 6c and tert-butyl piperazine-1-carboxylate as starting materials, 86 mg of yellow solid was obtained according to the preparation method of Example 1, with a yield of 53.1%. mp: 225.1-226.7℃. 1H-NMR (600MHz, DMSO-d6) δ8.72(s,1H),8.66(dd,J=9.0,4.9Hz,1H),8.56(d,J=8.8Hz,1H),8.32(d,J= 7.9Hz,1H),8.29(d,J=8.8Hz,1H),8.24(d,J=1.8Hz,1H),7.64(t,J=7.7Hz,1H),7.52(d,J=7.5Hz,1H) ,7.28(dd,J=8.6,2.8Hz,1H),7.11(td,J=9.0,2.9Hz,1H),5.04(s,2H),3.59(s,2H),3.27(s,2H),2.7 0(d,J=81.7Hz,4H),1.77(d,J=18.4Hz,2H),1.74-1.66(m,5H),1.49-1.42(m,2H),1.38-1.32(m,1H). 13 C NMR(151MHz,DMSO-d6)δ168.48,159.71,158.11,156.89,154.24,152.96,146.77,144.34,139.12,138.27,137.40,136.87,13 2.89,129.18,128.02,125.11,119.97,113.44,110.07,63.94,49.50,44.68,42.74,36.40,24.75,22.84.HRMS(ESI,m / z)calcd for C 31 H 31 FN6O[M+H] + ,523.2616;found,509.2637.

[0089] Example 16: Preparation of (3-(4-(5-fluoro-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)(piperazin-1-yl)methanone Using 6d and tert-butyl piperazine-1-carboxylate as starting materials, a yellow solid of 71 mg was obtained according to the preparation method of Example 1 with a yield of 43.7%. mp: 260.1-261.7°C. 1H-NMR (600MHz, DMSO-d6) δ8.73(s,1H),8.65(dd,J=9.0,4.9Hz,1H),8.57(d,J=8.8Hz,1H),8.33(d,J=7.9Hz, 1H),8.29(d,J=8.8Hz,1H),8.26(s,1H),7.66(t,J=7.7Hz,1H),7.53(d,J=7.5Hz,1H),7.36(dd,J=8.5,2.9Hz ,1H),7.13(td,J=8.9,2.9Hz,1H),5.17(s,2H),3.93(dd,J=11.8,4.5Hz,2H),3.60(s,2H),3.51(t,J=12.2Hz ,2H),3.32(s,2H),2.77(s,2H),2.62(d,J=12.9Hz,2H),2.02(td,J=13.1,4.8Hz,2H),1.66(d,J=13.2Hz,2H). 13 C-NMR(151MHz,DMSO-d6)δ168.49,159.72,158.12,156.96,154.22,153.02,146.73,142.83,139.33,138.24,137.41,136.88,1 32.89,129.23,127.99,125.22,119.89,113.63,110.34,64.34,63.38,48.58,45.96,43.37,42.07,36.44.HRMS(ESI,m / z)calcd for C 30 H 29 FN6O2[M+H] + ,525.2409;found,525.2437.

[0090] Example 17: Preparation of 2-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one

[0091] Step A: Preparation of 5-fluoroindoline (7)

[0092]

[0093] 5-Fluoroindole (2.0 g, 14.89 mmol) was placed in a 100 mL eggplant-shaped bottle, and 30 mL of acetic acid was added to dissolve. Sodium cyanoborohydride (2.44 g, 38.71 mmol) was added in batches under stirring at room temperature, and the reaction was carried out at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was poured into 200 mL of water, and the pH was adjusted to about 8 with saturated sodium hydroxide aqueous solution. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, extracted once with saturated brine, dried, and evaporated to obtain a light yellow oily product of 1.6 g, with a yield of 78.4%.

[0094] Step B: Preparation of 6-chloro-4-(5-fluoroindolin-1-yl)pyrido[3,2-d]pyrimidine (8)

[0095]

[0096] 4,6-Dichloropyrido[3,2-d]pyrimidine (500 mg, 2.51 mmol) was placed in a 100 mL eggplant-shaped bottle, 30 mL of isopropanol was added to dissolve, and then 7 (378 mg, 2.76 mmol) and triethylamine (380 mg, 3.77 mmol) were added to react at 50° C. After the reaction was completed as monitored by TLC, the product was filtered to obtain 650 mg of a yellow solid with a yield of 86.3%.

[0097] Step C: Preparation of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (9)

[0098]

[0099] 4-Pyrazoleboronic acid pinacol ester (500mg, 2.58mmol), ethyl bromoacetate (646mg, 3.87mmol) and cesium carbonate (1261mg, 3.87mmol) were placed in a 50mL eggplant-shaped bottle, 20mL acetonitrile was added to dissolve, and refluxed for reaction. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, the residue was dissolved in ethyl acetate, extracted with 10% HCl aqueous solution, water, saturated sodium bicarbonate aqueous solution, and saturated saline, respectively, the organic phase was dried, and the product was evaporated to dryness to obtain 433mg of a colorless oil, with a yield of 60%.

[0100] Step D: Preparation of 2-(4-(4-(5-fluoroindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)acetic acid (10)

[0101]

[0102] 8 (200 mg, 0.67 mmol), 9 (280 mg, 1 mmol), Pd (dppf) Cl2 (25 mg, 0.034 mmol) and potassium carbonate (138 mg, 1 mmol) were placed in a 50 mL eggplant-shaped bottle, 12 mL of 1,4-dioxane and 3 mL of water were added to dissolve, and the mixture was refluxed under nitrogen protection. After the reaction was completed by TLC monitoring, 2 mL of 2 mol / L NaOH aqueous solution was added to the reaction solution to continue the reaction. After TLC monitoring, the reaction was complete, 15 mL of ice water was added to the reaction solution to dilute it, and the aqueous phase was adjusted to pH 6 with 10% HCl aqueous solution to precipitate a yellow solid, which was filtered to obtain a yellow solid of 152 mg with a yield of 54.7%.

[0103] Steps E, F: Preparation of 2-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (Example 17) Using 10 and tert-butyl piperazine-1-carboxylate as starting materials, the product was obtained as a yellow solid (75 mg) in a yield of 42.0%. mp: 101.2-102.6°C. 1 H-NMR(600MHz,DMSO-d6)δ8.62(s,1H),8.48(dd,J=9.1,5.1Hz,1H),8.43(s,1H ),8.18(s,1H),8.17-8.12(m,2H),7.22(dd,J=8.4,3.0Hz,1H),7.07(td,J=8.9 ,3.1Hz,1H),5.24(s,2H),5.05(t,J=8.3Hz,2H),3.52-3.50(m,2H),3.46(t,J= 5.2Hz, 2H), 3.29 (t, J = 8.3Hz, 2H), 2.84 (t, J = 5.2Hz, 2H), 2.76 (t, J = 5.2Hz, 2H). 13 C-NMR(151MHz,DMSO-d6)δ165.14,156.90,153.28,149.56,145.97,140.44,137.98,136.26,135.59,132.74,131.51,12 4.76,122.68,119.39,118.38,116.39,112.63,111.97,54.30,53.08,45.11,44.77,41.86,28.82.HRMS(ESI,m / z)calcd for C 24 H 23 FN8O[M+H] + ,459.2052;found,459.2095.

[0104] Example 18: Preparation of (S)-2-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(3-methylpiperazin-1-yl)ethan-1-one Using 10 and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester as starting materials, the product was obtained as a yellow solid (90 mg) in a yield of 48.9%. mp: 67.8-68.1°C. 1 H-NMR (600MHz, DMSO-d6) δ8.64(s,1H),8.49(dd,J=9.0,5.0Hz,1H),8.41(d,J=7.2Hz,1H),8.20(s,1H),8.16(d,J=6 .0Hz,2H),7.22(dd,J=8.4,2.8Hz,1H),7.08(td,J=9.0,2.8Hz,1H),5.34-5.22(m,2H),5.05(t,J=8.2Hz,2H),4.18(d d,J=12.8,3.7Hz,1H),3.82-3.69(m,1H),3.29(t,J=8.3Hz,2H),3.23(ddd,J=12.4,9.2,2.9Hz,1H),3.08(ddd,J=37. 6,14.3,8.7Hz,2H),2.01(dt,J=9.3,4.2Hz,1H),1.89-1.72(m,1H),1.60(dq,J=19.5,10.5,9.9Hz,2H),1.40(s,1H). 13 C-NMR(151MHz,DMSO-d6)δ165.79,159.18,157.59,156.36,153.26,150.31,145.90,140.41,138.00,136.72,135.51,133.21, 132.02,124.75,122.78,119.42,112.65,111.43,54.28,53.62,46.18,45.69,44.16,28.81,22.50,8.18.HRMS(ESI,m / z)calcd for C 25 H 25 FN8O[M+Na] + ,495.2028;found,495.2084.

[0105] Example 19: Preparation of (S)-1-(3-aminopiperidin-1-yl)-2-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-one Using 10 and (S)-piperidin-3-ylcarbamic acid tert-butyl ester as starting materials, the product was obtained as a yellow solid (81 mg) in a yield of 44.0%. mp: 160.1-160.6°C. 1 H-NMR(600MHz,DMSO-d6)δ8.61(s,1H),8.48(dd,J=9.0,5.0Hz,1H),8.43(s,1H),8.17(s,1H),8.15-8.11(m,2H),7.2 1(dd,J=8.5,2.8Hz,1H),7.06(td,J=9.0,2.9Hz,1H),5.30(t,J=16.4Hz,1H),5.18(dd,J=16.6,11.1Hz,1H),5.03(t, J=8.3Hz,2H),4.22-4.15(m,1H),3.83(t,J=12.0Hz,1H),3.28(t,J=8.2Hz,2H),2.96(ddd,J=12.0,9.0,6.3Hz,1H),2 .78(d,J=8.4Hz,1H),2.72(ddd,J=25.6,12.8,2.9Hz,1H),2.60(td,J=11.8,2.9Hz,1H),1.04(dd,J=23.6,5.6Hz,3H). 13 C-NMR (151MHz, DMSO-d6) δ165.53,159.35,158.18,157.98,157.76,156.89,152.85,149.65,140.26,138.55,135.79,133.12, 131.46,124.97,122.73,119.67,112.74,111.28,54.40,52.97,45.71,42.28,37.96,28.82,15.44,8.60.HRMS(ESI,m / z)calcd for C 25 H 25 FN8O[M+Na] + ,495.2028;found,495.2114.

[0106] Example 20: Preparation of (R)-1-(3-aminopiperidin-1-yl)-2-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-one Using 10 and (R)-piperidin-3-ylcarbamic acid tert-butyl ester as starting materials, the product was obtained as a yellow solid (74 mg) according to the synthesis method of KA01, with a yield of 40.2%. mp: 154.1-155.0℃. 1 H-NMR (600MHz, DMSO-d6) δ8.62(s,1H),8.48(dd,J=9.0,5.0Hz,1H),8.43(s,1H),8.18(d,J=1.7Hz,1H),8.14(d,J=4.0Hz,2H),7 .22(dd,J=8.4,2.8Hz,1H),7.07(td,J=9.1,2.8Hz,1H),5.23(t,J=3.7Hz,2H),5.04(t,J=8.3Hz,2H),4.17(dd,J=12.6,4.0Hz,1H ),3.87(dd,J=13.0,3.7Hz,1H),3.75(d,J=13.4Hz,1H),3.29(t,J=8.3Hz,2H),3.06(ddd,J=13.9,11.0,3.1Hz,1H),2.97-2.89(m ,1H),2.76(ddd,J=88.6,9.2,4.9Hz,1H),2.56(dd,J=12.6,9.6Hz,1H),1.91-1.84(m,1H),1.79-1.66(m,1H),1.53-1.36(m,1H). 13 C-NMR(151MHz,DMSO-d6)δ164.97,159.15,157.56,156.88,153.26,149.57,145.95,140.43,137.91,136.24,135.56,132.72,1 31.53,124.73,122.64,119.43,112.62,111.79,54.28,47.87,44.46,41.31,32.69,28.81,24.00,22.81.HRMS(ESI,m / z)calcd for C 25 H 25 FN8O[M+Na] + ,495.2028;found,495.2114.

[0107] Example 21: Preparation of (R)-2-(4-(4-(5-fluoroindol-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethan-1-one Using 10 and (R)-pyrrolidin-3-ol as starting materials, the product was obtained as a yellow solid (79 mg) according to the synthesis method of Example 6, with a yield of 44.1%. mp: 219.2-220.8℃. 1 H-NMR(600MHz,DMSO-d6)δ8.63(s,1H),8.49(dd,J=9.0,5.0Hz,1H),8.45(s,1H),8.1 9(s,1H),8.18-8.13(m,2H),7.22(dd,J=8.4,2.7Hz,1H),7.07(td,J=9.1,2.8Hz,1H) ,5.16(d,J=7.2Hz,1H),5.13-5.09(m,2H),5.05(t,J=8.4Hz,2H),4.34(d,J=62.2Hz, 1H),3.69-3.56(m,2H),3.50-3.35(m,2H),3.29(t,J=8.2Hz,2H),2.08-1.73(m,3H). 13 C-NMR(151MHz,DMSO-d6)δ164.97,159.16,158.02,156.50,153.28,149.57,145.96,140.44,138.00,136.26,135.53,132.7 4,131.43,124.75,122.62,119.44,112.77,111.97,69.61,67.70,54.30,44.66,43.34,33.22,28.21.HRMS(ESI,m / z)calcd for C 24 H 22 FN7O2[M+Na] + ,482.1711;found,482.1760.

[0108] Example 22: Preparation of (S)-2-(4-(4-(5-fluoroindol-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethan-1-one Using 10 and (S)-pyrrolidin-3-ol as starting materials, the product was obtained as a yellow solid (65 mg) according to the synthesis method of Example 6, with a yield of 36.3%. mp: 254.1-255.3℃. 1H-NMR (600MHz, DMSO-d6) δ8.63(s,1H),8.49(dd,J=9.0,5.0Hz,1H),8.45(d,J=1.9Hz,1H),8. 19(s,1H),8.17-8.13(m,2H),7.22(dd,J=8.5,2.8Hz,1H),7.07(td,J=9.1,2.9Hz,1H),5.16(d ,J=7.2Hz,1H),5.13-5.08(m,1H),5.05(t,J=8.3Hz,2H),5.00(d,J=3.3Hz,1H),4.41-4.27(m, 1H),3.68-3.62(m,1H),3.62-3.44(m,1H),3.42-3.34(m,1H),3.29(s,1H),2.00-1.78(m,2H). 13 C-NMR(151MHz,DMSO-d6)δ164.97,159.64,157.57,156.90,153.28,149.57,145.96,140.44,138.00,136.26,135.53,132.7 4,131.43,124.76,122.62,119.39,112.77,110.99,69.61,67.70,54.30,43.92,42.79,33.95,28.81.HRMS(ESI,m / z)calcd for C 24 H 22 FN7O2[M+Na] + ,482.1711;found,482.1777.

[0109] Example 23: Preparation of 2-(4-(4-(5-fluoroindol-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-morpholinoethane-1-one Using 10 and morpholine as starting materials, according to the synthesis method of Example 6, the product was obtained as a yellow solid (90 mg) with a yield of 50.3%. mp: 229.2-230.7°C. 1H-NMR(600MHz,DMSO-d6)δ8.62(s,1H),8.49(dd,J=9.0,5.0Hz,1H),8.44(s,1H) ,8.19(s,1H),8.17-8.12(m,2H),7.22(dd,J=8.4,2.8Hz,1H),7.07(td,J=9.0,2 .9Hz,1H),5.26(s,2H),5.05(t,J=8.3Hz,2H),3.65(t,J=4.7Hz,2H),3.60(t,J= 4.8Hz, 2H), 3.55 (t, J = 4.7Hz, 2H), 3.47 (t, J = 4.8Hz, 2H), 3.29 (d, J = 8.4Hz, 2H). 13 C-NMR(151MHz,DMSO-d6)δ164.77,158.54,156.95,156.26,152.65,148.91,145.33,139.81,137.39,135.62,132.1 1,130.88,124.12,121.67,118.82,113.08,111.18,65.32,53.66,52.36,44.15,41.25,28.19.HRMS(ESI,m / z)calcd forC 24 H 22 FN7O2[M+H] + ,460.1892;found,460.1936.

[0110] Example 24: Preparation of 2-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-N-(piperidin-4-yl)acetamide Using 10 and tert-butyl 4-aminopiperidine-1-carboxylate as starting materials, the product was obtained as a yellow solid (89 mg) according to the synthesis method of Example 1, with a yield of 48.3%. mp: 225.1-226.7°C. 1H-NMR (600MHz, DMSO-d6) δ8.62(s,1H),8.48(q,J=5.0Hz,2H),8.24(d,J=7.7Hz,1H),8.18 (s,1H),8.16-8.12(m,2H),7.22(dd,J=8.5,2.8Hz,1H),7.06(td,J=9.0,2.8Hz,1H),5.04 (t,J=8.3Hz,2H),4.87(s,2H),3.65(dtt,J=11.2,8.0,4.0Hz,1H),3.28(t,J=8.3Hz,2H), 2.96(dt,J=13.0,3.9Hz,2H),2.57-2.53(m,2H),1.75(d,J=4.0Hz,2H),1.43-1.27(m,3H). 13 C-NMR(151MHz,DMSO-d6)δ165.31,159.16,157.57,156.89,153.29,149.50,145.96,140.43,138.28,136.25,135.57,133.37,1 31.47,124.75,122.49,119.36,112.77,111.81,65.03,53.87,46.24,43.89,31.96,28.28,18.65,13.55.HRMS(ESI,m / z)calcd forC 25 H 25 FN8O[M+H] + ,473.2208;found,473.2242.

[0111] Example 25: Preparation of 2-(4-(4-(5-fluoroindol-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(4-hydroxypiperidin-1-yl)ethan-1-one Using 10 and piperidin-4-ol as starting materials, the product was obtained as a yellow solid (67 mg) in a yield of 36.3%. mp: 185.1-186.2°C. 1H-NMR(600MHz,DMSO-d6)δ8.63(s,1H),8.49(dd,J=9.0,5.0Hz,1H),8.44(s,1H),8.18(s,1H),8.17-8.1 3(m,2H),7.22(dd,J=8.5,2.8Hz,1H),7.07(td,J=9.0,2.8Hz,1H),5.23(d,J=7.3Hz,2H),5.05(t,J=8.3H z,2H),4.79(d,J=4.0Hz,1H),3.89(dt,J=13.1,5.0Hz,1H),3.73(dd,J=8.5,4.3Hz,2H),3.29(s,2H),3.2 6-3.23(m,1H),3.08(td,J=9.6,4.7Hz,1H),1.82-1.71(m,2H),1.43(s,1H),1.29(dd,J=8.8,4.2Hz,1H). 13 C-NMR(151MHz,DMSO-d6)δ164.81,159.16,157.57,156.89,153.26,149.57,145.95,140.44,137.93,136.24,135.57,132.7 3,131.51,124.73,122.64,119.38,112.61,111.96,65.32,54.28,53.10,41.84,34.41,33.73,28.81.HRMS(ESI,m / z)calcd for C 25 H 24 FN7O2[M+Na] + ,496.1868;found,496.1933.

[0112] Example 26: Preparation of 4-(5-fluoroindolyl-1-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine

[0113] 8 (200 mg, 0.67 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (302 mg, 0.8 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol) and potassium carbonate (138 mg, 1.0 mmol) were placed in a 50 mL two-necked bottle, 12 mL of 1,4-dioxane and 3 mL of water were added to dissolve, and refluxed under nitrogen protection. After the reaction was completed as monitored by TLC, the reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane, extracted three times with water, extracted once with saturated brine, the organic phase was dried, and the crude product was evaporated to dryness, which was purified by column chromatography (dichloromethane: methanol = 250: 4) to obtain a yellow solid. Place it in a 100mL eggplant-shaped bottle, add 20mL of dichloromethane to dissolve, add 5mL of trifluoroacetic acid at room temperature, and react at room temperature. After the reaction is completed by TLC monitoring, evaporate the reaction solution to dryness, dissolve the residue with water, adjust the pH to about 8 with saturated sodium bicarbonate aqueous solution, extract the aqueous phase with dichloromethane: methanol = 10:1 5 times, combine the organic phases, dry, evaporate to dryness to obtain a crude product, and purify it by column chromatography to obtain the target compound as a yellow solid of 156mg, with a two-step yield of 55.6%. mp: 122.1-123.1℃. 1 H-NMR(600MHz,DMSO-d6)δ8.60(s,1H),8.52(s,1H),8.45(dd,J=8.9,5.1Hz,1H), 8.16(s,1H),8.12(q,J=8.8Hz,2H),7.21(dd,J=8.4,3.0Hz,1H),7.05(td,J=9.1,3 .1Hz,1H),5.02(t,J=8.3Hz,2H),4.27(tt,J=11.6,4.2Hz,1H),3.27(t,J=8.4Hz,2 H),3.06(dt,J=12.5,3.5Hz,2H),2.02-1.97(m,2H),1.85(qd,J=12.1,4.3Hz,2H). 13 C-NMR (151MHz, DMSO-d6) δ159.14,157.55,156.88,153.22,149.66,145.90,140.41,137.59,136.13,135.53,132.6 7,127.64,124.77,122.04,119.29,112.74,111.78,59.39,54.92,54.30,45.01,33.35,28.80.HRMS(ESI,m / z)calcd for C 23 H 22 FN7[M+H] +:416.1993 found 416.2029

[0114] Example 27: Preparation of 4-(5-fluoroindolyl-1-yl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine

[0115] Step A: Preparation of 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0116] Using 4-pyrazoleboronic acid pinacol ester and 1-bromo-2-methoxyethane as raw materials, the target product according to the synthetic method of 9 was 373 mg of white oil with a yield of 57.3%.

[0117] Intermediate 11b was prepared according to the method of 11a.

[0118] Step B: Preparation of 4-(5-fluoroindolin-1-yl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidine (Example 27)

[0119]

[0120] 8 (200 mg, 0.67 mmol), 11a (280 mg, 1 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol) and potassium carbonate (138 mg, 1 mmol) were placed in a 50 mL eggplant-shaped bottle, 12 mL of 1,4-dioxane and 3 mL of water were added to dissolve, and the mixture was refluxed under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, and the residue was purified by column chromatography (dichloromethane: methanol = 250: 6) to obtain a yellow solid product of 100 mg, with a yield of 57.1%. mp: 164.3-165.5℃. 1 H-NMR (600MHz, DMSO-d6) δ8.63(s,1H),8.48(d,J=3.3Hz,1H),8.20(s,1H),8.15(d,J=2.7Hz,2H),7.23(dd,J=8.4,2.8Hz,1H ),7.07(td,J=9.0,2.9Hz,1H),5.05(t,J=8.3Hz,2H),4.35(t,J=5.3Hz,2H),3.75(t,J=5.3Hz,2H),3.30(s,2H),3.26(s,3H). 13C-NMR (151MHz, DMSO-d6) δ159.16,157.57,156.90,153.25,149.54,145.90,140.41,138.04,136.19,135.53,13 2.70,130.34,124.73,122.34,119.38,112.76,111.96,70.32,58.00,54.31,51.46,28.79.HRMS(ESI,m / z)calcd for C 21 H 19 FN6O[M+H] + :391.1677 found 391.1719.

[0121] Example 28: Preparation of 2-(4-(4-(5-fluoroindol-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol Using 8 and 11b as starting materials, the target compound was obtained as a yellow solid (113 mg) in accordance with the preparation method of Example 27. The yield was 44.7%. mp: 197.3-198.1℃. 1 H-NMR (600MHz, DMSO-d6) δ8.61(s,1H),8.47(d,J=5.8Hz,2H),8.18(s,1H),8.13(d,J=5.0Hz,2H),7.21(dd,J=8.5,2.8Hz,1H),7.06(t d,J=9.1,2.8Hz,1H),5.03(t,J=8.4Hz,2H),4.97(t,J=5.3Hz,1H),4.23(t,J=5.6Hz,2H),3.80(q,J=5.5Hz,2H),3.28(t,J=8.3Hz,2H). 13 C-NMR(151MHz,DMSO-d6)δ159.15,157.56,156.89,153.22,149.64,145.90,140.42,137.97,136.18,135.58 ,132.70,130.37,124.73,122.20,119.38,112.76,111.80,59.94,54.40,54.30,28.79.HRMS(ESI,m / z)calcd for C 20 H 17 FN6O[M+Na] + :399.1340 found 399.1364.

[0122] Example 29: Preparation of 3-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)propan-1-ol Using 8 and 11c as raw materials, according to the synthesis method of Example 27, the target compound was obtained as a yellow solid (101 mg) with a yield of 67.9%. mp: 208.3-209.8℃. 1 H-NMR (600MHz, DMSO-d6) δ8.60(s,1H),8.51-8.43(m,2H),8.16(s,1H),8.11(s,2H),7.20(dd,J=8.5,2.8Hz,1H),7.05(td,J=9.1,2.9 Hz,1H),5.02(t,J=8.2Hz,2H),4.64(s,1H),4.25(t,J=7.1Hz,2H),3.43(d,J=6.4Hz,2H),3.27(t,J=8.3Hz,2H),1.99(p,J=6.6Hz,2H). 13 C-NMR (151MHz, DMSO-d6) δ159.16,157.57,156.88,153.20,149.60,145.84,140.40,137.93,136.12,135.54,13 2.67,129.83,124.73,122.22,119.34,112.75,111.95,57.67,54.31,48.84,32.98,28.81.HRMS(ESI,m / z)calcd for C 21 H 19 FN6O[M+H] + :393.1834 found 393.2149.

[0123] Example 30: Preparation of 2-(4-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-amine Using 8 and 11d as raw materials, according to the preparation method of Example 26, the target compound was obtained as a yellow solid (109 mg) with a yield of 64.7%. mp: 161.7-163.2℃. 1H NMR (600MHz, DMSO-d6) δ8.60(s,1H),8.46(d,J=14.5Hz,2H),8.17(s,1H),8.11(d,J=1.8Hz,2H),7.20(dd,J=8.4,2.7Hz,1 H),7.05(td,J=9.0,2.8Hz,1H),5.01(t,J=8.3Hz,2H),4.17(t,J=6.3Hz,2H),3.27(t,J=8.2Hz,2H),3.00(t,J=6.3Hz,2H). 13 C-NMR(151MHz,DMSO-d6)δ159.15,157.56,156.88,153.24,149.58,145.91,140.41,138.07,136.18,135.57 ,132.69,130.16,124.73,122.25,119.38,112.75,111.79,54.45,54.30,41.70,28.80.HRMS(ESI,m / z)calcd for C 20 H 18 FN7[M+H] + :376.1680 found 376.1708.

[0124] Example 31: Preparation of 6-(1-ethyl-1H-pyrazol-4-yl)-4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidine Using 8 and 11e as starting materials, the target compound was obtained as a yellow solid (155 mg) according to the preparation method of Example 27, with a yield of 64.3%. mp: 174.1-175.6℃. 1 H-NMR (600MHz, DMSO-d6) δ8.49(s,1H),8.16(s,1H),8.11(s,2H),7.23-7.18(m,1H),7.05(d,J=2.8 Hz,1H),5.02(t,J=8.3Hz,2H),4.22(q,J=7.3Hz,2H),3.27(t,J=8.2Hz,2H),1.44(t,J=7.3Hz,3H). 13C-NMR (151MHz, DMSO-d6) δ159.14,157.55,156.88,153.23,149.60,145.91,140.42,137.80,136.17,135. 57,132.69,124.69,122.31,119.31,112.59,111.79,54.30,46.60,28.80,15.44.HRMS(ESI,m / z)calcdfor C 20 H 17 FN6[M+H] + :361.1571 found 361.1611.

[0125] Example 32: Preparation of 5-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1-(2-oxo-2-(piperazin-1-yl)ethyl)pyridin-2(1H)-one

[0126] Step A: Ethyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (12a)

[0127]

[0128] 5-Bromopyridin-2(1H)-one (300 mg, 1.74 mmol) and ethyl bromoacetate (350 mg, 2.09 mmol) were placed in a 50 mL eggplant-shaped bottle, 15 mL of dry tetrahydrofuran was added to dissolve, sodium hydride (50 mg, 2.09 mmol) was added in batches under stirring at room temperature, and the mixture was reacted at room temperature. After the reaction was completed by TLC monitoring, ice water was added to the reaction solution to quench, the aqueous layer was extracted three times with ethyl acetate, the organic layers were combined, extracted once with a saturated sodium chloride aqueous solution, dried, and evaporated to obtain the product as a white solid of 318 mg, with a yield of 70.6%.

[0129] Intermediates 12b-12e were prepared according to the synthetic method of 12a.

[0130] Step B: Ethyl 2-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate (13a)

[0131]

[0132] 12a (300 mg, 1.16 mmol), biboronic acid pinacol ester (442 mg, 1.74 mmol), palladium acetate (27 mg, 0.12 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (114 mg, 0.24 mmol) and potassium acetate (341 mg, 3.48 mmol) were placed in a two-necked bottle, and dry 1,4-dioxane was added to dissolve, and refluxed under nitrogen protection. TLC monitored the reaction to be complete, the reaction solution was diluted with ethyl acetate, extracted once with water, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried, evaporated, and the residue was purified by column chromatography to obtain the target product as a colorless oil 261 mg, with a yield of 73.2%.

[0133] Intermediates 13b-13e were prepared according to the synthetic method of 13a.

[0134] Step C: 5-(4-(5-fluoroindolin-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1-(2-oxo-2-(piperazin-1-yl)ethyl)pyridin-2(1H)-one (Example 32)

[0135] Using 8, 13a and 1-Boc piperazine as raw materials, the product was obtained as a yellow solid (92 mg) according to the synthesis method of Example 17, with a yield of 48.4%. mp: 238.1-239.7℃. 1 H-NMR(600MHz,DMSO-d6)δ8.63(s,1H),8.58(d,J=2.7Hz,1H),8.44(dd,J=9.0,5.0Hz,1 H),8.29(dd,J=9.6,2.7Hz,1H),8.24-8.16(m,2H),7.21(dd,J=8.4,2.8Hz,1H),7.06(t d,J=9.0,2.9Hz,1H),6.57(d,J=9.5Hz,1H),5.01(t,J=8.2Hz,2H),4.93(s,2H),3.51(s ,2H),3.42(s,2H),3.27(d,J=8.3Hz,2H),2.82(t,J=4.9Hz,2H),2.71(t,J=5.1Hz,2H). 13C-NMR(151MHz,DMSO-d6)δ164.89,161.09,157.63,156.99,153.67,151.04,140.60,140.30,138.26,136.61,135.63,1 32.53,123.32,119.42,116.41,112.66,112.00,54.92,54.32,49.87,48.60,45.17,42.62,28.85.HRMS(ESI,m / z)calcd for C 26 H 24 FN7O2[M+Na] + :508.1868 found 508.1919.

[0136] Example 33: Preparation of 5-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1-methylpyridin-2(1H)-one Using 8 and 13b as raw materials, the synthetic method of Example 31 was used to obtain 195 mg of a yellow solid with a yield of 78.1%. mp: 222.9-224.2℃. 1 H-NMR (600MHz, DMSO-d6) δ8.68(d,J=2.7Hz,1H),8.63(s,1H),8.44(dd,J=9.0,4.9Hz,1H),8.32-8.24(m,2H),8.18(d,J=8.9Hz,1H),7. 21(dd,J=8.5,2.8Hz,1H),7.06(td,J=9.1,2.8Hz,1H),6.56(d,J=9.5Hz,1H),5.01(t,J=8.2Hz,2H),3.57(s,3H),3.28(t,J=8.3Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ161.55,159.21,157.99,156.86,153.58,151.03,146.10,140.13,13 7.87,136.46,135.60,132.41,124.05,117.99,116.47,112.77,111.95,54.24,38.07,28.81.

[0137] Example 34: Preparation of 5-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1-(2-hydroxyethyl)pyridin-2(1H)-one Using 8 and 13c as raw materials, the synthetic method of Example 31 was used to obtain 117 mg of a yellow solid with a yield of 76.1%. mp: 264.5-265.6℃. 1H-NMR(600MHz,DMSO-d6)δ8.64(s,1H),8.60(d,J=2.7Hz,1H),8.48-8.43(m,1H),8.29 (d,J=8.9Hz,1H),8.27(dd,J=9.4,2.7Hz,1H),8.19(d,J=8.9Hz,1H),7.22(dd,J=7.7, 2.1Hz,1H),7.07(td,J=9.0,2.9Hz,1H),6.57(d,J=9.4Hz,1H),5.03(t,J=8.3Hz,2H), 5.00-4.97(m,1H),4.10(t,J=5.4Hz,2H),3.71(q,J=5.4Hz,2H),3.27(t,J=8.3Hz,2H). 13 C-NMR(151MHz,DMSO-d6)δ161.13,159.22,157.63,156.86,153.59,151.13,146.08,140.44,140.28,137.87,136 .51,135.57,132.49,123.36,119.36,116.07,112.65,111.95,58.70,54.32,51.65,28.80.HRMS(ESI,m / z)calcd for C 22 H 18 FN5O2[M+Na] + :426.1337 found 426.1364.

[0138] Example 35: 5-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1,3-dimethylpyridin-2(1H)-one was prepared from 8 and 13d according to the synthesis method of Example 31 to obtain 171 mg of a yellow solid with a yield of 65.9%. mp: 266.4-267.5℃. 1 H-NMR (600MHz, DMSO-d6) δ8.60(s,1H),8.50(s,1H),8.38(dd,J=9.0,5.0Hz,1H),8.23(d,J=8.9Hz,1H),8.12(d,J=8.7Hz,1H),8.07(s ,1H),7.20(dd,J=8.4,3.1Hz,1H),7.05(td,J=8.9,2.9Hz,1H),4.95(t,J=8.3Hz,2H),3.55(s,3H),3.25(t,J=8.1Hz,2H),2.10(s,3H). 13C-NMR(151MHz,DMSO-d6)δ162.06,159.18,157.59,156.85,153.50,151.20,146.01,140.25,137.40,136.31,135.57 ,134.55,132.34,127.73,123.31,119.28,115.87,112.74,111.89,54.23,37.64,28.75,17.28.HRMS(ESI,m / z)calcd forC 22 H 18 FN5O[M+H] + :388.1568 found 388.1617.

[0139] Example 36: 5-(4-(5-fluoroindolyl-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1-(2-hydroxyethyl)-3-methylpyridin-2(1H)-one Using 8 and 13e as raw materials, the synthetic method of Example 31 was used to obtain 98 mg of a yellow solid with a yield of 61.9%. mp: 252.2-253.7°C. 1 H-NMR(600MHz,DMSO-d6)δ8.61(s,1H),8.45(d,J=2.9Hz,1H),8.43-8.38(m,1H) ,8.25(d,J=8.9Hz,1H),8.15(d,J=8.9Hz,1H),8.10(s,1H),7.21(dd,J=8.4,2.9H z,1H),7.06(td,J=9.0,2.9Hz,1H),4.99(t,J=8.3Hz,2H),4.96(t,J=5.4Hz,1H), 4.09(t,J=5.4Hz,2H),3.71(q,J=5.4Hz,2H),3.26(t,J=8.3Hz,2H),2.12(s,3H). 13 C-NMR (151MHz, DMSO-d6) δ161.63,159.18,157.60,156.91,153.52,151.37,145.98,140.26,137.78,136.38,135.58,134.6 6,132.44,127.77,123.37,119.33,115.46,112.61,111.92,58.73,54.34,51.88,48.59,28.75,17.30.HRMS(ESI,m / z)calcd for C 23 H 20 FN5O2[M+Na] +:440.1493 found 440.1509.

[0140] Example 37: Preparation of 1'-(6-(1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-5'-fluorospiro[cyclohexane-1,3'-indoline]

[0141] Step A: 5'-Fluorospiro[cyclohexane-1,3'-indoline] (14a)

[0142]

[0143] 4-Fluorophenylhydrazine hydrochloride (1.0 g, 6.17 mmol) and cyclohexanecarboxaldehyde (0.69 g, 6.17 mmol) were placed in a 100 mL eggplant-shaped bottle, 20 mL of acetic acid was added to dissolve, and the mixture was reacted at 60 °C. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, the reaction solution was diluted with 20 mL of 1,2-dichloroethane, and sodium triacetoxyborohydride (1.96 g, 9.26 mmol) was added in batches under stirring at room temperature, and the reaction was reacted at room temperature. After the reaction was completed by TLC monitoring, water was added to the reaction solution to quench, the pH was adjusted to about 8 with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, extracted once with saturated brine, dried, and evaporated to obtain a crude product as a brown oil, which was directly reacted in the next step without purification.

[0144] Step B: 1'-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-5'-fluorospiro[cyclohexane-1,3'-indoline] (15a)

[0145]

[0146] 4,6-Dichloropyrido[3,2-d]pyrimidine (666 mg, 3.33 mmol), 17 (1025 mg, 5 mmol) and triethylamine (505 mg, 5 mmol) were placed in a 100 mL eggplant-shaped bottle, 40 mL of isopropanol was added to dissolve, and the mixture was reacted at 50°C. After the reaction was completed by TLC monitoring, the crude product was directly filtered and purified by column chromatography to obtain 689 mg of a yellow solid product with a yield of 56.2%. mp:. 1 H-NMR (600MHz, DMSO-d6) δ8.74(s,1H),8.51(dd,J=9.0,5.0Hz,1H),8.25(d,J=8.7Hz,1H),7.94(d,J=8.9Hz,1H ),7.27(dd,J=8.6,2.8Hz,1H),7.10(td,J=9.1,2.9Hz,1H),4.78(s,2H),1.78-1.63(m,8H),1.40-1.33(m,2H).

[0147] Step C: 1'-(6-(1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-5'-fluorospiro[cyclohexane-1,3'-indoline] (implementation

[0148] Using 15a and 4-pyrazoleboronic acid pinacol ester as starting materials, the target compound was obtained as a yellow solid (126 mg) according to the synthesis method of Example 27, with a yield of 47.1%. mp: 113.5-114.5℃. 1 H-NMR (600MHz, DMSO-d6) δ13.28(s,1H),8.64(s,1H),8.51(q,J=4.9Hz,2H),8.20(t,J=9.3H z,2H),8.15(d,J=8.7Hz,1H),4.97(s,2H),1.81-1.64(m,7H),1.39(dd,J=49.1,11.0Hz,3H). 13 C-NMR (151MHz, DMSO-d6) δ159.52,157.93,156.76,153.31,149.81,146.02,144.15,139.19,137.60,136.25,13 2.70,128.10,125.00,122.15,119.55,113.16,109.80,63.74,44.23,36.11,24.79,22.95.HRMS(ESI,m / z)calcd for C 23 H 21 FN6[M+H] + :401.1884found401.1957.

[0149] Example 38: Preparation of 1'-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-5'-fluorospiro[cyclohexane-1,3'-indoline] Using 15a and 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester as starting materials, the target product was obtained as a yellow solid of 147 mg in a yield of 51.2%. mp: 173.5-175.2℃. 1H-NMR (600MHz, DMSO-d6) δ8.64(s,1H),8.28(dd,J=8.9,4.9Hz,1H),8.16(d,J=8.7Hz,1H),8.11(d,J=8.7Hz,1H),8.03(s,1H),7 .26-7.22(m,1H),7.06(td,J=9.0,2.8Hz,1H),4.81(s,2H),3.83(s,3H),2.61(s,3H),1.75-1.65(m,8H),1.36(d,J=4.5Hz,2H). 13 C-NMR(151MHz,DMSO-d6)δ159.45,157.86,157.15,153.26,151.08,145.72,144.68,139.18,137.95,137.57,136.22,1 32.75,126.19,119.39,119.22,113.20,109.88,63.71,44.46,36.36,35.88,24.75,22.74,10.96.HRMS(ESI,m / z)calcd for C 25 H 25 FN6[M+H] + :429.2197found429.2276.

[0150] Example 39: Preparation of 2-(4-(4-(5'-fluorospiro[cyclohexane-1,3'-indoline]-1'-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol Using 15a and 11b as raw materials, the product was obtained according to the synthesis method of Example 27 as a yellow solid of 103 mg, with a yield of 61.3%. mp:. 1 H-NMR (600MHz, DMSO-d6) δ8.64(s,1H),8.53(dd,J=9.0,5.0Hz,1H),8.47(s,1H),8.19-8.12(m,3H),7.25(dd,J=8.6,2.8Hz,1H),7.09(td, J=9.0,2.8Hz,1H),4.99(t,J=5.4Hz,1H),4.96(s,2H),4.23(t,J=5.5Hz,2H),3.80(q,J=5.3Hz,2H),1.84-1.69(m,7H),1.48-1.35(m,3H). 13C-NMR(151MHz,DMSO-d6)δ159.54,157.95,156.70,153.28,149.51,145.96,144.21,139.18,137.49,136.29,132.72,130.14, 124.77,122.41,119.56,113.33,109.81,63.76,59.83,54.91,54.67,44.22,36.16,24.77,22.90,13.51.HRMS(ESI,m / z)calcd for C 25 H 25 FN6O[M+Na] + :445.2147found445.2159.

[0151] Example 40: Preparation of 5-(4-(5'-fluorospiro[cyclohexane-1,3'-indoline]-1'-yl)pyrido[3,2-d]pyrimidin-6-yl)-1-methylpyridin-2(1H)-one Using 15a and 13b as raw materials, the product was obtained according to the synthesis method of Example 27 as a yellow solid (151 mg), with a yield of 51.2%. 1 H NMR (600MHz, DMSO-d6) δ8.70(s,1H),8.64(s,1H),8.55(dd,J=8.9,4.9Hz,1H),8.33-8.26(m,2H),8.18(d,J=8.7Hz,1H),7.25( dd,J=8.5,2.9Hz,1H),7.08(td,J=8.9,2.9Hz,1H),4.94(s,2H),3.56(s,3H),1.72(dd,J=31.1,8.7Hz,7H),1.46-1.30(m,3H).

[0152] Example 41: Preparation of 1'-(6-(1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[cyclohexane-1,3'-indoline]-5'-carbonitrile

[0153] Step B: Preparation of 1'-(6-chloropyrido[3,2-d]pyrimidin-4-yl)spiro[cyclohexane-1,3'-indoline]-5'-carbonitrile (14b)

[0154] 14b (254 mg, 1.2 mmol) was placed in a 25 mL eggplant-shaped bottle, 5 mL of N,N-dimethylformamide (DMF) was added to dissolve, the reaction solution was cooled to 0 ° C, sodium hydride (36 mg, 1.5 mmol) was added in batches, and the reaction was carried out at room temperature for 30 min. Subsequently, 4,6-dichloropyrido[3,2-d]pyrimidine (200 mg, 1.0 mmol) was dissolved in 3 mL of DMF, slowly added to the reaction system, and transferred to room temperature for reaction. TLC monitored the reaction. After the reaction was complete, ice water was added to the reaction solution to quench, the aqueous layer was extracted three times with ethyl acetate, the organic phases were combined, extracted once with saturated brine, dried, and evaporated to obtain a crude product as a yellow oil. The target product was purified by column chromatography as a yellow solid of 177 mg, with a yield of 47.1%.

[0155] Example 41: Preparation of 1'-(6-(1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[cyclohexane-1,3'-indoline]-5'-carbonitrile Using 15b and 4-pyrazoleboronic acid pinacol ester as starting materials, the target product was obtained as a yellow solid of 109 mg in a yield of 57.2% according to the synthesis method of Example 27. mp: 122.6-124.3℃. 1 H-NMR (600MHz, DMSO) δ13.25(s,1H),8.75(s,1H),8.51(d,J=8.5Hz,1H),8.36(s,2H),8.26(d,J=8.8Hz,1H),8.22 (d,J=8.8Hz,1H),7.84(s,1H),7.72(dd,J=8.5,1.9Hz,1H),4.95(s,2H),1.74(d,J=8.1Hz,7H),1.47-1.34(m,3H). 13 C-NMR (151MHz, DMSO) δ157.71,153.40,150.96,147.50,146.73,143.17,136.86,133.14,132.45,127. 01,125.92,122.36,119.93,118.53,104.93,64.25,44.49,36.51,25.11,23.19.HRMS(ESI,m / z)calcd for C 24 H 21 N7[M+Na] + :430.1751 found 430.1815.

[0156] Example 42: Preparation of 1'-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[cyclohexane-1,3'-indoline]-5'-carbonitrile Using 15b and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole as starting materials, the target product was obtained as a yellow solid of 111 mg in a yield of 54.3% according to the synthetic method of Example 27. mp: 232.3-233.5℃. 1 H-NMR (600MHz, DMSO-d6) δ8.76(s,1H),8.22(d,J=8.9Hz,1H),8.16(d,J=8.9Hz,1H),8.14(d,J=8.5Hz,1H),8.05(s,1H),7 .81(d,J=2.0Hz,1H),7.65(dd,J=8.5,1.8Hz,1H),4.74(s,2H),3.81(s,3H),2.53(s,3H),1.74-1.68(m,7H),1.35(s,3H). 13 C-NMR(151MHz,DMSO-d6)δ157.67,153.04,151.82,147.25,145.98,142.77,138.08,136.51,136.42,132.80,131.85,126.56, 119.58,118.94,117.64,111.35,104.25,63.54,44.28,36.34,36.24,35.83,24.71,22.60,10.83,9.61.HRMS(ESI,m / z)calcd for C 26 H 25 N7[M+Na] + :458.2064 found 458.2099.

[0157] Example 43: Preparation of 1'-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[cyclohexane-1,3'-indoline]-5'-carbonitrile Using 15b and 11b as starting materials, the target product was obtained as a yellow solid (67 mg) according to the synthesis method of Example 27, with a yield of 31.5%. mp: 201.6-203.0℃. 1H-NMR (600MHz, DMSO) δ8.74(s,1H),8.53(d,J=8.5Hz,1H),8.48(s,1H),8.21(s,2H),8.13(s,1H),7.83(d,J=1.9Hz,1H),7.71(dd,J=8.5,1.9 Hz,1H),5.00(s,1H),4.93(s,2H),4.22(t,J=5.6Hz,2H),3.80(t,J=5.6Hz,2H),1.78-1.72(m,7H),1.63-1.54(m,1H),1.43(d,J=20.1Hz,2H). 13 C-NMR(151MHz,DMSO-d6)δ157.24,153.00,150.18,147.07,146.28,142.77,137.63,136.52,132.74,132.09,130.37,126.64,125 .27,122.28,119.56,118.24,104.61,63.87,59.81,54.68,51.72,44.08,36.18,24.71,22.79,19.37,13.51.HRMS(ESI,m / z)calcd forC 26 H 25 N7O[M+Na] + :474.2013 found 474.2087.

[0158] Example 44: Preparation of 1'-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[cyclohexane-1,3'-indoline]-5'-carboxamide

[0159]

[0160] Example 42 (100 mg, 0.23 mmol) and potassium carbonate (48 mg, 0.35 mmol) were placed in a 10 mL eggplant-shaped bottle, 3 mL of dimethyl sulfoxide (DMSO) was added to dissolve, 1.5 mL of 30% hydrogen peroxide solution was slowly added under stirring, and the reaction was allowed to react at room temperature. The reaction was monitored by TLC. After the reaction was complete, sodium thiosulfate aqueous solution was added to the reaction solution to quench the reaction. The aqueous layer was extracted three times with ethyl acetate, the organic phases were combined, extracted once with saturated brine, dried, and evaporated to obtain a crude product. The target product was purified by column chromatography to obtain 70 mg of a yellow solid with a yield of 67.5%. mp: 283.2-284.7°C. 1HNMR(600MHz,DMSO-d6)δ8.73(s,1H),8.21-8.13(m,3H),8.05(s,1H),7.90(s,1H),7.88(d,J=2.0Hz,1H),7.78( dd,J=8.4,1.9Hz,1H),7.24(s,1H),4.78(s,2H),3.82(s,3H),2.57(s,3H),1.76-1.68(m,7H),1.45-1.31(m,3H). 13 C-NMR (151MHz, DMSO-d6) δ167.86,157.97,153.49,151.85,146.03,142.03,138.42,138.17,136.49,133.21,129.4 0,127.33,126.88,122.38,119.48,117.39,64.32,44.51,36.75,36.65,25.36,23.19,11.30.HRMS(ESI,m / z)calcd for C 26 H 27 N7O[M+H] + :454.2350 found 454.2421

[0161] Example 45: Preparation of 1'-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[cyclohexane-1,3'-indoline]-5'-carboxamide Using Example 43 as the raw material, the target product was obtained according to the synthesis method of Example 44 as a yellow solid of 73 mg, with a yield of 68.1%. mp: 172.4-173.5℃. 1 H-NMR (600MHz, DMSO) δ8.71(s,1H),8.52-8.46(m,2H),8.19(d,J=3.8Hz,2H),8.15(d,J=3.6Hz,1H),7.90(d,J=8.8Hz,2H),7.82(d,J=8.5 Hz,1H),7.25(s,1H),4.99(t,J=5.3Hz,1H),4.96(s,2H),4.25-4.21(m,2H),3.80(q,J=5.5Hz,2H),1.81-1.70(m,7H),1.50-1.36(m,3H). 13C-NMR (151MHz, DMSO) δ167.85,157.50,153.64,150.19,146.58,145.97,141.91,137.94,136.81,133.20,130.62,129 .51,127.50,125.37,122.76,122.40,117.71,64.49,60.20,55.04,44.28,36.95,25.35,23.32.HRMS(ESI,m / z)calcd for C 26 H 27 N7O2[M+H] + :470.2299found470.2346.

[0162] Example 46: Preparation of 5-fluoro-1-(6-phenylpyrido[3,2-d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]

[0163] Using 15c and phenylboronic acid pinacol ester as raw materials, the product was obtained according to the synthesis method of Example 26 as a yellow solid (60 mg) with a yield of 83.0%. mp: 192.3-192.8℃. 1 H-NMR (600MHz, DMSO)8.70(s,1H),8.63(dd,J=9.0,4.9Hz,1H),8.49(d,J=8.8Hz,1H) ,8.26(dd,J=11.5,8.2Hz,3H),7.59(t,J=7.5Hz,2H),7.54(t,J=7.2Hz,1H),7.22(dd ,J=8.4,2.8Hz,1H),7.12(td,J=9.0,2.8Hz,1H),5.11(s,2H),3.05(dt,J=12.6,3.2H z,2H),2.73(td,J=12.7,2.4Hz,2H),1.85(td,J=12.9,4.3Hz,2H),1.71-1.62(m,2H). 13 C-NMR (151MHz, DMSO)159.6,158.0,157.0,154.1,153.7,146.6,143.4,139.3,138.0,136.7,132 .8,129.9,129.1,127.0,124.7,119.9,113.7,110.0,63.6,43.0,42.8,36.2.LC-MS:412.21[M+H] + .

[0164] Example 47: Preparation of 3-(4-(5-fluorospiro[indoline-3,4'-piperidin]-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-N,N-dimethylbenzamide Using 15c and 3-(N,N-dimethylaminocarbonyl)phenylboronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 26 with a yield of 85.4%. mp: 214.4-215.3℃. 1 H-NMR (600MHz, DMSO)8.69(s,1H),8.58(dd,J=8.9,4.9Hz,1H),8.54(d,J=8.9Hz,1H),8.31(dt,J=8.0 ,1.5Hz,1H),8.27(d,J=2.9Hz,1H),8.25(s,1H),7.66(t,J=7.7Hz,1H),7.56(dt,J=7.5,1.4Hz,1H),7 .19(dd,J=8.4,2.8Hz,1H),7.12(td,J=8.9,2.8Hz,1H),5.07(s,2H),3.12(dt,J=12.8,3.3Hz,2H),3. 05(s,3H),2.96(s,3H),2.78(td,J=12.9,2.6Hz,2H),1.94(td,J=13.2,4.2Hz,2H),1.74-1.68(m,2H). 13 C-NMR(151MHz,DMSO)169.8,159.6,158.,157.0,154.2,153.0,146.7,142.8,139.2,138.0,137.6,136 .8,132.8,129.1,127.8,125.4,119.9,113.8,109.9,63.4,42.6,42.3,35.1,34.7.LC-MS:483.25[M+H] + .

[0165] Example 48: Preparation of 5-fluoro-1-(6-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine] Using 15c and 3-pyridineboronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 26 with a yield of 90.1%. mp: 237.5-238.2℃. 1H-NMR(600MHz,DMSO)9.44(d,J=2.3Hz,1H),8.71(dd,J=4.8,1.6Hz,1H),8.68(s,1H ),8.59-8.51(m,3H),8.27(d,J=8.8Hz,1H),7.61(dd,J=8.0,4.7Hz,1H),7.20(dd,J =8.4,2.8Hz,1H),7.11(td,J=8.9,2.8Hz,1H),5.04(s,2H),3.07(dt,J=12.6,3.3Hz ,2H),2.72(td,J=12.7,2.5Hz,2H),1.88(td,J=13.0,4.2Hz,2H),1.73-1.65(m,2H). 13 C-NMR(151MHz,DMSO)159.7,158.1,157.0,154.4,151.5,150.5,148.3,146.74,139.1,136.9,134 .3,133.4,133.0,124.9,124.0,119.9,113.7,110.0,63.5,43.0,42.8,36.0.LC-MS:413.20[M+H] + .

[0166] Example 49: Preparation of 1-(6-(1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-5-fluorospiro[indoline-3,4'-piperidine] Using 15c and 4-pyrazole boronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 26 with a yield of 76.8%. mp: 347.1-347.7℃. 1 H-NMR (600MHz, DMSO) 13.31 (s, 1H), 8.63 (s, 1H), 8.51 (dd, J = 8.9, 4.9Hz, 1H), 8. 37(s,2H),8.21(d,J=8.7Hz,1H),8.15(d,J=8.8Hz,1H),7.21(dd,J=8.5,2.8Hz, 1H),7.10(td,J=8.9,2.8Hz,1H),5.01(s,2H),3.01(dt,J=12.6,3.3Hz,2H),2.6 7(td,J=12.6,2.4Hz,2H), 1.82(td,J=12.6,4.2Hz,2H), 1.66(d,J=12.8Hz,2H). 13C-NMR(151MHz,DMSO)159.5,157.9,156.8,153.3,149.9,146.0,143.6,139.3,136.2, 132.7,125.0,122.1,119.6,113.4,109.9,63.4,43.2,43.1,36.5.LC-MS:402.21[M+H] + .

[0167] Example 50: Preparation of 5-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine] Using 15c and 1-methylpyrazole-4-boronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 26, and the yield was 80.1%. 1 H-NMR (600MHz, DMSO)8.60(s,1H),8.47(dd,J=9.0,4.8Hz,1H),8.42(s,1H),8.14-8.07(m,3H),7.18(dd,J=8.4,2.8Hz,1H),7.09(td,J=8.9 ,2.7Hz,1H),4.96(s,2H),3.93(s,3H),3.07(d,J=12.6Hz,2H),2.71(t,J=12.6Hz,2H),1.87(td,J=13.0,4.3Hz,2H),1.69(d,J=13.0Hz,2H). 13 C-NMR(151MHz,DMSO)159.5,157.9,156.8,153.3,149.5,146.0,139.3,137.6,136.3,132.7, 130.4,124.8,122.7,119.7,113.7,109.9,63.3,42.8,42.7,39.0,35.4.LC-MS:416.24[M+H] + .

[0168] Example 51: Preparation of 1-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-5-fluorospiro[indoline-3,4'-piperidine] Using 15c and 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 26 with a yield of 80.8%. mp: 241.5-242.3℃. 1H-NMR (600MHz, DMSO)8.66(s,1H),8.18(s,1H),8.17(s,2H),8.12(d,J=8.9 Hz,1H),8.06(s,1H),7.14(dd,J=8.4,2.7Hz,1H),7.10(td,J=9.0,2.7Hz,1 H),4.85(s,2H),3.82(s,3H),3.26(d,J=13.6Hz,4H),2.87(dt,J=14.1,7.1 Hz,2H),2.57(s,3H),2.06(td,J=13.6,4.2Hz,2H),1.86(d,J=13.7Hz,2H). 13 C-NMR (151MHz, DMSO)159.3,157.7,157.5,153.3,151.3,145.7,139.5,138.1,137.8,136.2,13 2.8,126.5,119.2,119.2,113.9,109.7,62.8,42.1,41.3,36.4,32.6,11.0.LC-MS:430.23[M+H] + .

[0169] Example 52: Preparation of 5-fluoro-1-(6-phenylpyrido[3,2-d]pyrimidin-4-yl)-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran] Using 5d and phenylboronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 27, with a yield of 67.5%. mp: 182.1-182.6℃. 1 H-NMR (600MHz, DMSO)8.69(s,1H),8.64(dd,J=8.9,4.8Hz,1H),8.47(d,J=8.8H z,1H),8.25(t,J=9.0Hz,3H),7.56(dt,J=23.9,7.3Hz,3H),7.34(dd,J=8.5,2. 8Hz,1H),7.11(td,J=9.0,2.8Hz,1H),5.17(s,2H),3.95(dd,J=11.9,4.5Hz,2H ),3.52(t,J=11.9Hz,2H),2.00(td,J=13.0,4.6Hz,2H),1.65(d,J=13.2Hz,2H). 13C-NMR (151MHz, DMSO)159.7,158.1,156.9,154.0,153.7,146.5,142.7,139.3,138.0,136.7,132 .8,129.9,129.0,127.0,124.7,119.9,113.7,110.3,64.3,63.3,42.0,36.3.LC-MS:413.18[M+H] + .

[0170] Example 53: Preparation of 3-(4-(5-fluoro-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-N,N-dimethylbenzamide Using 5d and 3-(N,N-dimethylaminocarbonyl)phenylboronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 27, with a yield of 64.2%. mp: 205.2-205.9℃. 1 H-NMR (600MHz, DMSO)8.70(s,1H),8.66(dd,J=9.0,4.9Hz,1H),8.54(d,J=8.9Hz,1H),8.30(d,J =7.9Hz,1H),8.28-8.25(m,2H),7.66(t,J=7.7Hz,1H),7.55(d,J=7.5Hz,1H),7.35(dd,J=8.5,2 .8Hz,1H),7.12(td,J=8.9,2.8Hz,1H),5.16(s,2H),3.93(dd,J=11.8,4.5Hz,2H),3.49(td,J=1 2.4,1.8Hz,2H),3.04(s,3H),2.95(s,4H),2.00(td,J=13.1,4.8Hz,3H),1.64(d,J=13.1Hz,2H). 13 C-NMR (151MHz, DMSO)170.2,160.2,158.6,157.4,154.7,153.5,147.2,143.3,139.8,138.6,138.2,137 .3,133.3,129.7,128.2,125.6,120.5,114.2,110.8,64.7,63.9,42.5,37.0,35.1.LC-MS:484.25[M+H] + .

[0171] Example 54: Preparation of 5-fluoro-1-(6-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yl)-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran] Using 5d and 3-pyridineboronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 27, with a yield of 74.2%. mp: 219.8-220.7℃. 1 H-NMR (600MHz, DMSO)9.45(d,J=2.4Hz,1H),8.71(dd,J=4.8,1.6Hz,1H),8.68(s,1H),8.60(dd,J =9.0,4.9Hz,1H),8.56(dt,J=8.0,2.0Hz,1H),8.53(d,J=8.8Hz,1H),8.27(d,J=8.7Hz,1H),7.60( dd,J=8.0,4.7Hz,1H),7.35(dd,J=8.5,2.8Hz,1H),7.11(td,J=8.9,2.8Hz,1H),5.13(s,2H),3.93 (dd,J=11.8,4.5Hz,2H),3.54-3.47(m,2H),2.00(td,J=13.0,4.7Hz,2H),1.64(d,J=13.2Hz,2H). 13 C-NMR (151MHz, DMSO)159.7,158.1,156.9,154.3,151.6,150.5,148.3,146.7,139.2,136.9,134. 3,133.4,133.0,124.9,123.9,119.9,113.8,110.3,64.3,63.2,,42.0,36.3.LC-MS:414.20[M+H] + .

[0172] Example 55: Preparation of 1-(6-(1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-5-fluoro-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran] Using 5d and 4-pyrazole boronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 27, with a yield of 71.2%. mp: 343.5-344.6℃. 1H-NMR (600MHz, DMSO)13.29(s,1H),8.65(s,1H),8.54(d,J=4.9Hz,1H),8.53(d,J=4.9Hz,1H),8.22(s,1H),8.21(s,1H),8 .16(d,J=8.8Hz,1H),7.34(dd,J=8.6,2.8Hz,1H),7.11(td,J=9.0,2.8Hz,1H),5.11(s,2H),3.95(dd,J=11.4,4.5Hz,2H). 13 C-NMR(151MHz,DMSO)159.5,158.0,156.8,153.3,149.9,146.0,142.7,139.4,136.3, 132.7,125.1,122.1,119.6,113.7,110.2,64.4,63.1,42.1,36.2.LC-MS:403.19[M+H] + .

[0173] Example 56: Preparation of 5-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran] Using 5d and 1-methylpyrazole-4-boronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 27, with a yield of 76.5%. mp: 229.6-230.8℃. 1 H-NMR (600MHz, DMSO)8.62(s,1H),8.50(dd,J=8.9,4.9Hz,1H),8.44(s,1H),8.15-8.10(m,3H),7.33(dd,J=8.5,2.8Hz,1H),7.10 (td,J=8.9,2.8Hz,1H),5.05(s,2H),3.96-3.91(m,5H),3.53-3.46(m,2H),1.98(td,J=12.9,4.7Hz,2H),1.66(d,J=13.2Hz,2H). 13 C-NMR(151MHz,DMSO)159.5,157.9,156.8,153.3,149.5,145.9,139.3,137.6,136.3,132.7, 130.4,124.8,122.7,119.6,113.5,110.0,64.4,63.1,42.0,39.0,36.1.LC-MS:417.19[M+H] + .

[0174] Example 57: Preparation of 1-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)-5-fluoro-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran] Using 5d and 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester as raw materials, the product was obtained as a yellow solid according to the synthesis method of Example 27, with a yield of 67.9%. mp: 238.7-239.5℃. 1 H-NMR (600MHz, DMSO)8.64(s,1H),8.28(dd,J=8.9,4.8Hz,1H),8.15(d,J=8.8H z,1H),8.10(d,J=8.8Hz,1H),8.04(s,1H),7.31(dd,J=8.6,2.8Hz,1H),7.07(t d,J=8.9,2.8Hz,1H),4.93(s,2H),3.92-3.87(m,2H),3.83(s,3H),3.46(td,J= 12.2,2.0Hz,2H),2.60(s,3H),1.97(td,J=13.0,4.7Hz,2H),1.67-1.60(m,2H). 13 C-NMR (151MHz, DMSO)159.5,157.9,157.2,153.2,151.2,145.7,139.4,138.0,137.6,136.2,13 2.8,126.3,119.4,119.2,113.5,110.1,64.2,63.1,42.3,36.4,35.9,11.0.LC-MS:431.22[M+H] + .

[0175] Example 58: Preparation of 2-(4-(4-(5-fluorospiro[indoline-3,4'-piperidin]-1-yl)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol Using 15c and 11b as raw materials, the product was obtained according to the synthesis method of Example 26 as a yellow solid (79 mg) with a yield of 37.8%. mp: 178.6-179.4℃. 1H-NMR (600MHz, DMSO-d6) δ8.62 (s, 1H), 8.54 (dd, J = 9.0, 5.0Hz, 1H), 8.47 (s, 1H),8.17-8.09(m,3H),7.21(dd,J=8.5,2.9Hz,1H),7.13-7.05(m,1H),4.99( s,2H),4.23(t,J=5.4Hz,2H),3.81(t,J=5.5Hz,2H),2.97(d,J=12.7Hz,2H), 2.66(t,J=11.5Hz,2H), 1.79(td,J=12.6,4.3Hz,2H), 1.61(d,J=11.6Hz,2H). 13 C-NMR(151MHz,DMSO-d6)δ159.53,157.93,156.66,153.26,149.51,145.98,143.68,139.31,137.56,136.29,13 2.70,130.16,124.75,122.36,119.68,113.43,109.97,63.45,59.83,54.64,43.22,36.78.HRMS(ESI,m / z)calcd for C 24 H 24 FN7O[M+H] + :468.1919found468.1966.

[0176] Example 59: Preparation of 1-(5-fluoro-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidin]-1'-yl)ethan-1-one

[0177] Steps A, B: Preparation of 1-(1-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-5-fluorospiro[indoline-3,4'-piperidin]-1'-yl)ethan-1-one (16)

[0178]

[0179] 15c (500 mg, 1.07 mmol) was placed in a 100 mL eggplant-shaped bottle, 20 mL of dichloromethane was added to dissolve, 5 mL of trifluoroacetic acid was added under stirring at room temperature, and the reaction was completed at room temperature. TLC monitored the reaction to be complete, the reaction solution was evaporated to dryness, the residue was dissolved with water, the pH was adjusted to about 8 with saturated sodium bicarbonate aqueous solution, a yellow solid was precipitated, and the product was filtered to obtain a yellow solid. It and triethylamine (82 mg, 0.81 mmol) were placed in a 50 mL eggplant-shaped bottle, 10 mL of dichloromethane was added to dissolve, acetyl chloride (47 mg, 0.59 mmol) was slowly added under stirring at room temperature, and the reaction was completed at room temperature. TLC monitored the reaction to be complete, the reaction solution was diluted with 100 mL of dichloromethane, extracted with 10% HCl aqueous solution, water, saturated sodium bicarbonate and saturated brine respectively, dried, and evaporated to obtain a crude product as a yellow oil, which was directly subjected to the next step of reaction without purification, and the yield was 78.4%.

[0180] Step C: Preparation of 1-(5-fluoro-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidin]-1'-yl)ethan-1-one (Example 59)

[0181]

[0182] Using 16 as raw material, the target compound was obtained as a yellow solid (93 mg) according to the synthesis method of Example 27, with a yield of 35.4%. mp: 296.7-297.5℃. 1 H-NMR (600MHz, DMSO-d6) δ8.65(s,1H),8.48(s,2H),8.18-8.14(m,3H),7.32(dd,J=8.7,2.9 Hz,1H),7.11(td,J=8.9,2.7Hz,1H),5.04(s,2H),4.99(t,J=5.4Hz,1H),4.49(d,J=13.8Hz, 1H),4.22(t,J=5.5Hz,2H),3.90(d,J=14.0Hz,1H),3.79(q,J=5.5Hz,2H),3.18(t,J=12.3Hz ,1H),2.67(t,J=10.9Hz,1H),2.06(s,3H),1.93(td,J=13.0,4.5Hz,2H),1.82-1.75(m,2H). 13C-NMR(151MHz,DMSO-d6)δ168.21,157.88,156.93,153.27,149.67,145.98,142.40,139.37,137.62,136.30,132.77,130.25, 124.88,122.35,119.45,113.70,110.27,62.79,59.83,54.91,54.59,43.06,38.32,35.86,35.26,21.40.HRMS(ESI,m / z)calcd for C 26 H 26 FN7O2[M+Na] + :510.2024found510.2099.

[0183] Study on the pharmacological effects of the product of the present invention

[0184] The activity of Mnk kinase was screened using the serine / threonine kinase kit from Bioduro-sundia.

[0185] The HTRF method was used to test the inhibition rate of the target compound at 100 nM on Mnk1 and Mnk2. The results are shown in Table

[0186]

[0187]

[0188] IC values ​​of some compounds against Mnk1 and Mnk2 50 value:

[0189]

[0190] As can be seen from the above table, some compounds showed good Mnk1 inhibitory activity, IC 50 The value was less than 20 nM. In addition, some compounds also showed good Mnk2 inhibitory activity, IC 50 The values ​​ranged from 17-71 nM.

[0191] Antiproliferative activity test:

[0192] Preparation of MTT: Weigh 100 mg of MTT, add 50 mL of phosphate buffer solution, stir for 30 minutes in the dark, filter through a 0.22 μM filter membrane to sterilize, and store at -20°C.

[0193] Preparation of drug solution: Dissolve the target compound in DMSO to prepare a mother solution of a certain concentration, and dilute the mother solution with ethanol and culture medium to form solutions of different concentrations. When adding the drug, the final concentration of DMSO in the solution should be less than 1‰, and the final concentration of ethanol should be less than 1%.

[0194] Drug addition and data processing: After HCT-116 cells adhered for 24 hours, drugs were added, and then the drugs and cells were incubated for 96 hours. After the incubation, MTT was added, and the plate was shaken after 3.5 hours. The blue-purple crystals were dissolved with DMSO, and the absorbance at 570nm was measured using an ELISA instrument. DMSO was used as a blank control, and the growth inhibition rate was calculated according to the following formula, and then the GI50 was calculated by linear regression based on the inhibition rate.

[0195]

[0196] The antiproliferative activity of some compounds against human colon cancer cell line HCT-116 was tested.

[0197]

[0198]

[0199] Note: “-” means that the enzyme activity or cell activity was not detected.

[0200] The results of antiproliferative activity test showed that some compounds showed good growth inhibition effect on HCT-116 cells, IC 50 Between 0.67-4.75 μM, it has potential anti-colorectal cancer ability.

[0201] The above experimental results show that the compounds of the general formula to be protected by the present invention have good inhibitory effects on Mnk1 and Mnk2 kinases and exhibit obvious anti-proliferation activity in solid tumor cells. The compounds of the present invention have good industrial application prospects.

Claims

1. A 4-indolinyl substituted pyrido[3,2-d]pyrimidine compound, characterized in that: The compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof: in, R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C2-4-6-yl, unsubstituted or substituted by at least one of the following groups which may be the same or different: 10 Alkyl, CONR9R 10 and SO2NR9R 10 , the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkoxy; R2, R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine oxide, C2-C 10 alkenyl, unsubstituted or substituted by at least one of the following groups which are the same or different 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12 ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl; Y is The left side of Y is connected to the pyridopyrimidine mother nucleus; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, Hydroxyl C2-C 10 Alkyl, amino C2-C 10 Alkyl, C1-C4 alkoxy C1-C4 alkyl, unsubstituted or substituted with at least one of the same or different halogen, amino, oxygen, C1-C 10 Alkyl-substituted C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C4-C8 heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CSNR9R 10 、-CH2CONR9R 10 、-SO2NR9R 10 、-OCONR9R 10 、-NHCONHR9R 10 ; R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, carbamoyl, dimethylphosphine, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Haloalkyl, CF3SO2-, CHF2SO2-, CH3SO2-, CH3SO2NH-; R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, haloalkyl (C1-C 10 )、C3-C 12 Cycloalkyl, C3-C 12 Heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

2. The compound according to claim 1, characterized in that: The compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof. in, R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C8 alkyl which is unsubstituted or substituted by at least one of the following groups which may be the same or different, CONR9R 10 and SO2NR9R 10 , the following groups are halogen, hydroxy, amino, cyano, C1-C4 alkoxy; R2 and R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12 ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl; Y is The left side of Y is connected to the pyridopyrimidine mother nucleus; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 C2-C8 alkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C8 alkoxy which is unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CSNR9R 10 、-CH2CONR9R 10 、-SO2NR9R 10 、-OCONR9R 10 、-NHCONHR9R 10 ; R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, carbamoyl, dimethylphosphine, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Haloalkyl; R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

3. The compound according to claim 2, characterized in that: The compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof. R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C8 alkyl which is unsubstituted or substituted by at least one of the following groups which may be the same or different, the following groups being halogen, hydroxyl, amino, cyano, C1-C4 alkoxy; R2 and R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12 ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl; Y is The left side of Y is connected to the pyridopyrimidine mother nucleus; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 C2-C8 alkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C8 alkoxy which is unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CH2CONR9R 10 、-OCONR9R 10 、-NHCONHR9R 10 ; R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Haloalkyl; R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

4. The compound according to claim 3, characterized in that: The compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof. R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl; R2 and R3 may be the same or different and are independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or, R2 and R3 together with the carbon atom to which they are attached form a C3-C 12 ring or a 4-10 membered substituted heterocyclic group substituted by at least one identical or different substituent; the substituent is halogen, hydroxyl, amino, cyano, C1-C4 alkoxy, C1-C4 acyl; Y is The left side of Y is connected to the pyridopyrimidine mother nucleus; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, C1-C 10 C2-C8 alkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C8 alkoxy which is unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -CONR9R 10 、-CH2CONR9R 10 ; R5, R6, R7, and R8 may be the same or different and are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, C1-C 10 Alkyl, C1-C 10 Haloalkyl; R9, R 10 may be the same or different and are independently selected from: hydrogen, unsubstituted or substituted by at least one of the following groups which may be the same or different, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atom to which they are connected, they form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group containing at least one heteroatom which is unsubstituted or substituted by at least one of the following groups; wherein the following groups are halogen, hydroxyl, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy.

5. The compound according to claim 4, characterized in that: The compound is the following compound, isomer and pharmaceutically acceptable salt, hydrate, solvate, metabolite thereof, 6. A pharmaceutical composition, characterized in that The composition comprises the compound, isomer and pharmaceutically acceptable salt, hydrate, solvate and metabolite thereof as described in any one of claims 1 to 5.

7. Use of the compound according to claim 1 or the composition according to claim 6, characterized in that: The compound or composition is used in preparing drugs for treating and / or preventing various cancer diseases or autoimmune diseases with abnormal expression of Mnk or Pim.

8. The use according to claim 7, characterized in that: The cancer is breast cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, liver cancer, bladder cancer, uterine cancer, pancreatic cancer, ovarian cancer, lymphoma, ovarian cancer, skin cancer or blood cancer.

9. The use according to claim 7, characterized in that: The autoimmune disease is septic shock or acute organ damage.

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