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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 4-anilino substituted pyrido [3, 2-d] pyrimidine compound and application thereof in preparation of a Mnk inhibitor and a medicine for treating and / or preventing various cancers, metabolic diseases, inflammatory diseases, autoimmune diseases and viral diseases. The compounds are compounds as shown in a general formula I, isomers and pharmaceutically acceptable salts, hydrates, solvates and metabolites thereof, wherein R1, R2, R3, R4 and Y are described in the claims and the description. # imgabs0 #

Description

Technical field:

[0001] The present invention belongs to the field of medical technology, and specifically relates to a 4-anilino-substituted pyrido[3,2-d]pyrimidine compound and its 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. In tumor cells, abnormal regulation of the MAPK signaling pathway usually exacerbates cell division, invasion, survival, etc., among which the disorder of cell metabolism and protein synthesis becomes the main reason. Eukaryotic cells strictly regulate protein synthesis by regulating mRNA translation, which mainly depends on the eukaryotic initiation factor 4F (eIF4F) complex that binds to the 5'7-methylguanylate of mRNA. The complex includes eukaryotic initiation factor 4E (eIF4E), helicase 4A (eIF4A) and skeleton protein eIF4G. Among them, eIF4E, as a key factor in the complex, becomes the key to tumor survival and proliferation mediated by the PI3K / Akt / mTOR and Ras / Raf / MEK / ERK signaling pathways. After ERK and p38 kinase activation, Mnk1 / 2 can be activated, which phosphorylates the serine at position 209 of the substrate protein eIF4E, and then promotes the nuclear-cytoplasmic transport and translation of tumor-related proteins with 5' cap structures at the mRNA level (such as c-Myc, cell cycle protein Cyclin D1, anti-apoptotic proteins Mcl-1, Bcl-2, vascular epidermal growth factor VEGF, HDM2, hypoxia-inducible factor HIF-1α, matrix metalloproteinase MMP-3 / 9, SNAIL, etc.). The phosphorylation of eIF4E by Mnk is the key to the latter's carcinogenic effect. Mnk regulates the translation of related proteins by mediating the phosphorylation of eIF4E. These proteins play an important role in the mechanisms of tumor cell survival, anti-apoptosis, metastasis and drug resistance; 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; 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] Provirus Integration in Maloneymurine leukemia virus (Pim) is a type of serine / threonine kinase that is highly activated in tumor cells and is expressed in three subtypes: Pim1, Pim2, and Pim3. A large number of studies have shown that overexpression and activation of Pim kinases are closely related to the induction and development of cancer. Pim kinases can mediate the survival of tumor cells through their own different functions. ①Pim kinase can mediate the transcription of certain tumorigenic proteins by phosphorylating histone H3 and c-Myc; ②Pim kinase can phosphorylate the pro-apoptotic protein BAD, causing it to bind to the 14-3-3 protein, preventing the latter from polymerizing, thereby increasing the activity of the anti-apoptotic protein Bcl-2 and promoting cell survival; ③Pim can phosphorylate cell cycle-related proteins, such as CDK kinase inhibitors p21 and p27, as well as cdc25a and cdc25c, to participate in the cell cycle regulation process and promote the proliferation of tumor cells; ④Pim can phosphorylate eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) at Ser65, causing eIF4E to dissociate from the 4E-BP1 / eIF4E complex, releasing eIF4E, allowing it to bind to the scaffold protein eIF4G and participate in the cap-dependent translation process. In short, Pim kinase can participate in various processes of tumor occurrence and development, and is expected to become a low-toxic and effective anti-tumor target. Summary of the invention:

[0004] The technical problem solved by the present invention is to provide a 4-anilino substituted pyrido[3,2-d]pyrimidine compound and its use in preparing Mnk inhibitors and drugs for treating and / or preventing various cancers, metabolic, inflammatory, autoimmune and viral diseases.

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

[0006] A 4-anilino-substituted pyrido[3,2-d]pyrimidine compound, characterized in that 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 the formula,

[0009] R 1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 10 Alkyl, CONR 9 R10 and SO 2 NR 9 R 10 , the following groups are halogen, hydroxyl, amino, cyano, C 1 -C 4 Alkoxy;

[0010] R 2 ,R 3 which may be the same or different and are independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine, C 2 -C 10 alkenyl, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Halogenated alkoxy, C 3 -C 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl, The following substituents are O, N, halogen, hydroxyl, amino, cyano, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy;

[0011] Y is

[0012]

[0013] The left side of Y is connected to the pyrido[3,2-d]pyrimidine core;

[0014] m and n may be the same or different and are independently an integer between 1 and 3;

[0015] X, Z are CH, N;

[0016] R 4 Selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, hydroxyl C 2 -C 10 Alkyl, amino C 2 -C 10 Alkyl, unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C 3 -C 12Cycloalkyl, C 4 -C 8 Heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -CONR 9 R 10 ,-CSNR 9 R 10 、-CH 2 CONR 9 R 10 、-SO 2 NR 9 R 10 、-OCONR 9 R 10 、-NHCONHR 9 R 10 ;

[0017] R 5 , R 6 , R 7 , R 8 may be the same or different and independently selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, carbamoyl, dimethylphosphine oxide, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 1 -C 10 Haloalkyl, CF 3 SO 2 -, CHF 2 SO 2 -、CH 3 SO 2 -、CH 3 SO 2 NH-;

[0018] R 9 , 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 C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 2 -C 10 Alkenyl, haloalkyl (C 1 -C 10 ), C 3 -C 12 Cycloalkyl, C 3 -C 12 Heterocyclic group, C 6 -C 10Aryl, 5-10 membered heteroaryl, or R 9 and R 10 Together with the nitrogen atoms to which they are attached, 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, C 1 -C 4 Alkyl or C 1 -C 4 Alkoxy;

[0019] R 11 , R 12 for hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, C 1 -C 10 alkyl;

[0020] R 13 For hydrogen, C 1 -C 4 alkyl.

[0021] Preferably, the compound is a compound represented by general formula I, an isomer, and a pharmaceutically acceptable salt, hydrate, solvate, or metabolite thereof.

[0022] Where:

[0023] R 1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 8 Alkyl; the following groups are halogen, hydroxyl, amino, cyano, C 1 -C 4 Alkoxy;

[0024] R 2 , R 3 which may be the same or different and are independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine oxide, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 1 -C 6 Halogenated alkoxy, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 8 Aryl and 5-8 membered heteroaryl, Wherein, the following substituents are O, N, halogen, hydroxyl, amino, cyano;

[0025] Y is -,

[0026] ,

[0027] The left side of Y is connected to the pyrido[3,2-d]pyrimidine core;

[0028] m and n may be the same or different and are independently 1 or 2;

[0029] X, Z are CH, N;

[0030] R 4 Selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C 1 -C 8 Alkyl, hydroxyl C 2 -C 8 Alkyl, amino C 2 -C 8 Alkyl, unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, C 3 -C 10 Cycloalkyl, C 4 -C 8 Heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -CONR 9 R 10 ,-CSNR 9 R 10 、-CH 2 CONR 9 R 10 、-SO 2 NR 9 R 10 、-OCONR 9 R 10 、-NHCONHR 9 R 10 ;

[0031] R 5 , R 6 , R 7 , R 8 may be the same or different and independently selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, amino, trifluoromethyl, cyano, carbamoyl, dimethylphosphine oxide, C 1 -C 10 Alkyl, C 2 -C 10 alkenyl;

[0032] R 9 , R 10may 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 C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 2 -C 8 Alkenyl, haloalkyl (C 1 -C 10 ), C 3 -C 10 Cycloalkyl, C 3 -C 10 Heterocyclic group, C 6 -C 10 Aryl, 5-10 membered heteroaryl, or R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form a 4-10 membered substituted heterocyclic group or a 5-10 membered heteroaryl group; wherein the following groups are halogen, hydroxyl, amino, cyano, C 1 -C 4 Alkyl or C 1 -C 4 Alkoxy;

[0033] R 11 , R 12 for hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, C 1 -C 10 alkyl;

[0034] R 13 For hydrogen, C 1 -C 4 alkyl.

[0035] More preferably, the compound is a compound represented by general formula I, an isomer thereof, and a pharmaceutically acceptable salt, hydrate, solvate, metabolite thereof, wherein

[0036] R 1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 4 Alkyl, the following groups are halogen, hydroxyl, amino, cyano;

[0037] R 2 , R 3 which may be the same or different and are independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine oxide, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 6 Alkyl, C 1 -C6 Alkoxy, C 1 -C 6 Halogenated alkoxy, C 3 -C 8 Cycloalkyl C 3 -C 8 Heterocyclic group, C 6 -C 8 Aryl and 5-8 membered heteroaryl, Wherein, the following substituents are O, N, halogen, hydroxyl, amino, cyano;

[0038] Y is -,

[0039]

[0040] The left side of Y is connected to the pyrido[3,2-d]pyrimidine core;

[0041] m and n may be the same or different and are independently 1 or 2;

[0042] X, Z are CH, N;

[0043] R 4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 3 -C 10 Cycloalkyl, hydroxyl C 2 -C 8 Alkyl, amino C 2 -C 8 Alkyl, C containing at least one heteroatom 4 -C 8 Cycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -CONR 9 R 10 ,-CSNR 9 R 10 、-CH 2 CONR 9 R 10 、-SO 2 NR 9 R 10 、-OCONR 9 R 10 、-NHCONHR 9 R 10 ;

[0044] R5 , R 6 , R 7 , R 8 may be the same or different and independently selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, amino;

[0045] R 11 ,R 12 is hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, unsubstituted alkyl (C 1 -C 10 );

[0046] R 13 is hydrogen, unsubstituted alkyl (C 1 -C 4 ).

[0047] Still more preferably, the compound is a compound represented by general formula I, an isomer thereof, and a pharmaceutically acceptable salt, hydrate, solvate, metabolite thereof, wherein

[0048] R 1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 4 Alkyl, the following groups are halogen, hydroxyl, amino, cyano;

[0049] R 2 , R 3 which may be the same or different and are independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine oxide, unsubstituted or substituted by at least one of the following groups which may be the same or different 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Halogenated alkoxy, C 3 -C 8 Cycloalkyl C 3 -C 8 Heterocyclic group, C 6 -C 8 Aryl and 5-8 membered heteroaryl, Wherein, the following substituents are O, N, halogen, hydroxyl, amino, cyano;

[0050] Y is

[0051]

[0052] The left side of Y is connected to the pyrido[3,2-d]pyrimidine core;

[0053] m and n may be the same or different and are independently 1 or 2;

[0054] X, Z are CH, N;

[0055] R 4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 3 -C 10 Cycloalkyl, hydroxyl C 2 -C 8 Alkyl, amino C 2 -C 8 Alkyl, C containing at least one heteroatom 4 -C 8 Cycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -CONR 9 R 10 ,-CSNR 9 R 10 、-CH 2 CONR 9 R 10 、-SO 2 NR 9 R 10 、-OCONR 9 R 10 、-NHCONHR 9 R 10 ;

[0056] R 5 , R 6 , R 7 , R 8 may be the same or different and independently selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, amino;

[0057] R 11 ,R 12 is hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, unsubstituted alkyl (C 1 -C 10 );

[0058] R 13 is hydrogen, unsubstituted alkyl (C 1 -C 4 ).

[0059] More preferably, the compound is the following compound, isomer and pharmaceutically acceptable salt, hydrate, solvate, metabolite thereof,

[0060]

[0061]

[0062]

[0063] A pharmaceutical composition comprises the compound, isomers and pharmaceutically acceptable salts, hydrates, solvates and metabolites thereof.

[0064] 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.

[0065] 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).

[0066] 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.

[0067] 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.

[0068] 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.

[0069] The autoimmune disease is septic shock or acute organ damage.

[0070] 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.

[0071] The examples and preparations provided below further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way. Specific implementation method:

[0072] 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.

[0073] The NMR spectra of the compounds were measured using a Bruker ARX-600 NMR spectrometer in DMSO-d 6 TMS was used as the internal standard and high-resolution mass spectrometry was measured using a Bruker micro-TOF-Q.

[0074] Example 1: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine

[0075] Step A: Preparation of 4-fluoro-2-isopropoxy-1-nitrobenzene (1a)

[0076]

[0077] 5-Fluoro-2-nitrophenol (1.00 g, 6.37 mmol), 2-iodopropane (1.62 g, 9.56 mmol) and potassium carbonate (1.32 g, 9.56 mmol) were placed in a 100 mL eggplant-shaped bottle, 40 mL of acetonitrile was added to dissolve, and refluxed for reaction. TLC monitored the reaction to be complete, the reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane, extracted with 2M NaOH aqueous solution and saturated brine respectively, the organic phase was dried, and the product was evaporated to dryness to obtain 1.1 g of a yellow oily substance, which was directly subjected to the next step of reaction without purification, and the yield was 86.4%.

[0078] 5-Fluoro-2-nitrophenol, bromomethylcyclohexane and bromocyclopentane were used as raw materials to obtain 1b and 16a according to the preparation method of 1a. Step B: Preparation of 4-fluoro-2-isopropoxyaniline (2a)

[0079]

[0080] 1a (1.1 g, 5.5 mmol) and ammonium formate (6.9 g, 110 mmol) were placed in a 100 mL two-necked bottle, 40 mL of ethanol was added to dissolve, and then palladium carbon (466 mg, 4.4 mmol) was added, and the reaction was carried out at 65° C. under nitrogen protection. TLC monitored the reaction to be complete, the reaction solution was evaporated to dryness, the residue was dissolved in ethyl acetate, extracted with water twice, the organic phase was dried, and the product was evaporated to dryness to obtain 0.81 g of a brown-yellow oil, which was directly used for the next step without purification, and the yield was 87.1%.

[0081] Using 1b-1f and 16a as raw materials, 2b-2f and 17a-17c were prepared according to the synthetic method of 2a.

[0082] Step C: Preparation of 6-chloro-N-(4-fluoro-2-isopropoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (3a)

[0083] 4,6-Dichloropyrido[3,2-d]pyrimidine (200 mg, 1.0 mmol), 2a (186 mg, 1.1 mmol) and triethylamine (152 mg, 1.5 mmol) were placed in a 50 mL eggplant-shaped bottle, 15 mL of isopropanol was added to dissolve, and the mixture was reacted at 50° C. The reaction was completed by TLC monitoring, and the product was directly filtered to obtain 260 mg of a yellow solid, which was directly used for the next step without purification, with a yield of 78.1%.

[0084] Using 4,6-dichloropyrido[3,2-d]pyrimidine and 2b-2f, 17a-17c as raw materials, 3b-3f, 18a-18c were prepared according to the synthetic method of 3a.

[0085] Step D: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (Example 1)

[0086]

[0087] 3a (200 mg, 0.6 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (271 mg, 0.72 mmol), Pd(dppf)Cl 2(22mg, 0.03mmol) and potassium carbonate (124mg, 0.9mmol) were placed in a 50mL two-necked bottle, 16mL 1,4-dioxane and 4mL water were added to dissolve, and refluxed under nitrogen protection. TLC monitored the reaction to be complete, evaporated the reaction solution, dissolved the residue with dichloromethane, extracted once with water and saturated brine respectively, dried the organic phase, evaporated the crude product to a brown-black oil, and purified by column chromatography to obtain a yellow solid. It was placed in a 100mL eggplant-shaped bottle, 20mL dichloromethane was added to dissolve, 5mL trifluoroacetic acid was added under stirring at room temperature, and the reaction was completed at room temperature. TLC monitored the reaction to be complete, evaporated the reaction solution, the residue was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was purified with V 二氯甲烷 :V 甲醇 =10:1 mixed solution was extracted 4 times, the organic phases were combined, dried, and evaporated to obtain a crude product, which was purified by column chromatography to obtain a yellow solid of 137 mg, with a two-step yield of 50.6%. mp: 191.4-192.6℃. 1 H-NMR(600MHz,DMSO)δ9.82(s,1H),8.78(dd,J=9.0,6.4Hz,1H),8.64(s,1H),8.59(s,1 H),8.24(s,1H),8.23-8.17(m,2H),7.15(dd,J=10.8,2.8Hz,1H),6.88(td,J=8.6,2.7Hz ,1H),4.89-4.80(m,1H),4.30(tt,J=11.4,4.1Hz,1H),3.12(dt,J=13.1,3.9Hz,2H),2. 72-2.65(m,2H),2.08(dd,J=10.9,3.5Hz,2H),1.92-1.82(m,2H),1.44(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ159.09,157.50,155.77,154.20,151.15,148.07,142.60,137.27,136.63,130.81,127.67,125.8 0,124.98,121.55,120.41,106.23,101.67,71.55,59.28,44.71,33.01,21.90.HRMS(ESI,m / z)calcd for C 24 H 26 FN 7 O[M+H] + :448.2256found448.2309.Retention Time:3.73min,Purity:98.70%.

[0088] Example 2: Preparation of 6-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-N-(4-fluoro-2-isopropoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine

[0089] Step A: Preparation of tert-butyl (2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (4)

[0090]

[0091] 4-Pyrazoleboronic acid pinacol ester (500mg, 2.58mmol), N-Boc bromoethylamine (693mg, 3.09mmol) and cesium carbonate (1262mg, 3.87mmol) were placed in a 100mL eggplant-shaped bottle, 40mL acetonitrile was added to dissolve, and refluxed for reaction. TLC monitored the reaction to be complete, the reaction solution was evaporated to dryness, the residue was dissolved in ethyl acetate, and extracted once with 10% HCl aqueous solution, water, saturated sodium bicarbonate aqueous solution and saturated brine respectively, the organic phase was dried, and the product was evaporated to dryness to obtain 508mg of a light yellow oily substance, which was directly subjected to the next step of reaction without purification, and the yield was 58.4%.

[0092] Step B: Preparation of 6-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-N-(4-fluoro-2-isopropoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (Example 2) Using 3a and 4 as raw materials, the product was obtained according to the synthesis method of Example 1 as a yellow solid (133 mg) with a yield of 79.6%. mp: 79.1-81.2℃. 1 H-NMR (600MHz, DMSO) δ9.84(s,1H),8.79(dd,J=9.0,6.4Hz,1H),8.64(s,1H),8.53(s,1H),8.24(s,1H),8.19(d,J=2.3Hz,2H),7.15(dd,J=1 0.9, 2.8Hz, 1H), 6.88 (td, J = 8.8, 2.9Hz, 1H), 4.85 (hept, J = 5.8Hz, 1H), 4.16 (t, J = 6.2Hz, 2H), 3.00 (t, J = 6.2Hz, 2H), 1.44 (d, J = 6.0Hz, 6H). 13 C NMR (151 MHz, DMSO-d 6)δ159.07,157.48,155.76,154.22,151.14,147.95,142.58,137.69,136.69,130.82,130.26,12 5.77,124.99,121.64,120.36,106.25,101.51,71.60,55.15,41.79,21.88.HRMS(ESI,m / z)calcd for C 21 H 22 FN 7 O[M+H] + :408.1943found408.1990.Retention Time:3.11min,Purity:96.99%.

[0093] Example 3: Preparation of 2-(4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one

[0094] Step A: Preparation of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (5)

[0095]

[0096] The product was obtained using 4-pyrazoleboronic acid pinacol ester and ethyl bromoacetate as raw materials according to the synthetic method of 4 as a light yellow oil (535 mg), which was directly used for the next step without purification, with a yield of 74.1%.

[0097] Step B: Preparation of ethyl 2-(4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)acetate (6a)

[0098]

[0099] 3a (200 mg, 0.6 mmol), 5 (202 mg, 0.72 mmol), Pd(dppf)Cl 2(22 mg, 0.03 mmol) and potassium carbonate (124 mg, 0.9 mmol) were placed in a 50 mL two-necked bottle, 16 mL of 1,4-dioxane and 4 mL of water were added to dissolve, and refluxed under nitrogen protection. TLC monitored the reaction to be complete, the reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane, extracted once with water and saturated brine respectively, the organic phase was dried, and evaporated to dryness to obtain a crude product as a brown-black oil, which was purified by column chromatography to obtain 101 mg of a yellow solid with a yield of 38.3%.

[0100] Step C: Preparation of 2-(4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)acetic acid (7a)

[0101]

[0102] 6a (101 mg, 0.23 mmol) was placed in a 50 mL eggplant-shaped bottle, 10 mL of methanol was added to dissolve, 2 mL of 2M NaOH aqueous solution was added under stirring at room temperature, and the temperature was raised to 50°C for reaction. TLC monitored the reaction to be complete, the reaction solution was evaporated to dryness, the residue was dissolved in water, the aqueous layer was adjusted to pH 6 with 10% HCl aqueous solution, the aqueous phase was extracted 4 times with dichloromethane, the organic phases were combined and dried, and the product was evaporated to dryness to obtain a yellow solid, which was directly used for the next step without purification.

[0103] Using 6b-6f as raw materials, 7b-7f were prepared according to the synthetic method of 7a.

[0104] Step D: Preparation of 2-(4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (Example 3)

[0105]

[0106] 7a (97 mg, 0.23 mmol), HATU (105 mg, 0.28 mmol) and DIPEA (45 mg, 0.35 mmol) were placed in a 25 mL eggplant-shaped bottle, 8 mL of tetrahydrofuran was added to dissolve, and the reaction was allowed to proceed at room temperature. The reaction was complete as monitored by TLC, 1-Boc piperazine (52 mg, 0.28 mmol) was added to the reaction system, and the reaction was continued at room temperature. The reaction was complete as monitored by TLC, the reaction solution was evaporated to dryness, the residue was dissolved in dichloromethane, and extracted once with 10% HCl aqueous solution, water, saturated sodium bicarbonate aqueous solution, and saturated saline, respectively. The organic phase was dried and evaporated to dryness to obtain a crude yellow oil, which was transferred to a 100 mL eggplant-shaped bottle and 20 mL of dichloromethane was added to dissolve. 5 mL of trifluoroacetic acid was added under stirring at room temperature, and the reaction was allowed to proceed at room temperature. The reaction was complete as monitored by TLC, the reaction solution was evaporated to dryness, the residue was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was washed with V 二氯甲烷 :V 甲醇 =10:1 mixed solution was extracted 4 times, the organic phases were combined, dried, and evaporated to dryness to obtain a crude product, which was purified by column chromatography to obtain a yellow solid product of 73 mg, with a two-step yield of 64.8%. mp: 135.4-136.2℃. 1 H-NMR (600MHz, DMSO) δ9.82 (s, 1H), 8.78 (dd, J = 9.0, 6.4Hz, 1H), 8.63 (s, 1H), 8.4 5(s,1H),8.22(s,1H),8.17(d,J=2.1Hz,2H),7.13(dd,J=10.7,2.9Hz,1H),6.87( td,J=8.7,2.8Hz,1H),5.24(s,2H),4.83(hept,J=6.1Hz,1H),3.51-3.46(m,2H), 3.44(s,2H),2.78(t,J=4.9Hz,2H),2.71(t,J=5.2Hz,2H),1.41(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.83,159.08,157.49,155.79,154.27,151.01,147.99,142.59,137.49,136.75,131.69,130.85,125.7 0,125.00,122.17,120.38,106.26,101.70,71.60,53.14,45.74,45.38,42.82,21.22.HRMS(ESI,m / z)calcd for C 25 H 27 FN 8 O 2 [M+H]+ :491.2314found491.2373.Retention Time:2.55min,Purity:99.54%.

[0107] Example 4: Preparation of (R)-1-(3-aminopiperidin-1-yl)-2-(4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-one Using 7a and (R)-piperidin-3-ylcarbamic acid tert-butyl ester as raw materials, the product was obtained according to the synthesis method of Example 3 as a yellow solid of 71 mg, with a yield of 61.2%. mp: 214.7-216.2℃. 1 H-NMR (600MHz, DMSO) δ9.86(s,1H),8.79(dd,J=9.0,6.4Hz,1H),8.66(s,1H),8.47(d,J=1.7Hz,1H),8.24(s,1H),8.21( d,J=3.3Hz,2H),7.16(dd,J=10.7,2.8Hz,1H),6.89(td,J=8.7,2.8Hz,1H),5.33-5.21(m,2H),4.85(hept,J=6.0Hz,1H), 4.20(dd,J=12.5,3.9Hz,1H),3.82(dd,J=18.5,14.0Hz,1H),3.18-3.06(m,1H),3.05-2.98(m,1H),2.92-2.76(m,1H),1. 92(d,J=27.4Hz,1H),1.81-1.71(m,1H),1.56-1.43(m,2H),1.42(d,J=6.0Hz,6H),1.40-1.29(m,1H),0.99-0.79(m,1H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.87,159.60,157.52,155.82,154.30,150.59,148.08,142.62,137.49,136.78,131.74,130.86,125.74,125. 01,122.16,120.35,106.29,101.56,71.62,53.23,47.36,44.48,32.44,23.93,22.73,21.84.HRMS(ESI,m / z)calcd for C 26 H 29 FN 8 O 2 [M+H] +:505.2470found505.2546.Retention Time:3.92min,Purity:99.89%.

[0108] Example 5: Preparation of (S)-1-(3-aminopiperidin-1-yl)-2-(4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-one Using 7a and (S)-piperidin-3-ylcarbamic acid tert-butyl ester as raw materials, the product was obtained according to the synthesis method of Example 3 as a yellow solid of 75 mg, with a yield of 65.1%. mp: 193.6-195.3℃. 1 H-NMR (600MHz, DMSO) δ9.86(s,1H),8.79(dd,J=9.0,6.4Hz,1H),8.66(s,1H),8.47(d,J=2.5Hz,1H),8.24(s,1H),8.20 (d,J=2.5Hz,2H),7.16(dd,J=10.7,2.8Hz,1H),6.89(td,J=8.7,2.8Hz,1H),5.32-5.20(m,2H),4.85(hept,J=6.1Hz,1 H),3.76(d,J=12.6Hz,1H),3.11-2.87(m,2H),2.80-2.61(m,1H),1.88(d,J=22.4Hz,1H),1.80-1.65(m,1H),1.50(ddd ,J=18.3,10.4,5.2Hz,1H),1.42(d,J=6.0Hz,6H),1.38-1.32(m,1H),1.25(dq,J=15.3,5.5Hz,1H),0.86-0.82(m,1H). 13 C-NMR (151 MHz, DMSO-d 6 )δ165.28,159.12,157.53,155.83,154.33,151.01,148.03,142.63,137.54,136.82,131.67,130.87,125.75,125. 01,122.19,120.45,106.31,101.77,71.63,53.23,53.07,47.31,46.74,44.33,23.22,21.84.HRMS(ESI,m / z)calcd for C 26 H 29 FN 8 O 2 [M+H] +:505.2470found 505.2553.RetentionTime:3.95min,Purity:99.72%.

[0109] Example 6: Preparation of N-(2-(cyclohexylmethoxy)-4-fluorophenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3b and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as raw materials, the product was obtained as a yellow solid of 140 mg according to the synthesis method of Example 1, with a yield of 68.1%. mp: 260.1-261.2℃. 1 H-NMR(600MHz,DMSO)δ9.70(s,1H),8.63-8.58(m,3H),8.19(dd,J=20.7,9.2Hz,3H),7.10(dd,J=10.7,2.8Hz ,1H),6.87(td,J=8.7,2.8Hz,1H),4.29(tt,J=11.7,4.1Hz,1H),3.98(d,J=6.5Hz,2H),3.09(dt,J=12.6,3.3 Hz,2H),2.64(td,J=12.4,2.4Hz,2H),2.06-2.00(m,2H),1.93-1.89(m,1H),1.88-1.82(m,4H),1.62(dt,J=1 3.0,3.6Hz,2H),1.58-1.53(m,1H),1.22(dddd,J=16.1,12.7,7.9,3.4Hz,2H),1.06(qt,J=12.3,6.4Hz,3H). 13 C-NMR (151 MHz, DMSO-d 6 )δ159.47,157.87,156.19,154.19,151.31,150.17,142.67,137.45,136.56,130.81,127.86,125.88,124. 03,121.46,106.00,100.52,74.05,59.48,44.93,36.87,33.31,29.12,25.92,24.95.HRMS(ESI,m / z)calcd for C 28 H 32 FN 7 O[M+H] +:502.2725found 502.2785.RetentionTime:7.55min,Purity:98.40%.

[0110] Example 7: Preparation of 2-(4-(4-((2-(cyclohexylmethoxy)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one Using 6b and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 3 as a yellow solid 77 mg, with a yield of 61.2%. mp: 240.1-241.3℃. 1 H-NMR(600MHz,DMSO)δ9.68(s,1H),8.66(dd,J=9.0,6.4Hz,1H),8.62(s,1H),8.48(s,1H),8.19(d d,J=14.7,8.3Hz,3H),7.10(dd,J=10.7,2.8Hz,1H),6.87(td,J=8.7,2.8Hz,1H),5.26(s,2H),3.9 8(d,J=6.5Hz,2H),3.48(t,J=5.1Hz,2H),3.43(t,J=5.1Hz,2H),2.79(t,J=5.0Hz,2H),2.72(t,J= 5.1Hz,2H),1.95-1.83(m,3H),1.70-1.57(m,3H),1.28-1.22(m,2H),1.07(pd,J=12.3,6.3Hz,3H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.91,159.41,157.82,156.15,154.22,151.11,150.03,142.75,137.64,136.21,131.73,130.85,125.16,123. 16,122.10,120.87,106.00,100.34,74.05,53.21,45.06,42.34,36.77,29.14,25.97,24.94.HRMS(ESI,m / z)calcd for C 29 H 33 FN 8 O 2 [M+H] + :545.2783found 545.2853.RetentionTime:4.79min,Purity:99.28%.

[0111] Example 8: Preparation of N-(4-fluoro-2-(oxetane-3-yloxy)phenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine

[0112] Step A: Preparation of 3-(5-fluoro-2-nitrophenoxy)oxetane (1c)

[0113]

[0114] 5-Fluoro-2-nitrophenol (1.00 g, 6.37 mmol), oxetan-3-ol (0.57 g, 7.64 mmol) and triphenylphosphine (3.34 g, 12.74 mmol) were placed in a 100 mL two-necked bottle, 30 mL of dry tetrahydrofuran was added to dissolve, and the mixture was cooled to 0°C. Diisopropyl azodicarboxylate (1.93 g, 9.56 mmol) was dissolved in 5 mL of dry tetrahydrofuran and slowly added to the reaction system. The mixture was reacted at room temperature under nitrogen protection. The reaction was complete after TLC monitoring. The reaction solution was evaporated to dryness, and the residue was purified by column chromatography (V petroleum ether: V ethyl acetate = 25:3) to obtain 1.1 g of a colorless oily product with a yield of 81.4%.

[0115] Using 5-fluoro-2-nitrophenol, tetrahydro-2H-pyran-4-ol, 2,2,2-trifluoroethane-1-ol, 3,3,3-trifluoro-1-propanol, (3S,6S)-hexahydrofuro[3,2-b]furan-3,6-diol and (3S,6S)-6-methoxyhexahydrofuro[3,2-b]furan-3-ol as raw materials, 1d-1f, 16b and 16c were obtained according to the preparation method of 1c.

[0116] Step B: Preparation of N-(4-fluoro-2-(oxetane-3-yloxy)phenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine (Example 8) Using 3c and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as raw materials, the product was obtained as a yellow solid of 135 mg according to the synthesis method of Example 1, with a yield of 71.6%. mp: 217.2-217.8℃. 1H-NMR(600MHz,DMSO)δ9.83(s,1H),8.69-8.59(m,3H),8.25(s,1H),8.22-8.16(m,2H) ,6.94(td,J=8.7,2.8Hz,1H),6.82(dd,J=10.3,2.8Hz,1H),5.49(p,J=5.3Hz,1H),5.05 (t,J=6.7Hz,2H),4.65(dd,J=7.5,4.7Hz,2H),4.25(dq,J=8.4,5.9Hz,1H),3.09-3.04 (m,2H),2.61(td,J=12.4,2.4Hz,2H),2.06-2.01(m,2H),1.82(qd,J=12.1,4.2Hz,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ159.25,157.66,156.17,154.18,151.24,147.75,142.63,137.32,136.56,130.75,128.20,12 6.26,124.33,122.36,107.17,100.81,76.74,71.35,59.70,45.07,33.54.HRMS(ESI,m / z)calcd for C 24 H 24 FN 7 O 2 [M+H] + :462.2048found462.2096.Retention Time:4.76min,Purity:92.19%

[0117] Example 9: Preparation of 2-(4-(4-((4-fluoro-2-(oxetane-3-yloxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one Using 7c and 1-Boc piperazine as raw materials, the target product was obtained as a yellow solid of 71 mg according to the synthesis method of Example 3, with a yield of 61.2%. mp: 202.1-202.7℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.87(s,1H),8.73-8.57(m,2H),8.49(s,1H),8.26(s,1H),8.23-8.17(m,2 H),6.95(td,J=8.7,2.7Hz,1H),6.81(dd,J=10.2,2.8Hz,1H),5.53-5.46(m,1 H),5.25(s,2H),5.05-5.00(m,2H),4.64(dd,J=7.5,4.8Hz,2H),3.47(t,J=5. 1Hz, 2H), 3.43 (t, J = 5.1Hz, 2H), 2.77 (t, J = 5.0Hz, 2H), 2.70 (t, J = 5.1Hz, 2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.90,159.20,157.60,156.15,154.27,151.10,147.57,142.63,137.64,136.70,131.81,130.80,125. 73,124.35,122.21,121.68,107.34100.63,76.69,71.31,53.14,45.51,45.10,42.46.HRMS(ESI,m / z)calcd for C 25 H 25 FN 8 O 3 [M+Na] + :527.1926found527.1990.Retention Time:3.66min,Purity:99.72%.

[0118] Example 10: Preparation of N-(4-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3d and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as raw materials, the product was obtained according to the synthesis method of Example 1 as a yellow solid of 143 mg, with a yield of 71.3%. mp: 186.5-186.9℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.76(s,1H),8.71(dd,J=9.0,6.4Hz,1H),8.62(s,1H),8.54(s,1H),8.25-8.19(m,2H),8.17(d,J=8.7Hz,1H),7. 26(dd,J=10.8,2.8Hz,1H),6.89(td,J=8.6,2.8Hz,1H),4.82(tt,J=8.6,4.1Hz,1H),4.28(tt,J=11.6,4.0Hz,1H), 3.89(dt,J=11.7,4.3Hz,2H), 3.51(ddd,J=12.0,9.5,2.7Hz,2H), 3.09(dt,J=12.8,3.2Hz,2H), 2.64(td,J=12.4,2 .4Hz,2H),2.16-2.10(m,2H),2.07-2.02(m,2H),1.85(qd,J=12.1,4.1Hz,2H),1.73(dtd,J=13.2,9.2,4.1Hz,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ159.24,157.65,155.95,154.21,151.27,147.76,142.68,137.40,136.64,130.84,127.51,125.86,1 24.96,121.59,121.17,106.76,101.83,73.22,64.59,59.44,44.86,33.21,31.86.HRMS(ESI,m / z)calcd for C 26 H 28 FN 7 O 2 [M+H] + :490.2361found 490.2421.Retention Time:5.08min,Purity:99.23%.

[0119] Example 11: Preparation of 2-(4-(4-((4-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one Using 7d and 1-Boc piperazine as raw materials, the target product was obtained as a yellow solid of 72 mg according to the synthesis method of Example 3, with a yield of 58.9%. mp: 49.9-51.8℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.80(s,1H),8.72(dd,J=9.0,6.4Hz,1H),8.64(s,1H),8.44(s,1H),8.23(s,1H),8.22-8.17(m,2H), 7.25(dd,J=10.7,2.8Hz,1H),6.90(td,J=8.7,2.8Hz,1H),5.24(s,2H),4.82(tt,J=8.5,4.0Hz,1H),3.8 7(dt,J=11.7,4.4Hz,2H),3.51(ddd,J=11.8,9.3,2.8Hz,2H),3.44(t,J=5.1Hz,2H),3.40(t,J=5.1Hz,2 H),2.74(t,J=5.0Hz,2H),2.67(t,J=5.1Hz,2H),2.14-2.07(m,2H),1.73(dtd,J=13.0,9.0,4.0Hz,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.86,159.20,157.61,155.94,154.27,151.13,147.72,142.67,137.64,136.75,131.67,130.88,125.79,1 25.02,122.17,121.05,106.65,101.90,73.19,64.52,53.14,45.60,45.20,42.60,31.74.HRMS(ESI,m / z)calcd forC 27 H 29 FN 8 O 3 [M+Na] + :555.2239found 555.2313.Retention Time:3.82min,Purity:99.81%.

[0120] Example 12: Preparation of N-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3e and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as raw materials, the product was obtained according to the synthesis method of Example 1 as a yellow solid of 142 mg, with a yield of 71.2%. mp: 225.7-226.9℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.67(d,J=3.3Hz,1H),8.70(dd,J=9.0,6.2Hz,1H),8.61(dd,J=24.3,2.2Hz,2H),8.2 7-8.21(m,2H),8.19(dd,J=8.7,2.6Hz,1H),7.31(dd,J=10.2,2.7Hz,1H),7.03(td,J=8 .7,4.3Hz,1H),5.02(q,J=8.7Hz,2H),4.31(tt,J=11.5,4.1Hz,1H),3.15(d,J=12.5Hz, 2H), 2.73 (t, J=12.1Hz, 2H), 2.09 (dd, J=12.6, 3.8Hz, 2H), 1.91 (qd, J=12.1, 4.0Hz, 2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ159.09,157.49,156.19,154.10,151.32,148.48,142.74,138.04,136.65,130.69,127.91 ,125.91,124.33,121.51,107.75,101.51,65.71,58.80,44.41,32.39.HRMS(ESI,m / z)calcd for C 23 H 21 F 4 N 7 O[M+H] + :488.1816found 488.1887.RetentionTime:4.33min,Purity:99.50%.

[0121] Example 13: Preparation of 2-(4-(4-((4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one Using 7e and 1-Boc piperazine as raw materials, the product was obtained as a yellow solid of 82 mg according to the synthesis method of Example 3, with a yield of 67.2%. mp: 146.9-147.4℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.70(s,1H),8.72(dd,J=9.0,6.3Hz,1H),8.64(s,1H),8.47(s,1H),8.24(s,1H),8.23-8.18(m,2H),7.30(dd,J=10.4,2.8Hz,1H),7.03(td,J =8.7,2.7Hz,1H),5.24(s,2H),5.01(q,J=8.7Hz,2H),3.52(t,J=5.1Hz,2H),3.47(t,J=5.1Hz,2H),2.84(t,J=5.0Hz,2H),2.76(t,J=5.2Hz,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.97,159.04,157.44,156.16,154.13,151.15,147.98,142.72,137.68,136.73,131.75,130.70, 125.80,124.34,122.13,121.86,108.12,101.64,65.72,53.10,44.65,41.73.HRMS(ESI,m / z)calcdfor C 24 H 22 F 4 N 8 O 2 [M+H] + :531.1875found531.1947.Retention Time:3.46min,Purity:99.72%.

[0122] Example 14: Preparation of N-(4-fluoro-2-(3,3,3-trifluoropropoxy)phenyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3f and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as raw materials, the product was obtained as a yellow solid of 158 mg according to the synthesis method of Example 1, with a yield of 77.1%. mp: 192.2-193.7℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.64(s,1H),8.65(dd,J=9.0,6.3Hz,1H),8.61(s,1H),8.59(s,1H),8.25(s,1H),8.22(d,J=8 .7Hz,1H),8.17(d,J=8.7Hz,1H),7.22(dd,J=10.6,2.8Hz,1H),6.94(td,J=8.6,2.7Hz,1H),4.44 (t,J=5.8Hz,2H),4.29(tt,J=11.6,4.1Hz,1H),3.10(dt,J=12.7,3.3Hz,2H),2.96(qt,J=11.3, 5.8Hz,2H),2.65(td,J=12.4,2.5Hz,2H),2.03(ddt,J=11.6,4.6,2.3Hz,2H),1.93-1.83(m,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ159.37,157.78,156.17,154.10,151.31,149.15,142.71,137.53,136.51,130.79,127.94,125.8 0,124.01,121.83,121.45,106.72,100.74,62.30,59.22,44.75,32.98,32.63.HRMS(ESI,m / z)calcd for C 24 H 23 F 4 N 7 O[M+H] + :502.1973found 502.2048.Retention Time:4.35min,Purity:96.64%.

[0123] Example 15: Preparation of 2-(4-(4-((4-fluoro-2-(3,3,3-trifluoropropoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one Using 7f and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 3 as a yellow solid of 83 mg, with a yield of 66.3%. mp: 216.0-217.8℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.66(s,1H),8.68(dd,J=9.0,6.3Hz,1H),8.62(s,1H),8.46(s,1H),8.24(s,1 H),8.19(q,J=8.7Hz,2H),7.21(dd,J=10.6,2.8Hz,1H),6.93(td,J=8.6,2.7Hz, 1H),5.24(s,2H),4.44(t,J=5.8Hz,2H),3.52(t,J=5.0Hz,2H),3.48(t,J=5.1Hz ,2H),2.94(qt,J=11.1,5.7Hz,2H),2.86(t,J=5.0Hz,2H),2.78(t,J=5.3Hz,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.99,159.34,157.75,156.18,154.17,151.14,149.17,142.74,137.75,136.67,131.75,130.83,125.7 8,124.07,122.15,121.60,106.23,100.60,62.34,53.06,44.92,44.54,41.61,32.64.HRMS(ESI,m / z)calcd for C 25 H 24 F 4 N 8 O 2 [M+Na] + :567.1851found 567.1922.Retention Time:3.51min,Purity:99.00%.

[0124] Example 16: Preparation of (4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)(piperazine-1-yl)methanone

[0125] Step A: Preparation of 1-(tert-butyl)4-(4-nitrophenyl)piperazine-1,4-dicarboxylate (8)

[0126]

[0127] 1-Boc piperazine (410 mg, 2.2 mmol) and triethylamine (303 mg, 3 mmol) were placed in a 50 mL eggplant-shaped bottle, 10 mL of dichloromethane was added to dissolve, 4-nitrophenyl methyl chlorate (400 mg, 2.0 mmol) was slowly added under stirring at room temperature, and the reaction was allowed to proceed 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 aqueous solution and saturated saline solution respectively, the organic phase was dried, and the product was evaporated to dryness to obtain 611 mg of a yellow oily substance, which was directly subjected to the next step of reaction without purification, and the yield was 87.1%.

[0128] Step B: Preparation of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate (9)

[0129]

[0130] Using 4-pyrazoleboronic acid pinacol ester and 8 as raw materials, the product was obtained according to the synthetic method of 4 as a light yellow oil (375 mg), which was directly used for the next step without purification, with a yield of 59.8%.

[0131] Step C: Preparation of (4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)(piperazin-1-yl)methanone (Example 16) Using 3a and 9 as raw materials, the product was obtained according to the method of Example 1 as a yellow solid (139 mg) with a yield of 71.2%. mp: 169.5-170.4°C. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.72(s,1H),8.94(s,1H),8.65(dd,J=8.9,6.3Hz,1H),8.57(s,1H),8.40(s,1H),8.27(d,J=8.6Hz,1H),8.13(d,J=8.6Hz,1H),7.07(d d,J=10.8,2.8Hz,1H),6.81(td,J=8.6,2.7Hz,1H),4.76(hept,J=6.3Hz,1H),3.67(s,4H),2.80(t,J=4.9Hz,4H),1.39(d,J=5.9Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6)δ159.31,157.72,155.91,154.75,150.17,149.60,148.30,142.97,140.02,136.82,131.35,130.89 ,126.10,124.82,123.24,120.82,106.22,101.61,71.65,47.42,45.56,21.95.HRMS(ESI,m / z)calcd for C 24 H 25 FN 8 O 2 [M+H] + :477.2157found477.2212.Retention Time:5.09min,Purity:98.22%.

[0132] Example 17: Preparation of (1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrrol-3-yl)(piperazine-1-yl)methanone

[0133] Step A: Preparation of tert-butyl 4-(1H-pyrrole-3-carbonyl)piperazine-1-carboxylate (10a)

[0134]

[0135] 1H-pyrrole-3-carboxylic acid (200 mg, 1.80 mmol), 1-Boc piperazine (402 mg, 2.16 mmol), HOBt (292 mg, 2.16 mmol), EDCI (415 mg, 2.16 mmol) and Et 3 N (273 mg, 2.70 mmol) was placed in a 50 mL eggplant-shaped bottle, 10 mL DMF was added to dissolve, and the reaction was carried out at room temperature. TLC monitored the reaction to be complete, 100 mL of water was poured into the reaction solution to dilute, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, extracted 3 times with saturated brine, dried, and evaporated to obtain a crude product as a light yellow oil, which was directly used for the next step without purification.

[0136] Intermediates 10b and 10c were prepared using 1H-pyrrole-3-carboxylic acid, (R)-piperidin-3-ylcarbamic acid tert-butyl ester and 1,4-diazepane-1-carboxylic acid tert-butyl ester as raw materials according to the synthetic method of 10a.

[0137] Step B: Preparation of (1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrrol-3-yl)(piperazin-1-yl)methanone (Example 17)

[0138]

[0139] 3a (200 mg, 0.60 mmol), 10a (184 mg, 0.66 mmol), palladium acetate (7 mg, 0.03 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos, 35 mg, 0.06 mmol) and cesium carbonate (293 mg, 0.90 mmol) were placed in a 50 mL two-necked bottle, 15 mL of dry 1,4-dioxane was added to dissolve, and 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 to obtain a yellow solid. The yellow solid was placed in a 100 mL eggplant-shaped bottle and 20 mL of dichloromethane was added to dissolve. 5 mL of trifluoroacetic acid was added under stirring at room temperature and reacted at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, the residue was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was purified by V 二氯甲烷 :V 甲醇 =10:1 mixed solution was extracted 4 times, the organic phases were combined, dried, evaporated to dryness to obtain a crude product, and purified by column chromatography (V 二氯甲烷 :V 甲醇 =20:1) The product was obtained as a yellow solid (72 mg), with a two-step yield of 23.0%. mp: 183.6-183.7°C. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.68(s,1H),8.66(s,1H),8.58(dd,J=8.9,6.4Hz,1H),8.41-8.34(m,2H) ,8.22(t,J=2.0Hz,1H),7.96(t,J=2.7Hz,1H),7.14(dd,J=10.9,2.8Hz,1H), 6.88(td,J=8.6,2.7Hz,1H),6.58(dd,J=3.2,1.7Hz,1H),4.81(hept,J=6.0 Hz, 1H), 3.61 (t, J = 4.8Hz, 4H), 2.77 (t, J = 5.0Hz, 4H), 1.38 (d, J = 6.0Hz, 6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.42,159.95,157.98,155.90,154.60,149.26,147.93,142.68,139.64,129.40,126.15,122.10, 121.54,120.28,118.79,112.34,106.28,100.23,71.58,54.92,45.48,21.82.HRMS(ESI,m / z)calcdfor C25 H 26 FN 7 O 2 [M+H] + :476.2205found476.2280.Retention Time:3.69min,Purity:99.60%.

[0140] Example 18: Preparation of (R)-(3-aminopiperidin-1-yl)(1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrrol-3-yl)methanone Using 3a and 10b as raw materials, the product was a yellow solid of 73 mg in the preparation method of Example 17, with a yield of 22.6%. mp: 150.3-151.0°C. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.66(s,1H),8.65(s,1H),8.62-8.56(m,1H),8.36(q,J=9.2Hz,2H),8.20(s,1H),7.95(t,J=2.9Hz,1 H),7.13(dd,J=10.9,2.9Hz,1H),6.87(td,J=8.6,2.8Hz,1H),6.57(d,J=3.2Hz,1H),4.81(hept,J=6.1 Hz,1H),4.17(d,J=97.8Hz,2H),2.86(s,2H),2.72(dq,J=10.5,6.1,5.0Hz,1H),1.93-1.88(m,1H),1.7 1(dt,J=13.4,3.9Hz,1H),1.48-1.41(m,1H),1.37(d,J=6.0Hz,7H),1.30(td,J=15.1,14.2,7.6Hz,1H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.53,159.52,157.92,155.83,154.56,148.77,147.93,142.64,139.63,129.40,124.68,122.43,12 1.38,120.15,118.72,112.32,106.26,101.56,71.58,48.54,32.99,26.33,21.80.HRMS(ESI,m / z)calcd for C 26 H 28 FN 7 O 2 [M+H] +:490.2361found 490.2362.RetentionTime:4.22min,Purity:99.58%.

[0141] Example 19: Preparation of (1,4-diazepan-1-yl)(1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrrol-3-yl)methanone Using 3a and 10c as raw materials, the product was a yellow solid of 71 mg according to the preparation method of Example 17, with a yield of 22.0%. mp: 172.4-173.4℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.61(s,1H),8.61(s,1H),8.57(dd,J=8.9,6.4Hz,1H),8.35(d,J=8.9Hz,1H),8.31(d, J=9.1Hz,1H),8.19(s,1H),7.91(t,J=2.7Hz,1H),7.10(dd,J=10.8,2.8Hz,1H),6.84(td ,J=8.5,2.7Hz,1H),6.59(s,1H),4.78(hept,J=6.0Hz,1H),3.71(d,J=26.3Hz,2H),3.62 (s,2H),2.93-2.90(m,2H),2.83-2.80(m,2H),1.84-1.74(m,2H),1.37(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ165.45,159.55,157.96,155.86,154.58,148.83,147.94,142.64,139.62,129.41,124.67,121.53,1 20.22,118.80,106.27,101.57,71.61,51.45,47.75,44.25,30.26,28.83,21.81.HRMS(ESI,m / z)calcd for C 26 H 28 FN 7 O 2 [M+H] + :490.2361found 490.2352.Retention Time:4.74min,Purity:98.97%.

[0142] Example 20: Preparation of (1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)(piperazine-1-yl)methanone

[0143] Step A: Preparation of methyl 1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazole-4-carboxylate (11)

[0144]

[0145] 2 (200 mg, 0.60 mmol), 1H-pyrazole-4-carboxylic acid methyl ester (83 mg, 0.66 mmol), palladium acetate (7 mg, 0.03 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos, 35 mg, 0.06 mmol) and cesium carbonate (293 mg, 0.90 mmol) were placed in a 50 mL two-necked bottle, 15 mL of dry 1,4-dioxane was added to dissolve, and 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 to obtain a product as a yellow solid of 156 mg, with a yield of 61.7%.

[0146] Step B: Preparation of (1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)(piperazin-1-yl)methanone (Example 20) Using 11 and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 3 as a yellow solid of 70 mg, with a yield of 64.2%. mp: 216.2-216.5℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.71(s,1H),9.17(s,1H),8.59(s,1H),8.41(d,J=9.0Hz,1H),8.37(d,J=8.9Hz,1H),8.26(dd,J=8.9,6.4Hz,1H),8.13(s,1H),7.10(dd,J= 10.9, 2.8Hz, 1H), 6.84 (td, J = 8.6, 2.8Hz, 1H), 4.74 (hept, J = 6.1Hz, 1H), 3.59 (t, J = 4.9Hz, 4H), 2.75 (t, J = 4.9Hz, 4H), 1.32 (d, J = 6.0Hz, 6H). 13 C-NMR (151 MHz, DMSO-d 6)δ161.84,160.30,158.70,156.63,155.17,150.38,147.90,143.48,142.43,139.86,129.20,128.68 ,124.19,123.77,120.04,118.58,106.37,101.25,71.38,48.14,42.50,21.80.HRMS(ESI,m / z)calcd forC 24 H 25 FN 8 O 2 [M+Na] + :499.1977found 499.1989.Retention Time:4.27min,Purity:99.76%.

[0147] Example 21: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-amine

[0148] Step A: Preparation of tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (12a)

[0149]

[0150] 2-Chloropyrimidine-5-boronic acid pinacol ester (500 mg, 2.08 mmol), 1-Boc piperazine (428 mg, 2.29 mmol) and triethylamine (315 mg, 3.12 mmol) were placed in a 50 mL eggplant-shaped bottle, 15 mL of anhydrous ethanol was added, and the temperature was raised to reflux. After the reaction was completed by TLC monitoring, the product was directly filtered to obtain 578 mg of a white solid, which was directly subjected to the next step of reaction without purification, and the yield was 71.2%.

[0151] 12b and 12c were prepared using 2-chloropyrimidine-5-boronic acid pinacol ester, (R)-piperidin-3-ylcarbamic acid tert-butyl ester and 1,4-diazepane-1-carboxylic acid tert-butyl ester as raw materials according to the synthetic method of 12a.

[0152] Step B: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-(2-(piperazin-1-yl)pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-4-amine (Example 21) 3a and 12a were used as raw materials and the product was obtained according to the synthesis method of Example 1 as a yellow solid of 124 mg with a yield of 65.8%. mp: 197.9-198.4℃. 1 H-NMR (600 MHz, DMSO-d6 )δ9.92(s,1H),9.27(s,2H),8.73(dd,J=9.0,6.3Hz,1H),8.65(s,1H),8.42(d,J=8.8Hz,1H),8.21(d,J=8.8Hz,1H),7.14(dd,J=10 .7,2.8Hz,1H),6.87(td,J=8.7,2.8Hz,1H),4.90-4.76(m,1H),3.84(t,J=5.1Hz,4H),2.87(t,J=5.2Hz,4H),1.41(d,J=5.9Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ161.11,159.17,157.58,156.87,155.91,154.68,151.94,148.07,142.88,136.93,130.26,12 6.52,124.31,120.44,119.13,106.28,101.68,71.61,44.48,43.97,22.19.HRMS(ESI,m / z)calcd for C 24 H 25 FN 8 O[M+H] + :461.2208found 461.2268.RetentionTime:7.39min,Purity:99.32%.

[0153] Example 22: Preparation of (R)-6-(2-(3-aminopiperidin-1-yl)pyrimidin-5-yl)-N-(4-fluoro-2-isopropoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine Using 3a and 12b as raw materials, the target product was obtained according to the synthesis method of Example 1 as a yellow solid (152 mg) with a yield of 78.1%. mp: 179.3-181.0℃. 1 H NMR (600 MHz, DMSO-d 6)δ9.81(s,1H),9.17(s,2H),8.69(dd,J=9.0,6.4Hz,1H),8.59(s,1H),8.33(d,J=8.8Hz,1H),8.12(d,J=8.8H z,1H),7.08(dd,J=10.8,2.8Hz,1H),6.82(td,J=8.7,2.8Hz,1H),4.78(hept,J=6.1Hz,1H),4.63(dd,J=12.7, 4.0Hz,1H),4.48(dt,J=13.2,4.1Hz,1H),3.10-3.04(m,1H),2.93(dd,J=12.6,9.6Hz,1H),2.86-2.83(m,1H), 1.98-1.93(m,1H),1.78(dq,J=12.8,3.6Hz,1H),1.51-1.44(m,1H),1.40(dd,J=6.0,2.1Hz,6H),1.20(s,1H). 13 C-NMR (151 MHz, DMSO-d 6 )δ161.06,159.07,157.48,156.75,155.74,154.55,151.43,147.96,142.76,136.77,130.75,124.88,124. 12,120.16,118.91,106.32,101.52,71.56,49.92,47.31,43.43,32.15,23.15,21.78.HRMS(ESI,m / z)calcd for C 25 H 27 FN 8 O[M+H] + :475.2365found 483.2371.Retention Time:6.30min,Purity:99.86%.

[0154] Example 23: Preparation of 6-(2-(1,4-diazepan-1-yl)pyrimidin-5-yl)-N-(4-fluoro-2-isopropoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine Using 3a and 12c as raw materials, the product was obtained according to the synthesis method of Example 1 as a yellow solid (146 mg) with a yield of 74.9%. mp: 238.5-239.5℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.93(s,1H),9.29(s,2H),8.71(dd,J=8.9,6.4Hz,1H),8.65(s,1H),8.43(d,J=8 .7Hz,1H),8.23(d,J=8.7Hz,1H),7.14(dd,J=10.9,2.7Hz,1H),6.87(td,J=8.7,2. 8Hz,1H),4.83(hept,J=6.1Hz,1H),4.08-4.03(m,2H),3.93(t,J=6.2Hz,2H),3.28 (t,J=5.4Hz,2H),3.19-3.15(m,2H),2.06(p,J=5.8Hz,2H),1.41(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ160.93,159.21,157.80,155.96,154.77,151.99,148.19,142.90,136.98,130.90,124.92,124.3 7,120.49,119.63,116.36,106.46,101.54,71.62,45.22,43.39,24.90,21.77.LC-MS:475.34[M+H] + .Retention Time:7.97min,Purity:98.17%.

[0155] Example 24: Preparation of 3-isopropoxy-4-((6-(3-(piperazine-1-carbonyl)-1H-pyrrol-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)benzonitrile

[0156] Step A: Preparation of 3-isopropoxy-4-nitrobenzonitrile (13)

[0157]

[0158] 3-Fluoro-4-nitrobenzonitrile (300 mg, 1.81 mmol) and isopropanol (130 mg, 2.17 mmol) were placed in a 25 mL eggplant-shaped bottle, 7 mL of tetrahydrofuran was added to dissolve, 1 mL of 2M sodium bis(trimethylsilyl)amide tetrahydrofuran solution was added at 0°C, and the mixture was transferred to room temperature for reaction. TLC monitored the reaction to be complete, water was added to the reaction solution to quench, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, extracted once with saturated brine, dried, and evaporated to obtain a yellow oily product, which was directly subjected to the next step of reaction without purification.

[0159] Using 2-fluoro-1-nitro-4-trifluoromethylbenzene as raw material, 22 was prepared according to the synthetic method of 13.

[0160] Step B: Preparation of 4-amino-3-isopropoxybenzonitrile (14)

[0161]

[0162] 13 (373 mg, 1.81 mmol) and stannous chloride dihydrate (1636 mg, 7.24 mmol) were placed in a 50 mL eggplant-shaped bottle, 20 mL of anhydrous ethanol was added to dissolve, and the reaction was refluxed. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, the residue was dissolved in ethyl acetate, the pH was adjusted to about 8 with saturated sodium bicarbonate aqueous solution, and suction filtered. The aqueous phase and the organic phase in the filtrate were separated, the aqueous phase was extracted twice 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 purified by column chromatography (V 石油醚 :V 乙酸乙酯 =25:3) to obtain the product as a yellow oil (236 mg), with a yield of 74.1%.

[0163] Using 22 as starting material, 23 was prepared according to the synthetic method of 14.

[0164] Step C: Preparation of 4-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-isopropoxybenzonitrile (15)

[0165] 4,6-Dichloropyrido[3,2-d]pyrimidine (200 mg, 1.0 mmol) and 14 (150 mg, 1.1 mmol) were placed in a 50 mL eggplant-shaped bottle, 15 mL of isopropanol was added to dissolve, and the temperature was raised to 50°C. Three drops of trifluoroacetic acid were added under stirring, and the reaction was carried out at 50°C. The reaction was complete when monitored by TLC, and the product was directly filtered to obtain 297 mg of a yellow solid with a yield of 87.6%.

[0166] 24 was prepared from 23 according to the synthetic method of 15.

[0167] Step D: Preparation of 3-isopropoxy-4-((6-(3-(piperazine-1-carbonyl)-1H-pyrrol-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)benzonitrile (Example 24) Using 15 and 10a as raw materials, the product was obtained according to the synthesis method of Example 17 as a yellow solid of 74 mg, with a yield of 67.2%. mp: 246.9-247.6℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.87(s,1H),8.96(d,J=8.4Hz,1H),8.78(s,1H),8.42(s,2H),8.20(s,1H),7.92(s,1H),7.64(s,1H),7.52(d,J=8.5Hz ,1H),6.64(d,J=3.2Hz,1H),4.92(p,J=6.1Hz,1H),3.74(d,J=16.0Hz,4H),3.00(t,J=5.2Hz,4H),1.43(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ164.89,156.22,154.23,148.18,146.29,142.95,139.92,132.69,129.36,125.81,121.71,120.6 6,119.45,119.11,118.82,115.72112.54,104.83,71.96,54.93,44.03,21.81.HRMS(ESI,m / z)calcd for C 26 H 26 N 8 O 2 [M+H] + :483.2251found 483.2348.Retention Time:4.09min,Purity:94.24%.

[0168] Example 25: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine

[0169] 3a (200 mg, 0.60 mmol) and 1-Boc piperazine (224 mg, 1.20 mmol) were placed in a 25 mL eggplant-shaped bottle, 5 mL of DMF was added to dissolve, and the temperature was raised to reflux for reaction. After TLC monitoring of the reaction was complete, the reaction solution was poured into 50 mL of ice water, the aqueous layer was extracted 3 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, which was purified by column chromatography (V 二氯甲烷 :V 甲醇 =50:1) to obtain the product as a yellow solid. Place it in a 100 mL eggplant-shaped bottle, add 16 mL of dichloromethane to dissolve, add 4 mL of trifluoroacetic acid under stirring at room temperature, and react at room temperature after the addition. TLC monitors the reaction to be complete, evaporate the reaction solution, adjust the pH of the residue to about 8 with saturated sodium bicarbonate aqueous solution, and the aqueous phase is washed with V 二氯甲烷 :V 甲醇=10:1 for 3 times, the organic phases were combined, dried and evaporated to obtain a crude product as a yellow oil, which was purified by column chromatography to obtain a yellow solid (V 二氯甲烷 :V 甲醇 =10:1) 109 mg, two-step yield 47.4%. mp: 150.7-152.2℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.45(s,1H),8.87(dd,J=9.0,6.4Hz,1H),8.47(s,1H),7.92(d,J=9.4Hz,1H),7.56(d,J=9.4Hz,1H),7.11(dd,J=10.8,2.9Hz, 1H), 6.84 (td, J = 8.7, 2.8Hz, 1H), 4.83 (hept, J = 6.0Hz, 1H), 3.69 (t, J = 5.1Hz, 4H), 2.86 (t, J = 5.1Hz, 4H), 1.36 (d, J = 6.0Hz, 6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.68,157.10,155.87,154.35,151.60,147.42,139.07,137.78,129.16,125.25, 119.55,116.76,105.76,101.27,71.37,45.45,42.31,21.75.HRMS(ESI,m / z)calcdfor C 20 H 23 FN 6 O[M+H] + :383.1990found383.2041.Retention Time:4.66min,Purity:95.86%.

[0170] Example 26: Preparation of N-(2-(cyclopentyloxy)-4-fluorophenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 18a and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 111 mg, with a yield of 45.2%. mp: 137.5-139.2℃. 1 H NMR (600 MHz, DMSO-d 6)δ9.29(s,1H),8.86(dd,J=9.0,6.4Hz,1H),8.47(s,1H),7.93(d,J=9.3Hz,1H),7. 57(d,J=9.3Hz,1H),7.01(dd,J=10.7,2.8Hz,1H),6.83(td,J=8.7,2.8Hz,1H),5.0 2(tt,J=5.9,2.6Hz,1H),3.73(t,J=5.1Hz,4H),2.95(t,J=5.2Hz,4H),2.04(dq,J= 13.1,6.8Hz,2H),1.79(d,J=5.8Hz,2H),1.75-1.68(m,2H),1.63(p,J=5.6Hz,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.44,157.99,157.79,156.86,156.42,154.24,150.97,147.41,138.70,137.40,129.40,125.12,11 9.29,118.28,116.44,116.29,105.81,100.91,80.33,44.62,44.53,32.38,23.96.HRMS(ESI,m / z)calcd for C 22 H 25 FN 6 O[M+H] + :409.2147found 409.2191.Retention Time:5.36min,Purity:96.24%.

[0171] Example 27: Preparation of N-(4-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3d and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid (109 mg) with a yield of 42.8%. mp: 198.1-199.7°C. 1 H-NMR (600 MHz, DMSO-d 6)δ9.39(s,1H),8.84(dd,J=9.0,6.4Hz,1H),8.48(s,1H),7.93(d,J=9.3Hz,1H),7.57(d,J= 9.3Hz, 1H), 7.24 (dd, J=10.7, 2.8Hz, 1H), 6.87 (td, J=8.7, 2.8Hz, 1H), 4.79 (tt, J=9.2, 4.3 Hz,1H),3.91(dt,J=11.8,4.0Hz,2H),3.71(t,J=5.1Hz,4H),3.50(td,J=11.1,2.4Hz,2H), 2.90(t,J=5.1Hz,4H),2.13-2.07(m,2H),1.90(s,1H),1.61(ddt,J=13.9,10.1,4.3Hz,2H). 13 C-NMR (151 MHz, DMSO-d 6 )δ156.51,154.23,150.91,146.66,138.61,137.35,129.44,125.58,119.40,118.36,116. 37,106.58,101.72,73.54,64.89,59.77,44.58,32.09,20.77,14.09.HRMS(ESI,m / z)calcd for C 22 H 25 FN 6 O 2 [M+H] + :425.2096found425.2150.Retention Time:4.35min,Purity:99.38%.

[0172] Example 28: Preparation of N-(4-fluoro-2-(3,3,3-trifluoropropoxy)phenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3f and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 108 mg, with a yield of 41.3%. mp: 220.8-222.0℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.24(s,1H),8.83(dd,J=9.0,6.3Hz,1H),8.47(s,1H),7.92(d,J=9.3Hz,1H),7.57(d,J=9.4Hz,1H),7.18(dd,J=10. 6,2.5Hz,1H),6.90(td,J=8.8,2.6Hz,1H),4.42(t,J=5.8Hz,2H),3.69(t,J=4.8Hz,4H),2.89(dt,J=14.5,5.4Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ156.98,154.79,151.26,148.43,139.15,137.76,128.03,126.19,125.06,12 0.21,116.90,107.10,100.97,62.72,45.43,33.33,33.14.HRMS(ESI,m / z)calcd for C 20 H 20 F 4 N 6 O[M+H] + :437.1707found437.1765.Retention Time:3.84min,Purity:99.27%.

[0173] Example 29: Preparation of (3S,6S)-6-(5-fluoro-2-((6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenoxy)hexahydrofuro[3,2-b]furan-3-ol Using 18b and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 105 mg, with a yield of 62.1%. mp: 68.8-70.2℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.41(s,1H),8.85(dd,J=9.0,6.3Hz,1H),8.50(s,1H),7.97(d,J=9.3Hz,1H),7.60(d,J=9.4Hz,1 H),7.22(dd,J=10.6,2.8Hz,1H),6.87(td,J=8.7,2.8Hz,1H),5.12(q,J=5.7Hz,1H),5.03(s,1H),4 .86(t,J=5.0Hz,1H),4.38(t,J=4.8Hz,1H),4.13(dt,J=8.6,5.8Hz,2H),3.93(dd,J=9.4,5.6Hz,1H ), 3.80 (t, J = 5.2Hz, 4H), 3.73 (dd, J = 8.0, 6.7Hz, 1H), 3.37 (t, J = 8.4Hz, 1H), 3.06 (d, J = 6.1Hz, 4H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.47,156.88,156.30,154.25,151.09,148.00,138.73,137.46,129.35,124.60,119.2 7,116.51,106.53,101.20,82.16,79.58,78.27,71.59,70.99,44.17.HRMS(ESI,m / z)calcd for C 23 H 25 FN 6 O 4 [M+H] + :469.1994found469.2047.Retention Time:3.61min,Purity:99.86%.

[0174] Example 30: Preparation of N-(4-fluoro-2-(((3S,6S)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl)oxy)phenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 18c and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 111 mg, with a yield of 63.9%. mp: 68.1-69.9℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.43(s,1H),8.86(dd,J=9.0,6.3Hz,1H),8.50(s,1H),7.96(d,J=9.3Hz,1H),7.60(d,J=9.4Hz,1H),7 .21(dd,J=10.7,2.8Hz,1H),6.86(td,J=8.7,2.8Hz,1H),5.14(q,J=5.4Hz,1H),4.93(t,J=5.2Hz,1H),4. 58(t,J=4.9Hz,1H),4.17-4.05(m,1H),3.97(dd,J=9.8,4.7Hz,1H),3.89(ddd,J=8.7,6.7,4.9Hz,1H),3 .82(dd,J=8.0,6.7Hz,1H),3.80-3.74(m,4H),3.43(t,J=8.4Hz,1H),3.36(s,3H),3.05(q,J=5.3Hz,4H). 13 C-NMR (151 MHz, DMSO-d 6 )δ156.32,154.22,151.09,147.94,138.70,137.45,129.35,124.55,119.09,118.31,116.50, 106.47,101.06,80.27,79.92,77.99,71.56,69.86,57.37,44.13,43.94.HRMS(ESI,m / z)calcd for C 24 H 27 FN 6 O 4 [M+H] + :483.2151found483.2206.Retention Time:3.82min,Purity:97.62%.

[0175] Using 1-bromo-5-fluoro-2-nitrobenzene, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials, intermediates 19a and 19b were obtained according to the synthetic method of 6a.

[0176] Using 19a and 19b as raw materials, 20a and 20b were prepared according to the synthetic method of 2a.

[0177] 21a-21b were prepared using 4,6-dichloropyrido[3,2-d]pyrimidine and 19a and 19b as raw materials according to the synthetic method of 15.

[0178] Example 31: Preparation of N-(4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 21a and 1-Boc piperazine as raw materials, the product was obtained according to the synthetic method of Example 25 as a yellow solid (63 mg) with a yield of 75.6%. mp: 164.4-164.6℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.29(s,1H),8.43(dd,J=9.0,5.6Hz,1H),8.36(s,1H),8.09(s,1H),7.90(d,J=9.4Hz,1H),7.81(s,1H),7.53(d,J=9.4H z,1H),7.30(dd,J=9.8,3.1Hz,1H),7.21(td,J=8.6,3.1Hz,1H),3.86(s,3H),3.58(t,J=5.1Hz,4H),2.86(t,J=5.1Hz,4H). 13 C-NMR (151 MHz, DMSO-d 6 )δ159.32,157.73,156.46,155.33,150.99,138.76,138.00,137.15,132.01,130.23,129.42 ,127.72,124.76,117.24,116.28,115.60,113.67,44.98,38.74,26.34.HRMS(ESI,m / z)calcd for C 21 H 21 FN 8 [M+H] + :405.1946found 405.1973.Retention Time:6.69min,Purity:99.80%.

[0179] Example 32: Preparation of N-(2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-fluorophenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 21b and 1-Boc piperazine as raw materials, the product was obtained according to the synthetic method of Example 25 as a yellow solid (66 mg) with a yield of 76.2%. mp: 175.1-175.3℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.09(s,1H),8.94(dd,J=9.2,5.5Hz,1H),8.47(s,1H),7.90(d,J=9.3Hz,1H),7.61(s,1H),7.52(d,J=9.4Hz,1H),7.28( td,J=8.7,3.1Hz,1H),7.08(dd,J=9.2,3.1Hz,1H),3.83(s,3H),3.46(t,J=5.1Hz,4H),2.88(t,J=5.1Hz,4H),2.16(s,3H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.18,156.59,156.31,154.35,150.85,138.62,137.36,137.12,133.50,129.26,12 5.76,121.04,117.24,116.45,114.35,114.21,44.66,36.54,9.51.HRMS(ESI,m / z)calcd for C 22 H 23 FN 8 [M+H] + :419.2102found 419.2137.Retention Time:7.64min,Purity:98.93%.

[0180] Example 33: Preparation of 3-isopropoxy-4-((6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)benzonitrile Using 15 and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 104 mg, with a yield of 74.5%. mp: 232.6-232.9℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.72(s,1H),9.05(d,J=8.4Hz,1H),8.55(s,1H),7.94(d,J=9.3Hz,1H),7.62-7.57(m,2H),7.49(dd,J =8.4,1.7Hz,1H),4.98-4.87(m,1H),3.69(t,J=5.0Hz,4H),2.85(t,J=5.0Hz,4H),1.37(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6)δ156.56,153.28,150.43,145.62,139.05,137.29,133.41,129.52,125.89,119.38,11 8.06,116.92,115.37,103.59,71.54,54.92,45.46,45.24,21.67.HRMS(ESI,m / z)calcd for C 21 H 23 N 7 O[M+H] + :390.2037found390.2071.Retention Time:5.09min,Purity:98.22%.Retention Time:7.34min,Purity:99.67%.

[0181] Example 34: Preparation of N-(2-isopropoxy-4-(trifluoromethyl)phenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 24 and 1-Boc piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 101 mg, with a yield of 64.8%. mp: 188.2-189.9℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.71(s,1H),9.08(d,J=8.4Hz,1H),8.56(s,1H),7.95(d,J=9.4Hz,1H),7.60(d,J=9.4Hz,1H),7.43-7. 37(m,2H),4.96(hept,J=6.0Hz,1H),3.70(t,J=5.1Hz,4H),2.85(t,J=5.1Hz,4H),1.38(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ156.59,153.72,150.96,145.83,138.91,137.31,132.56,129.52,125.30,123.5 0,122.10,117.92,116.80,71.50,48.59,45.56,45.30,21.68.HRMS(ESI,m / z)calcd for C 21 H 23 F 3 N 6 O[M+H] +:433.1958found433.1987.Retention Time:8.23min,Purity:98.98%.

[0182] Example 35: Preparation of (3-isopropoxy-4-((6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0183] Step A: Preparation of 4-bromo-2-isopropoxy-1-nitrobenzene (25)

[0184]

[0185] Using 5-bromo-2-nitrophenol and 2-iodopropane as raw materials, the product was obtained according to the synthetic method of 1 as a light yellow oil (217 mg), with a yield of 60.9%.

[0186] Step B: Preparation of (3-isopropoxy-4-nitrophenyl)dimethylphosphine oxide (26)

[0187]

[0188] 25 (217 mg, 0.84 mmol), dimethylphosphine oxide (78 mg, 1.01 mmol), palladium acetate (9 mg, 0.04 mmol), Xantphos (49 mg, 0.08 mmol) and cesium carbonate (411 mg, 1.26 mmol) were placed in a 50 mL two-necked bottle, and dry 1,4-dioxane was added to dissolve and refluxed for reaction. The reaction was complete after TLC monitoring, and the reaction solution was evaporated to dryness. The residue was purified by column chromatography (V 二氯甲烷 :V 甲醇 =250:1) The purified product was 138 mg of a light yellow oil with a yield of 64.3%.

[0189] Step C: Preparation of (4-amino-3-isopropoxyphenyl)dimethylphosphine oxide (27)

[0190]

[0191] Using 26 as the starting material, the product was obtained according to the synthetic method of 2a as a yellow oil (72 mg) with a yield of 58.9%.

[0192] Step D: Preparation of (3-isopropoxy-4-((6-(piperazin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (Example 35)

[0193]

[0194] Using 4,6-dichloropyrido[3,2-d]pyrimidine, 27 and 1-Boc piperazine as raw materials, the product was obtained as a yellow solid (79 mg) according to the synthesis method of Example 34, with a yield of 78.6%. mp: 83.5-83.7℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.69(s,1H),9.02(dd,J=8.2,3.0Hz,1H),8.55(s,1H),7.96(d,J=9.4Hz,1H),7.60(d,J=9.3Hz,1H),7.46-7.39(m,2 H), 4.92 (p, J = 6.0Hz, 1H), 3.73 (t, J = 5.1Hz, 4H), 2.90 (t, J = 5.1Hz, 4H), 1.66 (d, J = 13.2Hz, 6H), 1.39 (d, J = 6.0Hz, 6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ160.83,156.52,154.18,150.79,145.70,145.60,138.87,137.38,133.19,131.58,129.54,129.43,1 28.77,122.63,117.87,116.72,113.52,71.11,45.15,45.00,21.81,18.18,17.71.HRMS(ESI,m / z)calcd for C 22 H 29 N 6 O 2 P[M+H] + :441.2162found 441.2211.RetentionTime:6.21min,Purity:97.77%.

[0195] Example 36: Preparation of (S)-N-(4-fluoro-2-isopropoxyphenyl)-6-(3-methylpiperazin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3a and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 102 mg, with a yield of 71.2%. mp: 156.1-157.3℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.36(s,1H),8.84(dd,J=9.0,6.4Hz,1H),8.48(s,1H),7.95(d,J=9.3Hz,1H),7.62(d,J=9.4Hz,1H ),7.12(dd,J=10.8,2.8Hz,1H),6.85(td,J=8.7,2.8Hz,1H),4.83(hept,J=6.0Hz,1H),4.48(d,J=12 .9Hz,1H),4.38(d,J=12.9Hz,1H),3.14(dt,J=12.1,2.7Hz,1H),3.12-3.06(m,1H),2.97(t,J=6.6Hz ,1H),2.94-2.87(m,1H),2.80(dd,J=12.9,10.4Hz,1H),1.37(t,J=5.8Hz,6H),1.17(d,J=6.3Hz,3H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.50,156.91,156.45,154.15,150.78,147.16,138.54,137.25,129.50,125.52,119.20,1 16.56,106.15,101.30,71.43,51.81,50.25,44.98,44.74,21.86,19.32.HRMS(ESI,m / z)calcd for C 21 H 25 FN 6 O[M+H] + :397.2147found 397.2191.Retention Time:4.49min,Purity:92.96%.

[0196] Example 37: Preparation of 6-(4-amino-4-methylpiperidin-1-yl)-N-(4-fluoro-2-isopropoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine Using 3a and tert-butyl (4-methylpiperidin-4-yl)carbamate as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid (110 mg) with a yield of 74.3%. mp: 195.9-197.5℃. 1H-NMR (600MHz, DMSO) δ9.43(s,1H),8.89(dd,J=9.0,6.4Hz,1H),8.47(s,1H),7.91(d,J=9.3Hz,1H),7.60(d,J=9.4Hz,1H),7.13(dd,J=10.7,2.8H z,1H),6.85(td,J=8.7,2.7Hz,1H),4.84(h,J=6.0Hz,1H),3.84(tq,J=13 .7, 6.7Hz, 4H), 1.59 (t, J=6.0Hz, 4H), 1.36 (d, J=6.0Hz, 6H), 1.20 (s, 3H). 13 C-NMR (151MHz, DMSO) δ158.47,156.89,156.13,154.05,150.76,147.10,138.32,137.37,129.57,125 .56,119.00,116.52,106.32,101.46,71.34,48.64,41.03,37.30,27.89,21.79.HRMS(ESI,m / z)calcd for C 22 H 27 FN 6 O[M+H] + :411.2303found411.2339.Retention Time:4.75min,Purity:99.23%.

[0197] Example 38: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-(2,7-diazaspiro[3.5]nonane-7-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3a and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid of 102 mg, with a yield of 67.2%. mp: 210.5-212.3℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.42(s,1H),8.88(dd,J=9.0,6.4Hz,1H),8.48(s,1H),7.93(d,J=9.3Hz,1H),7.63(d,J=9.4Hz,1H),7.13(dd,J=10.8,2.8Hz,1H ),6.85(td,J=8.7,2.8Hz,1H),4.85(hept,J=6.0Hz,1H),3.81(s,4H),3.78-3.73(m,4H),1.92-1.86(m,4H),1.40(d,J=6.0Hz,6H).13 C-NMR (151 MHz, DMSO-d 6 )δ156.91,156.16,154.09,150.92,147.15,138.01,137.45,129.47,119.09,117.92,1 16.59,106.17,100.75,71.38,54.71,41.35,37.21,33.43,21.83.HRMS(ESI,m / z)calcd for C 23 H 27 FN 6 O[M+H] + :423.2303found423.2362.Retention Time:7.21min,Purity:98.97%.

[0198] Example 39: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyrido[3,2-d]pyrimidin-4-amine Using 3a and 1-methyl-4-(piperidin-4-yl)piperazine as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid (119 mg) with a yield of 69.1%. mp: 167.8-169.2℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.43(s,1H),8.88(dd,J=9.0,6.4Hz,1H),8.46(s,1H),7.89(d,J=9.3Hz,1H),7.58(d,J=9. 4Hz,1H),7.12(dd,J=10.7,2.8Hz,1H),6.84(td,J=8.7,2.8Hz,1H),4.83(hept,J=6.0Hz,1H), 4.55(d,J=13.0Hz,2H),3.04-2.97(m,2H),2.52(d,J=12.0Hz,1H),2.50-2.46(m,4H),2.31(s, 4H), 2.14 (s, 3H), 1.86 (d, J = 12.4Hz, 2H), 1.46 (qd, J = 12.1, 4.1Hz, 2H), 1.37 (d, J = 6.0Hz, 6H). 13 C-NMR (151 MHz, DMSO-d 6)δ158.44,156.12,154.07,150.76,147.03,138.33,136.57,129.53,125.54,118.97,115.92, 106.27,101.25,71.36,60.71,55.10,48.38,45.68,43.99,27.49,21.74.HRMS(ESI,m / z)calcd for C 26 H 34 FN 7 O[M+H] + :480.2882found480.2938.Retention Time:5.26min,Purity:98.96%.

[0199] Example 40: Preparation of 2-(1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidin-4-yl)propan-2-ol Using 3a and 2-(piperidin-4-yl)propan-2-ol as raw materials, the product was obtained as a yellow solid of 113 mg according to the synthesis method of Example 25, with a yield of 71.2%. mp: 206.4-207.2℃. 1 H-NMR(600MHz,DMSO)δ9.45(s,1H),8.89(dd,J=9.0,6.4Hz,1H),8.46(s,1H),7.89(d,J=9.3 Hz,1H),7.58(d,J=9.3Hz,1H),7.12(dd,J=10.7,2.8Hz,1H),6.85(td,J=8.7,2.8Hz,1H),4. 84(p,J=6.0Hz,1H),4.66(d,J=12.9Hz,2H),4.20(s,1H),2.94-2.87(m,2H),1.83(d,J=12.7 Hz,2H),1.56-1.48(m,1H),1.38(d,J=6.0Hz,6H),1.28(qd,J=12.6,4.0Hz,2H),1.05(s,6H). 13 C-NMR (151MHz, DMSO) δ158.44,156.85,156.16,154.04,150.65,147.07,138.24,137.25,129.60,125.59 ,118.87,116.50,106.15,101.25,71.35,70.15,46.85,45.14,26.93,26.19,21.76.HRMS(ESI,m / z)calcd for C 24 H 30 FN5 O 2 [M+H] + :440.2456found440.2495.Retention Time:4.72min,Purity:99.11%.

[0200] Example 41: Preparation of 4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazin-2-one Using 3a and piperazin-2-one as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid (119 mg) with a yield of 69.1%. mp: 226.5-227.2℃. 1 H NMR (600 MHz, DMSO-d 6 )δ9.41(s,1H),8.86(dd,J=9.0,6.4Hz,1H),8.49(s,1H),8.21(d,J=3.0H z,1H),7.96(d,J=9.3Hz,1H),7.55(d,J=9.3Hz,1H),7.11(dd,J=10.8,2.8 Hz,1H),6.84(td,J=8.7,2.8Hz,1H),4.82(hept,J=6.1Hz,1H),4.26(s,2H),3.92(dd,J=6.4,4.4Hz,2H),3.41-3.35(m,2H),1.40(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ166.64,158.55,156.96,155.15,154.20,151.05,147.24,138.70,137.53,129.37,12 5.44,119.13,116.27,106.20,101.37,71.56,48.39,41.46,21.83.HRMS(ESI,m / z)calcd for C 20 H 21 FN 6 O 2 [M+Na] + :419.1602found419.1649.Retention Time:3.96min,Purity:99.60%.

[0201] Example 42: Preparation of 1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-2-one Using 3a and tert-butyl 3-oxopiperazine-1-carboxylate as raw materials, the product was obtained according to the synthesis method of Example 17 as a yellow solid (58 mg) with a yield of 24.3%. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.51(s,1H),8.82(dd,J=9.0,6.4Hz,1H),8.68(s,1H),8.51(d,J=9.1Hz,1H),8.19(d,J=9.1Hz,1H),7.14(dd,J=10.8,2.8Hz,1H),6 .87(td,J=8.7,2.7Hz,1H),4.83(hept,J=5.9Hz,1H),4.09(t,J=5.6Hz,2H),3.56(s,2H),3.11(t,J=5.6Hz,2H),1.38(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ170.30,158.99,157.40,155.43,154.42,152.30,147.58,141.87,136.85,128.74,125.0 3,124.86,119.89,106.34,101.52,71.51,51.34,47.54,42.46,21.73.HRMS(ESI,m / z)calcd for C 20 H 21 FN 6 O 2 [M+Na] + :419.1602found 419.1639.Retention Time:3.91min,Purity:99.88%.

[0202] Example 43: Preparation of 1-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperidine-4-carboxamide Using 3a and piperidine-4-carboxamide as raw materials, the product was obtained according to the synthesis method of Example 25 as a yellow solid (104 mg) with a yield of 68.3%. mp: 270.1-271.6℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.44(s,1H),8.89(dd,J=9.0,6.4Hz,1H),8.47(s,1H),7.94-7.89(m,1H),7.60(dd,J=9.4 ,1.4Hz,1H),7.36-7.32(m,1H),7.12(dd,J=10.8,2.8Hz,1H),6.88-6.81(m,2H),4.84(hept, J=6.0Hz,1H),4.56(dt,J=13.4,3.5Hz,2H),3.06(td,J=12.8,2.8Hz,2H),2.45(tt,J=11.6,3 .9Hz, 1H), 1.85 (dd, J=13.4, 3.6Hz, 2H), 1.61 (qd, J=12.3, 4.1Hz, 2H), 1.37 (d, J=6.0Hz, 6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ176.02,158.44,156.86,156.21,153.67,150.78,147.11,138.36,137.34,129.53,125.9 6,118.98,116.54,106.29,101.45,71.37,44.24,41.49,27.94,21.76.HRMS(ESI,m / z)calcd for C 22 H 25 FN 6 O 2 [M+H] + :425.2096found425.2138.Retention Time:6.60min,Purity:99.62%.

[0203] Example 44: Preparation of 4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1-carboxamide

[0204] Example 25 (191 mg, 0.5 mmol), carbamide (90 mg, 1.5 mmol) and ferric nitrate nonahydrate (20 mg, 0.05 mmol) were placed in a 25 mL eggplant-shaped bottle, 5 mL of dry toluene was added to dissolve, and the mixture was refluxed for reaction. The reaction was complete after TLC monitoring, and the reaction solution was evaporated to dryness. The residue was purified by column chromatography (V 二氯甲烷 :V 甲醇 =25:1) The product was obtained as a yellow solid (166 mg), with a yield of 78.1%. mp: 244.1-245.6°C. 1 H-NMR (600 MHz, DMSO-d6 )δ9.42(s,1H),8.86(dd,J=9.0,6.4Hz,1H),8.48(s,1H),7.94(d,J=9.3Hz,1H),7.60(d,J=9.4Hz,1H),7.11(dd,J=10.9,2.9Hz,1H), 6.84(td,J=8.7,2.7Hz,1H),6.15(s,2H),4.84(h,J=6.1Hz,1H),3.74(t,J=5.2Hz,4H),3.48(t,J=5.2Hz,4H),1.39(d,J=5.9Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.49,158.12,156.91,156.26,154.15,151.01,147.18,138.62,137.40,129.38,12 5.46,119.09,116.52,106.11,101.41,71.41,44.25,42.87,21.82.HRMS(ESI,m / z)calcd forC 21 H 24 FN 7 O 2 [M+H] + :426.2048found 426.2098.Retention Time:3.93min,Purity:99.58%.

[0205] Example 45: Preparation of (S)-4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2-methylpiperazine-1-carboxamide Using Example 37 as the raw material, the product was obtained according to the synthesis method of Example 44 as a yellow solid of 134 mg, with a yield of 61.2%. mp: 244.5-245.6℃. 1 H NMR (600 MHz, DMSO-d 6)δ9.42(s,1H),8.88(dd,J=9.0,6.4Hz,1H),8.48(s,1H),7.94(d,J=9.3Hz,1H),7.62(d,J=9.4Hz, 1H),7.12(dd,J=10.9,2.8Hz,1H),6.85(td,J=8.7,2.8Hz,1H),6.10(s,2H),4.85(hept,J=6.1Hz, 1H),4.44(d,J=11.8Hz,1H),4.36(d,J=13.2Hz,1H),4.29(qd,J=6.8,4.2Hz,1H),3.86(s,1H),3.3 2-3.27(m,1H),3.12(dtd,J=31.2,11.7,3.3Hz,2H),1.40(d,J=6.0Hz,6H),1.10(d,J=6.6Hz,3H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.50,157.86,156.91,156.65,154.08,150.86,147.18,129.40,125.46,119.04,116.34, 106.12,101.39,71.37,48.23,46.54,44.34,37.90,26.34,21.84,15.38.HRMS(ESI,m / z)calcd for C 22 H 26 FN 7 O 2 [M+Na] + :462.2024found 462.2070.Retention Time:3.95min,Purity:99.41%.

[0206] Example 46: Preparation of 3-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[0207]

[0208] Using 28 as the raw material, the product was obtained according to the synthesis method of A44 as a yellow solid (147 mg), with a yield of 65.2%. mp: 227.1-228.3℃. 1 H-NMR (600 MHz, DMSO-d 6)δ9.45(s,1H),8.86(dd,J=9.0,6.4Hz,1H),8.48(s,1H),7.94(d,J=9.3Hz,1H), 7.52(d,J=9.3Hz,1H),7.12(dd,J=10.7,2.8Hz,1H),6.85(td,J=8.7,2.8Hz,1H), 6.23(s,2H),4.84(p,J=6.1Hz,1H),4.40(s,2H),4.18(d,J=12.2Hz,2H),3.18(d ,J=12.1Hz,2H),1.86-1.81(m,2H),1.69(t,J=6.8Hz,2H),1.39(d,J=5.9Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.50,157.16,154.19,150.94,147.19,138.63,137.21,129.35,125.51,119.1 0,116.24,106.17,101.32,71.46,52.37,49.72,27.12,20.96.HRMS(ESI,m / z)calcd for C 23 H 26 FN 7 O 2 [M+Na] + :474.2024found474.2054.Retention Time:4.06min,Purity:98.21%.

[0209] Example 47: Preparation of 4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1-thiocarboxamide

[0210]

[0211] Example 25 (100 mg, 0.26 mmol) was placed in a 50 mL eggplant-shaped bottle, 10 mL of THF was added to dissolve, and then 1,1'-thiocarbonyldiimidazole (56 mg, 0.31 mmol) was added and reacted at room temperature. After the reaction was completed by TLC monitoring, 3.25 mL of 0.4 M ammonia tetrahydrofuran solution was added to the reaction system and reacted at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness, and the residue was purified by column chromatography to obtain 68 mg of the product as a yellow solid with a yield of 59.5%. 1 H NMR (600 MHz, DMSO-d 6)δ9.45(s,1H),8.86(dd,J=9.0,6.4Hz,1H),8.49(s,1H),7.97(d,J=9.3Hz,1H),7.58(d,J=9.4Hz,1H),7.11(dd,J=10.8, 2.8Hz,3H),6.85(td,J=8.7,2.8Hz,1H),4.83(hept,J=6.1Hz,1H),3.98(s,4H),3.85-3.81(m,4H),1.39(d,J=5.9Hz,6H). 13 CNMR (151MHz, DMSO-d 6 )δ181.24,158.52,156.94,156.01,154.18,151.01,147.24,138.63,137.42,129.3 8,125.44,119.15,116.40,106.12,101.43,71.42,46.21,43.66,21.82.HRMS:calcd forC 21 H 24 FN 7 OS[M+H] + :442.1820found 442.1864.Retention Time:3.79min,Purity:97.62%.

[0212] Example 48: 4-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1-sulfonamide

[0213] Example 25 (100 mg, 0.26 mmol) was placed in a 25 mL eggplant-shaped bottle, 5 mL DMA was added to dissolve, aminosulfonyl chloride (36 mg, 0.31 mmol) and triethylamine (39 mg, 0.39 mmol) were added to the reaction system, and the reaction was carried out at 50°C. After the reaction was completed by TLC monitoring, the reaction solution was diluted with 50 mL of water, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and evaporated to dryness, and the residue was purified by column chromatography to obtain a product of 59 mg of a yellow solid with a yield of 43.9%. mp: 233.1-234.5°C. 1 H-NMR (600 MHz, DMSO-d 6)δ9.42(s,1H),8.86(dd,J=9.0,6.4Hz,1H),8.50(s,1H),7.98(d,J=9.3Hz,1H),7.64(d,J=9.4Hz,1H),7.12(dd,J=10.8,2.8Hz,1H),6 .92(s,2H),6.85(td,J=8.7,2.8Hz,1H),4.84(hept,J=6.0Hz,1H),3.88(t,J=5.1Hz,4H),3.12(t,J=5.0Hz,4H),1.38(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.55,156.96,156.12,154.21,151.30,147.19,138.81,137.62,129.30,12 5.36,119.16,116.65,106.25,101.37,71.31,45.47,43.77,21.74.HRMS:calcd for C 20 H 24 FN 7 O 3 S[M+H] + :462.1718found462.1733.RetentionTime:3.52min,Purity:98.28%.

[0214] Example 49: Preparation of 2-((4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-1-(piperazin-1-yl)ethan-1-one

[0215] Step A: Preparation of tert-butyl 4-(2-hydroxyacetyl)piperazine-1-carboxylate (29a)

[0216]

[0217] 2-Hydroxyacetic acid (152 mg, 2.0 mmol), 1-Boc piperazine (410 mg, 2.2 mmol), HATU (836 mg, 2.2 mmol) and DIPEA (387 mg, 3.0 mmol) were placed in a 50 mL eggplant-shaped bottle, 20 mL of dichloromethane was added to dissolve, and the mixture was reacted at room temperature. TLC monitored the reaction to be complete, the reaction solution was diluted with 200 mL of dichloromethane, and extracted once with 10% HCl aqueous solution, water, saturated sodium bicarbonate aqueous solution and saturated brine, respectively, the organic phase was dried, and the product was evaporated to dryness to obtain a colorless oil, which was directly subjected to the next step of reaction without purification.

[0218] 29b was prepared using 2-hydroxyacetic acid and tert-butyl (S)-piperidin-3-ylcarbamate as raw materials according to the preparation method of 29a. Step B: Preparation of tert-butyl 4-(2-((4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)acetyl)piperazine-1-carboxylate (30a)

[0219]

[0220] 3a (200 mg, 0.6 mmol), 29a (171 mg, 0.7 mmol), palladium acetate (7 mg, 0.03 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (293 mg, 0.9 mmol) were placed in a 50 mL two-necked bottle, 15 mL of dry 1,4-dioxane was added to dissolve, and refluxed under nitrogen protection. The reaction was complete after TLC monitoring, the reaction solution was evaporated to dryness, and the residue was purified by column chromatography to obtain a product of 176 mg of a yellow solid with a yield of 54.3%.

[0221] Using 3a and 29b as raw materials, 30b was prepared according to the preparation method of 30a.

[0222] Step C: Preparation of 2-((4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-1-(piperazin-1-yl)ethan-1-one (Example 49)

[0223]

[0224] 30a (176 mg, 0.33 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 allowed to proceed at room temperature. TLC monitored the reaction to be complete, the reaction solution was evaporated to dryness, the residue was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was washed with V 二氯甲烷 :V 甲醇 =10:1 extraction 3 times, the organic phases were combined, dried, evaporated to dryness to obtain a crude product, and purified by column chromatography to obtain a yellow solid product of 108 mg, with a yield of 74.1%. mp: 160.1-161.7℃. 1H-NMR (400MHz, DMSO) δ9.17(s,1H),8.60(s,1H),8.57(dd,J=9.0,6.4Hz,1H),8.17(d,J=9.0Hz,1H),7.47(d,J=9.0Hz,1H),7.12(dd,J=10.9,2.8H z,1H),6.86(td,J=8.7,2.8Hz,1H),5.30(s,2H),4.78(hept,J=5.9Hz,1H),3.40(d,J=17.0Hz,4H),2.69(d,J=34.2Hz,4H),1.35(d,J=6.0Hz,6H). 13 C-NMR (101MHz, DMSO) δ165.00,160.57,159.74,157.35,155.28,153.20,148.58,141.74,139.79,127. 80,124.75,121.61,119.90,106.42,101.91,71.66,63.75,45.81,42.56,21.79.HRMS(ESI,m / z)calcd for C 22 H 25 FN 6 O 3 [M+Na] + :463.1864found463.1912.Retention Time:3.67min,Purity:99.78%.

[0225] Example 50: Preparation of (S)-1-(3-aminopiperidin-1-yl)-2-((4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethanone Using 30b as the starting material, Example 50 was synthesized according to the preparation method of 30a to give a yellow solid of 117 mg with a yield of 78.1%. mp: 156.1-156.7°C. 1 H-NMR (600 MHz, DMSO-d 6)δ9.19(d,J=17.4Hz,1H),8.59(d,J=4.3Hz,1H),8.54(ddd,J=25.5,8.9,6.4Hz,1H),8.17(d,J=9.0 Hz,1H),7.47(d,J=9.0Hz,1H),7.15-7.09(m,1H),6.86(td,J=8.7,2.7Hz,1H),5.40-5.20(m,2H),4. 78(h,J=6.1Hz,1H),4.22-3.77(m,1H),3.70(d,J=13.1Hz,1H),3.03(s,1H),2.95-2.84(m,1H),2.8 2-2.57(m,1H),1.83(d,J=13.8Hz,1H),1.76-1.63(m,1H),1.55-1.41(m,1H),1.34(q,J=4.8Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ165.00,160.60,155.28,153.21,148.61,141.74,139.81,127.81,124.77,121.88,119.92,106.26,101. 87,71.60,63.80,52.23,48.88,47.79,47.38,44.64,41.81,32.60,26.34,24.09,22.78,21.76.HRMS:calcd for C 23 H 27 FN 6 O 3 [M+Na] + :477.2021 found 477.2069.

[0226] Example 51: Preparation of 6-(3-aminoprop-1-yn-1-yl)-N-(4-fluoro-2-isopropoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine

[0227] 3a (200 mg, 0.6 mmol), N-Boc-aminopropyne (112 mg, 0.7 mmol), bistriphenylphosphine palladium dichloride (42 mg, 0.06 mmol), cuprous iodide (11 mg, 0.06 mmol) and potassium carbonate (249 mg, 1.8 mmol) were placed in a 50 mL two-necked bottle, 15 mL of DMF was added to dissolve, and the temperature was raised to 100 ° C. After the reaction was completed by TLC monitoring, 100 mL of water was added to the reaction solution to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, extracted once with saturated brine, dried, evaporated to dryness to obtain a crude product, and the product was purified by column chromatography to obtain a yellow solid, which 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 monitoring of the reaction was complete, the reaction solution was evaporated to dryness, the residue was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was purified by V 二氯甲烷 :V 甲醇 =10:1 extraction 3 times, the organic phases were combined, dried, evaporated to dryness to obtain a crude product, and purified by column chromatography to obtain a yellow solid product of 63 mg, with a yield of 31.9%. mp: 88.7-89.5℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.82(s,1H),8.68(s,1H),8.61(dd,J=9.0,6.4Hz,1H),8.20(d,J=8.6Hz,1H),7.91(d,J=8.6Hz,1H),7.15(dd ,J=10.7,2.8Hz,1H),6.89(td,J=8.7,2.7Hz,1H),4.77(hept,J=6.1Hz,1H),3.62(s,2H),1.37(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.81,157.21,155.14,147.97,142.45,141.17,135.92,130.89,130.70,12 4.38,120.50,106.00,101.67,80.45,71.59,30.65,21.19.HRMS(ESI,m / z)calcd for C 19 H 18 FN 5 O[M+H] + :352.1568found352.1603.Retention Time:4.07min,Purity:99.16%.

[0228] Example 52: Preparation of N-(3-(4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)prop-2-yn-1-yl)piperazine-1-carboxamide

[0229]

[0230] Example 51 (100 mg, 0.28 mmol) and CDI (55 mg, 0.34 mmol) were placed in a 25 mL eggplant-shaped bottle, 8 mL of dichloromethane was added to dissolve, and the mixture was reacted at room temperature for 30 min. 1-Boc piperazine (63 mg, 0.34 mmol) was then added to the reaction solution and reacted at room temperature. After TLC monitoring, the reaction was complete, the reaction solution was diluted with 100 mL of dichloromethane, extracted twice with water, extracted once with saturated brine, dried, evaporated to obtain a crude product as a yellow oil, 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. After TLC monitoring, the solvent was evaporated, the residue was adjusted to pH 8 with a saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted 4 times with dichloromethane, the organic phases were combined, dried, evaporated to obtain a crude product, and the target product was purified by column chromatography to obtain 70 mg of a yellow solid, with a two-step yield of 54.1%. mp:90.1-91.7℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.81(s,1H),8.69(s,1H),8.61(dd,J=9.0,6.3Hz,1H),8.20(d,J=8.6Hz,1H),7.92(d,J=8.6Hz,1H),7.15(dd,J=10.7,2.8Hz,1H),7.09(t,J= 5.6Hz,1H),6.89(td,J=8.7,2.8Hz,1H),4.77(p,J=6.0Hz,1H),4.17(d,J=5.4Hz,2H),3.27(s,4H),2.69(d,J=7.1Hz,3H),1.36(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6 )δ158.84,157.24,156.34,155.20,148.08,142.53,140.84,135.96,130.78,124.35,120.62,1 14.61,106.01,101.82,90.45,79.84,71.60,69.18,44.57,29.62,21.24.HRMS(ESI,m / z)calcd for C 24 H 26 FN 7O 2 [M+H] + :464.2205found 464.2254.Retention Time:3.86min,Purity:97.52%.

[0231] Example 53: Preparation of (4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(piperazin-1-yl)methanone Step A: Preparation of N-(4-fluoro-2-isopropoxyphenyl)-6-vinylpyrido[3,2-d]pyrimidin-4-amine (31)

[0232] 3a (200 mg, 0.6 mmol), vinylboronic acid pinacol ester (111 mg, 0.72 mmol), Pd(dppf)Cl 2 (22 mg, 0.03 mmol) and potassium carbonate (124 mg, 0.9 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 the mixture was refluxed to react. The reaction was complete when monitored by TLC, and the reaction solution was evaporated to dryness. The residue was purified by column chromatography to obtain 147 mg of the product as a yellow solid with a yield of 75.6%.

[0233] Step B: Preparation of 4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidine-6-carbaldehyde (32)

[0234] 31 (147 mg, 0.45 mmol) and potassium osmate dihydrate (14 mg, 0.05 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 stirred at room temperature for 30 min. Sodium periodate (389 mg, 1.80 mmol) was then added and reacted at room temperature. TLC monitored the reaction to be complete, ice water was added to the reaction solution to quench, solids were precipitated, and the crude product was filtered out and purified by column chromatography (V 二氯甲烷 :V 甲醇 =125:1) to obtain the product as a light yellow solid (112 mg), with a yield of 76.2%.

[0235] Step C: Preparation of 4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidine-6-carboxylic acid (33)

[0236] 32 (112 mg, 0.34 mmol) was placed in a 50 mL eggplant-shaped bottle, 10 mL of acetic acid was added to dissolve, and 30% H 2 O 2The solution was heated to 50°C for reaction. TLC monitored the reaction to be complete, ice water was added to the reaction solution to quench, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, extracted once with saturated brine, dried, and evaporated to obtain the product as a yellow solid of 105 mg, with a yield of 90.2%.

[0237] Step D: Preparation of (4-((4-fluoro-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(piperazin-1-yl)methanone (Example 53)

[0238]

[0239] 33 (105 mg, 0.31 mmol), 1-Boc piperazine (64 mg, 0.34 mmol), FDPP (131 mg, 0.34 mmol) and DIPEA (60 mg, 0.47 mmol) were placed in a 25 mL eggplant-shaped bottle, 8 mL of tetrahydrofuran was added to dissolve, and the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC to be complete, the reaction solution was evaporated to dryness, the residue was dissolved in 100 mL of dichloromethane, and extracted once with 10% HCl aqueous solution, water, saturated sodium bicarbonate aqueous solution, water and saturated saline, respectively, and evaporated to dryness to obtain a yellow oily substance, which was transferred to a 100 mL eggplant-shaped bottle and 16 mL of dichloromethane was added to dissolve. 4 mL of trifluoroacetic acid was added under stirring at room temperature, and the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC to be complete, the reaction solution was evaporated to dryness, the residue was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was washed with V 二氯甲烷 :V 甲醇 =10:1 extraction for 3 times, the organic phases were combined, dried, and evaporated to obtain a crude product as a yellow oil, which was purified by column chromatography to obtain a yellow solid of 78 mg, with a two-step yield of 61.2%. mp: 144.4-144.6℃. 1 H-NMR (600 MHz, DMSO-d 6 )δ9.70(s,1H),8.80-8.73(m,2H),8.33(d,J=8.6Hz,1H),8.03(d,J=8.6Hz,1H),7.16(dd,J=10.7,2.9Hz,1H),6.89(td,J=8.7,2.8Hz,1H), 4.82(hept,J=6.1Hz,1H),3.65(t,J=4.9Hz,2H),3.38(t,J=4.9Hz,2H),2.82(t,J=4.9Hz,2H),2.71(t,J=4.9Hz,2H),1.38(d,J=6.0Hz,6H). 13 C-NMR (151 MHz, DMSO-d 6)δ165.73,159.27,157.67,156.32,156.06,152.96,148.15,143.98,137.42,129.83,127.84,1 24.80,120.63,106.47,101.88,71.94,48.33,46.02,45.40,43.00,21.76.HRMS(ESI,m / z)calcd for C 21 H 23 FN 6 O 2 [M+H] + :411.1939found411.1953.Retention Time:6.20min,Purity:99.67%.

[0240] Example 54: Preparation of 3-isopropoxy-4-((6-(2-oxopiperazin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)benzonitrile

[0241] Example 54 was synthesized using 15 and tert-butyl 3-oxopiperazine-1-carboxylate as raw materials according to the preparation method of Example 42. mp: 235.1-235.3°C. 1H-NMR (600 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.04 (d, J = 8.5 Hz, 1H), 8.77 (s, 1H), 8.55 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.3 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.51 (dd, J = 8.5, 1.7 Hz, 1H), 4.92 (hept, J = 6.0 Hz, 1H), 4.08 (t, J = 5.5 Hz, 2H), 3.57 (s, 2 H),3.11(t,J=5.6Hz,2H),1.40(d,J=6.0Hz,6H).13C-NMR(151MHz,DMSO-d6)δ170.40,155.31,153.99,152.57,145.88,142.1 5,136.97,132.73,128.65,125.78,125.31,119.21,118.67,115.46,104.46,72.22,51.39,47.53,42.41,21.68.HRMS:calcd for C21H21N7O2[M+Na]+:426.1649found 426.1716.Retention Time:3.73min,Purity:96.97%.

[0242] Example 55: Preparation of 4-((4-cyano-2-isopropoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)piperazine-1-carboxamide

[0243] Example 55 was synthesized using Example 33 as the raw material according to the preparation method of Example 44. mp: 255.2-255.8°C. 1H-NMR (600 MHz, DMSO-d 6 )δ9.72(s,1H),9.05(d,J=8.5Hz,1H),8.57(s,1H),7.98(d,J=9.3Hz,1H),7.70-7.58(m,2H),7.50(d,J=8.5Hz,1H),6.16 (s,2H),5.02-4.86(m,1H),3.76(t,J=5.3Hz,4H),3.49(q,J=5.4Hz,5H),1.40(d,J=6.0Hz,6H).13C-NMR(151MHz,DMSO-d 6 )δ158.12,156.34,153.92,150.60,145.68,139.20,137.44,133.35,129.45,125.88, 119.39,118.13,117.10,115.34,103.68,71.61,44.21,42.84,21.79.HRMS:calcdfor C 22 H 24 N 8 O 2 [M+Na] + :455.1914 found 455.1969. Retention Time: 3.69min, Purity: 96.94%. Pharmacological study of the product of the present invention

[0244] The activity of Mnk and Pim kinases was screened using the serine / threonine kinase kit from Bioduro-sundia, with eFT508 and TP-3654 as positive control drugs.

[0245] The inhibition rate of the target compound at 100 nM on Mnk1, Mnk2 and Pim1 was tested by HTRF. The results are shown in Table

[0246]

[0247] “-” means not tested.

[0248] IC of some compounds against Mnk1, Mnk2 and Pim1 50 value:

[0249]

[0250] The activity test results showed that some compounds exhibited good dual-target inhibitory activity, among which Examples 4, 5 and 10 had the best activity, with IC 50 The inhibitory activity against Pim1 was between 3-32 nM, and between 24-48 nM. Examples 37-39 showed good Pim1 inhibitory activity against Pim1, IC 50 The value is less than 10nM.

[0251] Antiproliferative activity test of some compounds:

[0252] 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.

[0253] Preparation of drug solution: The target compound obtained in the above examples is dissolved in DMSO to prepare a mother solution of a certain concentration, and the mother solution is diluted 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%.

[0254] Drug addition and data processing: After HCT-116 or PC-3 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 plates were shaken after 3.5 hours. The blue-purple crystals were dissolved with DMSO, and the absorbance at 570nm was measured using an ELISA reader. DMSO was used as a blank control, and the growth inhibition rate was calculated according to the following formula. Then, the IC was calculated by linear regression based on the inhibition rate. 50 .

[0255] Trypan blue staining was used to test the antiproliferative activity of some compounds on human leukemia Molm-13 cells. The corresponding cells were seeded into 24-well plates at a density of 50,000 cells per well, and different concentrations of compounds were added and incubated at 37°C for 72 hours. After the end, the cells were resuspended, 50 μL of cell fluid was aspirated and gently mixed with an equal volume of 0.4% trypan blue solution, and then 9 μL of the mixture was aspirated and placed on a blood cell counting plate. The total cell number was counted under a microscope. The growth inhibition rate was calculated by dividing the number of cells in the drug-treated group by the number of cells in the non-drug-treated group. The IC was calculated using Graphpad prism. 50 value.

[0256]

[0257] 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, Mnk2 and Pim1 kinases, and exhibit obvious anti-proliferation activity in solid tumor and blood tumor cells. The compounds of the present invention have good industrial application prospects.

Claims

1. A 4-anilino-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 the formula, 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, hydroxy, amino, cyano, C1-C4 alkoxy; R2 and R3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine, 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, Among them, the following substituents are O, N, halogen, hydroxyl, amino, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy; Y is The left side of Y is connected to the pyrido[3,2-d]pyrimidine core; m and n may be the same or different and are independently an integer between 1 and 3; X, Z are CH, N; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C 10 Alkyl, C2-C 10 Alkenyl, Hydroxyl C2-C 10 Alkyl, amino C2-C 10 Alkyl, unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen, 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 attached, 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; R 11 , R 12 is hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, C1-C 10 alkyl; R 13 It is hydrogen or C1-C4 alkyl.

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. Where: R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine, 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 are 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, dimethylphosphine oxide, C1-C8 alkyl, C1-C8 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C8 aryl and 5-8 membered heteroaryl, Wherein, the following substituents are O, N, halogen, hydroxyl, amino, cyano; Y is -, ， The left side of Y is connected to the pyrido[3,2-d]pyrimidine core; m and n may be the same or different and are independently 1 or 2; X, Z are CH, N; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C8 alkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C3-C8 alkyl which is unsubstituted or substituted by at least one of the same or different halogen, amino, oxygen 10 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; 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, C2-C8 alkenyl, haloalkyl (C1-C 10 )、C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, or R9 and R 10 Together with the nitrogen atoms to which they are attached, they form a 4-10 membered substituted heterocyclic group or a 5-10 membered heteroaryl group; wherein the following groups are halogen, hydroxy, amino, cyano, C1-C4 alkyl or C1-C4 alkoxy; R 11 , R 12 is hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, C1-C 10 alkyl; R 13 It is hydrogen or C1-C4 alkyl.

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. In the formula R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C4 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; R2 and R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C8 aryl and 5-8 membered heteroaryl, which are unsubstituted or substituted with at least one of the following groups which are the same or different, Wherein, the following substituents are O, N, halogen, hydroxyl, amino, cyano; Y is -, The left side of Y is connected to the pyrido[3,2-d]pyrimidine core; m and n may be the same or different and are independently 1 or 2; X, Z are CH, N; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C8 alkyl, C2-C8 alkenyl, C3-C 10 Cycloalkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C4-C8 cycloalkyl containing at least one heteroatom, 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: hydrogen, deuterium, halogen, hydroxyl, nitro, and amino; R 11 ,R 12 is hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, unsubstituted alkyl (C1-C 10 ); R 13 It is hydrogen, unsubstituted alkyl (C1-C4).

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. In the formula R1 is hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C4 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; R2 and R3 may be the same or different and each independently selected from hydrogen, deuterium, halogen, amino, cyano, carbamoyl, dimethylphosphine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C6-C8 aryl and 5-8 membered heteroaryl, which are unsubstituted or substituted with at least one of the following groups which are the same or different, Wherein, the following substituents are O, N, halogen, hydroxyl, amino, cyano; Y is The left side of Y is connected to the pyrido[3,2-d]pyrimidine core; m and n may be the same or different and are independently 1 or 2; X, Z are CH, N; R4 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, amino, cyano, carbamoyl, dimethylphosphine oxide, C1-C8 alkyl, C2-C8 alkenyl, C3-C 10 Cycloalkyl, hydroxy C2-C8 alkyl, amino C2-C8 alkyl, C4-C8 cycloalkyl containing at least one heteroatom, 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: hydrogen, deuterium, halogen, hydroxyl, nitro, and amino; R 11 ,R 12 is hydrogen, deuterium, oxygen, halogen, hydroxyl, nitro, amino, unsubstituted alkyl (C1-C 10 ); R 13 It is hydrogen, unsubstituted alkyl (C1-C4).

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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