Pyridopyrimidinone compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present application are a pyridopyrimidinone compound, and a preparation method therefor and the use thereof, wherein the pyridopyrimidinone compound, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof has a structure as shown in formula (I). The pyridopyrimidinone compound provided by the present application has an agonistic effect on an HsClpP protease, and can be used for treating diseases related to HsClpP receptor activation.

Description

A pyridopyrimidinone compound and a preparation method and application thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a pyridopyrimidinone compound and a preparation method and application thereof. BACKGROUND

[0002] Mitochondria play an important role in the occurrence, development and metastasis of various tumors. Among them, human casein protease P (HsClpP) is an unfolded peptide enzyme in the mitochondrial matrix, which controls the protein quality regulation of mitochondrial metabolism, maintains the integrity and enzyme activity of the mitochondrial respiratory chain. Studies have shown that the abnormality of HsClpP can cause mitochondrial dysfunction and various human diseases, including cancer, neurological diseases, diabetes, gastrointestinal diseases, cardiovascular diseases, skin diseases and aging, etc. ClpP is overexpressed in multiple myeloma, various lymphomas, chronic myeloid leukemia (CML) and part of solid tumors, and further activation of ClpP is expected to provide a new intervention means for the treatment of these tumors.

[0003] The possible mechanism of HsClpP participating in cancer is related to mitochondrial bioenergy and protein balance, production of reactive oxygen species (ROS) and activation of autophagy. HsClpP is related to members of the electron transport chain (ETC), especially SDHA and other enzymes involved in metabolism. Inhibition of HsClpP activity leads to the inability of the HsClpXP complex to effectively degrade damaged or erroneous proteins in oxidative phosphorylation, thereby affecting the mitochondrial oxidative phosphorylation (OXPHOS) of cells, inducing cell death; at the same time, inhibition of HsClpP activity also reduces the enzyme activity of SDHA in respiratory chain (RC) complex II, increases the production of mitochondrial ROS, and thus initiates non-apoptotic tumor cell death. In addition, excessive activation of HsClpP also inhibits the growth of cancer cells, and excessive activation of HsClpP can selectively induce cancer cell death by degrading ClpP substrates including RC complex proteins (SDHB and SDHB), damaging OXPHOS, and destroying the structure and function of mitochondria. Therefore, HsClpP is a unique tumor target, and inhibition or activation of HsClpP can inhibit the growth of tumors.

[0004] HsClpP is also highly expressed in acute myeloid leukemia (AML). In primary AML, about 45% of patients have higher HsClpP expression than normal hematopoietic progenitor cells. When HsClpP expression is blocked in vitro and in vivo, the growth and viability of each AML cell line is significantly reduced, and the development of tumors is significantly inhibited in vivo. In addition, the over-activation of HsClpP is also considered an effective strategy for treating AML. When HsClpP is activated, the proportion of primary AML cell death and apoptosis increases compared to normal cells, and HsClpP activators also reduce the leukemia burden in mice. HsClpP is also expressed in many other hematological malignancies, such as CML, multiple myeloma, and various lymphomas. Therefore, regulating HsClpP activity is considered a strategy for treating AML and other hematological malignancies.

[0005] HsClpP is also up-regulated in many solid tumors, including glioma, breast cancer, ovarian cancer, prostate cancer, liver cancer, lung cancer, thyroid cancer, and colon cancer. Overexpression of HsClpP is associated with shorter survival in patients with breast cancer and uveal melanoma. Inhibition of HsClpP can relieve the regulation of mitochondrial RC and oxidative stress, inhibit the proliferation, movement, and metastasis of tumor cells. In prostate cancer, inhibition of HsClpP activity can reduce the expression of cyclin A, B1, and D1, thereby inducing PC3 prostate cell cycle arrest and inhibiting PC3 cell proliferation. In the PC3 cell scratch test, interference with the expression of HsClpP inhibits tumor cell invasion and migration. In vivo, inhibition of HsClpP in tumor-bearing mice slows tumor disease progression and the extent of liver metastasis.

[0006] Therefore, it is necessary to develop a series of anti-tumor compounds targeting HsClpP. SUMMARY

[0007] The present application aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present application provides a pyridopyrimidinone compound, which has better HsClpP protease agonist effect and can be used for treating HsClpP receptor agonist related diseases.

[0008] The second aspect of the present application also provides a preparation method of the pyridopyrimidinone compound.

[0009] The third aspect of the present application also provides a pharmaceutical composition.

[0010] The fourth aspect of the present application also provides an application.

[0011] According to the first aspect of the present application, a pyridopyrimidinone compound, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, has a structure as shown in formula I:

[0012] wherein m, n, p and q are positive integers, 1≤n≤3; 1≤m≤5; 1≤p≤5; 1≤q≤5;

[0013] A ring is selected from C 6～20 aryl, C 3～18 heteroaromatic, C 3～8 cycloalkyl;

[0014] R1and R2are independently selected from hydrogen, halogen, cyano, C 1～6 alkyl, C 1～6 alkoxy, halogen-substituted C 1～6 alkyl, halogen-substituted C 1～6 alkoxy;

[0015] R3is selected from hydrogen, halogen, C 1～6 alkyl;

[0016] R4is selected from hydrogen, deuterium, C 1～6 alkyl or halogen;

[0017] R5is selected from wherein R6is selected from hydrogen, deuterium, C 1～6 alkyl or halogen; B ring is selected from C 6～20 aryl, C 3～18 heteroaromatic, C 3～8 cycloalkyl;

[0018] or R4and R5form a substituted or unsubstituted C 4～6 azacyclic ring; the substitution is substituted by C 1～6 alkyl or phenyl.

[0019] The pyridopyrimidinone compound according to the embodiments of the present application has at least the following beneficial effects:

[0020] The pyridopyrimidinone compound provided by the present application has HsClpP protease agonizing effect, and can be used for treating diseases related to HsClpP receptor agonism.

[0021] According to some embodiments of the present application, the pyridopyrimidinone compound has a structure as shown in formula I-1:

[0022] According to some embodiments of the present application, the A ring and the B ring are independently selected from phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, quinolinyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, C 4～8 a bridged cycloalkyl.

[0023] According to some embodiments of the present application, it has a structure as shown in formula I-2:

[0024] According to some embodiments of the present application, R1 and R2 are independently selected from hydrogen, halogen, cyano, methyl, tert-butyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy.

[0025] According to some embodiments of the present application, R3 is selected from hydrogen, methyl, ethyl.

[0026] According to some embodiments of the present application, the cycloalkyl group C 3～8 includes monocycloalkyl and bridged cycloalkyl.

[0027] According to some embodiments of the present application, the pyridopyrimidinone compound is selected from the following structural formula:

[0028] According to some embodiments of the second aspect of the present application, a method for preparing a pyridopyrimidinone compound is provided, comprising the following steps:

[0029] The compound of formula (1-6), the compound of formula (1-9), an organic solvent and an organic base are mixed to react to obtain;

[0030] wherein, the structural formula of the compound of formula (1-6) and the compound of formula (1-9) are as follows:

[0031] According to some embodiments of the present application, the organic base is selected from at least one of sodium methoxide, sodium ethoxide or sodium tert-butoxide.

[0032] According to some embodiments of the present application, the organic solvent is selected from at least one of methanol, ethanol, tert-butanol.

[0033] According to some embodiments of the present application, the temperature of the reaction is 80-120°C.

[0034] The third aspect of the present application provides a pharmaceutical composition comprising the pyridopyrimidinone compound described in the present application and a pharmaceutically acceptable excipient.

[0035] The fourth aspect of the present application provides use of the pyrimidinone compound, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture thereof, or the pharmaceutical composition described in the present application in the preparation of a medicament for treating a disease associated with HsClpP protease.

[0036] According to some embodiments of the present application, the disease comprises cancer.

[0037] According to some embodiments of the present application, the cancer comprises central nervous system tumor, brain tumor, brain glioma, peripheral nervous system tumor, pheochromocytoma, paraganglioma, neuroendocrine tumor, liver cancer, lung cancer, gastric cancer, colon cancer, rectal cancer, pancreatic cancer, breast cancer, prostate cancer, endometrial cancer, lung squamous carcinoma, diffuse large B-cell lymphoma, hematological malignancy and lymphatic system tumor.

[0038] Definitions and general terms

[0039] "C 1～6 alkyl" means an alkyl group having a total number of carbon atoms of 1-6, including C 1～6 linear alkyl, C 1～6 branched alkyl and C 3～6 cycloalkyl, for example, can be a linear alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkyl group having a total number of carbon atoms of 3, 4, 5 or 6, for example, can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, and the like.

[0040] "C 1～6 alkyl" is similar to the definition of "C 1～6 alkyl", except that any 1 H atom in "C 1～6 alkyl" is replaced by any halogen.

[0041] "C 1～6 alkoxy" means an alkoxy group having a total number of carbon atoms of 1-6, including C 1～6 linear alkoxy, C 1～6 branched alkoxy and C 2～6 cycloalkoxy, for example, can be a linear alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkoxy group having a total number of carbon atoms of 2, 3, 4, 5 or 6, for example, can be methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0042] "halogen-substituted C 1～6 "alkyl" and "C 1～6 "alkyl" and "C 1～6 "alkyl" and "C

[0043] "halogen" includes any one or two or more of fluorine, chlorine, bromine, iodine.

[0044] "C 6～20 "aryl" means a monocyclic or fused polycyclic group of all-carbon single or multiple rings having a fully conjugated pi-electron system; for example, benzene, naphthalene, indene, fluorene, and the like.

[0045] "C 3～18 "heteroaromatic" means a monocyclic or fused ring group of ring atoms containing one, two, three, or four ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and having a total of 3-18 carbon atoms, and additionally having a fully conjugated pi-electron system. Examples include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, indolizine, pyrazine, pyridazine, indole, azaindole, benzimidazole, benzotriazole, indoline, indolone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like. Preferred examples of such groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazolyl.

[0046] "C 3～8 "cycloalkyl" means a monocyclic or bridged cycloalkyl group having a total of 3-8 carbon atoms; for example, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, and the like.

[0047] Other features and advantages of the present application will be set forth in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following or can be learned by practice of the application. BRIEF DESCRIPTION OF DRAWINGS

[0048] The foregoing and / or additional aspects and advantages of the present application are achieved by providing what is described below and claimed herein.

[0049] FIG. 1 is a graph of experimental Example 3 relative to the prolongation of mouse survival in the molm13 diffuse model. DETAILED DESCRIPTION

[0050] The following are specific examples of the present application, and the technical solutions of the present application are further described in conjunction with the examples, but the present application is not limited to these examples.

[0051] The reagents, methods and apparatus employed in the present application are conventional reagents, methods and apparatus in the art unless otherwise specified.

[0052] The analytical data of the sample were determined by the following instruments: nuclear magnetic resonance was determined by AVANCE NEO 500 nuclear magnetic resonance instrument, TMS (tetramethylsilane) was internal standard, chemical shift unit was ppm, coupling constant unit was Hz; mass spectrum was determined by G6125C mass spectrometer.

[0053] Silica gel 200-300 mesh (Titan) was used for column chromatography; TLC silica gel plate was HSGF-254 type thin layer chromatography precast plate produced by Yantai Chemical Factory; petroleum ether boiling range was 60-90°C; UV lamp and iodine tank were used for color development. Unless otherwise specified, the conventional reagents and drugs used in the following examples were purchased from Bide Group, Anjie Group and Titan Group.

[0054] Example 1

[0055] Example 1 provides a pyridopyrimidinone compound, the structural formula of which is as follows:

[0056] The synthetic route map and preparation method thereof are as follows:

[0057] S1, compound 1-1 (5.0 g, 33.0 mmol), compound 1-2 (3.2 mL, 36.0 mmol), DBU (0.5 mL, 3.3 mmol) and triethylamine (4.5 mL, 33.0 mmol) were dissolved in dichloromethane (60 mL), stirred at 40°C for 24 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed by reduced pressure distillation, methyl tert-butyl ether was added and stirred for 30 minutes, then filtered, the filter cake was washed twice with methyl tert-butyl ether, and the combined organic phase was concentrated to obtain colorless oily compound 1-3 (5.8 g, yield 87%), which was directly used in the next step.

[0058] S2, compound 1-3 (2.9 g, 14.3 mmol) was dissolved in dichloromethane (60 mL), compound 1-4 (2.0 g, 15.0 mmol), 4A molecular sieve and acetic acid (1.2 g, 20 mmol) were added, and stirred at room temperature for 3 hours. NaBH(OAc)3 (6.2 g, 29.0 mmol) was added in batches, and the stirring was continued at room temperature for 24 hours. After the reaction was completed, the insoluble matter was filtered off with diatomite, the filtrate was quenched with saturated NaHCO3 aqueous solution (50 mL), and extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain yellowish oily compound 1-5 (3.0 g, yield 65%).

[0059] S3, Compound 1-5 (3.0 g, 9.3 mmol) was dissolved in tetrahydrofuran (20 mL), 1.0 M potassium tert-butoxide / tetrahydrofuran solution (10 mL) was added under ice bath, and the reaction was carried out at 0 °C for 4 hours. After the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 4: 1) gave Compound 1-6 (mixture, 2.3 g, total yield 87%) as a colorless oil.

[0060] S4, Compound 1-8 (1.46 g, 10.0 mmol) and diisopropylethylamine (1.9 mL, 11.0 mmol) were dissolved in acetonitrile (10 mL), and Compound 1-7 (1.34 g, 11.0 mmol) was added. The reaction was continuously stirred at room temperature for 24 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the slurry was prepared by adding methyl tert-butyl ether. After filtration and drying, Compound 1-9 was obtained as a white solid.

[0061] S5, Compound 1-6 (48 mg, 0.24 mmol) and Compound 1-9 (40 mg, 0.20 mmol) were dissolved in super-dry methanol (2.0 mL), and sodium methoxide (54 mg, 1.0 mmol) was added. The reaction was stirred at 80 °C for 16 hours. After the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (4% MeOH in DCM) gave Compound 1 (34 mg, 42%) as a pale yellow solid.

[0062] 1 H NMR (500 MHz, Chloroform-d) δ 7.64 (d, J = 8.5 Hz, 2H), 7.55 (dd, J = 15.4, 7.7 Hz, 2H), 7.47 - 7.36 (m, 2H), 7.27 (d, J = 15.2 Hz, 3H), 7.20 - 7.11 (m, 3H), 4.57 - 4.43 (m, 2H), 3.72 - 3.64 (m, 1H), 3.64 - 3.51 (m, 1H), 3.21 (s, 1H), 3.10 - 3.04 (m, 1H), 2.79 (dd, J = 17.5, 5.2 Hz, 1H), 2.41 - 2.33 (m, 2H), 2.32 (s, 3H), 1.09 (d, J = 6.6 Hz, 3H); LC-MS m / z 400.2 [M+H] + .

[0063] Example 2

[0064] Example 2 provides a pyridopyrimidinone compound, the structural formula of which is as follows:

[0065] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0066] 1 H NMR (500 MHz, Chloroform-d) δ 7.69 - 7.57 (m, 3H), 7.57 - 7.44 (m, 4H), 7.44 - 7.34 (m, 2H), 7.20 (t, J = 7.5 Hz, 2H), 7.18 - 7.03 (m, 5H), 5.32 (s, 1H), 4.52 - 4.46 (m, 3H), 3.84 - 3.70 (m, 1H), 3.70 - 3.62 (m, 1H), 3.57 (t, J = 12.6 Hz, 2H), 3.47 (q, J = 8.1, 6.0 Hz, 2H), 3.29 - 3.18 (m, 1H), 3.16 (s, 2H), 3.02 (q, J = 5.6 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.67 - 2.55 (m, 1H), 2.32 (s, 5H), 1.38 - 1.29 (m, 3H), 1.29 - 1.26 (m, 2H), 1.04 (d, J = 6.5 Hz, 3H); LC-MS m / z 400.2 [M+H] + .

[0067] Example 3

[0068] Example 3 provides a pyridopyrimidinone compound, which has the following structural formula:

[0069] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0070] Example 4

[0071] Example 4 provides a pyridopyrimidinone compound, which has the following structural formula:

[0072] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0073] 1H NMR (500 MHz, Chloroform-d) δ 7.70 - 7.55 (m, 4H), 7.53 - 7.48 (m, 2H), 7.43 - 7.33 (m, 4H), 6.72 (s, 1H), 4.57 (d, J = 5.4 Hz, 3H), 3.64 - 3.42 (m, 3H), 3.16 (s, 2H), 3.04 (dt, J = 6.8, 5.2 Hz, 1H), 2.85 - 2.72 (m, 1H), 2.39 - 2.24 (m, 1H), 1.38 - 1.21 (m, 2H), 1.20 - 1.09 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H); LC-MS m / z 404.2 [M+H] + .

[0074] Example 5

[0075] Example 5 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0076] The preparation method thereof is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced by

[0077] 1 H NMR (500 MHz, Chloroform-d) δ 7.70 - 7.55 (m, 4H), 7.53 - 7.48 (m, 2H), 7.43 - 7.33 (m, 4H), 6.72 (s, 1H), 4.57 (d, J = 5.4 Hz, 3H), 3.64 - 3.42 (m, 3H), 3.16 (s, 2H), 3.04 (dt, J = 6.8, 5.2 Hz, 1H), 2.85 - 2.72 (m, 1H), 2.39 - 2.24 (m, 1H), 1.38 - 1.21 (m, 2H), 1.20 - 1.09 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H); LC-MS m / z 404.2 [M+H] + .

[0078] Example 6

[0079] Example 6 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0080] The preparation method thereof is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced by

[0081] 1H NMR (500 MHz, Chloroform-d) δ 7.70 - 7.60 (m, 1H), 7.60 - 7.49 (m, 3H), 7.49 - 7.33 (m, 2H), 7.33 - 7.17 (m, 3H), 7.17 - 7.05 (m, 1H), 4.58 (td, J = 15.4, 14.9, 4.4 Hz, 1H), 3.72 - 3.63 (m, 1H), 3.53 (d, J = 14.1 Hz, 1H), 3.24 (s, 1H), 3.06 (p, J = 6.0 Hz, 1H), 2.80 (td, J = 18.0, 5.3 Hz, 1H), 2.64 (dq, J = 11.9, 6.7 Hz, 1H), 2.36 (q, J = 5.9, 4.2 Hz, 1H), 2.32 (s, 1H), 2.07 (s, 1H), 1.07 (d, J = 6.6 Hz, 3H); LC-MS m / z 464.1 [M+H] + .

[0082] Example 7

[0083] Example 7 provides a pyridopyrimidinone compound, which has the following structural formula:

[0084] The preparation method thereof is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced by

[0085] 1 H NMR (500 MHz, Chloroform-d) δ 7.78 - 7.33 (m, 9H), 7.20 (dt, J = 15.3, 7.8 Hz, 3H), 6.80 (s, 1H), 4.49 (d, J = 4.5 Hz, 3H), 3.70 - 3.44 (m, 3H), 3.19 (s, 2H), 3.05 (q, J = 5.7 Hz, 1H), 2.85 - 2.55 (m, 2H), 2.46 - 2.25 (m, 2H), 1.40 - 1.23 (m, 3H), 1.18 - 1.12 (m, 1H), 1.06 (d, J = 6.6 Hz, 3H); LC-MS m / z 464.1 [M+H] + .

[0086] Example 8

[0087] Example 8 provides a pyridopyrimidinone compound, which has the following structural formula:

[0088] The preparation method thereof is the same as that of Example 1, except that Substitute compound 1-7 in Example 1.

[0089] 1 H NMR (500 MHz, Chloroform-d) δ 7.70 - 7.55 (m, 4H), 7.53 - 7.48 (m, 2H), 7.43 - 7.33 (m, 4H), 6.72 (s, 1H), 4.57 (d, J = 5.4 Hz, 3H), 3.64 - 3.42 (m, 3H), 3.16 (s, 2H), 3.04 (dt, J = 6.8, 5.2 Hz, 1H), 2.85 - 2.72 (m, 1H), 2.39 - 2.24 (m, 1H), 1.38 - 1.21 (m, 2H), 1.20 - 1.09 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H); LC-MS m / z 464.1 [M+H] + .

[0090] Further, the obtained compound is subjected to a separation:

[0091] The first separation is performed using Thar 200 preparative SFC (SFC-10) using a (S,S) Whelk O1, 300 x 50 mm I.D., 10 pm column; mobile phase A: CO2, B: ethanol; flow gradient: B 60%; flow rate 200 mL / min; back pressure 100 bar; column temperature: 38 °C; monitoring wavelength: 220 nm; the separation time for one run is about 6 minutes; sample preparation: 2.5 g sample is dissolved in about 600 mL methanol / dichloromethane system, 20 mL for each injection for separation. The first separation can obtain a mixture of 8-P1 and 8-P2 and 8-P3.

[0092] 1 H NMR (500 MHz, Chloroform-d) δ 7.63 (d, J = 1.8 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.47 - 7.42 (m, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.46 (d, J = 5.5 Hz, 2H), 3.61 (d, J = 14.0 Hz, 1H), 3.49 (d, J = 14.0 Hz, 1H), 3.13 (s, 2H), 3.08 - 2.98 (m, 1H), 2.77 (dd, J = 17.9, 5.2 Hz, 1H), 2.32 (dd, J = 17.6, 4.2 Hz, 1H), 1.06 (d, J = 6.5 Hz, 3H).

[0093] The second split was resolved using MG II preparative SFC (SFC-13) using a ChiralPak AD, 250 x 30 mm I.D., 10 μιη column; mobile phase of A: C02, B: isopropyl alcohol; flow gradient: B 45%; flow rate: 80 mL / min; back pressure: 100 bar; column temperature: 38 °C; monitoring wavelength: 220 nm; time to complete one separation was about 12 minutes; sample preparation: 8-P1 and 8-P2 mixture was dissolved in about 60 mL of methanol / dichloromethane system, 3.6 mL per injection was separated. This split resolved 8-P1 and 8-P2.

[0094] 1 H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 1.7 Hz, 1H), 7.55 (ddt, J = 16.3, 7.7, 1.4 Hz, 2H), 7.45 - 7.38 (m, 3H), 7.22 - 7.12 (m, 2H), 6.85 (s, 1H), 4.48 (d, J = 5.1 Hz, 2H), 4.08 - 3.96 (m, 1H), 3.55 (d, J = 16.8 Hz, 3H), 3.01 - 2.88 (m, 1H), 2.63 (dt, J = 12.0, 4.5 Hz, 2H), 2.35 (dd, J = 16.7, 4.5 Hz, 1H), 1.21 (d, J = 6.1 Hz, 4H), 1.13 (d, J = 6.5 Hz, 3H).

[0095] 1 H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 1.7 Hz, 1H), 7.55 (ddt, J = 16.3, 7.7, 1.4 Hz, 2H), 7.45 - 7.38 (m, 3H), 7.22 - 7.12 (m, 2H), 6.85 (s, 1H), 4.48 (d, J = 5.1 Hz, 2H), 4.08 - 3.96 (m, 1H), 3.55 (d, J = 16.8 Hz, 3H), 3.01 - 2.88 (m, 1H), 2.63 (dt, J = 12.0, 4.5 Hz, 2H), 2.35 (dd, J = 16.7, 4.5 Hz, 1H), 1.21 (d, J = 6.1 Hz, 4H), 1.13 (d, J = 6.5 Hz, 3H).

[0096] Example 9

[0097] Example 9 provides a pyridopyrimidinone compound having the following structural formula:

[0098] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0099] 1 H NMR (500 MHz, Chloroform-d) δ 8.03 (d, J = 8.1 Hz, 1H), 7.91-7.72 (m, 2H), 7.68-7.19 (m, 9H), 6.57 (s, 1H), 5.08-4.89 (m, 2H), 3.45-3.18 (m, 2H), 3.10-2.87 (m, 2H), 2.83-2.67 (m, 1H), 2.32 (dd, J = 18.0, 4.7 Hz, 1H), 1.40-1.16 (m, 1H), 1.07-0.93 (m, 2H); LC-MS m / z 436.2 [M+H] + .

[0100] Example 10

[0101] Example 10 provides a pyridopyrimidinone compound, which has the following structural formula:

[0102] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0103] 1 H NMR (500 MHz, Chloroform-d) δ 7.70-7.55 (m, 4H), 7.53-7.48 (m, 2H), 7.43-7.33 (m, 4H), 6.72 (s, 1H), 4.57 (d, J = 5.4 Hz, 3H), 3.64-3.42 (m, 3H), 3.16 (s, 2H), 3.04 (dt, J = 6.8, 5.2 Hz, 1H), 2.85-2.72 (m, 1H), 2.39-2.24 (m, 1H), 1.38-1.21 (m, 2H), 1.20-1.09 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H); LC-MS m / z 454.2 [M+H] + .

[0104] Example 11

[0105] Example 11 provides a pyridopyrimidinone compound, which has the following structural formula:

[0106] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0107] Example 12

[0108] Example 12 provides a pyridopyrimidinone compound, which has the following structural formula:

[0109] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0110] Example 13

[0111] Example 13 provides a pyridopyrimidinone compound, which has the following structural formula:

[0112] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0113] 1 H NMR (500 MHz, Chloroform-d) δ 7.75 - 7.49 (m, 4H), 7.39 (t, J = 7.7 Hz, 1H), 7.16 - 7.05 (m, 2H), 7.00 (dt, J = 9.2, 2.6 Hz, 1H), 6.60 (s, 1H), 4.52 - 4.34 (m, 3H), 3.75 - 3.48 (m, 3H), 3.19 (s, 2H), 3.06 (dq, J = 11.8, 5.8 Hz, 1H), 2.79 (dd, J = 17.9, 5.2 Hz, 1H), 2.34 (dd, J = 18.0, 4.7 Hz, 1H), 1.41 - 1.24 (m, 2H), 1.15 (dd, J = 6.5, 3.3 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H); LC-MS m / z 422.2 [M+H] + .

[0114] Example 14

[0115] Example 14 provides a pyridopyrimidinone compound, which has the following structural formula:

[0116] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0117] Example 15

[0118] Example 15 provides a pyridopyrimidinone compound, which has the following structural formula:

[0119] The preparation method is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced with

[0120] 1 H NMR (500 MHz, Chloroform-d) δ 7.65 (t, J = 1.7 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.54 (ddt, J = 15.6, 7.7, 1.4 Hz, 2H), 7.43 - 7.32 (m, 2H), 7.22 - 7.12 (m, 1H), 7.08 (t, J = 8.6 Hz, 1H), 6.61 (s, 1H), 4.50 - 4.38 (m, 2H), 3.79 - 3.49 (m, 3H), 3.21 (s, 2H), 3.12 - 2.98 (m, 1H), 2.79 (dd, J = 17.8, 5.2 Hz, 2H), 2.48 - 2.18 (m, 2H), 1.43 - 1.19 (m, 3H), 1.08 (d, J = 6.5 Hz, 3H); LC-MS m / z 438.1 [M+H] + .

[0121] Example 16

[0122] Example 16 provides a pyridopyrimidinone compound, which has the following structural formula:

[0123] The preparation method is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced with

[0124] Example 17

[0125] Example 17 provides a pyridopyrimidinone compound, which has the following structural formula:

[0126] The preparation method is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced with

[0127] 1H NMR (500 MHz, Chloroform-d) δ 7.71 - 7.44 (m, 6 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.26 - 7.13 (m, 1 H), 7.06 (t, J = 8.4 Hz, 1 H), 6.69 (s, 1 H), 4.45 (d, J = 4.0 Hz, 2 H), 3.79 - 3.50 (m, 3 H), 3.21 (s, 2 H), 3.07 (h, J = 6.4 Hz, 1 H), 2.79 (dd, J = 17.8, 5.2 Hz, 1 H), 2.41 - 2.22 (m, 2 H), 1.09 (d, J = 6.5 Hz, 3 H); LC-MS m / z 482.1 [M+H] + .

[0128] Example 18

[0129] Example 18 provides a pyridopyrimidinone compound, having the following structural formula:

[0130] The preparation method thereof is the same as that of Example 1, except that is used to replace compound 1-7 in Example 1.

[0131] 1 H NMR (500 MHz, Chloroform-d) δ 7.77 - 7.35 (m, 10 H), 7.14 (t, J = 9.3 Hz, 1 H), 6.74 (s, 1 H), 4.47 (d, J = 5.3 Hz, 3 H), 3.73 - 3.43 (m, 3 H), 3.21 (s, 2 H), 3.11 - 2.99 (m, 1 H), 2.78 (dd, J = 17.9, 5.2 Hz, 1 H), 2.41 - 2.29 (m, 2 H), 1.08 (d, J = 6.5 Hz, 3 H); LC-MS m / z 472.2 [M+H] + .

[0132] Example 19

[0133] Example 19 provides a pyridopyrimidinone compound, having the following structural formula:

[0134] The preparation method thereof is the same as that of Example 1, except that is used to replace compound 1-7 in Example 1.

[0135] Example 20

[0136] Example 20 provides a pyridopyrimidinone compound, having the following structural formula:

[0137] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0138] 1 H NMR (500 MHz, Chloroform-d) δ 7.75 - 7.46 (m, 3H), 7.39 (td, J = 8.0, 7.0, 4.8 Hz, 2H), 7.11 (dd, J = 8.4, 2.6 Hz, 1H), 6.93 (td, J = 8.3, 2.6 Hz, 1H), 6.54 (s, 1H), 4.53 (qd, J = 15.7, 4.9 Hz, 2H), 3.78 - 3.50 (m, 2H), 3.24 (s, 1H), 3.07 (q, J = 5.7 Hz, 1H), 2.78 (dd, J = 17.8, 5.2 Hz, 1H), 2.34 (dd, J = 17.6, 4.7 Hz, 1H), 1.09 (d, J = 6.5 Hz, 2H); LC-MS m / z 438.1 [M+H] + .

[0139] Example 21

[0140] Example 21 provides a pyridopyrimidinone compound, which has the following structural formula:

[0141] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0142] 1 H NMR (500 MHz, Chloroform-d) δ 7.75 - 7.46 (m, 3H), 7.39 (td, J = 8.0, 7.0, 4.8 Hz, 2H), 7.11 (dd, J = 8.4, 2.6 Hz, 1H), 6.93 (td, J = 8.3, 2.6 Hz, 1H), 6.54 (s, 1H), 4.53 (qd, J = 15.7, 4.9 Hz, 2H), 3.78 - 3.50 (m, 2H), 3.24 (s, 1H), 3.07 (q, J = 5.7 Hz, 1H), 2.78 (dd, J = 17.8, 5.2 Hz, 1H), 2.34 (dd, J = 17.6, 4.7 Hz, 1H), 1.09 (d, J = 6.5 Hz, 2H); LC-MS m / z 438.1 [M+H] + .

[0143] Example 22

[0144] Example 22 provides a pyridopyrimidinone compound, which has the following structural formula:

[0145] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0146] 1 H NMR (500 MHz, Chloroform-d) δ 7.83 - 7.16 (m, 13H), 6.73 (s, 1H), 4.56 - 4.34 (m, 3H), 3.79 - 3.47 (m, 4H), 3.23 (s, 2H), 3.07 (q, J = 5.8 Hz, 1H), 2.79 (dd, J = 17.8, 5.3 Hz, 1H), 2.34 (dd, J = 17.9, 4.8 Hz, 2H), 1.09 (d, J = 6.6 Hz, 3H); LC-MS m / z 482.1 [M+H] + .

[0147] Example 23

[0148] Example 23 provides a pyridopyrimidinone compound, which has the following structural formula:

[0149] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0150] LC-MS m / z 478.1 [M+H] + .

[0151] Example 24

[0152] Example 24 provides a pyridopyrimidinone compound, which has the following structural formula:

[0153] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0154] 1H NMR (500 MHz, Chloroform-d) δ 7.78 - 7.50 (m, 5H), 7.41 (dt, J = 10.3, 7.6 Hz, 2H), 6.80 (s, 2H), 6.75 (d, J = 1.4 Hz, 3H), 5.95 - 5.90 (m, 2H), 4.55 - 4.34 (m, 3H), 3.72 - 3.48 (m, 4H), 3.20 (s, 2H), 3.05 (h, J = 6.1 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.51 - 2.18 (m, 2H), 1.20 - 1.14 (m, 1H), 1.07 (d, J = 6.6 Hz, 3H); LC-MS m / z 430.2 [M+H] + .

[0155] Example 25

[0156] Example 25 provides a pyridopyrimidinone compound, having the following structural formula:

[0157] The preparation method is the same as that of Example 1, except that is used to replace compound 1-7 in Example 1.

[0158] Example 26

[0159] Example 26 provides a pyridopyrimidinone compound, having the following structural formula:

[0160] The preparation method is the same as that of Example 1, except that is used to replace compound 1-7 in Example 1.

[0161] Example 27

[0162] Example 27 provides a pyridopyrimidinone compound, having the following structural formula:

[0163] The preparation method is the same as that of Example 1, except that is used to replace compound 1-7 in Example 1.

[0164] LC-MS m / z 478.1 [M+H] + .

[0165] Example 28

[0166] Example 28 provides a pyridopyrimidinone compound, having the following structural formula:

[0167] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0168] LC-MS m / z 478.1 [M+H] + .

[0169] Example 29

[0170] Example 29 provides a pyridopyrimidinone compound, which has the following structural formula:

[0171] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0172] 1 H NMR (500 MHz, Chloroform-d) δ 7.75-7.69 (m, 1H), 7.65-7.59 (m, 1H), 7.57-7.50 (m, 1H), 7.43 (td, J = 7.7, 2.5 Hz, 1H), 5.74 (d, J = 27.1 Hz, 1H), 3.88-3.56 (m, 3H), 3.37 (s, 1H), 3.23-3.00 (m, 3H), 2.86-2.61 (m, 2H), 2.46-2.30 (m, 1H), 1.33-1.25 (m, 3H), 1.14 (d, J = 6.6 Hz, 2H), 0.55-0.41 (m, 2H), 0.23-0.14 (m, 2H); LC-MS m / z 350.2 [M+H] + .

[0173] Example 30

[0174] Example 30 provides a pyridopyrimidinone compound, which has the following structural formula:

[0175] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0176] 1H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J = 1.8 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.34 (dd, J = 8.3, 6.6 Hz, 2H), 7.28 (td, J = 6.8, 1.5 Hz, 5H), 4.06 (t, J = 8.4 Hz, 1H), 3.82 - 3.67 (m, 2H), 3.65 - 3.45 (m, 5H), 3.35 (s, 2H), 3.15 - 3.06 (m, 1H), 2.86 - 2.76 (m, 1H), 2.46 - 2.30 (m, 2H), 2.17 - 2.01 (m, 2H), 1.37 - 1.25 (m, 3H), 1.12 (dd, J = 6.6, 1.7 Hz, 3H); LC-MS m / z 426.2 [M+H] + .

[0177] Example 31

[0178] Example 31 provides a pyridopyrimidinone compound, which has the following structural formula:

[0179] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0180] 1 H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J = 1.8 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.34 (dd, J = 8.3, 6.6 Hz, 2H), 7.28 (td, J = 6.8, 1.5 Hz, 5H), 4.06 (t, J = 8.4 Hz, 1H), 3.82 - 3.67 (m, 2H), 3.65 - 3.45 (m, 5H), 3.35 (s, 2H), 3.15 - 3.06 (m, 1H), 2.86 - 2.76 (m, 1H), 2.46 - 2.30 (m, 2H), 2.17 - 2.01 (m, 2H), 1.37 - 1.25 (m, 3H), 1.12 (dd, J = 6.6, 1.7 Hz, 3H); LC-MS m / z 426.2 [M+H] + .

[0181] Example 32

[0182] Example 32 provides a pyridopyrimidinone compound, having the following structural formula:

[0183] The preparation method is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced by

[0184] 1 H NMR (500 MHz, Chloroform-d) δ 7.71-7.65 (m, 1H), 7.60 (dd, J = 16.1, 5.4 Hz, 1H), 7.53 (dt, J = 7.7, 1.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.33-7.28 (m, 1H), 7.28-7.19 (m, 4H), 4.62-4.53 (m, 2H), 3.85-3.70 (m, 1H), 3.58 (d, J = 13.6 Hz, 1H), 3.34 (d, J = 15.7 Hz, 1H), 3.28 (d, J = 15.6 Hz, 1H), 3.10 (h, J = 6.2 Hz, 1H), 3.05-2.92 (m, 2H), 2.84-2.66 (m, 2H), 2.37 (dd, J = 17.7, 5.0 Hz, 1H), 1.84 (dd, J = 13.2, 3.5 Hz, 2H), 1.71 (d, J = 4.0 Hz, 1H), 1.67 (dd, J = 10.9, 2.9 Hz, 1H), 1.35-1.25 (m, 1H), 1.14 (d, J = 6.5 Hz, 2H); LC-MS m / z 440.2 [M+H] + .

[0185] Example 33

[0186] Example 33 provides a pyridopyrimidinone compound, having the following structural formula:

[0187] The preparation method is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced by

[0188] 1H NMR (500 MHz, Chloroform-d) δ 7.71 (d, J = 1.9 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.55 (td, J = 7.5, 7.1, 3.0 Hz, 4H), 7.41 (t, J = 7.7 Hz, 2H), 7.28 (td, J = 7.6, 1.3 Hz, 2H), 7.19 - 7.07 (m, 2H), 6.33 (t, J = 2.1 Hz, 1H), 4.97 - 4.89 (m, 1H), 4.86 (d, J = 16.8 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.70 - 3.60 (m, 2H), 3.34 (s, 2H), 3.11 (s, 3H), 3.10 - 3.04 (m, 1H), 2.80 (dt, J = 17.5, 3.3 Hz, 1H), 2.35 (dd, J = 17.7, 4.8 Hz, 1H), 1.12 (d, J = 6.6 Hz, 3H); LC-MS m / z 478.1 [M+H] + .

[0189] Example 34

[0190] Example 34 provides a pyridopyrimidinone compound, which has the following structural formula:

[0191] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0192] 1 H NMR (500 MHz, Chloroform-d) δ 7.72 - 7.67 (m, 1H), 7.64 - 7.57 (m, 1H), 7.53 (dt, J = 7.7, 1.5 Hz, 1H), 7.47 - 7.37 (m, 3H), 7.22 - 7.13 (m, 2H), 4.86 - 4.69 (m, 2H), 3.78 (dd, J = 29.0, 13.0 Hz, 1H), 3.72 - 3.58 (m, 2H), 3.27 (d, J = 2.2 Hz, 2H), 3.12 - 3.03 (m, 2H), 3.03 (s, 2H), 2.79 (dt, J = 17.8, 3.4 Hz, 1H), 2.34 (dd, J = 17.7, 5.0 Hz, 1H), 1.34 - 1.24 (m, 1H), 1.24 - 1.16 (m, 1H), 1.12 (d, J = 6.5 Hz, 2H); LC-MS m / z 478.1 [M+H] + .

[0193] Example 35

[0194] Example 35 provides a pyridopyrimidinone compound having the following structural formula:

[0195] The preparation method is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced with

[0196] 1 H NMR (500 MHz, Chloroform-d) δ 7.73-7.67 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.57-7.51 (m, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.44-7.37 (m, 2H), 7.12 (dd, J = 8.0, 5.8 Hz, 2H), 4.78 (t, J = 15.9 Hz, 1H), 4.69 (d, J = 15.8 Hz, 1H), 3.84-3.65 (m, 2H), 3.61 (d, J = 13.8 Hz, 1H), 3.25 (d, J = 2.2 Hz, 2H), 3.12-3.01 (m, 4H), 2.78 (dd, J = 17.8, 5.2 Hz, 1H), 2.34 (dt, J = 17.7, 5.1 Hz, 1H), 1.12 (d, J = 6.5 Hz, 3H); LC-MS m / z 478.1 [M+H] + .

[0197] Example 36

[0198] Example 36 provides a pyridopyrimidinone compound having the following structural formula:

[0199] The preparation method is the same as that of Example 1, except that compound 1-7 in Example 1 is replaced with

[0200] 1H NMR (500 MHz, Chloroform-d) δ 7.72 - 7.67 (m, 1H), 7.59 (dd, J = 7.9, 5.7 Hz, 3H), 7.53 (dt, J = 7.7, 1.4 Hz, 1H), 7.41 (q, J = 7.7, 7.2 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 4.95 - 4.85 (m, 1H), 4.82 (d, J = 16.0 Hz, 1H), 3.81 (d, J = 13.8 Hz, 1H), 3.61 (d, J = 13.8 Hz, 1H), 3.27 (d, J = 2.7 Hz, 2H), 3.08 (dd, J = 12.5, 6.1 Hz, 2H), 3.05 (s, 2H), 2.79 (dt, J = 17.8, 3.4 Hz, 1H), 2.34 (dd, J = 17.8, 4.9 Hz, 1H), 1.12 (d, J = 6.5 Hz, 3H); LC-MS m / z 468.2 [M+H] + .

[0201] Example 37

[0202] Example 37 provides a pyridopyrimidinone compound, having the following structural formula:

[0203] The preparation method is the same as that of Example 1, except that Compound 1-7 in Example 1 is replaced by

[0204] 1 H NMR (500 MHz, Chloroform-d) δ 7.72 - 7.67 (m, 1H), 7.59 (dd, J = 7.9, 5.7 Hz, 3H), 7.53 (dt, J = 7.7, 1.4 Hz, 1H), 7.41 (q, J = 7.7, 7.2 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 4.95 - 4.85 (m, 1H), 4.82 (d, J = 16.0 Hz, 1H), 3.81 (d, J = 13.8 Hz, 1H), 3.61 (d, J = 13.8 Hz, 1H), 3.27 (d, J = 2.7 Hz, 2H), 3.08 (dd, J = 12.5, 6.1 Hz, 2H), 3.05 (s, 2H), 2.79 (dt, J = 17.8, 3.4 Hz, 1H), 2.34 (dd, J = 17.8, 4.9 Hz, 1H), 1.12 (d, J = 6.5 Hz, 3H); LC-MS m / z 468.2 [M+H]

[0205] Example 38

[0206] Example 38 provides a pyridopyrimidinone compound, having the following structural formula:

[0207] The reaction equation and preparation method are as follows:

[0208] S1, Compound 1-1 (5.0 g, 33.0 mmol), compound 1-2 (3.2 mL, 36 mmol), DBU (0.5 mL, 3.3 mmol) and triethylamine (4.5 mL, 33.0 mmol) were dissolved in dichloromethane (60 mL) and stirred at 40°C for 12 hours. Then triethylamine (9.0 mL, 66.0 mmol) and Boc2O (9.0 mL, 39.0 mmol) were added and the reaction was continued at 40°C for 24 hours. After the completion of the reaction, it was cooled to room temperature, the solvent was removed under reduced pressure, methyl tert-butyl ether was added and stirred for 30 minutes, filtered, the filter cake was washed twice with methyl tert-butyl ether, the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain compound 38-1 (7.3 g, 75% yield) as a colorless oil, which was used directly in the next step.

[0209] S2, Compound 38-1 (10.6 g, 34.9 mmol) was dissolved in tetrahydrofuran (175 mL), 1.0 M potassium tert-butoxide / tetrahydrofuran solution (42 mL, 42.0 mmol) was added under ice bath, and the reaction was continued at 0°C for 4 hours. After the completion of the reaction, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 4:1) gave compound 38-2 (mixture, 9.6 g, 85% total yield) as a colorless oil.

[0210] S3, Compound 38-2 (2.7 g, 10.0 mmol) and compound 13-3 (4.5 g, 12.0 mmol) were dissolved in super dry methanol (20 mL), sodium methoxide (2.7 g, 50.0 mmol) was added, and stirred at 100°C for 16 hours. After the completion of the reaction, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (4% MeOH in DCM) gave compound 38-4 as a yellow solid.

[0211] S4, Compound 38-4 (2.3 g, 5.0 mmol) was added to a hydrochloric acid / ethyl acetate solution (10 mL) and stirred at room temperature. After the completion of the reaction, which was monitored by TLC, the solvent was removed under reduced pressure, saturated NaHCO3 aqueous solution was added to quench the reaction, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain compound 38-5 as an off-white solid.

[0212] S5, dissolve compound 38-5 (73 mg, 0.2 mmol) in acetonitrile (2 mL), add compound 38-6 (46 mg, 0.24 mmol) and DIPEA (130 mg, 1.0 mmol), stir at 60 °C overnight. After the reaction is completed, remove the solvent under reduced pressure, dilute the reaction with water, extract with dichloromethane. Dry the organic layer with anhydrous sodium sulfate and concentrate, separate and purify by column chromatography (4% MeOH in DCM) to obtain compound 38 as a yellow solid.

[0213] 1 H NMR (500 MHz, Chloroform-d) δ 7.51 (t, J = 8.3 Hz, 2H), 7.44 - 7.20 (m, 26H), 7.18 - 7.10 (m, 7H), 6.84 (s, 1H), 4.38 (d, J = 3.4 Hz, 5H), 3.66 (d, J = 13.6 Hz, 2H), 3.64 - 3.55 (m, 3H), 3.54 - 3.44 (m, 4H), 3.24 - 3.12 (m, 5H), 3.06 (q, J = 5.5 Hz, 2H), 2.83 - 2.71 (m, 4H), 2.30 (dp, J = 14.5, 6.5, 4.1 Hz, 4H), 1.05 (s, 3H).

[0214] Example 39

[0215] Example 39 provides a pyridopyrimidinone compound, which has the following structural formula:

[0216] The preparation method thereof is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced by .

[0217] Example 40

[0218] Example 40 provides a pyridopyrimidinone compound, which has the following structural formula:

[0219] The preparation method thereof is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced by .

[0220] Example 41

[0221] Example 41 provides a pyridopyrimidinone compound, which has the following structural formula:

[0222] The preparation method thereof is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced by .

[0223] Example 42

[0224] Example 42 provides a pyridopyrimidinone compound having the following structural formula:

[0225] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0226] Example 43

[0227] Example 43 provides a pyridopyrimidinone compound having the following structural formula:

[0228] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0229] Example 44

[0230] Example 44 provides a pyridopyrimidinone compound having the following structural formula:

[0231] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0232] Example 45

[0233] Example 45 provides a pyridopyrimidinone compound having the following structural formula:

[0234] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0235] Example 46

[0236] Example 46 provides a pyridopyrimidinone compound having the following structural formula:

[0237] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0238] Example 47

[0239] Example 47 provides a pyridopyrimidinone compound having the following structural formula: ​​​​​

[0240] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0241] Example 48

[0242] Example 48 provides a pyridopyrimidinone compound, having the following structural formula:

[0243] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0244] 1 H NMR (500 MHz, Chloroform-d) δ 7.53-7.47 (m, 1H), 7.45-7.39 (m, 1H), 7.32 (td, J = 7.8, 6.0 Hz, 4H), 7.20 (dt, J = 31.2, 8.1 Hz, 4H), 7.02 (dd, J = 7.9, 2.4 Hz, 1H), 5.32 (s, 1H), 4.50 (d, J = 4.9 Hz, 1H), 3.85 (dd, J = 22.6, 13.5 Hz, 1H), 3.73 (dt, J = 13.4, 6.7 Hz, 6H), 3.49 (d, J = 10.2 Hz, 1H), 3.15 (q, J = 7.4 Hz, 5H), 2.39-2.27 (m, 1H), 1.27 (s, 1H), 1.16 (t, J = 7.8 Hz, 3H); LC-MS m / z 505.1 [M+H] + .

[0245] Example 49

[0246] Example 49 provides a pyridopyrimidinone compound, having the following structural formula:

[0247] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0248] Example 50

[0249] Example 50 provides a pyridopyrimidinone compound, having the following structural formula:

[0250] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0251] Example 51

[0252] Example 51 provides a pyridopyrimidinone compound having the following structural formula:

[0253] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0254] Example 52

[0255] Example 52 provides a pyridopyrimidinone compound having the following structural formula:

[0256] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0257] Example 53

[0258] Example 53 provides a pyridopyrimidinone compound having the following structural formula:

[0259] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0260] Example 54

[0261] Example 54 provides a pyridopyrimidinone compound having the following structural formula:

[0262] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0263] Example 55

[0264] Example 55 provides a pyridopyrimidinone compound having the following structural formula:

[0265] The preparation method is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced with

[0266] Example 56

[0267] Example 56 provides a pyridopyrimidinone compound having the following structural formula:

[0268] The preparation method is same as that of Example 38, except that compound 38-6 in Example 38 is replaced by

[0269] Example 57

[0270] Example 57 provides a pyridopyrimidinone compound, having the following structural formula:

[0271] The preparation method is same as that of Example 38, except that compound 38-6 in Example 38 is replaced by

[0272] Example 58

[0273] Example 58 provides a pyridopyrimidinone compound, having the following structural formula:

[0274] The preparation method is same as that of Example 38, except that compound 38-6 in Example 38 is replaced by

[0275] Example 59

[0276] Example 59 provides a pyridopyrimidinone compound, having the following structural formula:

[0277] The preparation method is same as that of Example 38, except that compound 38-6 in Example 38 is replaced by

[0278] Example 60-1

[0279] Example 60-1 provides a pyridopyrimidinone compound, having the following structural formula:

[0280] The preparation method is same as that of Example 1, except that compound 1-6 in Example 1 is replaced by

[0281] 1H NMR (500 MHz, Chloroform-d) δ 7.33 - 7.18 (m, 7 H), 6.97 (dd, J = 9.8, 7.4 Hz, 2 H), 6.64 (s, 1 H), 4.45 (d, J = 5.0 Hz, 2 H), 3.53 (s, 2 H), 3.19 (s, 2 H), 2.60 (dd, J = 16.7, 5.3 Hz, 4 H). LC-MS m / z 365.2 [M+H] + .

[0282] Example 60-2

[0283] Example 60-2 provides a pyridopyrimidinone compound, having the following structural formula:

[0284] The preparation method is the same as that of Example 1, except that Compound 1-6 in Example 1 is replaced by

[0285] 1 H NMR (500 MHz, Chloroform-d) δ 7.58 - 7.06 (m, 9 H), 6.64 (s, 1 H), 4.44 (d, J = 5.2 Hz, 2 H), 3.50 (s, 2 H), 3.15 (s, 2 H), 2.66 - 2.49 (m, 4 H). LC-MS m / z 381.1 [M+H] + .

[0286] Example 60-3

[0287] Example 60-3 provides a pyridopyrimidinone compound, having the following structural formula:

[0288] The preparation method is the same as that of Example 1, except that Compound 1-6 in Example 1 is replaced by

[0289] 1 H NMR (500 MHz, Chloroform-d) δ 7.52 - 7.21 (m, 10 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.64 (s, 1 H), 4.43 (d, J = 5.2 Hz, 2 H), 3.51 (s, 2 H), 3.16 (s, 2 H), 2.59 (dd, J = 19.0, 5.4 Hz, 4 H). LC-MS m / z 425.1 [M+H] + .

[0290] Example 60-4

[0291] Example 60-4 provides a pyridopyrimidinone compound having the following structural formula:

[0292] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced with

[0293] 1 H NMR (500 MHz, Chloroform-d) δ 7.29 (d, J = 4.3 Hz, 4H), 7.25 (m, 1H), 7.15 (qd, J = 7.1, 6.6, 2.2 Hz, 3H), 4.51 (d, J = 3.8 Hz, 2H), 3.50 (s, 2H), 3.18 (s, 2H), 2.59 (d, J = 4.9 Hz, 4H), 2.31 (s, 3H). LC-MS m / z 361.2 [M+H] + .

[0294] Example 60-5

[0295] Example 60-5 provides a pyridopyrimidinone compound having the following structural formula:

[0296] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced with

[0297] 1 H NMR (500 MHz, Chloroform-d) δ 7.40 - 7.19 (m, 8H), 6.78 (q, J = 9.5, 8.8 Hz, 2H), 6.67 (s, 1H), 4.45 (d, J = 5.3 Hz, 2H), 3.59 (s, 2H), 3.24 (s, 2H), 2.62 (dt, J = 28.2, 6.1 Hz, 4H). LC-MS m / z 383.2 [M+H] + .

[0298] Example 60-6

[0299] Example 60-6 provides a pyridopyrimidinone compound having the following structural formula:

[0300] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced with

[0301] 1H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.31 - 7.17 (m, 6H), 6.95 (s, 1H), 4.52 (d, J = 5.2 Hz, 2H), 3.48 (s, 2H), 3.16 (s, 2H), 2.71 - 2.49 (m, 4H). LC-MS m / z 415.2 [M+H] + .

[0302] Example 61-1

[0303] Example 61-1 provides a pyridopyrimidinone compound, having the following structural formula:

[0304] The preparation method is the same as that of Example 1, except that is used to replace compound 1-6 in Example 1.

[0305] 1 H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.31 - 7.17 (m, 6H), 6.95 (s, 1H), 4.52 (d, J = 5.2 Hz, 2H), 3.48 (s, 2H), 3.16 (s, 2H), 2.71 - 2.49 (m, 4H). LC-MS m / z 415.2 [M+H] + .

[0306] Example 61-2

[0307] Example 61-2 provides a pyridopyrimidinone compound, having the following structural formula:

[0308] The preparation method is the same as that of Example 1, except that is used to replace compound 1-6 in Example 1.

[0309] 1H NMR (500 MHz, Chloroform-d) δ 11.42 (s, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.53 (dd, J = 7.7, 1.7 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.66 (s, 1H), 4.49 (d, J = 5.4 Hz, 2H), 3.45 (s, 2H), 3.10 (s, 2H), 2.58 (s, 4H). LC-MS m / z 406.1 [M+H] + .

[0310] Example 61-3

[0311] Example 61-3 provides a pyridopyrimidinone compound, having the following structural formula:

[0312] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced by

[0313] 1 H NMR (500 MHz, Chloroform-d) δ 11.42 (s, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.53 (dd, J = 7.7, 1.7 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.66 (s, 1H), 4.49 (d, J = 5.4 Hz, 2H), 3.45 (s, 2H), 3.10 (s, 2H), 2.58 (s, 4H). LC-MS m / z 406.1 [M+H] + .

[0314] Example 61-4

[0315] Example 61-4 provides a pyridopyrimidinone compound, having the following structural formula:

[0316] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced by

[0317] 1H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 1.7 Hz, 1H), 7.51 (tt, J = 9.3, 1.4 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.19 - 7.11 (m, 3H), 6.37 (s, 1H), 4.52 (d, J = 5.0 Hz, 2H), 3.43 (s, 2H), 3.09 (s, 2H), 2.57 (d, J = 3.5 Hz, 4H), 2.31 (s, 3H); LC-MS m / z 386.2 [M+H] + .

[0318] Example 61-5

[0319] Example 61-5 provides a pyridopyrimidinone compound, having the following structural formula:

[0320] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced with

[0321] 1 H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 1.7 Hz, 1H), 7.51 (tt, J = 9.3, 1.4 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.19 - 7.11 (m, 3H), 6.37 (s, 1H), 4.52 (d, J = 5.0 Hz, 2H), 3.43 (s, 2H), 3.09 (s, 2H), 2.57 (d, J = 3.5 Hz, 4H), 2.31 (s, 3H); LC-MS m / z 386.2 [M+H] + .

[0322] Example 61-6

[0323] Example 61-6 provides a pyridopyrimidinone compound, having the following structural formula:

[0324] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced with

[0325] 1H NMR (500 MHz, Chloroform-d) δ 7.67 - 7.49 (m, 6H), 7.47 - 7.32 (m, 4H), 6.67 (s, 1H), 5.26 (s, 1H), 4.59 (d, J = 5.2 Hz, 2H), 3.73 (s, 1H), 3.50 (s, 2H), 3.42 (s, 1H), 3.16 (s, 2H), 2.72 (t, J = 5.8 Hz, 1H), 2.60 (dt, J = 11.5, 5.3 Hz, 4H); LC-MS m / z 415.2 [M+H] + .

[0326] Example 62-1

[0327] Example 62-1 provides a pyridopyrimidinone compound, which has the following structural formula:

[0328] The reaction equation and preparation method are as follows:

[0329] S1, Compound 1 (1.8 g, 9.3 mmol), compound 2 (1.1 g, 11.2 mmol) and DBU (150 μL, 1.0 mmol) were mixed and stirred at 60°C for 24 hours. After the reaction was completed, purification was performed by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 3 (1.5 g, with a yield of 85%) in the form of colorless oil.

[0330] S2, Compound 3 (5.0 mmol) was dissolved in super dry tetrahydrofuran (20 mL), 1.0M potassium tert-butoxide / tetrahydrofuran solution (6 mL) was added under ice bath, and the reaction was carried out at 0°C for 4 hours. After the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to obtain compound 4 by column chromatography (petroleum ether: ethyl acetate = 4:1).

[0331] S3, Compound 4 (52 mg, 0.20 mmol) and compound 5 (53 mg, 0.24 mmol) were dissolved in super dry methanol (2.0 mL), sodium methoxide (54 mg, 1.0 mmol) was added, and stirring was carried out at 80°C for 16 hours. After the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated, and compound 6 was obtained in the form of light yellow solid by purification through column chromatography (3% MeOH in DCM).

[0332] 1H NMR (500 MHz, Chloroform-d) δ 7.41 - 7.19 (m, 7H), 6.92 - 6.83 (m, 1H), 6.80 - 6.72 (m, 2H), 4.53 - 4.32 (m, 2H), 3.57 (d, J = 2.0 Hz, 2H), 3.37 - 3.13 (m, 2H), 2.70 (ddd, J = 40.4, 12.0, 5.8 Hz, 2H), 2.29 (dd, J = 11.4, 6.4 Hz, 1H), 1.19 (d, J = 7.0 Hz, 3H); LC-MS m / z 397.2 [M+H] + .

[0333] Example 62-2

[0334] Example 62-2 provides a pyridopyrimidinone compound, which has the following structural formula:

[0335] The preparation method thereof is the same as that of Example 62-1, except that compound 5 in Example 62-1 is replaced by

[0336] 1 H NMR (500 MHz, Chloroform-d) δ 7.41 - 7.19 (m, 7H), 6.92 - 6.83 (m, 1H), 6.80 - 6.72 (m, 2H), 4.53 - 4.32 (m, 2H), 3.57 (d, J = 2.0 Hz, 2H), 3.37 - 3.13 (m, 2H), 2.70 (ddd, J = 40.4, 12.0, 5.8 Hz, 2H), 2.29 (dd, J = 11.4, 6.4 Hz, 1H), 1.19 (d, J = 7.0 Hz, 3H); LC-MS m / z 397.2 [M+H] + .

[0337] Example 63-1

[0338] Example 63-1 provides a pyridopyrimidinone compound, which has the following structural formula:

[0339] The reaction equation and preparation method are as follows:

[0340] ​S1, Compound 7 (1.8 g, 9.2 mmol) was dissolved in methanol (10 mL), and benzotriazole (1.1 g, 9.2 mmol) and 40% aqueous formaldehyde solution (0.92 mL, 12.0 mmol) were added under ice bath. The reaction was stirred at room temperature for 16 hours. The reaction was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 1:1) gave compound 8.

[0341] S2, Pre-activated zinc powder (0.62 g, 9.6 mmol) was added to super dry tetrahydrofuran (15 mL), and trimethylsilyl chloride (TMSCI, 0.57 g, 5.3 mmol) was stirred at room temperature for 10 minutes. Then ethyl bromodifluoroacetate (0.87 g, 4.8 mmol) was dissolved in super dry tetrahydrofuran (10 mL) and slowly added to the reaction system. Then a tetrahydrofuran (10 mL) solution of compound 8 (1.55 g, 4.8 mmol) was added dropwise. The reaction was reacted at room temperature for 16 hours. The reaction was quenched by pouring into water and filtered. The filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 1:1) gave compound 9.

[0342] S3, Compound 9 obtained in the previous step was dissolved in super dry tetrahydrofuran, and 1.2 equivalents of 1.0 M potassium tert-butoxide / tetrahydrofuran solution were added under ice bath. The reaction was reacted at 0°C for 4 hours. After the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 4:1) gave compound 10.

[0343] S4, Compound 10 (57 mg, 0.20 mmol) and compound 5 (53 mg, 0.24 mmol) were dissolved in super dry methanol (2.0 mL), and sodium methoxide (54 mg, 1.0 mmol) was added. The reaction was stirred at 80°C for 16 hours. After the reaction was completed, water was added for dilution, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (4% MeOH in DCM) gave compound 11 as a light yellow solid.

[0344] 1 H NMR (500 MHz, Chloroform-d) δ 7.59-7.54 (m, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.38-7.33 (m, 2H), 7.32-7.27 (m, 2H), 6.55 (s, 1H), 4.61 (d, J = 5.3 Hz, 2H), 3.64 (s, 2H), 3.28 (s, 2H), 3.10-2.89 (m, 3H). LC-MS m / z 419.1 [M+H] +.

[0345] Example 63-2

[0346] Example 63-2 provides a pyridopyrimidinone compound having the following structural formula:

[0347] The preparation method is the same as that of Example 63-1, except that compound 5 in Example 63-1 is replaced by .

[0348] 1 H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 2.1 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.38 - 7.32 (m, 4H), 7.29 (dq, J = 7.7, 2.8 Hz, 1H), 6.93 - 6.84 (m, 2H), 5.16 (s, 2H), 3.79 (s, 2H), 3.52 (t, J = 3.2 Hz, 2H), 3.03 (t, J = 11.7 Hz, 2H). LC-MS m / z 451.1 [M+H] + .

[0349] Example 64-1

[0350] Example 64-1 provides a pyridopyrimidinone compound having the following structural formula:

[0351] The preparation method is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced by .

[0352] 1 H NMR (500 MHz, Chloroform-d) δ 7.36 - 7.18 (m, 8H), 7.01 - 6.95 (m, 2H), 6.70 (s, 1H), 4.39 (qd, J = 15.1, 4.9 Hz, 2H), 3.58 (s, 2H), 3.27 - 3.06 (m, 2H), 2.82 (dq, J = 10.3, 5.2 Hz, 1H), 2.67 (dd, J = 17.8, 5.4 Hz, 1H), 2.38 (dd, J = 18.1, 5.0 Hz, 1H), 0.97 (t, J = 7.4 Hz, 3H); LC-MS m / z 393.2 [M+H] + .

[0353] Example 64-2

[0354] Example 64-2 provides a pyridopyrimidinone compound having the following structural formula:

[0355] The preparation method is the same as that of Example 1, except that is used to replace compound 1-6 in Example 1.

[0356] 1 H NMR (500 MHz, Chloroform-d) δ 7.41-7.19 (m, 7H), 7.19-7.14 (m, 2H), 6.74 (s, 1H), 4.38 (qd, J = 15.4, 5.1 Hz, 2H), 3.56 (dd, J = 14.9, 1.6 Hz, 2H), 3.26-3.12 (m, 2H), 2.88-2.74 (m, 1H), 2.66 (dd, J = 17.9, 5.3 Hz, 1H), 2.45-2.30 (m, 1H), 0.97 (dt, J = 10.3, 7.4 Hz, 3H); LC-MS m / z 409.2 [M+H] + .

[0357] Example 64-3

[0358] Example 64-3 provides a pyridopyrimidinone compound, which has the following structural formula:

[0359] The preparation method is the same as that of Example 1, except that is used to replace compound 1-6 in Example 1.

[0360] 1 H NMR (500 MHz, Chloroform-d) δ 7.41-7.19 (m, 7H), 7.19-7.14 (m, 2H), 6.74 (s, 1H), 4.38 (qd, J = 15.4, 5.1 Hz, 2H), 3.56 (dd, J = 14.9, 1.6 Hz, 2H), 3.26-3.12 (m, 2H), 2.88-2.74 (m, 1H), 2.66 (dd, J = 17.9, 5.3 Hz, 1H), 2.45-2.30 (m, 1H), 0.97 (dt, J = 10.3, 7.4 Hz, 3H); LC-MS m / z 409.2 [M+H] + .

[0361] Example 64-4

[0362] Example 64-4 provides a pyridopyrimidinone compound, which has the following structural formula:

[0363] The preparation method is the same as that of Example 1, except that Compound 1-6 in Example 1 is replaced.

[0364] 1 H NMR (500 MHz, Chloroform-d) δ 7.34 - 7.21 (m, 7H), 7.21 - 7.12 (m, 3H), 6.35 (s, 1H), 4.47 (qd, J = 15.0, 3.6 Hz, 2H), 3.70 - 3.41 (m, 2H), 3.28 - 3.09 (m, 2H), 2.87 - 2.74 (m, 1H), 2.67 (dd, J = 18.1, 5.3 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.31 (s, 3H), 1.64 (ddd, J = 13.2, 7.5, 5.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H); LC-MS m / z 389.2 [M+H] + .

[0365] Example 65

[0366] Example 65 provides a pyridopyrimidinone compound, which has the following structural formula:

[0367] The reaction equation and preparation method are as follows:

[0368] S1, Compound 12 (1.8 g, 20 mmol) was dissolved in methanol, and ammonia water was added, and stirred at 70°C overnight. After the reaction was completed, purification was performed by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain white solid compound 13 (1.5 g, with a yield of 85%).

[0369] S2, Compound 13 (2.56 g, 10.0 mmol) was dissolved in pyridine (20 mL), and ethyl isothiocyanate (1.0 mL, 10.0 mmol) was added, and the reaction was carried out at 90°C overnight. After the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to be directly used in the next step.

[0370] S3, The product obtained in the above step and DBU (53 mg, 0.24 mmol) were dissolved in tetrahydrofuran (20 mL), and methyl iodide (54 mg, 5.0 mmol) was added, and stirred in an ice bath for 16 hours. After the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated to be directly used in the next step.

[0371] S4, The product from the previous step was dissolved in dichloromethane, sodium acetate (456 mg, 5.56 mmol) and magnesium sulfate (4.15 g) were added, and the mixture was cooled to -70 °C, then m-CPBA (1.8 g, 10 mmol) was added. After the reaction was completed, the reaction was quenched with Na2SO3 aqueous solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound 16 (1.5 g, 85% yield) as a white solid.

[0372] S5, Compound 16 (2.78 mmol) was dissolved in 1,4-dioxane (10 mL), 4- bromobenzylamine (880 mg, 4.73 mmol), DIPEA (350 μL) and DMAP (34 mg) were added, and the mixture was stirred at 50 °C overnight. After the reaction was completed, the reaction was diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound 17.

[0373] S6, Compound 17 (52 mg, 1.0 mmol) was added to an ethyl acetate solution of hydrochloric acid (10 mL), and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure to give compound 18 as a light yellow solid.

[0374] S7, Compound 18 (80 mg, 0.2 mmol) was dissolved in 1,2-dichloroethane (2 mL), compound 1-4 (40 mg, 0.3 mmol), sodium acetate (16 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 3 hours. NaBH(OAc)3 (42 mg, 0.2 mmol) was added portionwise, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the insoluble matter was removed by filtration, and the filtrate was quenched with saturated NaHCO3 aqueous solution (10 mL), and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol = 20: 1) to give compound 19 (62 mg, 65% yield) as a light yellow solid.

[0375] LC-MS m / z 468.2 [M+H] + .

[0376] Example 66

[0377] Example 66 provides a pyridopyrimidinone compound, which has the following structural formula:

[0378] The preparation method thereof is the same as that of Example 1, except that compound 1-6 in Example 1 is replaced with .

[0379] Example 67

[0380] Example 67 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0381] The preparation method thereof is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced by

[0382] Example 68

[0383] Example 68 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0384] The preparation method thereof is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced by

[0385] Example 69

[0386] Example 69 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0387] The preparation method thereof is the same as that of Example 38, except that compound 38-6 in Example 38 is replaced by

[0388] Example 70

[0389] Example 70 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0390] The synthesis route and preparation method thereof are as follows:

[0391] S1, compound 1-1 (15.4 g, 100 mmol), compound 70-1 (9.5 mL, 105 mmol), DBU (1.5 mL, 10 mmol) and triethylamine (38 mL, 273 mmol) were dissolved in dichloromethane (200 mL), and stirred at 40°C for 24 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed by reduced pressure distillation, methyl tert-butyl ether was added, stirred for 30 minutes, then filtered, the filter cake was washed twice with methyl tert-butyl ether, and the organic phase was concentrated to obtain compound 70-2 in the form of colorless oil, which was directly used in the next step.

[0392] S2, Compound 70-2 obtained in previous step was dissolved in dichloromethane (200 mL), Boc20 (23.0 mL, 150 mmol) and triethylamine (46.0 mL, 330 mmol) were added and stirred at 40 °C for 24 h. After completion of the reaction, water (50 mL) was added to quench the reaction and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound 70-3 (24.7 g, 82% yield over two steps) as a light yellow oil.

[0393] S3, Compound 70-3 (2.9 g, 8.3 mmol) was dissolved in tetrahydrofuran (85 mL) and 1.0 M potassium tert-butoxide in tetrahydrofuran (10 mL) was added dropwise at -78 °C. The reaction was continued at -70 °C for 12 h. After completion of the reaction, water was added to dilute and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound 70-4 (1.8 g, 69% yield over all) as a colorless oil.

[0394] S4, Compound 70-4 (2.7 g, 11.0 mmol) and compound 70-5 (4.5 g, 10.0 mmol) were dissolved in super dry methanol (20 mL) and sodium methoxide (2.2 g, 40.0 mmol) was added. The reaction was stirred at 80 °C for 16 h. After completion of the reaction, water was added to dilute and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (5% MeOH in DCM) to give compound 70-6 (3.9 g, 88% yield) as a light yellow solid.

[0395] S5, Compound 70-6 (1.46 g, 10.0 mmol) was dissolved in DCM (20 mL) and HCl (4.0 M in Dioxane, 40 mL) was added. The reaction was stirred at room temperature for 24 h. After completion of the reaction, the solvent was removed under reduced pressure to give compound 70-7 (3.6 g, 100% yield) as a light yellow solid.

[0396] S6, Compound 70-7 (374 mg, 1.0 mmol) was dissolved in super dry DCM (2 mL) and compound 70-8 (40 mg, 1.2 mmol), acetic acid (58 μL, 1.0 mmol) were added. The reaction was stirred at room temperature for 3 h. NaBH(OAc)3 (422 mg, 2.0 mmol) was added portionwise and the reaction was continued to stir at room temperature for 24 h. After completion of the reaction, saturated aqueous NaHCO3 (10 mL) was added to quench the reaction and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to give compound 70 (248 mg, 58% yield) as a light yellow solid.

[0397] 1 H NMR (600 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.53 (d, J = 7.9 Hz, 2H), 7.35 - 7.29 (m, 4H), 7.24 (s, 1H), 6.93 (s, 1H), 4.66 - 4.45 (m, 2H), 3.76 (d, J = 13.2 Hz, 1H), 3.49 (d, J = 13.3 Hz, 1H), 3.05 - 2.88 (m, 2H), 2.65 - 2.57 (m, 1H), 2.16 (dd, J = 17.8, 5.1 Hz, 1H), 1.03 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.6, 159.4, 153.0, 145.0, 139.9, 129.0, 128.7, 128.3, 128.0 (q, J = 31.7 Hz), 127.3, 125.6 (q, J = 3.7 Hz), 124.8 (q, J = 271.8 Hz), 107.2, 57.6, 51.9, 46.0, 43.5, 38.9, 14.7. 19 F NMR (471 MHz, DMSO-d6) δ -60.79.

[0398] Example 71

[0399] Example 71 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0400] The preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0401] 1H NMR (600 MHz, Chloroform-d) δ 11.43 (br s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.17 (s, 1H), 4.69 (d, J = 5.1 Hz, 2H), 3.22 (s, 2H), 3.00 (d, J = 6.1 Hz, 1H), 2.73 (dd, J = 17.8, 5.2 Hz, 1H), 2.28 (dd, J = 17.8, 4.7 Hz, 1H), 2.20 (dd, J = 12.6, 7.4 Hz, 1H), 2.13 (dd, J = 12.4, 6.6 Hz, 1H), 1.76 - 1.61 (m, 5H), 1.45 - 1.33 (m, 1H), 1.23 - 1.10 (m, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.86 - 0.76 (m, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 163.8, 162.6, 152.7, 142.9, 129.5 (q, J = 32.3 Hz), 127.4, 125.5 (q, J = 3.7 Hz), 124.1 (q, J = 272.0 Hz), 106.8, 60.0, 51.4, 45.7, 43.8, 38.2, 35.8, 31.8, 31.7, 26.7, 26.1, 26.0, 13.7. 19 F NMR (471 MHz, Chloroform-d) δ -62.41.

[0402] Example 72

[0403] Example 72 provides a pyridopyrimidinone compound, which has the following structural formula:

[0404] The preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0405] 1H NMR (500 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 17.4, 7.8 Hz, 2H), 7.44 (dt, J = 18.3, 6.8 Hz, 5H), 7.35 - 7.23 (m, 3H), 4.43 (s, 2H), 4.28 (d, J = 13.1 Hz, 1H), 4.14 (d, J = 13.2 Hz, 1H), 3.54 (d, J = 15.6 Hz, 1H), 3.41 (d, J = 15.9 Hz, 1H), 2.82 (dd, J = 18.4, 5.2 Hz, 1H), 2.38 (dd, J = 18.1, 4.7 Hz, 1H), 1.25 (d, J = 6.4 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 167.6, 153.8, 142.7, 133.8, 132.1, 129.8, 128.8, 128.7, 127.5, 126.9, 126.5, 126.0, 125.6, 125.0, 123.6, 123.3, 104.0, 53.4, 52.4, 44.3, 43.8, 35.0, 14.4. 19 F NMR (471 MHz, Chloroform-d) δ -62.3. HRMS (ESI) calcd for C 27 H 26 F3N4O + 479.2053 [M+H] + , found 479.2068.

[0406] Example 73

[0407] Example 73 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0408] The preparation method thereof is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0409] 1H NMR (600 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.51 (s, 1H), 8.46 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.34 (dd, J = 7.8, 4.7 Hz, 1H), 6.86 (s, 1H), 4.55 (q, J = 10.9, 8.8 Hz, 2H), 3.77 (d, J = 13.5 Hz, 1H), 3.54 (d, J = 13.5 Hz, 1H), 3.10 (q, J = 15.6 Hz, 2H), 2.98 (q, J = 5.9 Hz, 1H), 2.60 (dd, J = 17.4, 5.3 Hz, 1H), 2.16 (dd, J = 17.6, 5.0 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.7, 159.5, 153.0, 150.3, 148.7, 145.0, 136.7, 135.3, 128.0 (d, J = 31.6 Hz), 125.6 (q, J = 3.9 Hz), 124.8 (q, J = 271.9 Hz), 123.9, 107.0, 54.8, 52.0, 45.3, 43.5, 38.7, 14.8. 19 F NMR (471 MHz, DMSO-d6) δ -60.8. HRMS (ESI) calcd for C 22 H 23 F3N5O + 430.1849 [M+H] + , found 430.1859.

[0410] Example 74

[0411] Example 74 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0412] The preparation method thereof is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0413] 1H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.50 (d, J = 5.0 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.53 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 4.9 Hz, 2H), 6.84 (s, 1H), 4.57 (q, J = 11.4, 7.0 Hz, 2H), 3.77 (d, J = 14.4 Hz, 1H), 3.57 (d, J = 14.4 Hz, 1H), 3.12 (q, J = 15.6 Hz, 2H), 3.04 - 2.90 (m, 2H), 2.61 (dd, J = 17.7, 5.0 Hz, 1H), 2.17 (dd, J = 17.8, 5.1 Hz, 1H), 1.03 (d, J = 6.6 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 161.6, 159.4, 153.0, 145.0, 149.3, 145.0, 128.3, 128.0 (q, J = 31.7 Hz), 125.6 (q, J = 3.6 Hz), 124.8 (q, J = 272.0 Hz), 124.0, 106.9, 56.3, 52.1, 45.6, 43.5, 38.6, 15.0. 19 F NMR (565 MHz, DMSO-d6) δ -60.77. HRMS (ESI) calcd for C 22 H 23 F3N5O + 430.1849 [M+H] + , found 430.1859.

[0414] Example 75

[0415] Example 75 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0416] The preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0417] 1H NMR (600 MHz, Chloroform-d) δ 11.36 (s, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.38 - 7.32 (m, 3H), 7.17 (q, J = 7.1 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.97 - 6.86 (m, 2H), 4.52 (s, 2H), 3.61 (d, J = 13.8 Hz, 1H), 3.52 (d, J = 13.8 Hz, 1H), 3.19 (s, 2H), 3.04 (q, J = 5.9 Hz, 1H), 2.73 (dd, J = 17.9, 5.2 Hz, 1H), 2.29 (dd, J = 17.9, 4.7 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 163.2, 162.7, 161.2 (d, J = 245.9 Hz), 152.5, 142.9, 130.8 (d, J = 4.4 Hz), 129.5 (q, J = 32.5 Hz), 128.6 (d, J = 8.1 Hz), 127.5, 125.8 (d, J = 13.8 Hz), 125.5 (q, J = 3.7 Hz), 124.2 (q, J = 272.3 Hz), 124.0 (d, J = 3.4 Hz), 115.2 (d, J = 21.9 Hz), 106.6, 51.5, 49.9, 44.9, 43.7, 38.6, 14.1. 19 F NMR (471 MHz, Chloroform-d) δ -62.41, -118.68. HRMS (ESI) calcd for C 23 H 23 F4N4O + 447.1812 [M+H] + , found 447.1812.

[0418] Example 76

[0419] Example 76 provides a pyridopyrimidinone compound, which has the following structural formula:

[0420] The preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0421] 1H NMR (600 MHz, Chloroform-d) δ 11.48 (br s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.22 (td, J = 7.9, 5.8 Hz, 1H), 7.12 - 6.95 (m, 3H), 6.90 (td, J = 8.3, 7.8, 2.1 Hz, 1H), 4.53 (s, 2H), 3.63 (d, J = 13.8 Hz, 1H), 3.46 (d, J = 13.8 Hz, 1H), 3.27 - 3.14 (m, 2H), 3.06 (h, J = 6.1 Hz, 1H), 2.76 (dd, J = 17.9, 5.2 Hz, 1H), 2.31 (dd, J = 17.9, 4.8 Hz, 1H), 1.05 (d, J = 6.6 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 163.4, 163.0 (d, J = 245.6 Hz), 162.3, 152.5, 142.8, 129.5 (q, J = 32.3 Hz), 129.7 (d, J = 8.1 Hz), 127.5, 127.1, 125.5 (q, J = 3.7 Hz), 124.1 (q, J = 272.0 Hz), 124.0 (d, J = 2.8 Hz), 115.2 (d, J = 21.4 Hz), 114.0 (d, J = 21.2 Hz), 106.5, 57.0, 51.3, 44.9, 43.7, 38.3, 14.1. 19 F NMR (471 MHz, Chloroform-d) δ -62.40, -113.48. HRMS (ESI) calcd for C 23 H 23 F4N4O + 447.1812 [M+H] + , found 447.1812.

[0422] Example 77

[0423] Example 77 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0424] Its preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0425] 1H NMR (600 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 7.35 (dd, J = 8.4, 5.7 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 6.82 (s, 1H), 4.64 - 4.43 (m, 2H), 3.73 (d, J = 13.2 Hz, 1H), 3.48 (d, J = 13.3 Hz, 1H), 3.08 (q, J = 15.7 Hz, 2H), 2.97 (h, J = 6.0 Hz, 1H), 2.59 (dd, J = 17.7, 5.1 Hz, 1H), 2.15 (dd, J = 17.6, 5.0 Hz, 1H), 1.02 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 162.4, 161.6, 160.2 (d, J = 205.6 Hz), 153.0, 145.0, 136.0 (d, J = 3.0 Hz), 130.8 (d, J = 7.9 Hz), 128.3, 127.9 (q, J = 31.7 Hz), 125.6 (q, J = 3.8 Hz), 124.8 (q, J = 271.8 Hz), 115.3 (d, J = 21.0 Hz), 107.1, 56.7, 51.8, 45.2, 43.5, 38.8, 14.7. 19 F NMR (471 MHz, DMSO-d6) δ -60.78, -116.19. HRMS (ESI) calcd for C 23 H 23 F4N4O + 447.1812 [M+H] + , found 447.1812.

[0426] Example 78

[0427] Example 78 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0428] The preparation method thereof is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0429] 1H NMR (600 MHz, Chloroform-d) δ 11.29 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 7.31 (s, 1H), 7.18 (d, J = 4.6 Hz, 2H), 7.15 (q, J = 4.7 Hz, 1H), 7.00 (s, 1H), 5.32 (s, 1H), 4.51 (s, 2H), 3.58 (d, J = 13.6 Hz, 1H), 3.42 (d, J = 13.7 Hz, 1H), 3.16 (s, 2H), 3.03 (d, J = 5.9 Hz, 1H), 2.76 (dd, J = 18.0, 5.2 Hz, 1H), 2.39 - 2.26 (m, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 163.2, 162.6, 152.5, 142.9, 141.3, 134.3, 129.6, 128.5, 127.5, 127.2, 126.6, 125.5, 125.4, 106.4, 56.9, 53.4, 51.4, 44.9, 43.7, 29.7, 22.7, 14.1. 19 F NMR (471 MHz, Chloroform-d) δ -62.37. HRMS (ESI) calcd for C 23 H 23 ClF3N4O + 463.1507 [M+H] + , found 463.1520.

[0430] Example 79 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0431] Example 79 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0432] The preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0433] 1H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.57 - 7.48 (m, 3H), 7.44 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.82 (s, 1H), 4.67 - 4.45 (m, 2H), 3.74 (d, J = 13.6 Hz, 2H), 3.51 (d, J = 13.6 Hz, 2H), 3.09 (q, J = 15.7 Hz, 2H), 2.98 (q, J = 5.9 Hz, 1H), 2.60 (dd, J = 17.7, 5.0 Hz, 1H), 2.16 (dd, J = 17.6, 5.1 Hz, 1H), 1.03 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 161.7, 159.5, 153.0, 144.9, 143.1, 131.5, 130.8, 130.1, 128.3, 128.00, 128.0 (q, J = 31.6 Hz), 125.6 (q, J = 3.8 Hz), 124.8 (q, J = 272.0 Hz), 122.1, 107.0, 56.8, 52.1, 45.4, 43.5, 38.7, 14.9. 19 F NMR (471 MHz, DMSO-d6) δ -60.78. HRMS (ESI) calcd for C 23 H 23 BrF3N4O + 507.1002 [M+H] + , found 507.1013.

[0434] Example 80

[0435] Example 80 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0436] Its preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0437] 1H NMR (600 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.76 (s, 1H), 7.74 - 7.65 (m, 4H), 7.56 - 7.50 (m, 3H), 6.98 (s, 1H), 4.64 - 4.46 (m, 2H), 3.79 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.8 Hz, 1H), 3.19 - 3.05 (m, 2H), 2.98 (h, J = 6.1 Hz, 1H), 2.61 (dd, J = 17.6, 5.3 Hz, 1H), 2.16 (dd, J = 17.7, 5.0 Hz, 1H), 1.03 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.6, 159.4, 153.1, 145.0, 142.0, 133.8, 132.3, 131.2, 129.9, 128.3, 127.9 (q, J = 31.7 Hz), 125.6 (q, J = 3.9 Hz), 124.8 (q, J = 271.8 Hz), 119.4, 111.7, 106.9, 56.6, 52.0, 45.4, 43.4, 38.6, 14.9. 19 F NMR (565 MHz, DMSO-d6) δ -60.79. HRMS (ESI) calcd for C 24 H 23 F3N5O + 454.1849 [M+H] + , found 454.1858.

[0438] Example 81

[0439] Example 81 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0440] The preparation method thereof is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0441] 1H NMR (600 MHz, Chloroform-d) δ 7.57 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.30 - 7.26 (m, 1H), 7.23 - 7.19 (m, 2H), 7.15 - 6.95 (m, 3H), 4.54 (s, 2H), 3.64 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H), 3.29 - 3.14 (m, 2H), 3.13 - 2.96 (m, 1H), 2.77 (dd, J = 17.7, 5.2 Hz, 1H), 2.31 (dd, J = 17.9, 4.6 Hz, 1H), 1.05 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 163.5, 162.1, 152.6, 149.4 (q, J = 1.8 Hz), 142.7, 141.5, 129.6, 129.6 (q, J = 32.3 Hz), 127.5, 126.7, 125.5 (q, J = 3.7 Hz), 124.1 (q, J = 271.9 Hz), 120.9, 120.5 (q, J = 256.9 Hz), 119.5, 106.4, 56.8, 51.1, 44.9, 43.8, 38.1, 13.9. 19 F NMR (471 MHz, Chloroform-d) δ -62.46, -67.21. HRMS (ESI) calcd for C 24 H 23 F6N4O2 + 513.1720 [M+H] + , found 513.1732.

[0442] Example 82

[0443] Example 82 provides a pyridopyrimidinone compound, which has the following structural formula:

[0444] The preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0445] 1H NMR (500 MHz, Chloroform-d) δ 11.25 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.18 (t, J = 7.8 Hz, 1H), 6.89 - 6.83 (m, 2H), 6.75 (dd, J = 8.2, 2.6 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.76 (s, 3H), 3.59 (d, J = 13.5 Hz, 1H), 3.40 (d, J = 13.4 Hz, 1H), 3.23 - 3.12 (m, 2H), 3.05 (q, J = 5.7 Hz, 1H), 2.76 (dd, J = 17.7, 5.2 Hz, 1H), 2.30 (dd, J = 17.8, 4.7 Hz, 1H), 1.03 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 163.1, 162.7, 152.5, 143.0, 138.8, 134.0, 129.4 (q, J = 32.4 Hz), 129.3, 128.2, 127.9, 127.6, 127.1, 125.6, 125.4 (q, J = 3.7 Hz), 124.2 (q, J = 272.0 Hz), 106.5, 57.5, 51.0, 45.0, 43.6, 38.7, 13.8. 19 F NMR (471 MHz, Chloroform-d) δ -62.35. HRMS (ESI) calcd for C 24 H 26 F3N4O2 + 459.2002 [M+H] + , found 459.2012.

[0446] Example 83

[0447] Example 83 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0448] Its preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0449] 1H NMR (500 MHz, Chloroform-d) δ 8.33 (s, 1H) 7.67 - 7.42 (m, 6H), 7.34 (dd, J = 20.6, 7.8 Hz, 3H), 4.54 (s, 2H), 3.96 - 3.70 (m, 2H), 3.29 (s, 2H), 3.16 (q, J = 6.2 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.36 (s, 1H), 1.12 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 153.2, 142.7, 142.4, 133.0, 132.7, 129.9, 129.3 (q, J = 31.7 Hz), 127.8, 127.5, 125.4, 125.4, 125.4, 124.1 (q, J = 272.3 Hz), 117.7, 112.7, 106.3, 55.4, 52.0, 44.6, 43.8. 19 F NMR (471 MHz, Chloroform-d) δ -62.32. HRMS (ESI) calcd for C 24 H 23 F3N5O + 454.1849 [M+H] + , found 454.1860.

[0450] Example 84 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0451] Example 84 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0452] The preparation method is the same as that of Example 70, except that Compound 70-8 in Example 70 is replaced by

[0453] 1H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.99 (s, 1H), 5.27 - 5.08 (m, 2H), 3.84 (d, J = 14.3 Hz, 1H), 3.66 (d, J = 14.4 Hz, 1H), 3.21 - 3.13 (m, 2H), 3.04 (q, J = 5.8 Hz, 1H), 2.66 (dd, J = 17.6, 5.1 Hz, 1H), 2.20 (dd, J = 17.9, 5.0 Hz, 1H), 1.06 (d, J = 6.4 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 160.9, 158.9, 154.3, 146.32, 141.6, 132.6, 129.8, 128.3, 127.9, 125.8 (q, J = 3.7 Hz), 122.9 (d, J = 271.7 Hz), 119.4, 110.0, 105.0, 57.1, 51.9, 46.0, 43.6, 38.1, 14.9. 19 F NMR (471 MHz, DMSO-d6) δ -60.92. HRMS (ESI) calcd for C 24 H 23 F3N5O + 454.1849 [M+H] + , found 454.1858.

[0454] Example 85

[0455] Example 85 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0456] The synthetic route and preparation method thereof are as follows:

[0457] S1, compound 1-1 (35.0 g, 228 mmol), compound 38-1 (33.4 mL, 228 mmol), DBU (22.8 mL, 3.4 mmol) and triethylamine (38 mL, 273 mmol) were dissolved in dichloromethane (300 mL), stirred at 40°C for 48 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed by reduced pressure distillation, methyl tert-butyl ether was added and stirred for 30 minutes, then filtered, the filter cake was washed twice with methyl tert-butyl ether, and the organic phase was concentrated to obtain compound 38-2 (45 g, yield 81%) in the form of colorless oil, which was directly used in the next step.

[0458] S2, Compound 38-2 (34 g, 14.3 mmol) was dissolved in dichloromethane (300 mL), compound 80-1 (44.2 g, 183 mmol), 4A molecular sieves and acetic acid (10.5 mL, 183 mmol) were added and stirred at room temperature for 15 minutes. NaBH(OAc)3 (44.2 g, 209 mmol) was added portionwise and stirring was continued at room temperature for 24 hours. After the reaction was completed, the insoluble materials were filtered off with celite, the filtrate was added to saturated aqueous NaHCO3 solution (50 mL) to quench the reaction, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound 85-1 (15.5 g, 31% yield) as a light yellow oil.

[0459] S3, Compound 85-1 (12.4 g, 34.4 mmol) was dissolved in tetrahydrofuran (340 mL), and 1.0 M potassium tert-butoxide / tetrahydrofuran solution (10 mL) was slowly added dropwise at -78°C, and the reaction was continued at 0°C for 12 hours. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain compound 85-2 (6.2 g, 55% total yield) as a colorless oil.

[0460] S4, Compound 29-1 (1.46 g, 10.0 mmol) and diisopropylethylamine (1.9 mL, 11.0 mmol) were dissolved in acetonitrile 10 mL, and compound 1-8 (1.34 g, 11.0 mmol) was added, and the reaction was continuously stirred at room temperature for 24 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and methyl tert-butyl ether was added to slurry, and filtered and dried to obtain compound 85-3 as a white solid.

[0461] S5, Compound 85-2 (361 mg, 1.0 mmol) and compound 85-3 (179 mg, 1.2 mmol) were dissolved in super dry methanol (5.0 mL), and sodium methoxide (216 mg, 4.0 mmol) was added, and stirred at 80°C for 16 hours. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (4% MeOH in DCM) to obtain compound 85 (300 mg, 66%) as a light yellow solid.

[0462] 1H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.89 - 7.65 (m, 3H), 7.55 (t, J = 7.8 Hz, 1H), 6.33 (s, 1H), 3.79 (d, J = 13.7 Hz, 1H), 3.60 (d, J = 13.9 Hz, 1H), 3.20 - 2.92 (m, 5H), 2.64 (d, J = 17.9 Hz, 1H), 2.18 (d, J = 17.6 Hz, 1H), 1.22 (dt, J = 29.2, 6.9 Hz, 1H), 1.07 - 1.02 (m, 3H), 0.44 (d, J = 7.8 Hz, 2H), 0.25 - 0.17 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 161.5, 159.5, 153.1, 142.0, 133.9, 132.3, 131.2, 123.0, 119.4, 111.7, 106.2, 56.6, 52.0, 46.0, 45.1, 38.6, 14.8, 11.1, 3.7. HRMS (ESI) calcd for C 24 H 22 F3N6O + 454.1849 [M+H] + , found 454.1860.

[0463] Example 86

[0464] Example 86 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0465] The preparation method thereof is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by

[0466] 1 ​H NMR (600 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 - 7.53 (m, 3H), 7.52 - 7.45 (m, 2H), 6.70 (s, 1H), 4.93 (tt, J = 15.1, 7.7 Hz, 2H), 3.80 (d, J = 13.8 Hz, 1H), 3.61 (d, J = 13.8 Hz, 1H), 3.17 - 3.08 (m, 2H), 3.02 (h, J = 6.5, 6.0 Hz, 1H), 2.67 (dd, J = 17.8, 5.2 Hz, 1H), 2.23 (dd, J = 17.7, 4.9 Hz, 1H), 1.06 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.5, 159.6, 152.9, 142.0, 134.8, 133.9, 133.8, 132.3, 131.3, 131.2, 129.9, 129.0, 128.2, 126.8, 126.4, 126.0, 125.8, 123.9, 119.4, 111.7, 106.8, 56.6, 52.1, 45.4, 42.1, 40.4, 40.3, 40.1, 40.0, 39.9, 39.7, 39.6, 38.7, 14.9. HRMS (ESI) calcd for C 27 H 26 N5O + 436.2132 [M+H] + , found 436.2139.

[0467] Example 87 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0468] Example 87 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0469] Its preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by

[0470] 1 ​H NMR (600 MHz, Chloroform-d) δ 11.37 (s, 1H), 7.58 (s, 1H), 7.48 (t, J = 8.1 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.18 - 7.10 (m, 3H), 6.50 (s, 1H), 4.47 (tt, J = 15.4, 7.8 Hz, 2H), 3.52 (d, J = 14.1 Hz, 1H), 3.42 (d, J = 14.3 Hz, 1H), 3.06 (s, 2H), 2.98 (h, J = 6.2 Hz, 1H), 2.75 (dd, J = 18.1, 5.3 Hz, 1H), 2.33 - 2.27 (m, 4H), 1.01 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 163.2, 162.3, 152.5, 141.2, 136.2, 136.1, 132.8, 131.9, 130.7, 130.4, 129.0, 127.8, 127.5, 126.1, 119.0, 112.4, 106.1, 56.6, 51.2, 44.9, 42.6, 38.3, 19.1, 14.2. HRMS (ESI) calcd for C 24 H 26 N5O + 400.2132 [M+H] + , found 400.2141.

[0471] Example 88 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0472] Example 88 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0473] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by compound 29-2.

[0474] 1H NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.76 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 4.49 - 4.35 (m, 2H), 3.78 (d, J = 13.8 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 3.17 - 3.06 (m, 2H), 3.00 (h, J = 6.0 Hz, 1H), 2.64 (dd, J = 17.5, 5.0 Hz, 1H), 2.29 (s, 3H), 2.19 (dd, J = 17.7, 5.0 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.8, 159.5, 153.1, 142.0, 139.6, 137.9, 133.8, 132.3, 131.2, 129.9, 128.7, 128.4, 128.1, 124.9, 119.4, 111.7, 106.7, 56.6, 52.0, 45.4, 43.9, 38.5, 21.5, 14.9. HRMS (ESI) calcd for C 24 H 26 N5O + 400.2132 [M+H] + , found 400.2142.

[0475] Example 89

[0476] Example 89 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0477] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by

[0478] 1 ​H NMR (500 MHz, Chloroform-d) δ 11.27 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 7.7 Hz, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 6.61 (s, 1H), 4.44 (q, J = 9.6, 7.7 Hz, 2H), 3.52 (d, J = 14.1 Hz, 1H), 3.42 (d, J = 14.1 Hz, 1H), 3.09 (s, 2H), 2.97 (ddd, J = 11.8, 6.8, 5.0 Hz, 1H), 2.74 (dd, J = 17.9, 5.3 Hz, 1H), 2.33 - 2.25 (m, 4H), 1.00 (d, J = 6.6 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 163.2, 162.2, 152.6, 141.2, 137.0, 135.4, 132.8, 131.9, 130.7, 129.3, 129.1, 127.4, 119.0, 112.4, 106.1, 56.6, 51.1, 45.0, 44.2, 38.4, 21.1, 14.0. HRMS (ESI) calcd for C 24 H 26 N5O + 400.2132 [M+H] + , found 400.2140.

[0479] Example 90

[0480] Example 90 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0481] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by

[0482] 1 ​H NMR (600 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.76 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.75 (s, 1H), 4.44 (tt, J = 15.3, 7.6 Hz, 2H), 3.78 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.8 Hz, 1H), 3.17 - 3.04 (m, 2H), 2.99 (q, J = 5.9 Hz, 1H), 2.62 (dd, J = 17.7, 5.1 Hz, 1H), 2.18 (dd, J = 17.7, 5.0 Hz, 1H), 1.03 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.6, 159.5, 153.0, 142.0, 138.9, 133.8, 132.3, 131.9, 131.2, 129.9, 129.6, 128.7, 119.4, 111.7, 106.8, 56.6, 52.0, 45.4, 43.2, 38.6, 14.9. HRMS (ESI) calcd for C 23 H 23 ClN5O + 420.1586 [M+H] + , found 420.1594.

[0483] Example 91 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0484] Example 91 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0485] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by compound 29-2.

[0486] 1H NMR (600 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 - 7.50 (m, 3H), 7.33 - 7.25 (m, 2H), 6.73 (s, 1H), 4.51 - 4.38 (m, 2H), 3.79 (d, J = 13.8 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 3.15 - 3.05 (m, 2H), 2.99 (h, J = 6.1 Hz, 1H), 2.62 (dt, J = 17.5, 3.4 Hz, 1H), 2.17 (dd, J = 17.6, 5.0 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.6, 159.5, 152.9, 142.0, 139.4, 133.9, 132.3, 131.6, 131.2, 130.0, 123.0, 120.3, 119.4, 111.7, 106.8, 56.6, 52.0, 45.4, 43.3, 38.6, 14.9. HRMS (ESI) calcd for C 23 H 23 BrN5O + 464.1080 [M+H] + , found 464.1090.

[0487] Example 92 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0488] Example 92 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0489] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by compound 29-2.

[0490] 1H NMR (600 MHz, Chloroform-d) δ 11.08 (brs, 1H), 7.63 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.42 - 7.32 (m, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 4.55 (qd, J = 15.9, 5.6 Hz, 2H), 3.63 (d, J = 14.0 Hz, 1H), 3.49 (d, J = 14.0 Hz, 1H), 3.20 (s, 2H), 3.02 (h, J = 6.0 Hz, 1H), 2.77 (dd, J = 17.8, 5.2 Hz, 1H), 2.32 (dd, J = 17.9, 4.6 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 163.2, 162.4, 152.5, 141.0, 137.5, 132.8, 132.7, 131.9, 130.7, 129.4, 129.1, 128.9, 127.5, 123.4, 119.0, 112.4, 106.4, 56.8, 51.4, 45.1, 44.6, 38.6, 14.2. HRMS (ESI) calcd for C 23 H 23 BrN5O + 464.1080 [M+H] + , found 464.1095.

[0491] Example 93 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0492] Example 93 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0493] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by .

[0494] 1H NMR (600 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.45 (d, J = 7.7 Hz, 1H), 7.31 (dt, J = 15.4, 7.7 Hz, 2H), 6.91 (s, 1H), 4.53 - 4.37 (m, 2H), 3.79 (d, J = 13.8 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 3.18 - 3.03 (m, 2H), 3.00 (q, J = 6.0 Hz, 1H), 2.63 (dd, J = 17.6, 5.1 Hz, 1H), 2.18 (dd, J = 17.6, 4.9 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.6, 159.4, 153.0, 142.8, 142.0, 133.9, 132.3, 131.2, 131.0, 130.5, 130.2, 129.9, 126.8, 122.1, 119.4, 111.7, 106.9, 56.6, 52.0, 46.1, 43.3, 38.6, 14.9. HRMS (ESI) calcd for C 23 H 23 BrN5O + 464.1080 [M+H] + , found 464.1095.

[0495] Example 94 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0496] Example 94 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0497] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by compound 29-2.

[0498] 1H NMR (600 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.31 (dd, J = 10.0, 1.9 Hz, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 6.80 (s, 1H), 4.56 - 4.34 (m, 2H), 3.79 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.8 Hz, 1H), 3.16 - 3.04 (m, 2H), 2.99 (p, J = 6.0 Hz, 1H), 2.61 (dd, J = 17.7, 5.2 Hz, 1H), 2.16 (dd, J = 17.6, 5.1 Hz, 1H), 1.03 (d, J = 6.5 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 161.6, 159.4, 157.8, 152.9, 142.8 (d, J = 6.4 Hz), 142.0, 133.8 (d, J = 15.5 Hz), 132.3, 131.2, 129.9, 125.3, 125.3, 119.4, 115.9 (d, J = 22.6 Hz), 111.7, 107.0, 106.4 (d, J = 20.6 Hz), 56.6, 52.0, 45.4, 43.0, 38.6, 14.9. 19 F NMR (565 MHz, DMSO-d6) δ -108.64. HRMS (ESI) calcd for C 23 H 23 BrFN5O + 482.0986 [M+H] + , found 482.1000.

[0499] Example 95

[0500] Example 95 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0501] Its preparation method is the same as that of Example 85, except that Compound 29-1 in Example 85 is replaced by

[0502] 1H NMR (600 MHz, Chloroform-d) δ 9.48 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 6.9 Hz, 2H), 7.48 - 7.40 (m, 2H), 5.54 (s, 1H), 3.95 (s, 2H), 3.91 - 3.79 (m, 4H), 3.65 (d, J = 13.9 Hz, 2H), 3.44 (s, 3H), 3.13 (h, J = 6.0 Hz, 2H), 2.85 (dd, J = 17.8, 5.2 Hz, 2H), 2.44 - 2.29 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 162.1, 160.9, 157.7, 155.1, 144.4, 141.0, 133.1, 132.2, 131.6, 130.8, 130.7, 130.6, 129.3, 129.1, 118.9, 112.5, 112.1, 57.1, 54.4, 51.7, 45.6, 45.2, 38.4, 14.3.

[0503] Example 96

[0504] Example 96 provides a pyridopyrimidinone compound, whose structural formula is as follows:

[0505] The preparation method is the same as that of Example 85, except that compound 29-1 in Example 85 is replaced by

[0506] 1 H NMR (600 MHz, Chloroform-d) δ 11.43 (s, 1H), 7.65 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.30 (t, J = 7.7 Hz, 2H), 7.24 (d, J = 7.5 Hz, 3H), 4.08 - 4.03 (m, 1H), 3.82 - 3.70 (m, 2H), 3.61 - 3.50 (m, 3H), 3.46 (p, J = 8.3 Hz, 1H), 3.31 (s, 2H), 3.06 (q, J = 6.4, 5.1 Hz, 1H), 2.85 - 2.66 (m, 1H), 2.50 - 2.24 (m, 2H), 2.15 - 1.95 (m, 1H), 1.09 (d, J = 5.6 Hz, 3H). 13 ​C NMR (151 MHz, Chloroform-d) δ 163.8, 161.4, 151.0, 141.3, 140.9, 133.0, 132.1, 130.7, 129.0, 128.8, 127.0, 126.9, 119.0, 112.3, 105.2, 56.7, 52.7, 51.6, 46.6, 45.0, 43.5, 38.4, 32.6, 14.4, 14.4.

[0507] Activity test

[0508] Experimental Example 1: Agonistic activity of compounds on HsClpP protease

[0509] HsClpP protein can recognize and cut the substrate AC-WLA-AMC, and the cut substrate can detect the AMC signal at 355 nm and 460 nm. In a 384 black bottom plate well plate, 20 μL of enzyme (final concentration 0.7 μM) was added to each well, 10 μL of compound (final concentration 20 μM, 3-fold gradient dilution of 11 concentrations) was added at the same time, and incubated at room temperature for 10 minutes, then 20 μL of substrate (final concentration 100 μM) was added, and incubated at 37°C for 4h, and the fluorescence signal was measured by multifunctional enzyme label instrument. The obtained data was processed by GraphPad Prism8.

[0510] Experimental Example 2: Evaluation of the proliferation inhibition activity of the above prepared compounds on leukemia cell line MV4-11, HL60 cell line and diffuse large B-cell lymphoma cell line OCI-LY10 by MTS method:

[0511] In a 96-well plate, 10,000 cells were inoculated in each well, and after stable for half an hour, the compound prepared in the example was added, DMSO was used as a control, 37°C, 5% CO2 culture for 72h, 20μL MTS was added, 37°C culture for 4h, the absorbance value of DMSO hole was measured at 490nm and 690nm by enzyme label instrument, the obtained data was processed by GraphPad Prism8, and the data was shown in Table 1.

[0512] Table 1: Note: In Table 1, "A" represents EC 50 or IC 50 less than 10 nM; "B" represents EC 50 or IC 50 between 10-100 nM; "C" represents EC 50 or IC 50 between 100-1000 nM; "D" represents EC 50 or IC50 between 1000-5000 nM; "E" represents EC 50 or IC 50 greater than 5000 nM.

[0513] Experimental Example 3: In vivo pharmacodynamic evaluation of molm13 diffuse model

[0514] Female B-NDG mice (18-22 g, 6-8 weeks old) were purchased from Baoxietu. The mice were raised in SPF level animal room, 12h day-night cycle, free feeding and drinking. HL60 cells (2x10 4 cells per mouse) were injected by tail vein, and the mice were randomly grouped for drug administration according to the body weight the day after inoculation. Equal amount of blank solvent was used as control (0.5% CMC-Na, p.o qd, n=10), ONC212 (10 mg / kg, p.o qd, n=10) Example 3 (10 mg / kg, p.o qd, n=10) according to the scheme, oral administration 3 days interval 2 days, 19 days after observation of mouse death. During the experiment, the body weight of the mice was measured every 3-4 days, and the growth state of the mice was observed. Statistical analysis was performed using GraphPad Prism 8.

[0515] wherein, ONC212 was synthesized according to the method in CN104860948A.

[0516] As shown in Figure 1, in the molm13 diffuse model, Example 8-P3 can relatively prolong the survival of mice compared with the solvent group.

[0517] The above is described in detail in combination with the embodiments of the present application, but the present application is not limited to the above embodiments, and various changes can be made within the knowledge range of ordinary skilled persons in the art without departing from the protection scope of the present application.

Claims

1. A pyridopyrimidinone compound, or its racemic mixture, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof, characterized in that, having a structure as shown in Formula I: wherein m, n, p and q are positive integers, 1≤n≤3; 1≤m≤5; 1≤p≤5; 1≤q≤5; A ring is selected from C 6～20 aryl, C 3～18 heteroaromatic, C 3～8 cycloalkyl; R1and R2are independently selected from hydrogen, halogen, cyano, C 1～6 alkyl, C 1～6 alkoxy, halogen-substituted C 1～6 alkyl, halogen-substituted C 1～6 alkoxy; R3is selected from hydrogen, halogen, C 1～6 alkyl; R4is selected from hydrogen, deuterium, C 1～6 alkyl or halogen; R5is selected from wherein R6is selected from hydrogen, deuterium, C 1～6 alkyl or halogen; B ring is selected from C 6～20 aryl, C 3～18 heteroaromatic, C 3～8 cycloalkyl; or R4 and R5 form a substituted or unsubstituted C 4～6 nitrogen heterocycle; the substitution is by C 1～6 alkyl or phenyl.

2. The pyridopyrimidinone compound according to claim 1, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof, characterized in that, having a structure as shown in Formula I-1:

3. The pyridopyrimidinone compound according to claim 1 or 2, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof, characterized in that, the A and B rings are independently selected from phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzimidazolyl, quinolinyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, C 4～8 bridged cycloalkyl.

4. The pyridopyrimidinone compound according to claim 1, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt thereof or a mixture thereof, characterized in that, having a structure as shown in Formula I-2:

5. The pyridopyrimidinone compound according to claim 1, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt thereof or a mixture thereof, characterized in that, R1and R2are independently selected from hydrogen, halogen, cyano, methyl, tert-butyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy.

6. The pyridopyrimidinone compound according to any one of claims 1 to 5, or a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt thereof or a mixture thereof, characterized in that, The pyridopyrimidinone compound is selected from the following structural formula:

7. Process for the preparation of pyrido-pyrimidinone compounds according to any one of claims 1 to 6, characterized in that, The method comprises the following steps: The compound of formula (1-6), the compound of formula (1-9), an organic solvent and an organic base are mixed to react to obtain the compound of formula (1-10). wherein the compounds of formula (1-6), (1-9) have the following structural formula:

8. The method for preparing pyridopyrimidine ketone compounds according to claim 7, characterized in that, The organic base is at least one selected from sodium methoxide, sodium ethoxide or sodium tert-butoxide.

9. A pharmaceutical composition, characterized by, The pyridopyrimidinone compound of any one of claims 1-5, and a pharmaceutically acceptable excipient.

10. Use of the pyridopyrimidinone compound of any one of claims 1-6, or a racemate, R-enantiomer, S-enantiomer, pharmaceutically acceptable salt thereof or a mixture thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating a disease associated with HsClpP protease. Preferably, the disease comprises cancer, preferably, the cancer comprises central nervous system tumor, brain tumor, brain glioma, peripheral nervous system tumor, pheochromocytoma, paraganglioma, neuroendocrine tumor, liver cancer, lung cancer, gastric cancer, colon cancer, rectal cancer, pancreatic cancer, breast cancer, prostate cancer, endometrial cancer, lung squamous carcinoma, diffuse large B-cell lymphoma, hematological malignancy and lymphatic system tumor.

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