Imidazopyridine pyrimidone compound, preparation method therefor and use thereof

Abstract

An imidazopyridine pyrimidone compound, a preparation method therefor and a use thereof. The imidazopyridine pyrimidone compound, or a racemate thereof, an R-isomer thereof, an S-isomer thereof, a pharmaceutically acceptable salt thereof or a mixture thereof has a structure represented by formula I or formula II. R1 and R2 are each independently selected from phenyl, naphthyl, and phenyl substituted by at least one of halogen, C1-6 alkyl, C1-6 alkoxy, halogen-substituted C1-6 alkyl, and cyano; R3 is one or more substituents; and R3 is selected from C1-4 alkyl, halogen-substituted C1-4 alkyl, and halogen. The compound can have a better HsClpP protease agonist effect than the currently reported positive compounds, and can be used for treating HsClpP receptor agonist-related diseases.

Description

Imidazolopyridopyrimidone compound and its preparation method and application Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to an imidazopyridopyrimidone compound, a preparation method and an application thereof. Background Art

[0002] Mitochondria play an important role in the occurrence, development, and metastasis of various tumors. Human caseinolytic enzyme P (HsClpP) is an unfolding peptidase in the mitochondrial matrix that controls protein quality, regulates mitochondrial metabolism, and maintains the integrity and enzyme activity of the mitochondrial respiratory chain. Studies have shown that abnormalities in HsClpP can lead to mitochondrial dysfunction and a variety of human diseases, including cancer, neurological diseases, diabetes, gastrointestinal diseases, cardiovascular diseases, skin diseases, and aging. ClpP is overexpressed in multiple myeloma, various lymphomas, chronic myeloid leukemia (CML), and some solid tumors. Further activation of ClpP is expected to provide new interventions for the treatment of these tumors.

[0003] The potential mechanisms by which HsClpP may participate in cancer are related to mitochondrial bioenergetics and proteostasis, reactive oxygen species (ROS) production, and autophagy activation. HsClpP is associated with members of the electron transport chain (ETC), particularly SDHA and other enzymes involved in metabolism. Inhibition of HsClpP activity results in the inability of the HsClpXP complex to effectively degrade damaged or malfunctioning proteins involved in oxidative phosphorylation, thereby affecting mitochondrial oxidative phosphorylation (OXPHOS) and inducing cell death. Furthermore, HsClpP inhibition reduces the enzymatic activity of SDHA in respiratory chain (RC) complex II, increasing mitochondrial ROS production and initiating non-apoptotic tumor cell death. Furthermore, overactivation of HsClpP can inhibit cancer cell growth. Overactivation of HsClpP can degrade ClpP substrates, including RC complex proteins (SDHB and SDHB), impair OXPHOS, disrupt mitochondrial structure and function, and selectively induce cancer cell death. Therefore, HsClpP is a unique tumor target, and both inhibition and activation of HsClpP can inhibit tumor growth.

[0004] HsClpP is also highly expressed in acute myeloid leukemia (AML). In primary AML, approximately 45% of patients have elevated HsClpP expression compared to normal hematopoietic progenitor cells. Blocking HsClpP expression in vitro and in vivo significantly reduced the growth and viability of various AML cell lines and significantly inhibited tumor development in vivo. Furthermore, overactivation of HsClpP has been proposed as an effective therapeutic strategy for AML. When HsClpP is activated, the rates of cell death and apoptosis in primary AML cells increase compared to normal cells, and HsClpP activators also reduce leukemia burden in mice. HsClpP expression is also elevated in many other hematological malignancies, such as CML, multiple myeloma, and various lymphomas. Therefore, modulating HsClpP activity is considered a therapeutic strategy for AML and other hematological malignancies.

[0005] HsClpP is also overregulated in many solid tumors, including gliomas, 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 deregulate mitochondrial RC and oxidative stress, inhibiting tumor cell proliferation, motility, and metastasis. In prostate cancer, inhibition of HsClpP activity reduces the expression of cyclins A, B1, and D1, thereby inducing cell cycle arrest in PC3 prostate cancer cells and inhibiting PC3 cell proliferation. In a PC3 cell wound wound assay, interference with HsClpP expression inhibited tumor cell invasion and migration. In tumor-bearing mice, inhibition of HsClpP slowed tumor progression and the extent of liver metastasis.

[0006] Therefore, developing anti-tumor drugs with new mechanisms targeting HsClpP will help improve the therapeutic effect of anti-tumor drugs and effectively prolong the survival of patients.

[0007] Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, in a first aspect, the present invention provides an imidazopyridopyrimidone compound that has a better HsClpP protease agonist effect than the currently reported positive compounds and can be used to treat diseases related to HsClpP receptor agonism.

[0009] The second aspect of the present invention also provides a method for preparing imidazopyridopyrimidone compounds.

[0010] The third aspect of the present invention also provides an application of an imidazopyridopyrimidone compound.

[0011] According to the first aspect of the present invention, an imidazopyridopyrimidone compound, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof is provided, having a structure as shown in Formula I or Formula II:

[0012] R1 and R2 are each independently selected from phenyl, naphthyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 a phenyl group substituted with at least one of an alkyl group and a cyano group;

[0013] R3 is one or more substituents, R3 is selected from C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, halogen.

[0014] The imidazopyridopyrimidone compounds according to the embodiments of the present invention have at least the following beneficial effects:

[0015] The imidazopyridopyrimidone compounds provided by the present invention can have better HsClpP protease agonist effects than the positive compounds reported previously, and can be used to treat diseases related to HsClpP receptor agonist effects.

[0016] According to some embodiments of the invention, R3 is selected from methyl or halogen.

[0017] According to some embodiments of the present invention, the imidazopyridopyrimidone compound, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, has a structure as shown in Formula (I-1), Formula (I-2) or Formula (II-1), Formula (II-2):

[0018] R1 and R2 are each independently selected from phenyl, naphthyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 A phenyl group substituted by at least one of an alkyl group and a cyano group.

[0019] According to some embodiments of the present invention, R1 and R2 are each independently selected from phenyl, naphthyl, fluorine, chlorine, bromine, C 1-6 Alkyl, C 1-3 Alkoxy, C substituted by 1-3 halogen atoms 1-3 A phenyl group substituted by at least one of an alkyl group and a cyano group.

[0020] According to some embodiments of the present invention, R1 and R2 are each independently selected from phenyl, naphthyl, and phenyl substituted by at least one of fluorine, chlorine, bromine, methyl, tert-butyl, methoxy, trifluoromethyl, and cyano.

[0021] According to some embodiments of the present invention, the imidazopyridopyrimidone compound is selected from one of the following structures:

[0022] According to the second aspect of the present invention, the method for preparing the imidazopyridopyrimidone compound provided in the embodiment comprises the following steps:

[0023] The compound of formula (1-6), the compound of formula (1-10), a first organic solvent and a first organic base are mixed and reacted to obtain a product;

[0024] Alternatively, the compound of formula (1-6), the compound a-1, the second organic solvent, and the second organic base are mixed and reacted to obtain the product;

[0025] Among them, the structural formulas of the compound of formula (1-6), the compound of formula (1-10), and the compound a-1 are as follows:

[0026] According to some embodiments of the present invention, the first organic base or the second organic base is independently selected from at least one of sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0027] According to some embodiments of the present invention, the first organic solvent or the second organic solvent is independently selected from at least one of methanol and ethanol.

[0028] According to some embodiments of the present invention, the reaction temperature is 80-120°C.

[0029] According to some embodiments of the present invention, the compound 1-10 is prepared by the following method:

[0030] Compound 1-8 and compound 1-9 are directly reacted in tetrahydrofuran, and then beaten and treated to obtain compound 10;

[0031] The structural formulas of compounds 1-8 and 1-9 are as follows:

[0032] According to some embodiments of the present invention, the compound 1-8 is prepared by the following method:

[0033] Compound 1-7 and iodomethane are refluxed in methanol to obtain compound 1-8;

[0034] The structural formula of compound 1-7 is as follows:

[0035] A third aspect of the present invention provides a use of the above-mentioned imidazopyridopyrimidone compound in the preparation of a drug for treating and / or preventing diseases mediated by HsClpP.

[0036] According to some embodiments of the present invention, the diseases mediated by HsClpP include HsClpP-mediated nervous system diseases, metabolic syndrome and tumors.

[0037] According to some embodiments of the present invention, the tumor includes central nervous system tumors, brain tumors, peripheral nervous system tumors, pheochromocytomas, paragangliomas, neuroendocrine tumors, liver cancer, lung cancer, gastric cancer, colon cancer, rectal cancer, pancreatic cancer, breast cancer, prostate cancer, endometrial cancer, hematological malignancies and lymphatic system tumors.

[0038] A fourth aspect of the present invention provides a ClpP protease agonist, wherein the ClpP protease agonist comprises the above-mentioned imidazopyridopyrimidone compound.

[0039] The fifth aspect of the present invention provides a pharmaceutical composition, characterized in that it includes the above-mentioned imidazopyridopyrimidone compound, or a pharmaceutically acceptable excipient thereof.

[0040] Definitions and General Terms

[0041] “C 1-6 "alkyl" means an alkyl group having a total carbon number of 1 to 6, including C 1-6 Straight chain alkyl, C 1-6 Branched alkyl and C 3-6 The cycloalkyl group may be, for example, a straight-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, a branched-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a n-hexyl group, a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclopentyl group, a methylcyclopentyl group, a cyclohexyl group, and the like.

[0042] "Halogen-substituted C 1-6 Alkyl" and "C 1-6 The definition of "C1-6 alkyl substituted by halogen" is similar to that of "C1-6 alkyl substituted by halogen", except that any one H atom in "C1-6 alkyl substituted by halogen" is replaced by any halogen.

[0043] “C 1-6 "alkoxy" means an alkoxy group having a total carbon number of 1 to 6, including C 1-6Straight chain alkoxy, C 1-6 The branched alkoxy and C2-6 cycloalkoxy groups may be, for example, straight chain alkoxy groups having a total of 1, 2, 3, 4, 5 or 6 carbon atoms, branched chain alkoxy groups having a total of 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkoxy groups having a total of 2, 3, 4, 5 or 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc. 1-3 The "alkoxy group" has a similar explanation, except that the number of carbon atoms is different.

[0044] As described herein, pharmaceutically acceptable excipients, such as those used in the present invention, include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, glidant or lubricant, etc., suitable for the specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of these documents indicate that various excipients can be used in the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except to the extent that any conventional excipients are incompatible with the compounds of the present invention, for example by producing any adverse biological effects or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0045] Examples of pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives. Biological agents such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coatings; sweeteners; flavoring agents; fragrances; preservatives and antioxidants.

[0046] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0048] FIG1 is a concentration-time curve of the compounds in mouse plasma after oral administration of 50 mg / kg of Example 9 and Example 12;

[0049] FIG2 is a graph showing that Example 9 and Example 12 relatively prolonged the survival of mice in the HL60 diffusion model. DETAILED DESCRIPTION

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

[0051] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

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

[0053] Column chromatography used silica gel 200-300 mesh (produced by Titan); TLC silica gel plates were HSGF-254 thin-layer chromatography preformed plates produced by Yantai Chemical Plant; petroleum ether had a boiling range of 60-90°C; and color development was performed using a UV lamp and an iodine flask. Unless otherwise noted, all conventional reagents and chemicals used in the following examples were purchased from BID Group, Anage Group, and Titan Group. Reagents and solvents used in the experiments were adjusted according to the specific reaction conditions.

[0054] Example 1

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

[0056] Its synthetic route and preparation method 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) and stirred at 40°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. 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 phases were concentrated to give a colorless oil 1-3 (5.8 g, yield 87%), which was used directly in the next step.

[0058] S2. Compound 1-3 (2.9 g, 14.3 mmol) was dissolved in dichloromethane (60 mL), and 1-4 (3.0 g, 28.6 mmol) and acetic acid (1.2 g, 20 mmol) were added. The mixture was stirred at room temperature for 30 minutes. NaBH(OAc)3 (6.2 g, 29.0 mmol) was added to the system in batches and stirred at room temperature for 24 hours. After the reaction was completed, saturated NaHCO3 (50 mL) was added to quench the reaction and the mixture was 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 1-5 (2.0 g, 47% yield) as a light yellow oil.

[0059] S3. Dissolve compound 1-5 (2.0 g, 6.6 mmol) in tetrahydrofuran (20 mL). Add 1.0 M potassium tert-butoxide / tetrahydrofuran solution (8 mL) under ice-cooling and react at 0°C for 4 hours. After completion of the reaction, dilute with water and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a colorless oil 1-6 (mixture, 1.5 g, total yield 85%).

[0060] S4. Compound 1-7 (10.2 g, 100.0 mmol) was dissolved in MeOH (100 mL), and iodomethane (110.0 mmol, 6.8 mL) was slowly added. The reaction was stirred under reflux for 8 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and methyl tert-butyl ether was added to slurry. The mixture was filtered and dried to obtain 1-8 as a white solid (24.2 g, 99% yield).

[0061] S5. Compound 1-8 (2.4 g, 10.0 mmol) was added to ultra-dry tetrahydrofuran (10 mL), followed by compound 1-9 (1.4 g, 11.0 mmol), and the mixture was reacted at 40°C for 24 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, methyl tert-butyl ether was added for slurrying, and the mixture was filtered and dried to obtain 1-10 (2.8 g, 87% yield) as a white solid.

[0062] S6. Compound 1-6 (52 mg, 0.24 mmol) and compound 1-10 (71 mg, 0.20 mmol) were dissolved in ultra-dry methanol (2.0 mL), sodium methoxide (54 mg, 1.0 mmol) was added, and the mixture was stirred at 100°C for 16 hours. After the reaction was completed, water was added to dilute the mixture, and the mixture was 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 1 (34 mg, 42%) as a light yellow solid.

[0063] 1 H NMR(500MHz,Chloroform-d)δ7.46(dt,J=8.5,4.5Hz,2H),7.43–7.26(m,5H),6.95 (td,J=8.8,6.7Hz,2H),5.06–4.94(m,2H),3.99–3.82(m,2H),3.79(d,J=13.2Hz,1 H),3.53(d,J=13.1Hz,1H),3.30(q,J=2.2Hz,2H),3.11–3.03(m,1H),2.66–2.44(m ,1H),2.12(dt,J=17.4,2.8Hz,1H),1.30–1.19(m,2H),1.11(d,J=6.6Hz,3H).LC-MS m / z 405.2[M+H] + .

[0064] Example 2

[0065] Example 2 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0066] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0067] 1 H NMR(500MHz,Chloroform-d)δ7.46(dt,J=8.5,4.5Hz,2H),7.43–7.26(m,5H),6.95 (td,J=8.8,6.7Hz,2H),5.06–4.94(m,2H),3.99–3.82(m,2H),3.79(d,J=13.2Hz,1 H),3.53(d,J=13.1Hz,1H),3.30(q,J=2.2Hz,2H),3.11–3.03(m,1H),2.66–2.44(m ,1H),2.12(dt,J=17.4,2.8Hz,1H),1.30–1.19(m,2H),1.11(d,J=6.6Hz,3H).LC-MS m / z 421.2[M+H] + .

[0068] Example 3

[0069] Example 3 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0070] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0071] 1 H NMR(500MHz,Chloroform-d)δ7.46(dt,J=8.5,4.5Hz,2H),7.43–7.26(m,5H),6.95 (td,J=8.8,6.7Hz,2H),5.06–4.94(m,2H),3.99–3.82(m,2H),3.79(d,J=13.2Hz,1 H),3.53(d,J=13.1Hz,1H),3.30(q,J=2.2Hz,2H),3.11–3.03(m,1H),2.66–2.44(m ,1H),2.12(dt,J=17.4,2.8Hz,1H),1.30–1.19(m,2H),1.11(d,J=6.6Hz,3H).LC-MS m / z 465.1[M+H] + .

[0072] Example 4

[0073] Example 4 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0074] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0075] 1 H NMR(500MHz,Chloroform-d)δ7.39–7.19(m,5H),7.17–6.96(m,4H),5.04(d,J=2. 0Hz,2H),4.00–3.84(m,4H),3.81(s,1H),3.55(d,J=13.1Hz,1H),3.33(dt,J=3.7, 1.9Hz,2H),3.17–3.06(m,1H),2.68(ddt,J=17.4,5.1,2.2Hz,1H),2.40(d,J=3.5 Hz,3H),2.19(d,J=4.4Hz,1H),1.25(d,J=6.6Hz,2H),1.14(d,J=6.5Hz,3H).LC-MS m / z 401.2[M+H] + .

[0076] Example 5

[0077] Example 5 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0078] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0079] 1 H NMR(500MHz,Chloroform-d)δ7.43–7.21(m,8H),6.80–6.72(m,2H),5.08(dd, J=12.7,3.4Hz,2H),3.95–3.84(m,1H),3.81(d,J=13.2Hz,5H),3.53(d,J=13.1 Hz,1H),3.30(d,J=2.0Hz,1H),3.14–3.05(m,2H),2.64(dd,J=5.2,2.5Hz,1H) ,2.15(dt,J=17.2,2.9Hz,1H),1.30–1.21(m,2H),1.13(d,J=6.6Hz,3H).LC-MS m / z 423.2[M+H] + .

[0080] Example 6

[0081] Example 6 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0082] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0083] 1 H NMR(500MHz,Chloroform-d)δ7.61–7.49(m,7H),7.40(td,J=7.7,4.4Hz,1H),5.15–5.03(m,2H),3.98–3.85(m,4H),3.78(dd,J=19.1,14 .0Hz,1H),3.09(dtd,J=11.4,6.5,4.7Hz,1H),2.72–2.62(m,1H),2.24–2.13(m,1H),1.23(d,J=6.4Hz,1H),1.13(d,J=6.6Hz,2H).LC-MS m / z 455.2[M+H] + .

[0084] Example 7

[0085] Example 7 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0086] The preparation method is the same as that of Example 1, except that Substitute compound 1-4 in Example 1.

[0087] 1H NMR(500MHz,Chloroform-d)δ7.66(s,1H),7.54(dd,J=7.9,1.7Hz,2H),7.50–7.44(m,2H),7.40( t,J=7.7Hz,1H),6.96(td,J=8.7,6.2Hz,2H),4.99(s,2H),3.91(dt,J=9.4,3.8Hz,4H),3.79(d,J= 13.8Hz,1H),3.58(d,J=13.8Hz,1H),3.26(d,J=2.0Hz,2H),3.08(q,J=5.6Hz,1H),2.65(ddd,J=17 .3,5.1,2.5Hz,1H),2.15(dd,J=17.3,4.5Hz,1H),1.30–1.16(m,1H),1.13(d,J=6.5Hz,3H).LC-MS m / z 430.2[M+H] + .

[0088] Example 8

[0089] Example 8 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0090] The preparation method is the same as that of Example 7, except that Substitute compound 1-9 in Example 7.

[0091] 1 H NMR(500MHz,Chloroform-d)δ7.66(s,1H),7.54(d,J=7.8Hz,2H),7.41(dd,J=8.3,3.0Hz ,3H),7.27–7.21(m,3H),4.99(s,2H),3.95–3.85(m,4H),3.78(dd,J=18.8,14.0Hz,1H), 3.58(d,J=13.8Hz,1H),3.25(s,2H),3.08(q,J=5.7Hz,1H),2.65(dd,J=17.3,5.4Hz,1H) ,2.16(dd,J=17.3,4.4Hz,1H),1.24(dd,J=11.9,4.3Hz,1H),1.13(d,J=6.5Hz,2H).LC-MS m / z 446.2[M+H] + .

[0092] Example 9

[0093] Example 9 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referred to Example 1.

[0094] Furthermore, the obtained compound was separated:

[0095] The first separation was performed using a Water 150 preparative SFC (SFC-29) column with a ChiralPak AD, 250×30 mm ID, 10 μm column. The mobile phases were A: CO2, B: ethanol (0.1% NH3H2O). The mobile phase gradient was 30% B. The flow rate was 150 mL / min, the back pressure was 100 bar, the column temperature was 38°C, and the monitoring wavelength was 220 nm. The separation lasted approximately 10 minutes. Sample preparation: 995 mg of sample was dissolved in approximately 30 mL of methanol / dichloromethane, and 2 mL was injected each time for separation. The first separation yielded 9-P1 and a mixture of 9-P2 and 9-P3.

[0096] 1 H NMR(500MHz,Chloroform-d)δ7.68(d,J=1.7Hz,1H),7.61–7.53(m,2H),7.46–7.35(m,5H),5.02(d,J=2.7Hz,2H),3.92(d,J=4.7Hz,4H),3.83 –3.61(m,3H),3.06–2.92(m,1H),2.70(dd,J=12.9,6.7Hz,1H),2.63–2.46(m,1H),2.21(ddd,J=17.7,4.7,1.4Hz,1H),1.25(d,J=6.4Hz,3H).

[0097] The second separation was performed using a Water 150 preparative SFC (SFC-29) column with a ChiralPak IC, 250×30 mm ID, 10 μm column. The mobile phases were A: CO2, B: ethanol (0.1% NH3H2O), mobile phase gradient: B 40%, flow rate: 150 mL / min, back pressure: 100 bar, column temperature: 38°C, monitoring wavelength: 220 nm. The separation took approximately 6 minutes. Sample preparation: The 9-P2 and 9-P3 mixture was dissolved in approximately 60 mL of methanol / dichloromethane, and 3 mL was injected each time for separation. This time, 9-P2 and 9-P3 were resolved.

[0098] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=1.8Hz,1H),7.64–7.52(m,2H),7.47– 7.34(m,5H),5.01(d,J=2.7Hz,2H),3.92(d,J=4.5Hz,4H),3.82–3.61(m,4H), 2.99(ddd,J=12.8,10.6,4.6Hz,1H),2.70(dd,J=12.9,6.8Hz,1H),2.54(ddd, J=17.6,10.7,7.0Hz,1H),2.21(dd,J=17.6,4.4Hz,1H),1.25(d,J=6.5Hz,3H).

[0099] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.7Hz,1H),7.56(dt,J=8.0,1.7Hz, 2H),7.49–7.32(m,5H),4.99(d,J=1.5Hz,2H),3.96–3.90(m,4H),3.81(d,J=1 3.8Hz,1H),3.60(d,J=13.8Hz,1H),3.27(d,J=1.8Hz,2H),3.16–3.04(m,1H), 2.67(ddt,J=17.4,5.5,2.1Hz,1H),2.24–2.11(m,1H),1.15(d,J=6.6Hz,3H).

[0100] Example 10

[0101] Example 10 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referred to Example 1.

[0102] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=1.7Hz,1H),7.57(ddt,J=17.7,7.7,1.4Hz,2H ),7.42(t,J=7.7Hz,1H),7.22–7.04(m,4H),5.11–4.99(m,2H),4.10–3.99(m,1H),3.9 9–3.87(m,3H),3.81–3.72(m,1H),3.71–3.51(m,2H),2.92(d,J=14.9Hz,1H),2.63–2. 59(m,1H),2.59–2.47(m,2H),2.43(q,J=3.8,3.1Hz,3H),1.39(d,J=6.7Hz,3H).LC-MS m / z 426.2[M+H] + .

[0103] Example 11

[0104] Example 11 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referred to Example 1.

[0105] 1 H NMR(500MHz,Chloroform-d)δ7.67(q,J=2.5,1.7Hz,1H),7.59–7.51(m,2H),7.4 7–7.32(m,1H),7.32–7.22(m,2H),6.82–6.72(m,2H),5.08(dd,J=12.5,3.4Hz,2 H),3.99–3.89(m,4H),3.87–3.74(m,1H),3.69–3.55(m,1H),3.30–3.24(m,2H), 3.10(dtd,J=11.4,6.5,4.7Hz,1H),2.26–2.15(m,1H),1.30–1.21(m,3H).LC-MS m / z 426.2[M+H] + .

[0106] Example 12

[0107] Example 12 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referred to Example 1.

[0108] Furthermore, the compound prepared in Example 12 was resolved:

[0109] The first separation was performed using a WATERS150 preparative SFC (SFC-26) column with a ChiralPak AD, 250×30 mm ID, 10 μm column. The mobile phases were A: CO₂, B: ethanol (0.1% NH₃H₂O), with a gradient of 30% B at a flow rate of 150 mL / min and a back pressure of 100 bar. The column temperature was 38°C, and the monitoring wavelength was 220 nm. The separation lasted approximately 6 minutes. Sample preparation involved dissolving 490 mg of sample in 20 mL of methanol / dichloromethane, with 2 mL injected each time. The first separation yielded 12-P1 and 12-P4, as well as a mixture of 12-P2 and 12-P3.

[0110] 1 H NMR(500MHz,Chloroform-d)δ7.65(d,J=1.8Hz,1H),7.54(q,J=8.9,8.0Hz,6 H),7.39(t,J=7.7Hz,1H),5.16–5.00(m,2H),3.94–3.86(m,4H),3.79–3.72(m ,2H),3.71–3.64(m,2H),3.04–2.89(m,1H),2.68(dd,J=12.8,6.7Hz,1H),2. 60–2.45(m,1H),2.19(ddd,J=17.7,4.8,1.4Hz,1H),1.30–1.08(m,3H).LC-MS m / z 480.2[M+H] + .

[0111] 1 H NMR(500MHz,Chloroform-d)δ7.65(d,J=1.8Hz,1H),7.59–7.49(m,6H),7.39(t,J=7. 7Hz,1H),5.15–5.01(m,2H),3.98–3.86(m,4H),3.75(dd,J=13.4,6.7Hz,2H),3.70–3 .59(m,2H),2.96(ddd,J=12.9,10.6,4.6Hz,1H),2.68(dd,J=12.9,6.7Hz,1H),2.61– 2.45(m,2H),2.19(ddd,J=17.7,4.7,1.5Hz,1H),1.21(dd,J=12.3,6.7Hz,3H).LC-MS m / z 480.2[M+H] + .

[0112] The second separation was performed using a WATERS 150 preparative SFC (SFC-26) column with a (S,S) Whelk O1, 250×30 mm ID, 10 μm column. The mobile phases were A: CO2, B: ethanol (0.1% NH3H2O), mobile phase gradient: B 40%, flow rate: 150 mL / min, back pressure: 100 bar, column temperature: 38°C, monitoring wavelength: 220 nm. The separation took approximately 12 minutes. Sample preparation: The 12-P2 and 12-P3 mixture was dissolved in approximately 20 mL of methanol / dichloromethane, and 8 mL was injected each time for separation. This time, 12-P2 and 12-P3 were resolved.

[0113] 1 H NMR(500MHz,Chloroform-d)δ7.65(d,J=1.7Hz,1H),7.61–7.48(m,6H),7.40(t, J=7.7Hz,1H),5.07(d,J=1.8Hz,2H),3.91(q,J=3.2Hz,4H),3.80(d,J=13.8Hz,1H ),3.58(d,J=13.8Hz,1H),3.25(d,J=1.8Hz,2H),3.09(dtd,J=11.4,6.4,4.6Hz,1 H),2.72–2.60(m,1H),2.17(dt,J=17.5,3.0Hz,2H),1.13(d,J=6.6Hz,3H).LC-MS m / z 480.2[M+H] + .

[0114] 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J=1.7Hz,1H),7.58–7.51(m,6H),7.40(t,J =7.7Hz,1H),5.08(d,J=1.6Hz,2H),3.92(dt,J=5.0,2.5Hz,4H),3.80(d,J=13.8Hz ,1H),3.71(q,J=7.0Hz,1H),3.58(d,J=13.8Hz,1H),3.26(d,J=1.9Hz,2H),3.09(d t,J=6.7,4.9Hz,1H),2.76–2.56(m,1H),2.24–2.10(m,1H),1.13(d,J=6.5Hz,3H). 13C NMR(126MHz,CDCl3)δ 14.27,33.04,44.86,44.99,46.90,50.47,50.80,56.96,76.78,77.04,77.29,100.77,112.57,118.92,123.09,1 25.26,125.30,128.86,129.21,129.36,130.94,132.09,132.97,140.50,140.72,145.08,153.03,161.26.LC-MS m / z 480.2[M+H] + .

[0115] Example 13

[0116] Example 13 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0117] The reaction equation and preparation method are as follows:

[0118] 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. Triethylamine (9.0 mL, 66.0 mmol) and Boc2O (9.0 mL, 39.0 mmol) were then added and the reaction continued at 40°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. Methyl tert-butyl ether was added and stirred for 30 minutes, then 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 give a colorless oil 34-1 (7.3 g, 75% yield), which was used directly in the next step.

[0119] S2. Dissolve compound 13-1 (10.6 g, 34.9 mmol) in tetrahydrofuran (175 mL). Add 1.0 M potassium tert-butoxide / tetrahydrofuran solution (42 mL, 42.0 mmol) under ice-cooling. React at 0°C for 4 hours. After completion of the reaction, dilute with water and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain a colorless oil 13-2 (mixture, 9.6 g, total yield 85%).

[0120] S3. Compound 13-2 (2.7 g, 10.0 mmol) and compound 13-3 (4.5 g, 12.0 mmol) were dissolved in ultra-dry methanol (20 mL). Sodium methoxide (2.7 g, 50.0 mmol) was added and stirred at 100°C for 16 hours. After the reaction was completed, the mixture 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 13-4 as a yellow solid.

[0121] S4. Compound 13-4 (2.3 g, 5.0 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the reaction was quenched by addition of saturated aqueous NaHCO₃. The mixture was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (8% MeOH in DCM) to afford 13-5 as an off-white solid.

[0122] S5. Compound 13-5 (73 mg, 0.2 mmol) was dissolved in acetonitrile (2 mL), and 13-6 (46 mg, 0.24 mmol) and cesium carbonate (130 mg, 0.4 mmol) were added. The mixture was stirred at 80°C overnight. After the reaction, the solvent was removed by distillation under reduced pressure. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (4% MeOH in DCM) to obtain 13 as a yellow solid.

[0123] 1 H NMR(500MHz,Chloroform-d)δ7.71–7.53(m,2H),7.52(dd,J=8.6,6.0Hz,5H),7.4 8(dd,J=7.8,1.5Hz,1H),7.34(td,J=7.5,1.5Hz,1H),5.06(s,2H),3.99–3.85(m,5 H),3.78(d,J=13.7Hz,1H),3.25(q,J=2.3Hz,3H),2.75(ddt,J=17.5,5.1,2.2Hz, 1H),2.18(dt,J=17.3,2.7Hz,1H),1.32–1.23(m,1H),1.18(d,J=6.6Hz,3H).LC-MS m / z 480.2[M+H] + .

[0124] Example 14

[0125] Example 14 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method is similar to that of Example 13.

[0126] 1 H NMR(500MHz,Chloroform-d)δ7.62(s,1H),7.68–7.58(m,1H),7.61–7.50(m,5H),7.45(t, J=7.9Hz,2H),5.08(dd,J=12.5,3.4Hz,2H),3.91(dt,J=3.9,2.3Hz,4H),3.80(dd,J=20.3 ,14.3Hz,1H),3.60(d,J=14.1Hz,1H),3.26(d,J=1.8Hz,1H),3.08(dtd,J=11.5,6.5,4.8H z,1H),2.76–2.60(m,1H),2.18(tdd,J=17.4,5.5,1.7Hz,1H),1.13(d,J=6.6Hz,3H).LC-MS m / z 480.2[M+H] + .

[0127] Example 15

[0128] Example 15 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0129] 1 H NMR(500MHz,Chloroform-d)δ7.68–7.47(m,4H),7.30–7.21(m,1H),7.13–7.02(m,2H),6.93 (ddd,J=10.4,8.1,2.7Hz,1H),5.09(dd,J=11.5,2.6Hz,2H),3.90(dd,J=4.0,2.6Hz,3H),3.9 1–3.79(m,1H),3.75(dd,J=25.5,13.7Hz,1H),3.54(d,J=13.5Hz,1H),3.29(s,1H),3.08(ddd ,J=13.0,6.5,4.6Hz,1H),2.76–2.60(m,1H),2.22–2.10(m,1H),1.11(d,J=6.5Hz,3H).LC-MS m / z 473.2[M+H] + .

[0130] Example 16

[0131] Example 16 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method is similar to that of Example 13.

[0132] 1 H NMR(500MHz,Chloroform-d)δ7.67–7.47(m,4H),7.37(td,J=7.5,1.8Hz,1H),7.22(tdd,J=7.5,5.2,1.8Hz ,1H),7.08(td,J=7.5,1.2Hz,1H),7.01(ddd,J=9.7,8.2,1.2Hz,1H),5.07(d,J=2.5Hz,2H),3.95–3.84(m, 4H),3.80(dd,J=13.3,1.2Hz,1H),3.62(d,J=13.4Hz,1H),3.34(d,J=1.9Hz,2H),3.11(dtd,J=11.5,6.5,4 .6Hz,1H),2.63(ddt,J=17.4,5.5,2.1Hz,1H),2.19–2.10(m,1H),1.25(s,1H),1.15(d,J=6.6Hz,3H).LC-MS m / z 473.2[M+H] + .

[0133] Example 17

[0134] Example 17 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method is similar to that of Example 13.

[0135] 1 H NMR(500MHz,Chloroform-d)δ7.55(p,J=8.4Hz,6H),7.28(td,J=8.0,5.4Hz,3H),6.98(td,J=8.7,2.2Hz,3H),5.09(dd,J=12.2,2.7Hz,3H),3.99–3.84(m ,6H),3.81–3.69(m,1H),3.58–3.42(m,1H),3.27(d,J=2.0Hz,2H),3.14–3.0 0(m,1H),2.79–2.35(m,2H),2.23–2.06(m,2H),1.11(d,J=6.5Hz,3H).LC-MS m / z 473.2[M+H] + .

[0136] Example 18

[0137] Example 18 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0138] 1H NMR(500MHz,Chloroform-d)δ7.62–7.48(m,4H),7.14(ddd,J=7.6,4.7,1.7Hz,1 H),7.09–7.01(m,1H),7.04–6.97(m,1H),5.08(d,J=2.1Hz,2H),3.96–3.84(m,4 H),3.81(dd,J=13.6,1.5Hz,1H),3.68–3.61(m,1H),3.33(d,J=2.1Hz,2H),3.16 –3.07(m,1H),2.69–2.60(m,1H),2.22–2.12(m,1H),1.16(d,J=6.5Hz,3H).LC-MS m / z 491.5[M+H] +

[0139] Example 19

[0140] Example 19 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method is similar to that of Example 13.

[0141] 1 H NMR(500MHz,Chloroform-d)δ7.61–7.47(m,4H),7.22–7.11(m,1H),7.09–6.97(m,2H),5.09(dd,J=11.3,1.9Hz,2H),3.96–3.85(m,4H),3.85–3. 60(m,2H),3.33(d,J=1.9Hz,1H),3.12(dt,J=6.7,5.0Hz,1H),2.64(ddt,J=17.5,5.2,2.1Hz,1H),2.19–2.11(m,1H),1.16(d,J=6.6Hz,3H).LC-MS m / z 491.5[M+H] +

[0142] Example 20

[0143] Example 20 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0144] 1H NMR(500MHz,Chloroform-d)δ7.55(q,J=8.3Hz,5H),6.87(qd,J=6.6,3.4Hz,2H),6.6 8(tt,J=8.9,2.4Hz,1H),5.09(d,J=2.1Hz,2H),4.00–3.85(m,4H),3.75(d,J=13.9Hz, 1H),3.54(d,J=13.9Hz,1H),3.29(d,J=1.9Hz,2H),3.14–3.05(m,1H),2.66(ddt,J=1 7.3,5.1,2.1Hz,1H),2.16(ddt,J=17.3,3.5,1.6Hz,1H),1.11(d,J=6.6Hz,3H).LC-MS m / z 491.5[M+H] +

[0145] Example 21

[0146] Example 21 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0147] 1 H NMR(500MHz,Chloroform-d)δ7.68–7.48(m,4H),7.16(dddd,J=21.4,8.8,5.7,3.2Hz,1H ),6.96(td,J=9.1,4.5Hz,1H),6.95–6.85(m,1H),5.09(dd,J=9.7,1.9Hz,2H),4.00–3.8 3(m,4H),3.86–3.71(m,1H),3.61(d,J=14.1Hz,1H),3.33(d,J=1.8Hz,1H),3.12(dtd,J= 11.6,6.5,4.6Hz,1H),2.70–2.51(m,1H),2.26–2.12(m,1H),1.15(d,J=6.6Hz,3H).LC-MS m / z491.5[M+H] +

[0148] Example 22

[0149] Example 22 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0150] 1H NMR(500MHz,Chloroform-d)δ7.64–7.50(m,4H),7.37–7.31(m,1H),7.28–7.1 4(m,3H),5.09(dd,J=11.6,2.4Hz,2H),3.99–3.89(m,2H),3.90(d,J=3.3Hz,2H ),3.74(dd,J=24.8,13.6Hz,1H),3.52(d,J=13.5Hz,1H),3.29(s,1H),3.13–3 .04(m,1H),2.75–2.61(m,1H),2.22–2.11(m,1H),1.12(d,J=6.6Hz,3H).LC-MS m / z 491.5[M+H] +

[0151] Example 23

[0152] Example 23 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0153] 1 H NMR(500MHz,Chloroform-d)δ7.69–7.50(m,4H),7.02–6.91(m,2H),5.09(dd,J=10.3,2.8Hz,2H),3.91(q,J=2.9Hz,4H),3.77–3.63(m,1H),3.48(d,J= 14.0Hz,1H),3.25(d,J=2.3Hz,1H),3.07(hept,J=5.3,4.5Hz,1H),2.72–2. 61(m,1H),2.18(td,J=19.2,17.3,4.4Hz,1H),1.11(d,J=6.6Hz,2H).LC-MS m / z 509.2[M+H] +

[0154] Example 24

[0155] Example 24 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0156] 1H NMR (500MHz, Chloroform-d) δ7.66–7.54(m,1H),7.53(s,4H),6.71–6.59(m,2H),5.08(s,2H),3.97–3.86(m,3H),3.89–3.82(m,1H),3.80(d,J=12. 6Hz,1H),3.57(d,J=12.7Hz,1H),3.34(s,2H),3.12(q,J=5.5Hz,1H),2.6 7–2.53(m,1H),2.15(dt,J=17.4,3.1Hz,1H),1.18(d,J=6.5Hz,3H).LC-MS m / z 509.2[M+H] +

[0157] Example 25

[0158] Example 25 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0159] 1 H NMR(500MHz,Chloroform-d)δ7.70–7.41(m,4H),5.10(d,J=11.5Hz,2H),4.01–3.80(m,5H),3.68(dd,J=29.7,13.0Hz,1H), 3.33(s,1H),3.21–2.99(m,1H),2.81–2.48(m,1H),2.19(ddd,J=27.9,17.6,5.2Hz,1H),1.23(dd,J=33.9,6.6Hz,4H).LC-MS m / z 545.2[M+H] +

[0160] Example 26

[0161] Example 26 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0162] 1H NMR(500MHz,Chloroform-d)δ7.65–7.51(m,6H),7.26–7.17(m,2H),5.10(s,2H),3.94(q,J=3.0Hz,4H),3.82(d,J=14.5Hz,1H),3.62(d,J=14 .5Hz,1H),3.28(d,J=1.9Hz,2H),3.15–3.05(m,1H),2.67(dd,J=17.3,5.1Hz,1H),2.18(dd,J=17.2,4.6Hz,1H),1.13(d,J=6.6Hz,3H).LC-MS m / z 498.2[M+H] +

[0163] Example 27

[0164] Example 27 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0165] 1 H NMR(500MHz,Chloroform-d)δ7.62(dd,J=8.6,5.3Hz,1H),7.58–7.48(m,4H),7.39–7 .28(m,1H),7.25–7.14(m,1H),7.04(tt,J=8.2,2.9Hz,1H),5.08(d,J=15.8Hz,2H),3. 92(dt,J=4.9,3.0Hz,4H),3.89–3.75(m,2H),3.27(d,J=1.9Hz,1H),3.24–3.18(m,1H ),2.85–2.54(m,1H),2.19(ddd,J=17.3,7.2,4.2Hz,1H),1.17(d,J=6.6Hz,3H).LC-MS m / z 498.2[M+H] +

[0166] Example 28

[0167] Example 28 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0168] 1H NMR(500MHz,Chloroform-d)δ7.65–7.47(m,5H),7.37(dq,J=8.0,2.0Hz,1H),7.2 7–7.21(m,1H),7.17(td,J=7.7,3.5Hz,1H),5.09(dd,J=11.4,2.4Hz,2H),3.98–3. 79(m,4H),3.73(dd,J=23.5,13.6Hz,1H),3.51(d,J=13.5Hz,1H),3.29(s,1H),3.1 3–3.04(m,1H),2.74–2.61(m,1H),2.23–2.11(m,1H),1.11(d,J=6.5Hz,3H).LC-MS m / z 489.2[M+H] + .

[0169] Example 29

[0170] Example 29 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0171] 1 H NMR(500MHz,Chloroform-d)δ7.64–7.50(m,4H),7.37–7.31(m,1H),7.28–7.1 4(m,3H),5.09(dd,J=11.6,2.4Hz,2H),3.99–3.89(m,2H),3.90(d,J=3.3Hz,2H ),3.74(dd,J=24.8,13.6Hz,1H),3.52(d,J=13.5Hz,1H),3.29(s,1H),3.13–3 .04(m,1H),2.75–2.61(m,1H),2.22–2.11(m,1H),1.12(d,J=6.6Hz,3H).LC-MS m / z 533.1[M+H] + .

[0172] Example 30

[0173] Example 30 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0174] 1H NMR(500MHz,Chloroform-d)δ7.59(dd,J=13.7,8.3Hz,2H),7.53(dd,J=14.2,6.0Hz,4 H),7.49(d,J=1.7Hz,1H),7.46–7.38(m,1H),5.09(dd,J=12.7,2.6Hz,2H),3.97–3.84 (m,4H),3.81(dd,J=21.1,13.7Hz,1H),3.61(d,J=13.6Hz,1H),3.29(d,J=1.7Hz,1H), 3.14–3.05(m,1H),2.74–2.61(m,1H),2.23–2.12(m,1H),1.13(d,J=6.6Hz,3H).LC-MS m / z 523.2[M+H] + .

[0175] Example 31

[0176] Example 31 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0177] 1 H NMR(500MHz,Chloroform-d)δ7.62(d,J=8.0Hz,0H),7.59–7.48(m,5H),7.26–7.09(m,3H),7.09(s,0H),7.0 8–7.03(m,1H),5.15–5.02(m,2H),3.99–3.83(m,5H),3.77(d,J=13.1Hz,1H),3.49(d,J=13.0Hz,1H),3.30(q ,J=1.8Hz,2H),3.13–3.04(m,1H),2.64(ddt,J=17.4,5.6,2.1Hz,1H),2.57(d,J=3.3Hz,0H),2.45–2.32(m, 1H),2.32(s,3H),2.14(ddt,J=17.4,4.6,1.6Hz,1H),1.26(s,1H),1.25(s,1H),1.12(d,J=6.6Hz,3H).LC-MS m / z 469.2[M+H] + .

[0178] Example 32

[0179] Example 32 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0180] 1 H NMR(500MHz,Chloroform-d)δ7.54(q,J=8.3Hz,5H),7.21(dd,J=8.6,7.0Hz,1H),6.94–6.86(m ,2H),6.78(ddd,J=8.2,2.6,1.0Hz,1H),5.09(dd,J=10.6,2.2Hz,2H),3.98–3.89(m,2H),3.89 –3.80(m,3H),3.80–3.66(m,5H),3.52(d,J=13.2Hz,1H),3.31(dt,J=4.3,1.9Hz,2H),3.14–3. 04(m,1H),2.64(ddt,J=17.4,5.6,2.1Hz,1H),2.20–2.09(m,2H),1.10(d,J=6.6Hz,3H).LC-MS m / z 485.2[M+H] + .

[0181] Example 33

[0182] Example 33 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0183] 1 H NMR(500MHz,Chloroform-d)δ8.34–8.18(m,1H),7.84(dt,J=7.2,2.6Hz,1H),7.77(dd,J= 7.7,1.5Hz,1H),7.66–7.35(m,10H),5.18–4.98(m,3H),4.26(d,J=13.0Hz,1H),3.98–3.79 (m,6H),3.44(dt,J=15.5,1.6Hz,1H),3.31(dt,J=15.7,2.1Hz,1H),3.16(td,J=6.0,3.8H z,1H),2.68–2.58(m,1H),2.11(ddd,J=17.3,3.6,1.8Hz,1H),1.18(d,J=6.6Hz,3H).LC-MS m / z 505.2[M+H] + .

[0184] Example 34

[0185] Example 34 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0186] 1H NMR(500MHz,Chloroform-d)δ7.63–7.47(m,5H),7.32(dd,J=8.3,1.9Hz,2H),7.27–7.2 1(m,2H),5.09(dd,J=11.4,2.9Hz,2H),3.94–3.81(m,5H),3.74(dd,J=29.4,13.2Hz,1H) ,3.52(d,J=13.1Hz,1H),3.36–3.25(m,2H),3.11(dq,J=10.7,6.3Hz,1H),2.65(dd,J=1 6.9,5.1Hz,1H),2.20–2.10(m,1H),1.31(d,J=2.8Hz,11H),1.12(d,J=6.5Hz,3H).LC-MS m / z 511.3[M+H] + .LC-MS m / z 511.3[M+H] + .

[0187] Example 35

[0188] Example 35 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 13.

[0189] 1 H NMR(500MHz,Chloroform-d)δ8.24–8.18(m,1H),7.83(dt,J=8.2,2.2Hz,1H),7.73(d,J=8.0Hz,1H),7.70–7.63( m,1H),7.63–7.53(m,1H),7.56–7.49(m,3H),7.52–7.44(m,1H),7.48–7.37(m,2H),7.40–7.35(m,1H),7.32(dd, J=7.1,1.3Hz,1H),5.56(s,2H),4.01–3.86(m,4H),3.80(dd,J=17.9,14.1Hz,1H),3.60(d,J=13.8Hz,1H),3.30( d,J=1.9Hz,2H),3.18–3.08(m,1H),2.71(ddt,J=17.4,5.3,2.1Hz,1H),2.32–2.17(m,1H),1.16(d,J=6.5Hz,3H).

[0190] Example 36

[0191] Example 36 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0192] 1 H NMR(500MHz,Chloroform-d)δ7.66(dt,J=3.6,1.7Hz,1H),7.60(dt,J=6.9,1.9Hz,1H),7. 60–7.52(m,1H),7.56–7.51(m,1H),7.46–7.32(m,3H),7.19–7.11(m,1H),5.01(dd,J=13.4 ,2.9Hz,2H),3.92(q,J=3.8,3.2Hz,4H),3.92–3.71(m,2H),3.59(d,J=13.8Hz,1H),3.26( d,J=1.8Hz,1H),3.10(hept,J=6.0,5.4Hz,1H),2.73–2.62(m,1H),2.24–2.13(m,1H),1.14 (d,J=6.5Hz,3H).LC-MS m / z 490.1[M+H] + .

[0193] Example 37

[0194] Example 37 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0195] 1 H NMR(500MHz,Chloroform-d)δ7.77(td,J=6.6,2.2Hz,1H),7.72–7.63(m,2H),7.59–7.51(m,2 H),7.40(td,J=7.7,3.7Hz,1H),7.10(dt,J=10.2,7.7Hz,1H),5.04(dd,J=13.8,3.3Hz,2H),3. 99–3.87(m,4H),3.78(dd,J=17.7,14.0Hz,2H),3.62(dd,J=34.5,13.9Hz,1H),3.26(d,J=1.9 Hz,2H),3.14–3.04(m,1H),2.74–2.61(m,1H),2.25–2.11(m,1H),1.13(d,J=6.5Hz,3H).LC-MS m / z 498.2[M+H] + .

[0196] Example 38

[0197] Example 38 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0198] 1 H NMR(500MHz,Chloroform-d)δ7.66(dt,J=3.7,1.7Hz,1H),7.54(dt,J=8.0,1.8Hz,2H),7.40(td,J =7.7,4.0Hz,1H),7.34(dddd,J=11.2,7.8,5.9,2.2Hz,1H),7.21(dtt,J=8.0,3.8,2.0Hz,1H),7.1 0–7.01(m,1H),4.98(dd,J=13.0,3.0Hz,2H),3.92(dt,J=4.4,2.7Hz,4H),3.84–3.53(m,2H),3.09 (dtd,J=12.9,6.5,4.7Hz,1H),2.71–2.59(m,1H),2.29–2.05(m,1H),1.13(d,J=6.5Hz,3H).LC-MS m / z 448.2[M+H] + .

[0199] Example 39

[0200] Example 39 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0201] 1 H NMR(500MHz,Chloroform-d)δ7.66(q,J=2.2,1.7Hz,1H),7.54(dd,J=7.4,2.3 Hz,3H),7.49–7.32(m,2H),7.08–7.00(m,1H),5.01–4.92(m,2H),3.97–3.87( m,4H),3.90–3.73(m,2H),3.59(d,J=13.8Hz,1H),3.26(t,J=1.8Hz,2H),3.14 –3.04(m,1H),2.76–2.62(m,1H),2.24–2.12(m,1H),1.24–1.11(m,3H).LC-MS m / z 464.2[M+H] + .

[0202] Example 40

[0203] Example 40 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0204] 1H NMR(500MHz,Chloroform-d)δ7.66(q,J=2.1Hz,1H),7.59–7.53(m,1H),7.53(t,J=1.7Hz ,1H),7.48–7.37(m,2H),7.14(td,J=7.9,2.0Hz,1H),4.99(dd,J=12.9,2.9Hz,2H),3.92 (p,J=2.4,1.8Hz,4H),3.78(dd,J=19.1,13.6Hz,1H),3.25(d,J=1.9Hz,1H),2.72–2.62(m,1H),2.24–2.13(m,1H),1.13(d,J=6.5Hz,3H).LC-MS m / z 508.2[M+H] + .

[0205] Example 41

[0206] Example 41 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0207] 1 H NMR(500MHz,Chloroform-d)δ7.75–7.63(m,1H),7.60–7.51(m,2H),7.41(q,J=7.6Hz,1H),7. 29–7.17(m,3H),6.97(dd,J=8.3,5.3Hz,1H),5.05–4.88(m,2H),4.00–3.87(m,4H),3.80(dd,J =18.7,14.1Hz,1H),3.63(dd,J=39.2,13.9Hz,1H),3.11(hept,J=5.5,4.7Hz,1H),2.70(ddd,J =17.3,5.4,2.4Hz,1H),2.38(d,J=3.1Hz,3H),2.32–2.16(m,1H),1.16(d,J=6.6Hz,3H).LC-MS m / z 504.1[M+H] + .

[0208] Example 42

[0209] Example 42 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0210] The reaction equation and preparation method are as follows:

[0211] S1. Mix 42-1 (1.8 g, 9.3 mmol), 42-2 (1.1 g, 11.2 mmol), and DBU (150 μL, 1.0 mmol) and stir at 60°C for 24 hours. After the reaction, the mixture was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 42-3 (1.5 g, 85% yield) as a colorless oil.

[0212] S2. Dissolve 42-3 (5.0 mmol) in ultra-dry tetrahydrofuran (20 mL). Add 1.0 M potassium tert-butoxide / tetrahydrofuran solution (6 mL) under ice-cooling. React at 0°C for 4 hours. After completion of the reaction, dilute with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to afford 42-4.

[0213] S3. Compound 42-4 (52 mg, 0.24 mmol) and compound 42-5 (71 mg, 0.20 mmol) were dissolved in ultra-dry methanol (2.0 mL). Sodium methoxide (54 mg, 1.0 mmol) was added and stirred at 100°C for 16 hours. After the reaction, the mixture 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 42 as a pale yellow solid.

[0214] 1 H NMR(500MHz,Chloroform-d)δ7.38–7.28(m,5H),7.17–7.05(m,4H),5.25–4.8 3(m,2H),4.09–3.98(m,1H),3.94–3.83(m,3H),3.80(d,J=13.2Hz,1H),3.69( dd,J=15.0,1.1Hz,1H),3.51(d,J=13.2Hz,1H),2.94(dd,J=15.0,1.4Hz,1H), 2.63(dt,J=11.2,1.6Hz,1H),2.54–2.34(m,5H),1.37(d,J=6.7Hz,3H).LC-MS m / z 401.2[M+H] + .

[0215] Example 43

[0216] Example 43 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 42.

[0217] 1H NMR(500MHz,Chloroform-d)δ7.36–7.23(m,6H),6.77(tdd,J=11.2,5.7,2.7Hz, 2H),5.14–5.03(m,2H),4.09–3.98(m,1H),3.88(dd,J=4.6,2.5Hz,3H),3.87–3. 73(m,1H),3.70–3.58(m,1H),3.52(d,J=13.1Hz,1H),2.91(dd,J=15.0,1.3Hz,1 H),2.63(dt,J=11.1,1.6Hz,1H),2.47–2.31(m,2H),1.35(d,J=6.7Hz,3H).LC-MS m / z 423.2[M+H] + .

[0218] Example 44

[0219] Example 44 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 42.

[0220] 1 H NMR(500MHz,Chloroform-d)δ7.60–7.51(m,4H),7.41–7.15(m,5H),5.25–4.92 (m,2H),4.08–3.96(m,1H),3.94–3.82(m,3H),3.78(d,J=13.1Hz,1H),3.67(d, J=15.0Hz,1H),3.52(d,J=13.2Hz,1H),2.91(d,J=15.0Hz,1H),2.62(dt,J=11. 1,1.5Hz,1H),2.39(ddd,J=14.7,11.2,4.8Hz,2H),1.34(d,J=6.7Hz,3H).LC-MS m / z 455.2[M+H] + .

[0221] Example 45

[0222] Example 45 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0223] The reaction equation and preparation method are as follows:

[0224] S1. Dissolve 42-4 (783 mg, 3.0 mmol) in methanol (20 mL), add 10% Pd / C (78 mg), and react at room temperature under hydrogen atmosphere overnight. After the reaction, filter out Pd / C through celite, and spin-dry the filtrate to obtain 45-1.

[0225] S2. Dissolve 45-1 (514 mg, 3.0 mmol), 3-cyanobenzaldehyde (524 mg, 6.0 mmol), and DIPEA (390 mg, 6.0 mmol) obtained in the previous step in 1,2-dichloroethane (20 mL) and stir at room temperature for 30 minutes. NaBH(OAc)3 (844 mg, 6.0 mmol) was added portionwise to the system and stirred at room temperature for 24 hours. After the reaction, saturated NaHCO3 (30 mL) was added to quench the reaction and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 45-2.

[0226] S3. Compound 45-2 (52 mg, 0.24 mmol) and compound 1-10 (mg, 0.20 mmol) were dissolved in ultra-dry methanol (2.0 mL). Sodium methoxide (54 mg, 1.0 mmol) was added and stirred at 100°C for 16 hours. After the reaction was completed, water was added to dilute the mixture and the mixture was 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 45 as a pale yellow solid.

[0227] 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–7.35 (m,3H),6.94(d,J=8.7Hz,2H),5.05–4.91(m,2H),4.09–3.94(m,1H),3.97–3.83(m, 3H),3.73(d,J=13.6Hz,1H),3.58(d,J=13.6Hz,2H),2.88(d,J=14.8Hz,1H),2.58 (d,J=10.5Hz,1H),2.44(dq,J=12.8,5.5,4.5Hz,2H),1.34(d,J=6.8Hz,3H).LC-MS m / z 430.2[M+H] + .

[0228] Example 46

[0229] Example 46 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 45.

[0230] 1 H NMR(500MHz,Chloroform-d)δ7.68–7.64(m,1H),7.61–7.50(m,2H),7.50–7 .33(m,3H),7.28–7.21(m,2H),5.05–4.94(m,2H),4.06–3.95(m,1H),3.93– 3.83(m,1H),3.86–3.71(m,3H),3.60(t,J=14.3Hz,2H),2.88(d,J=14.8Hz, 1H),2.58(d,J=10.4Hz,1H),2.49–2.37(m,2H),1.35(d,J=6.8Hz,3H).LC-MS m / z 446.2[M+H] + .

[0231] Example 47

[0232] Example 47 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 45.

[0233] 1 H NMR(500MHz,Chloroform-d)δ7.66(t,J=1.8Hz,1H),7.56(ddt,J=12.0,7.7,1.4Hz,2H),7.49–7.26(m,5H),5.04–4.93(m,2H),4.09–3.99(m,1H),3.95– 3.85(m,3H),3.85–3.71(m,1H),3.71–3.49(m,2H),2.88(d,J=14.8Hz,1H),2 .58(dt,J=11.2,1.9Hz,1H),2.49–2.37(m,2H),1.35(d,J=6.9Hz,3H).LC-MS m / z 490.2[M+H] + .

[0234] Example 48

[0235] Example 48 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 45.

[0236] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=1.7Hz,1H),7.57(ddt,J=17.2,7.7,1.4Hz, 2H),7.42(d,J=7.7Hz,1H),7.16–6.95(m,5H),5.11–4.91(m,3H),4.10–3.99(m,1H), 3.89(d,J=4.5Hz,3H),3.76(d,J=13.6Hz,1H),3.66–3.52(m,2H),2.92(d,J=14.9Hz, 1H),2.65–2.56(m,1H),2.53–2.45(m,2H),2.40(s,3H),1.39(d,J=6.8Hz,3H).LC-MS m / z 426.2[M+H] + .

[0237] Example 49

[0238] Example 49 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 45.

[0239] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.8Hz,1H),7.62–7.49(m,2H),7.42(t,J= 7.7Hz,1H),7.27(d,J=10.7Hz,2H),6.86–6.68(m,2H),5.13–5.03(m,2H),4.09–4.01(m,1H),3.91(ddt,J=7.4,5.2,3.1Hz,4H),3.74 LC-MS m / z 448.2[M+H] + .

[0240] Example 50

[0241] Example 50 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0242] The reaction equation and preparation method are as follows:

[0243] S1. Dissolve compound 42-1 (1.8 g, 9.2 mmol) in methanol (10 mL). Add benzotriazole (1.1 g, 9.2 mmol) and 40% aqueous formaldehyde (0.92 mL, 12.0 mmol) under ice-cooling. Stir at room temperature for 16 hours. After the reaction, extract with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 50-1.

[0244] S2. Preactivated zinc powder (0.62 g, 9.6 mmol) was added to ultra-dry tetrahydrofuran (15 mL), and trimethylsilyl chloride (TMSCl, 0.57 g, 5.3 mmol) was added and stirred at room temperature for 10 minutes. Subsequently, methyl 2-bromoisobutyrate (0.87 g, 4.8 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL) and slowly added to the reaction system. A solution of 50-1 (1.55 g, 4.8 mmol) in tetrahydrofuran (10 mL) was then added dropwise. The reaction was allowed to react at room temperature for 16 hours. After the reaction was completed, the mixture was poured into water to quench and filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 50-2.

[0245] S3. Dissolve 50-2 obtained in the previous step in ultra-dry tetrahydrofuran. Add 1.2 equivalents of a 1.0 M potassium tert-butoxide / tetrahydrofuran solution under an ice bath. React at 0°C for 4 hours. After the reaction, dilute with water and extract with ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 50-3.

[0246] S4. Dissolve 50-3 (783 mg, 3.0 mmol) in methanol (20 mL), add 10% Pd / C (78 mg), and react at room temperature under hydrogen atmosphere overnight. After the reaction, filter out Pd / C through celite, and spin-dry the filtrate to obtain 50-4.

[0247] S5. Dissolve 50-4 (370 mg, 2.0 mmol), 3-cyanobenzaldehyde (524 mg, 4.0 mmol), and diisopropylethylamine (390 mg, 3.0 mmol) in 1,2-dichloroethane (20 mL) and stir at room temperature for 15 minutes. Add NaBH(OAc)3 (844 mg, 4.0 mmol) in portions and continue stirring at room temperature for 24 hours. After the reaction is complete, saturated NaHCO3 (30 mL) is added to quench the reaction and the mixture is extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain 50-5.

[0248] S6. Compound 50-5 (52 mg, 0.24 mmol) and compound 1-10 (71 mg, 0.20 mmol) were dissolved in ultra-dry methanol (2.0 mL). Sodium methoxide (54 mg, 1.0 mmol) was added and stirred at 100°C for 16 hours. After the reaction was completed, the mixture 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 50 as a pale yellow solid.

[0249] 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–7.35(m,3H),6.94(d,J=8.7Hz,2H),5 .02(s,2H),4.09(t,J=9.0Hz,2H),3.84(t,J=9.0Hz,2H),3.60(s,2H),3.29(s,2H),2.28(s,2H),1.25(s,6H).LC-MS m / z 444.2[M+H] + .

[0250] Example 51

[0251] Example 51 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 50.

[0252] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.8Hz,1H),7.66–7.52(m,2H),7.54–7.36(m,3H),6.95(d,J=8.7Hz,2H),5 .03(s,2H),4.10(t,J=9.0Hz,2H),3.85(t,J=9.0Hz,2H),3.60(s,2H),3.29(s,2H),2.28(s,2H),1.26(s,6H).LC-MS m / z 460.2[M+H] + .

[0253] Example 52

[0254] Example 52 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 50.

[0255] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–7.35(m,3H),6.94(d,J=8.7Hz,2H),5 .02(s,2H),4.09(t,J=9.0Hz,2H),3.84(t,J=9.0Hz,2H),3.60(s,2H),3.29(s,2H),2.28(s,2H),1.26(s,6H).LC-MS m / z 506.1[M+H] + .

[0256] Example 53

[0257] Example 53 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 50.

[0258] 1 H NMR(500MHz,Chloroform-d)δ7δ7.68(d,J=1.7Hz,1H),7.57(ddt,J=17.2,7.7,1.4Hz,2H),7.42(d,J=7.7Hz,1H),7.16–6.95(m,4H) ,5.02(s,2H),4.09(t,J=9.0Hz,2H),3.84(t,J=9.0Hz,2H),3.60(s,2H),3.29(s,2H),2.40(s,3H),2.28(s,2H),1.26(s,6H).LC-MS m / z440.2[M+H] + .

[0259] Example 54

[0260] Example 54 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 50.

[0261] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–7.35(m,3H),6.94(d,J=8.7Hz,2H),5 .02(s,2H),4.09(t,J=9.0Hz,2H),3.84(t,J=9.0Hz,2H),3.60(s,2H),3.29(s,2H),2.28(s,2H),1.26(s,6H).LC-MS m / z 494.2[M+H] +.

[0262] Example 55

[0263] Example 55 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0264] The reaction equation and preparation method are as follows:

[0265] S1. Add preactivated zinc powder (0.62 g, 9.6 mmol) to ultra-dry tetrahydrofuran (15 mL), add trimethylsilyl chloride (0.57 g, 5.3 mmol), and stir at room temperature for 10 minutes. Then, dissolve ethyl bromodifluoroacetate (0.97 g, 4.8 mmol) in ultra-dry tetrahydrofuran (10 mL) and slowly add it to the reaction system. Then, add a solution of 50-1 (1.55 g, 4.8 mmol) in tetrahydrofuran (10 mL). The reaction is allowed to react at room temperature for 16 hours. After the reaction is completed, pour it into water to quench and filter, and the filtrate is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 55-1.

[0266] S2. Dissolve 55-1 obtained in the previous step in tetrahydrofuran. Add 1.2 equivalents of a 1.0 M potassium tert-butoxide / tetrahydrofuran solution under ice-cooling and stir at 0°C for 4 hours. After the reaction, dilute with water and extract with ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain 55-2.

[0267] S3. Compound 55-2 (52 mg, 0.24 mmol) and compound 1-10 (71 mg, 0.20 mmol) were dissolved in ultra-dry methanol (2.0 mL). Sodium methoxide (54 mg, 1.0 mmol) was added and stirred at 100°C for 16 hours. After the reaction was completed, water was added to dilute the mixture and the mixture was 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 55 as a pale yellow solid.

[0268] 1 H NMR(500MHz,Chloroform-d)δ7.51–7.45(m,2H),7.37–7.25(m,5H),7.01–6.92(m,2H),5.03(s,2H),4.11(t, J=9.1Hz,2H),3.93(dd,J=9.8,8.4Hz,2H),3.72(s,2H),3.38(t,J=4.4Hz,2H),2.98(t,J=12.0Hz,2H).LC-MS m / z 417.2[M+H]+ .

[0269] Example 56

[0270] Example 56 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 55.

[0271] 1 H NMR(500MHz,Chloroform-d)δ7.45–7.39(m,2H),7.37–7.20(m,5H),5.02(s,2H),4.11(t,J=9.1Hz, 2H),3.92(dd,J=9.8,8.4Hz,2H),3.72(s,2H),3.38(t,J=4.4Hz,2H),2.98(t,J=12.0Hz,2H).LC-MS m / z 443.2[M+H] + .

[0272] Example 57

[0273] Example 57 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 55.

[0274] 1 H NMR(500MHz,Chloroform-d)δ7.44–7.39(m,2H),7.38–7.25(m,5H),5.01(s,2H),4.11(t,J=9. 1Hz,2H),3.95–3.88(m,2H),3.73(s,2H),3.38(t,J=4.4Hz,2H),2.98(t,J=12.0Hz,2H).LC-MS m / z 487.1[M+H] + .

[0275] Example 58

[0276] Example 58 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 55.

[0277] 1H NMR(500MHz,Chloroform-d)δ7.41–7.27(m,5H),7.19–7.04(m,4H),5.07(s,2H),4.15(t,J=9.1Hz,2H),3 .90(dd,J=9.8,8.5Hz,2H),3.74(s,2H),3.41(t,J=4.4Hz,2H),3.01(t,J=12.0Hz,2H),2.41(s,3H).LC-MS m / z 423.2[M+H] + .

[0278] Example 59

[0279] Example 59 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 55.

[0280] 1 H NMR(500MHz,Chloroform-d)δ7.37–7.19(m,6H),6.83–6.74(m,2H),5.11(s,2H),4.13(t,J=9.1Hz, 2H),3.91(dd,J=9.8,8.5Hz,2H),3.73(s,2H),3.39(t,J=4.4Hz,2H),3.00(t,J=12.0Hz,2H).LC-MS m / z 445.2[M+H] + .

[0281] Example 60

[0282] Example 60 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 55.

[0283] 1 H NMR(500MHz,Chloroform-d)δ7.60–7.50(m,4H),7.37–7.24(m,5H),5.11(s,2H),4.13(t,J=9.1Hz, 2H),3.92(dd,J=9.8,8.5Hz,2H),3.73(s,2H),3.39(t,J=4.3Hz,2H),2.99(t,J=12.0Hz,2H).LC-MS m / z 477.2[M+H] + .

[0284] Example 61

[0285] Example 61 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0286] The reaction equation and preparation method are as follows:

[0287] S1. Compound 61-2 (3.2 g, 20.0 mmol) was dissolved in methanol (30 mL), and compound 61-1 (4.0 g, 22.0 mmol) and 4A molecular sieves were added, and stirred at room temperature overnight. The reaction system was then cooled to -10°C, and NaBH4 (4.6 g, 120.0 mmol) was added portionwise. After the addition was complete, stirring was continued at room temperature for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, 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 to obtain 61-3 (4.3 g, yield 63%).

[0288] S2. Compound 61-3 was dissolved in ethyl acetate (10 mL), HCl (4.0 M in EA) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 1 M aqueous NaOH was added to quench the mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford an oily product 61-4 (3.0 g, 95% yield).

[0289] S3. Compound 61-4 was dissolved in anhydrous ethanol, and cyanogen bromide was added in batches with vigorous stirring for 5 hours. After the reaction, the crude product 61-5 was concentrated under reduced pressure and purified by adding ethyl acetate to obtain a white solid 66-5 (3.6 g, yield 83%).

[0290] S4. Compound 61-5 (57 mg, 0.20 mmol) and compound 1-6 (85 mg, 0.24 mmol) were dissolved in ultra-dry methanol (2.0 mL), sodium methoxide (54 mg, 1.0 mmol) was added, and the mixture was stirred at 100°C for 6 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 a solid compound (34 mg, 35% yield).

[0291] 1H NMR(500MHz,Chloroform-d)δ7.52(dd,J=6.4,2.2Hz,1H),7.41–7.21(m,8H),7.09 (t,J=8.4Hz,1H),4.58(s,2H),3.99–3.88(m,2H),3.84(d,J=13.3Hz,1H),3.61(d, J=13.2Hz,1H),3.56–3.44(m,3H),3.46–3.37(m,1H),3.18(td,J=6.2,4.1Hz,1H), 2.79–2.68(m,1H),2.17(ddd,J=16.9,3.9,1.9Hz,1H),1.13(d,J=6.5Hz,3H); LC-MS m / z 483.12[M+H] + .

[0292] Example 62

[0293] Example 62 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0294] 1 H NMR(500MHz,Chloroform-d)δ7.37–7.29(m,4H),7.23(tt,J=13.9,7.2Hz,5H),4.76–4.57(m,2H),3.98–3.82(m,3H),3.62(d,J=13.3Hz,1H),3 .55–3.38(m,4H),3.18(td,J=6.3,4.1Hz,1H),2.74(ddt,J=16.9,5.2,2.3Hz,1H),2.35(s,3H),2.25–2.08(m,1H),1.14(d,J=6.5Hz,3H).LC-MS m / z 401.23[M+H] + .

[0295] Example 63

[0296] Example 63 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0297] LC-MS m / z 401.23[M+H] + .

[0298] Example 64

[0299] Example 64 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0300] LC-MS m / z 401.23[M+H] + .

[0301] Example 65

[0302] Example 65 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0303] LC-MS m / z 405.21[M+H] + .

[0304] Example 66

[0305] Example 66 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0306] LC-MS m / z 405.21[M+H] + .

[0307] Example 67

[0308] Example 67 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0309] 1 H NMR(500MHz,Chloroform-d)δ7.37–7.27(m,8H),7.25(s,2H),7.03(t,J=8.6Hz,2H),4.60(s,2H),4.00–3.86(m,2H),3.84(d,J=13.2Hz,1H),3.61(d, J=13.3Hz,1H),3.55–3.46(m,3H),3.46–3.37(m,1H),3.17(td,J=6.1,4.0 Hz,1H),2.78–2.68(m,1H),2.21–2.11(m,1H),1.12(d,J=6.5Hz,3H); LC-MS m / z 405.21[M+H] + .

[0310] Example 68

[0311] Example 68 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0312] LC-MS m / z 421.18[M+H] + .

[0313] Example 69

[0314] Example 69 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0315] LC-MS m / z 421.18[M+H] + .

[0316] Example 70

[0317] Example 70 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0318] LC-MS m / z 421.18[M+H] + .

[0319] Example 71

[0320] Example 71 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0321] LC-MS m / z 465.13[M+H] + .

[0322] Example 72

[0323] Example 72 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0324] LC-MS m / z 465.13[M+H] + .

[0325] Example 73

[0326] Example 73 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0327] LC-MS m / z 455.21[M+H] + .

[0328] Example 74

[0329] Example 74 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0330] 1 H NMR(500MHz,Chloroform-d)δ7.61(d,J=7.9Hz,2H),7.46(d,J=8.0Hz,2H),7.39–7.22( m,6H),4.70(s,2H),4.01–3.88(m,2H),3.84(d,J=13.2Hz,1H),3.61(d,J=13.2Hz,1H),3 .57–3.47(m,3H),3.42(dt,J=16.8,2.3Hz,1H),3.18(pd,J=6.4,4.1Hz,1H),2.74(ddt,J =16.9,5.2,2.4Hz,1H),2.17(ddt,J=16.9,3.8,1.8Hz,1H),1.13(d,J=6.5Hz,3H); LC-MS m / z 455.21[M+H] + .

[0331] Example 75

[0332] Example 75 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0333] LC-MS m / z 423.20[M+H] + .

[0334] Example 76

[0335] Example 76 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0336] LC-MS m / z 423.20[M+H] + .

[0337] Example 77

[0338] Example 77 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 61.

[0339] LC-MS m / z 483.12[M+H] + .

[0340] Example 78

[0341] Example 78 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0342] The reaction equation and preparation method are as follows:

[0343] S1. Compound 69-2 (3.2 g, 20.0 mmol) was dissolved in methanol (30 mL), and compound 69-1 (4.0 g, 22.0 mmol) and 4A molecular sieves were added, and stirred at room temperature overnight. The reaction system was then cooled to -10°C, and NaBH4 (4.6 g, 120.0 mmol) was added portionwise. After the addition was complete, stirring was continued at room temperature for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the mixture 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 to obtain 62-3 (4.3 g, 63% yield).

[0344] S2. Dissolve compound 69-3 in methanol (10 mL), add HCl (4.0 M in Dioxane), and stir at room temperature overnight. After the reaction, concentrate to remove the solvent, quench with 1N aqueous NaOH, and extract three times with DCM. The organic phase is dried over anhydrous sodium sulfate and concentrated to afford an oily product 69-4 (3.0 g, 95% yield).

[0345] S3. Compound 69-4 was dissolved in anhydrous ethanol and cyanogen bromide was added in portions with vigorous stirring for 5 hours. After the reaction, the crude product 69-5 was concentrated under reduced pressure and purified by adding ethyl acetate to obtain a-2 (3.6 g, 83% yield) as a white solid.

[0346] S4. Compound a-2 (57 mg, 0.20 mmol) and compound a-1 (85 mg, 0.24 mmol) were dissolved in ultra-dry methanol (2.0 mL), sodium methoxide (54 mg, 1.0 mmol) was added, and the mixture was stirred at 100°C for 6 hours. After the reaction was completed, water was added to dilute the mixture, and the mixture was 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 solid compound 69 (39 mg, 38% yield).

[0347] 1H NMR(500MHz,Chloroform-d)δ7.71(d,J=1.9Hz,1H),7.60(d,J=7.8Hz,1H),7.53(dt,J=6.3,1.9Hz,2H) ,7.41(t,J=7.7Hz,1H),7.25(ddd,J=8.2,4.6,2.2Hz,1H),7.12(t,J=8.3Hz,1H),4.61–4.45(m,2H),4.0 6(t,J=8.7Hz,2H),3.85(d,J=13.9Hz,1H),3.64(d,J=13.9Hz,1H),3.51(t,J=8.7Hz,2H),3.40(d,J=2. 0Hz,2H),3.11(q,J=5.6Hz,1H),2.91–2.77(m,1H),2.38(dd,J=17.8,4.7Hz,1H),1.14(d,J=6.5Hz,3H);

[0348] Example 79

[0349] Example 79 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0350] 1 H NMR(500MHz,Chloroform-d)δ7.70(t,J=1.7Hz,1H),7.56(ddt,J=12.2,7.8,1.5Hz, 2H),7.42(t,J=7.7Hz,1H),7.28–7.15(m,4H),4.74–4.59(m,2H),4.00–3.89(m,2H) ,3.85(d,J=13.9Hz,1H),3.65(d,J=13.9Hz,1H),3.55–3.34(m,4H),3.24–3.09(m,1 H),2.86–2.71(m,1H),2.35(s,3H),2.28–2.11(m,1H),1.16(d,J=6.5Hz,3H); LC-MS m / z 426.23[M+H] + .

[0351] Example 80

[0352] Example 80 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0353] LC-MS m / z 426.23[M+H] + .

[0354] Example 81

[0355] Example 81 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0356] LC-MS m / z 426.23[M+H] + .

[0357] Example 82

[0358] Example 82 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0359] LC-MS m / z 430.20[M+H] + .

[0360] Example 83

[0361] Example 83 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0362] LC-MS m / z 430.20[M+H] + .

[0363] Example 83

[0364] Example 83 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0365] 1 H NMR(500MHz,Chloroform-d)δ7.69(d,J=1.7Hz,1H),7.60–7.51(m,2H),7.41(t,J=7.7Hz ,1H),7.37–7.27(m,3H),7.10–6.97(m,2H),4.61(s,2H),4.01–3.92(m,2H),3.83(d,J=13 .9Hz,1H),3.64(d,J=13.9Hz,1H),3.53(t,J=8.5Hz,2H),3.46–3.33(m,2H),3.23–3.10(m ,1H),2.80–2.70(m,1H),2.21(ddt,J=16.9,3.9,1.8Hz,1H),1.14(d,J=6.5Hz,3H); LC-MS m / z 430.20[M+H] + .

[0366] Example 84

[0367] Example 84 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0368] LC-MS m / z 446.17[M+H] + .

[0369] Example 85

[0370] Example 85 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0371] LC-MS m / z 446.17[M+H] + .

[0372] Example 86

[0373] Example 86 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0374] LC-MS m / z 490.12[M+H] + .

[0375] Example 87

[0376] Example 87 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0377] LC-MS m / z 490.12[M+H] + .

[0378] Example 87

[0379] Example 87 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0380] C-MS m / z 490.12[M+H] + .

[0381] Example 88

[0382] Example 88 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0383] LC-MS m / z 480.20[M+H] + .

[0384] Example 89

[0385] Example 89 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0386] 1 H NMR(500MHz,Chloroform-d)δ7.69(d,J=2.2Hz,1H),7.60(d,J=8.0Hz,2H),7.59– 7.51(m,2H),7.49–7.34(m,4H),4.70(s,2H),4.03–3.92(m,3H),3.83(d,J=13.9Hz ,1H),3.65(d,J=13.9Hz,1H),3.55(t,J=8.5Hz,2H),3.46–3.34(m,3H),3.23–3.1 4(m,1H),2.81–2.72(m,1H),2.26–2.14(m,1H),1.14(dd,J=6.6,3.1Hz,3H); LC-MS m / z 480.20[M+H] + .

[0387] Example 90

[0388] Example 90 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0389] LC-MS m / z 448.19[M+H] + .

[0390] Example 91

[0391] Example 91 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0392] LC-MS m / z 448.19[M+H] + .

[0393] Example 92

[0394] Example 92 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 78.

[0395] LC-MS m / z 508.11[M+H]+ .

[0396] Example 93

[0397] Example 93 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0398] The reaction equation and preparation method are as follows:

[0399] S1. To a mixture of compound 1 (535 mg, 5.0 mmol) and compound 2 (571 mg, 5.0 mmol), add Bi(NO3)3·5H2O (121 mg, 0.25 mmol), and stir at room temperature overnight. After the reaction is completed, add DCM to dilute, filter, concentrate, dry, and purify by column chromatography to obtain compound 3 (658 mg, 3.0 mmol, yield is 60%).

[0400] S2. Methyl acrylate (3.3 mmol, 285 mg) and DBU (0.15 mmol, 23 mg) were added to the compound 3 obtained in the previous step, and the mixture was stirred at 60°C overnight. After the reaction, DCM was added for dispersion, and the mixture was concentrated and purified by column chromatography to obtain compound 4.

[0401] S3. Dissolve compound 4 obtained in ultra-dry tetrahydrofuran. Add 1.2 equivalents of a 1.0 M potassium tert-butoxide / tetrahydrofuran solution under an ice bath. React at 0°C for 4 hours. After the reaction is complete, dilute with water and extract with ethyl acetate. Wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 5.

[0402] S3. Compound 5 (52 mg, 0.24 mmol) and compound 6 (71 mg, 0.20 mmol) were dissolved in ultra-dry methanol (2.0 mL), and sodium methoxide (54 mg, 1.0 mmol) was added. The mixture was stirred at 100°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 a light yellow solid compound.

[0403] LC-MS m / z 419.2[M+H] + .

[0404] Example 94

[0405] Example 94 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0406] LC-MS m / z 435.2[M+H] + .

[0407] Example 95

[0408] Example 95 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0409] LC-MS m / z 479.1[M+H] + .

[0410] Example 96

[0411] Example 96 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0412] LC-MS m / z 415.2[M+H] + .

[0413] Example 97

[0414] Example 97 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0415] LC-MS m / z 469.2[M+H] + .

[0416] Example 98

[0417] Example 98 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0418] The preparation method is the same as that of Example 93, except that Substitute compound 2 in Example 93.

[0419] LC-MS m / z 433.23[M+H] + .

[0420] Example 99

[0421] Example 99 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0422] LC-MS m / z 449.2[M+H] + .

[0423] Example 100

[0424] Example 100 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0425] LC-MS m / z 493.2[M+H] + .

[0426] Example 101

[0427] Example 101 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0428] LC-MS m / z 429.3[M+H] + .

[0429] Example 101

[0430] Example 101 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0431] LC-MS m / z 451.2[M+H] + .

[0432] Example 102

[0433] Example 102 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0434] The preparation method is the same as that of Example 1, except that Substitute compound 2 in Example 93.

[0435] LC-MS m / z 401.2[M+H] + .

[0436] Example 103

[0437] Example 103 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 1.

[0438] LC-MS m / z 455.2[M+H] + .

[0439] Comparative Example 1

[0440] Comparative Example 1 provides two compounds, ONC201 and ONC212; ONC201 and ONC212 were synthesized according to the method described in CN104860948.

[0441] Comparative Example 2

[0442] Comparative Example 2 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0443] The reaction equation and preparation method are as follows:

[0444] S1. Dissolve compound 1 (10.0 mmol) in methanol (5 mL), add a solution of compound 2 (22.0 mmol) in methanol (10 mL) dropwise, and heat under reflux overnight after the addition is complete. After the reaction is complete, spin dry the mixture and remove the excess compound 2 under vacuum to obtain compound 3 as a colorless oil.

[0445] S2. Dissolve compound 3 obtained in tetrahydrofuran, add 1.2 equivalents of a 1.0 M potassium tert-butoxide / tetrahydrofuran solution under ice-cooling, and stir at 0°C for 4 hours. After the reaction is complete, dilute with water and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 4.

[0446] S3. Compound 4 (52 mg, 0.24 mmol) and compound 5 (71 mg, 0.20 mmol) were dissolved in ultra-dry methanol (2.0 mL), sodium methoxide (54 mg, 1.0 mmol) was added, and the mixture was stirred at 100°C for 16 hours. After the reaction was completed, water was added to dilute the mixture, and the mixture was 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 a light yellow solid compound.

[0447] 1 H NMR(500MHz,Chloroform-d)δ7.39–7.14(m,6H),6.90–6.72(m,2H),5.08(d,J=4.2Hz,2H),3.98–3.77(m,4H),3.66–3. 46(m,2H),3.10(dd,J=14.7,2.3Hz,1H),2.74(dt,J=10.3,4.7Hz,1H),2.48–2.29(m,3H),1.43(d,J=6.7Hz,3H).LC-MS m / z 423.2[M+H] + .

[0448] Comparative Example 3

[0449] Comparative Example 3 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Comparative Example 2.

[0450] 1 H NMR(500MHz,Chloroform-d)δ7.59–7.44(m,4H),7.39–7.14(m,5H),5.09(d,J=2.9Hz,2H),4.02–3.77(m,4H),3.64–3. 47(m,2H),3.10(dd,J=14.8,2.6Hz,1H),2.73(dd,J=10.8,6.0Hz,1H),2.51–2.27(m,3H),1.44(d,J=6.7Hz,3H).LC-MS m / z 455.2[M+H] + .

[0451] Comparative Example 4

[0452] Comparative Example 4 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Comparative Example 2.

[0453] 1 H NMR(500MHz,Chloroform-d)δ7.63(s,1H),7.55–7.51(m,3H),7.39(dd,J=15.3,7.9Hz,3H),7.31–7.25(m,2H),3.95–3.76 (m,5H),3.71–3.55(m,4H),3.26–3.10(m,2H),2.69–2.61(m,2H),2.46(q,J=7.0,6.3Hz,3H),1.81(d,J=7.2Hz,3H).LC-MS m / z 490.1[M+H] + .

[0454] Activity test

[0455] Experimental Example 1: Agonist activity of compounds on HsClpP protease

[0456] The HsClpP protein can recognize the cleavage substrate AC-WLA-AMC, and the cleaved substrate can detect AMC signals at 355nm and 460nm. In a 384-well black-bottom plate, 20uL of enzyme (final concentration 0.7μM) was added to each well, along with 10μL of compound (final concentration 20μM, 3-fold serial dilution to 11 concentrations), incubated at room temperature for 10 minutes, and then 20μL of substrate (final concentration 100μM) was added. The cells were incubated at room temperature for 4h, and the fluorescence signal was measured using a multifunctional microplate reader. The data were processed using GraphPad Prism8.

[0457] Experimental Example 2: The MTS method was used to evaluate the proliferation inhibitory activity of the modified compound on MV4-11 and HL60 cell lines:

[0458] In a 96-well plate, 10,000 cells were seeded per well. After stabilization for half an hour, the compounds prepared in the Examples and Comparative Examples were added, and DMSO was used as a control. The cells were cultured at 37°C, 5% CO2 for 72 h. 20 μL of MTS was added, and the cells were cultured at 37°C for 4 h. The absorbance of the DMSO wells was measured at 490 nm and 690 nm using a microplate reader, and the absorbance was 0.6-0.8. The data were processed using GraphPad Prism 8. The data are shown in Table 1.

[0459] Table 1:

[0460] Note: In Table 1, “A” indicates EC 50 or IC 50 Less than 10nM; "B" indicates EC 50 or IC 50 Between 10-100 nM; “C” represents EC 50 or IC 50 Between 100-1000 nM; "D" indicates EC 50 or IC 50 Between 1000-5000nM; "E" indicates EC 50 or IC 50 Greater than 5000nM.

[0461] Experimental Example 3: Pharmacokinetic Evaluation of Examples 9 and 12

[0462] To evaluate the pharmacokinetic characteristics of Example 9 and Example 12 after oral administration, we conducted a pharmacokinetic test on ICR mice by oral administration of a single dose of 50 mg / kg, as shown in FIG1 and Table 2.

[0463] Table 2 Pharmacokinetic parameters of Example 9 and Example 12 in mice (IG 50 mg / kg)

[0464] Experimental Example 4: In vivo pharmacodynamic evaluation of HL60 diffusion model

[0465] Female B-NDG mice (18-22 g, 6-8 weeks old) were purchased from White Oseito. Mice were housed in an SPF animal room with a 12-h day-night cycle and free access to food and water. HL60 cells (5×10 6 Mice were inoculated via tail vein injection (cell / mouse). After a 5-day interval, mice were randomly divided into groups based on body weight. Following 21 days of continuous administration with an equal volume of blank solvent (0.5% CMC-Na, orally administered daily, n=9), ONC212 (10 mg / kg, orally administered daily, n=9), Example 9 (10 mg / kg, orally administered daily, n=9), and Example 12 (10 mg / kg, orally administered daily, n=9), mice were observed for mortality. During the experiment, oral administration was administered daily, and mice were weighed every 3-4 days to monitor their growth. Statistical analysis was performed using GraphPad Prism 8.

[0466] As shown in FIG2 , in the HL60 diffusion model, with the solvent group as the control, after continuous drug administration for 21 days, Examples 9 and 12 were able to relatively prolong the survival time of mice.

[0467] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the scope of the present invention.

Claims

1. An imidazopyridopyrimidone compound, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: Having a structure as shown in Formula I or Formula II: R1 and R2 are each independently selected from phenyl, naphthyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 phenyl substituted by at least one of an alkyl group and a cyano group; R3 is one or more substituents, R3 is selected from C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, halogen.

2. The imidazopyridopyrimidone compound according to claim 1, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: Having a structure as shown in formula (I-1), formula (I-2) or formula (II-1), formula (II-2): R1 and R2 are each independently selected from phenyl, naphthyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen-substituted C 1-6 A phenyl group substituted by at least one of an alkyl group and a cyano group.

3. The imidazopyridopyrimidone compound according to claim 1 or 2, characterized in that: The R1 and R2 are each independently selected from phenyl, naphthyl, fluorine, chlorine, bromine, C 1-6 Alkyl, C 1-3 Alkoxy, C substituted by 1-3 halogen atoms 1-3 A phenyl group substituted by at least one of an alkyl group and a cyano group.

4. The imidazopyridopyrimidone compound according to claim 1 or 2, characterized in that: The R1 and R2 are each independently selected from phenyl, naphthyl, and phenyl substituted by at least one of fluorine, chlorine, bromine, methyl, tert-butyl, methoxy, trifluoromethyl, and cyano.

5. The imidazopyridopyrimidone compound according to any one of claims 1 to 4, characterized in that: The imidazopyridopyrimidone compound is selected from one of the following structures:

6. The method for preparing the imidazopyridopyrimidone compound according to any one of claims 1 to 5, characterized in that: The steps include: The compound of formula (1-6), the compound of formula (1-10), a first organic solvent and a first organic base are mixed and reacted to obtain; Alternatively, the compound of formula (1-6), the compound a-1, the second organic solvent and the second organic base are mixed and reacted to obtain the product; Among them, the structural formulas of the compound of formula (1-6), the compound of formula (1-10), and the compound a-1 are as follows:

7. The method for preparing the imidazopyridopyrimidone compound according to claim 6, characterized in that: The first organic base or the second organic base is independently selected from at least one of sodium methoxide, sodium ethoxide or sodium tert-butoxide.

8. Use of the imidazopyridopyrimidone compound according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or preventing a disease mediated by HsClpP.

9. A HsClpP protease agonist, characterized in that The HsClpP protease agonist comprises the imidazopyridopyrimidone compound according to any one of claims 1 to 5.

10. A pharmaceutical composition, characterized in that The invention comprises the imidazopyridopyrimidone compound according to any one of claims 1 to 5, or a pharmaceutically acceptable excipient thereof.

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