Imidazopyridino pyrimidinone compound as well as preparation method and application thereof

Abstract

The invention discloses an imidazo pyridopyrimidone compound as well as a preparation method and application thereof, and the imidazo pyridopyrimidone compound, or a racemate, an R-isomer, an S-isomer, pharmaceutically acceptable salt or a mixture of the racemate, the R-isomer, the S-isomer and the pharmaceutically acceptable salt of the imidazo pyridopyrimidone compound or the racemate, the R-isomer, the S-isomer and the pharmaceutically acceptable salt. The compound has a structure as shown in a formula I or a formula II: # imgabs0 # R1 and R2 are respectively and independently selected from phenyl, naphthyl, phenyl substituted by at least one of halogen, alkyl of C1-6, alkoxy of C1-6, alkyl of C1-6 substituted by halogen and cyano; and R3 is one or more substituent groups and is selected from C1-4 alkyl groups, halogen substituted C1-4 alkyl groups and halogen. The compound provided by the invention has a better HsClpP protease excitation effect than the currently reported positive compound, and can be used for treating HsClpP receptor excitation related diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to an imidazopyridopyrimidone compound and a preparation method and 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 intervention methods for the treatment of these tumors.

[0003] The possible mechanism of HsClpP involvement in cancer is related to mitochondrial bioenergetics and protein balance, the generation of reactive oxygen species (ROS), and the activation of autophagy. HsClpP is associated with members of the electron transport chain (ETC), especially SDHA and other enzymes involved in metabolism. Inhibition of HsClpP activity results in 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 and inducing cell death; at the same time, inhibition of HsClpP activity also reduces the enzymatic activity of SDHA in complex II of the respiratory chain (RC), increases the generation of mitochondrial ROS, and thus initiates non-apoptotic tumor cell death. In addition, overactivation of HsClpP can also inhibit the growth of cancer cells. Overactivation 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 tumor growth.

[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 was blocked in vitro and in vivo, the growth and viability of various AML cell lines decreased significantly, and tumor development was significantly inhibited in vivo. In addition, overactivation of HsClpP is also considered an effective strategy for the treatment of AML. When HsClpP is activated, the proportion of primary AML cell death and apoptosis increases compared with normal cells. At the same time, HsClpP activators also reduce the leukemia burden in mice. HsClpP expression is also increased in many other hematological malignancies, such as CML, multiple myeloma, and various lymphomas. Therefore, regulating HsClpP activity is considered a strategy for the treatment of AML and other hematological malignancies.

[0005] HsClpP is also upregulated 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 deregulate mitochondrial RC and oxidative stress, inhibiting the proliferation, movement and metastasis of tumor cells. In prostate cancer, inhibition of HsClpP activity can reduce the expression of cyclins A, B1 and D1, thereby inducing PC3 prostate cancer cell cycle arrest and inhibiting PC3 cell proliferation. In the PC3 cell scratch experiment, interference with HsClpP expression inhibited the invasion and migration of tumor cells. In tumor-bearing mice, inhibition of HsClpP slowed down tumor disease progression and the extent of liver metastasis.

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

[0007] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the first aspect of the present invention provides an imidazopyridopyrimidone compound, which can have a better HsClpP protease agonist effect than the positive compounds reported previously, and can be used to treat HsClpP receptor agonist-related diseases.

[0008] The second aspect of the present invention also provides a method for preparing imidazopyridopyrimidone compounds.

[0009] The third aspect of the present invention also provides an application of an imidazopyridopyrimidone compound.

[0010] 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:

[0011]

[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 by 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 effect than the positive compounds reported previously, and can be used to treat diseases related to HsClpP receptor agonist.

[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]

[0019] 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.

[0020] 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 to 3 halogen atoms 1～3 A phenyl group substituted by at least one of an alkyl group and a cyano group.

[0021] 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.

[0022] According to some embodiments of the present invention, the imidazopyridopyrimidone compound is selected from one of the following structures:

[0023]

[0024]

[0025]

[0026]

[0027]

[0028] According to the second aspect of the present invention, the method for preparing the imidazopyridopyrimidone compound provided in the embodiment comprises the following steps:

[0029] 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;

[0030] 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;

[0031] 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:

[0032]

[0033] 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.

[0034] 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.

[0035] According to some embodiments of the present invention, the reaction temperature is 80-120°C.

[0036] According to some embodiments of the present invention, the compound 1-10 is prepared by the following method:

[0037] Compound 1-8 and compound 1-9 are directly reacted in tetrahydrofuran, and then beaten and treated to obtain compound 10;

[0038] The structural formulas of compounds 1-8 and 1-9 are as follows:

[0039]

[0040] According to some embodiments of the present invention, the compound 1-8 is prepared by the following method:

[0041] Compound 1-7 and methyl iodide are refluxed in methanol to obtain compound 1-8;

[0042] The structural formula of compound 1-7 is as follows:

[0043]

[0044] The third aspect of the present invention provides a use of the above-mentioned imidazopyridopyrimidone compounds in the preparation of drugs for treating and / or preventing diseases mediated by HsClpP.

[0045] According to some embodiments of the present invention, the diseases mediated by HsClpP include nervous system diseases, metabolic syndrome and tumors mediated by HsClpP.

[0046] 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.

[0047] The fourth aspect of the present invention provides a ClpP protease agonist, wherein the ClpP protease agonist comprises the above-mentioned imidazopyridopyrimidone compound.

[0048] The fifth aspect of the present invention provides a pharmaceutical composition, characterized in that it comprises the above-mentioned imidazopyridopyrimidone compound, or a pharmaceutically acceptable excipient thereof.

[0049] Definitions and general terms

[0050] “C 1-6 "alkyl" means an alkyl group having 1 to 6 carbon atoms, including C 1-6 Straight chain alkyl, C 1-6 The branched alkyl and C 3-6The 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, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a 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.

[0051] "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 substituted by any halogen.

[0052] “C 1～6 "alkoxy" means an alkoxy group having 1 to 6 carbon atoms, including C 1-6 Straight chain alkoxy, C 1-6 The branched alkoxy group and the cycloalkoxy group of C2-6 may be, for example, a straight chain alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms, a branched alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a cycloalkoxy group having 2, 3, 4, 5 or 6 carbon atoms, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, etc. 1-3 The "alkoxy group" has a similar explanation, except that the number of carbon atoms is different.

[0053] As described in the present invention, pharmaceutically acceptable excipients of the present invention, 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 a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are combined to show that different excipients can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional excipients are incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0054] Substances that can be used as 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; polyvinyl pyrrolidone; 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, such as carboxymethyl cellulose sodium cellulose, 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; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0055] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0057] Figure 1 is the drug-time curve of the compound in mouse plasma after oral administration of 50 mg / kg of Example 9 and Example 12;

[0058] Figure 2 This is a graph showing that Example 9 and Example 12 relatively prolonged the survival of mice in the HL60 diffusion model. DETAILED DESCRIPTION

[0059] 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.

[0060] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0061] The analytical data of the samples were measured by the following instruments: NMR was measured by AVANCE NEO 500 NMR 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.

[0062] Silica gel 200-300 mesh (produced by Titan) was used for column chromatography; TLC silica gel plate was HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Plant; petroleum ether boiling range was 60-90°C; ultraviolet lamp and iodine cylinder were used for color development. Unless otherwise specified, conventional reagents and drugs used in the following examples were purchased from Bitec Group, Anage Group and Titan Group. The reagents and solvents used in the experiment were handled according to the specific conditions of the reaction.

[0063] Example 1

[0064] Example 1 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0065]

[0066] Its synthetic route and preparation method are as follows:

[0067]

[0068] 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, it 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, and then filtered. The filter cake was washed twice with methyl tert-butyl ether, and the organic phases were combined and concentrated to obtain a colorless oil 1-3 (5.8 g, yield 87%), which was directly used in the next step.

[0069] S2. Dissolve compound 1-3 (2.9 g, 14.3 mmol) in dichloromethane (60 mL), add 1-4 (3.0 g, 28.6 mmol) and acetic acid (1.2 g, 20 mmol), and stir at room temperature for 30 minutes. Add NaBH(OAc)3 (6.2 g, 29.0 mmol) to the system in batches and continue stirring at room temperature for 24 hours. After the reaction is completed, add saturated NaHCO3 (50 mL) to quench the reaction and extract with dichloromethane. The organic layer is dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain a light yellow oil 1-5 (2.0 g, yield 47%).

[0070] 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 bath, and react at 0°C for 4 hours. After the reaction is completed, 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%).

[0071] S4, compound 1-7 (10.2 g, 100.0 mmol) was dissolved in MeOH (100 mL), iodomethane (110.0 mmol, 6.8 mL) was slowly added, and the reaction was stirred under reflux for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, methyl tert-butyl ether was added for pulping, and the mixture was filtered and dried to obtain a white solid 1-8 (24.2 g, yield 99%).

[0072] S5. Compound 1-8 (2.4 g, 10.0 mmol) was added to ultra-dry tetrahydrofuran (10 mL), and compound 1-9 (1.4 g, 11.0 mmol) was added, and the mixture was reacted at 40° C. for 24 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, methyl tert-butyl ether was added for pulping, and the mixture was filtered and dried to obtain a white solid 1-10 (2.8 g, with a yield of 87%).

[0073] 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 stirred at 100° C. for 16 hours. After the reaction was completed, water was added to dilute and extracted with ethyl acetate. The organic layer was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a light yellow solid compound 1 (34 mg, 42%).

[0074] 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] + .

[0075] Example 2

[0076] Example 2 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0077]

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

[0079] 1H 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] + .

[0080] Example 3

[0081] Example 3 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0082]

[0083] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0084] 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] + .

[0085] Example 4

[0086] Example 4 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0087]

[0088] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0089] 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] + .

[0090] Example 5

[0091] Example 5 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0092]

[0093] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0094] 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] + .

[0095] Example 6

[0096] Example 6 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0097]

[0098] The preparation method is the same as that of Example 1, except that Substitute compound 1-9 in Example 1.

[0099] 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] + .

[0100] Example 7

[0101] Example 7 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0102]

[0103] The preparation method is the same as that of Example 1, except that Replace compound 1-4 in Example 1.

[0104] 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] + .

[0105] Example 8

[0106] Example 8 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0107]

[0108] The preparation method is the same as that of Example 7, except that Substitute compound 1-9 in Example 7.

[0109] 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] + .

[0110] Example 9

[0111] Example 9 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referenced to Example 1.

[0112]

[0113] Further, the obtained compound is separated:

[0114] The first splitting was performed using Water 150preparative SFC (SFC-29), with ChiralPak AD, 250×30mm ID, 10μm column; mobile phase A: CO2, B: ethanol (0.1% NH3H2O); mobile gradient: B30%; flow rate: 150mL / min; back pressure: 100bar; column temperature: 38°C; monitoring wavelength: 220nm; separation time was about 10 minutes; sample preparation: 995mg sample was dissolved in about 30mL methanol / dichloromethane system, and 2mL was injected each time for separation. The first splitting yielded 9-P1 and a mixture of 9-P2 and 9-P3.

[0115]

[0116] 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).

[0117] The second splitting was performed using Water 150preparative SFC (SFC-29), with ChiralPak IC, 250×30mm ID, 10μm column; mobile phase A: CO2, B: ethanol (0.1% NH3H2O); mobile gradient: B40%; flow rate: 150mL / min; back pressure: 100bar; column temperature: 38℃; monitoring wavelength: 220nm; the time to complete a separation was about 6 minutes; sample preparation: the mixture of 9-P2 and 9-P3 was dissolved in about 60ml of methanol / dichloromethane system, and 3mL was injected each time for separation. This time, 9-P2 and 9-P3 can be separated.

[0118]

[0119] 1 H 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).

[0120]

[0121] 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).

[0122] Example 10

[0123] Example 10 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referenced to Example 1.

[0124]

[0125] 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] + .

[0126] Embodiment 11

[0127] Example 11 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referenced to Example 1.

[0128]

[0129] 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] + .

[0130] Example 12

[0131] Example 12 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method thereof is referenced to Example 1.

[0132]

[0133] Furthermore, the compound prepared in Example 12 was resolved:

[0134] The first split was performed using WATERS150preparative SFC (SFC-26), with ChiralPak AD, 250×30mm ID, 10μm column; mobile phase A: CO2, B: ethanol (0.1% NH3H2O); mobile gradient: B30%; flow rate: 150mL / min; back pressure: 100bar; column temperature: 38℃; monitoring wavelength: 220nm; separation time is about 6min; sample preparation: 490mg sample was dissolved in 20mL methanol / dichloromethane system, and 2mL was injected each time for separation. The first split can obtain 12-P1 and 12-P4 and a mixture of 12-P2 and 12-P3.

[0135]

[0136] 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] + .

[0137]

[0138] 1H 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]+.

[0140] The second splitting was performed using WATERS150preparative SFC (SFC-26), with a chromatographic column of (S,S)Whelk O1, 250×30mm ID, 10μm; mobile phase A: CO2, B: ethanol (0.1% NH3H2O); mobile gradient: B 40%; flow rate: 150mL / min; back pressure: 100bar; column temperature: 38℃; monitoring wavelength: 220nm; the time to complete a separation was about 12 minutes; sample preparation: the mixture of 12-P2 and 12-P3 was dissolved in about 20ml of methanol / dichloromethane system, and 8mL was injected each time for separation. This time, 12-P2 and 12-P3 can be separated.

[0141]

[0142] 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] + .

[0143]

[0144] 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). 13 CNMR(126MHz, CDCl3)δ14.27,33.04,44.86,44.99,46.90,50.47,50.80,56.96,76.78,77.04,77.29,100.77,112.57,118.9 2,123.09,125.26,125.30,128.86,129.21,129.36,130.94,132.09,132.97,140.50,140.72,145.08,153.03,161.26.LC-MS m / z 480.2[M+H] + .

[0145] Embodiment 13

[0146] Example 13 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0147]

[0148] The reaction equation and preparation method are as follows:

[0149]

[0150] 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. Subsequently, 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 reaction was completed, it was cooled to room temperature, the solvent was removed by distillation under reduced pressure, methyl tert-butyl ether was added, stirred for 30 minutes, and then filtered. The filter cake was washed twice with methyl tert-butyl ether, and the organic phase was combined and dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oil 34-1 (7.3 g, yield 75%), which was directly used in the next step.

[0151] 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 bath, and react at 0°C for 4 hours. After 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%).

[0152] 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, water was added to dilute, and extracted with ethyl acetate. The organic layer was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a yellow solid 13-4.

[0153] 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 the reaction was completed by TLC monitoring, the solvent was removed by distillation under reduced pressure, saturated NaHCO3 aqueous solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic layer was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (8% MeOH in DCM) to obtain an off-white solid 13-5.

[0154] S5. Compound 13-5 (73 mg, 0.2 mmol) was dissolved in acetonitrile (2 mL), 13-6 (46 mg, 0.24 mmol) and cesium carbonate (130 mg, 0.4 mmol) were added, and the mixture was stirred at 80°C overnight. After the reaction was completed, the solvent was removed by distillation under reduced pressure, the reaction was diluted with water, and extracted with dichloromethane. The organic layer was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain 13 as a yellow solid.

[0155] 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] + .

[0156] Embodiment 14

[0157] Example 14 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0158]

[0159] 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]+ .

[0160] Embodiment 15

[0161] Example 15 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0162]

[0163] 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] + .

[0164] Example 16

[0165] Example 16 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0166]

[0167] 1H 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] + .

[0168] Embodiment 17

[0169] Example 17 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0170]

[0171] 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] + .

[0172] Embodiment 18

[0173] Example 18 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0174]

[0175] 1 H 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] +

[0176] Embodiment 19

[0177] Example 19 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0178]

[0179] 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] +

[0180] Embodiment 20

[0181] Example 20 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0182]

[0183] 1HNMR(500MHz,Chloroform-d)δ7.55(q,J=8.3Hz,5H),6.87(qd,J=6.6,3.4Hz,2H),6. 68(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] +

[0184] Embodiment 21

[0185] Example 21 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0186]

[0187] 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 / z 491.5[M+H] +

[0188] Embodiment 22

[0189] Example 22 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0190]

[0191] 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] +

[0192] Embodiment 23

[0193] Example 23 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0194]

[0195] 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] +

[0196] Embodiment 24

[0197] Example 24 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0198]

[0199] 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] +

[0200] Embodiment 25

[0201] Example 25 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0202]

[0203] 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] +

[0204] Embodiment 26

[0205] Example 26 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0206]

[0207] 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] +

[0208] Embodiment 27

[0209] Example 27 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0210]

[0211] 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),3.9 2(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-MSm / z 498.2[M+H] +

[0212] Embodiment 28

[0213] Example 28 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0214]

[0215] 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] + .

[0216] Embodiment 29

[0217] Example 29 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0218]

[0219] 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] + .

[0220] Embodiment 30

[0221] Example 30 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0222]

[0223] 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] + .

[0224] Embodiment 31

[0225] Example 31 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0226]

[0227] 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]+.

[0229] Embodiment 32

[0230] Example 32 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0231]

[0232] 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] + .

[0233] Embodiment 33

[0234] Example 33 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0235]

[0236] 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] + .

[0237] Embodiment 34

[0238] Example 34 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0239]

[0240] 1 HNMR(500MHz,Chloroform-d)δ7.63–7.47(m,5H),7.32(dd,J=8.3,1.9Hz,2H),7.27–7. 21(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] + .

[0241] Embodiment 35

[0242] Example 35 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 13.

[0243]

[0244] 1H 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).

[0245] Embodiment 36

[0246] Example 36 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0247]

[0248] 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] + .

[0249] Embodiment 37

[0250] Example 37 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0251]

[0252] 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] + .

[0253] Embodiment 38

[0254] Example 38 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0255]

[0256] 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] + .

[0257] Embodiment 39

[0258] Example 39 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0259]

[0260] 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] + .

[0261] Embodiment 40

[0262] Example 40 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0263]

[0264] 1 H 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] + .

[0265] Embodiment 41

[0266] Example 41 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0267]

[0268] 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] + .

[0269] Embodiment 42

[0270] Example 42 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0271]

[0272] The reaction equation and preparation method are as follows:

[0273]

[0274] 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, 42-3 (1.5 g, yield 85%) was obtained by column chromatography (petroleum ether: ethyl acetate = 4:1).

[0275] 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 bath, and react at 0°C for 4 hours. After the reaction is completed, dilute with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 42-4.

[0276] 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 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 and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a light yellow solid compound 42.

[0277] 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] + .

[0278] Embodiment 43

[0279] Example 43 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 42.

[0280]

[0281] 1 H 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] + .

[0282] Embodiment 44

[0283] Example 44 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 42.

[0284]

[0285] 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] + .

[0286] Embodiment 45

[0287] Example 45 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0288]

[0289] The reaction equation and preparation method are as follows:

[0290]

[0291] S1. Dissolve 42-4 (783 mg, 3.0 mmol) in methanol (20 mL), add 10% Pd / C (78 mg), and react overnight at room temperature under hydrogen atmosphere. After the reaction, filter out Pd / C through diatomaceous earth, and spin-dry the filtrate to obtain 45-1.

[0292] 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. Add NaBH(OAc)3 (844 mg, 6.0 mmol) to the system in batches and continue stirring at room temperature for 24 hours. After the reaction is completed, add saturated NaHCO3 (30 mL) to quench the reaction and extract with dichloromethane. The organic layer is dried and concentrated with anhydrous sodium sulfate and purified by column chromatography (petroleum ether: ethyl acetate = 9:1) to obtain 45-2.

[0293] 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 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 and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a light yellow solid compound 45.

[0294] 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–

[0295] 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=

[0296] 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

[0297] [M+H] + .

[0298] Embodiment 46

[0299] Example 46 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 45.

[0300]

[0301] 1 H NMR(5000MHz,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] + .

[0302] Embodiment 47

[0303] Example 47 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 45.

[0304]

[0305] 1 H NMR(5000MHz,Chloroform-d)δ7.66(t,J=1.8Hz,1H),7.56(ddt,J=12.0,7.7,1.4Hz,2 H),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–

[0306] 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] + .

[0307] Embodiment 48

[0308] Example 48 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 45.

[0309]

[0310] 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]+.

[0312] Embodiment 49

[0313] Example 49 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 45.

[0314]

[0315] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.8Hz,1H),7.62–7.49(m,2H),7.42(t,J=7.7H z,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(d,J=13.6Hz,1H),3.60(t,J=13.7Hz,2H),2.8 9(d,J=14.9Hz,1H),2.64–2.51(m,1H),2.51–2.42(m,2H),1.37(d,J=6.9Hz,3H).LC-MS m / z448.2[M+H] + .

[0316] Embodiment 50

[0317] Example 50 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0318]

[0319] The reaction equation and preparation method are as follows:

[0320]

[0321] 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% formaldehyde aqueous solution (0.92 mL, 12.0 mmol) under ice bath, and stir at room temperature for 16 hours. After the reaction, extract with dichloromethane. The organic layer is dried and concentrated with anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound 50-1.

[0322] S2, add preactivated zinc powder (0.62g, 9.6mmol) to ultra-dry tetrahydrofuran (15mL), add trimethylsilyl chloride (TMSCl, 0.57g, 5.3mmol) and stir at room temperature for 10 minutes, then dissolve methyl 2-bromoisobutyrate (0.87g, 4.8mmol) in ultra-dry tetrahydrofuran (10mL) and slowly add it to the reaction system. Then drop 50-1 (1.55g, 4.8mmol) in tetrahydrofuran (10mL). The reaction was allowed to react at room temperature for 16 hours. After the reaction was completed, it was poured into water to quench and filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried and concentrated with anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 50-2.

[0323] S3. Dissolve 50-2 obtained in the previous step in ultra-dry tetrahydrofuran, add 1.2 equivalents of 1.0M potassium tert-butoxide / tetrahydrofuran solution under ice bath, and react at 0°C for 4 hours. After the reaction is completed, add water to dilute and extract with ethyl acetate. Wash the organic layer with saturated brine, dry and concentrate over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 50-3.

[0324] S4, 50-3 (783 mg, 3.0 mmol) was dissolved in methanol (20 mL), 10% Pd / C (78 mg) was added, and the mixture was reacted at room temperature overnight under a hydrogen atmosphere. After the reaction, Pd / C was filtered off through diatomaceous earth, and the filtrate was dried to obtain 50-4.

[0325] 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) to the system in batches and continue stirring at room temperature for 24 hours. After the reaction is completed, add saturated NaHCO3 (30 mL) to quench the reaction and extract with dichloromethane. The organic layer is dried and concentrated with anhydrous sodium sulfate and purified by column chromatography (petroleum ether: ethyl acetate = 9:1) to obtain 50-5.

[0326] 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 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 and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a light yellow solid compound 50.

[0327] 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–

[0328] 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] + .

[0329] Embodiment 51

[0330] Example 51 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 50.

[0331]

[0332] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.8Hz,1H),7.66–7.52(m,2H),7.54–

[0333] 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] + .

[0334] Embodiment 52

[0335] Example 52 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 50.

[0336]

[0337] 1 H NMR(500MHz,Chloroform-d)δ7.68(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–

[0338] 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] + .

[0339] Embodiment 53

[0340] Example 53 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 50.

[0341]

[0342] 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]+ .

[0343] Embodiment 54

[0344] Example 54 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 50.

[0345]

[0346] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.8Hz,1H),7.65–7.51(m,2H),7.53–

[0347] 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] + .

[0348] Embodiment 55

[0349] Example 55 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0350]

[0351] The reaction equation and preparation method are as follows:

[0352]

[0353] 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 50-1 (1.55 g, 4.8 mmol) / tetrahydrofuran (10 mL) solution. The reaction was allowed to react at room temperature for 16 hours. After the reaction was completed, pour into water to quench and filter, and the filtrate was extracted with ethyl acetate. The organic phase was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 55-1.

[0354] S2. Dissolve 55-1 obtained in the previous step in tetrahydrofuran, add 1.2 equivalents of 1.0M potassium tert-butoxide / tetrahydrofuran solution under ice bath, and stir at 0°C for 4 hours. After the reaction is completed, dilute with water and extract with ethyl acetate. Wash the organic layer with saturated brine, dry and concentrate over anhydrous sodium sulfate, and purify by column chromatography to obtain 55-2.

[0355] 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 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 and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a light yellow solid compound 55.

[0356] 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] + .

[0357] Embodiment 56

[0358] Example 56 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 55.

[0359]

[0360] 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] + .

[0361] Embodiment 57

[0362] Example 57 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 55.

[0363]

[0364] 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] + .

[0365] Embodiment 58

[0366] Example 58 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 55.

[0367]

[0368] 1 H 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] + .

[0369] Embodiment 59

[0370] Example 59 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 55.

[0371]

[0372] 1H 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] + .

[0373] Embodiment 60

[0374] Example 60 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 55.

[0375]

[0376] 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] + .

[0377] Embodiment 61

[0378] Example 61 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0379]

[0380] The reaction equation and preparation method are as follows:

[0381]

[0382] S1. Dissolve compound 61-2 (3.2 g, 20.0 mmol) in methanol (30 mL), add compound 61-1 (4.0 g, 22.0 mmol) and 4A molecular sieve, and stir at room temperature overnight. Then cool the reaction system to -10 ° C, add NaBH4 (4.6 g, 120.0 mmol) in batches, and continue stirring at room temperature for 16 hours. After the reaction is completed, distill under reduced pressure to remove the solvent, add water to dilute, and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography to obtain 61-3 (4.3 g, yield is 63%).

[0383] 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, solid Na2CO3 was added and stirred overnight, and the insoluble matter was filtered through celite. The filtrate was dried over anhydrous sodium sulfate and concentrated to give an oily substance 61-4 (3.0 g, yield 95%).

[0384] S3, compound 61-4 was dissolved in anhydrous ethanol, and cyanogen bromide was added in batches under vigorous stirring to react for 5 hours. After the reaction was completed, the crude product 61-5 was concentrated under reduced pressure, and ethyl acetate was added to slurry for purification to obtain a white solid 66-5 (3.6 g, yield 83%).

[0385] 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 stirred at 100° C. for 6 hours. After the reaction was completed, water was added to dilute and extracted with ethyl acetate. The organic layer was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a solid compound (34 mg, yield 35%).

[0386] 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] + .

[0387] Embodiment 62

[0388] Example 62 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0389]

[0390] 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] + .

[0391] Embodiment 63

[0392] Example 63 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0393]

[0394] LC-MS m / z 401.23[M+H] + .

[0395] Embodiment 64

[0396] Example 64 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0397]

[0398] LC-MS m / z 401.23[M+H] + .

[0399] Embodiment 65

[0400] Example 65 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0401]

[0402] LC-MS m / z 405.21[M+H] + .

[0403] Embodiment 66

[0404] Example 66 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0405]

[0406] LC-MS m / z 405.21[M+H] + .

[0407] Embodiment 67

[0408] Example 67 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0409]

[0410] 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]+ .

[0411] Embodiment 68

[0412] Example 68 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0413]

[0414] LC-MS m / z 421.18[M+H] + .

[0415] Embodiment 69

[0416] Example 69 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0417]

[0418] LC-MS m / z 421.18[M+H] + .

[0419] Embodiment 70

[0420] Example 70 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0421]

[0422] LC-MS m / z 421.18[[M+H] + .

[0423] Embodiment 71

[0424] Example 71 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0425]

[0426] LC-MS m / z 465.13[M+H] + .

[0427] Embodiment 72

[0428] Example 72 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0429]

[0430] LC-MS m / z 465.13[M+H]+ .

[0431] Embodiment 73

[0432] Example 73 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0433]

[0434] LC-MS m / z 455.21[M+H] + .

[0435] Embodiment 74

[0436] Example 74 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0437]

[0438] 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 / z455.21[M+H] + .

[0439] Embodiment 75

[0440] Example 75 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0441]

[0442] LC-MS m / z 423.20[M+H] + .

[0443] Embodiment 76

[0444] Example 76 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0445]

[0446] LC-MS m / z 423.20[M+H] + .

[0447] Embodiment 77

[0448] Example 77 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 61.

[0449]

[0450] LC-MS m / z 483.12[M+H] + .

[0451] Embodiment 78

[0452] Example 78 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0453] The reaction equation and preparation method are as follows:

[0454]

[0455] S1. Dissolve compound 69-2 (3.2 g, 20.0 mmol) in methanol (30 mL), add compound 69-1 (4.0 g, 22.0 mmol) and 4A molecular sieve, and stir overnight at room temperature. Then cool the reaction system to -10 ° C, add NaBH4 (4.6 g, 120.0 mmol) in batches, and continue stirring at room temperature for 16 hours. After the reaction is completed, distill under reduced pressure to remove the solvent, add water to dilute, and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography to obtain 62-3 (4.3 g, yield is 63%).

[0456] S2. Compound 69-3 was dissolved in methanol (10 mL), HCl (4.0 M in Dioxane) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration, and 1N NaOH aqueous solution was added to quench the mixture, and then the mixture was extracted three times with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oily product 69-4 (3.0 g, yield 95%).

[0457] S3, compound 69-4 was dissolved in anhydrous ethanol, and cyanogen bromide was added in batches under vigorous stirring to react for 5 hours. After the reaction was completed, the crude product 69-5 was obtained by concentrating under reduced pressure, and ethyl acetate was added to slurry for purification to obtain a white solid a-2 (3.6 g, yield 83%).

[0458] 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 stirred at 100° C. for 6 hours. After the reaction was completed, water was added to dilute and extracted with ethyl acetate. The organic layer was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain solid compound 69 (39 mg, yield was 38%).

[0459] 1 H 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);

[0460] Embodiment 79

[0461] Example 79 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0462]

[0463] 1H 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 / z426.23[M+H] + .

[0464] Embodiment 80

[0465] Example 80 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0466] LC-MS m / z 426.23[M+H] + .

[0467] Embodiment 81

[0468] Example 81 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0469]

[0470] LC-MS m / z 426.23[M+H] + .

[0471] Embodiment 82

[0472] Example 82 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0473]

[0474] LC-MS m / z 430.20[M+H] + .

[0475] Embodiment 83

[0476] Example 83 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0477]

[0478] LC-MS m / z 430.20[M+H] + .

[0479] Embodiment 83

[0480] Example 83 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0481]

[0482] 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] + .

[0483] Embodiment 84

[0484] Example 84 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0485]

[0486] LC-MS m / z 446.17[M+H] + .

[0487] Embodiment 85

[0488] Example 85 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0489]

[0490] LC-MS m / z 446.17[M+H] + .

[0491] Embodiment 86

[0492] Example 86 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0493]

[0494] LC-MS m / z 490.12[M+H] + .

[0495] Embodiment 87

[0496] Example 87 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0497]

[0498] LC-MS m / z 490.12[M+H] + .

[0499] Embodiment 87

[0500] Example 87 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0501]

[0502] C-MS m / z 490.12[M+H] + .

[0503] Embodiment 88

[0504] Example 88 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0505]

[0506] LC-MS m / z 480.20[M+H] + .

[0507] Embodiment 89

[0508] Example 89 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0509]

[0510] 1H 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] + .

[0511] Embodiment 90

[0512] Example 90 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0513]

[0514] LC-MS m / z 448.19[[M+H] + .

[0515] Embodiment 91

[0516] Example 91 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0517]

[0518] LC-MS m / z 448.19[M+H] + .

[0519] Embodiment 92

[0520] Example 92 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 78.

[0521]

[0522] LC-MS m / z 508.11[M+H] + .

[0523] Embodiment 93

[0524] Example 93 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0525]

[0526] The reaction equation and preparation method are as follows:

[0527]

[0528] S1. Add Bi(NO3)3·5H2O (121 mg, 0.25 mmol) to a mixture of compound 1 (535 mg, 5.0 mmol) and compound 2 (571 mg, 5.0 mmol), and stir at room temperature overnight. After the reaction is completed, add DCM to dilute the mixture. Filter, concentrate and dry, and purify by column chromatography to obtain compound 3 (658 mg, 3.0 mmol, yield is 60%).

[0529] S2. Add methyl acrylate (3.3 mmol, 285 mg) and DBU (0.15 mmol, 23 mg) to the compound 3 obtained in the previous step, and stir overnight at 60° C. After the reaction, add DCM to disperse and concentrate, and purify by column chromatography to obtain compound 4.

[0530] S3. Dissolve the compound 4 obtained in the previous step in ultra-dry tetrahydrofuran, add 1.2 equivalents of 1.0M potassium tert-butoxide / tetrahydrofuran solution under ice bath, and react at 0°C for 4 hours. After the reaction is completed, dilute with water and extract with ethyl acetate. Wash the organic layer with saturated brine, dry and concentrate with anhydrous sodium sulfate, and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 5.

[0531] 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), 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 and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a light yellow solid compound.

[0532] LC-MS m / z 419.2[M+H] + .

[0533] Embodiment 94

[0534] Example 94 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 93.

[0535]

[0536] LC-MS m / z 435.2[M+H] +.

[0537] Embodiment 95

[0538] Example 95 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 93.

[0539]

[0540] LC-MS m / z 479.1[M+H] + .

[0541] Embodiment 96

[0542] Example 96 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 93.

[0543]

[0544] LC-MS m / z 415.2[M+H] + .

[0545] Embodiment 97

[0546] Example 97 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 93.

[0547]

[0548] LC-MS m / z 469.2[M+H] + .

[0549] Embodiment 98

[0550] Example 98 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0551]

[0552] Its preparation method is the same as that of Example 93, except that Replace compound 2 in Example 93.

[0553] LC-MS m / z 433.23[M+H] + .

[0554] Embodiment 99

[0555] Example 99 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: the preparation method refers to Example 93.

[0556]

[0557] LC-MS m / z 449.2[M+H] + .

[0558] Embodiment 100

[0559] Example 100 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 93.

[0560]

[0561] LC-MS m / z 493.2[M+H] + .

[0562] Embodiment 101

[0563] Example 101 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 93.

[0564]

[0565] LC-MS m / z 429.3[M+H] + .

[0566] Embodiment 101

[0567] Example 101 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 93.

[0568]

[0569] LC-MS m / z 451.2[M+H] + .

[0570] Embodiment 102

[0571] Example 102 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0572]

[0573] The preparation method is the same as that of Example 1, except that Replace compound 2 in Example 93.

[0574] LC-MS m / z 401.2[M+H] + .

[0575] Embodiment 103

[0576] Example 103 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Example 1.

[0577]

[0578] LC-MS m / z 455.2[M+H] + .

[0579] Comparative Example 1

[0580] Comparative Example 1 provides two compounds, ONC201 and ONC212; ONC201 and ONC212 are synthesized according to the method described in CN104860948.

[0581]

[0582] Comparative Example 2

[0583] Comparative Example 2 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows:

[0584]

[0585] The reaction equation and preparation method are as follows:

[0586]

[0587] 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 completed, spin dry and remove excess compound 2 under vacuum to obtain compound 3 as a colorless oil.

[0588] S2. Dissolve the compound 3 obtained in the previous step in tetrahydrofuran, add 1.2 equivalents of 1.0M potassium tert-butoxide / tetrahydrofuran solution under ice bath, and stir at 0°C for 4 hours. After the reaction is completed, dilute with water and extract with ethyl acetate. Wash the organic layer with saturated brine, dry and concentrate with anhydrous sodium sulfate, and purify by column chromatography to obtain compound 4.

[0589] 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 and concentrated over anhydrous sodium sulfate, and purified by column chromatography (4% MeOH in DCM) to obtain a light yellow solid compound.

[0590] 1H 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] + Comparative Example 3

[0591] Comparative Example 3 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Comparative Example 2.

[0592]

[0593] 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] + Comparative Example 4

[0594] Comparative Example 4 provides an imidazopyridopyrimidone compound, the structural formula of which is as follows: The preparation method refers to Comparative Example 2.

[0595]

[0596] 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 / z490.1[M+H] + .Activity test

[0597] Experimental Example 1: Agonist activity of compounds on HsClpP protease

[0598] 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 enzyme (final concentration 0.7μM) was added to each well, and 10μL of compound (final concentration 20μM, 3-fold gradient dilution 11 concentrations) was added at the same time, incubated at room temperature for 10 minutes, and then 20μL of substrate (final concentration 100μM) was added, incubated at room temperature for 4h, and the fluorescence signal was measured using a multifunctional microplate reader, and the data obtained was processed using GraphPad Prism8.

[0599] Experimental Example 2: The MTS method was used to evaluate the proliferation inhibition activity of the modified compounds on MV4-11 and HL60 cell lines:

[0600] In a 96-well plate, 10,000 cells were inoculated in each 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 hours. 20 μL of MTS was added and the cells were cultured at 37°C for 4 hours. The absorbance of the DMSO wells was measured at 490 nm and 690 nm using an ELISA reader and was found to be 0.6-0.8. The data were processed using GraphPad Prism8. The data are shown in Table 1.

[0601] Table 1:

[0602]

[0603]

[0604]

[0605] Note: In Table 1, “A” stands for EC 50 or IC 50 Less than 10nM; "B" indicates EC 50 or IC 50 Between 10-100nM; "C" indicates EC 50 or IC 50 Between 100-1000nM; "D" means EC 50 or IC 50 Between 1000-5000nM; "E" stands for EC 50 or IC 50 Greater than 5000nM.

[0606] Experimental Example 3: Pharmacokinetic Evaluation of Examples 9 and 12

[0607] To evaluate the pharmacokinetic characteristics of Example 9 and Example 12 after oral administration, we conducted pharmacokinetic tests on ICR mice at a single oral dose of 50 mg / kg. Figure 1 And as shown in Table 2.

[0608] Table 2 Pharmacokinetic parameters of Example 9 and Example 12 in mice (IG 50 mg / kg)

[0609]

[0610]

[0611] Experimental Example 4: In vivo pharmacodynamic evaluation of HL60 diffusion model

[0612] Female B-NDG mice (18-22 g, 6-8 weeks old) were purchased from White Ossett. The 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 The mice were randomly divided into groups according to their body weight after 5 days of inoculation. According to the protocol, the mice were treated with an equal amount of blank solvent control (0.5% CMC-Na, po qd, n=9), ONC212 (10 mg / kg, po qd, n=9), Example 9 (10 mg / kg, po qd, n=9), and Example 12 (10 mg / kg, p.o qd, n=9) for 21 days and then observed for the death of mice. During the experiment, the mice were orally administered every day, and the mice were weighed every 3-4 days to observe their growth status. Statistical analysis was performed using GraphPad Prism 8.

[0613] like Figure 2 In the HL60 diffusion model, with the solvent group as the control, after continuous administration for 21 days, Examples 9 and 12 were able to relatively prolong the survival period of mice.

[0614] 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 scope of ordinary technicians in the relevant technical field without departing from the purpose 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 to 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 an 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 drug 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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