Imidazolone compound as well as preparation method and application thereof

Abstract

The invention discloses a heterocycloalkyl carboxylic acid compound, an intermediate and a preparation method and application thereof, and relates to the technical field of medicinal chemistry. The imidazolone compound provided by the invention has a structure as shown in a formula I or a formula II, and in-vitro activity experiments prove that the imidazolone compound has good DNA damage repair and can be used for treating various diseases. # imgabs0 #

Description

Technical Field

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

[0002] DNA is the most important genetic material for cell life activities, and it is of great significance to maintain its integrity and stability. The DNA of human cells is exposed to a variety of endogenous and exogenous damage factors every day, such as reactive oxygen, aldehydes, ultraviolet rays, ionizing radiation, and chemotherapeutic drugs. Therefore, nucleotide changes such as insertion, deletion, and substitution may occur, leading to DNA damage such as single-strand breaks or double-strand breaks. In order to cope with the serious adverse reactions caused by DNA damage, cells have evolved a complex signaling pathway network - collectively known as DNA damage response (DDR), including: sensing DNA damage signals, activating cell cycle checkpoints, slowing down or blocking cell cycle progression, activating different DNA repair mechanisms or cell apoptosis mechanisms, etc. DDR recognizes damage, initiates a cascade reaction, and determines the fate of cells according to the degree of damage: if the DDR damage is severe and difficult to repair, the cell will enter apoptosis or even necrosis; if the damage is mild and can be repaired, the cell will continue to survive and initiate the repair program, complete the damage repair through multiple repair pathways, and maintain genetic integrity.

[0003] At present, DNA damage repair has been used as a therapeutic entry point for many diseases. Cheng Hongyan et al. reviewed the key molecules and potential tumor therapeutic targets of DNA damage repair and related DDR pathways, and described the research on synthetic lethal targets of DNA damage repair-related pathways and their application in ovarian cancer. Chen Hong et al. studied the biological characteristics of H2AX and its family, the detection method of γH2AX, H2AX phosphorylation in DNA damage and repair, and its application in reproductive-related cells. Zhao Simin et al. reviewed the research progress on DNA damage repair and ovarian aging, including the role and mechanism of DNA damage repair genes in multiple processes such as primordial germ cell development, oocyte meiosis, and follicle maintenance and development, as well as the relationship between gene mutations in this pathway and premature ovarian failure, and explored the intervention strategy of delaying ovarian aging by targeting DNA damage repair pathways, hoping to provide a new way to protect female fertility. Zhang Weina et al. reviewed the intrinsic relationship between DNA damage repair and aging, summarized the latest research progress on the mechanism of DNA damage-induced aging, and explored the possibility and potential risks of delaying aging by targeting DNA damage repair.

[0004] At present, the targets of DNA damage repair mechanism include ATR, ATM and DNA-PK. In recent years, synthetic lethality has been considered as a paradigm of anti-cancer therapy. The emergence of more synthetic lethal targets has led to a gradual expansion of the application scope of synthetic lethality. The causes of tumor formation are very complex, and the effect of single-target drug therapy is not ideal. The synergistic effect of multiple targets is the development trend of tumor treatment. The study of Johann Gout et al. (Gout J, et al. Gut 2021; 70: 743-760.) showed that in ATM-deficient pancreatic ductal cancer cells and tumor tissues, olaparib (PARP inhibitor), VE-822 (ATR inhibitor) and CC-115 (DNA-PK and mTOR dual-target inhibitor) were combined for administration, and in vitro and in vivo data showed that the combination of three drugs had the best effect. Audrey Turchick et al. (Mol Cancer Ther; 22(7)July 2023) showed that the combination of ATR inhibitor M4344 and ATM inhibitor M4076 was significantly more effective than ATR alone in treating triple-negative breast cancer in a human tumor xenograft model. Ankur Karmokar et al. (Ankur Karmokar, et al. Cancers 2023, 15, 4195) showed that in a human ATM mutant tumor xenograft model, the combination of AZD6738 (ATR inhibitor), AZD7648 (DNA-PK inhibitor) and olaparib (PARP inhibitor) was much more effective than single drugs. XRD-0394 is a small molecule compound with dual targets of ATM and DNA-PK developed by XRad Therapeutics. Its in vitro and in vivo efficacy showed significant dose-proportional radiosensitization effect without obvious toxicity. The compound has entered a clinical trial combined with palliative radiotherapy for the treatment of solid tumors (NCT05002140). These research results show that the combination of drugs targeting multiple targets such as ATR, ATM, DNA-PK and mTOR has better therapeutic effects.

[0005] ATR (Ataxia Telangiectasia and Rad3-related) inhibitors are an important focus of cancer research in recent years. Its scientific background stems from the core role of ATR protein in cell cycle checkpoint control and DNA damage repair. ATR is a serine / threonine kinase belonging to the PI3K-like protein family. It maintains genome stability by responding to DNA single-strand breaks and replication fork stagnation (Chen et al., Oncogene, 37 (4), 423-433, 2018). The main function of ATR is to start and coordinate multiple DNA damage response pathways. It pauses the cell cycle by phosphorylating downstream target proteins such as CHK1 and BRCA1, providing time for DNA repair (Liu et al., Cold Spring Harbor perspectives in biology, 11 (2), a028798, 2019). In addition, ATR is also involved in the protection of RNA polymerase II to prevent transcription interruption during replication stress (Zou & Elledge, Nature, 421 (6925), 792-797, 2003). Therefore, ATR inhibitors can block these repair pathways, making it impossible for tumor cells to recover normally when they encounter DNA damage, leading to cell death, especially those cancers that rely on these repair mechanisms (such as ovarian cancer and breast cancer with BRCA mutations) have highly selective toxicity (Lord & Ashworth, Nature Reviews Cancer, 17 (8), 473-486, 2017). Preclinical studies have shown that ATR inhibitors such as VE-821 and AZD6738 exhibit anti-tumor activity against a variety of cancers in in vitro and in vivo experiments (Jackson & Bartek, Cell, 141 (6), 847-856, 2010). Further clinical trials are exploring the possibility of using these inhibitors as monotherapy or in combination with other chemotherapeutic drugs, PARP inhibitors, etc. to enhance the anti-cancer effect (Robson et al., New England Journal of Medicine, 379 (5), 429-439, 2018).

[0006] ATM (Ataxia-telangiectasia mutated) inhibitors are a type of targeted therapy developed based on their central role in the DNA damage repair pathway. ATM is a key kinase that is activated when cells encounter DNA double-strand breaks, which in turn initiates multiple repair mechanisms, including non-homologous end joining and homologous recombination repair. ATM is partially involved in G2 / M checkpoint regulation, controls the G1 / S checkpoint, and is responsible for removing inhibitory phosphorylation of CDK. In addition, studies have shown that ATM has a synthetic lethal relationship with PARP, ATR, BRAC1, DNA-PK, and Polθ in the DNA damage response. The main theoretical basis of ATM inhibitors is that by blocking this key molecule, the ability of tumor cells to repair DNA damage can be weakened, especially for tumors that rely on the ATM pathway, such as ovarian and breast cancer with BRCA mutations. In clinical applications, ATM inhibitors have shown potential anti-tumor activity. Early in vitro and animal model studies have shown that ATM inhibitors can enhance the effects of radiotherapy and chemotherapy, especially in tumors with BRCA mutations. For example, the combination of ATM inhibitors such as KU-55933 and NMS-P937 with PARP inhibitors has demonstrated significant synergistic effects on BRCA1 / 2 mutant tumors in in vitro experiments. In addition, some clinical trials, such as NCT02400472, are exploring the combination of ATM inhibitors with standard treatment regimens to evaluate their safety and efficacy in patients with advanced or metastatic breast and ovarian cancer. Introduction to DNA-PK targets and their inhibitors:

[0007] DNA-PK (DNA-dependent protein kinase) inhibitors have been one of the focuses of cancer treatment research in recent years because of their key role in the DNA repair pathway. DNA-PK is mainly involved in the non-homologous end joining (NHEJ) repair mechanism, which is essential for maintaining genome stability. However, in tumor cells, overactive NHEJ may lead to excessive DNA damage repair, thereby promoting the survival and proliferation of tumor cells (Smith et al., Oncotarget, 9 (32), 22354-22369, 2018).

[0008] NHEJ is a DSB repair mechanism used by cells outside the G2 / S phase or when HR is impaired. The anti-cancer strategy of DNA-PK inhibitors is mainly based on blocking this repair pathway, making it impossible for tumor cells to effectively repair DNA damage such as chemotherapy or radiotherapy, thereby inducing cell apoptosis. For example, Liu et al. (2019) found in in vitro and in vivo experiments that DNA-PK inhibitors combined with chemotherapy drugs can significantly enhance the killing effect on ovarian cancer and breast cancer cells, which provides new possibilities for clinical treatment.

[0009] Introduction to mTOR targets and their inhibitors:

[0010] mTOR (mammalian target of rapamycin) is a key regulator of cell growth and proliferation. It is located in the PI3K / AKT / mTOR signaling pathway, which is often abnormally activated in a variety of tumors. By blocking this pathway, mTOR inhibitors can inhibit protein synthesis in tumor cells, induce cell cycle arrest, and promote cell apoptosis, thereby showing significant anti-tumor activity (Liu et al., 2018). Many studies have shown that the mTOR signaling pathway is closely related to the DNA damage repair mechanism, and many factors important for DDR are also involved in the mTOR signaling pathway. (Yinxing Ma, et al., BBA-Molecular Cell Research, 2018). Adiel Cohen et al.'s study showed that γH2A aggregates during DNA damage and quiescence, and TORC2-Gad8 signaling is essential for the aggregation of γH2A. Inhibiting the aggregation of γH2A may affect the structure and function of chromatin to some extent. γH2A is closely associated with DNA double-strand breaks (Adiel Cohen, et al., J Biol Chem. 2024 Aug; 300(8): 107531). Common mTOR inhibitors include rapamycin and its derivatives sirolimus and everolimus. mTOR inhibitors have shown broad application potential in the treatment of various cancers. In ovarian cancer, mTOR inhibitors can inhibit tumor angiogenesis, reduce tumor growth rate, and may reverse chemotherapy resistance (Wang et al., 2019).

[0011] At present, compounds that act on the above-mentioned targets to achieve DNA damage repair are very rare. In view of this, the present invention provides an imidazolones compound with a new structure based on this mechanism. The in vitro activity experiments have proved that the imidazolones have good DNA damage repair properties and can be used in the treatment of various diseases. Summary of the invention

[0012] The purpose of the present invention is to provide an imidazolidone compound and a preparation method and application thereof, which can be used in DNA damage repair and the treatment of various diseases.

[0013] To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

[0014] In the first aspect, the present invention provides an imidazolidone compound, which is a compound represented by Formula I or Formula II, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0015]

[0016] R1 is selected from H, alkyl, alkoxy, halogen, alkenyl, alkynyl;

[0017] R2 is selected from aryl or heteroaryl substituted or unsubstituted by 1 to 5 substituents;

[0018] Wherein, when R2 in the compound of formula I is an aryl group substituted by 1 to 5 substituents, the substituents are each independently selected from:

[0019]

[0020] C 1-6 Alkoxy, -CF3, halogen, C 1-6 Alkyl, cyano;

[0021] When R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from:

[0022] Substituted or unsubstituted C 1-6 Ester group, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclylaryl, heteroaryl, C 1-6 Haloalkyl, C 1-6 Alkylamino, phenylamino, halogen, cyano, -NH2, hydroxyl; wherein the substituted substituent is selected from halogen, carbonyl, hydroxyl, C 1-5 Alkyl, aryl, cyano, -NH2;

[0023] R3 is selected from heteroaryl substituted or unsubstituted by 1-5 substituents, wherein the 1-5 substituents are selected from: substituted amino, C 2-8 Heterocyclic group, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 ester group amino, and halogen, cyano, -NH2, hydroxyl; wherein the substituted substituent is selected from C 1-6 Alkyl, hydroxy, halogen, alkylhydroxy, alkylamino.

[0024] The preferred solution for R1 is:

[0025] Preferably, R1 is selected from alkyl; more preferably C 1-10 Alkyl; more preferably C 1-5 Alkyl; more preferably C 1-3 Alkyl; more preferably methyl.

[0026] The preferred solution for R2 is:

[0027] Preferably, when R2 in the compound of formula I is aryl substituted by 1-5 substituents, the substituents are each independently selected from:

[0028]

[0029] Methoxy, -CF3, F, methyl, ethyl, cyano.

[0030] Further preferably, in the compound of formula I, R2 is aryl substituted by 1-2 substituents, and the substituents are each independently selected from:

[0031]

[0032] Methoxy, -CF3, F, methyl, ethyl, cyano.

[0033] Preferably, when R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from:

[0034] Substituted C 1-6 Alkyl and C 1-6 Alkoxy, -CF3, halogen, C 1-6 Alkyl, cyano; the substituted substituent is cyano.

[0035] Further preferably, when R2 in the compound of formula I is a heteroaryl substituted by 1-5 substituents, or in the compound of formula II, the substituents are each independently selected from:

[0036] Substituted C 1-6 Alkyl and C 1-6 Alkoxy, -CF3, halogen, C 1-6 Alkyl, cyano; the substituted substituent is cyano.

[0037] More preferably, when R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from: substituted C 1-6 Alkyl, -CF 3，， The substituted substituent is a cyano group.

[0038] More preferably, when R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from: substituted C 2-4 Alkyl, -CF 3，， The substituted substituent is a cyano group.

[0039] Further preferably, when R2 in the compound of formula I is a heteroaryl substituted by 1-5 substituents, or in the compound of formula II, the substituents are each independently selected from: -CF3.

[0040] The preferred solution for R3 is:

[0041] Preferably, R3 is selected from phenyl substituted with 1-2 N, wherein the substituted substituent is selected from: substituted amino, C 2-8 Heterocyclic group, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 ester group amino, and halogen, cyano, -NH2, hydroxyl; wherein the substituted substituent is selected from C 1-6 Alkyl, hydroxy, halogen, alkylhydroxy, alkylamino.

[0042] More preferably, R3 is selected from phenyl substituted with 1-2 N, wherein the substituted substituent is selected from: substituted C 2-8 heterocyclic group, and cyano, -NH2, -NHCH2CH2NHCH3, -NHCOCH2NHCH3; wherein the substituted substituent is selected from C 1-6 Alkyl, alkylhydroxy, alkylamino.

[0043] More preferably, R3 is selected from phenyl substituted with 1-2 N, wherein the substituted substituent is selected from: substituted amino, C 4-6 Nitrogen heterocycle, C 1-6 wherein the substituted substituent is selected from C 1-6 Alkyl, hydroxyl.

[0044] Further preferably, R3 is selected from phenyl substituted by 1-2 N, wherein the substituted substituent is selected from:

[0045] Preferably, the compound represented by formula I is selected from:

[0046]

[0047]

[0048]

[0049] More preferably, the following compounds are:

[0050] FP-313, FP-318, FP-337, FP-345, FP-353, FP-360, FP-364, FP-378, FP-416, FP-622, FP-921, FP-937, FP-938, FP-942, FP-943, FP-949.

[0051] More preferably, the following compounds are:

[0052] FP-318, FP-360, FP-364, FP-378, FP-416, FP-622, FP-921, FP-937, FP-938, FP-943.

[0053] More preferably, the following compounds are:

[0054] FP-318, FP-622, FP-921, FP-937, FP-938, FP-943.

[0055] More preferably, the following compounds are:

[0056] FP-921, FP-943.

[0057] FP-943 is most preferred.

[0058] More preferably, the following compounds are:

[0059] FP-318, FP-374, FP-378, FP-416, FP-622, FP-937, FP-938, FP-286, FP-356, FP-364, FP-921, FP-943, FP-948, FP-949.

[0060] More preferably, the following compounds are:

[0061] FP-286, FP-356, FP-364, FP-921, FP-943, FP-948.

[0062] In a second aspect, the present invention provides an intermediate of the aforementioned imidazolidinone compound, selected from the following structures:

[0063]

[0064] R1, R2, and R3 have the same meanings as above;

[0065] M1 is halogen.

[0066] In a third aspect, the present invention provides a method for preparing the aforementioned imidazolidinone compound, comprising the following reaction steps:

[0067]

[0068] or

[0069]

[0070] or

[0071]

[0072] or

[0073]

[0074] R1, R2, and R3 have the same meanings as above;

[0075] M1 is halogen, M2 is a protecting group or does not exist, and M3 is a protecting group.

[0076] Preferably, the protecting group is selected from Boc,

[0077] In a fourth aspect, the present invention provides the use of the aforementioned imidazolones, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof in the preparation of ATM kinase inhibitors.

[0078] In a fifth aspect, the present invention provides the use of the aforementioned imidazolidinone compounds, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of mTOR kinase inhibitors.

[0079] In a sixth aspect, the present invention provides the use of the aforementioned imidazolidinone compounds, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of DNA-PK kinase inhibitors.

[0080] In a seventh aspect, the present invention provides the use of the aforementioned imidazolidinone compounds, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of ATR kinase inhibitors.

[0081] In an eighth aspect, the present invention provides the use of the aforementioned imidazolidinone compounds, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of inhibitors that simultaneously inhibit ATM kinase, ATR kinase, mTOR kinase and DNA-PK kinase.

[0082] In a ninth aspect, the present invention provides the use of the aforementioned imidazolidinone compounds, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of DNA damage repair agents.

[0083] In the tenth aspect, the present invention provides the use of the aforementioned imidazolidinone compounds, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of drugs for treating and / or preventing ATM kinase, ATR kinase, mTOR kinase, DNA-PK kinase or DNA damage-mediated diseases.

[0084] Preferably, the disease is selected from at least one of tumors (e.g., leukemia, malignant lymphoma, multiple myeloma, gastrointestinal stromal tumors, colon cancer, rectal cancer, breast cancer, liver cancer, gastric cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, choriocarcinoma, lung cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, glioblastoma, mast cell tumor, brain tumor, germ cell tumor, melanoma, sarcoma, including dermatofibrosarcoma protuberans, osteosarcoma), metabolic diseases (e.g., diabetes, obesity), and cardiovascular diseases (e.g., atherosclerosis).

[0085] In the eleventh aspect, the present invention provides a pharmaceutical composition comprising the aforementioned imidazolidinone compound, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier or excipient.

[0086] The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable materials, components or vehicles that are suitable for administering the compounds of the present invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that participate in carrying or transporting the subject substance from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation or not injurious to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium methyl cellulose, ethyl cellulose and cellulose acetate; tragacanth, 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; glycols such as propylene glycol, polyols such as glycerol, behenyl alcohol, glycerol ... Sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogenic water, isotonic saline, ethanol, phosphate buffer, and other nontoxic compatible substances used in pharmaceutical preparations, wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and stearic acid esters, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated benzoic acid (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal compounds, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0087] Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohol, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, sugars (e.g., lactose, amylose or starch), polyethylene glycol, magnesium stearate, talc, silicic acid, viscous paraffin, essential oils, fatty acid esters, methylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical composition may be sterilized and, if desired, may be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt buffers that affect osmotic pressure, colorants, flavorings and / or aromatic substances, etc., which do not deleteriously react with the active compounds.

[0088] Composition can also contain the wetting agent, emulsifier or pH buffer of minor amount.Composition can be liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release preparation or powder.Composition can be formulated into suppository with conventional adhesive and carrier (such as triglyceride).Oral preparation can comprise standard carrier such as pharmaceutical grade mannitol, lactose, magnesium stearate, polyvinylpyrrolidone, saccharin sodium, cellulose, magnesium carbonate etc.

[0089] According to ordinary methods, the composition can be formulated into a pharmaceutical composition suitable for human intravenous administration. When needed, the composition may also include a stabilizer and a local anesthetic to alleviate the pain at the injection site. Generally, the composition is supplied separately or mixed together in a unit dosage form, for example, in a sealed container such as an ampoule or a sachet showing the amount of the active agent as a dry freeze-dried powder or anhydrous concentrate. When the composition is administered by infusion, it can be dispersed with an infusion bottle containing pharmaceutical grade sterile water, saline or glucose water. When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the composition can be mixed before administration.

[0090] The pharmaceutical compositions of the present invention may also include an agent that controls the release of the compound of the present invention, thereby providing a timed or sustained release composition.

[0091] The pharmaceutical compositions of the present invention include compositions suitable for oral, rectal, topical, vaginal and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any particular case depends on the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions can be prepared by any method known in the art of pharmacy.

[0092] The active ingredient can be administered orally in a solid dosage form or a liquid dosage form, such as capsules, tablets, lozenges, lozenges, granules and powders, and the liquid dosage form is such as elixirs, syrups, emulsions, dispersions and suspensions. The active ingredient can also be administered parenterally in a sterile liquid dosage form such as a dispersion, suspension or solution. Other dosage forms that can be used to administer the active ingredient include ointments, creams, drops, transdermal patches or powders for topical administration; ophthalmic solutions or suspension forms for eye administration, i.e., eye drops; sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration. Gelatin capsules contain active ingredients and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as sustained-release products to provide sustained release of drugs over several hours. Compressed tablets can be coated with sugar or film to cover any unpleasant taste and protect the tablet from air, or can be enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can include coloring agents and flavoring agents to increase the patient's acceptance. Generally speaking, water, suitable oil, saline, dextrose (glucose) aqueous solution and related sugar solution and glycols such as propylene glycol or polyethylene glycol are suitable carriers of parenteral solutions. The solution for parenteral administration preferably includes water-soluble salts of active ingredients, suitable stabilizers and buffer substances used as required. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid alone or in combination are suitable stabilizers. Citric acid and its salts and sodium EDTA can also be used. In addition, parenteral solutions can also include preservatives, such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol.

[0093] For inhalation administration, the compound of the present invention can be conveniently delivered in the form of a spray from a pressurized package or a nebulizer. The compound can also be delivered in the form of a powder for preparation, and the powder composition can be inhaled with the help of a powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which can be formulated into a suspension or solution of the compound of formula I in a suitable propellant, such as a fluorocarbon or a hydrocarbon. For eye administration, ophthalmic preparations can be prepared with a solution or suspension of a suitable weight percentage of the compound of formula I in a suitable ophthalmic carrier, thereby keeping the compound in contact with the surface of the eye for enough time to allow the compound to penetrate into the cornea and the inner area of ​​the eye.

[0094] Useful pharmaceutical dosage forms for administering the compounds of the present invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injection solutions, and oral suspensions.

[0095] When the compounds of the present invention are administered stepwise or in combination with other therapeutic agents, the same dosage forms as described above may be used. When the drugs are administered in physical combination, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. The compounds of the present invention may be administered as the sole active ingredient or in combination with a second active ingredient, including active ingredients known to be useful for treating related diseases.

[0096] In a twelfth aspect, the present invention provides a method for regulating (e.g., down-regulating) the activity of a protein kinase, comprising contacting the protein kinase with an effective amount of the above-mentioned imidazolones, their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs. The method can be used in vivo or in vitro. Preferably, the protein kinase is selected from at least one of ATM, ATR, mTOR and DNA-PK.

[0097] In a thirteenth aspect, the present invention provides a method for repairing DNA damage, comprising administering to an individual an effective amount of the protein kinase and an effective amount of the above-mentioned imidazolones, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof. The method can be used in vivo or in vitro. The individual can be a mammal, such as a human.

[0098] In a fourteenth aspect, the present invention provides a method for treating ATM kinase, ATR kinase, mTOR kinase, DNA-PK kinase or a disease mediated by DNA damage, the method comprising administering to an individual an effective amount of the protein kinase and an effective amount of the above-mentioned compound, its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug. The method can be used in vivo or in vitro. The individual can be a mammal, such as a human.

[0099] The pharmaceutical composition is a unit dosage form suitable for single administration of an exact dose. In other embodiments, the amount of the compound is in the range of about 0.001 mg / kg body weight / day to about 1000 mg / kg body weight / day. In other embodiments, the amount of the compound ranges from about 0.5 mg / kg body weight / day to about 50 mg / kg body weight / day. In some embodiments, the amount of the compound is about 0.001 g / day to about 7 g / day. In other embodiments, the amount of the compound is about 0.002 g / day to about 6 g / day. In other embodiments, the amount of the compound is about 0.005 g / day to about 5 g / day. In other embodiments, the amount of the compound is about 0.01 g / day to about 5 g / day. In other embodiments, the amount of the compound is about 0.02 g / day to about 5 g / day. In other embodiments, the amount of the compound is about 0.05 g / day to about 2.5 g / day. In other embodiments, the amount of the compound is about 0.1 g / day to about 1 g / day. In other embodiments, dosage levels below the lower limit of the above range may be sufficient. In other embodiments, dosage levels above the upper limit of the above range may be required. In some embodiments, the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses, more than once a day. In some embodiments, the compound is administered twice a day. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day. In some embodiments, the individual to whom the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.

[0100] Terminology Note:

[0101] Unless otherwise defined, all technical terms herein have the same meaning as those commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent inventions, and public materials cited throughout this article are incorporated herein by reference in their entirety. If there are multiple definitions of a term in this article, the definition in this chapter shall prevail.

[0102] It should be understood that the above brief description and the following detailed description are exemplary and are only used for explanation, and do not limit the subject matter of the present invention in any way. In the present invention, unless otherwise specifically stated, the use of the singular also includes the plural. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

[0103] Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the descriptions in a plurality of summary and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0104] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2.

[0105] Unless otherwise indicated, the general chemical terms used, such as but not limited to, "alkyl", "amine", "aryl" are equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.

[0106] The term "optional / arbitrary" or "optionally / arbitrarily" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, according to the definition below, "optionally substituted alkyl" means "unsubstituted alkyl" (alkyl not substituted by substituents) or "substituted alkyl" (alkyl substituted by substituents).

[0107] The C1-C n Including C1-C2, C1-C3, ... C1-C n. For example, the "C1-C4" group refers to a group having 1-4 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, for example, "C1-C4 alkyl" refers to an alkyl group having 1-4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Numerical ranges herein, such as "1-10" refer to individual integers in a given range, such as "1-10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0108] The term "alkyl" used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein preferably may have 1 to about 20 carbon atoms, for example, 1 to about 10 carbon atoms, 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms, or 1 to about 3 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl, etc. When a group as defined herein, such as "alkyl" appears in a numerical range, for example, "C1-C6 alkyl" or "C1-C6 alkyl" 1-6 The term "alkyl" refers to an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkyl group herein also includes the case where no numerical range is specified.

[0109] The "alkyl" used in combination herein refers to an alkyl group linked to other groups, such as the alkyl group in alkoxy, the alkyl group in alkylthio, the hydroxyalkyl group, the haloalkyl group, the cyanoalkyl group, the monoalkylamino group, the dialkylamino group, and the like.

[0110] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group (O-alkyl). Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0111] The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon group having at least one C=C double bond. The alkenyl group has, but is not limited to, 2 to about 18 carbon atoms, for example, 2 to about 10 carbon atoms, or 2 to about 8 carbon atoms, 2 to about 6 carbon atoms, 2 to about 4 carbon atoms. The double bonds in these groups can be in cis or trans conformations and should be understood to include the two isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl and 1,3-butadienyl, etc. When a numerical range appears for an alkenyl group as defined herein, for example, "C2-C6 alkenyl" or "C 2-6 The term "alkenyl" refers to an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkenyl group herein also includes the case where no numerical range is specified.

[0112] The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted linear or branched monovalent hydrocarbon group having at least one C≡C triple bond. The alkynyl group has, but is not limited to, 2 to about 18 carbon atoms, for example, 2 to about 10 carbon atoms, or 2 to about 8 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, etc. When a numerical range appears for an alkynyl group as defined herein, for example, "C2-C6 alkynyl" or "C 2-6 The term "alkynyl" refers to an alkynyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkynyl group herein also includes the case where no numerical range is specified.

[0113] The term "halo" or "halogen-substituted" as used herein, alone or in combination, refers to an optionally substituted group (such as alkyl, alkenyl, and alkynyl) in which at least one hydrogen atom is replaced with a halogen (such as fluorine, chlorine, bromine, iodine, or a combination thereof). In some embodiments, two or more hydrogens are replaced with halogens that are identical to each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogens are replaced with halogens that are not identical to each other (e.g., 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl are fluoromethyl and bromoethyl. Non-limiting examples of haloalkenyl are bromoethenyl. Non-limiting examples of haloalkynyl are chloroethynyl.

[0114] The term "aromatic group / aryl" used herein alone or in combination refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20, such as 6 to 12 or 6 to 10 ring-forming carbon atoms, which can be a monocyclic aromatic group, a bicyclic aromatic group or a polycyclic aromatic group. A bicyclic aromatic group or a polycyclic aromatic group can be a monocyclic aromatic group fused with other independent rings, such as an alicyclic ring, a heterocyclic ring, an aromatic ring, or an aromatic heterocyclic ring. Non-limiting examples of monocyclic aromatic groups include monocyclic aromatic groups having 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms, such as phenyl; bicyclic aromatic groups are, for example, naphthyl; polycyclic aromatic groups are, for example, phenanthrenyl, anthracenyl, and azulenyl.

[0115] The term "heteroaryl" used herein alone or in combination refers to an arbitrarily substituted heteroaryl group containing about 5 to about 20, such as 5 to 12 or 5 to 10 skeleton ring atoms, wherein at least one (such as 1-4, 1-3, 1-2) ring atom is a heteroatom, and the heteroatom is independently selected from the heteroatoms in oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited thereto. The ring of the group does not contain two adjacent O or S atoms. Heteroaryl includes monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings) or polycyclic heteroaryl (having more than two rings). In embodiments where two or more heteroatoms appear in the ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. Bicyclic heteroaryl or more cyclic heteroaryl may be a monocyclic heteroaryl fused with other independent rings, such as alicyclic, heterocyclic, aromatic, aromatic heterocyclic (collectively referred to as fused ring heteroaryl). Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups having 5 to about 12, 5 to about 10, 5 to about 7 or 6 backbone ring atoms, for example, non-limiting examples thereof include pyridinyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl. Other examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, indole, indazole, quinoline, isoquinoline, purine, carbazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine, and the like; acridinyl, phenazinyl, benzoxazolyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, isoquinolinyl, indolizinyl, isothiazolyl, and the like. The invention also includes oxadiazolyl, isothiazolyl, isoindolyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl, quinazolinyl, quinoxalinyl, triazinyl and thiadiazolyl, and oxides thereof, such as pyridyl N-oxide, and the like.

[0116] The term "heterocycle" or "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocycle, including a saturated heterocycle or an unsaturated heterocycle (containing an unsaturated bond). One or more (e.g., 1-4, 1-3, 1-2) of the atoms forming the ring are heteroatoms, such as oxygen, nitrogen or sulfur atoms. The heterocycle may include a monocyclic heterocycle (having one ring) or a bicyclic heterocycle (having two bridged rings) or a polycyclic heterocycle (having more than two bridged rings); spirocycles are also included. The heterocyclic group may have 3 to about 20, such as 3 to about 10, 3 to about 8, 4 to 8, 4 to 7, 5 to about 8 or 5 to about 6 ring-forming atoms. Non-limiting examples of heterocyclic groups include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiocyclohex ... The term also includes saccharides such as thiazolinyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolizinyl. The term also includes all cyclic forms of saccharides, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Examples also include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidinyl, and the like.Heterocyclic groups also include heterocyclic rings with one or more aromatic rings fused (i.e., having a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzodioxolane, benzo-1,4-dioxane, phthalimide, and naphthalimide. Heterocyclic groups with one or more aromatic fusions can be connected to other groups through aromatic rings or non-aromatic rings. Other groups can be combined with heterocyclic rings through heteroatoms or carbon atoms (i.e., heterocyclic rings are connected to the parent molecule or further substituted).

[0117] The term "carbocycle" or "carbocyclyl" used herein alone or in combination refers to a non-aromatic carbon-containing ring, including a saturated carbocycle (such as a cycloalkyl) or an unsaturated carbocycle (such as a cycloalkenyl). Carbocycles include monocarbocycles (having one ring), for example, monocyclic cycloalkyls; bicarbocycles (having two rings), for example, bicyclic cycloalkyls; polycarbocycles (having more than two rings). Between the rings can be bridged or spirocycles. Carbocycles (such as cycloalkyl or cycloalkenyl) can have 3 to 20 carbon atoms, for example, 3-about 15 ring-forming carbon atoms or 3-about 10 ring-forming carbon atoms or 3-6 ring-forming carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, adamantyl, etc.

[0118] "Halogen" refers to fluorine, chlorine, bromine, and iodine. Fluorine, chlorine, and bromine are preferred. Cyano refers to "-CN"; hydroxyl refers to "-OH"; mercapto refers to "-SH"; and amino refers to "-NH2".

[0119] The term "substituted" means that one or more hydrogens on a specified atom are replaced with the specified radicals and if the normal valency of the specified atom is not exceeded under existing conditions, the substitution results in a stable compound.

[0120] Unless explicitly stated, all ranges listed herein are inclusive. For example, "the value of n is an integer between 0 and 2" means that n can be 0, 1 or 2.

[0121] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be easily prepared from an inorganic base or an organic base. Salts derived from such inorganic bases include salts of aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganous), potassium, sodium, zinc, etc. Preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Salts prepared from organic bases include primary, secondary and tertiary amines derived from natural and synthetic sources. Pharmaceutically acceptable organic non-toxic bases that can form salts include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compound of the present invention is basic, its corresponding salt can be easily prepared from inorganic or organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0122] The term "solvate" refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula I) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is referred to as a hydrate. Hydrates include, but are not limited to, hemihydrates, monohydrates, one and a half hydrates, dihydrates, and trihydrates.

[0123] The term "prodrug" is a functional derivative of a compound of the invention that is easily converted into the desired compound in vivo. Various prodrug forms are well known in the art. See, for example, Pro-drugs as Novel Delivery Systems (1987) Vol. 14 of the ACSSymposium Series by T. Higuchi and V. Stella, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press for a discussion of prodrugs. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, the above documents are incorporated herein by reference.

[0124] "Subject", "patient" or "individual" refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0125] The term "treat" and other similar synonyms include relieving, alleviating or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a prophylactic effect. The therapeutic effect refers to the cure or improvement of the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve. In terms of a prophylactic effect, the composition can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not yet been made, the composition can be administered to a patient who has one or more physiological symptoms of the disease.

[0126] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

[0127] As used herein, the terms "administering", "administering", "dosing", etc. refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0128] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no long-term detrimental effect on the general health of the subject being treated.

[0129] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0130] The term "pharmaceutical composition" refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients.

[0131] The term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0132] The term "metabolic disease" refers to diseases caused by metabolic problems, including metabolic disorders and hypermetabolism, mainly including the following diseases: diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, osteoporosis, etc.

[0133] The term "cardiovascular disease" is also called circulatory system disease. It is a series of diseases involving the circulatory system. The circulatory system refers to the organs and tissues in the human body that transport blood, mainly including the heart and blood vessels (arteries, veins, capillaries). It can be subdivided into acute and chronic, and is generally related to arteriosclerosis. Cardiovascular diseases include: heart disease, hypotension, hypertension, hyperglycemia, stroke, myocardial infarction, thrombosis, arteriosclerosis, etc.

[0134] The beneficial effects of the present invention are as follows: the present invention provides an imidazolones compound with a new structure and a preparation method thereof, which has a significant inhibitory effect on the expression of multiple protein kinases and has inhibitory activity on multiple tumor cells. DETAILED DESCRIPTION

[0135] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present application.

[0136] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0137] The compounds of the present invention having the various formulas described herein can be prepared from commercially available starting materials or starting materials that can be prepared using literature processes according to the processes described in the following general synthetic routes 1-7. The variables (e.g., R1, R2, and R3, etc.) in each general synthetic route are as defined herein. One of ordinary skill in the art should note that in the reaction procedures and synthetic schemes described herein, the order of certain steps may vary, such as the introduction and removal of protecting groups.

[0138] General synthetic route 1

[0139]

[0140] General synthetic route 2

[0141]

[0142] General synthetic route 3

[0143]

[0144] General synthetic route 4

[0145]

[0146] It is worth noting that intermediate 4500 in the present invention is Example 56 of patent WO2014079364A1, and the synthesis method and route are exactly the same; intermediate 9a is intermediate 9A of patent CN104447740A, and the synthesis method and route are the same as intermediate 9A; intermediate 208d is intermediate 208 of patent CN104447740A, and the synthesis method and route are the same as intermediate 208.

[0147] Example 1 Synthesis of Compound FP-286 (4005)

[0148]

[0149] Intermediate 4000: 2-(4-((6-chloro-3-nitro-1,5-naphthyridin-4-yl)amino)phenyl)-2-methylpropionitrile

[0150]

[0151] Dissolve 5.0g (31.2mmol) of 2-(4-aminophenyl)-2-methylpropionitrile in 40mL of acetic acid, add 7.6g (31.1mmol) of 2,8-dichloro-7-nitro-1,5-naphthyridine, stir at room temperature for 5 hours, and solid precipitates. TLC detection, filter after the reaction, wash the filter cake with acetic acid, and vacuum dry the filter cake to obtain 10.6g of yellow powder product, with a yield of 92.6%. LC-MS (ESI) m / z: 368.1, 370.1 [M+H] + .

[0152] Intermediate 4001: 2-(4-((3-amino-6-chloro-1,5-naphthyridin-4-yl)amino)phenyl)-2-methylpropionitrile

[0153]

[0154] 5.6 g (15.23 mmol) of intermediate 4000 was dissolved in 50 mL of tetrahydrofuran, 0.56 g of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and after the reaction was completed, the platinum carbon was filtered out, and the filtrate was dried to obtain 5.14 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 338.1, 340.1 [M+H] + .

[0155] Intermediate 4002: 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)phenyl)-2-methylpropionitrile

[0156]

[0157] Under an ice-water bath, 5.14 g (15.2 mmol) of intermediate 4001 was dissolved in 30 mL of dichloromethane, and then 3.1 g (30.4 mmol) of triethylamine was added. Then, 20 mL of triphosgene (1.63 g, 5.5 mmol) in dichloromethane was added dropwise to the system, and the reaction was stirred for 3 hours under an ice bath. After the reaction was completed, 60 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, stirred for 10 minutes, and the organic phase was separated. The aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V / V) to obtain 3.8 g of a yellow powder product with a yield of 68.7%. LC-MS (ESI) m / z: 364.1, 366.1 [M+H] + .

[0158] Intermediate 4003: 2-(4-(8-chloro-3-methyl-2-oxo-2,3-dihydro-1H-imidazole[4,5-c][1,5]naphthyridin-1-yl)phenyl)-2-methylpropionitrile

[0159]

[0160] 3.8g (10.5mmol) of intermediate 4002 was dissolved in 50mL of dichloromethane, 0.034g (0.105mmol) of tetrabutylammonium bromide and 50mL of sodium hydroxide aqueous solution (10%) were added, and the mixture was stirred for 10 minutes, and then 4.5g (31.5mmol) of iodomethane was added, and the mixture was stirred at room temperature for 4 hours. TLC was used for detection. After the reaction was completed, the mixture was allowed to stand and the layers were separated. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined and dried, filtered, and the filtrate was dried to obtain 2.7g of a yellow solid product with a yield of 68.1%. LC-MS (ESI) m / z: 378.1, 380.1 [M+H] + .

[0161] Intermediate 4004: tert-butyl (5-(1-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-8-yl)pyridin-2-yl]carbamate

[0162]

[0163] Under nitrogen protection, 200 mg (0.53 mmol) of intermediate 4003 and 253 mg (0.79 mmol) of 2-(BOC-amino)pyrrolidine-5-boronic acid pinacol ester were dissolved in 15 mL of dioxane, and 518 mg (1.59 mmol) of cesium carbonate, 5 mL of 2M sodium carbonate aqueous solution and 56 mg (0.053 mmol) of [1,1-bis(di-phenylphosphino)ferrocene]palladium chloride were added in sequence, and stirred at 110°C for 5 hours. TLC detection, after the reaction was completed, most of the solvent was removed by concentration, diluted with water, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, V:V) to obtain 150 mg of a khaki powder product with a yield of 52.8%. LC-MS (ESI) m / z: 536.2 [M+H] + .

[0164] Compound 4005: 2-(4-(8-(6-aminopyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazole[4,5-c][1,5]naphthyridin-1-yl)phenyl)-2-methylpropionitrile

[0165]

[0166] 150 mg (0.28 mmol) of intermediate 4004 was dissolved in 2.5 mL of methanol, and 2.5 mL of 2M hydrogen chloride in 1,4-dioxane solution was added thereto. The mixture was stirred at room temperature for 4 hours, and solids precipitated. TLC detection was performed, and after the reaction was completed, the mixture was filtered, and the filter cake was washed with a small amount of methanol. The pH value was then adjusted to 8-9 with a saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solid was filtered and discarded. The filtrate was dried to obtain a crude product, which was purified by preparative TLC (dichloromethane / methanol = 10 / 1, V:V) to obtain 90 mg of a yellow powder product with a yield of 73.8%. LC-MS (ESI) m / z: 436.2 [M+H] + .

[0167] 1 H NMR (600MHz, DMSO) δ9.31(s,1H),8.74(d,J=1.9Hz,1H),8.64(d,J=9.1Hz,1H),8.35(d,J=9.1Hz,1H),7.89(d d,J=8.9,2.4Hz,1H),7.80-7.79(m,2H),7.71-7.69(m,2H),6.87(d,J=9.4Hz,1H),3.66(s,3H),1.86(s,6H).

[0168] Example 2 Synthesis of Compound FP-309 (4105)

[0169]

[0170] Intermediate 4101: 6-Bromo-N-(4-tert-butyl)phenyl-3-nitroquinolin-4-amine

[0171]

[0172] 2.6g (9.0mmol) of compound 6-bromo-4-chloro-3-nitroquinoline and 1.5g (10.0mmol) of 4-(tert-butyl)aniline were dissolved in 20mL of glacial acetic acid and stirred at room temperature overnight. TLC detection, after the reaction was completed, water was added to dilute, and a large amount of solid precipitated, filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.6g of yellow solid product, with a yield of 99.5%. LC-MS (ESI) m / z: 400.2, 402.2 [M+H] + .

[0173] Intermediate 4102: 6-Bromo-N 4 (4-(tert-Butyl)phenyl)-quinoline-3-4-diamine

[0174]

[0175] 3.6 g (9.0 mmol) of intermediate 4101 was dissolved in 20 mL of tetrahydrofuran, 0.5 g of platinum carbon (5%) was added, hydrogen was introduced, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 3.0 g of a dark yellow solid product with a yield of 90.1%. LC-MS (ESI) m / z: 370.2, 372.2 [M+H] + .

[0176] Intermediate 4103: 8-Bromo-1-(4-(tert-butyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0177]

[0178] 3.0 g (8.1 mmol) of intermediate 4102 was dissolved in 10 mL of dichloromethane, and 10 mL of triphosgene (1.2 g, 4.05 mmol) in dichloromethane was added dropwise thereto, and stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added to the reaction solution and stirred for 10 minutes. Solids precipitated, and the solids were collected by filtration and dried under reduced pressure to obtain 2.5 g of a yellow powdery solid product with a yield of 77.9%. LC-MS (ESI) m / z: 396.2, 398.2 [M+H] + .

[0179] Intermediate 4104: 8-Bromo-1-(4-(tert-butyl)phenyl)-3-methyl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

[0180]

[0181] 2.5 g (6.3 mmol) of intermediate 4103 was dissolved in 100 mL of dichloromethane, 0.24 g (0.75 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added, and the mixture was stirred for 10 minutes, and then 1.41 mL (22.6 mmol) of iodomethane was added, and the mixture was stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the mixture was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.0 g of a yellow solid product with a yield of 77.2%. LC-MS (ESI) m / z: 410.2, 412.2 [M+H] + .

[0182] Compound 4105: 1-(4-(tert-butyl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0183]

[0184] Under nitrogen protection, 100 mg (0.24 mmol) of intermediate 4104 and 75 mg (0.26 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, and 50 mg (0.4 mmol) of sodium carbonate, 2 mL of water and 13.86 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were added in sequence, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 18 mg of a white solid product with a yield of 15.4%. LC-MS (ESI) m / z: 489.3 [M+H] + .

[0185] 1 H NMR (600MHz, DMSO) δ9.00(s,1H),8.42(d,J=2.0Hz,1H),8.26(s,1H),8.11(d,J=8.9Hz,1H),7.97(s,1H),7.75(d,J=8.4Hz,2H),7.70(dd,J=8.3 ,2.3Hz,1H),7.59(d,J=8.1Hz,2H),7.53(d,J=8.5Hz,1H),7.44(d,J=8.5Hz,1H),7.12(d,J=1.6Hz,1H),3.90(s,3H),3.61(s,3H),1.45(s,9H).

[0186] Example 3 Synthesis of Compound FP-310 (4201)

[0187]

[0188] Product 4201: 8-(6-aminopyridin-3-yl)-1-(4-(tert-butyl)phenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0189] 5 ml of tert-butyl alcohol, 100 mg (0.24 mmol) of intermediate 4104, 80 mg (0.37 mmol) of 2-aminopyridine-5-boronic acid pinacol ester, 51 mg (0.48 mmol) of Na2CO3, 1 ml of water and 35 mg (0.03 mmol) of Pd(PPh3)4 were added to the reaction bottle in sequence, and heated to 80°C in a N2 atmosphere and stirred to react overnight. TLC detection, after the reaction is completed, the solvent is concentrated to remove, and then 20 ml of water is added to dilute, and then 20 ml of dichloromethane is added to extract the aqueous phase, the organic phase is dried over anhydrous sodium sulfate and filtered, and the filtrate is concentrated to obtain a crude product. The crude product is purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1, V / V) to obtain 36.7 mg of the product, with a yield of 36.1%. LC-MS (ESI): 424.3 [M+H] + .

[0190] 1 H NMR (600MHz, DMSO) δ9.47(s,1H),8.52(d,J=8.9Hz,1H),8.29(d,J=2.0Hz,1H),8.22(d,J=9.1Hz,1H),7.79(d,J=8.5Hz,2H) ,7.65(d,J=8.4Hz,2H),7.46(dd,J=9.3,2.2Hz,1H),7.08(d,J=1.8Hz,1H),7.06(d,J=9.3Hz,1H),3.67(s,3H),1.42(s,9H).

[0191] Example 4 Synthesis of Compound FP-313 (4305)

[0192]

[0193] Intermediate 4301: 4-((6-bromo-3-nitroquinolin-4-yl)amino)-N,N-dimethylbenzamide

[0194]

[0195] Add 10ml DMF (N,N-dimethylformamide), 1.75g ​​(6.09mmol) 6-bromo-4-chloro-3-nitroquinoline, 1g (6.09mmol) compound 4-amino-N,N-dimethylbenzamide and 1g (9.88mmol) triethylamine to the reaction bottle in sequence, and stir at room temperature to react overnight. TLC detection, after the reaction is completed, add 20ml water to dilute, a yellow solid precipitates, continue stirring for 20min, filter, discard the filtrate, and dry the filter cake to obtain 1.4g yellow solid product, with a yield of 55.4%. LC-MS (ESI): 415.1, 417.1 [M+H] + .

[0196] Intermediate 4302: 4-((3-amino-6-bromoquinolin-4-yl)amino)-N,N-dimethylbenzamide

[0197]

[0198] 20 ml of tetrahydrofuran, 1.0 g (2.41 mmol) of intermediate 4301 and 0.2 g of platinum carbon were added to the reaction bottle in sequence, hydrogen was introduced, and the reaction was stirred at room temperature for 24 hours. TLC detection was performed, and after the reaction was completed, the solid was discarded, and the filtrate was concentrated under reduced pressure to obtain 0.93 g of a light yellow solid product with a yield of 100%. LC-MS (ESI): 385.1, 387.1 [M+H] + .

[0199] Intermediate 4303: 4-(8-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N,N-dimethylbenzamide

[0200]

[0201] 0.8 g (2.08 mmol) of intermediate 4302 was dissolved in 10 ml of dichloromethane, and then 10 ml of triphosgene (0.37 g, 1.25 mmol) in dichloromethane was added dropwise. After the addition was complete, the reaction was stirred at room temperature overnight. TLC was performed. After the reaction was completed, 20 ml of petroleum ether was added. Solids precipitated, filtered, the filtrate was discarded, and the filter cake was dried to obtain 0.86 g of a yellow solid product with a yield of 100%. LC-MS (ESI): 411.1, 413.1 [M+H] + .

[0202] Intermediate 4304: 4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N,N-dimethylbenzamide

[0203]

[0204] 10 ml of dichloromethane, 0.86 g (2.08 mmol) of intermediate 4303, 0.068 g (0.21 mmol) of tetrabutylammonium bromide, 0.92 g (6.48 mmol) of iodomethane and 10 ml of NaOH aqueous solution (10%) were added to the reaction flask in sequence, stirred evenly and reacted at room temperature for 8 hours. TLC detection, after the reaction was completed, 20 ml of water was added to dilute the reaction solution, and then 40 ml of dichloromethane was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1, V / V) to obtain 0.42 g of a red solid product with a yield of 47.5%. LC-MS (ESI): 425.1, 427.1 [M+H] + .

[0205] Compound 4305: N,N-Dimethyl-4-(3-methyl-8-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzamide

[0206]

[0207] 10 ml of tert-butyl alcohol, 100 mg (0.24 mmol) of intermediate 4304, 71 mg (0.25 mmol) of 9a, 53 mg (0.5 mmol) of Na2CO3, 2 ml of water and 29 mg (0.025 mmol) of Pd(PPh3)4 were added to the reaction bottle in sequence, stirred evenly, heated to 80°C in a N2 atmosphere and stirred to react overnight. TLC detection, after the reaction is completed, the solvent is concentrated to remove, and then 20 ml of water is added to dilute, and then 40 ml of dichloromethane is added to extract the aqueous phase, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain a crude product, which is purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1, V / V) to obtain 30 mg of the product, with a yield of 24.8%. LC-MS (ESI): 504.3 [M+H] + .

[0208] 1H NMR (600MHz, DMSO) δ9.02(s,1H),8.48-8.46(m,1H),8.30(s,1H),8.14(d,J=8.8Hz,1H),8.02(d,J=0.6Hz,1H),7.95(dd,J=8.9,2.0 Hz,1H),7.77-7.70(m,5H),7.61(dd,J=8.2,0.5Hz,1H),7.30(d,J=1.9Hz,1H),3.91(s,3H),3.62(s,3H),3.08(s,3H),3.01(s,3H).

[0209] Example 5 Synthesis of FP-318 (4405)

[0210]

[0211] Intermediate 4401: 1-(4-((6-bromo-3-nitroquinolin-4-yl)amino)phenyl)ethan-1-one

[0212]

[0213] 2.6 g (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.5 g (11.1 mmol) of 4-aminoacetophenone were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added to precipitate the solid, which was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.5 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 386.2, 388.2 [M+H] + .

[0214] Intermediate 4402: 1-(4-((3-amino-6-bromoquinolin-4-yl)amino)phenyl)ethan-1-one

[0215]

[0216] 2.4 g (6.2 mmol) of intermediate 4401 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.2 g of dark yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 356.2, 358.2 [M+H] + .

[0217] Intermediate 4403: 1-(4-acetylphenyl)-8-bromo-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0218]

[0219] 2.2 g (6.2 mmol) of intermediate 4402 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solid was precipitated, and the precipitate was collected by filtration and dried under reduced pressure to obtain 2.3 g of yellow powder product with a yield of 97.4%. LC-MS (ESI) m / z: 382.2, 384.2 [M+H] + .

[0220] Intermediate 4404: 1-(4-Acetylphenyl)-8-bromo-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0221]

[0222] 2.3 g (6.0 mmol) of intermediate 4403 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added thereto, and stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, and the organic phase was separated. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.0 g of a yellow solid product with a yield of 84.0%. MS (ESI) m / z: 396.2, 398.2 [M+H] + .

[0223] Compound 4405: 1-(4-acetylphenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0224]

[0225] Under nitrogen protection, 100 mg (0.25 mmol) of intermediate 4404 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 13 mg of a white solid product with a yield of 10.9%. LC-MS (ESI) m / z: 475.2 [M+H] + .

[0226] 1 H NMR (600MHz, DMSO) δ9.04(s,1H),8.49(d,J=1.9Hz,1H),8.30(s,1H),8.28(d,J=8.4Hz,2H),8.15(d,J=8.8Hz,1H),8.01(s,1H),7.96(dd,J=8.9,1 .9Hz, 1H), 7.86 (d, J=8.4Hz, 2H), 7.71 (dd, J=8.3, 2.4Hz, 1H), 7.63 (d, J= 8.2Hz,1H),7.27(d,J=1.7Hz,1H),3.89(s,3H),3.62(s,3H),2.74(s,3H).

[0227] Example 6 Synthesis of Compound FP-334 (4501)

[0228] Compound 4501: 2-Methyl-2-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)phenyl)propanamide

[0229]

[0230] 100 mg (0.2 mmol) of compound 4500 was added to 2 mL of concentrated hydrochloric acid and stirred at 60 ° C for 12 hours. After the reaction was completed, the solution was dried to obtain a solid, and then the pH value was adjusted to 8-9 with a saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was dried to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane / methanol=10 / 1, V / V) to obtain 12 mg of a white powder product with a yield of 11.6%. LC-MS (ESI) m / z: 519.2 [M+H]+ .

[0231] 1 H NMR (600MHz, DMSO) δ9.07(s,1H),8.57(d,J=1.8Hz,1H),8.46(d,J=8.9Hz,1H),8.29(d,J=9.0Hz,1H),8.27(s,1H),8.1 9(dd,J=8.4,2.4Hz,1H),8.03(s,1H),7.67(d,J=8.3Hz,1H),7.59-7.53(m,4H),3.92(s,3H),3.64(s,3H),1.65(s,6H).

[0232] Example 7 Synthesis of Compound FP-337 (4605)

[0233]

[0234] Intermediate 4601: 1-(4-((6-bromo-3-nitroquinolin-4-yl)amino)phenyl)ethanol

[0235]

[0236] 1g (3.48mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.57g (4.17mmol) of 1-(4-aminophenyl)ethanol were dissolved in 10mL of dichloromethane, and 0.70g (6.96mmol) of triethylamine was added thereto. The mixture was stirred overnight at room temperature, and solid was precipitated. After TLC detection, the reaction was filtered, the filter cake was washed with dichloromethane, and the filter cake was dried under vacuum to obtain 1.1g of yellow solid product with a yield of 81.5%. LC-MS (ESI) m / z: 388.1, 390.1 [M+H] + .

[0237] Intermediate 4602: 1-(4-((3-amino-6-bromoquinolin-4-yl)amino)phenyl)ethanol

[0238]

[0239] 1.1 g (2.83 mmol) of intermediate 4601 was dissolved in 10 mL of ethanol, 0.11 g of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature for 12 hours. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with a small amount of ethanol, and the filtrate was dried to obtain 1.0 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 358.1, 360.1 [M+H] + .

[0240] Intermediate 4603: 8-Bromo-1-(4-(1-hydroxyethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0241]

[0242] Under ice water bath, 1.0g (2.79mmol) of intermediate 4602 was dissolved in 10mL of dichloromethane, 0.98g (9.7mmol) of triethylamine was added, 10mL of triphosgene (0.31g, 1.03mmol) in dichloromethane solution was added dropwise, and the reaction was stirred at room temperature for 5 hours, and solid precipitated. TLC detection, after the reaction was completed, the filter cake was washed with a small amount of dichloromethane, and the filter cake was dried to obtain 0.8g of product, with a yield of 74.6%. LC-MS (ESI) m / z: 384.1, 386.1 [M+H] + .

[0243] Intermediate 4604: 8-Bromo-1-(4-(1-hydroxyethyl)phenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0244]

[0245] 0.8 g (2.08 mmol) of intermediate 4603 was added to 10 mL of N, N-dimethylformamide, followed by 0.58 g (4.16 mmol) of potassium carbonate. After stirring for 10 minutes, 0.59 g (4.16 mmol) of iodomethane was added and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 0.6 g of a yellow solid product with a yield of 72.5%. LC-MS (ESI) m / z: 398.1, 400.1 [M+H] + .

[0246] Compound 4605: 1-(4-(1-hydroxyethyl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0247]

[0248] Under nitrogen protection, 0.1 g (0.25 mmol) of intermediate 4604 and 0.11 g (0.37 mmol) of intermediate 9a were dissolved in 10 mL of 1,4-dioxane, and then 0.24 g (0.75 mmol) of cesium carbonate, 1 mL of 2M sodium carbonate aqueous solution and 0.024 g (0.025 mmol) of [1,1-bis (di-phenylphosphino) ferrocene] palladium chloride were added thereto in sequence, and the reaction was stirred at 110 ° C for 5 hours. TLC detection, after the reaction was completed, most of the solvent was concentrated to remove, the residue was diluted with water, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane / methanol = 10 / 1, V / V) to obtain 31 mg of white powder product with a yield of 26.0%. LC-MS (ESI) m / z: 477.2 [M+H] + .

[0249] 1 H NMR (600MHz, DMSO) δ9.50(s,1H),8.49(d,J=9.0Hz,2H),8.46(d,J=2.2Hz,1H),8.45(s,1H),8.36(dd,J=9.0,1.9Hz,1H),8.14(s,1H),7 .79(d,J=9.6Hz,4H),7.71(d,J=1.5Hz,1H),7.24(d,J=1.8Hz,1H),5.04-4.95(m,2H),3.93(s,3H),3.68(s,3H),1.49(d,J=6.5Hz,3H).

[0250] Example 8 Synthesis of Compound FP-342 (4705)

[0251]

[0252] Intermediate 4701: 6-Bromo-3-nitro-N-(6-(trifluoromethyl)pyridin-3-yl)quinolin-4-amine

[0253]

[0254] Dissolve 1g (3.48mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.68g (4.17mmol) of 5-amino-2-trifluoromethylpyridine in 10mL of acetic acid, stir and react overnight at room temperature, and solid precipitates. TLC detection, filter after the reaction, wash the filter cake with glacial acetic acid, and vacuum dry to obtain 1.44g of yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 413.0, 415.0 [M+H] + .

[0255] Intermediate 4702: 6-Bromo-N 4 -(6-(Trifluoromethyl)pyridin-3-yl)quinoline-3,4-diamine

[0256]

[0257] 1.44 g (3.48 mmol) of intermediate 4701 was dissolved in 10 mL of ethanol, 0.15 g of platinum carbon was added, hydrogen was introduced, and the reaction was stirred at room temperature for 12 hours. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with ethanol, and the filtrate was dried to obtain 1.33 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 383.0, 385.0 [M+H] + .

[0258] Intermediate 4703: 8-Bromo-1-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0259]

[0260] Under an ice-water bath, 1.33 g (3.48 mmol) of intermediate 4702 was dissolved in 15 mL of dichloromethane, 1.05 g (10.44 mmol) of triethylamine was added, and then 10 mL of triphosgene (0.35 g, 1.16 mmol) in dichloromethane was added dropwise. The mixture was stirred at room temperature for 5 hours, and solids precipitated. After TLC detection, the reaction was filtered, and the filter cake was washed with dichloromethane. After the filter cake was dried, 0.9 g of the product was obtained, with a yield of 63.2%. LC-MS (ESI) m / z: 409.0, 411.0 [M+H] + .

[0261] Intermediate 4704: 8-Bromo-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0262]

[0263] 0.9 g (2.20 mmol) of intermediate 4703 was added to 10 mL of dichloromethane, 0.07 g (0.22 mmol) of tetrabutylammonium bromide and 10 mL of sodium hydroxide solution (10%) were added, and after stirring for 10 minutes, 0.94 g (6.60 mmol) of methyl iodide was added and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 0.7 g of a yellow solid product with a yield of 75.3%. LC-MS (ESI) m / z: 423.0, 425.0 [M+H] + .

[0264] Compound 4705: 3-Methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0265]

[0266] Under nitrogen protection, 0.1 g (0.24 mmol) of intermediate 4704 and 0.10 g (0.35 mmol) of intermediate 9a were dissolved in 10 mL of 1,4-dioxane, and 0.22 g (0.69 mmol) of cesium carbonate, 1 mL of 2M sodium carbonate aqueous solution and 0.020 g (0.024 mmol) of [1,1-bis (di-phenylphosphino) ferrocene] palladium chloride were added thereto in turn, and the mixture was stirred at 110 ° C for 5 hours. After the reaction was completed, most of the solvent was removed by concentration, water was added for dilution, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane / methanol = 10 / 1, V / V) to obtain 21 mg of a white powder product with a yield of 17.4%. LC-MS (ESI) m / z: 502.2 [M+H] + .

[0267] 1H NMR (600MHz, DMSO) δ9.17 (d, J = 2.3Hz, 1H), 9.07 (s, 1H), 8.56-8.55 (m, 1H), 8. 53(dd,J=8.2,2.2Hz,1H),8.34(d,J=8.4Hz,1H),8.31(s,1H),8.17(d,J=8.8H z,1H),8.01(d,J=0.5Hz,1H),7.98(dd,J=8.9,2.0Hz,1H),7.71(dd,J=8.3,2. 5Hz,1H),7.63-7.59(m,1H),7.18(d,J=1.9Hz,1H),3.90(s,3H),3.63(s,3H).

[0268] Example 9 Synthesis of Compound FP-345 (4805)

[0269]

[0270] Intermediate 4801: 4-((6-bromo-3-nitroquinolin-4-yl)amino)-N-isopropylbenzamide

[0271]

[0272] Dissolve 1g (3.48mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.74g (4.17mmol) of 4-amino-N-isopropylbenzamide in 10mL of acetic acid, stir and react overnight at room temperature, and solid precipitates. After the reaction is completed, filter, wash the filter cake with glacial acetic acid, and vacuum dry the filter cake to obtain 1.49g of yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 429.1, 431.1 [M+H] + .

[0273] Intermediate 4802: 4-((3-amino-6-bromoquinolin-4-yl)amino)-N-isopropylbenzamide

[0274]

[0275] 1.49 g (3.48 mmol) of intermediate 4801 was dissolved in 10 mL of ethanol, 0.16 g of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with a small amount of ethanol, and the filtrate was dried to obtain 1.39 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 399.1, 401.1 [M+H] + .

[0276] Intermediate 4803: 4-(8-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N-isopropylbenzamide

[0277]

[0278] Under ice water bath, 1.39g (3.48mmol) of intermediate 4802 was dissolved in 15mL of dichloromethane, 1.05g (10.44mmol) of triethylamine was added, and 10mL of triphosgene (0.34g, 1.16mmol) in dichloromethane solution was added dropwise, and stirred at room temperature for 5 hours, and solid precipitated. After TLC detection, after the reaction was completed, the reaction was filtered, and the filter cake was washed with a small amount of dichloromethane, and the filter cake was dried to obtain 1.2g of product, with a yield of 81.1%. LC-MS (ESI) m / z: 425.1, 427.1 [M+H] + .

[0279] Intermediate 4804: 4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N-isopropylbenzamide

[0280]

[0281] 1.2 g (2.82 mmol) of intermediate 4803 was added to 12 mL of dichloromethane, followed by 0.09 g (0.28 mmol) of tetrabutylammonium bromide and 12 mL of sodium hydroxide solution (10%). After stirring for 10 minutes, 1.16 g (8.19 mmol) of methyl iodide was added and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 0.9 g of a yellow solid product with a yield of 72.7%. LC-MS (ESI) m / z: 439.1, 441.1 [M+H] + .

[0282] Compound 4805: N-isopropyl-4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzamide

[0283]

[0284] Under nitrogen protection, 100 mg (0.23 mmol) of intermediate 4804 and 100 mg (0.35 mmol) of intermediate 9a were dissolved in 5 mL of dioxane, and then 225 mg (0.69 mmol) of cesium carbonate, 1 mL of 2M sodium carbonate aqueous solution and 19 mg (0.023 mmol) of [1,1-bis (di-phenylphosphino) ferrocene] palladium chloride were added in sequence, and the reaction was stirred at 110 ° C for 5 hours. TLC detection, after the reaction was completed, most of the solvent was removed by concentration, water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane / methanol = 10 / 1, V / V) to obtain 37 mg of white powder product with a yield of 31.1%. LC-MS (ESI) m / z: 518.2 [M+H] + .

[0285] 1 H NMR(600MHz,DMSO)δ9.03(s,1H),8.49-8.46(m,2H),8.28(s,1H),8.19-8.1 5(m,2H),8.14(d,J=8.9Hz,1H),7.97(s,1H),7.95(dd,J=8.9,2.0Hz,1H),7. 81-7.75(m,2H),7.70(dd,J=8.3,2.4Hz,1H),7.60(d,J=8.3Hz,1H),7.23(d, J=1.9Hz,1H),4.19(m,1H),3.89(s,3H),3.62(s,3H),1.22(d,J=6.6Hz,6H).

[0286] Example 10 Synthesis of Compound FP-346 (4905)

[0287]

[0288] Intermediate 4901: 4-((6-bromo-3-nitroquinolin-4-yl)amino)-N-methylbenzamide

[0289]

[0290] Dissolve 1g (3.48mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.63g (4.17mmol) of 4-amino-N-methylbenzamide in 10mL of acetic acid and stir overnight at room temperature to precipitate solids. After the reaction is completed, filter and wash the filter cake with glacial acetic acid and vacuum dry to obtain 1.4g of yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 401.1, 403.1 [M+H] + .

[0291] Intermediate 4902: 4-((3-amino-6-bromoquinolin-4-yl)amino)-N-methylbenzamide

[0292]

[0293] 1.4 g (3.48 mmol) of intermediate 4901 was dissolved in 20 mL of ethanol, 0.17 g of platinum carbon (5%) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with a small amount of ethanol, and the filtrate was dried to obtain 1.29 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 371.1, 373.1 [M+H] + .

[0294] Intermediate 4903: 4-(8-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylbenzamide

[0295]

[0296] Under an ice-water bath, 1.29 g (3.48 mmol) of intermediate 4902 was dissolved in 15 mL of dichloromethane, 1.05 g (10.44 mmol) of triethylamine was added, and 10 mL of triphosgene (0.35 g, 1.16 mmol) in dichloromethane was added dropwise. The mixture was stirred at room temperature for 5 hours, and solids were precipitated. After the reaction was completed, the mixture was filtered, and the filter cake was washed with a small amount of dichloromethane. The filter cake was dried to obtain 0.8 g of the product with a yield of 57.9%. LC-MS (ESI) m / z: 397.1, 399.1 [M+H] + .

[0297] Intermediate 4904: 4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylbenzamide

[0298]

[0299] 0.8 g (2.01 mmol) of intermediate 4903 was added to 10 mL of dichloromethane, followed by 0.064 g (0.20 mmol) of tetrabutylammonium bromide and 10 mL of sodium hydroxide solution (10%). After stirring for 10 minutes, 0.86 g (6.03 mmol) of methyl iodide was added and the mixture was stirred at room temperature for 4 hours. TLC detection: after the reaction was completed, the mixture was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 0.6 g of a yellow solid product with a yield of 72.6%. LC-MS (ESI) m / z: 411.1, 413.1 [M+H] + .

[0300] Compound 4905: N-methyl-4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzamide

[0301]

[0302] Under nitrogen protection, 100 mg (0.24 mmol) of intermediate 4904 and 101 mg (0.36 mmol) of intermediate 9a were dissolved in 5 mL of 1,4-dioxane, and then 233 mg (0.62 mmol) of cesium carbonate, 1 mL of 2M sodium carbonate aqueous solution and 19.5 mg (0.024 mmol) of [1,1-bis (di-phenylphosphino) ferrocene] palladium chloride were added in sequence, and the reaction was stirred at 110 ° C for 5 hours. TLC detection, after the reaction was completed, most of the solvent was removed by concentration, water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane / methanol = 10 / 1, V / V) to obtain 44 mg of white powder product with a yield of 37.0%. LC-MS (ESI) m / z: 490.2 [M+H] + .

[0303] 1H NMR (600MHz, DMSO) δ9.03(s,1H),8.75(q,J=4.4Hz,1H),8.48(d,J=1.8Hz,1H),8.31(s,1H),8.18-8.12(m,3H),8.00(s,1H),7.95(dd,J=8.8,1.6Hz,1 H),7.78(d,J=8.3Hz,2H),7.70(dd,J=8.2,2.2Hz,1H),7.62(d,J=8.2Hz,1 H),7.27(d,J=1.4Hz,1H),3.89(s,3H),3.62(s,3H),2.88(d,J=4.4Hz,3H).

[0304] Example 11 Synthesis of Compound FP-353 (5005)

[0305]

[0306] Intermediate 5001: 6-Bromo-N-(4-fluorophenyl)-3-nitroquinolin-4-amine

[0307]

[0308] 2.6 g (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.2 g (11.1 mmol) of 4-fluoroaniline were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added to precipitate the solid, which was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.3 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 362.0, 364.0 [M+H] + .

[0309] Intermediate 5002: 6-Bromo-N4-(4-fluorophenyl)quinoline-3,4-diamine

[0310]

[0311] 2.2 g (6.6 mmol) of intermediate 5001 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.1 g of dark yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 332.0, 334.0 [M+H] + .

[0312] Intermediate 5003: 8-Bromo-1-(4-fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0313]

[0314] 2.1 g (6.2 mmol) of intermediate 5002 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solid was precipitated, and the precipitate was collected by filtration and dried under reduced pressure to obtain 2.2 g of yellow powder product with a yield of 99.1%. LC-MS (ESI) m / z: 358.1, 360.1 [M+H] + .

[0315] Intermediate 5004: 8-Bromo-1-(4-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0316]

[0317] 2.2 g (6.0 mmol) of intermediate 5003 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added thereto, and stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.0 g of a yellow solid product with a yield of 89.6%. LC-MS (ESI) m / z: 372.0, 374.0 [M+H] + .

[0318] Compound 5005: 1-(4-Fluorophenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0319]

[0320] Under nitrogen protection, 93 mg (0.25 mmol) of intermediate 5004 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 27 mg of a white solid product with a yield of 24%. LC-MS (ESI) m / z: 451.2 [M+H] + .

[0321] 1 H NMR (600MHz, DMSO) δ9.01(s,1H),8.49(d,J=2.2Hz,1H),8.34(s,1H),8.14(d,J=8.8Hz,1H),8.04(s,1H),7.96(dd,J=8.9,2.0Hz,1H) ,7.78-7.75(m,2H),7.75(d,J=2.4Hz,1H),7.69(d,J=8.3Hz,1H),7.61-7.56(m,2H),7.24(d,J=2.0Hz,1H),3.90(s,3H),3.61(s,3H).

[0322] Example 12 Synthesis of Compound FP-356 (5105)

[0323]

[0324] Intermediate 5101: 4-((6-bromo-3-nitroquinolin-4-yl)amino)-3-fluorobenzonitrile

[0325]

[0326] 2.6 g (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.5 g (11.1 mmol) of 4-amino-3-fluorobenzonitrile were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added to precipitate the solid, which was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.5 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 387.1, 389.1 [M+H] + .

[0327] Intermediate 5102: 4-((3-amino-6-bromoquinolin-4-yl)amino)-3-fluorobenzonitrile

[0328]

[0329] 2.4 g (6.2 mmol) of intermediate 5101 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.2 g of dark yellow solid product, with a yield of 100%. MS (ESI) m / z: 357.0, 359.0 [M+H] + .

[0330] Intermediate 5103: 2-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-5-fluorobenzonitrile

[0331]

[0332] 2.2 g (6.2 mmol) of intermediate 5102 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solids were precipitated, and the solids were collected by filtration and dried under reduced pressure to obtain 2.3 g of a yellow powder product with a yield of 96.8%. LC-MS (ESI) m / z: 383.1, 385.1 [M+H] + .

[0333] Intermediate 5104: 2-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-5-fluorobenzonitrile

[0334]

[0335] 2.3 g (6.0 mmol) of intermediate 5103 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added thereto, and stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.0 g of a yellow solid product with a yield of 83.9%. LC-MS (ESI) m / z: 397.0, 399.0 [M+H] + .

[0336] Compound 5105: 5-Fluoro-2-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile

[0337]

[0338] Under nitrogen protection, 100 mg (0.25 mmol) of intermediate 5104 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 15 mg of a white solid product with a yield of 12.6%. LC-MS (ESI) m / z: 476.2 [M+H] + .

[0339] 1 H NMR (600MHz, DMSO) δ9.08(s,1H),8.55(d,J=2.3Hz,1H),8.39(d,J=9.8Hz,1H),8.34(s,1H),8.19(d,J=8.8Hz,1H),8.15-8.09(m,2H) ,8.04(s,1H),8.00(dd,J=8.8,1.8Hz,1H),7.82(dd,J=8.3,2.4Hz,1H),7.70(d,J=8.2Hz,1H),7.30(s,1H),3.90(s,3H),3.64(s,3H).

[0340] Example 13 Synthesis of Compound FP-360 (5205)

[0341]

[0342] Intermediate 5201: 2-(5-((6-bromo-3-nitroquinolin-4-yl)amino)pyridin-2-yl)-2-methylpropionitrile

[0343]

[0344] 2.6g (9.1mmol) 6-bromo-4-chloro-3-nitroquinoline and 1.8g (11.1mmol) 2-(5-aminopyridin-2-yl)-2-methylpropionitrile were dissolved in 20mL glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added for dilution. Solids were precipitated, filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.8g yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 412.1, 414.1 [M+H] + .

[0345] Intermediate 5202: 2-(5-((3-amino-6-bromoquinolin-4-yl)amino)pyridin-2-yl)-2-methylpropionitrile

[0346]

[0347] 2.6 g (6.2 mmol) of intermediate 5201 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.4 g of dark yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 382.1, 384.1 [M+H] + .

[0348] Intermediate 5203: 2-(5-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyridin-2-yl)-2-methylpropionitrile

[0349]

[0350] 2.4 g (6.2 mmol) of intermediate 5202 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solids precipitated, and the solids were filtered and collected. The solids were dried under reduced pressure to obtain 2.5 g of a yellow powder product with a yield of 98.8%. LC-MS (ESI) m / z: 408.1, 410.1 [M+H] + .

[0351] Intermediate 5204: 2-(5-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyridin-2-yl)-2-methylpropionitrile

[0352]

[0353] 2.5 g (6.0 mmol) of intermediate 5203 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide (10%) aqueous solution were added thereto, stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the crude product was obtained by spin drying. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.0 g of yellow solid product, with a yield of 78.9%. LC-MS (ESI) m / z: 422.1, 424.1 [M+H] + .

[0354] Compound 5205: 2-methyl-2-(5-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyridin-2-yl)propanenitrile

[0355]

[0356] Under nitrogen protection, 106 mg (0.25 mmol) of intermediate 5204 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 22 mg of a white solid product with a yield of 17.6%. LC-MS (ESI) m / z: 501.2 [M+H] + .

[0357] 1 H NMR (600MHz, DMSO) δ9.54(s,1H),9.03(d,J=2.1Hz,1H),8.53(d,J=8.3Hz,2H),8.44(s,1H),8.40-8.35(m,2H),8.14( s,1H),8.07(d,J=8.4Hz,1H),7.91(d,J=7.4Hz,1H),7.79(m,1H),7.24(s,1H),3.93(s,3H),3.70(s,3H),1.88(s,6H).

[0358] Example 14 Synthesis of Compound FP-364 (5305)

[0359]

[0360] Intermediate 5301: 6-Bromo-N-(4-methoxyphenyl)-3-nitroquinolin-4-amine

[0361]

[0362] 2.6 g (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.4 g (11.4 mmol) of 4-methoxyaniline were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with water and a large amount of solid was precipitated. The mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.4 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 374.0, 376.0 [M+H] + .

[0363] Intermediate 5302: 6-Bromo-N 4 -(4-Methoxyphenyl)quinoline-3,4-diamine

[0364]

[0365] 2.3 g (6.2 mmol) of intermediate 5301 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.1 g of dark yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 344.1, 346.1 [M+H] + .

[0366] Intermediate 5303: 8-Bromo-1-(4-methoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0367]

[0368] 2.1 g (6.2 mmol) of intermediate 5302 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solids were precipitated, and the solids were collected by filtration and dried under reduced pressure to obtain 2.2 g of a yellow powder product with a yield of 95.9%. LC-MS (ESI) m / z: 370.1, 372.1 [M+H] + .

[0369] Intermediate 5304: 8-Bromo-1-(4-methoxyphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0370]

[0371] 2.2 g (6.0 mmol) of intermediate 5303 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added thereto, stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.0 g of a yellow solid product with a yield of 86.8%. LC-MS (ESI) m / z: 384.1, 386.1 [M+H] + .

[0372] Compound 5305: 1-(4-methoxyphenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0373]

[0374] Under nitrogen protection, 99 mg (0.25 mmol) of intermediate 5304 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 9 mg of a white solid product with a yield of 7.8%. LC-MS (ESI) m / z: 463.2 [M+H] + .

[0375] 1H NMR (600MHz, DMSO) δ9.00(s,1H),8.51(d,J=2.0Hz,1H),8.34(s,1H),8.12(d,J=8.8Hz,1H),8.04(s,1H),7.95(dd,J=8.9,2.0Hz,1H ),7.75(dd,J=8.3,2.4Hz,1H),7.67(d,J=8.2Hz,1H),7.61-7.58(m,2H),7.28-7.25(m,3H),3.93(s,3H),3.90(s,3H),3.60(s,3H).

[0376] Example 15 Synthesis of Compound FP-374 (5405)

[0377]

[0378] Intermediate 5401: 6-Bromo-N-(4-isopropoxyphenyl)-3-nitroquinolin-4-amine

[0379]

[0380] 2.6 g (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.7 g (11.1 mmol) of 4-isopropoxyaniline were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added to precipitate the solid, which was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.7 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 402.1, 404.1 [M+H] + .

[0381] Intermediate 5402: 6-Bromo-N 4 -(4-isopropoxyphenyl)quinoline-3,4-diamine

[0382]

[0383] 2.5 g (6.2 mmol) of intermediate 5401 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.3 g of dark yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 372.1, 374.1 [M+H] + .

[0384] Intermediate 5403: 8-Bromo-1-(4-isopropoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0385]

[0386] 2.3 g (6.2 mmol) of intermediate 5402 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solids were precipitated, and the solids were collected by filtration and dried under reduced pressure to obtain 2.4 g of a yellow powder product with a yield of 96.8%. LC-MS (ESI) m / z: 398.1, 400.1 [M+H] + .

[0387] Intermediate 5404: 8-Bromo-1-(4-isopropoxyphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0388]

[0389] 2.4 g (6.0 mmol) of intermediate 5403 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added thereto, and stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the crude product was obtained by spin drying. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.2 g of yellow solid product, with a yield of 88.9%. LC-MS (ESI) m / z: 412.1, 414.1 [M+H] + .

[0390] Compound 5405: 1-(4-isopropoxyphenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0391]

[0392] Under nitrogen protection, 103 mg (0.25 mmol) of intermediate 5404 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 19 mg of a white solid product with a yield of 15.5%. LC-MS (ESI) m / z: 491.2 [M+H] + .

[0393] 1 H NMR(600MHz,DMSO)δ8.99(s,1H),8.49-8.47(m,1H),8.30(s,1H),8.12(d,J=8 .8Hz,1H),8.01(d,J=0.5Hz,1H),7.94(dd,J=8.9,2.1Hz,1H),7.76(dd,J=8.3, 2.5Hz,1H),7.63(d,J=8.3Hz,1H),7.57-7.53(m,2H),7.24(d,J=2.0Hz,1H),7. 24-7.21(m,2H),4.79(m,1H),3.90(s,3H),3.60(s,3H),1.37(d,J=6.0Hz,6H).

[0394] Example 16 Synthesis of Compound FP-378 (5505)

[0395]

[0396] Intermediate 5501: 6-Bromo-N-(3-fluoro-4-methoxyphenyl)-3-nitroquinolin-4-amine

[0397]

[0398] 2.6 g (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.6 g (11.1 mmol) of 3-fluoro-4-methoxyaniline were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added for dilution. Solids were precipitated, filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.6 g of yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 392.1, 394.1 [M+H] + .

[0399] Intermediate 5502: 6-Bromo-N 4 -(3-Fluoro-4-methoxyphenyl)quinoline-3,4-diamine

[0400]

[0401] 2.4 g (6.2 mmol) of intermediate 5501 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.2 g of dark yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 362.1, 364.1 [M+H] + .

[0402] Intermediate 5503: 8-Bromo-1-(3-fluoro-4-methoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0403]

[0404] 2.2 g (6.2 mmol) of intermediate 5502 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solids were precipitated, and the solids were collected by filtration and dried under reduced pressure to obtain 2.3 g of a yellow powdery solid product with a yield of 96.8%. LC-MS (ESI) m / z: 388.0, 390.0 [M+H] + .

[0405] Intermediate 5504: 8-Bromo-1-(3-fluoro-4-methoxyphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0406]

[0407] 2.3 g (6.0 mmol) of intermediate 5503 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added thereto, and stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, and the organic phase was separated. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.1 g of a yellow solid product with a yield of 87.0%. LC-MS (ESI) m / z: 402.1, 404.1 [M+H] + .

[0408] Compound 5505: 1-(3-Fluoro-4-methoxyphenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0409]

[0410] Under nitrogen protection, 100 mg (0.25 mmol) of intermediate 5504 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 22 mg of a white solid product with a yield of 18.3%. LC-MS (ESI) m / z: 481.2 [M+H] + .

[0411] 1H NMR (600MHz, DMSO) δ8.99(s,1H),8.52(d,J=2.1Hz,1H),8.34(s,1H),8.12(d,J=8.8Hz,1H),8.04(s,1H),7.95(dd,J=8.9,2.0Hz,1H),7.75(dd,J=8 .3,2.5Hz,1H),7.72-7.69(m,1H),7.68(d,J=8.3Hz,1H),7.52(dd,J=3.9, 1.6Hz,2H),7.27(d,J=1.9Hz,1H),4.02(s,3H),3.90(s,3H),3.59(s,3H).

[0412] Example 17 Synthesis of Compound FP-416 (5605)

[0413]

[0414] Intermediate 5601: 6-Bromo-3-nitro-N-(3-(trifluoromethyl)phenyl)quinolin-4-amine

[0415]

[0416] 2.6g (9.1mmol) 6-bromo-4-chloro-3-nitroquinoline and 1.8g (11.1mmol) 3-(trifluoromethyl)aniline were dissolved in 20mL glacial acetic acid and stirred at room temperature overnight. TLC detection, after the reaction was completed, water was added to dilute, a large amount of solid precipitated, filtered, the filter cake was washed with water, and the filter cake was dried to obtain 3.8g of yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 412.0, 414.0 [M+H] + .

[0417] Intermediate 5602: 6-Bromo-N 4 -(3-(Trifluoromethyl)phenyl)quinoline-3,4-diamine

[0418]

[0419] 2.6 g (6.2 mmol) of intermediate 5601 was dissolved in 20 mL of tetrahydrofuran, and then 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after the reaction was completed. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 2.4 g of dark yellow solid product, with a yield of 100%. LC-MS (ESI) m / z: 382.0, 384.0 [M+H] + .

[0420] Intermediate 5603: 8-Bromo-1-(3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0421]

[0422] 2.4 g (6.2 mmol) of intermediate 5602 was dissolved in 20 mL of dichloromethane, and 10 mL of triphosgene (1.9 g, 6.4 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added and stirred for 10 minutes. Solids were precipitated, and the solids were collected by filtration and dried under reduced pressure to obtain 2.5 g of a yellow powdery solid product with a yield of 96.8%. LC-MS (ESI) m / z: 408.0, 410.0 [M+H] + .

[0423] Intermediate 5604: 8-Bromo-3-methyl-1-(3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0424]

[0425] 2.5 g (6.0 mmol) of intermediate 5603 was dissolved in 100 mL of dichloromethane, and 0.24 g (0.7 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added thereto, and stirred for 10 minutes, and then 1.12 mL (20.5 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 2.3 g of a yellow solid product with a yield of 90.8%. LC-MS (ESI) m / z: 422.0, 424.0 [M+H] + .

[0426] Compound 5605: 3-Methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0427]

[0428] Under nitrogen protection, 106 mg (0.25 mmol) of intermediate 5604 and 157 mg (0.55 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 106 mg (1 mmol) of sodium carbonate, 1 ml of water and 28.8 mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 35 mg of a white solid product with a yield of 28%. LC-MS (ESI) m / z: 501.2 [M+H] + .

[0429] 1 H NMR(600MHz,DMSO)δ9.05(s,1H),8.49(d,J=1.7Hz,1H),8.33(s,1H),8.21(s,1 H),8.15(d,J=8.8Hz,1H),8.09(d,J=8.0Hz,1H),8.06(d,J=7.2Hz,1H),8.03(s ,1H),7.98(d,J=7.9Hz,1H),7.96(dd,J=8.8,2.0Hz,1H),7.68(dd,J=8.3,2.4H z,1H),7.65(d,J=7.9Hz,1H),7.19(d,J=1.9Hz,1H),3.90(s,3H),3.62(s,3H).

[0430] Example 18 Synthesis of Compound FP-622 (5704)

[0431] Compound 5704: 3-Methyl-8-(6-((2-(methylamino)ethyl)amino)pyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0432]

[0433] Intermediate 5701: tert-Butyl 2-(5-bromopyridin-2-ylamino)ethyl(methyl)carbamate

[0434]

[0435] Dissolve 1.0g (5.7mmol) of N-Boc-N-methylethylenediamine and 1.0g (5.7mmol) of 5-bromo-2-fluoropyridine in 25mL of DMF, add 1.15g (11.4mmol) of triethylamine, and stir at 110°C for 12 hours. After the reaction is completed, add 25mL of water and stir for 30 minutes, separate the layers, extract the aqueous phase with dichloromethane, dry the organic phase over anhydrous sodium sulfate, filter and discard the solid, and spin-dry the filtrate to obtain a crude product. The crude product is purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 1.1g of colorless oil with a yield of 58.5%. LC-MS (ESI) m / z: 330.1, 332.1 [M+H] + .

[0436] Intermediate 5703: tert-Butyl methyl (2-(5-(3-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-amino)ethyl)carbamate

[0437]

[0438] Under nitrogen protection, 100 mg (0.30 mmol) of intermediate 5701, 90 mg (0.36 mmol) of biboric acid pinacol ester, 59 mg (0.60 mmol) of potassium acetate and 17 mg (0.015 mmol) of tetrakis (triphenylphosphine) palladium were added to 10 ml of tert-butyl alcohol, heated to 80 ° C and stirred for 2 hours. TLC detection, after the reaction was completed, the reaction solution was cooled to room temperature, 95 mg (0.25 mmol) of intermediate 5604, 63 mg (0.6 mmol) of sodium carbonate, 2 ml of water and 17 mg (0.015 mmol) of tetrakis (triphenylphosphine) palladium were added thereto in sequence, and then heated to 80 ° C and stirred for 5 hours. TLC detection, after the reaction was completed, water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1, V:V) to obtain 28 mg of a white solid product with a yield of 15.7%. LC-MS (ESI) m / z: 593.2 [M+H] + .

[0439] Compound 5704: 3-Methyl-8-(6-((2-(methylamino)ethyl)amino)pyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0440]

[0441] Add 28 mg (0.047 mmol) of intermediate 5703 to the reaction bottle, then add 1 ml of methanol and 1 ml of 1,4-dioxane solution (2 mol / L) of hydrogen chloride, and stir at room temperature for 2 hours. After the reaction is completed, add 5 ml of methyl tert-butyl ether to dilute, solid precipitates, filter to obtain solid, then adjust the pH value to 8-9 with saturated sodium bicarbonate solution, extract the aqueous phase with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and discard the solid, and spin dry the filtrate to obtain 12 mg of solid product, yield: 54.5%. LC-MS (ESI): 493.2 [M+H] + .

[0442] Example 19 Synthesis of Compound FP-628 (5803)

[0443]

[0444] Intermediate 5801: N-(5-bromopyridin-2-yl)-2-(methylamino)acetamide

[0445]

[0446] 500 mg (2.84 mmol) of 5-bromo-2-fluoropyridine and 250 mg (2.84 mmol) of 2-(methylamino)acetamide were dissolved in 30 ml of N, N-dimethylformamide, and 1.1 g (8.52 mmol) of N, N-diisopropylethylamine was added thereto, and the reaction was stirred at room temperature for 10 hours. TLC detection was performed, and after the reaction was completed, 20 ml of water and 20 ml of ethyl acetate were added, and the liquid was separated by standing, and the organic phase was separated. The aqueous phase was extracted twice with 20 ml of ethyl acetate, and the organic phases were combined. The organic phase was washed twice with 20 ml of saturated brine, and then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, V / V) to obtain 560 mg of the product with a yield of 80.6%. LC-MS (ESI) m / z: 244, 246 [M+H] + .

[0447] Intermediate 5802: 2-(Methylamino)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide

[0448]

[0449] Under nitrogen protection, 100 mg (0.4 mmol) of intermediate 5801 and 107 mg (0.48 mmol) of biboronic acid pinacol ester were dissolved in 10 ml of tert-butyl alcohol, 16 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium and 117 mg (1.2 mmol) of potassium acetate were added, and the mixture was stirred at 80°C for 5 hours. After TLC detection, the reaction was directly used for the next step.

[0450] Product FP-628 (5803) N-(5-(1-(4-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl)-2-(methylamino)acetamide

[0451]

[0452] 116 mg (0.4 mmol) of intermediate 5802, 154 mg (0.4 mmol) of intermediate 5304 and 128 mg (0.8 mmol) of Na2CO3 were dissolved in 10 ml of tert-butyl alcohol, and then 2 ml of water and 16 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was reacted at 80°C overnight under N2 protection. TLC detection was performed. After the reaction was completed, the mixture was concentrated under reduced pressure to remove most of the solvent, and then 20 ml of water was added for dilution, and the mixture was extracted twice with 20 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1, V / V) to obtain 38 mg of a solid product with a yield of 20.2%. LC-MS (ESI): 469.3 [M+H] + .

[0453] Example 20 Synthesis of Compound FP-921 (5906)

[0454]

[0455] Intermediate 5901: tert-Butyl 4-(4-((6-bromo-3-nitroquinolin-4-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0456]

[0457] 1 g (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.3 g (3.83 mmol) of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After TLC detection, water was added to dilute the reaction, and a large amount of solid precipitated. The solid was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 2.0 g of a yellow solid product with a yield of 99.5%. LC-MS (ESI) m / z: 596.1, 598.1 (M+H + ).

[0458] Intermediate 5902: tert-Butyl 4-(4-((3-amino-6-bromoquinolin-4-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0459]

[0460] 2.0 g (3.35 mmol) of intermediate 5901 was dissolved in 20 mL of tetrahydrofuran, 500 mg of platinum carbon (5%) was added thereto, hydrogen was introduced, and the mixture was stirred at room temperature overnight. TLC detection was performed, and the reaction was filtered after completion. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 1.7 g of a dark yellow solid product with a yield of 90.1%. LC-MS (ESI) m / z: 566.2, 568.2 (M+H + ).

[0461] Intermediate 5903: tert-Butyl 4-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0462]

[0463] 1.7 g (3.0 mmol) of intermediate 5902 was dissolved in 10 mL of dichloromethane, and 10 mL of triphosgene (1.4 g, 4.67 mmol) in dichloromethane was added dropwise thereto, and stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added to the reaction solution and stirred for 10 minutes. Solids precipitated, and the solids were collected by filtration and dried under reduced pressure to obtain 1.4 g of a yellow powdery solid product with a yield of 78.6%. LC-MS (ESI) m / z: 592.2, 594.2 [M+H] + .

[0464] Intermediate 5904: tert-Butyl 4-(4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0465]

[0466] 1.4 g (2.4 mmol) of intermediate 5903 was dissolved in 100 mL of dichloromethane, 0.24 g (0.24 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added, and the mixture was stirred for 10 minutes, and then 1 g (7.2 mmol) of iodomethane was added and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the mixture was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 1.12 g of a yellow solid product with a yield of 78.3%. LC-MS (ESI) m / z: 606.2, 608.2 [M+H] + .

[0467] Intermediate 5905: tert-Butyl 4-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0468]

[0469] Under nitrogen protection, 100.0 mg (0.16 mmol) of intermediate 5904 and 56.0 mg (0.19 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, and 34.0 mg (0.32 mmol) of sodium carbonate, 2 mL of water and 13.9 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were added in sequence, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the solvent was concentrated to remove, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 25 mg of a white solid product with a yield of 23.2%. LC-MS (ESI) m / z: 685.3 [M+H] + .

[0470] Product 5906: (FP-921) 3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0471]

[0472] Add 25 mg (0.04 mmol) of intermediate 5905 to the reaction bottle, then add 5 ml of water and 5 ml of 1.4-dioxane solution (2 mol / L) of hydrogen chloride, and stir at room temperature for 2 hours. After the reaction is completed, add 10 ml of methyl tert-butyl ether to dilute, solid precipitates, filter to obtain solid, then adjust the pH value to 8-9 with saturated sodium bicarbonate solution, extract the aqueous phase with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter and discard the solid, and spin dry the filtrate to obtain 12 mg of solid product, yield: 54.5%. LC-MS (ESI): 585.3 [M+H] + .

[0473] 1 H NMR(600MHz,DMSO)δ9.52(s,1H),8.56(s,1H),8.53(d,J=9.0Hz,1H),8.47(d,J =1.4Hz,1H),8.38(d,J=7.7Hz,1H),8.22(d,J=2.2Hz,1H),8.20(s,1H),8.15(d d,J=8.5,2.1Hz,1H),7.97(d,J=8.5Hz,1H),7.90(d,J=6.9Hz,1H),7.86(d,J=8 .2Hz,1H),7.17(d,J=1.2Hz,1H),3.94(s,3H),3.69(s,3H),3.39-3.22(m,8H).

[0474] Example 21 Synthesis of Compound FP-936 (6006)

[0475]

[0476] Intermediate 6001: tert-Butyl 4-(4-((6-bromo-3-nitroquinolin-4-yl)amino)phenyl)piperazine-1-carboxylate

[0477]

[0478] 1.0 g (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.1 g (3.83 mmol) of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added for dilution, and a large amount of solid was precipitated. The solid was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 1.8 g of a yellow solid product with a yield of 97.8%. LC-MS (ESI) m / z: 528.1, 530.1 [M+H] + .

[0479] Intermediate 6002: tert-Butyl 4-(4-((3-amino-6-bromoquinolin-4-yl)amino)phenyl)piperazine-1-carboxylate

[0480]

[0481] 1.8 g (3.41 mmol) of intermediate 6001 was dissolved in 20 mL of tetrahydrofuran, 500 mg of platinum carbon (5%) was added, hydrogen was introduced, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 1.57 g of a dark yellow solid product with a yield of 92.4%. LC-MS (ESI) m / z: 498.1, 500.1 [M+H] + .

[0482] Intermediate 6003: tert-Butyl 4-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)piperazine-1-carboxylate

[0483]

[0484] 1.57 g (3.15 mmol) of intermediate 6002 was dissolved in 10 mL of dichloromethane, and 10 mL of triphosgene (1.4 g, 4.73 mmol) in dichloromethane was added dropwise thereto, and stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added to the reaction solution and stirred for 10 minutes. Solids precipitated, and the solids were filtered and collected, and dried under reduced pressure to obtain 1.32 g of a yellow powdery solid product with a yield of 80.0%. LC-MS (ESI) m / z: 524.1, 524.1 [M+H] + .

[0485] Intermediate 6004: tert-butyl 4-(4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)piperazine-1-carboxylate

[0486]

[0487] 1.32 g (2.52 mmol) of intermediate 6003 was dissolved in 100 mL of dichloromethane, 0.25 g (0.25 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added, and the mixture was stirred for 10 minutes, and then 1 g (7.5 mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the mixture was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 1.15 g of a yellow solid product with a yield of 84.7%. LC-MS (ESI) m / z: 538.1, 540.1 [M+H] + .

[0488] Intermediate 6005: tert-butyl 4-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)piperazine-1-carboxylate

[0489]

[0490] Under nitrogen protection, 100 mg (0.18 mmol) of intermediate 6004 and 53 mg (0.18 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, and 38 mg (0.36 mmol) of sodium carbonate, 2 mL of water and 13 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were added in sequence, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 27 mg of a white solid product with a yield of 23.6%. LC-MS (ESI) m / z: 617.4 [M+H] + .

[0491] Product 6006 (FP-936): 3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(4-(piperazin-1-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0492]

[0493] Add 27 mg (0.04 mmol) of intermediate 6005 to the reaction bottle, then add 5 ml of water and 5 ml of 1.4-dioxane solution (2 mol / L) of hydrogen chloride, and stir the reaction at room temperature for 2 hours. After the reaction is completed, add 10 ml of methyl tert-butyl ether to dilute the reaction system, a large amount of solid precipitates, filter, collect the solid, and then adjust the pH value to 8-9 with saturated sodium bicarbonate solution, extract the aqueous phase with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter and discard the solid, and spin-dry the filtrate to obtain 15 mg of the product, with a yield of 66.3%. LC-MS (ESI): 517.3 [M+H] + .

[0494] 1 H NMR (600MHz, DMSO) δ9.47(s,1H),8.76(s,1H),8.57(d,J=1.5Hz,1H),8.51(d,J=9.0Hz,1H),8.37(d,J=9.1Hz,1H),8.30(s,1H),7.93(d,J=8.2Hz ,1H),7.79(d,J=7.4Hz,1H),7.61(d,J=8.7Hz,2H),7.37(d,J=8.7Hz,2H) ,7.31(s,1H),3.95(s,3H),3.67(s,3H),3.66-3.64(m,4H),3.32(s,4H).

[0495] Example 22 Synthesis of Compound FP-937 (6105)

[0496]

[0497] Intermediate 6101: 2-(4-(4-((6-bromo-3-nitroquinolin-4-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-ol

[0498]

[0499] 1 g (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.1 g (3.80 mmol) of 2-(4-(4-amino-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethane-1-ol were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added to dilute the mixture, and a large amount of solid was precipitated. The mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 1.79 g of a yellow solid product with a yield of 95.2%. LC-MS (ESI) m / z: 540.1, 542.1 [M+H] + .

[0500] Intermediate 6102: 2-(4-(4-((3-amino-6-bromoquinolin-4-yl)amino)-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-ol

[0501]

[0502] 1.79 g (3.31 mmol) of intermediate 6101 was dissolved in 20 mL of tetrahydrofuran, 500 mg of platinum carbon (5%) was added thereto, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, after the reaction was completed, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain 1.67 g of dark yellow solid product, with a yield of 98.8%. LC-MS (ESI) m / z: 510.1, 512.1 [M+H] + .

[0503] Intermediate 6103: 8-Bromo-1-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0504]

[0505] 1.67 g (3.27 mmol) of intermediate 6102 was dissolved in 10 mL of dichloromethane, and 10 mL of triphosgene (1.4 g, 4.73 mmol) in dichloromethane was added dropwise thereto, and stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added to the reaction solution and stirred for 10 minutes. Solids precipitated, and the solids were filtered and collected, and dried under reduced pressure to obtain 1.36 g of yellow powdery solid product with a yield of 77.7%. LC-MS (ESI) m / z: 536.1, 538.1 [M+H] + .

[0506] Intermediate 6104: 8-Bromo-1-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0507]

[0508] 1.36 g (2.54 mmol) of intermediate 6103 was dissolved in 100 mL of dichloromethane, 0.25 g (0.25 mmol) of tetrabutylammonium bromide and 100 mL of sodium hydroxide aqueous solution (10%) were added, and the mixture was stirred for 10 minutes, and then 1 g (7.5 mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the mixture was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 0.99 g of a yellow solid product with a yield of 71.0%. LC-MS (ESI) m / z: 550.1, 552.1 [M+H] + .

[0509] Product 6105 (FP-937): 1-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0510]

[0511] Under nitrogen protection, 100 mg (0.18 mmol) of intermediate 6104 and 53 mg (0.18 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, and 38 mg (0.36 mmol) of sodium carbonate, 2 mL of water and 13 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were added in sequence, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, the majority of the tert-butanol was removed by concentration under reduced pressure, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 23 mg of a white solid product with a yield of 20.3%. LC-MS (ESI) m / z: 629.3 [M+H] + .

[0512] 1H NMR (600MHz, DMSO) δ9.45 (s, 1H), 8.47-8.42 (m, 3H), 8.32 (d, J = 8.8Hz, 1H) ,8.23(d,J=2.2Hz,1H),8.17-8.14(m,1H),8.12(d,J=6.1Hz,1H),7.97(d,J =8.4Hz,1H),7.86(d,J=6.7Hz,1H),7.79(d,J=8.1Hz,1H),7.16(s,1H),3. 93(s,3H),3.90-3.86(m,2H),3.68(s,3H),3.50(m,2H),3.38-3.26(m,8H).

[0513] Example 23 Synthesis of Compound FP-938 (6202)

[0514]

[0515] Intermediate 6201: tert-Butyl (2-(4-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)carbamate

[0516]

[0517] 100 mg (0.17 mmol) of compound 5906 and 38 mg (0.17 mmol) of (2-bromoethyl) tert-butyl carbamate were dissolved in 10 ml of N, N-dimethylformamide, and 65 mg (0.51 mmol) of N, N-diisopropylethylamine were added, and the reaction was stirred at room temperature for 10 hours. TLC detection, after the reaction was completed, 20 ml of water was added for dilution, and then extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, the organic phases were washed twice with an appropriate amount of saturated brine, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, V / V) to obtain 29 mg of the product, with a yield of 23.4%. LC-MS (ESI) m / z: 728.4 [M+H] + .

[0518] Product 6202 (FP-938): 1-(4-(4-(2-aminoethyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0519]

[0520] Add 29 mg (0.04 mmol) of intermediate 6201 to the reaction bottle, then add 5 ml of water and 5 ml of 1,4-dioxane solution (2 mol / L) of hydrogen chloride, and stir at room temperature for 2 hours. After the reaction is completed, add 10 ml of methyl tert-butyl ether to dilute, solid precipitates, filter, collect the solid, and then adjust the pH value to 8-9 with saturated sodium bicarbonate solution, extract the aqueous phase with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter and discard the solid, and spin dry the filtrate to obtain 24 mg of solid product, yield: 96.0%. LC-MS (ESI): 628.3 [M+H] + .

[0521] Example 24 Synthesis of Compound FP-938 (6302)

[0522]

[0523] Intermediate 6301: tert-Butyl 4-(4-(8-(2-(hydroxymethyl)pyrimidin-5-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0524]

[0525] Under nitrogen protection, 100 mg (0.16 mmol) of intermediate 5904 and 39 mg (0.16 mmol) of (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrimidin-2-yl)methanol were dissolved in 10 mL of tert-butanol, and 38 mg (0.36 mmol) of sodium carbonate, 2 mL of water and 13 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium were added in sequence, and the mixture was stirred at 80°C for 5 hours. After the reaction was completed, most of the tert-butanol was removed by concentration by TLC detection, and then water was added to dilute the mixture. The aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 26 mg of a white solid product with a yield of 24.8%. LC-MS (ESI) m / z: 635.3 [M+H] + .

[0526] Product 6302 (FP-942): 8-(2-(Hydroxymethyl)pyrimidin-5-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0527]

[0528] Add 26 mg (0.04 mmol) of intermediate 6301 to the reaction bottle, then add 5 ml of water and 5 ml of 1.4-dioxane solution (2 mol / L) of hydrogen chloride, and stir at room temperature for 2 hours. After the reaction is completed, add 10 ml of methyl tert-butyl ether to dilute, and a precipitate is precipitated. Filter and collect the solid, then adjust the pH value to 8-9 with saturated sodium bicarbonate solution, extract the aqueous phase with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter and discard the solid, and spin dry the filtrate to obtain 20 mg of solid product, with a yield of 91.3%. LC-MS (ESI): 536.2 [M+H] + .

[0529] Example 25 Synthesis of Compound FP-943 (6402)

[0530]

[0531] Intermediate 6401: tert-Butyl 4-(4-(3-methyl-8-(2-(methylamino)pyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0532]

[0533] Under nitrogen protection, 100 mg (0.16 mmol) of intermediate 5904 and 39 mg (0.16 mmol) (N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) pyrimidine-2-amine were dissolved in 10 mL of tert-butanol, and 38 mg (0.36 mmol) of sodium carbonate, 2 mL of water and 13 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were added in sequence, and the mixture was stirred at 80°C for 5 hours. After the reaction was completed, the mixture was concentrated to remove most of the tert-butanol, and then diluted with water. The aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 25.0 mg of a white solid product with a yield of 23.9%. LC-MS (ESI) m / z: 635.3 [M+H] + .

[0534] Product 6402 (FP-943): 3-methyl-8-(2-(methylamino)pyrimidin-5-yl)-1-(4-(piperazin-1-yl)-3(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0535]

[0536] Add 25.0 mg (0.04 mmol) of intermediate 6401 to the reaction bottle, then add 5 ml of water and 5 ml of 1,4-dioxane solution (2 mol / L) of hydrogen chloride, and react at room temperature for 2 hours. After the reaction is completed, add 10 ml of methyl tert-butyl ether to dilute, and a precipitate is precipitated. Filter and collect the solid, then adjust the pH value to 8-9 with saturated sodium bicarbonate solution, extract the aqueous phase with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and discard the solid, and spin dry the filtrate to obtain 20 mg of solid product, yield: 93.5%. LC-MS (ESI): 535.3 [M+H] + .

[0537] Example 26 Synthesis of Compound FP-947 (6501)

[0538]

[0539] Product FP-947(6501): 4-(4-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-oxobutanoic acid

[0540] 100 mg (0.17 mmol) FP-921 (5906) and 17 mg (0.17 mmol) succinic anhydride were dissolved in 10 ml N, N-dimethylformamide, and 66 mg (0.51 mmol) N, N-diisopropylethylamine was added, and the mixture was stirred at room temperature for 10 hours. TLC detection was performed, and after the reaction was completed, 20 ml of water was added to dilute the mixture, and then the mixture was extracted twice with an appropriate amount of ethyl acetate, and the organic phases were combined, washed twice with saturated brine, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V / V) to obtain 36 mg of the product with a yield of 30.8%. LC-MS (ESI) m / z: 685.1 [M+H] + .

[0541] 1H NMR (600MHz, DMSO) δ9.02 (s, 1H), 8.37 (d, J = 1.7Hz, 1H), 8.28 (s, 1H), 8.14-8.10 (m,2H),8.04-8.00(m,2H),7.96(d,J=8.8Hz,1H),7.91(d,J=8.5Hz,1H),7.78(dd ,J=8.2,1.9Hz,1H),7.64(d,J=8.2Hz,1H),7.02(s,1H),3.92(s,3H),3.76(m,2H) ,3.65-3.56(m,5H),3.14-2.94(m,4H),2.67-2.60(m,2H),2.48(t,J=6.4Hz,2H).

[0542] Example 27 Synthesis of Compound FP-948 (6607)

[0543]

[0544] Intermediate 6601: (1-(4-nitro-2-(trifluoromethyl)phenyl)piperidin-4-yl)methanol

[0545]

[0546] 1g (4.4mmol) of the compound 1-chloro-4-nitro-2-(trifluoromethyl)benzene and 613mg (5.3mmol) of piperidine-4-methanol were dissolved in 10mL of N,N-dimethylformamide, and then 1.22g (8.9mmol) of potassium carbonate was added and stirred at 90°C for overnight reaction. TLC detection, after the reaction was completed, appropriate amount of water was added for dilution, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined and washed twice with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1, V:V) to obtain 1.3g of yellow oily product with a yield of 100%. LC-MS (ESI) m / z: 305.1 [M+H] + .

[0547] Intermediate 6602: (1-(4-amino-2-(trifluoromethyl)phenyl)piperidin-4-yl)methanol

[0548]

[0549] 1.3 g (4.4 mmol) of compound 6601 was dissolved in 20 mL of ethanol, and then 4 g (17.6 mmol) of stannous chloride was added, and the reaction was stirred at room temperature overnight. TLC detection, after the reaction was completed, most of the ethanol was removed by concentration, ethyl acetate was added to dilute, and then 10% sodium hydroxide aqueous solution was added to adjust the pH value of the solution to alkaline. After stirring for ten minutes, diatomaceous earth was used for filtering, and the filtrate was allowed to stand for stratification, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 1 g of a yellow oily product with a yield of 85.3%. LC-MS (ESI) m / z: 275.2 [M + H] + .

[0550] Intermediate 6603: (1-(4-((6-bromo-3-nitroquinolin-4-yl)amino)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methanol

[0551]

[0552] 1.2g (4.2mmol) 6-bromo-4-chloro-3-nitroquinoline, 1g (3.6mmol) intermediate 6602 and 738mg (7.3mmol) triethylamine were dissolved in 20mL N,N-dimethylformamide and stirred at room temperature overnight. TLC detection, after the reaction, dilute with water, then extract twice with ethyl acetate, combine the organic phases and wash twice with saturated brine, dry over anhydrous sodium sulfate, filter and discard the solid, spin dry the filtrate to obtain a crude product, and purify the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1, V:V) to obtain 1.3g yellow solid product with a yield of 67.7%. LC-MS (ESI) m / z: 525.1, 527.1 [M+H] + .

[0553] Intermediate 6604: (1-(4-((3-amino-6-bromoquinolin-4-yl)amino)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methanol

[0554]

[0555] 1.3g (2.5mmol) of intermediate 6603 was dissolved in 20mL of ethanol, and then 2.2g (10.0mmol) of stannous chloride was added, and the reaction was stirred at room temperature overnight. TLC detection, after the reaction was completed, concentrated to remove most of the ethanol, added ethyl acetate to dilute, and then added 10% sodium hydroxide aqueous solution to adjust the solution pH to alkaline, stirred for ten minutes, filtered with diatomaceous earth, the filtrate was allowed to stand for stratification, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed twice with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 0.9g of product, with a yield of 73.2%. LC-MS (ESI) m / z: 495.1, 497.1 [M+H] + .

[0556] Intermediate 6605: 8-Bromo-1-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0557]

[0558] 0.9 g (1.8 mmol) of intermediate 6604 was dissolved in 10 mL of dichloromethane, and 10 mL of triphosgene (0.26 g, 0.9 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 40 ml of petroleum ether was added for dilution and stirred for 10 minutes. A precipitate was precipitated, and the solid was collected by filtration and dried under reduced pressure to obtain 0.94 g of a yellow powder product with a yield of 100%. LC-MS (ESI) m / z: 521.1, 523.1 [M+H] + .

[0559] Intermediate 6606: 8-Bromo-1-(4-(4-(hydroxymethyl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0560]

[0561] 0.94 g (1.8 mmol) of intermediate 6605 was dissolved in 10 mL of dichloromethane, and 0.06 g (0.2 mmol) of tetrabutylammonium bromide and 10 mL of sodium hydroxide aqueous solution (10%) were added thereto, stirred for 10 minutes, and then 0.55 mL (8.8 mmol) of iodomethane was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1:20, V:V) to obtain 0.3 g of a yellow solid product with a yield of 31.2%. LC-MS (ESI) m / z: 535.1, 537.1 [M+H] + .

[0562] Compound 6607: 1-(4-(4-(Hydroxymethyl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0563]

[0564] Under nitrogen protection, 300 mg (0.56 mmol) of intermediate 6606 and 285 mg (1 mmol) of intermediate 9a were dissolved in 10 mL of tert-butanol, 142 mg (1.34 mmol) of sodium carbonate, 2 ml of water and 39 mg (0.03 mmol) of tetrakis (triphenylphosphine) palladium were added thereto, and the reaction was stirred at 80 ° C for 5 hours. TLC detection, after the reaction was completed, most of the tert-butanol was removed by concentration, and then water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1, V:V) to obtain 167 mg of a white solid product with a yield of 48.6%. LC-MS (ESI) m / z: 614.3 [M+H] + .

[0565] Example 28 Synthesis of Compound FP-949 (6706)

[0566]

[0567] Intermediate 6701: tert-Butyl 4-(4-(6-chloro-3-nitro-1,5-naphthyridine-4-amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0568]

[0569] 1 g (4.10 mmol) of 2,8-dichloro-7-nitro-1,5-naphthyridine and 1.2 g (3.47 mmol) of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate were dissolved in 20 mL of glacial acetic acid and stirred at room temperature overnight. After the reaction was completed, water was added for dilution, and a large amount of solid was precipitated. The solid was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 1.7 g of a yellow solid product with a yield of 88.5%. LC-MS (ESI) m / z: 553.2.

[0570] Intermediate 6702: tert-Butyl 4-(4-(3-amino-6-chloro-1,5-naphthyridine-4-amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0571]

[0572] 1.7 g (3.07 mmol) of intermediate 6701 was dissolved in 20 mL of ethanol, 0.35 g (5%) of platinum carbon was added, hydrogen was introduced, and the reaction was stirred at room temperature for 12 hours. TLC detection was performed, and the reaction was filtered after the reaction was completed, and the filtrate was dried to obtain 1.6 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 523.2 [M+H] + .

[0573] Intermediate 6703: tert-Butyl 4-(4-(8-chloro-2-oxo-2,3-dihydroimidazo[4,5-c][1,5]naphthyridin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0574]

[0575] Under ice water bath, 1.6g (3.07mmol) of intermediate 6702 was dissolved in 20mL of dichloromethane, 1.24g (12.28mmol) of triethylamine was added, and 20mL of triphosgene (0.77g, 1.95mmol) in dichloromethane solution was added dropwise, and stirred at room temperature for 5 hours, and solid precipitated. TLC detection, after the reaction was completed, the filter cake was washed with dichloromethane, and 1.2g of product was obtained after drying, with a yield of 71.2%. LC-MS (ESI) m / z: 549.2 [M+H] +

[0576] Intermediate 6704: tert-Butyl 4-(4-(8-chloro-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c][1,5]naphthyridin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0577]

[0578] 1.2 g (2.19 mmol) of intermediate 6703 was added to 30 mL of dichloromethane, 0.11 g (0.34 mmol) of tetrabutylammonium bromide and 30 mL of sodium hydroxide solution (10%) were added, and after stirring for 10 minutes, 1.49 g (10.38 mmol) of methyl iodide was added and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 0.9 g of a yellow solid product with a yield of 73.2%. LC-MS (ESI) m / z: 563.2 [M+H] + .

[0579] Intermediate 6705: tert-Butyl 4-(4-(3-methyl 8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydroimidazo[4,5-c][1,5]naphthyridin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0580]

[0581] Under nitrogen protection, 0.1 g (0.18 mmol) of intermediate 6704 and 0.18 g (0.63 mmol) of intermediate 9a were dissolved in 10 mL of dioxane, and then 0.47 g (1.44 mmol) of cesium carbonate, 10 mL of 2M sodium carbonate aqueous solution and 0.025 g (0.031 mmol) of [1,1-bis (di-phenylphosphino) ferrocene] palladium chloride were added in sequence, and the reaction was stirred at 110 ° C for 5 hours. TLC detection, after the reaction was completed, most of the solvent was removed by concentration, diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane / methanol = 10 / 1, V / V) to obtain 41 mg of white powder product with a yield of 33.2%. LC-MS (ESI) m / z: 686.3 [M+H] + .

[0582] Compound 6706: 3-Methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2(3H)-one

[0583]

[0584] 41 mg (0.06 mmol) of intermediate 6705 was dissolved in 2 mL of methanol, and 2 mL (2 mol / L) of hydrogen chloride in 1,4-dioxane was added thereto. The reaction was stirred at room temperature for 4 hours, and solids precipitated. TLC detection, after the reaction was completed, filtered, the filtrate was discarded, the filter cake was washed with a small amount of methanol, and then the pH value was adjusted to 8-9 with a saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by preparative TLC (dichloromethane / methanol=10 / 1, V:V) to obtain 16 mg of a white powder product with a yield of 45.7%. LC-MS (ESI) m / z: 586.3 [M+H] + .

[0585] Example 29 Synthesis of Compound FP-953 (6802)

[0586]

[0587] The synthesis method of the above compound 6802 is specifically as follows:

[0588] Intermediate 1001: Synthesis of tert-butyl (2-(5-bromopyridin-2-oxy)ethyl)carbamate:

[0589]

[0590] 1g (6.2mmol) of N-(tert-butyloxycarbonyl)ethanolamine and 1.09g (6.2mmol) of 5-bromo-2-fluoropyridine were dissolved in 25mL of DMF (N,N-dimethylformamide), and 0.27g (6.82mmol) of sodium hydride was added thereto, and stirred at room temperature overnight. After the reaction was completed, 25mL of water was added and stirred for 30 minutes, the aqueous phase was extracted with dichloromethane, the organic phase was washed twice with saturated brine, and then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.6g of colorless oil product with a yield of 80.6%. LC-MS (ESI) m / z: 317.0, 319.0 [M+H] + .

[0591] Intermediate 6801: Synthesis of tert-butyl 4-(4-(8-(6-(2-(tert-butoxycarbonyl)ethoxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate:

[0592] Under nitrogen protection, 300 mg (0.95 mmol) of intermediate 1001, 285 mg (1.11 mmol) of biboric acid pinacol ester, 180 mg (1.86 mmol) of potassium acetate and 54 mg (0.045 mmol) of tetrakis (triphenylphosphine) palladium were added to 10 ml of tert-butyl alcohol, heated to 80 ° C and stirred for 2 hours. TLC detection, after the reaction was completed, the reaction solution was cooled to room temperature, 422 mg (0.75 mmol) of intermediate 6704, 180 mg (1.86 mmol) of sodium carbonate, 4 ml of water and 54 mg (0.045 mmol) of tetrakis (triphenylphosphine) palladium were added thereto in sequence, and then heated to 80 ° C and stirred for 5 hours. TLC detection, after the reaction was completed, water was added for dilution, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 114 mg of a white solid product with a yield of 15.7%. LC-MS (ESI) m / z: 764.3 [M+H] + .

[0593] Product 6802: 8-(6-(2-aminoethoxy)pyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0594]

[0595] 114 mg (0.15 mmol) of intermediate 6801 was dissolved in 2.5 mL of methanol, and 2.5 mL of 1,4-dioxane solution (2 M) of hydrogen chloride was added. The reaction was stirred at room temperature for 4 hours, and solids precipitated. After the reaction was completed, the solids were filtered and collected, and then the pH value was adjusted to 8-9 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solids were filtered and discarded, and the filtrate was dried to obtain 53 mg of yellow solid product with a yield of 63.1%. LC-MS (ESI) m / z: 564.3 [M+H] + .

[0596] Comparative Example 1 (Compound 6705) Synthesis of FP-347

[0597]

[0598] Intermediate 6701: 6-Bromo-N-(4-pentafluorosulfonylphenyl)-3-nitroquinolin-4-amine

[0599]

[0600] Dissolve 1g (3.48mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.91g (4.17mmol) of 4-(pentafluorosulfonyl)aniline in 10mL of acetic acid and stir at room temperature to react overnight. After TLC detection, filter and wash the filter cake with glacial acetic acid and vacuum dry to obtain 1.8g of yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 472.0, 474.0 [M+H] + .

[0601] Intermediate 6702: 6-Bromo-N-(4-pentafluorosulfonylphenyl)-3-aminoquinolin-4-amine

[0602]

[0603] 1.8 g (3.48 mmol) of intermediate 6701 was dissolved in 20 mL of ethanol, 0.18 g of platinum carbon (5%) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solid was filtered and discarded, and the filtrate was dried to obtain 1.7 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 440.0, 442.0 [M+H] + .

[0604] Intermediate 6703: 8-Bromo-1-(4-pentafluorosulfonylphenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0605]

[0606] Under ice water bath, 1.7g (3.48mmol) of intermediate 6702 was dissolved in 15mL of dichloromethane, 1.09g (10.44mmol) of triethylamine was added, and 0.38g (1.16mmol) of triphosgene dissolved in 10mL of dichloromethane was added dropwise, and stirred for 5 hours, and solid precipitated. After TLC detection, after the reaction was completed, the solid was filtered, washed with dichloromethane, and dried to obtain 1.1g of product, with a yield of 68.7%. LC-MS (ESI) m / z: 468.0, 470.0 [M+H] + .

[0607] Intermediate 6704: 8-Bromo-1-(4-pentafluorosulfonylphenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0608]

[0609] 1.1 g (2.36 mmol) of intermediate 6703 was added to 10 mL of dichloromethane, 0.081 g (0.24 mmol) of tetrabutylammonium bromide and 10 mL of sodium hydroxide solution (10%) were added, and after stirring for 10 minutes, 0.99 g (7.08 mmol) of methyl iodide was added and stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 0.8 g of a yellow solid product with a yield of 70.7%. LC-MS (ESI) m / z: 482.0, 484.0 [M+H] + .

[0610] Compound 6705: 1-(4-Pentafluorosulfonylphenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0611]

[0612] Under nitrogen protection, 100 mg (0.20 mmol) of intermediate 6704 and 85 mg (0.30 mmol) of intermediate 9a were dissolved in 5 mL of 1,4-dioxane, 197 mg (0.60 mmol) of cesium carbonate, 1 mL of 2M sodium carbonate aqueous solution, and 22 mg (0.02 mmol) of [1,1-bis(di-phenylphosphino)ferrocene]palladium chloride were added, and the reaction was stirred at 110°C for 5 hours. TLC detection, after the reaction was completed, most of the solvent was concentrated to remove, water was added to dilute the residue, and it was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane / methanol=10 / 1, V / V) to obtain 47 mg of white powder product with a yield of 38.2%. LC-MS (ESI) m / z: 559.1 [M+H] + .

[0613] Comparative Example 2 (Compound 6802) Synthesis of FP-352

[0614]

[0615] Intermediate 6801: tert-Butyl (5-(1-(4-pentafluorosulfonylphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-yl)carbamate

[0616]

[0617] Under nitrogen protection, 200 mg (0.41 mmol) of intermediate 6704 and 199 mg (0.62 mmol) of 2-(BOC-amino)pyrrolidine-5-boronic acid pinacol ester were dissolved in 10 mL of 1,4-dioxane, 267 mg (0.82 mmol) of cesium carbonate, 2 mL of sodium carbonate aqueous solution (2M), 47 mg (0.041 mmol) of [1,1-bis(di-phenylphosphino)ferrocene]palladium chloride were added, and the mixture was stirred at 110°C for 5 hours. After TLC detection, most of the solvent was removed, water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, V:V) to obtain 140 mg of off-white powder product with a yield of 56.6%. LC-MS (ESI) m / z: 594.2 [M+H] + .

[0618] Compound 6802: 8-(6-aminopyridin-3-yl)-1-(4-pentafluorosulfonylphenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one

[0619]

[0620] 140 mg (0.23 mmol) of intermediate 6801 was dissolved in 2.5 mL of methanol, and 2.5 mL of 1,4-dioxane solution (2 M) of hydrogen chloride was added. The reaction was stirred at room temperature for 4 hours, and solids precipitated. After the reaction was completed, the solids were filtered and collected, and then the pH value was adjusted to 8-9 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solids were filtered and discarded, and the filtrate was dried to obtain 75 mg of yellow solid product with a yield of 66.4%. LC-MS (ESI) m / z: 494.1 [M+H] + .

[0621] Comparative Example 3 Synthesis of Compound 3006

[0622]

[0623] (1) Synthesis of Intermediate 3001: 6-bromo-N-(4-fluorophenyl)-3-nitroquinolin-4-amine:

[0624]

[0625] Dissolve 1g (3.28mmol) of 6-bromo-4-chloro-7-fluoro-3-nitroquinoline and 0.28g (4.88mmol) of cyclopropylamine in 10mL of DMF, add 0.72g (6.52mmol) of triethylamine, and stir overnight at room temperature. After the reaction is completed, add water and stir for 30 minutes. Solid precipitates, filter, wash the filter cake with water, and vacuum dry to obtain 1.07g of yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 326.0, 328.0 [M+H] + .

[0626] (2) Intermediate 3002: 6-bromo-N 4 -Synthesis of cyclopropyl-7-fluoroquinoline-3,4-diamine:

[0627]

[0628] 1.07 g (3.28 mmol) of intermediate 3001 was dissolved in 20 mL of ethanol, 0.15 g of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was filtered, the solid was discarded, and the filtrate was dried to obtain 0.97 g of a yellow solid product with a yield of 100%. LC-MS (ESI) m / z: 296.0, 298.0 [M+H] + .

[0629] (3) Intermediate 3003: Synthesis of 8-bromo-1-cyclopropyl-7-fluoro-1H-imidazo[4,5-c]quinolin-2(3H)-one:

[0630]

[0631] Under an ice-water bath, 0.97 g (3.48 mmol) of intermediate 3002 was dissolved in 20 mL of dichloromethane, 1.06 g (10.38 mmol) of triethylamine was added, and then 10 mL of triphosgene (0.35 g, 1.15 mmol) in dichloromethane was added dropwise. The reaction was stirred at room temperature for 5 hours, and solids precipitated. After the reaction was completed, the reaction was filtered and the filter cake was washed with a small amount of dichloromethane. The filter cake was dried to obtain 0.61 g of the product with a yield of 54.0%. LC-MS (ESI) m / z: 322.0, 324.0 [M+H] + .

[0632] (4) Intermediate 3004: Synthesis of 8-bromo-1-cyclopropyl-7-fluoro-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one:

[0633]

[0634] 0.61 g (1.90 mmol) of intermediate 3003 was dissolved in 15 mL of dichloromethane, and 0.061 g (0.19 mmol) of tetrabutylammonium bromide and 15 mL of sodium hydroxide (10%) solution were added thereto. After stirring for 10 minutes, 0.54 g (3.78 mmol) of methyl iodide was added and the reaction was stirred at room temperature for 4 hours. TLC detection, after the reaction was completed, the layers were allowed to stand, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, the solid was filtered and discarded, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 0.55 g of a yellow solid product with a yield of 85.9%. LC-MS (ESI)

[0635] m / z:336.0,338.0[M+H] + .

[0636] (5) Final Steps:

[0637]

[0638] Under nitrogen protection, 100 mg (0.39 mmol) of 3-((5-bromopyridin-2-yl)oxy)-N, N-dimethylpropane-1-amine, 99 mg (0.39 mmol) of biboric acid pinacol ester, 76 mg (0.78 mmol) of potassium acetate and 45 mg (0.039 mmol) of tetrakis(triphenylphosphine)palladium were added to 10 ml of tert-butyl alcohol, heated to 80°C and stirred for 2 hours. After TLC detection, the reaction solution was cooled to room temperature, 131 mg (0.39 mmol) of intermediate 3004, 82 mg (0.78 mmol) of sodium carbonate, 5 ml of tert-butyl alcohol, 2 ml of water and 45 mg (0.039 mmol) of tetrakis(triphenylphosphine)palladium were added thereto in sequence, and then heated to 80°C and stirred for 5 hours. After TLC detection, water was added to dilute the reaction, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol=10 / 1, V:V) to obtain 63 mg of a white solid product with a yield of 37.1%.

[0639] LC-MS (ESI) m / z: 436.2 [M+H] + .

[0640] 1H NMR (600MHz, DMSO) δ8.90(s,1H),8.82(d,J=8.5Hz,1H),8.51(s,1H),8.10-8.05(m,1H),7.92(d,J=12.0Hz,1H),7.01(d,J=8.6Hz,1H ), 4.40 (t, J = 6.4Hz, 2H), 3.53 (m, 1H), 3.48 (s, 3H), 2.86 (m, 2H) 2.48 (s, 6H), 2.11-2.04 (m, 2H), 1.29-1.21 (m, 2H), 1.16-1.10 (m, 2H).

[0641] Comparative Example 4 Synthesis of Compound 3105

[0642]

[0643] (1) Synthesis of Intermediate 3101: tert-butyl (5-bromo-2-iodopyridin-3-yl)carbamate:

[0644]

[0645] 1g (3.3mmol) 5-bromo-2-iodo-3-pyridinamine, 1.09g (5.0mmol) Boc anhydride and 0.67g (6.6mmol) triethylamine were dissolved in 20mL dichloromethane and stirred at room temperature overnight. TLC detection, after the reaction was completed, water was added and stirred for 30 minutes, and the organic phase was separated by standing, and the aqueous phase was extracted with dichloromethane, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether=1 / 1, V / V) to obtain 1.1g yellow solid product with a productive rate of 84.7%.

[0646] LC-MS(ESI)m / z:398.9,400.9[M+H] + .

[0647] (2) Intermediate 3102: Synthesis of tert-butyl (5-bromo-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)carbamate:

[0648]

[0649] Under nitrogen protection, 1.1 g (2.75 mmol) of intermediate 3101, 0.69 g (3.3 mmol) of 1-methylpyrazole-4-boronic acid pinacol ester, 1.78 g (5.5 mmol) of cesium carbonate and 0.114 g (0.14 mmol) of [1,1-bis (di-phenylphosphino) ferrocene] palladium chloride were dissolved in 30 mL of dioxane and 3 mL of water and heated at 110 ° C for 8 hours. TLC detection, after the reaction was completed, the dioxane was removed by vacuum concentration, water was added to dilute, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, the filter residue was discarded by filtration, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 20 / 1, V:V) to obtain 0.7 g of a white solid product with a yield of 70.3%.

[0650] LC-MS(ESI)m / z:353.1,355.1[M+H] + .

[0651] (3) Intermediate 3104: Synthesis of tert-butyl (5-(1-((1s,4s)-4-hydroxycyclohexyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)carbamate:

[0652]

[0653] Under nitrogen protection, 300 mg (0.85 mmol) of intermediate 3102, 215 mg (0.85 mmol) of biboric acid pinacol ester, 166 mg (1.7 mmol) of potassium acetate and 98 mg (0.085 mmol) of tetrakis (triphenylphosphine) palladium were added to 10 ml of tert-butyl alcohol, heated to 80 ° C and stirred for 2 hours. TLC detection, after the reaction was completed, the reaction solution was cooled to room temperature, 320 mg (0.85 mmol) of 208d, 180 mg (1.7 mmol) of sodium carbonate, 5 ml of tert-butyl alcohol, 2 ml of water and 98 mg (0.085 mmol) of tetrakis (triphenylphosphine) palladium were added thereto in sequence, and then heated to 80 ° C and stirred for 5 hours. TLC detection, after the reaction was completed, water was added for dilution, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol=10 / 1, V:V) to obtain 220 mg of a white solid product with a yield of 44.7%.

[0654] LC-MS (ESI) m / z: 570.3 [M+H] + .

[0655] (4) Final Steps:

[0656]

[0657] Under an ice-water bath, 220 mg (0.38 mmol) of intermediate 3104 was dissolved in 2 mL of methanol, and 2 mL of 2M hydrogen chloride in 1,4-dioxane solution was added. The mixture was stirred for 1 hour, and solids precipitated. After the reaction was completed, the filtrate was filtered and discarded, and the solids were washed with methyl tert-butyl ether, and then the pH value was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solids were filtered and discarded, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1, V:V) to obtain 129 mg of a yellow solid product with a yield of 71.0%.

[0658] LC-MS (ESI) m / z: 470.3 [M+H] + .

[0659] Comparative Example 5 Synthesis of Compound 3201

[0660]

[0661] The synthesis method of the above compound is specifically the following steps:

[0662] In an ice-water bath, 100 mg (0.21 mmol) of compound 3105 (the preparation method of compound 3105 is the same as that of comparative example 4), 29 mg (0.25 mmol) of methanesulfonyl chloride and 63 mg (0.63 mmol) of triethylamine were dissolved in 5 mL of dichloromethane and stirred for 5 hours. After the reaction was completed, water was added for dilution and the mixture was allowed to stand for stratification.

[0663] The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, the residue was discarded by filtration, and the filtrate was dried to obtain a crude product. The crude product was purified by preparative TLC (dichloromethane / methanol=10 / 1, V:V) to obtain 85 mg of a white solid product with a yield of 71.4%.

[0664] LC-MS (ESI) m / z: 548.2 [M+H] + .

[0665] 1H NMR (600MHz, DMSO) δ9.67(s,1H),9.38(s,1H),8.93(s,1H),8.47(d,J=9.0Hz,1H),8.42(s,1H),8.36(s,1H),8.09(s,1H),8.0 5(s,1H),4.92(s,1H),3.89(s,3H),3.62-3.55(m,4H),3.27-3.17(m,1H),3.02(s,3H),2.90-2.70(s,2H),1.95-1.60(m,6H).

[0666] Results

[0667] 1. Cell Viability Detection

[0668] 1. Experimental purpose: To detect the effects of the compounds in the examples and comparative examples on the growth of MV4-11, PC-3, BT474, MB436, LOVO and Granta-519 cells.

[0669] 2. Test method: CTG method

[0670] ATP is a must-have for the metabolic activities of living cells, and its content is linearly related to the number of living cells. Based on this principle, the CTG method is a universal method for detecting the number of living cells in cultured cells. After adding the CellTiter-Glo reagent, cell lysis can be induced and a chemiluminescent signal can be generated that is proportional to the amount of ATP in the well plate, so that the viability of cell proliferation in the well plate can be measured by the chemiluminescent reading.

[0671] 3. Test steps:

[0672] 3.1 Cell plating

[0673] Various cell plating: plating density is 5,000 cells / well, 100 μl / well;

[0674] Incubate at 37°C, 5% CO2 overnight.

[0675] 3.2 Compound preparation

[0676] The compound stock solution concentration was prepared to 10 mM.

[0677] 3.3 Preparation of working solution (2x)

[0678] Compounds were prepared at 20 μM.

[0679] 3.4 Intermediate plate configuration (2x)

[0680] Prepare 18 ml of compound dilution containing 0.2% DMSO and add it to the wells of the middle plate except the third column, 120 μl per well. Add the compound working solution in the 1.5 ml EP tube prepared above to the third column of the middle plate, 200 μl per well. Take out 60 μl from the third column with a spray gun and add it to the fourth column, mix well, and dilute it 3 times down to the last column, a total of 8 concentration gradients. Set up 2 replicate wells for each concentration gradient.

[0681] 3.5 Compound addition

[0682] Take out the cell culture plate from the incubator, add the compound working solution prepared in the middle plate above to the cell culture plate, starting from the 12th column to the 3rd column, from low concentration to high concentration, 100 μl per well. Set up blank control wells (culture medium) and negative control wells (culture medium and cells), and culture in a 37°C, 5% CO2 incubator.

[0683] The highest final compound addition concentration was: the compound was prepared at 10 μM.

[0684] 3.6CTG detection:

[0685] Cell activity detection kit, Nanjing Novozymes Biotech Co., Ltd., catalog number: DD1101-02;

[0686] After adding the compound, the cells were cultured for 72 h, the cell culture plate was removed, 100 μl of supernatant was discarded from each well, and 50 μl of CTG substrate was added. After addition, the cells were immediately shaken on an oscillator for 2 min. After being placed in a dark environment for 10 min, the chemiluminescent signal was read at full wavelength using an enzyme reader.

[0687] Relative cell viability = (RLU value of the assay well - RLU value of the blank control) / (RLU value of the cell control group - RLU value of the blank control);

[0688] RLU: relative fluorescence unit.

[0689] The cell viability data are as follows:

[0690]

[0691]

[0692] In the table, -- indicates no test data.

[0693] 2. Enzyme activity data test

[0694] ATM enzyme: All compounds were prepared as 10 mM DMSO solutions and diluted to 100 times the final concentration. Dilutions were made with 100% DMSO and 50 nL of the compounds were transferred to a 384-well reaction plate (PROXIPLATE-384PLUS) using an Echo 650. Add 2.5 μL of ATM enzyme solution (final ATM concentration 20 nM) prepared with 1x kinase buffer (50 mM HEPES pH 7.5, 20 mM MgCl2, 5 mM MnCl2, 200 mM NaCl, 1 mM DTT, 1 mM Na3VO4 and 0.0055% Brij-35) and incubate at room temperature for 10 minutes. Add 2.5 μL of ATM substrate solution (final ATM substrate peptide concentration 200 uM, final ATP concentration 13 μM) prepared with 1x kinase buffer and react at 37°C for 4 hours, then add 5 μl ADP-Glo ​​reagent 1 and incubate at 37°C for 2 hours. Add 10 μl ADP-Glo ​​reagent 2 to the reaction wells of the 384-well plate to terminate the reaction, let stand at 37°C for 60 minutes, read the luminescence value on the Envision 2104 Multilabel Reader, copy the luminescence value RLU, and convert the luminescence reading value into inhibition percentage by formula.

[0695] The data were imported into MS Excel and curve fitting was performed using XLFit excel add-in version 5.4.0.8. The fitting formula was: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X) ^ HillSlope.

[0696] ATR enzyme: This experiment uses the fluorescence microfluidic mobility detection technology (Mobility-Shift Assay) to detect the inhibitory effect of small molecule inhibitors on kinases. Kinase catalyzes ATP to remove a phosphate group to generate ADP, and transfers the phosphate group to the substrate peptide. The substrate peptide is fluorescently labeled, and the product has a change in charge due to the addition of a phosphate group. During electrophoresis, the substrate and phosphorylated product are separated due to different mobilities and detected separately, and their amounts are proportional to the fluorescent signal. The amount of substrate and product is measured using the Caliper instrument, and the conversion rate of the product is calculated, and then the inhibition rate is calculated.

[0697] All compounds were prepared with 100% DMSO at 1000 / 3 times the initial concentration, and 50 μL was transferred to a 384-well Echo plate; dilutions were made with 100% DMSO according to customer requirements, and 50 μL of 100% DMSO was transferred to two empty wells as controls without compound and enzyme. 60 nL of compound was transferred to a 384-well reaction plate using an Echo 550 (Corning 3573). 10 μL of ATR (final concentration 5 nM) 2x kinase solution prepared with 1x kinase buffer (25 mM HEPES pH 8, 10 mM MnCl2, 1 mM DTT and 0.0055% Brij-35) was transferred to a 384-well reaction plate, and 1x kinase buffer was added to the negative control wells. After mixing, incubate at room temperature for 10 minutes; add FAM-labeled polypeptide (final concentration of 5uM, FAM-RAD17) and ATP (final concentration of 2μM) to 1x kinase buffer to form a 2x substrate solution; transfer 10μL of the above 2x substrate solution to a 384-well plate reaction plate to initiate the reaction; incubate at 28°C for 4 hours, and add 25μL of stop solution (100mM HEPES pH 7.5, 50mM EDTA, 0.2% Coating Reagent#3and 0.015% Brij-35) to the 384-well plate reaction plate to terminate the reaction.

[0698] The conversion rate data were read on CaliperEZ ReaderⅡ (Down stream voltages: -500V, Up stream voltages: -2250V, Base pressure-0.5PSI, Screen pressure-1.2PSI). The conversion rate was converted into inhibition rate data Percent inhibition = [(MA-X) / (MA-MI)] × 100%. "MI" is the reading of the control well without enzyme; "MA" is the reading of the control well with DMSO added; "X" is the reading of different wells with different compounds. IC50 values ​​were fitted using XLFitexcel add-in version 5.4.0.8. Fitting formula: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X) ^ Hill Slope).

[0699] mTOR enzyme: All compounds were prepared as 10mM DMSO solutions and diluted to 100 times the final concentration. Dilutions were made with 100% DMSO and 200nL of compounds were transferred to a 384-well reaction plate (OptiPlate-384) using an Echo 550. 10μL of mTOR enzyme solution (final concentration 4nM) prepared with 1x kinase buffer (50mM HEPES pH 7.5, 10mM MgCl2, 2mM DTT, 1mM EGTA, 3mM MnCl2 and0.01% Tween-20) was added and incubated at room temperature for 10 minutes. 10μL of substrate peptide solution (substrate ULight-4E-BP1 peptide final concentration 15nM, ATP final concentration 8μM) prepared with 1x kinase buffer was added. React at room temperature for 30 minutes, add 20 μL stop reagent (10x Detection Buffer, final concentration of 0.5 nM Eu-anti-phospho-4E-BP1 antibody, final concentration of 20 mM EDTA). Stand at room temperature for 60 minutes, read the fluorescence value on Envision2104 Multilabel Reader, and copy the numerical ratio of the fluorescence reading (Lance signal ratio (665 nm / 615 nm). The above data are converted into inhibition percentage by the formula: Percent inhibition = (max-Sample Lance signal ratio) / (max-min) * 100.

[0700] "min" is the reading of the control well without adding enzyme; "max" is the reading of the control well with DMSO added. The data were imported into MS Excel and curve fitting was performed using XLFit excel add-in version 5.4.0.8. The fitting formula was: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X)^HillSlope).

[0701] DNA-PK enzyme: All compounds were prepared as 10 mM DMSO solutions and diluted to 100 times the final concentration. Dilutions were made with 100% DMSO, and 50 nL of the compounds were transferred to a 384-well reaction plate (PROXIPLATE-384PLUS) using an Echo 650. Add 2.5 μL of DNAPK enzyme solution (DNAPK final concentration 1u / ul, DNA-PK activation solution final concentration 5ug / ml) prepared with 1x kinase buffer (40mM Tris pH7.5, 20mM MgCl2, 0.05mM DTT and 0.0055% Brij-35) and incubate at room temperature for 10 minutes. Add 2.5 μL of DNAPK substrate solution (DNA-PK substrate peptide final concentration 0.2μg / μl, ATP final concentration 20μM) prepared with 1x kinase buffer and react at 28°C for 3 hours. Add 5μl ADP-Glo ​​reagent 1 and incubate at 28°C for 2 hours. Add 10μl ADP-Glo ​​reagent 2 to the 384-well plate reaction wells to terminate the reaction. Let it stand at room temperature for 30 minutes, read the luminescence value on Envision2104Multilabel Reader, copy the luminescence value RLU, and convert the luminescence reading value into inhibition percentage through the formula. The data were imported into MS Excel and curve fitting was performed using XLFit excel add-in version 5.4.0.8. The fitting formula was: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X) ^ HillSlope.

[0702] The enzyme activity data are shown in the following table:

[0703]

[0704]

[0705] In the table, -- indicates no test data.

[0706] Conclusion: The results of cell activity and enzyme activity tests show that the compounds of the examples have strong inhibitory effects on a variety of cells, which are significantly stronger than those of the comparative examples, indicating that the compounds prepared by the present invention are a class of highly active multi-target anti-tumor compounds.

[0707] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. An imidazolidone compound, characterized in that The compound represented by Formula I or Formula II, its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug: R1 is selected from H, alkyl, alkoxy, halogen, alkenyl, alkynyl; R2 is selected from aryl or heteroaryl substituted or unsubstituted by 1 to 5 substituents; Wherein, when R2 in the compound of formula I is an aryl group substituted by 1 to 5 substituents, the substituents are each independently selected from: C 1-6 Alkoxy, -CF3, halogen, C 1-6 Alkyl, cyano; When R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from: Substituted or unsubstituted C 1-6 Ester group, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclylaryl, heteroaryl, C 1-6 Haloalkyl, C 1-6 Alkylamino, phenylamino, halogen, cyano, -NH2, hydroxyl; wherein the substituted substituent is selected from halogen, carbonyl, hydroxyl, C 1-5 Alkyl, aryl, cyano, -NH2; R3 is selected from heteroaryl substituted or unsubstituted by 1-5 substituents, wherein the 1-5 substituents are selected from: substituted amino, C 2-8 Heterocyclic group, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 ester group amino, and halogen, cyano, -NH2, hydroxyl; wherein the substituted substituent is selected from C 1-6 Alkyl, hydroxy, halogen, alkylhydroxy, alkylamino.

2. The imidazolidinone compound according to claim 1, characterized in that R1 is selected from alkyl, preferably C 1-5 The alkyl group is more preferably a methyl group.

3. The imidazolidinone compound according to claim 1, characterized in that When R2 in the compound of formula I is aryl substituted by 1 to 5 substituents, the substituents are each independently selected from: Methoxy, -CF3, F, methyl, ethyl, cyano; when R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from: Substituted C 1-6 Alkyl and C 1-6 Alkoxy, -CF3, halogen, C 1-6 Alkyl, cyano; the substituted substituent is cyano; Preferably, in the compound of formula I, R2 is aryl substituted by 1-2 substituents, each of which is independently selected from: Methoxy, -CF3, F, methyl, ethyl, cyano; when R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from: Substituted C 1-6 Alkyl and C 1-6 Alkoxy, -CF3, halogen, C 1-6 Alkyl, cyano; the substituted substituent is cyano.

4. The imidazolidinone compound according to claim 1, characterized in that When R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from: substituted C 1-6 Alkyl, -CF3, the substituted substituent is cyano; Preferably, when R2 in the compound of formula I is a heteroaryl substituted with 1 to 5 substituents, or in the compound of formula II, the substituents are each independently selected from: substituted C 2-4 Alkyl, -CF3, the substituted substituent is cyano; Further preferably, when R2 in the compound of formula I is a heteroaryl substituted by 1-5 substituents, or in the compound of formula II, the substituents are each independently selected from: -CF3.

5. The imidazolidinone compound according to claim 1, characterized in that R3 is selected from phenyl substituted with 1-2 N, wherein the substituted substituent is selected from: substituted amino, C 2-8 Heterocyclic group, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 ester group amino, and halogen, cyano, -NH2, hydroxyl; wherein the substituted substituent is selected from C 1-6 Alkyl, hydroxy, halogen, alkylhydroxy, alkylamino; Preferably, R3 is selected from phenyl substituted with 1-2 N, wherein the substituted substituent is selected from: substituted C 2-8 heterocyclic group, and cyano, -NH2, -NHCH2CH2NHCH3, -NHCOCH2NHCH3; wherein the substituted substituent is selected from C 1-6 Alkyl, alkylhydroxy, alkylamino; More preferably, R3 is selected from phenyl substituted with 1-2 N, wherein the substituted substituent is selected from: substituted amino, C 4-6 Nitrogen heterocycle, C 1-6 wherein the substituted substituent is selected from C 1-6 Alkyl, hydroxyl; More preferably, R3 is selected from phenyl substituted with 1-2 N, wherein the substituted substituent is selected from:

6. The imidazolidinone compound according to any one of claims 1 to 5, characterized in that The compound represented by formula I is selected from the following compounds: Preferred are the following compounds: FP-313, FP-318, FP-337, FP-345, FP-353, FP-360, FP-364, FP-378, FP-416, FP-622, FP-921, FP-937, FP-938, FP-942, FP-943, FP-949; more preferred are the following compounds: FP-318, FP-360, FP-364, FP-378, FP-416, FP-622, FP-921, FP-937, FP-938, FP-943; further preferred are the following compounds: FP-318, FP-622, FP-921, FP-937, FP-938, FP-943; more preferred are the following compounds: FP-921, FP-943; and most preferred is FP-943.

7. The imidazolidinone compound according to claim 6, characterized in that For the following compounds: FP-318, FP-374, FP-378, FP-416, FP-622, FP-937, FP-938, FP-286, FP-356, FP-364, FP-921, FP-943, FP-948, FP-949, preferably the following compounds: FP-286, FP-356, FP-364, FP-921, FP-943, FP-948, more preferably the following compounds: FP-921, FP-943, most preferably FP-943.

8. The intermediate of the imidazolidinone compound according to any one of claims 1 to 7, characterized in that: Select from the following structures: R1, R2, and R3 have the same meanings as in any one of claims 1 to 7; M1 is halogen.

9. The method for preparing the imidazolidinone compound according to any one of claims 1 to 7, characterized in that: The process comprises the following reaction steps: or or or R1, R2, and R3 have the same meanings as in any one of claims 1 to 7; M1 is a halogen, M2 is a protecting group or does not exist, M3 is a protecting group, Preferably, the protecting group is selected from Boc, 10. Use of the imidazolidinone compound according to any one of claims 1 to 7, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of at least one of the following inhibitors: ATM kinase inhibitors, mTOR kinase inhibitors, DNA-PK kinase inhibitors, ATR kinase inhibitors.

11. Use of the imidazolidinone compound according to any one of claims 1 to 7, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of an inhibitor that simultaneously inhibits ATM kinase, ATR kinase, mTOR kinase and DNA-PK kinase.

12. Use of the imidazolidinone compound according to any one of claims 1 to 7, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of a DNA damage repair agent.

13. Use of the imidazolidinone compound according to any one of claims 1 to 7, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of drugs for treating and / or preventing ATM kinase, ATR kinase, mTOR kinase, DNA-PK kinase or DNA damage-mediated diseases.

14. The use according to claim 13, characterized in that The disease is selected from at least one of tumors, metabolic diseases, and cardiovascular diseases. Preferably, the tumor is selected from the group consisting of leukemia, malignant lymphoma, multiple myeloma, gastrointestinal stromal tumor, colon cancer, rectal cancer, breast cancer, liver cancer, gastric cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, choriocarcinoma, lung cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, glioblastoma, mast cell tumor, brain tumor, germ cell tumor, melanoma, sarcoma; The metabolic diseases include diabetes and obesity; The cardiovascular diseases include atherosclerosis.

15. A pharmaceutical composition comprising the imidazolidone compound according to any one of claims 1 to 7, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier or excipient.

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