CN119661531A - Imidazolone compound as well as preparation method and application thereof - Google Patents

Abstract

The present invention discloses a heterocyclic alkyl carboxylic acid compound, an intermediate, a preparation method and a use thereof, and relates to the technical field of pharmaceutical chemistry. The imidazolone compound provided by the present invention has a structure as shown in Formula I or Formula II, and has good DNA damage repair properties as shown in in vitro activity experiments, and can be used in the treatment of various diseases.

Description

Imidazolone compound as well as preparation method and application thereof

Technical Field

The invention relates to the technical field of pharmaceutical chemistry, in particular to an imidazolone compound, a preparation method and application thereof.

Background

DNA is important as the most important genetic material for cell vital activity, and it is important to maintain its integrity and stability. Human cell DNA is subjected to various endogenous and exogenous damage factors such as active oxygen, aldehydes, ultraviolet rays, ionizing radiation, chemotherapeutics and the like every day, so that nucleotide changes such as insertion, deletion, substitution and the like can be generated, and DNA damage such as single strand break or double strand break and the like can be caused. To address the serious adverse effects of DNA damage, cells evolved a complex network of signal pathways-collectively known as DNA Damage Response (DDR), including sensing DNA damage signals, activating cell cycle checkpoints, slowing or blocking cell cycle progression, activating different DNA repair mechanisms or apoptosis mechanisms, etc. DDR recognizes damage, starts cascade reaction, and decides cell fate according to damage degree, namely if DDR damage is serious and is difficult to repair, cells can enter apoptosis and even necrosis, if damage is slight and can repair, cells can continue to survive and start repair procedures, damage repair is completed through various repair paths, and gene integrity is maintained.

Currently, DNA damage repair has been used as an entry point for the treatment of a variety of diseases. Cheng Hongyan et al review the key molecules of DNA damage repair and related DDR pathways and potential tumor therapeutic targets, and illustrate the research of synthetic lethal targets of DNA damage repair related pathways and application in ovarian cancer. Chen Gong et al studied the biological characteristics of H2AX and its family, methods for detecting gamma H2AX, H2AX phosphorylation in DNA damage and repair, and its use in germ-associated cells. Zhao Saimin et al reviewed the progress of research on DNA damage repair and ovarian aging, including the role and mechanism of DNA damage repair genes in several processes such as primordial germ cell development, oocyte meiosis and follicular maintenance and development, and the relationship between the pathway gene mutation and premature ovarian failure, and explored the strategy of intervention targeting DNA damage repair pathways to delay ovarian aging, hopefully providing a new approach for female fertility protection. Zhang Weina et al reviewed the inherent association of DNA damage repair with senescence, summarized the recent progress of research on the mechanism by which DNA damage induces senescence to occur, and discussed the possibility and potential risk of targeting DNA damage repair to delay senescence.

At present, target points of DNA damage repair mechanisms include ATR, ATM, DNA-PK and the like. Synthetic lethality has been considered an example of anti-cancer therapies in recent years. The range of applications in which more synthetic lethal targets appear to lead to synthetic lethality is expanding. The formation cause of the tumor is very complex, the single-target drug treatment effect is not ideal, and the multi-target synergistic effect is the development trend of tumor treatment. Studies by Johann Gout et al (Gout J, et al, gun 2021; 70:743-760.) have shown that three-drug combination therapy is best demonstrated in vivo and in vitro data using Olaparib (PARP inhibitor), VE-822 (ATR inhibitor) and CC-115 (DNA-PK and mTOR dual-target inhibitor) in pancreatic ductal carcinoma cells and tumor tissues where ATMs are missing. Audrey Turchick et al (Mol CANCER THER;22 (7) July 2023) showed that the combined use of ATR inhibitor M4344 and ATM inhibitor M4076 was significantly stronger than the effect of ATR alone in treating triple negative breast cancer in a xenograft model of a human tumor. Ankur Karmokar et al (Ankur Karmokar, et al cancer 2023,15,4195) showed that in a xenograft model of a humanized ATM mutant tumor, treatment was performed with AZD6738 (ATR inhibitor), AZD7648 (DNA-PK inhibitor) and olaparib (PARP inhibitor) in combination, which was significantly better than the single drug. XRD-0394 is a small molecule compound of ATM and DNA-PK dual targets developed by XRad Therapeutics company, which has been introduced into a clinical trial for the treatment of solid tumors in combination with palliative radiation therapy (NCT 05002140), and shows remarkable dose-scale radiosensitization with no significant toxicity in both in vitro and in vivo therapeutic effects. The research results show that ATR, ATM, DNA-PK, mTOR and other target drugs are combined, so that the treatment effect is better.

ATR (Ataxia TELANGIECTASIA AND RAD-related) inhibitors are an important focus in the field of cancer research in recent years, the scientific background of which stems from the central role of ATR protein in cell cycle checkpoint control and DNA damage repair processes. ATR is a serine/threonine kinase belonging to the PI3K-like protein family that maintains genomic stability by responding to DNA single strand breaks and replication fork arrest (Chen et al, oncogene,37 (4), 423-433, 2018). The main function of ATR is to initiate and coordinate a variety of 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). Furthermore, ATR is also involved in RNA polymerase II protection against transcriptional interruption during replication stress (Zou & Elledge, nature,421 (6925), 792-797, 2003). ATR inhibitors are therefore able to block these repair pathways, rendering tumor cells unable to recover normally when subjected to DNA damage, resulting in cell death, particularly highly selective for cancers that rely on these repair mechanisms (e.g. BRCA mutated ovarian and breast cancers) (Lord & Ashworth, nature REVIEWS CANCER,17 (8), 473-486, 2017). Preclinical studies have shown that ATR inhibitors such as VE-821 and AZD6738 exhibit antitumor activity against a variety of cancers 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 chemotherapeutics, PARP inhibitors, etc. to enhance anticancer effects (Robson et al, NEW ENGLAND Journal of Medicine,379 (5), 429-439, 2018).

ATM (Ataxia-TELANGIECTASIA MUTATED) inhibitors are a targeted therapy developed based on their central role in DNA damage repair pathways. ATM is a key kinase that is activated when cells encounter DNA double strand breaks, thereby initiating a variety of repair mechanisms, including non-homologous end joining and homologous recombination repair. The ATM moiety is involved in G2/M check node regulation, controls G1/S check nodes, and is responsible for removing inhibitory phosphorylation of CDKs. In addition, studies have shown that ATM has a synthetic lethal relationship with PARP, ATR, BRAC a, DNA-PK, and Pol theta in DNA damage reactions. 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 impaired, especially for those tumors that rely on ATM pathways, such as BRCA mutated ovarian and breast cancers. ATM inhibitors have been shown to have potential anti-tumor activity in clinical applications. Early in vitro and animal model studies have shown that ATM inhibitors can enhance the effects of radiation therapy and chemotherapy, particularly in BRCA mutated tumors. For example, the combination of ATM inhibitors such as KU-55933 and NMS-P937 with PARP inhibitors has demonstrated significant potentiation of BRCA1/2 mutant tumors in vitro experiments. Furthermore, some clinical trials, such as NCT02400472, are exploring the use of ATM inhibitors in combination with standard treatment regimens to assess their safety and efficacy in patients with advanced or metastatic breast and ovarian cancer. DNA-PK target and inhibitor profile:

DNA-PK (DNA-dependent protein kinase) inhibitors are one of the focus of cancer treatment research in recent years due to their critical role in the DNA repair pathway. DNA-PK is primarily involved in Non-homologous end joining (Non-Homologous End Joining, NHEJ) repair mechanisms, a process that is critical for maintaining genomic stability, but in tumor cells, overactive NHEJ may cause DNA damage to repair too rapidly, thereby promoting survival and proliferation of tumor cells (Smith et al, oncotarget,9 (32), 22354-22369,2018).

NHEJ is the mechanism of DSB repair used by cells outside the G2/S phase or when HR is impaired. The anticancer strategy of DNA-PK inhibitor is mainly based on blocking this repair path, so that tumor cells cannot be effectively repaired when being damaged by DNA such as chemotherapy or radiotherapy, and apoptosis is induced. For example, liu et al (2019) found in vitro and in vivo experiments that DNA-PK inhibitors in combination with chemotherapeutic drugs could significantly enhance the killing effect on ovarian and breast cancer cells, which provides new possibilities for clinical treatment.

MTOR target and inhibitor profile thereof:

mTOR (mammalian target of rapamycin) is a key regulator of cell growth and proliferation, which is located in the PI3K/AKT/mTOR signaling pathway, which is often aberrantly activated in a variety of tumors. mTOR inhibitors, by blocking this pathway, can inhibit protein synthesis by tumor cells, induce cell cycle arrest, and promote apoptosis, thus exhibiting significant anti-tumor activity (Liu et al, 2018). Many studies have shown that the mTOR signaling pathway is closely related to DNA damage repair mechanisms, and that 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 have shown that gamma H2A is aggregated during DNA damage and silence, whereas the TORC2-Gad8 signal is necessary for gamma H2A aggregation, inhibiting gamma H2A aggregation, possibly affecting chromatin structure and function to some extent, gamma H2A being closely associated with DNA double strand breaks (Adiel Cohen, et al, J Biol chem.2024Aug;300 (8): 107531). Common mTOR inhibitors include Rapamycin (Rapamycin) and its derivatives Sirolimus (Sirolimus) and everolimus (Everolimus). mTOR inhibitors have shown wide application potential in the treatment of a variety of cancers. In ovarian cancer, mTOR inhibitors can inhibit tumor angiogenesis, reduce tumor growth rate, and potentially reverse chemotherapy resistance (Wang et al, 2019).

At present, the compounds acting on the targets to realize DNA damage repair are very rare, and in view of the fact, the invention provides the imidazolone compounds with novel structures around the mechanism, and in-vitro activity experiments prove that the imidazolone compounds have good DNA damage repair and can be used for treating various diseases.

Disclosure of Invention

The invention aims to provide an imidazolone compound, a preparation method and application thereof, which can be used for DNA damage repair and treatment of various diseases.

In order to achieve the above purpose, the technical scheme of the invention is as follows:

In a first aspect, the present invention provides an imidazolone compound, which is a compound represented by formula I or formula II, a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

R ₁ is selected from H, alkyl, alkoxy, halogen, alkenyl, alkynyl;

R ₂ is selected from aryl, heteroaryl substituted or unsubstituted with 1-5 substituents;

wherein, when R ₂ is aryl substituted with 1-5 substituents in a compound of formula I, the substituted substituents are each independently selected from:

C _1-6 alkoxy, -CF ₃, halogen, C _1-6 alkyl, cyano;

When R ₂ is heteroaryl substituted with 1-5 substituents in a compound of formula I, or in a compound of formula II, the substituents are each independently selected from:

A 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, and halogen, cyano, -NH ₂, hydroxy, wherein the substituted substituent is selected from halogen, carbonyl, hydroxy, C _1-5 alkyl, aryl, cyano, -NH ₂;

R ₃ is selected from heteroaryl substituted or unsubstituted with 1-5 substituents selected from substituted amino, C _2-8 heterocyclyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 esteramino, and halogen, cyano, -NH ₂, hydroxy, wherein the substituted substituents are selected from C _1-6 alkyl, hydroxy, halogen, alkyl hydroxy, alkylamino.

Preferred scheme for R1:

Preferably, R ₁ 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.

Preferred scheme for R ₂:

preferably, when R ₂ is aryl substituted with 1-5 substituents in a compound of formula I, the substituted substituents are each independently selected from:

Methoxy, -CF ₃, F, methyl, ethyl, cyano.

Further preferred, in the compounds of formula I R ₂ is aryl substituted with 1-2 substituents each independently selected from:

Methoxy, -CF ₃, F, methyl, ethyl, cyano.

Preferably, when R ₂ is heteroaryl substituted with 1-5 substituents in a compound of formula I, or in a compound of formula II, the substituents are each independently selected from:

substituted C _1-6 alkyl and C _1-6 alkoxy, -CF ₃, halogen, C _1-6 alkyl and cyano, wherein the substituent for substitution is cyano.

Further preferred, when in the compound of formula I R ₂ is heteroaryl substituted with 1-5 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, -CF ₃, halogen, C _1-6 alkyl and cyano, wherein the substituent for substitution is cyano.

Still more preferably, when R ₂ is heteroaryl substituted with 1-5 substituents in a compound of formula I, or when in a compound of formula II, the substituents are each independently selected from substituted C _1-6 alkyl, -CF _3,,, the substituted substituent being cyano.

Still more preferably, when R ₂ is heteroaryl substituted with 1-5 substituents in a compound of formula I, or when in a compound of formula II, the substituents are each independently selected from substituted C _2-4 alkyl, -CF _3,,, the substituted substituent being cyano.

Still further preferred, when R ₂ is heteroaryl substituted with 1-5 substituents in a compound of formula I, or in a compound of formula II, the substituents are each independently selected from:-CF₃。

preferred scheme for R ₃:

Preferably, R ₃ is selected from phenyl substituted with 1-2N, the substituted substituents are selected from substituted amino, C _2-8 heterocyclyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 esteramino, and halogen, cyano, -NH ₂, hydroxy, wherein the substituted substituents are selected from C _1-6 alkyl, hydroxy, halogen, alkyl hydroxy, alkylamino.

Further preferably, R ₃ is selected from phenyl substituted with 1-2N, the substituted substituents are selected from substituted C _2-8 heterocyclyl, and cyano, -NH ₂、-NHCH₂CH₂NHCH₃、-NHCOCH₂NHCH₃, wherein the substituted substituents are selected from C _1-6 alkyl, alkyl hydroxy, alkylamino.

Further preferably, R ₃ is selected from phenyl substituted with 1-2N, the substituted substituents are selected from substituted amino, C _4-6 nitrogen heterocycle, C _1-6 alkyl, wherein the substituted substituents are selected from C _1-6 alkyl, hydroxy.

Further preferably, R ₃ is selected from phenyl substituted with 1-2N, the substituted substituents are selected from:

preferably, the compound represented by formula I is selected from:

Still more 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.

Still 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。

Still more preferred are the following compounds:

FP-318、FP-622、FP-921、FP-937、FP-938、FP-943。

Still more preferred are the following compounds:

FP-921、FP-943。

And most preferably FP-943.

Still more preferred are 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。

Still more preferred are the following compounds:

FP-286、FP-356、FP-364、FP-921、FP-943、FP-948。

In a second aspect, the present invention provides an intermediate of the aforementioned imidazolone compounds selected from the following structures:

r ₁、R₂、R₃ has the same definition as previously described;

m ₁ is halogen.

In a third aspect, the invention provides a preparation method of the imidazolone compound, which comprises the following reaction steps:

Or alternatively

Or alternatively

Or alternatively

R ₁、R₂、R₃ has the same definition as previously described;

M ₁ is halogen, M ₂ is a protecting group or is absent, and M ₃ is a protecting group.

Preferably, the protecting group is selected from Boc,

In a fourth aspect, the present invention provides the use of the aforementioned imidazolone compounds, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, for the preparation of an ATM kinase inhibitor.

In a fifth aspect, the invention provides the use of an imidazolone, stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof as hereinbefore described in the preparation of an mTOR kinase inhibitor.

In a sixth aspect, the present invention provides the use of the aforementioned imidazolones, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, for the preparation of a DNA-PK kinase inhibitor.

In a seventh aspect, the present invention provides the use of the aforementioned imidazolone compounds, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, for the preparation of an ATR kinase inhibitor.

In an eighth aspect, the present invention provides the use of the aforementioned imidazolone compounds, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, for the preparation of an inhibitor for simultaneous inhibition of ATM kinase, ATR kinase, mTOR kinase and DNA-PK kinase.

In a ninth aspect, the present invention provides the use of the aforementioned imidazolone compounds, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof for the preparation of a DNA damage repair agent.

In a tenth aspect, the present invention provides the use of the aforementioned imidazolone compounds, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases mediated by ATM kinase, ATR kinase, mTOR kinase, DNA-PK kinase or DNA damage.

Preferably, the disease is selected from at least one of a tumor (e.g. leukemia, malignant lymphoma, multiple myeloma, gastrointestinal stromal tumor, colon cancer, rectal cancer, breast cancer, liver cancer, stomach 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 fibrosarcoma of the carina skin, osteosarcoma), a metabolic disease (e.g. diabetes, obesity), a cardiovascular disease (e.g. atherosclerosis).

In an eleventh aspect, the present invention provides a pharmaceutical composition comprising the aforementioned imidazolone compound, a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

The phrase "pharmaceutically acceptable carrier" is well known in the art and includes pharmaceutically acceptable materials, components, or carriers that are suitable for administering the compounds of the present invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that assist in carrying or transporting the subject matter from one organ or body part to another organ or body part. Each carrier must be "acceptable" in terms of compatibility with other ingredients of the formulation or not deleterious to the subject. Some examples of materials that may be used as pharmaceutically acceptable carriers include sugars such as lactose, dextrose, sucrose, starches such as corn starch and potato starch, celluloses and derivatives thereof such as sodium antelope methyl cellulose, ethylcellulose and cellulose acetate, cetostearyl gum, 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, sorbitol, mannitol, and polyethylene glycols, cooling agents such as ethyl oleate and ethylene laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen water, isotonic saline, ethanol, phosphate buffers and other non-toxic compatible material wetting agents used in pharmaceutical formulations, emulsifying agents and lubricants such as sodium lauryl sulfate and stearic acid, and colorants, spacers, coating agents, sweetening agents, flavoring and aromatic 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, and the like, oil-soluble antioxidants such as ascorbyl palmitate, butylated benzoic acid (BHA), ding Huaqing-yl toluene (BHT), lecithin, propyl gallate, a-tocopherol, and the like, and metal complexes such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Suitable pharmaceutically acceptable carriers include, but are not limited to, water, saline solutions (e.g., naC 1), alcohols, acacia, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, sugars (e.g., lactose, amylose or starch), polyethylene glycol, magnesium stearate, talc, silicic acid, viscous paraffin, aromatic oils, fatty acid cool, antelope methylcellulose, polyvinylpyrrolidone, and the like. The pharmaceutical compositions may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt buffers for influencing osmotic pressure, coloring, flavoring and/or aromatic substances, and the like, which do not deleteriously react with the active compounds.

The composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. The composition may be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder. The compositions may be formulated as suppositories with conventional binders and carriers such as triglycerides. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate, and the like.

The composition may be formulated into a pharmaceutical composition suitable for intravenous administration to a human according to conventional methods. The composition may also include stabilizers and local anesthetics to reduce pain at the injection site, if desired. Typically, the ingredients are supplied separately or mixed together in unit dosage form, for example as a dry lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or sachet showing the amount of active agent. When the composition is to be administered by infusion, it may be dispersed with an infusion bottle containing pharmaceutical grade sterile water, saline or dextrose water. When the composition is to be administered by injection, a vial of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.

The pharmaceutical compositions of the present invention may also include agents that control the release of the compounds of the present invention, thereby providing timed or sustained release compositions.

Pharmaceutical compositions of the invention include those suitable for oral, rectal, topical, vaginal and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any particular case will depend on the particular subject, the nature and severity of the condition to which the active ingredient is to be administered. The pharmaceutical composition may be prepared by any method known in the art of pharmacy.

The active ingredient may be administered orally in solid dosage forms such as capsules, tablets, troches, lozenges, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient may also be administered parenterally in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Other dosage forms which may be used for the administration of the active ingredient are ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspensions for ocular 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 the active ingredient together with powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. 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 the drug over several hours. Compressed tablets may be sugar or film coated to mask any unpleasant taste and protect the tablet from air, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavoring agents to increase patient acceptance. Generally, water, suitable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably comprise a water-soluble salt of the active ingredient, a suitable stabilizer and a buffer substance as required. Antioxidants such as sodium bisulphite, sodium sulphite or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts and sodium EDTA may also be used. In addition, parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.

For administration by inhalation, the compounds of the invention may conveniently be delivered in the form of a spray from a pressurized pack or nebulizer. The compounds may also be delivered in the form of formulated powders which may be inhaled with the aid of an insufflation powder inhaler device. A preferred delivery system for inhalation is a Metered Dose Inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of formula I in a suitable propellant, such as a fluorocarbon or hydrocarbon. For ocular administration, ophthalmic formulations may be formulated with a suitable weight percent solution or suspension of a compound of formula I in a suitable ophthalmic carrier, so as to maintain the compound in contact with the surface of the eye for a time sufficient to allow penetration of the compound into the cornea and interior areas of the eye.

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

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 according to the compatibility of the combined drugs. The compounds of the invention may be administered as the sole active ingredient or in combination with a second active ingredient, including active ingredients whose use is known to be useful in the treatment of related diseases.

In a twelfth aspect, the present invention provides a method of modulating (down-regulating) the activity of a protein kinase, comprising contacting the protein kinase with an effective amount of an imidazolone compound, stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof described above. 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.

In a thirteenth aspect, the invention provides a method of repairing DNA damage comprising administering to a subject an effective amount of the protein kinase in combination with an effective amount of an imidazolone, stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The method can be used in vivo or in vitro. The individual may be a mammal, such as a human.

In a fourteenth aspect, the invention provides a method of treating an ATM kinase, ATR kinase, mTOR kinase, DNA-PK kinase, or a DNA damage mediated disease, comprising administering to a subject an effective amount of said protein kinase in combination with an effective amount of a compound, stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The method can be used in vivo or in vitro. The individual may be a mammal, such as a human.

The pharmaceutical composition is in a unit dosage form suitable for single administration of a precise dose. In other embodiments, the amount of the compound is in the range of about 0.001mg/kg body weight/day to about 1000mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5mg/kg body weight/day to about 50mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from 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 desired. In some embodiments, the compound is administered in a single dose, once daily. In other embodiments, the compounds are administered in multiple doses, more than once a day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times per day. In other embodiments, the compound is administered four times per day. In other embodiments, the compound is administered more than four times per day. In some embodiments, the individual to whom the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.

Description of the terminology:

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent inventions, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present invention, the singular is used to include the plural unless specifically stated otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.

Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy, and pharmacological methods, unless specifically defined, terms used herein in analytical chemistry, organic synthetic chemistry, and related descriptions of drugs and pharmaceutical chemistry are known in the art, the above techniques and methods may be generally performed according to a number of general and more specific references cited and discussed in the present specification, according to conventional methods well known in the art in this specification, groups and substituents thereof may be selected by one of ordinary skill in the art to provide stable moieties and compounds in this specification.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, CH ₂ O is equivalent to OCH ₂.

Unless otherwise indicated, general chemical terms used, such as, but not limited to, "alkyl", "amine", "aryl", and the like, are equivalent to optionally substituted versions thereof. For example, "alkyl" as used herein includes optionally substituted alkyl.

The term "optionally/arbitrarily" or "optionally/arbitrarily" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, according to the definition below, "optionally substituted alkyl" refers to "unsubstituted alkyl" (alkyl substituted with a substituent) or "substituted alkyl" (alkyl substituted with a substituent).

As used herein, C ₁-C_n includes C ₁-C₂、C₁-C₃、……C₁-C_n. For example, the "C ₁-C₄" group refers to a moiety having 1 to 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, reference to "C ₁-C₄ alkyl" means an alkyl group having from 1 to 4 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Numerical ranges, for example, "1-10" herein refers to each integer in the given range, e.g., "1-10 carbon atoms" refers to the group can 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.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein may preferably have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms, or from 1 to about 3 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl and octyl and the like. Where a numerical range is present for a group as defined herein, such as "alkyl", for example "C ₁-C₆ alkyl" or "C _1-6 alkyl" refers to an alkyl group that may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkyl groups herein also include those instances where a numerical range is not specified.

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

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

The term "alkenyl", as used herein alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon radical 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 may be in either cis or trans conformation and should be understood to include both isomers. Examples include, but are not limited to, vinyl (ch=ch ₂), 1-propenyl (CH ₂CH＝CH₂), isopropenyl (C (CH ₃)＝CH₂), butenyl, and 1, 3-butadienyl, and the like, where alkenyl groups as defined herein appear in numerical ranges, for example, "C ₂-C₆ alkenyl" or "C _2-6 alkenyl" refers to alkenyl groups that may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkenyl groups herein are also intended to cover instances where numerical ranges are not specified.

The term "alkynyl", as used herein alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical 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, it has 2 to about 10 carbon atoms, or has 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, 1, 3-butadiynyl, and the like. Where alkynyl groups are defined herein to have a numerical range, for example "C ₂-C₆ alkynyl" or "C _2-6 alkynyl" refers to alkynyl groups that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified.

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

The term "aryl/aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon group having from 6 to about 20, such as from 6 to 12 or from 6 to 10, ring-forming carbon atoms, which may be a monocyclic aryl, bicyclic aryl or more. The bicyclic aryl or more can be a monocyclic aryl fused to other independent rings, such as alicyclic, heterocyclic, aromatic heterocyclic rings. Non-limiting examples of monocyclic aryl groups include monocyclic aryl groups of 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms, such as phenyl, bicyclic aryl groups such as naphthyl, polycyclic aryl groups such as phenanthryl, anthracyl, azulenyl.

The term "heteroaryl" as used herein, alone or in combination, refers to an optionally substituted heteroaryl group comprising from about 5 to about 20, such as 5 to 12 or 5 to 10, backbone ring atoms, wherein at least one (e.g., 1-4, 1-3, 1-2) ring atoms are heteroatoms independently selected from heteroatoms in the group consisting of 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 are present in the ring, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another. The bicyclic heteroaryl or more heteroaryl groups may be a monocyclic heteroaryl group fused to other independent rings, such as alicyclic, heterocyclic, aromatic heterocyclic rings (which may be collectively referred to as fused-ring heteroaryl groups). Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups of 5 to about 12, 5 to about 10, 5 to about 7, or 6 framework ring atoms, for example non-limiting examples of which include pyridyl, fused-ring heteroaryl groups include benzimidazolyl (benzimidazolyl), quinolinyl (quinolinyl), acridinyl (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, benzotriazole, isoquinolyl, azoindenyl (indolizinyl), isothiazolyl (isothiazolyl), isoxazolidinyl (isoindolyl), oxadiazolyl (oxadiazolyl), purinyl (purinyl), phthalazinyl (phthalazinyl), pteridinyl (pteridinyl), quinazolinyl (quinazolinyl), quinoxalinyl (quinoxalinyl), triazinyl (triazinyl), thiadiazolyl (thiadiazolyl), and the like, and oxides thereof, such as pyridine-N-oxide (pyridylN, and the like.

The term "heterocycle" or "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocycle that includes saturated or unsaturated heterocycles (containing unsaturation). Wherein one or more (e.g., 1-4, 1-3, 1-2) of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen or sulfur atoms. Heterocycles may include mono-heterocycles (having one ring) or bi-heterocycles (having two bridged rings) or multi-heterocycles (having more than two bridged rings), as well as spiro rings. The heterocyclyl may have 3 to about 20, such as 3 to about 10, 3 to about 8, 4 to 7, 5 to about 8, or 5 to about 6 ring forming atoms. Non-limiting examples of heterocyclyl groups include azinyl (azinyl), azetidinyl (azetidinyl), oxetanyl (oxetanyl), thietanyl (thietanyl), homopiperidinyl (homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl (1, 2,3, 6-tetrahydropyridinyl), 2-pyrrolinyl (2-pyrrolinyl), and, 3-pyrrolinyl (3-pyrrolinyl), indolinyl (indolinyl), 2H-pyranyl (2 Hpyranyl), 4H-pyranyl (4H-pyranyl), dioxacyclohexyl (dioxanyl), 1, 3-dioxolanyl (1, 3-d ioxolanyl), pyrazolinyl (pyra zolinyl), dithiocyclohexyl (D ITHIANYL), dithiocyclopentyl (dithiolanyl), dihydropyranyl (dihydropyranyl), dihydrothienyl (dihydrothienyl), and, Dihydrofuryl (dihydrofuranyl), pyrazolidinyl (pyrazolidinyl), imidazolinyl (imidazolinyl), imidazolidinyl (imidazolidinyl), 3-azabicyclo [3.1.0] hexyl (3-azabicyclo [3.1.0] hexyl), 3-azabicyclo [4.1.0] heptyl (3-azabicyclo [4.1.0] hepyl), 3H-indolyl (3H-indolyl), quinolinyl (quinolizinyl), and the like. 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 heterocycles having 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, naphthalimide. Heterocyclic groups having one or more aromatic linkages may be attached to other groups through aromatic or non-aromatic ring moieties. other groups may be bound to the heterocycle through a heteroatom or carbon atom (i.e., the heterocycle is attached to the parent molecule or further substituted).

The term "carbocycle" or "carbocyclyl" as used herein, alone or in combination, refers to a non-aromatic carbon-containing ring, including a saturated carbocycle (e.g., cycloalkyl) or an unsaturated carbocycle (e.g., cycloalkenyl). Carbocycles include monocycles (having one ring), such as monocyclic cycloalkyl, bicyclic carbocycles (having two rings), such as bicyclic cycloalkyl, and multicyclic (having more than two rings). The rings may be bridged or spiro. Carbocycles (e.g., cycloalkyl or cycloalkenyl) can have 3 to 20 carbon atoms, for example, 3 to about 15 ring-forming carbon atoms, or 3 to about 10 ring-forming carbon atoms, or 3 to 6 ring-forming carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, adamantyl and the like.

"Halogen" means fluorine, chlorine, bromine, iodine. Most preferred are fluorine, chlorine and bromine. Cyano refers to "-CN", hydroxy refers to "-OH", mercapto refers to "-SH", and amino refers to "-NH ₂".

The term "substituted" means that one or more hydrogens on a particular atom are replaced with a selection of moieties, where the normal valence of the selected atom is not exceeded, as in the present case, the result is a stable compound.

All ranges set forth herein are inclusive unless explicitly stated. For example, "n has a value of an integer between 0 and 2" means that n may be 0,1 or 2.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from inorganic or organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganous), potassium, sodium, zinc, and the like. Preferred are salts of ammonium, calcium, magnesium, potassium, sodium, and the like. Salts prepared from organic bases include primary, secondary and tertiary amines of natural and synthetic origin. Pharmaceutically acceptable organic non-toxic bases that can form salts include arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention are basic, their corresponding salts can be readily 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.

The term "solvate" refers to a variable stoichiometric complex formed from 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, the hemihydrate, the mono-hemihydrate, the di-hemihydrate, and the tri-hydrate.

The term "prodrug" is a functional derivative of a compound of the invention that is readily converted in vivo to the desired compound. Various prodrug forms are well known in the art. See, chapter Pro-drugs as Novel Delivery Systems(1987)Vol.14of the A.C.S.Symposium Series,BioreversibleCarriers in Drug Design,(1987)Edward B.Roche,ed.,American Pharmaceutical Association and Pergamon Press, discussed .Design ofProdrugs,Bundgaard,A.Ed.,Elseview,1985and Method in Enzymology,Widder,K.etal.,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,, pages 113-191, and Bundgaard, H., advanced Drug DELIVERY REVIEW,1992,8,1-38, incorporated herein by reference, for prodrugs.

"Subject," "patient," or "individual" refers to an individual having a disease, disorder, or condition, and the like, and includes 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), domestic animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs and cats, laboratory animals including rodents such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.

The term "treating" and other similar synonyms include alleviating, alleviating or ameliorating symptoms of a disease or disorder, preventing other symptoms, ameliorating or preventing underlying metabolic causes that lead to symptoms, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating symptoms that result from a disease or disorder, or halting symptoms of a disease or disorder, and furthermore, the term encompasses prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, the cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in patient condition is observed, although the patient may still be affected by the underlying disease. In terms of prophylactic effect, the composition may be administered to a patient at risk of developing a particular disease, or even if a disease diagnosis has not been made, to a patient exhibiting one or more physiological symptoms of the disease.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. The skilled artisan is familiar with the techniques of administration that can be used with 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.

The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term deleterious effect on the general health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

The term "pharmaceutical composition" refers to a biologically active compound optionally admixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and/or excipients.

The term "carrier" refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.

The term "metabolic disease" refers to a disease caused by metabolic problems, including metabolic disorders and metabolic hyperactivity, and mainly includes diabetes, diabetic ketoacidosis, hyperglycemic hypertonic syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, osteoporosis, and the like.

The term "cardiovascular disease" is also known as circulatory disease and is a series of diseases involving the circulatory system, which refers to organs and tissues in the human body that carry blood, mainly including the heart, blood vessels (arteries, veins, micro-blood vessels), and can be subdivided into acute and chronic diseases, typically associated with arteriosclerosis. Cardiovascular diseases include heart disease, hypotension, hypertension, hyperglycemia, apoplexy, myocardial infarction, thrombosis, arteriosclerosis, etc.

The invention has the beneficial effects that the imidazolone compound with a novel structure and the preparation method thereof have obvious inhibition effect on the expression of various protein kinases and have inhibition activity on various tumor cells.

Detailed Description

The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the application and are not intended to limit the application in any way. The following is merely exemplary of the scope of the application as claimed and many variations and modifications of the application will be apparent to those skilled in the art in light of the disclosure, which are intended to be within the scope of the application as claimed.

The invention is further illustrated by means of the following specific examples. The various chemical reagents used in the examples of the present invention were obtained by conventional commercial means unless otherwise specified. Unless otherwise specified, the contents are mass contents in the following. Unless otherwise indicated, it is understood that it is carried out at room temperature.

The compounds of the invention having the formulae described herein can be prepared from commercially available starting materials or starting materials that can be prepared using literature procedures according to the procedures illustrated in the general schemes 1-7 below. Variables in each general synthetic route (e.g., R ₁、R₂ and R ₃, etc.) are as defined herein. It should be noted by those of ordinary skill in the art that the order of certain steps may be varied in the reaction procedures and synthetic schemes described herein, such as the introduction and removal of protecting groups.

General scheme 1

General scheme 2

General scheme 3

General scheme 4

It should be noted that, in the present invention, the intermediate 4500 is example 56 of patent WO2014079364A1, the synthesis method and route are identical, the intermediate 9A is intermediate 9A of patent CN104447740a, the synthesis method and route are identical to those of intermediate 9A, and the intermediate 208d is intermediate 208 of patent CN104447740a, the synthesis method and route are identical to those of intermediate 208.

EXAMPLE 1 Synthesis of Compound FP-286 (4005)

Intermediate 4000:2- (4- ((6-chloro-3-nitro-1, 5-naphthyridin-4-yl) amino) phenyl) -2-methylpropanenitrile

5.0G (31.2 mmol) of 2- (4-aminophenyl) -2-methylpropanenitrile are dissolved in 40mL of acetic acid, 7.6g (31.1 mmol) of 2, 8-dichloro-7-nitro-1, 5-naphthyridine are added and stirred at room temperature for 5 hours, and a solid is precipitated. TLC detection, filtration after completion of the reaction, washing of the cake with acetic acid, and vacuum drying of the cake gave 10.6g of a yellow powdery product in 92.6% yield. LC-MS (ESI) m/z 368.1,370.1[ M+H ] ⁺.

Intermediate 4001:2- (4- ((3-amino-6-chloro-1, 5-naphthyridin-4-yl) amino) phenyl) -2-methylpropanenitrile

5.6G (15.23 mmol) of intermediate 4000 was dissolved in 50mL of tetrahydrofuran, 0.56g of platinum carbon (5%) was added thereto, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection is carried out, platinum carbon is removed by filtration after the reaction is finished, and the filtrate is dried by spin to obtain 5.14g of yellow solid product with 100 percent yield. LC-MS (ESI) m/z 338.1,340.1[ M+H ] ⁺.

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

5.14G (15.2 mmol) of intermediate 4001 was dissolved in 30mL of methylene chloride under ice-water bath, then 3.1g (30.4 mmol) of triethylamine was added, followed by dropwise addition of a solution of 20mL of triphosgene (1.63 g,5.5 mmol) in methylene chloride to the system, and the reaction was stirred under ice-bath for 3 hours. After the completion of the reaction, the reaction was quenched by adding 60mL of saturated aqueous sodium bicarbonate, stirred for 10 minutes, 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 spun-dried to give a crude product. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, V/V) afforded 3.8g of the product as a yellow powder in 68.7% yield. LC-MS (ESI) m/z 364.1,366.1[ M+H ] ⁺.

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

3.8G (10.5 mmol) of intermediate 4002 was dissolved in 50mL of methylene chloride, 0.034g (0.105 mmol) of tetrabutylammonium bromide and 50mL of aqueous sodium hydroxide solution (10%) were added, stirred for 10 minutes, and 4.5g (31.5 mmol) of methyl iodide were added, and stirred at room temperature for 4 hours. TLC detection, standing and layering after the reaction is finished, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying, filtering, and spin-drying filtrate to obtain 2.7g of yellow solid product, wherein the yield is 68.1%. LC-MS (ESI) m/z 378.1,380.1[ M+H ] ⁺.

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

200Mg (0.53 mmol) of intermediate 4003 and 253mg (0.79 mmol) of 2- (BOC-amino) pyrrolidine-5-boronic acid pinacol ester are dissolved in 15mL of dioxane under nitrogen, 518mg (1.59 mmol) of cesium carbonate, 5mL of 2M aqueous sodium carbonate solution and 56mg (0.053 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride are added in succession and stirred at 110℃for 5 hours. TLC detection is carried out, after the reaction is finished, most of the solvent is removed by concentration, water is added for dilution, dichloromethane is used for extracting water phase, the organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is dried by spin to obtain crude product. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1, v: v) to give 150mg of the product as a yellowish powder in 52.8% yield. LC-MS (ESI) m/z 536.2[ M+H ] ⁺.

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

150Mg (0.28 mmol) of intermediate 4004 was dissolved in 2.5mL of methanol, to which was added 2.5mL of a 2M solution of 1, 4-dioxane in hydrogen chloride, and stirred at room temperature for 4 hours, and a solid was precipitated. TLC detection, filtering after the reaction is finished, washing a filter cake with a small amount of methanol, then regulating the pH value to 8-9 with saturated sodium bicarbonate solution, extracting an aqueous phase with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering and discarding solids, and spinning the filtrate to obtain a crude product, wherein the crude product is purified by preparative TLC (dichloromethane/methanol=10/1, V: V), so that 90mg of yellow powdery product is obtained, and the yield is 73.8%. LC-MS (ESI) m/z 436.2[ M+H ] ⁺.

¹H 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(dd,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).

EXAMPLE 2 Synthesis of Compound FP-309 (4105)

Intermediate 4101:6-bromo-N- (4-tert-butyl) phenyl-3-nitroquinolin-4-amine

2.6G (9.0 mmol) of the compound 6-bromo-4-chloro-3-nitroquinoline and 1.5g (10.0 mmol) of 4- (tert-butyl) aniline are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, water dilution after the reaction, massive solid precipitation, filtration, water washing of filter cake, and filter cake drying, 3.6g yellow solid product is obtained, and the yield is 99.5%. LC-MS (ESI) m/z 400.2,402.2[ M+H ] ⁺.

Intermediate 4102:6-bromo-N ⁴ (4- (tert-butyl) phenyl) -quinoline-3-4-diamine

3.6G (9.0 mmol) of intermediate 4101 was dissolved in 20mL of tetrahydrofuran, 0.5g of platinum carbon (5%) was added thereto, hydrogen was introduced thereinto, and the mixture was stirred at room temperature overnight. TLC detection, after completion of the reaction, filtration, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 3.0g of a dark yellow solid product in 90.1% yield. LC-MS (ESI) m/z 370.2,372.2[ M+H ] ⁺.

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

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

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

2.5G (6.3 mmol) of intermediate 4103 was dissolved in 100mL of methylene chloride, 0.24g (0.75 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, stirred for 10 minutes, then 1.41mL (22.6 mmol) of methyl iodide was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, V:V) to obtain 2.0g of yellow solid product, wherein the yield is 77.2%. LC-MS (ESI) m/z 410.2,412.2[ M+H ] ⁺.

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

100Mg (0.24 mmol) of intermediate 4104 and 75mg (0.26 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, and 50mg (0.4 mmol) of sodium carbonate, 2mL of water and 13.86mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto and reacted at 80℃for 5 hours with stirring. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting aqueous phase, organic phase is dried by anhydrous sodium sulfate and filtered, and the filtrate is dried by spinning to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) afforded 18mg of the product as a white solid in 15.4% yield. LC-MS (ESI) m/z 489.3[ M+H ] ⁺.

¹H 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).

EXAMPLE 3 Synthesis of Compound FP-310 (4201)

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

To the reaction flask were successively added 5ml of t-butanol, 100mg (0.24 mmol) of intermediate 4104, 80mg (0.37 mmol) of 2-aminopyridine-5-boronic acid pinacol ester, 51mg (0.48 mmol) of Na ₂CO₃, 1ml of water and 35mg (0.03 mmol) of Pd (PPh ₃)₄) in an atmosphere of N ₂, heated to 80℃and stirred overnight for reaction.

¹H 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).

EXAMPLE 4 Synthesis of Compound FP-313 (4305)

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

To the reaction flask were successively added 10ml of DMF (N, N-dimethylformamide), 1.75g (6.09 mmol) of 6-bromo-4-chloro-3-nitroquinoline, 1g (6.09 mmol) of the compound 4-amino-N, N-dimethylbenzamide and 1g (9.88 mmol) of triethylamine, and the reaction was stirred at room temperature overnight. After the reaction is finished, 20ml of water is added for dilution, yellow solid is separated out, stirring is continued for 20min, filtering is carried out, filtrate is removed, and filter cake is dried to obtain 1.4g of yellow solid product, and the yield is 55.4%. LC-MS (ESI): 415.1,417.1[ M+H ] ⁺.

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

To the reaction flask, 20ml of tetrahydrofuran, 1.0g (2.41 mmol) of intermediate 4301 and 0.2g of platinum carbon were successively added, and hydrogen was introduced thereinto to stir the reaction at room temperature for 24 hours. TLC detection, filtering after the reaction is finished, discarding solids, and concentrating the filtrate under reduced pressure to obtain 0.93g of pale yellow solid product with 100% yield. LC-MS (ESI): 385.1,387.1[ M+H ] ⁺.

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

0.8G (2.08 mmol) of the intermediate 4302 was dissolved in 10ml of methylene chloride, and then a solution of 10ml of triphosgene (0.37 g,1.25 mmol) in methylene chloride was added dropwise thereto, and after the completion of the addition, the reaction was stirred at room temperature overnight. After the TLC detection, 20ml petroleum ether is added to the reaction, solid is separated out, the filtration is carried out, the filtrate is removed, and the filter cake is dried to obtain 0.86g yellow solid product, and the yield is 100%. LC-MS (ESI): 411.1,413.1[ M+H ] ⁺.

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

To the reaction flask were successively added 10ml of methylene chloride, 0.86g (2.08 mmol) of intermediate 4303, 0.068g (0.21 mmol) of tetrabutylammonium bromide, 0.92g (6.48 mmol) of methyl iodide and 10ml of aqueous NaOH solution (10%), stirred well and reacted at room temperature for 8 hours. After the reaction is finished, 20ml of water is added to the reaction liquid for dilution, 40ml of dichloromethane is added for extraction, the organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to obtain a crude product. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, V/V) afforded 0.42g of the product as a red solid in 47.5% yield. LC-MS (ESI): 425.1,427.1[ M+H ] ⁺.

Compound 4305N, 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

To the reaction flask were successively added 10ml of t-butanol, 100mg (0.24 mmol) of intermediate 4304, 71mg (0.25 mmol) of 9a, 53mg (0.5 mmol) of Na ₂CO₃, 2ml of water and 29mg (0.025 mmol) of Pd (PPh ₃)₄, stirred well, heated to 80℃in an atmosphere of N ₂ and stirred overnight for TLC detection, after completion of the reaction the solvent was removed by concentration, then diluted with 20ml of water, then 40ml of dichloromethane was added to extract the aqueous phase, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give a crude product which was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, V/V) to give 30mg of the product in 24.8% LC-MS (ESI): 504.3[ M+H ] ⁺.

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＝8.9,2.0Hz,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).

Example 5 Synthesis of FP-318 (4405)

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

2.6G (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.5g (11.1 mmol) of 4-aminoacetophenone are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. After TLC detection, water is added to separate out solid, filtering is carried out, a filter cake is washed by water, and the filter cake is dried to obtain 3.5g of yellow solid product, and the yield is 100%. LC-MS (ESI) m/z 386.2,388.2[ M+H ] ⁺.

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

2.4G (6.2 mmol) of intermediate 4401 was dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.2g of a dark yellow solid product in 100% yield. LC-MS (ESI) m/z 356.2,358.2[ M+H ] ⁺.

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

2.2G (6.2 mmol) of intermediate 4402 was dissolved in 20mL of methylene chloride, and a solution of 10mL of triphosgene (1.9 g,6.4 mmol) in methylene chloride was added dropwise thereto, and the reaction was stirred at room temperature for 4 hours. After the completion of the reaction, 40ml of petroleum ether was added and stirred for 10 minutes, and a solid was precipitated, collected by filtration, and dried under reduced pressure to give 2.3g of a yellow powdery product in 97.4% yield. LC-MS (ESI) m/z 382.2,384.2[ M+H ] ⁺.

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

2.3G (6.0 mmol) of intermediate 4403 was dissolved in 100mL of methylene chloride, to which 0.24g (0.7 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, stirred for 10 minutes, and 1.12mL (20.5 mmol) of methyl iodide was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, V:V) to obtain 2.0g of a yellow solid product, wherein the yield is 84.0%. MS (ESI) m/z 396.2,398.2[ M+H ] ⁺.

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

100Mg (0.25 mmol) of intermediate 4404 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were added 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol=20/1, v: v) to give 13mg of the product as a white solid in 10.9% yield. LC-MS (ESI) m/z 475.2[ M+H ] ⁺.

¹H 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).

EXAMPLE 6 Synthesis of Compound FP-334 (4501)

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

100Mg (0.2 mmol) of compound 4500 is added to 2mL of concentrated hydrochloric acid and the reaction is stirred at 60℃for 12 hours. TLC detection is carried out, after the reaction is finished, the solution is dried to obtain solid, then saturated sodium bicarbonate solution is used for adjusting the pH value to 8-9, ethyl acetate is used for extracting aqueous phase, organic phase is dried by anhydrous sodium sulfate, solid is filtered and removed, and filtrate is dried to obtain crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol=10/1, V/V) to give 12mg of the product as a white powder in 11.6% yield. LC-MS (ESI) m/z 519.2[ M+H ] ⁺.

¹H 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),8.19(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).

EXAMPLE 7 Synthesis of Compound FP-337 (4605)

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

1G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.57g (4.17 mmol) of 1- (4-aminophenyl) ethanol were dissolved in 10mL of methylene chloride, to which 0.70g (6.96 mmol) of triethylamine was added, and stirred at room temperature overnight, and a solid was precipitated. TLC detection, filtration after completion of the reaction, washing of the cake with dichloromethane and vacuum drying of the cake gave 1.1g of a yellow solid product in 81.5% yield. LC-MS (ESI) m/z 388.1,390.1[ M+H ] ⁺.

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

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

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

1.0G (2.79 mmol) of intermediate 4602 was dissolved in 10mL of methylene chloride in an ice-water bath, 0.98g (9.7 mmol) of triethylamine was added thereto, and a 10mL methylene chloride solution of triphosgene (0.31 g,1.03 mmol) was added dropwise thereto, and the reaction was stirred at room temperature for 5 hours to precipitate a solid. TLC detection, filtration after completion of the reaction, washing of the filter cake with a small amount of dichloromethane, and drying of the filter cake gave 0.8g of product in 74.6% yield. LC-MS (ESI) m/z 384.1,386.1[ M+H ] ⁺.

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

0.8G (2.08 mmol) of intermediate 4603 was added to 10mL of N, N-dimethylformamide, followed by 0.58g (4.16 mmol) of potassium carbonate, and after stirring for 10 minutes, 0.59g (4.16 mmol) of methyl iodide was added thereto, and stirring was carried out at room temperature for 4 hours. TLC detection is carried out, standing and layering are carried out after the reaction is finished, an organic phase is separated, an aqueous phase is extracted by methylene dichloride, the organic phases are combined and dried, filtration is carried out, and a crude product is obtained by spin-drying filtrate. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) afforded 0.6g of the product as a yellow solid in 72.5% yield. LC-MS (ESI) m/z 398.1,400.1[ M+H ] ⁺.

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

0.1G (0.25 mmol) of intermediate 4604 and 0.11g (0.37 mmol) of intermediate 9a were dissolved in 10mL of 1, 4-dioxane under nitrogen, and then 0.24g (0.75 mmol) of cesium carbonate, 1mL of 2M aqueous sodium carbonate and 0.024g (0.025 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were sequentially added thereto, and the reaction was stirred at 110℃for 5 hours. After the completion of the reaction, the reaction mixture was concentrated to remove most of the solvent, 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 give a crude product. The crude product was purified by prep. silica gel plate (dichloromethane/methanol=10/1, V/V) to give 31mg of the product as a white powder in 26.0% yield. LC-MS (ESI) m/z 477.2[ M+H ] ⁺.

¹H 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).

EXAMPLE 8 Synthesis of Compound FP-342 (4705)

Intermediate 4701:6-bromo-3-nitro-N- (6- (trifluoromethyl) pyridin-3-yl) quinolin-4-amine

1G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.68g (4.17 mmol) of 5-amino-2-trifluoromethylpyridine were dissolved in 10mL of acetic acid, and the reaction was stirred at room temperature overnight to precipitate a solid. TLC detection, filtration after completion of the reaction, washing of the cake with glacial acetic acid and vacuum drying gave 1.44g of yellow solid product in 100% yield. LC-MS (ESI) m/z 413.0,415.0[ M+H ] ⁺.

Intermediate 4702:6-bromo-N ⁴ - (6- (trifluoromethyl) pyridin-3-yl) quinoline-3, 4-diamine

1.44G (3.48 mmol) of intermediate 4701 was dissolved in 10mL of ethanol, 0.15g of platinum carbon was added thereto, and the reaction was stirred at room temperature for 12 hours by introducing hydrogen. TLC detection, filtration after completion of the reaction, washing of the cake with ethanol, spin-drying of the filtrate gave 1.33g of a yellow solid product, 100% yield. LC-MS (ESI) m/z 383.0,385.0[ M+H ] ⁺.

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

1.33G (3.48 mmol) of intermediate 4702 was dissolved in 15mL of methylene chloride in an ice-water bath, 1.05g (10.44 mmol) of triethylamine was added thereto, and then a solution of 10mL of triphosgene (0.35 g,1.16 mmol) in methylene chloride was added dropwise thereto, followed by stirring at room temperature for 5 hours, whereby a solid was precipitated. TLC detection, filtration after completion of the reaction, washing of the cake with dichloromethane and drying of the cake gave 0.9g of product in 63.2%. LC-MS (ESI) m/z 409.0,411.0[ M+H ] ⁺.

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

0.9G (2.20 mmol) of intermediate 4703 was added to 10mL of methylene chloride, 0.07g (0.22 mmol) of tetrabutylammonium bromide and 10mL of sodium hydroxide solution (10%) were added, and after stirring for 10 minutes, 0.94g (6.60 mmol) of methyl iodide was added, and stirring was carried out at room temperature for 4 hours. TLC detection, standing and layering after the reaction is finished, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering to remove solids, and spinning the filtrate to obtain a crude product. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) afforded 0.7g of the product as a yellow solid in 75.3% yield. LC-MS (ESI) m/z 423.0,425.0[ M+H ] ⁺.

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

0.1G (0.24 mmol) of intermediate 4704 and 0.10g (0.35 mmol) of intermediate 9a were dissolved in 10mL of 1, 4-dioxane under nitrogen, and 0.22g (0.69 mmol) of cesium carbonate, 1mL of 2M aqueous sodium carbonate solution and 0.020g (0.024 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added thereto in this order and reacted at 110℃for 5 hours with stirring. TLC detection, concentration and removal of most of the solvent after the reaction is finished, water dilution is added, the aqueous phase is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate, filtration and spin-drying of the filtrate are carried out to obtain crude products. The crude product was purified by prep. silica gel plate (dichloromethane/methanol=10/1, V/V) to give 21mg of the product as a white powder in 17.4% yield. LC-MS (ESI) m/z 502.2[ M+H ] ⁺.

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＝8.8Hz,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).

EXAMPLE 9 Synthesis of Compound FP-345 (4805)

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

1G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.74g (4.17 mmol) of 4-amino-N-isopropylbenzamide were dissolved in 10mL of acetic acid, and the reaction was stirred at room temperature overnight to precipitate a solid. TLC detection, after completion of the reaction, filtration, washing of the cake with glacial acetic acid, and vacuum drying of the cake gave 1.49g of a yellow solid product in 100% yield. LC-MS (ESI) m/z 429.1,431.1[ M+H ] ⁺.

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

1.49G (3.48 mmol) of intermediate 4801 was dissolved in 10mL of ethanol, 0.16g of platinum carbon (5%) was added thereto, and the reaction was stirred at room temperature for 12 hours by introducing hydrogen. TLC detection, after completion of the reaction, filtration, washing of the cake with a small amount of ethanol, spin-drying of the filtrate gave 1.39g of a yellow solid product in 100% yield. LC-MS (ESI) m/z 399.1,401.1[ M+H ] ⁺.

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

1.39G (3.48 mmol) of intermediate 4802 was dissolved in 15mL of methylene chloride in an ice-water bath, 1.05g (10.44 mmol) of triethylamine was added thereto, a solution of 10mL of triphosgene (0.34 g,1.16 mmol) in methylene chloride was added dropwise thereto, and the mixture was stirred at room temperature for 5 hours, whereby a solid was precipitated. TLC detection, after completion of the reaction, filtration, washing of the cake with a small amount of dichloromethane, and drying of the cake gave 1.2g of the product in 81.1% yield. LC-MS (ESI) m/z 425.1,427.1[ M+H ] ⁺.

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

1.2G (2.82 mmol) of intermediate 4803 was added to 12mL of methylene chloride, followed by 0.09g (0.28 mmol) of tetrabutylammonium bromide and 12mL of sodium hydroxide solution (10%), followed by stirring for 10 minutes, and then 1.16g (8.19 mmol) of methyl iodide was added thereto, and the reaction was stirred at room temperature for 4 hours. TLC detection, standing and layering after the reaction is finished, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering to remove solids, and spinning the filtrate to obtain a crude product. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) to give 0.9g of a yellow solid product in 72.7% yield. LC-MS (ESI) m/z 439.1,441.1[ M+H ] ⁺.

Compound 4805N-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

100Mg (0.23 mmol) of intermediate 4804 and 100mg (0.35 mmol) of intermediate 9a were dissolved in 5mL of dioxane under nitrogen, then 225mg (0.69 mmol) of cesium carbonate, 1mL of 2M aqueous sodium carbonate solution and 19mg (0.023 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were sequentially added and reacted at 110℃for 5 hours with stirring. TLC detection is carried out, after the reaction is finished, most of the solvent is removed by concentration, water is added for dilution, dichloromethane is used for extracting water phase, the organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is dried by spin to obtain crude products. The crude product was purified by prep. silica gel plate (dichloromethane/methanol=10/1, V/V) to give 37mg of the product as a white powder in 31.1% yield. LC-MS (ESI) m/z 518.2[ M+H ] ⁺.

¹H NMR(600MHz,DMSO)δ9.03(s,1H),8.49-8.46(m,2H),8.28(s,1H),8.19-8.15(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).

EXAMPLE 10 Synthesis of Compound FP-346 (4905)

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

1G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.63g (4.17 mmol) of 4-amino-N-methylbenzamide were dissolved in 10mL of acetic acid, and the mixture was stirred at room temperature overnight to precipitate a solid. TLC detection, after completion of the reaction, filtration, washing of the cake with glacial acetic acid and vacuum drying gave 1.4g of a yellow solid product in 100% yield. LC-MS (ESI) m/z 401.1,403.1[ M+H ] ⁺.

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

1.4G (3.48 mmol) of intermediate 4901 was dissolved in 20mL of ethanol, 0.17g of platinum carbon (5%) was added thereto, and hydrogen was introduced thereinto and stirred at room temperature for 12 hours. TLC detection, after completion of the reaction, filtration, washing of the cake with a small amount of ethanol, spin-drying of the filtrate gave 1.29g of a yellow solid product in 100% yield. LC-MS (ESI) m/z 371.1,373.1[ M+H ] ⁺.

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

1.29G (3.48 mmol) of intermediate 4902 was dissolved in 15mL of methylene chloride in an ice water bath, 1.05g (10.44 mmol) of triethylamine was added thereto, a solution of 10mL of triphosgene (0.35 g,1.16 mmol) in methylene chloride was added dropwise thereto, and the mixture was stirred at room temperature for 5 hours, whereby a solid was precipitated. TLC detection, after completion of the reaction, filtration, washing of the cake with a small amount of dichloromethane, and drying of the cake gave 0.8g of the product in 57.9% yield. LC-MS (ESI) m/z 397.1,399.1[ M+H ] ⁺.

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

0.8G (2.01 mmol) of intermediate 4903 was added to 10mL of methylene chloride, followed by 0.064g (0.20 mmol) of tetrabutylammonium bromide and 10mL of sodium hydroxide solution (10%), followed by stirring for 10 minutes, and then 0.86g (6.03 mmol) of methyl iodide was added, and the reaction was stirred at room temperature for 4 hours. TLC detection is carried out, after the reaction is finished, standing is carried out, layering is carried out, an organic phase is separated, a water phase is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate, filtering is carried out, and a filtrate is dried by spinning to obtain a crude product. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) afforded 0.6g of the product as a yellow solid in 72.6% yield. LC-MS (ESI) m/z 411.1,413.1[ M+H ] ⁺.

Compound 4905N-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

100Mg (0.24 mmol) of intermediate 4904 and 101mg (0.36 mmol) of intermediate 9a were dissolved in 5mL of 1, 4-dioxane under nitrogen, then 233mg (0.62 mmol) of cesium carbonate, 1mL of 2M aqueous sodium carbonate solution and 19.5mg (0.024 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added in this order, and the reaction was stirred at 110℃for 5 hours. TLC detection, concentration and removal of most of the solvent after the reaction is finished, water dilution is added, the aqueous phase is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate, filtration and spin-drying of the filtrate are carried out to obtain crude products. The crude product was purified by preparative silica gel plate (dichloromethane/methanol=10/1, V/V) to give 44mg of the product as a white powder in 37.0% yield. LC-MS (ESI) m/z 490.2[ M+H ] ⁺.

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,1H),7.78(d,J＝8.3Hz,2H),7.70(dd,J＝8.2,2.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.27(d,J＝1.4Hz,1H),3.89(s,3H),3.62(s,3H),2.88(d,J＝4.4Hz,3H).

EXAMPLE 11 Synthesis of Compound FP-353 (5005)

Intermediate 5001:6-bromo-N- (4-fluorophenyl) -3-nitroquinolin-4-amine

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

Intermediate 5002:6-bromo-N4- (4-fluorophenyl) quinoline-3, 4-diamine

2.2G (6.6 mmol) of intermediate 5001 were dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) were added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.1g of a dark yellow solid product in 100% yield. LC-MS (ESI) m/z 332.0,334.0[ M+H ] ⁺.

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

2.1G (6.2 mmol) of intermediate 5002 was dissolved in 20mL of methylene chloride, and a solution of 10mL of triphosgene (1.9 g,6.4 mmol) in methylene chloride was added dropwise thereto, and the reaction was stirred at room temperature for 4 hours. After the completion of the reaction, 40ml of petroleum ether was added and stirred for 10 minutes, and a solid was precipitated, collected by filtration, and dried under reduced pressure to give 2.2g of a yellow powdery product in 99.1% yield. LC-MS (ESI) m/z 358.1,360.1[ M+H ] ⁺.

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

2.2G (6.0 mmol) of intermediate 5003 was dissolved in 100mL of methylene chloride, to which 0.24g (0.7 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, stirred for 10 minutes, and 1.12mL (20.5 mmol) of methyl iodide was added, and stirred at room temperature for 4 hours. TLC detection, standing and layering after the reaction is finished, separating an organic phase, extracting an aqueous phase by using methylene dichloride, combining the organic phases and drying the organic phase by using anhydrous sodium sulfate, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/methylene dichloride=1:20, V:V) to obtain 2.0g of yellow solid product, wherein the yield is 89.6%. LC-MS (ESI) m/z 372.0,374.0[ M+H ] ⁺.

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

93Mg (0.25 mmol) of intermediate 5004 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were added 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol=20/1, v: v) to give 27mg of the product as a white solid in 24% yield. LC-MS (ESI) m/z 451.2[ M+H ] ⁺.

¹H 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).

EXAMPLE 12 Synthesis of Compound FP-356 (5105)

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

2.6G (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.5g (11.1 mmol) of 4-amino-3-fluorobenzonitrile are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. After TLC detection, water is added to separate out solid, filtering is carried out, a filter cake is washed by water, and the filter cake is dried to obtain 3.5g of yellow solid product, and the yield is 100%. LC-MS (ESI) m/z 387.1,389.1[ M+H ] ⁺.

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

2.4G (6.2 mmol) of intermediate 5101 was dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) was added thereto, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.2g of a dark yellow solid product in 100% yield. MS (ESI) m/z 357.0,359.0[ M+H ] ⁺.

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

2.2G (6.2 mmol) of intermediate 5102 was dissolved in 20mL of methylene chloride, and a solution of 10mL of triphosgene (1.9 g,6.4 mmol) in methylene chloride was added dropwise thereto, and the reaction was stirred at room temperature for 4 hours. After the completion of the reaction, 40ml of petroleum ether was added and stirred for 10 minutes, and a solid was precipitated, collected by filtration and dried under reduced pressure to give 2.3g of a yellow powdery product in 96.8% yield. LC-MS (ESI) m/z 383.1,385.1[ M+H ] ⁺.

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

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

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

100Mg (0.25 mmol) of intermediate 5104 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were added 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) gave 15mg of the product as a white solid in 12.6% yield. LC-MS (ESI) m/z 476.2[ M+H ] ⁺.

¹H 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).

EXAMPLE 13 Synthesis of Compound FP-360 (5205)

Intermediate 5201:2- (5- ((6-bromo-3-nitroquinolin-4-yl) amino) pyridin-2-yl) -2-methylpropanenitrile

2.6G (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.8g (11.1 mmol) of 2- (5-aminopyridin-2-yl) -2-methylpropanenitrile are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, after the reaction, adding water for dilution, separating out solids, filtering, washing a filter cake with water, and drying the filter cake to obtain 3.8g of yellow solid product, wherein the yield is 100%. LC-MS (ESI) m/z 412.1,414.1[ M+H ] ⁺.

Intermediate 5202:2- (5- ((3-amino-6-bromoquinolin-4-yl) amino) pyridin-2-yl) -2-methylpropanenitrile

2.6G (6.2 mmol) of intermediate 5201 was dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.4g of a dark yellow solid product in 100% yield. LC-MS (ESI) m/z 382.1,384.1[ M+H ] ⁺.

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

2.4G (6.2 mmol) of intermediate 5202 was dissolved in 20mL of methylene chloride, and a solution of 10mL of triphosgene (1.9 g,6.4 mmol) in methylene chloride was added dropwise thereto, and the reaction was stirred at room temperature for 4 hours. After completion of the reaction, 40ml of petroleum ether was added and stirred for 10 minutes, and solids were precipitated, filtered and collected, and dried under reduced pressure to give 2.5g of a yellow powdery product in 98.8% yield. LC-MS (ESI) m/z 408.1,410.1[ M+H ] ⁺.

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-methylpropanenitrile

2.5G (6.0 mmol) of intermediate 5203 was dissolved in 100mL of methylene chloride, to which was added 0.24g (0.7 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide (10%) were added, and stirred for 10 minutes, and 1.12mL (20.5 mmol) of methyl iodide was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and spin-drying to obtain a crude product, wherein the crude product is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, V:V) to obtain 2.0g of a yellow solid product, and the yield is 78.9%. LC-MS (ESI) m/z 422.1,424.1[ M+H ] ⁺.

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) propionitrile

106Mg (0.25 mmol) of intermediate 5204 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, and 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto and reacted at 80℃for 5 hours with stirring. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) gave 22mg of the product as a white solid in 17.6% yield. LC-MS (ESI) m/z 501.2[ M+H ] ⁺.

¹H 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).

EXAMPLE 14 Synthesis of Compound FP-364 (5305)

Intermediate 5301:6-bromo-N- (4-methoxyphenyl) -3-nitroquinolin-4-amine

2.6G (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.4g (11.4 mmol) of 4-methoxyaniline are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, after the reaction, adding water for dilution, precipitating a large amount of solids, filtering, washing a filter cake with water, and drying the filter cake to obtain 3.4g of yellow solid product, wherein the yield is 100%. LC-MS (ESI) m/z 374.0,376.0[ M+H ] ⁺.

Intermediate 5302:6-bromo-N ⁴ - (4-methoxyphenyl) quinoline-3, 4-diamine

2.3G (6.2 mmol) of intermediate 5301 was dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.1g of a dark yellow solid product in 100% yield. LC-MS (ESI) m/z 344.1,346.1[ M+H ] ⁺.

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

2.1G (6.2 mmol) of intermediate 5302 was dissolved in 20mL of methylene chloride, and a solution of 10mL of triphosgene (1.9 g,6.4 mmol) in methylene chloride was added dropwise thereto, and the reaction was stirred at room temperature for 4 hours. After the completion of the reaction, 40ml of petroleum ether was added and stirred for 10 minutes, and a solid was precipitated, collected by filtration and dried under reduced pressure to give 2.2g of a yellow powdery product in a yield of 95.9%. LC-MS (ESI) m/z 370.1,372.1[ M+H ] ⁺.

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

2.2G (6.0 mmol) of intermediate 5303 was dissolved in 100mL of methylene chloride, to which 0.24g (0.7 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, and stirred for 10 minutes, and 1.12mL (20.5 mmol) of methyl iodide was further added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases and drying the organic phases by using anhydrous sodium sulfate, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, V:V) to obtain 2.0g of yellow solid product, wherein the yield is 86.8%. LC-MS (ESI) m/z 384.1,386.1[ M+H ] ⁺.

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

99Mg (0.25 mmol) of intermediate 5304 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were added 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) gave 9mg of the product as a white solid in 7.8% yield. LC-MS (ESI) m/z 463.2[ M+H ] ⁺.

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).

EXAMPLE 15 Synthesis of Compound FP-374 (5405)

Intermediate 5401:6-bromo-N- (4-isopropoxyphenyl) -3-nitroquinolin-4-amine

2.6G (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.7g (11.1 mmol) of 4-isopropoxy aniline are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. After TLC detection, water is added to separate out solid, filtering is carried out, a filter cake is washed by water, and the filter cake is dried to obtain 3.7g of yellow solid product, and the yield is 100%. LC-MS (ESI) m/z 402.1,404.1[ M+H ] ⁺.

Intermediate 5402:6-bromo-N ⁴ - (4-isopropoxyphenyl) quinoline-3, 4-diamine

2.5G (6.2 mmol) of intermediate 5401 was dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.3g of a dark yellow solid product in 100% yield. LC-MS (ESI) m/z 372.1,374.1[ M+H ] ⁺.

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

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

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

2.4G (6.0 mmol) of intermediate 5403 was dissolved in 100mL of methylene chloride, to which 0.24g (0.7 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, and stirred for 10 minutes, and 1.12mL (20.5 mmol) of methyl iodide was further added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, and spin-drying to obtain a crude product, wherein the crude product is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, V:V) to obtain 2.2g of a yellow solid product, and the yield is 88.9%. LC-MS (ESI) m/z 412.1,414.1[ M+H ] ⁺.

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

103Mg (0.25 mmol) of intermediate 5404 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were added 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) afforded 19mg of the product as a white solid in 15.5% yield. LC-MS (ESI) m/z 491.2[ M+H ] ⁺.

¹H 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).

EXAMPLE 16 Synthesis of Compound FP-378 (5505)

Intermediate 5501:6-bromo-N- (3-fluoro-4-methoxyphenyl) -3-nitroquinolin-4-amine

2.6G (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.6g (11.1 mmol) of 3-fluoro-4-methoxyaniline are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, after the reaction, adding water for dilution, separating out solids, filtering, washing a filter cake with water, and drying the filter cake to obtain 3.6g of yellow solid product, wherein the yield is 100%. LC-MS (ESI) m/z 392.1,394.1[ M+H ] ⁺.

Intermediate 5502:6-bromo-N ⁴ - (3-fluoro-4-methoxyphenyl) quinoline-3, 4-diamine

2.4G (6.2 mmol) of intermediate 5501 was dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.2g of a dark yellow solid product in 100% yield. LC-MS (ESI) m/z 362.1,364.1[ M+H ] ⁺.

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

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

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

2.3G (6.0 mmol) of intermediate 5503 was dissolved in 100mL of methylene chloride, to which 0.24g (0.7 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, and stirred for 10 minutes, and 1.12mL (20.5 mmol) of methyl iodide was further added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, v:v) to obtain 2.1g of a yellow solid product, wherein the yield is 87.0%. LC-MS (ESI) m/z 402.1,404.1[ M+H ] ⁺.

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

100Mg (0.25 mmol) of intermediate 5504 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were added 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol=20/1, v: v) to give 22mg of the product as a white solid in 18.3% yield. LC-MS (ESI) m/z 481.2[ M+H ] ⁺.

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).

EXAMPLE 17 Synthesis of Compound FP-416 (5605)

Intermediate 5601:6-bromo-3-nitro-N- (3- (trifluoromethyl) phenyl) quinolin-4-amine

2.6G (9.1 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.8g (11.1 mmol) of 3- (trifluoromethyl) aniline are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, after the reaction, adding water for dilution, precipitating a large amount of solids, filtering, washing a filter cake with water, and drying the filter cake to obtain 3.8g of yellow solid product, wherein the yield is 100%. LC-MS (ESI) m/z 412.0,414.0[ M+H ] ⁺.

Intermediate 5602:6-bromo-N ⁴ - (3- (trifluoromethyl) phenyl) quinoline-3, 4-diamine

2.6G (6.2 mmol) of intermediate 5601 was dissolved in 20mL of tetrahydrofuran, then 500mg of platinum carbon (5%) was added, hydrogen was introduced, and the reaction was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 2.4g of a dark yellow solid product in 100% yield. LC-MS (ESI) m/z 382.0,384.0[ M+H ] ⁺.

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

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

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

2.5G (6.0 mmol) of intermediate 5603 was dissolved in 100mL of methylene chloride, to which 0.24g (0.7 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, and stirring was performed for 10 minutes, and 1.12mL (20.5 mmol) of methyl iodide was further added, and stirring was performed at room temperature for 4 hours. TLC detection, standing and layering after the reaction is finished, separating an organic phase, extracting an aqueous phase by using methylene dichloride, combining the organic phases and drying the organic phase by using anhydrous sodium sulfate, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/methylene dichloride=1:20, V:V) to obtain 2.3g of yellow solid product, wherein the yield is 90.8%. LC-MS (ESI) m/z 422.0,424.0[ M+H ] ⁺.

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

106Mg (0.25 mmol) of intermediate 5604 and 157mg (0.55 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, and 106mg (1 mmol) of sodium carbonate, 1mL of water and 28.8mg (0.025 mmol) of tetrakis (triphenylphosphine) palladium were added thereto and reacted at 80℃for 5 hours with stirring. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol=20/1, v: v) to give 35mg of the product as a white solid in 28% yield. LC-MS (ESI) m/z 501.2[ M+H ] ⁺.

¹H NMR(600MHz,DMSO)δ9.05(s,1H),8.49(d,J＝1.7Hz,1H),8.33(s,1H),8.21(s,1H),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＝8.3,2.4Hz,1H),7.65(d,J＝7.9Hz,1H),7.19(d,J＝1.9Hz,1H),3.90(s,3H),3.62(s,3H).

EXAMPLE 18 Synthesis of Compound FP-622 (5704)

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

Intermediate 5701 tert-butyl 2- (5-bromopyridin-2-ylamino) ethyl (methyl) carbamate

1.0G (5.7 mmol) of N-Boc-N-methyl ethylenediamine and 1.0g (5.7 mmol) of 5-bromo-2-fluoropyridine were dissolved in 25mL of DMF, 1.15g (11.4 mmol) of triethylamine was added and stirred at 110℃for 12 hours. After the completion of the reaction, 25mL of water was added and stirred for 30 minutes, the layers were separated, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was dried by spinning to give a crude product. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) gave 1.1g of a colourless oil in 58.5% yield. LC-MS (ESI) m/z 330.1,332.1[ M+H ] ⁺.

Intermediate 5703 tert-butylmethyl (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

100Mg (0.30 mmol) of intermediate 5701, 90mg (0.36 mmol) of pinacol biborate, 59mg (0.60 mmol) of potassium acetate and 17mg (0.015 mmol) of tetrakis (triphenylphosphine) palladium are added to 10ml of tert-butanol under nitrogen, heated to 80℃and stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 95mg (0.25 mmol) of intermediate 5604, 63mg (0.6 mmol) of sodium carbonate, 2ml of water and 17mg (0.015 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto, followed by heating to 80℃and stirring for reaction for 5 hours. TLC detection is carried out, water is added for dilution after the reaction is finished, dichloromethane is used for extracting an aqueous phase, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and a filtrate is dried by spin to obtain a crude product. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) to give 28mg of the product as a white solid in 15.7% yield. LC-MS (ESI) m/z 593.2[ M+H ] ⁺.

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

28Mg (0.047 mmol) of intermediate 5703 and 1ml of methanol and 1ml of 1, 4-dioxane solution (2 mol/L) of hydrogen chloride were added to the reaction flask, and the reaction was stirred at room temperature for 2 hours. After the reaction, 5ml of methyl tertiary butyl ether is added for dilution, solid is separated out, the solid is obtained by filtration, then saturated sodium bicarbonate solution is used for adjusting the pH value to 8-9, ethyl acetate is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, the solid is filtered and discarded, and filtrate is dried by spin to obtain 12mg of solid product, and the yield is 54.5%. LC-MS (ESI): 493.2[ M+H ] ⁺.

EXAMPLE 19 Synthesis of Compound FP-628 (5803)

Intermediate 5801N- (5-bromopyridin-2-yl) -2- (methylamino) acetamide

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

Intermediate 5802:2- (methylamino) -N- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) acetamide

100Mg (0.4 mmol) of intermediate 5801 and 107mg (0.48 mmol) of pinacol biborate are dissolved in 10ml of tert-butanol under nitrogen, 16mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium, 117mg (1.2 mmol) of potassium acetate are added thereto and the reaction is stirred at 80℃for 5 hours. TLC detection is carried out, and the reaction is directly carried out in the next step after the reaction is finished.

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

116Mg (0.4 mmol) of intermediate 5802, 154mg (0.4 mmol) of intermediate 5304 and 128mg (0.8 mmol) of Na ₂CO₃ were dissolved in 10ml of tert-butanol, to which was then added 2ml of water, 16mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium and reacted overnight at 80℃under N ₂. After TLC detection, after the reaction was completed, the solvent was mostly removed by vacuum concentration, followed by dilution with 20ml of water, extraction twice with 20ml of dichloromethane, combining the organic phases, drying the organic phases over anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain crude product, and purifying the crude product by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, V/V) to obtain 38mg of solid product with a yield of 20.2%. LC-MS (ESI) 4639.3 [ M+H ] ⁺.

EXAMPLE 20 Synthesis of Compound FP-921 (5906)

Intermediate 5901 4- (4- ((6-bromo-3-nitroquinolin-4-yl) amino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

1G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.3g (3.83 mmol) of tert-butyl 4- (4-amino-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, water dilution after the reaction, massive solid precipitation, filtration, water washing of filter cake, and filter cake drying, thus obtaining 2.0g yellow solid product with 99.5% yield. LC-MS (ESI) M/z 596.1,598.1 (M+H2 ⁺).

Intermediate 5902 4- (4- ((3-amino-6-bromoquinolin-4-yl) amino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

2.0G (3.35 mmol) of intermediate 5901 was dissolved in 20mL of tetrahydrofuran, 500mg of platinum carbon (5%) was added thereto, hydrogen was introduced, and the mixture was stirred at room temperature overnight. TLC detection, filtration after completion of the reaction, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 1.7g of a dark yellow solid product in 90.1% yield. LC-MS (ESI) M/z 566.2,568.2 (M+H2 ⁺).

Intermediate 5903 4- (4- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

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

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

1.4G (2.4 mmol) of intermediate 5903 was dissolved in 100mL of methylene chloride, 0.24g (0.24 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, stirred for 10 minutes, then 1g (7.2 mmol) of methyl iodide was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, v:v), thereby obtaining 1.12g of yellow solid product with a yield of 78.3%. LC-MS (ESI) m/z 606.2,608.2[ M+H ] ⁺.

Intermediate 5905 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-carboxylic acid tert-butyl ester

100.0Mg (0.16 mmol) of intermediate 5904 and 56.0mg (0.19 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, and 34.0mg (0.32 mmol) of sodium carbonate, 2mL of water and 13.9mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto, and the reaction was stirred at 80℃for 5 hours. TLC detection, concentration and removal of most of the solvent after the reaction is finished, then water is added for dilution, dichloromethane is used for extracting the water phase, the organic phase is dried by anhydrous sodium sulfate, filtration and spin-drying of the filtrate are carried out to obtain a crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) gave 25mg of the product as a white solid in 23.2% yield. LC-MS (ESI) m/z 685.3[ M+H ] ⁺.

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

To the reaction flask, 25mg (0.04 mmol) of intermediate 5905 was added, followed by 5ml of water and 5ml of a1, 4-dioxane solution (2 mol/L) of hydrogen chloride, and the reaction was stirred at room temperature for 2 hours. After the reaction, 10ml of methyl tertiary butyl ether is added for dilution, solid is separated out, the solid is obtained by filtration, then saturated sodium bicarbonate solution is used for adjusting the pH value to 8-9, ethyl acetate is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, the solid is filtered and discarded, and filtrate is dried by spin to obtain 12mg of solid product, and the yield is 54.5%. LC-MS (ESI): 585.3[ M+H ] ⁺.

¹H 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(dd,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).

Synthesis of Compound FP-936 (6006) of example 21

Intermediate 6001:4- (4- ((6-bromo-3-nitroquinolin-4-yl) amino) phenyl) piperazine-1-carboxylic acid tert-butyl ester

1.0G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.1g (3.83 mmol) of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate were dissolved in 20mL of glacial acetic acid and the reaction stirred at room temperature overnight. TLC detection, water dilution after the reaction, massive solid precipitation, filtration, water washing of filter cake, and filter cake drying, 1.8g yellow solid product is obtained, and the yield is 97.8%. LC-MS (ESI) m/z 528.1,530.1[ M+H ] ⁺.

Intermediate 6002:4- (4- ((3-amino-6-bromoquinolin-4-yl) amino) phenyl) piperazine-1-carboxylic acid tert-butyl ester

1.8G (3.41 mmol) of intermediate 6001 was dissolved in 20mL of tetrahydrofuran, 500mg of platinum carbon (5%) was added, hydrogen gas was introduced, and the mixture was stirred at room temperature overnight. TLC detection, after completion of the reaction, filtration, washing of the cake with tetrahydrofuran, and concentration of the filtrate under reduced pressure gave 1.57g of a dark yellow solid product in 92.4% yield. LC-MS (ESI) m/z 498.1,500.1[ M+H ] ⁺.

Intermediate 6003:4- (4- (8-bromo-2-oxo-2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

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

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

1.32G (2.52 mmol) of the intermediate 6003 was dissolved in 100mL of methylene chloride, 0.25g (0.25 mmol) of tetrabutylammonium bromide and 100mL of an aqueous sodium hydroxide solution (10%) were added, and stirring was performed for 10 minutes, then 1g (7.5 mmol) of methyl iodide was added, and stirring was performed at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, v:v), thereby obtaining 1.15g of yellow solid product with a yield of 84.7%. LC-MS (ESI) m/z 538.1,540.1[ M+H ] ⁺.

Intermediate 6005:4- (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-carboxylic acid tert-butyl ester

100Mg (0.18 mmol) of intermediate 6004 and 53mg (0.18 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, 38mg (0.36 mmol) of sodium carbonate, 2mL of water and 13mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting aqueous phase, organic phase is dried by anhydrous sodium sulfate and filtered, and the filtrate is dried by spinning to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) gave 27mg of the product as a white solid in 23.6% yield. LC-MS (ESI) m/z 617.4[ M+H ] ⁺.

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

27Mg (0.04 mmol) of the intermediate 6005 was added to the reaction flask, followed by 5ml of water and 5ml of a1, 4-dioxane solution (2 mol/L) of hydrogen chloride, and the reaction was stirred at room temperature for 2 hours. After the reaction is finished, 10ml of methyl tertiary butyl ether is added into the reaction system to dilute, a large amount of solid is precipitated, the solid is filtered and collected, then saturated sodium bicarbonate solution is used for adjusting the pH value to 8-9, ethyl acetate is used for extracting aqueous phase, organic phase is dried by anhydrous sodium sulfate, the solid is filtered and discarded, and the filtrate is dried by spin to obtain 15mg of product, and the yield is 66.3%. LC-MS (ESI) 517.3[ M+H ] ⁺.

¹H 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).

EXAMPLE 22 Synthesis of Compound FP-937 (6105)

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

1G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 1.1g (3.80 mmol) of 2- (4- (4-amino-2- (trifluoromethyl) phenyl) piperazin-1-yl) ethan-1-ol are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, water dilution after the reaction, massive solid precipitation, filtration, water washing of filter cake, and filter cake drying, 1.79g of yellow solid product is obtained, and the yield is 95.2%. LC-MS (ESI) m/z 540.1,542.1[ M+H ] ⁺.

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

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

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

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

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

1.36G (2.54 mmol) of intermediate 6103 was dissolved in 100mL of dichloromethane, 0.25g (0.25 mmol) of tetrabutylammonium bromide and 100mL of aqueous sodium hydroxide solution (10%) were added, stirred for 10 minutes, then 1g (7.5 mmol) of methyl iodide was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, spinning the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, V:V) to obtain 0.99g of yellow solid product, wherein the yield is 71.0%. LC-MS (ESI) m/z 550.1,552.1[ M+H ] ⁺.

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

100Mg (0.18 mmol) of intermediate 6104 and 53mg (0.18 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were successively added 38mg (0.36 mmol) of sodium carbonate, 2mL of water and 13mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium, and reacted at 80℃for 5 hours with stirring. After the TLC detection, the reaction is finished, the majority of tertiary butanol is removed by decompression concentration, then water is added for dilution, the water phase is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate, and the filtrate is dried by rotation to obtain a crude product. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol=20/1, v: v) to give 23mg of the product as a white solid in 20.3% yield. LC-MS (ESI) m/z 629.3[ M+H ] ⁺.

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).

EXAMPLE 23 Synthesis of Compound FP-938 (6202)

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

100Mg (0.17 mmol) of compound 5906 and 38mg (0.17 mmol) of tert-butyl (2-bromoethyl) carbamate are dissolved in 10ml of N, N-dimethylformamide, 65mg (0.51 mmol) of N, N-diisopropylethylamine are added and the reaction is stirred at room temperature for 10 hours. TLC detection, after the reaction, adding 20ml of water for dilution, then extracting 2 times with a proper amount of ethyl acetate, merging organic phases, washing 2 times with a proper amount of saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a crude product, purifying the crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1, V/V) to obtain 29mg of a product, and obtaining 23.4% LC-MS (ESI) m/z:728.4[ M+H ] ⁺.

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

29Mg (0.04 mmol) of intermediate 6201 and 5ml of water and 5ml of 1, 4-dioxane solution (2 mol/L) of hydrogen chloride were added to the reaction flask, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 10ml of methyl tert-butyl ether was added to dilute the mixture, the mixture was precipitated as a solid, the solid was collected by filtration, the pH was adjusted to 8 to 9 with a saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was dried by spin-drying to give 24mg of a solid product in 96.0% yield. LC-MS (ESI): 628.3[ M+H ] ⁺.

EXAMPLE 24 Synthesis of Compound FP-938 (6302)

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

100Mg (0.16 mmol) of intermediate 5904 and 39mg (0.16 mmol) of (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrimidin-2-yl) methanol were dissolved in 10mL of t-butanol under nitrogen, 38mg (0.36 mmol) of sodium carbonate, 2mL of water and 13mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting aqueous phase, organic phase is dried by anhydrous sodium sulfate and filtered, and the filtrate is dried by spinning to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) gave 26mg of the product as a white solid in 24.8% yield. LC-MS (ESI) m/z 635.3[ M+H ] ⁺.

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

26Mg (0.04 mmol) of intermediate 6301 and 5ml of water and 5ml of 1, 4-dioxane solution (2 mol/L) of hydrogen chloride were added to the reaction flask, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 10ml of methyl tert-butyl ether was added to dilute, precipitate was precipitated, and the solid was filtered and collected, then the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was dried by spin to give 20mg of a solid product in 91.3% yield. LC-MS (ESI): 536.2[ M+H ] ⁺.

EXAMPLE 25 Synthesis of Compound FP-943 (6402)

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

100Mg (0.16 mmol) of intermediate 5904 and 39mg (0.16 mmol) of (N-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyrimidin-2-amine were dissolved in 10mL of t-butanol under nitrogen, 38mg (0.36 mmol) of sodium carbonate, 2mL of water and 13mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium were added thereto in this order, and the reaction was stirred at 80℃for 5 hours.

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

Into the reaction flask, 25.0mg (0.04 mmol) of the intermediate 6401 was added, followed by 5ml of water and 5ml of a1, 4-dioxane solution (2 mol/L) of hydrogen chloride, and the mixture was reacted at room temperature for 2 hours. After the reaction, 10ml of methyl tertiary butyl ether was added for dilution, precipitation was carried out, the solid was collected by filtration, then the pH value was adjusted to 8-9 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was dried by spin to give 20mg of a solid product in 93.5% yield. LC-MS (ESI) 535.3[ M+H ] ⁺.

EXAMPLE 26 Synthesis of Compound FP-947 (6501)

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

100Mg (0.17 mmol) of FP-921 (5906) and 17mg (0.17 mmol) of succinic anhydride were dissolved in 10ml of N, N-dimethylformamide, 66mg (0.51 mmol) of N, N-diisopropylethylamine was added, and the reaction was stirred at room temperature for 10 hours. TLC detection, after the reaction, adding 20ml of water for dilution, then extracting 2 times with a proper amount of ethyl acetate, combining organic phases, washing the organic phases with saturated saline water 2 times, then drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, V/V), thus obtaining 36mg of the product with a yield of 30.8%. LC-MS (ESI) m/z 685.1[ M+H ] ⁺.

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).

EXAMPLE 27 Synthesis of Compound FP-948 (6607)

Intermediate 6601 (1- (4-nitro-2- (trifluoromethyl) phenyl) piperidin-4-yl) methanol

1G (4.4 mmol) of the compound 1-chloro-4-nitro-2- (trifluoromethyl) benzene and 613mg (5.3 mmol) of piperidine-4-methanol were dissolved in 10mL of N, N-dimethylformamide, and then 1.22g (8.9 mmol) of potassium carbonate was added and the reaction stirred at 90℃overnight. TLC detection, after the reaction, adding a proper amount of water for dilution, extracting the water phase with ethyl acetate for 2 times, combining the organic phases, washing with saturated saline water for 2 times, drying with anhydrous sodium sulfate, carrying out spin-drying on the organic phase to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1:1, V: V) to obtain 1.3g of yellow oily product, wherein the yield is 100%. LC-MS (ESI) m/z 305.1[ M+H ] ⁺.

Intermediate 6602 (1- (4-amino-2- (trifluoromethyl) phenyl) piperidin-4-yl) methanol

1.3G (4.4 mmol) of compound 6601 was dissolved in 20mL of ethanol, followed by the addition of 4g (17.6 mmol) of stannous chloride and stirring at room temperature overnight. TLC detection, after the reaction is finished, concentrating to remove most of ethanol, adding ethyl acetate for dilution, then adding 10% sodium hydroxide aqueous solution for adjusting the pH value of the solution to be alkaline, stirring for ten minutes, filtering with kieselguhr, standing and layering the filtrate, separating out an organic phase, extracting an aqueous phase with ethyl acetate, merging the organic phases, washing the organic phase with saturated saline solution for 2 times, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain 1g of yellow oily product with the yield of 85.3%. LC-MS (ESI) m/z 275.2[ M+H ] ⁺.

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

1.2G (4.2 mmol) of 6-bromo-4-chloro-3-nitroquinoline, 1g (3.6 mmol) of intermediate 6602 and 738mg (7.3 mmol) of triethylamine are dissolved in 20mLN, N-dimethylformamide and the reaction is stirred at room temperature overnight. TLC detection, after the reaction, water was added to dilute, then ethyl acetate was used for 2 times, the organic phases were combined and washed with saturated brine for 2 times, dried over anhydrous sodium sulfate, the solid was filtered off, the filtrate was spin-dried to give a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether=1:1, v: v) to give 1.3g of a yellow solid product in 67.7% yield. LC-MS (ESI) m/z 525.1,527.1[ M+H ] ⁺.

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

1.3G (2.5 mmol) of intermediate 6603 was dissolved in 20mL of ethanol, followed by the addition of 2.2g (10.0 mmol) of stannous chloride and stirring at room temperature overnight. TLC detection, after the reaction, concentrating to remove most of ethanol, adding ethyl acetate for dilution, then adding 10% sodium hydroxide aqueous solution for adjusting the pH value of the solution to be alkaline, stirring for ten minutes, then filling diatomite for filtering, standing and layering the filtrate, separating an organic phase, extracting an aqueous phase by using ethyl acetate, combining the organic phases, washing the organic phases for 2 times by using saturated saline, drying the organic phases by using anhydrous sodium sulfate, filtering, and spinning the filtrate to obtain 0.9g of product, wherein the yield is 73.2%. LC-MS (ESI) m/z 495.1,497.1[ M+H ] ⁺.

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

0.9G (1.8 mmol) of intermediate 6604 was dissolved in 10mL of methylene chloride, to which was added dropwise a solution of 10mL of triphosgene (0.26 g,0.9 mmol) in methylene chloride, and the reaction was stirred at room temperature for 4 hours. After the completion of the reaction, 40ml of petroleum ether was added to dilute and stir for 10 minutes, and a precipitate was precipitated, and the solid was collected by filtration and dried under reduced pressure to give 0.94g of a yellow powdery product in 100% yield. LC-MS (ESI) m/z 521.1,523.1[ M+H ] ⁺.

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

0.94G (1.8 mmol) of intermediate 6605 was dissolved in 10mL of methylene chloride, to which were added 0.06g (0.2 mmol) of tetrabutylammonium bromide and 10mL of aqueous sodium hydroxide solution (10%), stirred for 10 minutes, and then 0.55mL (8.8 mmol) of methyl iodide was added, and stirred at room temperature for 4 hours. TLC detection, after the reaction, standing and layering, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases and drying the organic phases with anhydrous sodium sulfate, filtering, spin-drying the filtrate to obtain a crude product, and purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20, v:v), thereby obtaining 0.3g of a yellow solid product with a yield of 31.2%. LC-MS (ESI) m/z 535.1,537.1[ M+H ] ⁺.

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

300Mg (0.56 mmol) of intermediate 6606 and 285mg (1 mmol) of intermediate 9a were dissolved in 10mL of t-butanol under nitrogen, to which were added 142mg (1.34 mmol) of sodium carbonate, 2mL of water and 39mg (0.03 mmol) of tetrakis (triphenylphosphine) palladium, and the reaction was stirred at 80℃for 5 hours. TLC detection is carried out, after the reaction is finished, most tertiary butanol is removed by concentration, then water is added for dilution, dichloromethane is used for extracting water phase, organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and filtrate is dried by spin to obtain crude product. Purification of the crude product by silica gel column chromatography (dichloromethane/methanol=20/1, v: v) gave 167mg of the product as a white solid in 48.6% yield. LC-MS (ESI) m/z 614.3[ M+H ] ⁺.

EXAMPLE 28 Synthesis of Compound FP-949 (6706)

Intermediate 6701 tert-butyl 4- (4- (6-chloro-3-nitro-1, 5-naphthyridine-4-amino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

1G (4.10 mmol) of 2, 8-dichloro-7-nitro-1, 5-naphthyridine and 1.2g (3.47 mmol) of tert-butyl 4- (4-amino-2- (trifluoromethyl) phenyl) piperazine-1-carboxylate are dissolved in 20mL of glacial acetic acid and the reaction is stirred at room temperature overnight. TLC detection, water dilution after the reaction, massive solid precipitation, filtration, water washing of filter cake, and filter cake drying, 1.7g of yellow solid product is obtained, and the yield is 88.5%. LC-MS (ESI) m/z 553.2.

Intermediate 6702 tert-butyl 4- (4- (3-amino-6-chloro-1, 5-naphthyridine-4-amino) -2- (trifluoromethyl) phenyl) piperazine-1-carboxylate

1.7G (3.07 mmol) of intermediate 6701 was dissolved in 20mL of ethanol, 0.35g (5%) of platinum carbon was added thereto, and hydrogen was introduced thereinto, and the reaction was stirred at room temperature for 12 hours. TLC detection, filtration after completion of the reaction, and spin-drying of the filtrate gave 1.6g of a yellow solid product in 100% yield. LC-MS (ESI) m/z 523.2[ M+H ] ⁺.

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

1.6G (3.07 mmol) of intermediate 6702 was dissolved in 20mL of methylene chloride in an ice-water bath, 1.24g (12.28 mmol) of triethylamine was added thereto, a solution of 20mL of triphosgene (0.77 g,1.95 mmol) in methylene chloride was added dropwise thereto, and the mixture was stirred at room temperature for 5 hours, whereby a solid was precipitated. TLC detection, filtering after the reaction, washing the filter cake with dichloromethane, and drying to obtain 1.2g of the product, wherein the yield is 71.2%. LC-MS (ESI) m/z 549.2[ M+H ] ⁺

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

1.2G (2.19 mmol) of intermediate 6703 was added to 30mL of methylene chloride, 0.11g (0.34 mmol) of tetrabutylammonium bromide and 30mL of sodium hydroxide solution (10%) were added, and after stirring for 10 minutes, 1.49g (10.38 mmol) of methyl iodide was added and stirred at room temperature for 4 hours. TLC detection is carried out, after the reaction is finished, standing is carried out, layering is carried out, an organic phase is separated, a water phase is extracted by dichloromethane, the organic phases are combined and dried by anhydrous sodium sulfate, filtration is carried out, and a crude product is obtained by spin-drying filtrate. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) afforded 0.9g of the product as a yellow solid in 73.2% yield. LC-MS (ESI) m/z 563.2[ M+H ] ⁺.

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

0.1G (0.18 mmol) of intermediate 6704 and 0.18g (0.63 mmol) of intermediate 9a were dissolved in 10mL of dioxane under nitrogen, then 0.47g (1.44 mmol) of cesium carbonate, 10mL of 2M aqueous sodium carbonate solution and 0.025g (0.031 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added in this order and reacted at 110℃for 5 hours with stirring. After the completion of the reaction, the reaction mixture was concentrated to remove most of the solvent, diluted with water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol=10/1, V/V) to give 41mg of the product as a white powder in 33.2% yield. LC-MS (ESI) m/z 686.3[ M+H ] ⁺.

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

41Mg (0.06 mmol) of intermediate 6705 was dissolved in 2mL of methanol, to which 2mL (2 mol/L) of a 1, 4-dioxane solution of hydrogen chloride was added, and the reaction was stirred at room temperature for 4 hours, whereby a solid was precipitated. TLC detection, after the reaction, filtration, discarding of the filtrate, washing of the filter cake with a small amount of methanol, then adjusting the pH to 8-9 with saturated sodium bicarbonate solution, extraction of the aqueous phase with ethyl acetate, drying of the organic phase over anhydrous sodium sulfate, filtration of the discarded solids, spin-drying of the filtrate to give crude product, purification of the crude product by preparative TLC (dichloromethane/methanol=10/1, V: V) gives 16mg of white powdery product in 45.7% yield. LC-MS (ESI) m/z 586.3[ M+H ] ⁺.

EXAMPLE 29 Synthesis of Compound FP-953 (6802)

The synthesis method of the compound 6802 specifically comprises the following steps:

intermediate 1001 Synthesis of tert-butyl (2- (5-bromopyridine-2-oxy) ethyl) carbamate:

1g (6.2 mmol) of N- (t-butoxycarbonyl) ethanolamine and 1.09g (6.2 mmol) of 5-bromo-2-fluoropyridine were dissolved in 25mL of DMF (N, N-dimethylformamide), to which 0.27g (6.82 mmol) of sodium hydride was added and stirred at room temperature overnight. TLC (thin layer chromatography) was used to examine, after the completion of the reaction, 25mL of water was added and stirred for 30 minutes, the aqueous phase was extracted with methylene chloride, the organic phase was washed with saturated brine 2 times, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1.6g of a colorless oily product in 80.6% yield. LC-MS (ESI) m/z 317.0,319.0[ M+H ] ⁺.

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:

300mg (0.95 mmol) of intermediate 1001, 285mg (1.11 mmol) of pinacol biborate, 180mg (1.86 mmol) of potassium acetate and 54mg (0.045 mmol) of tetrakis (triphenylphosphine) palladium are added to 10ml of tert-butanol under nitrogen, heated to 80℃and stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 422mg (0.75 mmol) of intermediate 6704, 180mg (1.86 mmol) of sodium carbonate, 4ml of water and 54mg (0.045 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto, followed by heating to 80℃and stirring for reaction for 5 hours. TLC detection, after the reaction, adding water for dilution, extracting aqueous phase with dichloromethane, drying organic phase by anhydrous sodium sulfate, filtering, decompressing and concentrating filtrate to obtain crude product. Purification of the crude product by silica gel chromatography (eluent: dichloromethane/methanol=10/1, v: v) afforded 114mg of the product as a white solid in 15.7% yield. LC-MS (ESI) m/z 764.3[ M+H ] ⁺.

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

114Mg (0.15 mmol) of intermediate 6801 was dissolved in 2.5mL of methanol, and 2.5mL of 1, 4-dioxane solution (2M) of hydrogen chloride was added thereto, followed by stirring at room temperature for 4 hours, whereby a solid was precipitated. TLC detection, after the reaction, filtration, collection of solid, then with saturated sodium bicarbonate solution to adjust pH 8-9, ethyl acetate extraction aqueous phase, organic phase through anhydrous sodium sulfate drying, filtration, solid removal, filtrate spin dry, obtained 53mg yellow solid product, yield 63.1%. LC-MS (ESI) m/z 564.3[ M+H ] ⁺.

Comparative example 1 (Compound 6705) Synthesis of FP-347

Intermediate 6701:6-bromo-N- (4-pentafluorosulfonylphenyl) -3-nitroquinolin-4-amine

1G (3.48 mmol) of 6-bromo-4-chloro-3-nitroquinoline and 0.91g (4.17 mmol) of 4- (pentafluorosulfonyl) aniline are dissolved in 10mL of acetic acid and the reaction is stirred at room temperature overnight. TLC detection, after completion of the reaction, filtration, washing of the cake with glacial acetic acid and vacuum drying gave 1.8g of yellow solid product in 100% yield. LC-MS (ESI) m/z 472.0,474.0[ M+H ] ⁺.

Intermediate 6702:6-bromo-N- (4-pentafluorosulfonylphenyl) -3-aminoquinolin-4-amine

1.8G (3.48 mmol) of intermediate 6701 was dissolved in 20mL of ethanol, 0.18g of platinum carbon (5%) was added thereto, and hydrogen was introduced thereinto and stirred at room temperature for 12 hours. TLC detection, after completion of the reaction, filtration of the discarded solids, spin-drying of the filtrate gave 1.7g of a yellow solid product, 100% yield. LC-MS (ESI) m/z 440.0,442.0[ M+H ] ⁺.

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

1.7G (3.48 mmol) of intermediate 6702 was dissolved in 15mL of methylene chloride in an ice-water bath, 1.09g (10.44 mmol) of triethylamine was added thereto, and a solution of 0.38g (1.16 mmol) of triphosgene in 10mL of methylene chloride was added dropwise thereto, followed by stirring for 5 hours, whereby a solid was precipitated. TLC detection, after completion of the reaction, filtration, washing of the solid with dichloromethane and drying gave 1.1g of the product in 68.7% yield. LC-MS (ESI) m/z 468.0,470.0[ M+H ] ⁺.

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

1.1G (2.36 mmol) of intermediate 6703 was added to 10mL of methylene chloride, 0.081g (0.24 mmol) of tetrabutylammonium bromide and 10mL of sodium hydroxide solution (10%) were added, and after stirring for 10 minutes, 0.99g (7.08 mmol) of methyl iodide was added and stirring was carried out at room temperature for 4 hours. TLC detection, standing and layering after the reaction is finished, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering to remove solids, and spinning the filtrate to obtain a crude product. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) to give 0.8g of a yellow solid product in 70.7% yield. LC-MS (ESI) m/z 482.0,484.0[ M+H ] ⁺.

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

100Mg (0.20 mmol) of intermediate 6704 and 85mg (0.30 mmol) of intermediate 9a were dissolved in 5mL of 1, 4-dioxane under nitrogen, 197mg (0.60 mmol) of cesium carbonate was added, 1mL of 2M aqueous sodium carbonate solution, 22mg (0.02 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride was added, and the reaction was stirred at 110℃for 5 hours. TLC detection, after completion of the reaction, concentration to remove most of the solvent, dilution of the residue with water, extraction with dichloromethane, combining the organic phases, drying over anhydrous sodium sulfate, filtration to remove the solids, and spin-drying of the filtrate to obtain crude product. The crude product was purified by prep. silica gel plate (dichloromethane/methanol=10/1, V/V) to give 47mg of the product as a white powder in 38.2% yield. LC-MS (ESI) m/z 559.1[ M+H ] ⁺.

Comparative example 2 (Compound 6802) Synthesis of FP-352

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

200Mg (0.41 mmol) of intermediate 6704 and 199mg (0.62 mmol) of 2- (BOC-amino) pyrrolidine-5-boronic acid pinacol ester were dissolved in 10mL of 1, 4-dioxane under nitrogen, 267mg (0.82 mmol) of cesium carbonate and 2mL of aqueous sodium carbonate (2M) were added, 47mg (0.041 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were added and the reaction was stirred at 110℃for 5 hours. After the TLC detection, most of the solvent is spun off after the reaction is finished, water is added for dilution, the aqueous phase is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate, the solid is filtered and removed, and the filtrate is spun to obtain a crude product. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1, v: v) to give 140mg of the product as an off-white powder in 56.6% yield. LC-MS (ESI) m/z 594.2[ M+H ] ⁺.

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

140Mg (0.23 mmol) of intermediate 6801 was dissolved in 2.5mL of methanol, 2.5mL of 1, 4-dioxane solution (2M) of hydrogen chloride was added, and the reaction was stirred at room temperature for 4 hours, whereby a solid was precipitated. TLC detection, after the reaction, filtering, collecting solid, then using saturated sodium bicarbonate solution to regulate pH value to 8-9, using ethyl acetate to extract aqueous phase, drying organic phase by using anhydrous sodium sulfate, filtering and removing solid, and spin-drying filtrate so as to obtain 75mg of yellow solid product, and its yield is 66.4%. LC-MS (ESI) m/z 494.1[ M+H ] ⁺.

Comparative example 3 Synthesis of Compound 3006

(1) Synthesis of intermediate 3001:6-bromo-N- (4-fluorophenyl) -3-nitroquinolin-4-amine:

1g (3.28 mmol) of 6-bromo-4-chloro-7-fluoro-3-nitroquinoline and 0.28g (4.88 mmol) of cyclopropylamine are dissolved in 10mL of DMF, 0.72g (6.52 mmol) of triethylamine are added and stirred at room temperature overnight. After the completion of the reaction, TLC was checked, water was added and stirred for 30 minutes, and a solid was precipitated, filtered, and the cake was washed with water and dried in vacuo to give 1.07g of a yellow solid product in 100% yield. LC-MS (ESI) m/z 326.0,328.0[ M+H ] ⁺.

(2) Synthesis of intermediate 3002:6-bromo-N ⁴ -cyclopropyl-7-fluoroquinoline-3, 4-diamine:

1.07g (3.28 mmol) of intermediate 3001 was dissolved in 20mL of ethanol, 0.15g of platinum carbon (5%) was added thereto, and hydrogen was introduced thereinto, and the reaction was stirred at room temperature for 12 hours. TLC detection, after completion of the reaction, filtration, discarding of solid, spin-drying of the filtrate gave 0.97g of a yellow solid product, 100% yield. LC-MS (ESI) m/z 296.0,298.0[ M+H ] ⁺.

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

0.97g (3.48 mmol) of intermediate 3002 was dissolved in 20mL of methylene chloride in an ice-water bath, 1.06g (10.38 mmol) of triethylamine was added thereto, and then 10mL of triphosgene (0.35 g,1.15 mmol) in methylene chloride was added dropwise thereto, and the reaction was stirred at room temperature for 5 hours, whereby a solid was precipitated. TLC detection, after completion of the reaction, filtration and washing of the cake with a small amount of dichloromethane. The filter cake was dried to give 0.61g of product in 54.0% yield. LC-MS (ESI) m/z 322.0,324.0[ M+H ] ⁺.

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

0.61g (1.90 mmol) of intermediate 3003 was dissolved in 15mL of methylene chloride, to which was added 0.061g (0.19 mmol) of tetrabutylammonium bromide and 15mL of sodium hydroxide (10%) solution, and after stirring for 10 minutes, 0.54g (3.78 mmol) of methyl iodide was further added, and the reaction was stirred at room temperature for 4 hours. TLC detection, standing and layering after the reaction is finished, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering to remove solids, and spin-drying filtrate to obtain a crude product. Purification of the crude product by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1, v: v) afforded 0.55g of the product as a yellow solid in 85.9% yield. LC-MS (ESI)

m/z:336.0,338.0[M+H]⁺。

(5) The final steps are as follows:

100mg (0.39 mmol) of 3- ((5-bromopyridin-2-yl) oxy) -N, N-dimethylpropan-1-amine, 99mg (0.39 mmol) of pinacol biborate, 76mg (0.78 mmol) of potassium acetate and 45mg (0.039 mmol) of tetrakis (triphenylphosphine) palladium were added to 10ml of tert-butanol under nitrogen, heated to 80℃and stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 131mg (0.39 mmol) of intermediate 3004, 82mg (0.78 mmol) of sodium carbonate, 5ml of t-butanol, 2ml of water and 45mg (0.039 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto, followed by heating to 80℃and stirring for reaction for 5 hours. TLC detection is carried out, water is added for dilution after the reaction is finished, dichloromethane is used for extracting an aqueous phase, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and a filtrate is dried by spin to obtain a crude product. Purification of the crude product by silica gel chromatography (eluent: dichloromethane/methanol=10/1, v: v) afforded 63mg of the product as a white solid in 37.1% yield.

LC-MS(ESI)m/z:436.2[M+H]⁺。

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).

Synthesis of Compound 3105 of comparative example 4

(1) Synthesis of tert-butyl 5-bromo-2-iodopyridin-3-yl) carbamate as intermediate 3101:

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

LC-MS(ESI)m/z:398.9,400.9[M+H]⁺。

(2) Synthesis of intermediate 3102 (5-bromo-2- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) carbamic acid tert-butyl ester:

1.1g (2.75 mmol) of intermediate 3101, 0.69g (3.3 mmol) of 1-methylpyrazole-4-boronic acid pinacol ester, 1.78g (5.5 mmol) of cesium carbonate and 0.114g (0.14 mmol) of [1, 1-bis (diphenylphosphino) ferrocene ] palladium chloride were dissolved in 30mL of dioxane and 3mL of water under nitrogen and heated at 110℃for 8 hours. TLC detection is carried out, after the reaction is finished, most dioxane is removed by decompression concentration, water is added for dilution, dichloromethane is used for extracting water phase, organic phases are combined and dried by anhydrous sodium sulfate, filter residue is removed by filtration, and a crude product is obtained by spin-drying filtrate. Purification of the crude product by silica gel chromatography (dichloromethane/methanol=20/1, v: v) afforded 0.7g of the product as a white solid in 70.3% yield.

LC-MS(ESI)m/z:353.1,355.1[M+H]⁺。

(3) Synthesis of (5- (1- ((1 s,4 s) -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) carbamic acid tert-butyl ester:

300mg (0.85 mmol) of intermediate 3102, 215mg (0.85 mmol) of pinacol biborate, 166mg (1.7 mmol) of potassium acetate and 98mg (0.085 mmol) of tetrakis (triphenylphosphine) palladium are added to 10ml of tert-butanol under nitrogen, heated to 80℃and stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 320mg (0.85 mmol) of 208d, 180mg (1.7 mmol) of sodium carbonate, 5ml of t-butanol, 2ml of water and 98mg (0.085 mmol) of tetrakis (triphenylphosphine) palladium were sequentially added thereto, followed by heating to 80℃and stirring for reaction for 5 hours. TLC detection is carried out, water is added for dilution after the reaction is finished, the water phase is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate, and the crude product is obtained by filtering and spin-drying filtrate. The crude product was purified by silica gel chromatography (eluent: dichloromethane/methanol=10/1, v: v) to give 220mg of the product as a white solid in 44.7% yield.

LC-MS(ESI)m/z:570.3[M+H]⁺。

(4) The final steps are as follows:

220mg (0.38 mmol) of intermediate 3104 was dissolved in 2mL of methanol under ice-water bath, and 2mL of a 2M 1, 4-dioxane solution of hydrogen chloride was added thereto, followed by stirring for 1 hour, whereby a solid was precipitated. TLC detection, after the reaction, filtering and discarding the filtrate, washing the solid with methyl tertiary butyl ether, then adjusting the pH value to 8-9 with saturated sodium bicarbonate solution, extracting the water phase with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering and discarding the solid, spinning the filtrate to obtain a crude product, purifying the crude product by a silica gel chromatographic column (eluent: dichloromethane/methanol=10/1, V: V), and obtaining 129mg of yellow solid product with the yield of 71.0%.

LC-MS(ESI)m/z:470.3[M+H]⁺。

Synthesis of Compound 3201 of comparative example 5

The synthesis method of the compound specifically comprises the following steps:

100mg (0.21 mmol) of compound 3105 (compound 3105 was prepared in the same manner as in comparative example 4), 29mg (0.25 mmol) of methylsulfonyl chloride and 63mg (0.63 mmol) of triethylamine were dissolved in 5mL of dichloromethane under ice-water bath, and stirred for 5 hours. TLC detection, adding water for dilution after the reaction is finished, standing for layering,

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 removed by filtration, and the filtrate was dried by spinning to give a crude product. Purification of the crude product by preparative TLC (dichloromethane/methanol=10/1, v: v) gave 85mg of the product as a white solid in 71.4% yield.

LC-MS(ESI)m/z:548.2[M+H]⁺。

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),8.05(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).

Result detection

1. Cell activity assay

1. The effect of the compounds of each of the examples and comparative examples on the growth of MV4-11, PC-3, BT474, MB436, LOVO and Granta-519 cells was examined.

2. Test method CTG method

ATP is necessarily produced during the metabolic activity of living cells and its content is linearly related to the number of living cells. CTG is a general method for detecting the number of living cells in cultured cells based on this principle. Cell lysis can be induced and chemiluminescent signals proportional to the amount of ATP in the well plate can be generated upon addition of CellTiter-Glo reagent, such that the viability of cell proliferation in the well plate can be measured by chemiluminescent readings.

3. The test steps are as follows:

3.1 cell plating

Plating of various cells at a plating density of 5,000cells/well, 100. Mu.l/well;

37 ℃,5% CO ₂ incubator overnight.

3.2 Compound formulation

The concentration of the compound mother liquor was set to 10mM.

3.3 Working fluid preparation (2 x)

The compound was formulated at 20. Mu.M.

3.4 Middle plate formulation (2 x)

18Ml of a compound dilution containing 0.2% DMSO was prepared and added to each well of the intermediate plate except column 3, 120. Mu.l each. The compound working solution in the 1.5ml EP tube prepared above was added to the middle plate column 3, 200 μl per well. 60 μl was removed from column 3 with a row gun and added to column 4, mixed well, diluted 3-fold down in sequence until the last column, totaling 8 concentration gradients. 2 duplicate wells were set per concentration gradient.

3.5 Addition of Compounds

The cell culture plates were removed from the incubator, and the compound working fluid, which had been prepared in the intermediate plate above, was added to the cell culture plates starting from column 12 to column 3, from low to high concentration, 100 μl per well. And a blank control well (medium) and a negative control well (medium and cells) were set up for culture in a 37 ℃ 5% co ₂ incubator.

The highest concentration of final compound addition was 10. Mu.M compound.

3.6CTG detection:

Cell activity detection kit, nanjinouzan biotechnology Co., ltd., product number DD1101-02;

After adding the compound, culturing for 72h, taking out the cell culture plate, removing 100 μl of supernatant from each well, adding 50 μl of CTG substrate, immediately shaking on a shaker for 2min after adding, standing for 10min under the dark condition, and reading chemiluminescent signals at full wavelength by using an enzyme-labeled instrument.

Relative cell viability= (assay well RLU value-blank RLU value)/(cell control group RLU value-blank RLU value);

RLU: relative fluorescence units.

Cell activity data were as follows:

in the table, no test data is indicated.

2. Enzyme Activity data test

ATM enzyme all compounds were prepared as 10mM DMSO solutions, diluted to 100 times the final concentration. Dilutions were made with 100% DMSO and 50nL of compound was transferred to 384 well reaction plates using Echo 650 (PROXIPLATE-384 PLUS). 2.5. Mu.L of an ATM enzyme solution prepared with 1-fold kinase buffer (50mM HEPES pH 7.5,20mM MgCl₂,5mM MnCl₂,200mM NaCl,1mM DTT,1mM Na₃VO₄and 0.0055％ Brij-35) (final concentration of ATM: 20 nM) was added and incubated at room temperature for 10 minutes, 2.5. Mu.L of an ATM substrate solution prepared with 1-fold kinase buffer (final concentration of ATM substrate peptide: 200. Mu.M, final concentration of ATP: 13. Mu.M) was added and reacted for 4 hours at 37℃and then 5. Mu.L of ADP-Glo reagent 1 was added, incubated at 37℃for 2 hours, 10. Mu.L of ADP-Glo reagent 2 was added to a 384-well plate reaction well and the reaction was stopped, and the reaction was allowed to stand at 37℃for 60 minutes, and the luminescence value was read on Envision 2104Multilabel Reader, and the luminescence value RLU was reproduced to convert the luminescence reading value to a percent inhibition by the formula.

The data was imported into MS Excel and curve fitted using XLFIT Excel add-in version 5.4.0.8, fitting equation Y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ^{^} HillSlope.

ATR enzyme the present experiment detects the inhibition of kinase by small molecule inhibitors by using fluorescence microfluidic Mobility detection technology (Mobility-SHIFT ASSAY). Kinase catalyzes ATP to remove a phosphate group to generate ADP, and transfers the phosphate group to a substrate peptide, wherein the substrate peptide is provided with a fluorescent label, the product is added with a phosphate group, the charge is changed, and during electrophoresis, the substrate and the phosphorylated product are separated due to different mobilities and are respectively detected, and the quantity of the substrate and the phosphorylated product is proportional to a fluorescent signal. And measuring the amount of the substrate and the product by using a Caliper instrument, and calculating the conversion rate of the product, thereby calculating the inhibition rate.

All compounds were formulated with 100% DMSO at 1000/3 times the initial concentration, transferred to 50. Mu.L to 384 well Echo plates, diluted with 100% DMSO as required by the customer, and transferred to 50. Mu.L of 100% DMSO to two empty wells as controls without compound and without enzyme. 60nL of compound was transferred into 384 well reaction plates using Echo 550 (Corning 3573). Transfer 10. Mu.L of ATR (final concentration 5 nM) 2-fold kinase solution in 1-fold kinase buffer (25mM HEPES pH 8,10mM MnCl ₂, 1mM DTT and 0.0055% Brij-35) to 384-well plate and add 1-fold kinase buffer to negative control wells. After mixing, incubation is performed at room temperature for 10 minutes, FAM-labeled polypeptide (final concentration 5. Mu.M, FAM-RAD 17) and ATP (final concentration 2. Mu.M) are added to a 1-fold kinase buffer to form a 2-fold substrate solution, 10. Mu.L of the 2-fold substrate solution is transferred to a 384-well plate to initiate a reaction, incubation is performed at 28℃for 4 hours, and 25. Mu.L of a stop solution (100mM HEPES pH 7.5,50mM EDTA,0.2% of a Coating Reagent #3and 0.015% of Brij-35) is added to the 384-well plate to terminate the reaction.

CaliperEZ ReaderⅡ(Down stream voltages:-500V,Up stream voltages:-2250V,Base pressure-0.5PSI,Screen pressure-1.2PSI) Conversion data were read. Conversion was converted to inhibition data Percent inhibition = [ (MA-X)/(MA-MI) ]x100%. "MI" is the control well reading for reactions without enzyme, "MA" is the control well reading with DMSO added, and "X" is the compound different well reading. IC50 values were fit with XLFIT excel add-in version 5.4.0.8. Fitting formula y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ^{^} HillSlope).

MTOR enzyme all compounds were prepared as 10mM DMSO solutions, diluted to 100 times the final concentration. Dilutions were made with 100% DMSO and 200nL of compound was transferred to 384 well reaction plates using Echo 550 (OptiPlate-384). mu.L of mTOR enzyme solution (final concentration 4 nM) in 1-fold kinase buffer (50mM HEPES pH 7.5,10mM MgCl ₂,2mM DTT,1mM EGTA,3mM MnCl₂ and 0.01% Tween-20) was added and incubated for 10 min at room temperature. mu.L of substrate peptide solution (substrate ULight-4E-BP1 peptide final concentration 15nM, ATP final concentration 8. Mu.M) in 1-fold kinase buffer was added. After 30 minutes at room temperature, 20. Mu.L of a termination reagent (10 x Detection Buffer, 0.5nM final concentration of Eu-anti-phospho-4E-BP1 anti-body, 20mM final concentration of EDTA) was added. Resting for 60 minutes at room temperature, the fluorescence values were read on Envision 2104Multilabel Reader, the ratio of the values of the fluorescence readings (LANCE SIGNAL ratio (665 nm/615 nm)) was replicated, the above data was converted to percent inhibition by the formula. Percent inhibition = (max-SAMPLE LANCE SIGNAL ratio)/(max-min) 100.

"Min" is the control well reading for the reaction without enzyme and "max" is the control well reading with DMSO added, the data was imported into MS Excel and curve fitted using XLFIT Excel add-in version 5.4.0.8, fitting equation Y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ≡ HillSlope).

DNA-PK enzyme all compounds were prepared as 10mM DMSO solutions, diluted to 100-fold final concentration. Dilutions were made with 100% DMSO and 50nL of compound was transferred to 384 well reaction plates using Echo 650 (PROXIPLATE-384 PLUS). 2.5. Mu.L of DNAPK enzyme solution (DNAPK final concentration 1u/ul, DNA-PK activator final concentration 5 ug/ml) prepared with 1-fold kinase buffer (40mM Tris pH7.5,20mM MgCl2,0.05mM DTT and 0.0055% Brij-35) was added and incubated at room temperature for 10 minutes, 2.5. Mu.L of DNAPK substrate solution (DNA-PK substrate peptide final concentration 0.2. Mu.g/. Mu.L, ATP final concentration 20. Mu.M) prepared with 1-fold kinase buffer was added and reacted for 3 hours at 28℃and then 5. Mu.L of ADP-Glo reagent 1 was added and incubated at 28℃for 2 hours, 10. Mu.L of ADP-Glo reagent 2 was added to 384 well plates and the reaction was stopped, and at room temperature for 30 minutes, the luminescence values were read on Envision 2104Multilabel Reader, the luminescence values RLU were replicated and the values of the luminescence readings were converted to percent inhibition by the formula. The data was imported into MS Excel and curve fitted using XLFIT Excel add-in version 5.4.0.8, fitting equation Y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ^{^} HillSlope.

Enzyme activity data are shown in the following table:

in the table, no test data is indicated.

The conclusion is that the compound of the embodiment has stronger inhibition effect on various cells through the cell activity and enzyme activity test results, which is obviously stronger than the comparison example, thus indicating that the compound prepared by the invention is a multi-target antitumor compound with extremely high activity.

Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims (15)

1. An imidazolidinone compound, characterized in that it 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: R ₁ is selected from H, alkyl, alkoxy, halogen, alkenyl, alkynyl; _R2 is selected from aryl or heteroaryl which is substituted or unsubstituted with 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, -CF ₃ , 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, 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, -NH ₂ , hydroxyl; wherein the substituted substituent is selected from halogen, carbonyl, hydroxyl, C _1-5 alkyl, aryl, cyano, -NH ₂ ; R ₃ is selected from heteroaryl which is substituted or unsubstituted by 1-5 substituents, wherein the 1-5 substituents are selected from substituted amino, C _2-8 heterocyclyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 esteramino, halogen, cyano, -NH ₂ , hydroxyl; wherein the substituted substituents are selected from C _1-6 alkyl, hydroxyl, halogen, alkylhydroxyl, alkylamino. 2. The imidazolidinone compound according to claim 1, characterized in that _R1 is selected from an alkyl group, preferably a _C1-5 alkyl group, and more preferably a methyl group. 3. The imidazolones according to claim 1, characterized in that, when _R2 in the compound of formula I is an aryl group substituted by 1-5 substituents, the substituted substituents are each independently selected from: Methoxy, -CF ₃ , F, methyl, ethyl, cyano; when R ₂ in the compound of formula I is a heteroaryl substituted by 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, -CF ₃ , 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, -CF ₃ , F, methyl, ethyl, cyano; when R ₂ in the compound of formula I is a heteroaryl substituted by 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, -CF ₃ , halogen, C _1-6 alkyl, cyano; the substituted substituent is cyano. 4. The imidazolones according to claim 1, characterized in that when R ₂ in the compound of formula I is a heteroaryl substituted by 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 , and the substituted substituent is cyano; Preferably, when R ₂ 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 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: -CF ₃ . 5. The imidazolones according to claim 1, characterized in that R ₃ is selected from phenyl substituted by 1-2 N, and the substituted substituent is selected from: substituted amino, C _2-8 heterocyclic group, C _1-6 alkyl, C _{1-6 alkylamino, C 1-6 esteramino} , and halogen, cyano, -NH ₂ , hydroxyl; wherein the substituted substituent is selected from C _1-6 alkyl, hydroxyl, halogen, alkylhydroxyl, alkylamino; Preferably, R ₃ is selected from phenyl substituted with 1-2 N, and the substituted substituent is selected from: substituted C _2-8 heterocyclic group, and cyano, -NH ₂ , -NHCH ₂ CH ₂ NHCH ₃ , -NHCOCH ₂ NHCH ₃ ; wherein the substituted substituent is selected from C _1-6 alkyl, alkylhydroxyl, alkylamino; Further preferably, R ₃ is selected from phenyl substituted by 1-2 N, and the substituted substituent is selected from: substituted amino, C _4-6 nitrogen heterocycle, C _1-6 alkyl; wherein the substituted substituent is selected from C _1-6 alkyl, hydroxyl; More preferably, _R3 is selected from phenyl substituted by 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 imidazolide compound according to claim 6, characterized in that it is the following compound: 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 it is selected from the following structures: R ₁ , R ₂ , and R ₃ have the same definitions 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 it comprises the following reaction steps: or or or R ₁ , R ₂ , and R ₃ have the same definitions as in any one of claims 1 to 7; _M1 is 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 at least one selected from 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.