Isoquinoline-5,8-dione derivative, preparation method therefor and use thereof

Abstract

The present invention relates to the technical field of pharmaceuticals, and provides an isoquinoline-5,8-dione tricyclic derivative, a preparation method therefor, and a use thereof. The isoquinoline-5,8-dione tricyclic derivative provided by the present invention is a compound represented by formula I. The compound comprises a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound has a relatively high pharmacological activity, a relatively good water solubility and drug-likeness, and can effectively treat and prevent infectious diseases, tumors, inflammatory diseases, respiratory diseases, autoimmune diseases, cardiovascular and cerebrovascular diseases, and other related diseases.

Description

An isoquinoline-5,8-dione derivative and its preparation method and application

[0001] This application claims priority to Chinese patent application No. 2024100721297, filed with the Patent Office of China on January 17, 2024, entitled “A kind of isoquinoline-5,8-dione derivative, its preparation method and application”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention relates to the field of pharmaceutical technology, and in particular to an isoquinoline-5,8-dione derivative and a preparation method and application thereof. Background Art

[0003] Quinone compounds are widely present in nature and serve as important mediators of electron transfer within organisms through reversible redox reactions. Reported biological activities of quinone compounds include, but are not limited to, antitumor, antibacterial, antifungal, antiviral, anti-neurodegenerative, and antimalarial activities.

[0004] Patent CN101838248A, for example, provides a class of 1,4-naphthoquinone compounds having a structure of Formula II, with the substituents defined as described above. These compounds possess a piperazine or piperidine linker ring structure and exhibit significant anti-tumor activity, providing a new option for the clinical preparation of anti-tumor drugs. The structural formula is shown below:

[0005] Patent CN158056A relates to the synthesis of a novel naphthoquinone-phosphorus heterocyclic compound. This compound exhibits excellent anti-tumor, anti-viral, bactericidal, and anti-HIV biological activities and can be developed into a new class of polycyclic quinone heterocyclic drugs with anti-tumor, anti-viral, bactericidal, and anti-HIV activities in clinical applications. Its structure is shown below:

[0006] Among them, phenylpropionic acid [g] isoquinoline-5,10-dione compounds are a special class of nitrogen-containing heterocyclic anthraquinone compounds, which exist in many plants and have multiple biological activities such as anti-tumor, anti-bacterial, anti-fungal and anti-tuberculosis. For example, benzo[g]isoquinoline-5,10-dione extracted from the aerial parts of Mitracarpus shirtus has stronger anti-Helicobacter pylori activity than metronidazole, and also exhibits high anti-biofilm activity. Its ability to kill biofilm-encapsulated Helicobacter pylori is stronger than that of metronidazole. 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione, also known as pisantrone, is a topoisomerase II inhibitor and DNA intercalator that can induce cell death in multiple cancer cell lines. Its cardiotoxicity and bone marrow suppression are less than those of mitoxantrone, and it has a good effect in the treatment of recurrent and aggressive non-Hodgkin's lymphoma. There are also some 1- and 3-substituted benzo[g]isoquinoline-5,10-dione compounds that have good anti-tuberculosis activity.

[0007] The chemical formulas of benzo[g]isoquinoline-5,10-dione, pixantrone, and substituted benzo[g]isoquinoline-5,10-dione are shown below from left to right.

[0008] Although benzo[g]isoquinoline-5,10-dione compounds possess a wide range of pharmacological activities, quinone derivatives often exhibit significant cellular toxicity, driven by mechanisms including redox cycling, arylation, induced DNA strand damage, and free radical generation. Furthermore, the physicochemical properties of benzo[g]isoquinoline-5,10-dione compounds require improvement, as their anthraquinone nucleus results in poor water solubility and low bioavailability. Current efforts to modify the structure of anthraquinone compounds focus primarily on enhancing the bioactivity, improving bioavailability, and reducing the cytotoxicity of the anthraquinone nucleus. However, existing research rarely addresses tricyclic isoquinoline-5,8-dione derivatives containing benzo[g]isoquinoline-5,10-dione substituted at the 8-position or 1H-imidazole[4,5-g]isoquinoline-4,9-dione substituted at both the 1- and 2-positions. Summary of the Invention

[0009] Based on the above analysis, in view of the characteristics of poor drugability, strong lipid solubility and low bioavailability of benzo[g]isoquinoline-5,8-dione compounds, and the difficulty in the prior art to provide an 8-substituted benzo[g]isoquinoline-5,10-dione compound or a 1H-imidazole[4,5-g]isoquinoline-4,9-dione compound substituted at both the 1 and 2 positions, its synthesis method and application in the medical field, the present invention aims to provide an isoquinoline-5,8-dione derivative, its preparation method and application.

[0010] To achieve the above objectives, in one aspect, the present invention provides a compound represented by Formula I, characterized in that the compound also includes stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof; Formula I is the structural formula of the compound,

[0011] wherein X is independently selected from Y is independently selected from N, CH;

[0012] R1 is independently selected from alkoxy, cyano, alkanoyl, alkanoyl, alkanoyloxy, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, alkyl, alkenyl, alkynyl, carbonyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, amidino, heteroaryl;

[0013] R2 is independently selected from hydrogen, hydroxy, alkoxy, cyano, alkanoyl, alkanoyl, alkanoyloxy, carboxyl; substituted or unsubstituted halogen, amino, sulfonyl, alkyl, alkenyl, alkynyl, carbonyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, amidino, heteroaryl;

[0014] The substituents are selected from halogen, nitro, cyano, amino, alkyl, haloalkyl, hydroxyl, hydroxymethyl, hydroxyethyl, aminoethyl, sulfhydryl, carboxyl, aldehyde, ester, aryl, heterocyclic, aroyl, cyanoaroyl, haloalkyl aroyl, heterocyclic alkenyl acyl, alkyl monosubstituted acyl, alkyl disubstituted acyl, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclic carbonyloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclicoxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclic carbonylamino, aminocarbonyl, alkoxyformamido, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid, phosphate, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformamido.

[0015] Preferably, the structural formula of the compound is selected from or

[0016] Preferably, the R1 is independently selected from alkoxy, cyano, alkanoyl, alkanoyl, alkanoyl, alkoxyacyl, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, C1-C 10 Alkyl, C1-C 10 Alkenyl, C1-C 10 Alkynyl, carbonyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, C3-C 10 Heterocyclic group, C6-C 10 heteroaryl, amidino;

[0017] R2 is independently selected from alkanoyl, alkanoyl, alkanoyloxy, alkoxyacyl; substituted or unsubstituted halogen, amino, sulfonyl, C1-C 10 Alkyl, C1-C 10 Alkenyl, C1-C 10 Alkynyl, carbonyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, C3-C 10 Heterocyclic group, C6-C 10 heteroaryl, amidino;

[0018] The substituted substituents are independently selected from halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, sulfhydryl, carboxyl, ester, aminocarbonyl, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid, phosphoric acid, C6-C 10 Aryl, C3-C 10 Heterocyclic group, C1-C 10 Alkyl monosubstituted amino, C1-C 10 Alkyl disubstituted amine, C1-C 10 Alkoxy, C1-C 10 Alkylcarbonyloxy, C3-C 10 Cycloalkylcarbonyloxy, C3-C 10 Heterocyclylcarbonyloxy, C1-C 10 Alkoxycarbonyl, C1-C 10 Cycloalkoxycarbonyl, C3-C 10 Heterocyclic oxycarbonyl, C1-C 10 Alkylcarbonylamino, C3-C 10 Cycloalkylcarbonylamino, C3-C 10 Heterocyclic carbonylamino, C1-C 10 Alkoxycarboxamide, polyhydroxy C1-C 10 Alkoxycarbonyl, carboxyl C1-C 10 Alkoxy, carboxyl C1-C 10 Alkylformyloxy.

[0019] More preferably, the R1 is independently selected from alkoxy, cyano, alkanoyl, alkanoyl, alkanoyloxy, alkoxyacyl, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6-C 10 Aryl, C3-C6 heterocyclic, C6-C 10 heteroaryl, N-carbamimidoyl;

[0020] R2 is independently selected from alkanoyl, alkanoyl, alkanoyloxy, alkoxyacyl; substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6-C 10 Aryl, C3-C6 heterocyclic, C6-C 10 heteroaryl;

[0021] The substituted substituents are independently selected from halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, sulfhydryl, carboxyl, ester, aminocarbonyl, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid, phosphoric acid, C6-C 10 Aryl, C3-C6 heterocyclic group, C1-C6 alkyl monosubstituted amino group, C1-C6 alkyl disubstituted amino group, C1-C6 alkoxy group, C1-C6 alkylcarbonyloxy group, C3-C6 cycloalkylcarbonyloxy group, C3-C6 heterocyclic carbonyloxy group, C1-C6 alkoxycarbonyl group, C1-C6 cycloalkyloxycarbonyl group, C3-C6 heterocyclic oxycarbonyl group, C1-C6 alkylcarbonylamino group, C3-C6 cycloalkylcarbonylamino group, C3-C6 heterocyclic carbonylamino group, C1-C6 alkoxyformamido group, polyhydroxy C1-C6 alkoxycarbonyl group, carboxyl C1-C6 alkoxy group, carboxyl C1-C6 alkylformyloxy group.

[0022] More preferably, the R1 is independently selected from alkoxy, cyano, alkanoyl, alkanoyl, alkanoyloxy, alkoxyacyl, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, C1-C3 alkyl, C1-C3 alkenyl, C1-C3 alkynyl, carbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6-C 10 Aryl, C3-C6 heterocyclic, C6-C 10 heteroaryl;

[0023] R2 is independently selected from alkanoyl, alkanoyl, alkanoyloxy, alkoxyacyl, carboxyl; substituted or unsubstituted C1-C3 alkyl, carbonyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C6 heterocyclic group;

[0024] The substituted substituents are independently selected from halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, sulfhydryl, carboxyl, ester, aminocarbonyl, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid, phosphoric acid, C6-C 10Aryl, C3-C6 heterocyclic group, C1-C3 alkyl monosubstituted amine, C1-C3 alkyl disubstituted amine, C1-C3 alkoxy, C1-C3 alkylcarbonyloxy, C3-C3 cycloalkylcarbonyloxy, C3-C6 heterocyclic carbonyloxy, C1-C6 alkoxycarbonyl, C1-C6 cycloalkyloxycarbonyl, C3-C6 heterocyclic oxycarbonyl, C1-C6 alkylcarbonylamino, C3-C6 cycloalkylcarbonylamino, C3-C6 heterocyclic carbonylamino, C1-C6 alkoxyformamido, polyhydroxy C1-C6 alkoxycarbonyl, carboxyl C1-C6 alkoxy, carboxyl C1-C6 alkylformyloxy.

[0025] Preferably, and as an example of the present invention, the compound is selected from any one of the following compounds:

[0026] Unless otherwise specified, the term "alkyl" as used herein includes branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, including all isomers. "Alkenyl" refers to branched and straight-chain aliphatic hydrocarbon groups containing a carbon-carbon double bond (olefinic bond), and "alkynyl" refers to branched and straight-chain aliphatic hydrocarbon groups containing a carbon-carbon triple bond (alkyne bond). Common abbreviations for alkyl groups include, for example, "Me" or CH3 for methyl, "Et" or CH2CH3 for ethyl, "Pr" or CH2CH2CH3 for propyl, and "Bu" or CH2CH2CH2CH3 for butyl.

[0027] The term "carbonyl" refers to an organic functional group composed of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0028] The terms "cycloalkyl" and "cycloalkenyl" refer to hydrocarbon groups having a monocyclic ring system of carbon atoms which may be saturated or unsaturated.

[0029] The term "aryl" refers to aromatic mono- and polycyclic carbocyclic ring systems, wherein the carbon rings in the polycyclic ring system are fused or connected to each other by single bonds. In the case of polycyclic rings, as long as one carbon ring is aromatic, typical aryl groups include phenyl, naphthyl and biphenylene.

[0030] The term "heterocyclyl" refers to a cyclic structure composed of carbon atoms and non-carbon atoms, such as nitrogen, oxygen, and sulfur. The heterocyclyl may be a monocyclic heterocyclyl having 4-8 ring atoms, or a bicyclic heterocyclyl having 7-11 ring atoms. In the bicyclic heterocyclyl, as long as one ring is a heterocycle, the other ring may be aromatic or non-aromatic, containing or not containing heteroatoms. In addition, the bicyclic heterocyclyl may be a paracyclic structure, a spirocyclic structure, or two heterocycles directly connected. Examples of heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.

[0031] The term "heteroaryl" refers to an aromatic ring group containing 1-4 heteroatoms as ring members. Heteroatoms refer to nitrogen, oxygen, or sulfur. A heteroaryl group can be a monocyclic heteroaryl group having 5-7 ring atoms, or a bicyclic heteroaryl group having 7-11 ring atoms. In the bicyclic heteroaryl group, as long as one ring is a heteroaromatic ring, the other ring can be aromatic or non-aromatic, containing or not containing heteroatoms. In addition, the bicyclic heteroaryl group can be a paracyclic structure, a spirocyclic structure, or two heterocyclic rings directly connected. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, and the like.

[0032] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

[0033] In the present invention, "C1-C8 alkyl" refers to a straight chain or branched chain alkyl group with a specific number of carbon atoms (1-8), including all isomers, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, etc. "C2-C8 alkenyl" refers to a straight chain or branched chain alkyl group with a specific number of carbon atoms (2-8), including all isomers, including but not limited to vinyl, allyl, etc. "C3-C8 cycloalkyl or cycloalkenyl" refers to a hydrocarbon group with a saturated or unsaturated ring of 3-8 carbon atoms in a monocyclic system, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclohexenyl, etc. Similarly, the term "C1-C8 alkyl" refers to a straight chain or branched chain alkyl group with a specific number of carbon atoms (2-8), including all isomers, including but not limited to vinyl, allyl, etc. 10 Alkyl", "C2-C 10 Alkenyl", "C1-C8 carbonyl", "C3-C8 cycloalkenyl", "C6-C 10 Aryl", "C5-C 10 Heterocyclic group", "C5-C 10 "Heteroaryl" and the like have similar meanings.

[0034] Unless otherwise specified, all ranges listed herein are inclusive. For example, "1-4" includes 1, 2, 3, and 4.

[0035] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be readily prepared from an inorganic or organic base. Salts derived from such inorganic bases include salts of aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganous), potassium, sodium, zinc, and the like. Preferred are salts of ammonium, calcium, magnesium, potassium, and sodium. Salts prepared from organic bases include primary, secondary, and tertiary amines derived from natural and synthetic sources. Pharmaceutically acceptable organic non-toxic bases that can form salts include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compound of the present invention is basic, its corresponding salt can be easily prepared from inorganic or organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. In the present invention, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, tannic acid, lithium, sodium, potassium, calcium, magnesium, or lysine are preferred.

[0036] The term "solvate" refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula I) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is referred to as a hydrate. Hydrates include, but are not limited to, hemihydrates, monohydrates, monosesquihydrates, dihydrates, and trihydrates.

[0037] The term "prodrug" refers to a functional derivative of the compound of the present invention that is easily converted into the desired compound in vivo. In the present invention, various derivatives after reducing quinone to diphenol or other substituents are preferred as prodrug derivatives.

[0038] In another aspect, the present invention provides a method for preparing the compound represented by Formula I, wherein the reaction route is selected from at least one of the following six types:

[0039] Reaction Scheme I:

[0040] Unless otherwise specified, all reactions were performed under argon atmosphere.

[0041] Reaction route I of the present invention uses pyridine-3,4-dicarboxylic anhydride 1 and anisole 2 as starting materials to obtain compound 3 through Friedel-Crafts acylation reaction, compound 3 is reduced by zinc powder and formic acid to obtain compound 4, compound 4 undergoes intramolecular Friedel-Crafts acylation under the action of trifluoroacetic anhydride to obtain compound 5, compound 5 is further oxidized to obtain compound S1, and then demethylated by boron tribromide to obtain compound 6, compound 6 reacts with trifluoromethanesulfonic anhydride to obtain compound 7, and finally compound 7 can be subjected to multiple derivatization reactions to obtain target compounds S2-S30, wherein R has the same definition as that in the claims.

[0042] Furthermore, step c is specifically as follows: compound 4 is placed in a pressure-resistant tube, trifluoroacetic anhydride (TFAA) is added, and then the pressure-resistant tube is sealed to react to obtain compound 5.

[0043] Furthermore, the reaction is carried out in the presence of a solvent and under heating conditions. Furthermore, the solvent is trifluoroacetic anhydride. Furthermore, the heating temperature is 40-65° C. Further, the reaction time is 30-72 hours.

[0044] Furthermore, step d is specifically as follows: compound 5 is placed in a single-necked flask, stirred in a sealed container at room temperature for reaction, and oxygen is introduced to oxidize the compound 5 into compound S1.

[0045] Furthermore, the reaction is carried out in the presence of a solvent under alkaline conditions. Furthermore, the solvent is selected from at least one of methanol, ethanol, tetrahydrofuran, dioxane, acetone, acetonitrile, and N,N-dimethylformamide, with N,N-dimethylformamide being most preferred. Furthermore, the alkaline conditions are selected from at least one of sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, and sodium bicarbonate, with potassium carbonate being most preferred. Furthermore, the reaction time is 0.5-2.5 hours.

[0046] Reaction route II:

[0047] Unless otherwise specified, all reactions were performed under argon atmosphere.

[0048] Using Reaction Scheme I, compound 7 reacts with zinc cyanide under palladium catalysis to obtain compound S2. Compound S2 is hydrolyzed in a H2O2 / K2CO3 / DMSO system to obtain S31; alternatively, it is hydrolyzed under strong alkaline conditions to obtain carboxylic acid intermediate 8, which is then esterified or reacted with acid-amine condensation to obtain compounds S32-S33, wherein R has the same meaning as in claims 1-5.

[0049] Reaction route III:

[0050] Using reaction route I, compound 7 reacts with acetamide under palladium catalysis to obtain compound S5, which is hydrolyzed under acidic conditions to obtain S34; S34 reacts with DMF activated by TAFF to obtain compound S35; S34 can also be prepared into diazonium salts 9-11, which are then converted to obtain S36-S37 and azide intermediate 12; S37 undergoes a coupling reaction to obtain S38; 12 can undergo a click reaction to obtain S39.

[0051] Reaction Scheme IV:

[0052] Unless otherwise specified, all reactions were performed under argon atmosphere.

[0053] Reaction route IV of the present invention uses 5-hydroxyisoquinoline 13 as a raw material, and is oxidized with [bis(trifluoroacetoxy)iodine]benzene to obtain isoquinoline-5,8-dione 14. Compound 14 reacts with sodium azide in acetic acid solvent to obtain compound 15. Compound 15 reacts with N-bromosuccinimide to quantitatively obtain compound 16. Compound 16 undergoes a solvolysis reaction in acetic anhydride as a solvent under the catalysis of concentrated sulfuric acid to obtain an acetylated intermediate 17. Compound 17 reacts with a primary amine to obtain a deep red solid 18. Compound 18 is ring-closed under alkaline conditions to obtain a series of compounds S40-S60, wherein R2 has the same definition as that of claims 1-5.

[0054] Furthermore, step a is specifically as follows: 5-hydroxyisoquinoline is suspended in acetonitrile, PIFA is dissolved in a mixed solvent of acetonitrile and water, and the PIFA solution is slowly added dropwise into the reaction flask under ice bath conditions, maintained at low temperature, and stirred for reaction.

[0055] Furthermore, the reaction is carried out in the presence of a solvent and in an ice bath. Furthermore, the solvent is a mixture of acetonitrile and water. Furthermore, the temperature of the ice bath is between -5°C and 0°C. Furthermore, the reaction time is 1 hour.

[0056] Furthermore, step b is specifically as follows: compound 14 and sodium azide are placed in a single-necked bottle, glacial acetic acid is added, and the reaction yields 15.

[0057] Furthermore, the reaction is carried out in the presence of a solvent and under heating conditions. Furthermore, the solvent is glacial acetic acid. Furthermore, the heating temperature is 65-75° C. Further, the reaction time is 2-3 hours.

[0058] Furthermore, step c is specifically as follows: compound 15 and N-bromosuccinimide are placed in a single-necked bottle, methanol is added, and the reaction is carried out to obtain 16.

[0059] Furthermore, the reaction is carried out in the presence of a solvent at room temperature. Furthermore, the solvent is methanol. Furthermore, the room temperature is 25-30° C. Furthermore, the reaction time is 10-12 hours.

[0060] Furthermore, step d is specifically as follows: compound 16 and acetic anhydride are placed in a single-necked bottle, concentrated sulfuric acid is added, and the mixture is reacted at room temperature to obtain 17.

[0061] Furthermore, the reaction is carried out in the presence of a solvent at room temperature. Furthermore, the solvent is acetic anhydride. Furthermore, the room temperature is 25-30° C. Furthermore, the reaction time is 5-10 minutes.

[0062] Furthermore, step e is specifically as follows: compound 17 and a primary amine are placed in a single-necked bottle, toluene is added, and the mixture is reacted at room temperature to obtain compound 18.

[0063] Furthermore, the reaction is carried out in the presence of a solvent at room temperature. Furthermore, the solvent is toluene. Furthermore, the room temperature is 25-30° C. Furthermore, the reaction time is 1-2 hours.

[0064] Furthermore, step f is specifically as follows: compound 18 is placed in a single-necked bottle, aqueous sodium hydroxide solution is added, and the reaction is carried out at room temperature to obtain compounds S40-S60.

[0065] Furthermore, the reaction is carried out in the presence of a solvent and at room temperature. Furthermore, the solvent is ethanol. Furthermore, the sodium hydroxide aqueous solution is a 2 mol / L sodium hydroxide aqueous solution, the room temperature is 25-30° C., and the reaction time is 1-2 hours.

[0066] Reaction Scheme V:

[0067] Using Reaction Scheme IV, compound 16 and isobutyric anhydride are acylated in the presence of sulfuric acid to obtain intermediate 19. Compound 19 is reacted with a primary amine in toluene to obtain compound 20. Compound 19 is reacted under alkaline conditions to obtain compounds S61-S77, wherein R has the same meaning as in claims 1-5;

[0068] Reaction Scheme VI:

[0069] Using reaction route IV, compound 15 is reacted with di-tert-butyl dicarbonate and p-dimethylaminopyridine in tetrahydrofuran to obtain intermediate 21. Compound 21 is reacted with a primary amine to obtain intermediate 22. Compound 22 is deprotected under acidic conditions of hydrochloric acid to obtain primary amine compound 23. Compound 24 is reacted with benzoyl chloride and triethylamine in dichloromethane to obtain intermediate 24. Compound 24 is ring-closed under alkaline conditions to obtain compounds S78-S86, wherein R has the same definition as that of claims 1-5.

[0070] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and one or more pharmaceutically acceptable carriers, diluents, and excipients.

[0071] In the context of pharmaceutical compositions, the term "composition" includes a product comprising an active ingredient and an inert ingredient (pharmaceutically acceptable excipient) constituting a carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of two or more ingredients, or the decomposition of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical compositions of the present invention include any composition prepared by mixing a compound of Formula I, other active ingredients, and a pharmaceutically acceptable excipient.

[0072] The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragees, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions and suspensions.

[0073] 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 a physical combination, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. The compounds of the present invention may be administered as the sole active ingredient or in combination with a second active ingredient.

[0074] The term "effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The effective amount is determined based on the age, condition, and course of treatment of the subject.

[0075] The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels suitable for human use and having sufficient purity and sufficiently low toxicity. "Compatibility" as used herein refers to the ability of the components of the composition to blend with the compound of the invention, and with each other, without significantly reducing the compound's efficacy. Examples of pharmaceutically acceptable carriers include sugars (e.g., glucose, sucrose, lactose), starches (e.g., corn starch, potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol), emulsifiers (e.g., Tween), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0076] In another aspect, the present invention provides a compound of Formula I or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of a pharmaceutical composition containing the compound of Formula I in the preparation of drugs for treating infectious diseases, inflammatory diseases and autoimmune diseases, tumors or cardiovascular and cerebrovascular diseases, wherein the infectious diseases do not include infectious diseases caused by Helicobacter pylori infection.

[0077] Among them, cardiovascular and cerebrovascular diseases include but are not limited to diseases of the heart and vascular system, for example, sepsis, hypertension, hyperlipidemia, hypertriglyceridemia, atherosclerosis, transient ischemic attack, systolic dysfunction, diastolic dysfunction, aneurysm, aortic dissection, myocardial ischemia, acute myocardial infarction (AMI), acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), angina pectoris, unstable angina (UA) and stable angina (SA), myocardial infarction, congestive heart failure, congestive dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, cor pulmonale, arrhythmia, valvular heart disease, endocarditis, pulmonary embolism, venous thrombosis, peripheral vascular disease and peripheral arterial disease.

[0078] Respiratory diseases include a variety of respiratory diseases, including but not limited to viral infections such as influenza and the common cold, as well as allergies, sinusitis, rhinitis, etc.

[0079] Among them, the tumor includes but is not limited to at least one of solid tumors or hematological malignancies, such as lymphoma, bladder cancer, bone cancer, childhood brainstem glioma, adult brain tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, craniopharyngioma, ependymoma, breast cancer, bronchiolar cancer, central nervous system lymphoma, cervical cancer, chronic lymphocytic leukemia, colon cancer, colorectal cancer, esophageal cancer, eye cancer, gallbladder cancer, gastric cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, prostate cancer, intestinal cancer, thyroid cancer, etc.

[0080] Preferably, the infectious diseases include infectious diseases caused by fungal infection, infectious diseases caused by bacterial infection other than Helicobacter pylori, and infectious diseases caused by viral infection.

[0081] Preferably, the tumor is selected from at least one of leukemia, multiple myeloma, lymphoma, lung cancer, head and neck cancer, esophageal cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, breast cancer, cervical cancer, and prostate cancer.

[0082] Preferably, the inflammatory disease and autoimmune disease is at least one selected from rheumatoid arthritis, chronic obstructive pulmonary disease, acute lung injury, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis.

[0083] Preferably, the cardiovascular and cerebrovascular diseases include coronary heart disease, myocardial infarction, angina pectoris, thrombolytic therapy or percutaneous coronary artery lumen-related acute vascular occlusion, transient ischemic attack, stroke, intermittent claudication or coronary or peripheral artery bypass grafting, vascular lumen stenosis, restenosis after coronary artery or venous angioplasty, maintenance of vascular access patency in long-term hemodialysis patients, pulmonary thromboembolism, and heart failure caused by anthraquinone drugs.

[0084] Compared with the prior art, the present invention has the following beneficial effects:

[0085] A type of isoquinoline-5,8-dione derivative is proposed, including an 8-substituted benzo[g]isoquinoline-5,10-dione compound or a 1H-imidazole[4,5-g]isoquinoline-4,9-dione compound substituted at both the 1- and 2-positions. The derivative has high pharmacological activity, good water solubility and drug-like properties, and can effectively treat and prevent infectious diseases, tumors, inflammatory diseases, respiratory diseases, autoimmune diseases, cardiovascular and cerebrovascular diseases, and other related diseases and conditions. DETAILED DESCRIPTION

[0086] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further illustrated below in conjunction with specific embodiment, but the following embodiment is only a preferred embodiment of the present invention, not all. Based on the embodiment in the embodiment, other embodiments obtained by those skilled in the art without making creative work all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their source is not specifically limited. The technology and scientific terms used in the embodiment have the meaning commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0087] Reaction Scheme I of the compound of formula (I):

[0088] Example 1

[0089] Preparation of 4-(4-methoxybenzoyl)nicotinic acid (3)

[0090] Pyridine-3,4-dicarboxylic anhydride (6.0 g, 40 mmol) and AlCl₃ (21.3 g, 160 mmol) were weighed and placed in a 250 mL two-necked flask. A magnetic stirrer was added and the atmosphere was replaced with argon several times. 1,2-Dichloroethane (80 mL) was added, followed by anisole (12.8 mL, 120 mmol) with stirring. The reaction mixture was heated to 90°C for 6 h. After the reaction was complete, heating was stopped and the reaction mixture was cooled to room temperature. The mixture was slowly added to ice water and stirred for 30 minutes. Filtering afforded a white or light yellow solid, compound 3. The filtrate was extracted with dichloromethane and isopropanol (3:1) (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent removed by rotary evaporation to yield a yellow viscous mixture. Appropriate amounts of ethyl acetate and petroleum ether were added to the mixture at low temperature to solidify the mixture. Filtering afforded a white or light yellow solid, compound 3. The two solids were combined (9.2 g, 89%) and used directly in the next step without further purification.

[0091] Example 2

[0092] Preparation of 4-(4-methoxybenzyl)nicotinic acid (4)

[0093] Compound 3 (9.0 g, 35 mmol) prepared in Example 1 was weighed and placed in a 100 mL pressure tube equipped with a magnetic stirrer. 45 mL of formic acid and 15 mL of water were added. Zinc powder (6.83 g, 105 mmol) was added portionwise at room temperature. The mixture was sealed and stirred at room temperature for 15-25 minutes. The temperature was then raised to 80°C and allowed to react for 3-4 hours. After the reaction was complete, heating was stopped and the reaction mixture was cooled to room temperature. The off-white solid was removed by filtration. The residue was washed with formic acid and water (3:1) (5 mL x 3). The filtrate was collected and rotary evaporated to remove most of the formic acid and water, yielding a viscous mixture. An appropriate amount of methanol was added to the mixture to slurry and solidify it. After filtration, a white or light yellow solid, compound 4 (6.0 g, 71%), was obtained. 1 H-NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.48 (d, J = 5.2Hz, 1H), 7.24 (d, J = 6.0H z, 1H), 7.20 (d, J = 8.8Hz, 2H), 6.76 (d, J = 8.8Hz, 2H), 4.38 (s, 2H), 3.65 (s, 3H).

[0094] Example 3

[0095] Preparation of 8-methoxybenzo[g]isoquinolin-10(5H)-one (5)

[0096] Compound 4 (11.0 g, 45.2 mmol) obtained in Example 2 was weighed and placed in a 100 mL pressure tube. 60 mL of trifluoroacetic anhydride was added, and the mixture was sealed and heated to 65°C for 30-40 hours. After the reaction was complete, heating was stopped and the mixture was cooled to room temperature. The trifluoroacetic anhydride was removed by rotary evaporation to obtain a viscous dark red mixture. After adding an appropriate amount of methanol to the mixture, the methanol was removed by rotary evaporation, and a red solid was precipitated. Appropriate amounts of petroleum ether and ethyl acetate were then added to the mixture to make a slurry. After filtration, a red solid, compound 5 (6.1 g, 60%), was obtained. 1 H-NMR (400MHz, CD3OD) δ9.85(s,1H),8.16(d,J=6.8Hz,1H),8.06(s,1H),8.04(d,J=2 .0Hz,1H),7.87(d,J=2.8Hz,1H,7.50(d,J=9.2,2.4Hz,1H),4.94(s,2H),4.04(s,3H).

[0097] Example 4

[0098] Preparation of 8-methoxybenzo[g]isoquinoline-5,10-dione (S1)

[0099] 5 (2.25 g, 10 mmol) prepared in Example 3 and potassium carbonate (1.79 g, 13 mmol) were weighed and placed in a 250 mL single-necked flask equipped with a magnetic stirrer. 150 mL of N,N-dimethylformamide was added to dissolve the mixture. After several oxygen replacements, the mixture was stirred and reacted at 25°C with oxygen bubbling for 1-2 hours. After the reaction was complete, 100 mL of ethyl acetate and 150 mL of water were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layers were combined. The organic layer was then washed with water (100 mL x 3) and once with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the ethyl acetate was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography [developing solvent: V(PE):V(DCM):V(EA) = 10:2:1] to obtain S1 (1.33 g, 56%) as a yellow solid. 1 H-NMR (400MHz, CDCl3) δ9.52 (s, 1H), 9.08 (d, J = 4.8Hz, 1H), 8.24 (d, J = 8.8Hz, 1H), 8. 05(d,J=4.8Hz,1H), 7.71(d,J=2.8Hz,1H), 7.29(dd,J=8.8,2.8Hz,1H), 4.00(s,3H); 13 C-NMR (101MHz, CDCl3) δ182.7, 181.3, 165.1, 155.5, 149.6, 138.8, 135.2, 130.1, 126.7, 126.5, 121.7, 119.2, 110.1, 56.2.

[0100] Example 5

[0101] Preparation of 8-hydroxybenzo[g]isoquinoline-5,10-dione (6)

[0102] Weigh S1 (0.96 g, 4.0 mmol) prepared in Example 4 and place it in a 250 mL two-necked flask with a magnetic stirrer, and replace the argon several times. Add 40 mL of anhydrous dichloromethane to dissolve S1. After cooling the reaction solution to -78 ° C, slowly add 40 mmol of boron tribromide (1 mol / L dichloromethane solution, 40 mL). After the addition is complete, the reaction solution is stirred at -78 ° C for 1 hour, then naturally warmed to -40 ° C and reacted overnight. Finally, the reaction solution is naturally warmed to room temperature and reacted for 3 to 5 hours. After the reaction is complete, 5 mL of ice water is slowly added to the reaction solution under an ice bath to quench the excess boron tribromide. After quenching, the dichloromethane is removed by rotary evaporation to obtain a yellow-brown solid-liquid mixture. Slowly add 2M sodium hydroxide aqueous solution to the mixture until the reaction solution turns completely red, then add a small amount of ethyl acetate and heat with stirring, separate the liquid and remove the organic layer to remove a small amount of raw material 6. 1N hydrochloric acid was slowly added dropwise to the red aqueous layer with stirring. The aqueous layer first turned yellow and then immediately red. When the aqueous layer had completely turned yellow and did not turn red again within 30 seconds, the addition of 1N hydrochloric acid was stopped. A large amount of yellow solid precipitated. The solid-liquid mixture was heated and stirred for 30 minutes. The mixture was filtered while hot to obtain a yellow residue. The yellow residue was washed with a small amount of acetone or methanol and dried to obtain a yellow solid, 6 (0.73 g, 81%). 1 H-NMR (400MHz, DMSO-d6) δ11.32(s,1H),9.31(s,1H),9.11(d,J=5.2Hz,1H),8.08(d,J =8.4Hz,1H),7.98(d,J=5.2Hz,1H),7.48(d,J=2.8Hz,1H),7.26(dd,J=8.4,2.8Hz,1H); 13 C-NMR (101MHz, DMSO-d6) δ 183.4, 181.6, 164.8, 156.5, 149.3, 139.5, 136.0, 131.0, 127.3, 125.9, 122.8, 119.8, 113.1.

[0103] Example 6

[0104] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-trifluoromethanesulfonate (6)

[0105] Compound 6 (0.45 g, 2.0 mmol) prepared in Example 5 and DMAP (24.4 mg, 0.2 mmol) were weighed and placed in a 50 mL two-necked flask with a magnetic stirrer. The atmosphere was replaced with argon several times. 20 mL of anhydrous dichloromethane was added and the mixture was cooled to -15°C. Triethylamine (1.1 mL, 8.0 mmol) was added, and trifluoromethanesulfonic anhydride (0.84 mL, 5.0 mmol) was slowly added dropwise. After the addition was complete, the mixture was maintained at -15°C for 15-25 minutes. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The layers were separated, and the aqueous layer was extracted with dichloromethane (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate and rotary evaporated to remove the dichloromethane to obtain the crude product. The crude product was purified by silica gel column chromatography [developing solvent: V(PE):V(DCM):V(EA) = 10:1:1] to yield compound 7 (0.50 g, 70%) as a white or light yellow solid. 1 H-NMR (400MHz, CDCl3) δ9.63 (s, 1H), 9.20 (d, J = 5.2Hz, 1H), 8.49 (d, J = 8.8Hz, 1H), 8.24(d,J=2.4Hz,1H), 8.13(d,J=5.2Hz,1H), 7.78(dd,J=8.8,2.4Hz,1H); 13 C-NMR (101MHz, CDCl3) δ181.1,180.8,156.1,153.9,150.0,138.1,135.4,132.5,130.6,127.4,125.9,120.3,120.1,119.2,117.1.

[0106] Example 7

[0107] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carbonitrile (S2)

[0108] Intermediate 7 (357 mg, 1.0 mmol) prepared in Example 6 was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. Zn(CN)2 (351 mg, 3.0 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were added, and the atmosphere was replaced with argon several times. 5 mL of N,N-dimethylformamide was added, and the mixture was heated to 100°C for 0.5-1 hour. After the reaction was complete, 2M sodium hydroxide was added, and a large amount of solid precipitated. Filtering afforded the crude solid, S2. The filtrate was extracted with ethyl acetate (30 mL x 3). The organic layer was washed with water (50 mL x 3), then with saturated brine, and finally dried over anhydrous sodium sulfate. The ethyl acetate was removed by rotary evaporation to afford another portion of the crude product. The crude product was purified by slurrying with appropriate amounts of dichloromethane and methanol to afford S2 (200 mg, 85%) as a yellow-green solid. 1H-NMR (400MHz, CDCl3) δ9.62 (s, 1H), 9.19 (d, J = 5.2Hz, 1H), 8.64 (s, 1H), 8.45 (d, J = 8.0Hz, 1H), 8.11 (m, 2H); 13 C-NMR (101MHz, CDCl3) δ181.5, 180.7, 156.2, 150.1, 138.0, 137.2, 135.1, 133.4, 131.5, 128.3, 125.7, 119.2, 118.8, 116.9.

[0109] Example 8

[0110] Preparation of 8-ethynylbenzo[g]isoquinoline-5,10-dione (S3)

[0111] The intermediate 7 (180 mg, 0.5 mmol) prepared in Example 6 was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. CuI (29 mg, 0.15 mmol) and PdCl2(PPh3)2 (55 mg, 0.075 mmol) were added and the argon atmosphere was replaced several times. 5 mL of anhydrous tetrahydrofuran was added, followed by triethylamine (126 mg, 1.25 mmol) and trimethylsilyl acetylene (147 mg, 1.5 mmol), and the mixture was reacted at 25°C for 2 to 3 hours. After the reaction was complete, the insoluble matter was removed by filtration, the filter residue was washed with dichloromethane, the filtrate was extracted with dichloromethane (10 mL × 3), the combined organic layers were washed with saturated brine, and finally dried over anhydrous sodium sulfate. The organic solvent was then removed by rotary evaporation to obtain a crude product of S3a.

[0112] The crude product was directly dissolved in methanol and dichloromethane, and potassium carbonate (138 mg, 1.0 mmol) was added. The reaction was allowed to proceed at 25°C for 10-15 minutes. After the reaction was complete, water was added, the layers were separated, and the aqueous layer was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with saturated brine and finally dried over anhydrous sodium sulfate. The organic solvent was then removed by rotary evaporation to obtain crude S3. The crude product was purified by silica gel column chromatography to obtain S3 (82 mg, 70% over two steps) as a white or light yellow solid. 1 H-NMR (400MHz, CDCl3) δ9.61 (s, 1H), 9.17 (d, J = 5.2Hz, 1H), 8.45 (d, J = 1.6Hz, 1H), 8. 31 (d, J=8.0Hz, 1H), 8.11 (d, J=5.2Hz, 1H), 7.94 (dd, J=8.0, 1.6Hz, 1H), 3.47 (s, 1H); 13C-NMR (101MHz, CDCl3) δ182.0, 181.9, 155.7, 149.9, 138.4, 137.6, 133.0, 132.4, 131.0, 129.4, 127.6, 126.1, 119.1, 83.0, 81.8.

[0113] Example 9

[0114] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)formamide (S4)

[0115] Intermediate 7 (71 mg, 0.2 mmol) prepared in Example 6 was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. Formamide (18 mg, 0.4 mmol), Cs2CO3 (98 mg, 0.3 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), 17 mg, 0.03 mmol) were added, and the atmosphere was replaced with argon several times. 2 mL of dioxane was added, and the mixture was heated to 100°C for 30 minutes. After the reaction was complete, water was added, the layers were separated, and the aqueous layer was extracted with dichloromethane (5 mL x 3). The organic layer was washed with 1 M sodium hydroxide until the aqueous layer was almost colorless, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S4 (26 mg, 52%) as a yellow solid. 1 H-NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 9.37 (s, 1H), 9.14 (d, J=4.8Hz, 1H), 8.51-8. 41 (m, 2H), 8.21 (d, J=8.4Hz, 1H), 8.08 (dd, J=8.4, 2.0Hz, 1H), 8.02 (d, J=4.8Hz, 1H); 13 C-NMR (101MHz, DMSO-d6) δ182.7, 181.5, 161.2, 156.0, 148.9, 144.6, 139.0, 134.6, 129.3, 128.7, 126.8, 124.6, 119.3, 116.3.

[0116] Example 10

[0117] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)acetamide (S5)

[0118] The preparation of compound S5 was the same as that of compound S4 in Example 9, except that formamide was replaced with acetamide (118 mg, 2.0 mmol, 2.0 equiv). After purification, a yellow solid, S5 (204 mg, 77%), was obtained. 1 H-NMR (400MHz, DMSO-d6) δ10.68 (s, 1H), 9.37 (s, 1H), 9.14 (d, J = 5.2Hz, 1H), 8.45 (d, J = 2.4Hz , 1H), 8.19 (d, J=8.4Hz, 1H), 8.11 (dd, J=8.4, 2.4Hz, 1H), 8.02 (d, J=4.8Hz, 1H), 2.16 (s, 3H); 13 C-NMR (101MHz, DMSO-d6) δ182.9, 181.5, 170.0, 156.0, 148.9, 145.8, 139.1, 134.5, 129.2, 128.1, 126.9, 124.2, 119.3, 116.0, 24.8.

[0119] Example 11

[0120] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzamide (S6)

[0121] The preparation of compound S8 was the same as that of compound S4 in Example 9, except that formamide was replaced with benzamide (48 mg, 0.4 mmol, 2.0 equiv). After purification, a yellow solid, S6 (61 mg, 93%), was obtained. 1 H-NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 9.36 (s, 1H), 9.13 (d, J=4.8Hz, 1H), 8.66 (s, 1H), 8.37 (dd, J=8.8, 2.4Hz, 1H), 8.20 (d, J=8.8Hz, 1H), 8.05-8.00 (m, 3H), 7.69-7.65 (m, 1H), 7.61-7.57 (m, 2H); 13 C-NMR (101MHz, DMSO-d6) δ182.8, 181.6, 166.7, 156.0, 148.9, 145.9, 139.0, 134.6, 134.3, 132.7 , 129.0(129.03), 129.0(128.95), 128.5(128.51), 128.5(128.46), 126.8, 125.3, 119.3, 117.3.

[0122] Example 12

[0123] Preparation of 4-cyano-N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzamide (S7)

[0124] The preparation of compound S7 was the same as that of compound S4 in Example 9, except that formamide was replaced with 4-cyanobenzamide (58 mg, 0.4 mmol, 2.0 equiv). After purification, a white solid, S7 (53 mg, 75%), was obtained. 1 H-NMR (400MHz, DMSO-d6) δ11.12 (s, 1H), 9.38 (s, 1H), 9.14 (d, J = 4.8Hz, 1H), 8.66 (d, J = 2.4Hz, 1H), 8.37 (dd, J=8.8, 2.4Hz, 1H), 8.25 (d, J=8.8Hz, 1H), 8.21-8.17 (m, 2H), 8.12-8.07 (m, 2H), 8.03 (dd, J=4.8, 0.8Hz, 1H); 13 C-NMR (101MHz, DMSO-d6) δ182.8, 181.6, 165.4, 156.0, 149.0, 145.3, 139.0, 138. 5, 134.4, 133.1, 129.3, 129.0, 128.9, 126.9, 125.5, 119.3, 118.8, 117.5, 114.9.

[0125] Example 13

[0126] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)-4-trifluoromethylbenzamide (S8)

[0127] The preparation of compound S8 was the same as that of compound S4 in Example 9, except that formamide was replaced with 4-trifluoromethylbenzamide (74 mg, 0.4 mmol, 2.0 equiv). After purification, a white solid, S8 (53 mg, 75%), was obtained. 1 H-NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 9.35 (s, 1H), 9.12 (d, J=5.2Hz, 1H), 8.62 (s, 1H), 8 .35 (dd, J=8.8, 2.4Hz, 1H), 8.24-8.18 (m, 3H), 7.99 (d, J=5.2Hz, 1H), 7.96 (d, J=8.0Hz, 2H); 13C-NMR (101MHz, DMSO-d6) δ182.7, 181.5, 165.5, 156.0, 148.9, 145.4, 138.9, 138.3, 134.3, 12 9.4, 129.0, 128.8 (128.82), 128.8 (128.75), 126.8, 126.0 (q, J=3.0Hz), 125.4, 119.3, 117.4.

[0128] Example 14

[0129] Preparation of (E)-N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)-3-(pyridin-3-yl)acrylamide (S9)

[0130] The preparation of compound S9 was the same as that of compound S4 in Example 9, except that formamide was replaced with (E)-3-(pyridin-3-yl)acrylamide (59 mg, 0.4 mmol, 2.0 equiv). The product was purified by slurrying with appropriate amounts of methanol and dichloromethane to obtain a yellow solid, S9 (62 mg, 87%). 1 H-NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 9.12 (d, J = 5.2Hz, 1H), 8.85 (d, J = 2.0Hz, 1H), 8.60-8.53 (m, 2H), 8.12 (d, J = 8.0H z, 3H), 8.02 (d, J = 5.2Hz, 1H), 7.61 (d, J = 16.0Hz, 1H), 7.47 (dd, J = 8.0, 4.8Hz, 1H), 7.16 (d, J = 16.0Hz, 1H), 3.39 (s, 1H); 13 C-NMR (101MHz, DMSO-d6) δ183.2, 181.1, 162.1, 155.9, 150.7, 149.9, 148.9, 1 39.3, 137.1, 134.6, 134.4, 131.3, 129.1, 126.9, 125.7, 124.5, 119.3, 117.5.

[0131] Example 15

[0132] Preparation of 8-((2-aminoethyl)amino)benzo[g]isoquinoline-5,10-dione (S10)

[0133] Intermediate 7 (71 mg, 0.2 mmol) was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. KCO (41 mg, 0.3 mmol), Pd(OAc) (4.5 mg, 0.02 mmol), and BINAP (12 mg, 0.02 mmol) were added, and the atmosphere was replaced with argon several times. Dioxane (2 mL) and N-tert-butyloxycarbonyl-1,2-ethylenediamine (38 mg, 0.24 mmol) were added, and the reaction was heated to 100°C for 4-6 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to yield crude product S10a.

[0134] S10a was dissolved in ethyl acetate and then added with hydrogen chloride in ethyl acetate. The reaction was allowed to proceed at 25°C for 2-3 hours. After the reaction was complete, the pH was adjusted to 13 with 1M aqueous sodium hydroxide solution. The mixture was extracted with a 3:1 mixture of dichloromethane and isopropanol (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S10 (21 mg, 39% over two steps) as a red solid. 1 H-NMR (400MHz, CD3OD) δ9.32 (s, 1H), 9.02 (d, J = 5.2Hz, 1H), 8.07 (d, J = 5.2Hz, 1H), 8.04 (d, J = 8.8Hz , 1H), 7.35 (d, J=2.4Hz, 1H), 7.01 (dd, J=8.8, 2.4Hz, 1H), 3.46 (t, J=6.4Hz, 2H), 3.11-2.92 (m, 2H); 13 C-NMR (101MHz, CD3OD) δ182.9, 179.6, 154.5, 148.0, 140.0, 135.0, 129.8, 127.1, 121.9, 119.1, 116.6, 108.1, 48.3, 48.1, 47.9, 47.6, 47.4, 47.2, 47.0, 43.8, 39.5.

[0135] Example 16

[0136] Preparation of 8-anilinobenzo[g]isoquinoline-5,10-dione (S11)

[0137] Intermediate 7 (71 mg, 0.2 mmol) was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. K2CO3 (41 mg, 0.3 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and BINAP (12 mg, 0.02 mmol) were added, and the atmosphere was replaced with argon several times. 2 mL of dioxane and aniline (22 mg, 0.24 mmol) were added, and the reaction was heated to 100°C for 4-6 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S11 (34 mg, 57%) as a red solid. 1 H-NMR (400MHz, DMSO-d6) δ9.48 (s, 1H), 9.30 (s, 1H), 9.11 (d, J = 5.2Hz, 1H), 8.06 (d, J = 8.8Hz, 1H), 7.99 (d , J=4.8Hz, 1H), 7.67 (d, J=2.4Hz, 1H), 7.43 (q, J=7.6Hz, 3H), 7.29 (d, J=8.0Hz, 2H), 7.15 (t, J=7.6Hz, 1H); 13 C-NMR (101MHz, DMSO-d6) δ183.3, 180.1, 156.0, 151.1, 148.8, 140.5, 139. 5, 135.1, 130.3, 130.1, 126.8, 124.1, 123.8, 121.4, 119.3, 119.2, 110.8.

[0138] Example 17

[0139] Preparation of 8-(piperidin-1-yl)benzo[g]isoquinoline-5,10-dione (S12)

[0140] The preparation of compound S12 was the same as that of compound S11 in Example 16, except that aniline was replaced with piperidine (20 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S12 (32 mg, 56%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.51 (s, 1H), 9.08 (d, J = 4.8Hz, 1H), 8.18 (d, J = 8.8Hz, 1H), 8.08 (d, J=4.8Hz, 1H), 7.64 (d, J=2.8Hz, 1H), 7.17 (dd, J=8.8, 2.8Hz, 1H), 3.60 (m, 4H), 1.76 (m, 6H); 13C-NMR (101MHz, CDCl3) δ183.8, 180.2, 155.3, 154.8, 149.3, 139.7, 134.8, 130.3, 126.8, 122.1, 119.1, 117.8, 110.2, 48.3, 25.4, 24.4.

[0141] Example 18

[0142] Preparation of 8-(4-(2-hydroxyethyl)piperidin-1-yl)benzo[g]isoquinoline-5,10-dione (S13)

[0143] The preparation of compound S13 was the same as that of compound S11 in Example 16, except that aniline was replaced with 4-piperidineethanol (31 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S13 (37 mg, 55%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.47 (s, 1H), 9.03 (d, J = 4.8Hz, 1H), 8.14 (d, J = 8.8Hz, 1H) , 8.04 (d, J=4.8Hz, 1H), 7.60 (d, J=2.8Hz, 1H), 7.14 (dd, J=9.2, 2.8Hz, 1H), 4.10 ( d, J=13.2Hz, 2H), 3.75 (t, J=6.4Hz, 2H), 3.04 (t, J=12.4Hz, 2H), 1.89 (d, J=16.4H z, 2H), 1.85-1.75 (m, 1H), 1.57 (q, J=6.8Hz, 2H), 1.46 (s, 1H), 1.39-1.26 (m, 2H); 13 C-NMR (101MHz, CDCl3) δ183.7, 180.2, 155.3, 154.7, 149.3, 139.6, 134.8, 130.3, 126.8, 122.3, 119.1, 118.0, 110.3, 60.2, 47.6, 39.1, 32.5, 31.7.

[0144] Example 19

[0145] Preparation of 8-(4-morpholinopiperidin-1-yl)benzo[g]isoquinoline-5,10-dione (S14)

[0146] The preparation of compound S14 was the same as that of compound S11 in Example 16, except that aniline was replaced with 4-morpholinopiperidine (41 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S14 (31 mg, 41%), was obtained. 1H-NMR (400MHz, CDCl3) δ9.52 (s, 1H), 9.09 (d, J = 4.8Hz, 1H), 8.19 (d, J = 8.8Hz, 1H), 8.08 (d, J = 4.8Hz, 1H), 7.66 (d, J = 2.8Hz, 1H), 7.20 (dd, J = 8.8, 2.8Hz , 1H), 4.21-4.13(m, 2H), 3.78(t, J=4.8Hz, 4H), 3.16-3.06(m, 2H), 2.63(t, J=4.8Hz, 4H), 2.58-2.50 (m, 1H), 2.06 (d, J=12.8Hz, 2H), 1.74-1.63 (m, 2H); 13 C-NMR (101MHz, CDCl3) δ183.6, 180.3, 155.4, 154.4, 149.3, 139.5, 134.8, 130.2, 126.7, 122.6, 119.1, 118.2, 110.4, 67.2, 61.6, 49.9, 46.6, 27.8.

[0147] Example 20

[0148] Preparation of 8-morpholinobenzo[g]isoquinoline-5,10-dione (S15)

[0149] The preparation of compound S15 was the same as that of compound S11 in Example 16, except that aniline was replaced with morpholine (21 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S15 (21 mg, 36%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.50 (s, 1H), 9.06 (d, J = 5.2Hz, 1H), 8.20 (d, J = 8.8Hz, 1H), 8.05 (d, J = 5.2Hz, 1H), 7.64 (d, J=2.8Hz, 1H), 7.18 (dd, J=8.8, 2.8Hz, 1H), 3.90 (t, J=4.8Hz, 4H), 3.50 (t, J=4.8Hz, 4H); 13 C-NMR (101MHz, CDCl3) δ183.4, 180.6, 155.5, 155.0, 149.4, 139.4, 134.7, 130.1, 126.7, 123.7, 119.1, 118.2, 110.4, 66.4, 47.0.

[0150] Example 21

[0151] Preparation of (S)-8-(3-methylmorpholinyl)benzo[g]isoquinoline-5,10-dione (S16)

[0152] The preparation of compound S16 was the same as that of compound S11 in Example 16, except that aniline was replaced with (S)-3-methylmorpholine (24 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S16 (18 mg, 29%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.49 (s, 1H), 9.06 (d, J = 4.8Hz, 1H), 8.20 (d, J = 8.8Hz , 1H), 8.05 (d, J=4.8Hz, 1H), 7.60 (d, J=2.8Hz, 1H), 7.13 (dd, J=8.8, 2.8Hz, 1 H), 4.18-4.07 (m, 2H), 3.89-3.80 (m, 2H), 3.69 (td, J=12.0, 3.2Hz, 1H), 3.59 (dd, J=12.8, 3.2Hz, 1H), 3.37 (td, J=12.4, 4.0Hz, 1H), 1.30 (d, J=6.8Hz, 3H); 13 C-NMR (101MHz, CDCl3) δ183.6, 180.5, 155.4, 154.0, 149.4, 139.5, 134.8, 130.2, 126.7, 123.1, 119.1, 117.7, 109.9, 71.1, 66.6, 49.4, 41.5, 12.8.

[0153] Example 22

[0154] Preparation of 8-(4-methylpiperazin-1-yl)benzo[g]isoquinoline-5,10-dione (S17)

[0155] The preparation of compound S17 was the same as that of compound S11 in Example 16, except that aniline was replaced with 4-methylpiperazine (24 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S17 (22 mg, 36%), was obtained. 1 HNMR (400MHz, CDCl3) δ9.52 (s, 1H), 9.09 (d, J = 5.2Hz, 1H), 8.21 (d, J = 8.8Hz, 1H), 8.08 (d, J = 5.2Hz, 1H), 7. 67 (d, J=2.8Hz, 1H), 7.21 (dd, J=9.2, 2.8Hz, 1H), 3.59 (t, J=5.2Hz, 5H), 2.63 (t, J=5.2Hz, 5H), 2.41 (s, 3H); 13C-NMR (101MHz, CDCl3) δ183.6, 180.5, 155.4, 154.8, 149.4, 139.5, 134.7, 130.1, 126.7, 123.1, 119.1, 118.2, 110.5, 54.6, 46.8, 46.1.

[0156] Example 23

[0157] Preparation of 8-(4-phenylpiperazin-1-yl)benzo[g]isoquinoline-5,10-dione (S18)

[0158] The preparation of compound 18 was the same as that of compound S11 in Example 16, except that aniline was replaced with N-phenylpiperazine (39 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S18 (37 mg, 50%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.53 (s, 1H), 9.09 (d, J = 5.2Hz, 1H), 8.23 ​​(d, J = 8.8Hz, 1H), 8.09 (d, J = 5.2Hz, 1H), 7.71 (d, J = 2.8Hz, 1H), 7.38-7.32 (m, 2H), 7.25 (dd, J=8.8, 2.8Hz, 1H), 7.04-7.00 (m, 2H), 6.96 (t, J=7.2Hz, 1H), 3.79-3.71 (m, 4H), 3.46-3.38 (m, 4H); 13 C-NMR (101MHz, CDCl3) δ183.5, 180.5, 155.4, 154.7, 150.7, 149.4, 139.4, 134. 7, 130.2, 129.4, 126.7, 123.3, 120.6, 119.1, 118.2, 116.4, 110.5, 48.9, 46.9.

[0159] Example 24

[0160] Preparation of 4-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)piperazine-1-carboxaldehyde (S19)

[0161] The preparation of compound S19 was the same as that of compound S11 in Example 16, except that aniline was replaced with 1-formylpiperazine (27 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S19 (38 mg, 59%), was obtained. 1H-NMR (400MHz, CDCl3) δ9.50 (s, 1H), 9.07 (d, J = 5.2Hz, 1H), 8.20 (d, J = 8.8Hz, 1H), 8.16 (s, 1H), 8.05 (d, J = 5.2 Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 7.21 (dd, J=8.8, 2.4Hz, 1H), 3.78-3.73 (m, 2H), 3.59 (s, 4H), 3.57-3.52 (m, 2H); 13 C-NMR (101MHz, CDCl3) δ183.3, 180.6, 160.9, 155.5, 154.5, 149.5, 139.2, 134.8, 13 0.2, 126.6, 124.1, 119.1(119.13), 119.1(119.08), 111.2, 48.0, 46.8, 44.9, 39.6.

[0162] Example 25

[0163] Preparation of 8-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzo[g]isoquinoline-5,10-dione (S20)

[0164] The preparation of compound S20 was the same as that of compound S11 in Example 16, except that aniline was replaced with cis-2,6-dimethylpiperazine (27 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S20 (41 mg, 64%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.52 (s, 1H), 9.08 (d, J=4.8Hz, 1H), 8.19 (dd, J=8.8, 1.6Hz, 1H), 8.08 (dd, J=5.2, 1.6Hz, 1H), 7. 65 (s, 1H), 7.21-7.17 (m, 1H), 3.93 (d, J=13.2Hz, 2H), 3.11-2.98 (m, 2H), 2.62 (t, J=11.2Hz, 2H), 1.23 (d, J=6.3Hz, 6H); 13 C-NMR (101MHz, CDCl3) δ183.7, 180.4, 155.4, 154.6, 149.3, 139.5, 134.7, 130.1, 126.7, 122.8, 119.1, 118.1, 110.3, 53.6, 50.5, 19.7.

[0165] Example 26

[0166] Preparation of 8-(4-methoxyphenyl)benzo[g]isoquinoline-5,10-dione (S21)

[0167] Intermediate 7 (71 mg, 0.2 mmol) prepared in Example 6 was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. K2CO3 (41 mg, 0.3 mmol), Pd(PPh3)4 (11.6 mg, 0.01 mmol), and 4-methoxyphenylboronic acid (36 mg, 0.24 mmol) were added, and the atmosphere was replaced with argon several times. 2 mL of dioxane was added, and the mixture was heated to 100°C for 4-6 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was washed with saturated sodium bicarbonate solution (15 mL x 3), dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S21 (40 mg, 63%) as a yellow solid. 1 H-NMR (400MHz, CDCl3) δ9.60 (s, 1H), 9.14 (d, J = 5.2Hz, 1H), 8.50 (d, J = 2.0Hz, 1H), 8.35 (d, J = 8.4Hz, 1H) , 8.10 (d, J=5.2Hz, 1H), 8.03 (dd, J=8.0, 2.0Hz, 1H), 7.74-7.67 (m, 2H), 7.09-7.02 (m, 2H), 3.91 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ182.8, 182.2, 160.7, 155.5, 149.7, 147.4, 138.7, 1 33.5, 132.1, 131.0, 130.8, 128.6, 128.3, 126.4, 124.8, 119.1, 114.7, 55.5.

[0168] Example 27

[0169] Preparation of 8-(3,4-dimethoxyphenyl)benzo[g]isoquinoline-5,10-dione (S22)

[0170] The preparation of compound S22 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 3,4-dimethoxyphenylboronic acid (44 mg, 0.24 mmol, 1.2 equiv). After purification, an orange solid, S22x (51 mg, 74%), was obtained. 1H-NMR (400MHz, CDCl3) δ9.62 (s, 1H), 9.15 (d, J = 4.8Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.38 (d, J = 8.0Hz, 1H), 8.12 (d, J = 5.2Hz, 1H), 8.06 (dd, J=8.4, 2.0Hz, 1H), 7.35 (dd, J=8.4, 2.0Hz, 1H), 7.25 (d, J=2.0Hz, 1H), 7.04 (d, J=8.4Hz, 1H), 4.04 (s, 3H), 4.00 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ182.8, 182.2, 155.6, 150.3, 149.8, 149.6, 147.6, 138.7, 133. 5, 132.3, 131.3, 131.2, 128.3, 126.4, 125.0, 120.3, 119.1, 111.6, 110.2, 56.2, 56.1.

[0171] Example 28

[0172] Preparation of 8-(4-morpholinylphenyl)benzo[g]isoquinoline-5,10-dione (S23)

[0173] The preparation of compound S23 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 4-morpholinophenylboronic acid (50 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S25 (44 mg, 59%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.57 (s, 1H), 9.10 (d, J = 4.8Hz, 1H), 8.49 (s, 1H), 8.31 (d, J = 8.0Hz, 1H), 8.07 (d, J = 5.2Hz, 1H ), 8.01 (d, J = 8.4Hz, 1H), 7.68 (d, J = 8.4Hz, 2H), 7.01 (d, J = 8.4Hz, 2H), 3.89 (t, J = 4.8Hz, 4H), 3.27 (t, J = 4.8Hz, 4H); 13 C-NMR (101MHz, CDCl3) δ182.9, 182.1, 155.5, 151.9, 149.7, 147.4, 138.8, 133.5, 131.6, 130.8, 129.0, 128.3(128.33), 128.3(128.25), 126.4, 124.4, 119.1, 115.4, 66.8, 48.5.

[0174] Example 29

[0175] Preparation of 8-([1,1'-biphenyl]-4-yl)benzo[g]isoquinoline-5,10-dione (S24)

[0176] The preparation of compound S24 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 4-biphenylboronic acid (48 mg, 0.24 mmol, 1.2 equiv). After purification, a yellow solid, S24 (57 mg, 79%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.61 (s, 1H), 9.13 (d, J = 5.2Hz, 1H), 8.61 (s, 1H), 8.40 (d, J = 8.0Hz, 1H), 8.16-8.08 (m, 2H ), 7.83 (d, J = 8.0Hz, 2H), 7.76 (d, J = 8.0Hz, 2H), 7.66 (d, J = 7.2Hz, 2H), 7.49 (t, J = 7.6Hz, 2H), 7.44-7.38 (m, 1H); 13 C-NMR (101MHz, CDCl3) δ182.7, 182.3, 155.6, 149.8, 147.4, 142.2, 140.1, 138.7, 137.4 , 133.5, 132.7, 131.7, 129.0, 128.4, 128.0, 127.9, 127.8, 127.2, 126.4, 125.5, 119.1.

[0177] Example 30

[0178] Preparation of 8-(4-fluorophenyl)benzo[g]isoquinoline-5,10-dione (S25)

[0179] The preparation of compound S25 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 4-fluorophenylboronic acid (34 mg, 0.24 mmol, 1.2 equiv). After purification, a yellow solid, S25 (52 mg, 86%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.63 (s, 1H), 9.16 (d, J = 4.8Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.40 (d, J = 8.0Hz, 1 H), 8.13 (d, J=4.8Hz, 1H), 8.05 (dd, J=8.4, 2.0Hz, 1H), 7.75 (dd, J=8.4, 5.2Hz, 2H), 7.33-7.24 (m, 2H); 13C-NMR (101MHz, CDCl3) δ182.6, 182.2, 163.6 (d, J = 250.5Hz), 155.6, 149.8, 146.8, 138.6, 134.8 (d, J =3.0Hz), 133.5, 132.7, 131.6, 129.2 (d, J = 8.1Hz), 128.4, 126.3, 125.5, 119.1, 116.4 (d, J = 22.2Hz).

[0180] Example 31

[0181] Preparation of 4-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzonitrile (S26)

[0182] The preparation of compound S26 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 4-cyanophenylboronic acid (36 mg, 0.24 mmol, 1.2 equiv). After purification, a white solid, S26 (20 mg, 32%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.61 (s, 1H), 9.15 (d, J=5.2Hz, 1H), 8.56 (d, J=2.0Hz, 1H), 8.44 (d, J=8.0Hz, 1H), 8.15-8.03 (m, 2H), 7.89-7.81 (m, 4H); 13 C-NMR (101MHz, CDCl3) δ182.4, 182.2, 155.8, 150.0, 145.7, 143.0, 138.5, 13 3.7, 133.1, 133.0, 132.6, 128.6, 128.2, 126.2, 126.1, 119.2, 118.5, 113.0.

[0183] Example 32

[0184] Preparation of 2-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzonitrile (S27)

[0185] The preparation of compound S27 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 2-cyanophenylboronic acid (36 mg, 0.24 mmol, 1.2 equiv). After purification, a yellow solid, S27 (31 mg, 50%), was obtained. 1H-NMR (400MHz, CDCl3) δ9.64 (s, 1H), 9.18 (d, J = 5.2Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 8.49 (d, J = 8.0Hz, 1H), 8.15 (d, J = 5.2Hz, 1H), 8.12 (d d, J=8.0, 2.0Hz, 1H), 7.89 (dd, J=8.0, 1.2Hz, 1H), 7.80 (td, J=7.6, 1.2Hz, 1H), 7.67 (dd, J=8.0, 1.2Hz, 1H), 7.62 (td, J=7.6, 1.2Hz, 1H); 13 C-NMR (101MHz, CDCl3) δ182.2, 155.8, 149.9, 144.8, 143.1, 138.5, 134.8, 13 4.1, 133.4, 132.7, 130.1, 129.2, 128.2, 127.8, 126.2, 119.2, 118.0, 111.4.

[0186] Example 33

[0187] Preparation of 8-(4-trifluoromethylphenyl)benzo[g]isoquinoline-5,10-dione (S28)

[0188] The preparation of compound S28 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 4-trifluoromethylphenylboronic acid (46 mg, 0.24 mmol, 1.2 equiv). After purification, a white solid, S28 (40 mg, 57%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.65 (s, 1H), 9.18 (d, J=5.2Hz, 1H), 8.60 (s, 1H), 8.46 (d, J=8.0Hz, 1H), 8.17-8.01 (m, 2H), 7.92-7.80 (m, 4H); 13 C-NMR (101MHz, CDCl3) δ182.4, 182.2, 155.7, 149.9, 146.3, 142.1, 138.5, 133.6, 133.0, 132.3 , 131.0 (q, J=33.3Hz), 128.5, 127.8, 126.3 (q, J=4.0Hz), 126.0, 124.0 (q, J=273.7Hz), 119.1;.

[0189] Example 34

[0190] Preparation of 8-(3,4-bis(trifluoromethyl)phenyl)benzo[g]isoquinoline-5,10-dione (S29)

[0191] The preparation of compound S29 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with 2,4-bis(trifluoromethyl)phenylboronic acid (62 mg, 0.24 mmol, 1.2 equiv). After purification, a white solid, S29 (45 mg, 53%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.64 (s, 1H), 9.19 (d, J = 4.8Hz, 1H), 8.44 (d, J = 8.0Hz, 1H), 8.34 (d, J = 2.0Hz, 1H), 8.17 (d, J=4.8Hz, 1H), 8.12 (d, J=2.0Hz, 1H), 7.99-7.95 (m, 1H), 7.86 (dd, J=8.0, 1.6Hz, 1H), 7.59 (d, J=8.0Hz, 1H); 13 C-NMR (101MHz, CDCl3) δ182.2 (182.22), 182.2 (182.19), 155.8, 149.9, 145.2, 142.5, 138.4, 134.8, 132.8, 132.7, 132.3, 131.5, 131.2, 12 9.6, 129.3, 128.8(128.78), 128.8(128.75), 128.7, 127.7, 127.5, 12 6.2, 123.9(123.92), 123.9(123.88), 123.9(123.85), 123.8, 119.2.

[0192] Example 35

[0193] Preparation of (E)-8-phenylvinylbenzo[g]isoquinoline-5,10-dione (S30)

[0194] The preparation of compound S30 was the same as that of compound S21 in Example 26, except that 4-methoxyphenylboronic acid was replaced with trans-β-phenyleneboronic acid (36 mg, 0.24 mmol, 1.2 equiv). After purification, a yellow solid, S30 (27 mg, 43%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.58 (s, 1H), 9.11 (d, J = 5.2Hz, 1H), 8.42 (d, J = 1.6Hz, 1H), 8.29 (d, J = 8.0Hz, 1H), 8.08 ( d, J=5.2Hz, 1H), 7.92 (dd, J=8.4, 2.0Hz, 1H), 7.58 (d, J=7.2Hz, 2H), 7.45-7.32 (m, 4H), 7.22 (d, J=16.4Hz, 1H); 13C-NMR (101MHz, CDCl3) δ182.2, 181.4, 154.9, 149.1, 143.7, 138.2, 135.5, 13 3.3, 132.9, 131.4, 131.0, 128.5, 128.4, 127.7, 126.6, 125.8, 124.2, 118.5.

[0195] Reaction Scheme II of Formula I compound:

[0196] Example 36

[0197] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carboxamide (S31)

[0198] Intermediate S2 (47 mg, 0.2 mmol) prepared in Example 8 was weighed and placed in a 25 mL single-necked flask equipped with a magnetic stirrer. K2CO3 (41 mg, 0.3 mmol) was added. 2 mL of ethanol, 1 mL of hydrogen peroxide, and 0.5 mL of dimethyl sulfoxide were added and reacted at 25°C for 3-4 hours. After the reaction was complete, the ethanol was removed by rotary evaporation, and the mixture was extracted with a 3:1 mixture of dichloromethane and isopropanol (20 mL x 3), dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain S31 (22 mg, 44%) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.17 (d, J = 4.8Hz, 1H), 8.68 (s, 1H), 8.49 (s, 1 H), 8.39 (d, J=7.6Hz, 1H), 8.29 (d, J=7.6Hz, 1H), 8.06 (d, J=4.8Hz, 1H), 7.82 (s, 1H); 13 C-NMR (101MHz, DMSO-d6) δ 182.6 (182.58), 128.6 (182.56), 166.7, 156.0, 149.1, 140.1, 139.0, 135.1, 133.7, 133.4, 127.6, 126.8, 126.2, 119.3.

[0199] Example 37

[0200] Preparation of N-methyl-5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carboxamide (S32)

[0201] Intermediate S2 (47 mg, 0.2 mmol) prepared in Example 8 was weighed and placed in a 25 mL single-necked flask equipped with a magnetic stirrer. KOH (112 mg, 2 mmol) was added. 2 mL of ethanol and 2 mL of water were added, and the mixture was reacted at 100°C for 3-4 hours. After the reaction was complete, the ethanol was removed by rotary evaporation, and 2N HCl was added to slowly adjust the pH to approximately 2. A brown solid precipitated, which was filtered to obtain Intermediate 8 without further purification.

[0202] The intermediate 8 obtained above was placed in a Schlenk reaction tube equipped with a magnetic stirrer, and methylamine hydrochloride (27 mg, 0.4 mmol) and HATU (167 mg, 0.44 mmol) were added. The atmosphere was replaced with argon several times. 2 mL of DMF and DIPEA (129 mg, 1.0 mmol) were added, and the reaction was allowed to proceed at 25°C for 2-3 hours. After the reaction was complete, water and ethyl acetate were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed several times with water, then washed with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S32 (18 mg, 34% over two steps) as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.17 (d, J = 5.2Hz, 1H), 8.98 (q, J = 4.4Hz, 1H), 8.65 (s, 1H) , 8.36 (dd, J=8.0, 2.0Hz, 1H), 8.30 (d, J=8.0Hz, 1H), 8.06 (d, J=5.2Hz, 1H), 2.87 (d, J=4.4Hz, 3H); 13 C-NMR (101MHz, DMSO-d6) δ182.6, 182.5, 165.4, 156.0, 149.1, 140.2, 139.0, 135.0, 133.5, 133.4, 127.7, 126.8, 125.7, 119.3, 27.0.

[0203] Example 38

[0204] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carboxylic acid methyl ester (S33)

[0205] Intermediate S2 (47 mg, 0.2 mmol) prepared in Example 8 was weighed and placed in a 25 mL single-necked flask equipped with a magnetic stirrer. KOH (112 mg, 2 mmol) was added. 2 mL of ethanol and 2 mL of water were added, and the mixture was reacted at 100°C for 3-4 hours. After the reaction was complete, the ethanol was removed by rotary evaporation, and 2N HCl was added to slowly adjust the pH to approximately 2. A brown solid precipitated, which was filtered to obtain Intermediate 8 without further purification.

[0206] The intermediate 7 obtained above was placed in a 25 mL single-necked flask with a magnetic stirrer, and 5 mL of methanol and a few drops of concentrated sulfuric acid were added. The reaction was allowed to proceed at 80°C for 4-5 hours. After the reaction was complete, saturated aqueous sodium bicarbonate solution and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S33 (15 mg, 28% over two steps) as a white solid. 1 H-NMR (400MHz, CDCl3) δ9.65 (s, 1H), 9.18 (d, J = 4.8Hz, 1H), 9.00 (s, 1H), 8.52 (d d, J=8.0, 1.6Hz, 1H), 8.43 (d, J=8.0Hz, 1H), 8.13 (d, J=4.8Hz, 1H), 4.06 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ182.2, 181.8, 165.3, 155.8, 150.0, 138.3, 136.0, 135.5, 135.1, 133.2, 128.8, 127.8, 126.1, 119.1, 53.0.

[0207] Reaction Scheme III of Formula I compound:

[0208] Example 39

[0209] Preparation of 8-aminobenzo[g]isoquinoline-5,10-dione (S34)

[0210] Intermediate S5 (266 mg, 1.0 mmol) prepared in Example 10 was weighed and placed in a 25 mL single-necked flask equipped with a magnetic stirrer. 5 mL of ethanol and 1 mL of concentrated hydrochloric acid were added and reacted at 100°C for 5-6 hours. After the reaction was complete, the ethanol was removed by rotary evaporation and the solution was adjusted to a strong alkaline state with 2 M aqueous sodium hydroxide solution. A red solid precipitated and the crude product was filtered. The crude product was purified by slurrying with appropriate amounts of dichloromethane and methanol to obtain S34 (200 mg, 89%) as a red solid. 1H-NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 9.08 (d, J = 5.2Hz, 1H), 7.96 (d, J = 5.2Hz, 1H), 7.93 (d, J = 8.4Hz, 1H), 7.29 (s, 1H), 7.01-6.86 (m, 3H); 13 C-NMR (101MHz, DMSO-d6) δ183.7, 179.6, 155.9, 148.6, 139.7, 135.3, 130.4, 126.9, 121.3, 119.3, 118.7, 110.1.

[0211] Example 40

[0212] Preparation of (E)-N'-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)-N,N-dimethylformamidine (S35)

[0213] Intermediate S34 (45 mg, 0.2 mmol) prepared in Example 40 was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. The argon atmosphere was replaced several times. 2 mL of anhydrous DMF was added, followed by triethylamine (202 mg, 2.0 mmol) and trifluoroacetic anhydride (210 mg, 1.0 mmol). The reaction was allowed to proceed overnight at 25°C. After the reaction was complete, saturated aqueous sodium bicarbonate solution and ethyl acetate were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed several times with water and finally with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S35 (24 mg, 43%) as a red solid. 1 H-NMR (400MHz, CDCl3) δ9.54 (s, 1H), 9.10 (d, J=5.2Hz, 1H), 8.23 ​​(d, J=8.4Hz, 1H), 8.09 (d , J=5.2Hz, 1H), 7.82-7.78 (m, 2H), 7.40 (dd, J=8.4, 2.4Hz, 1H), 3.18 (s, 3H), 3.15 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ183.4, 181.5, 158.7, 155.3, 154.3, 149.5, 139.2, 134.4, 129.4, 128.3, 127.5, 126.6, 119.1, 117.6, 40.8, 34.9.

[0214] Example 41

[0215] Preparation of 8-fluorobenzo[g]isoquinoline-5,10-dione (S36)

[0216] Intermediate S34 prepared in Example 39 (45 mg, 0.2 mmol) was weighed and placed in a 25 mL single-necked flask equipped with a magnetic stirrer. 1 mL each of 37% HCl and HBF4 was added. The mixture was cooled to 0°C, and an aqueous solution of sodium nitrite (21 mg, 0.3 mmol) was added dropwise. The mixture was reacted at 0°C for 15 minutes, during which a large amount of yellow-brown solid precipitated. Filtration afforded Intermediate 9.

[0217] 9 was placed in a 25 mL single-necked flask with a magnetic stirrer, 2 mL of toluene was added, and the reaction was allowed to proceed at 90°C overnight. After the reaction was complete, water and ethyl acetate were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S36 (17 mg, 37% over two steps) as a white solid. 1 H-NMR (400MHz, CDCl3) δ9.62 (s, 1H), 9.18 (s, 1H), 8.41 (dd, J=8.4, 5.2Hz, 1H), 8.13 (d, J=4.8Hz, 1H), 8.01 (dd, J=8.4, 2.4Hz, 1H), 7.56 (td, J=8.4, 2.8Hz, 1H); 13 C-NMR (101MHz, CDCl3) δ181.6, 181.3, 166.9 (d, J=261.6Hz), 155.8, 149.8, 138.4, 135.9 (d, J=8.1Hz ), 131.0 (d, J=9.1Hz), 129.7 (d, J=3.0Hz), 126.3, 122.1 (d, J=23.2Hz), 119.3, 114.1 (d, J=23.2Hz).

[0218] Example 42

[0219] Preparation of 8-bromobenzo[g]isoquinoline-5,10-dione (S37)

[0220] Intermediate S34 prepared in Example 39 (45 mg, 0.2 mmol) was weighed and placed in a 25 mL single-necked flask with a magnetic stirrer. 48% HBr (1 mL) was added and the mixture was cooled to 0°C. An aqueous solution of sodium nitrite (21 mg, 0.3 mmol) was then added dropwise. After reacting at 0°C for 15 minutes to form the diazonium salt intermediate 10, an aqueous solution of CuBr2 (67 mg, 0.3 mmol) was added dropwise and allowed to react overnight at 25°C. After the reaction was complete, water and ethyl acetate were added, the layers separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S37 (26 mg, 45% over two steps) as a white solid. 1 H-NMR (400MHz, CDCl3) δ9.61 (d, J=0.8Hz, 1H), 9.18 (d, J=4.8Hz, 1H), 8.50 (d, J=2.0Hz , 1H), 8.22 (d, J=8.4Hz, 1H), 8.12 (dd, J=4.8, 0.8Hz, 1H), 8.02 (dd, J=8.4, 2.0Hz, 1H); 13 C-NMR (101MHz, CDCl3) δ181.9, 181.5, 155.9, 149.9, 138.3, 137.8, 134.0, 131.6, 131.0, 130.5, 129.2, 125.9, 119.1.

[0221] Example 43

[0222] Preparation of 8-(1-methyl-1H-pyrazol-4-yl)benzo[g]isoquinoline-5,10-dione (S38)

[0223] Intermediate S37 (45 mg, 0.2 mmol) prepared in Example 43 was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. Cesium carbonate (98 mg, 0.3 mmol), 1-methyl-1H-pyrazole-4-boronic acid (38 mg, 0.3 mmol), and Pd(PPh3)4 (46 mg, 0.04 mmol) were added, and the atmosphere was replaced with argon several times. 1.6 mL of dioxane and 0.4 mL of water were added, and the reaction was carried out at 100°C for 3-4 hours. After the reaction was complete, water and ethyl acetate were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S38 (32 mg, 55%) as a yellow solid. 1H-NMR (400MHz, CDCl3) δ9.60 (s, 1H), 9.15 (d, J = 5.2Hz, 1H), 8.39 (d, J = 2.0Hz, 1H), 8.32 (d, J = 8.4Hz, 1H), 8.12 (dd, J=4.8, 0.8Hz, 1H), 7.99 (d, J=0.8Hz, 1H), 7.94 (dd, J=8.2, 2.0Hz, 1H), 7.91 (s, 1H), 4.04 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ182.8, 181.9, 155.5, 149.7, 139.9, 138.8, 137.5, 133.7, 130.7, 130.6, 128.6, 128.4, 123.3, 121.3, 119.2, 39.5.

[0224] Example 44

[0225] Preparation of 8-(1H-1,2,3-triazol-1-yl)benzo[g]isoquinoline-5,10-dione (S39)

[0226] The intermediate S36 prepared in Example 40 (45 mg, 0.2 mmol) was weighed and placed in a 25 mL single-necked flask with a magnetic stirrer. 1 mL of 37% HCl aqueous solution was added, cooled to 0°C, and then an aqueous solution of sodium nitrite (21 mg, 0.3 mmol) was added dropwise. After reacting at 0°C for 15 minutes to form the diazonium salt intermediate 9, an aqueous solution of NaN3 (20 mg, 0.3 mmol) was added dropwise and reacted at 0°C for 1 to 2 hours. After the reaction was complete, water and ethyl acetate were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product of the azide intermediate 12 without further purification.

[0227] 12 was placed in a Schlenk reaction tube equipped with a magnetic stirrer, and CuI (4 mg, 0.02 mmol) was added. The atmosphere was replaced with argon several times. 2 mL of dioxane, triethylamine (51 mg, 0.5 mmol), and trimethylsilyl acetylene (24 mg, 0.24 mmol) were added, and the reaction was carried out at 50°C for 3-4 hours. After the reaction was complete, water and ethyl acetate were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude intermediate S39a.

[0228] S39a was placed in a 25 mL single-necked flask with a magnetic stirrer, and potassium carbonate (55 mg, 0.4 mmol) and 2 mL of methanol were added. The reaction was allowed to proceed at 25°C for 2-3 hours. After the reaction was complete, water and dichloromethane were added, the layers were separated, and the aqueous layer was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and finally rotary evaporated to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain S39 (19 mg, 34% over three steps) as a red solid. 1 H-NMR (400MHz, DMSO-d6) δ9.40-9.00 (m, 2H), 7.98 (d, J=4.4Hz, 1H), 7.95 (d, J =8.8Hz, 1H), 7.30 (d, J = 2.4Hz, 1H), 6.97 (dd, J = 8.8, 2.4Hz, 1H), 6.90 (s, 2H); 13 C-NMR (101MHz, DMSO-d6) δ183.7, 179.7, 155.9 (155.94), 155.9 (155.93), 155.9 (155.90), 148.6, 139.7, 135.3, 130.4, 121.4, 118.7, 110.1.

[0229] Reaction Scheme IV of the compound of formula I:

[0230] Example 45

[0231] Preparation of 7-aminoisoquinoline-5,8-dione (15)

[0232] Weigh 5-hydroxyisoquinoline (0.73 g, 5 mmol) and place it in a two-necked flask. Add 10 mL of acetonitrile, weigh [bis(trifluoroacetyloxy)iodo]benzene (2.6 g, 6 mmol) and dissolve it in 20 mL of acetonitrile / water (v:v=3:1). Under argon protection and ice bath conditions, slowly add PIFA dropwise to the reaction flask. After the addition is complete, the reaction solution turns black and is stirred at low temperature for 30 minutes. The reaction solution is poured into 150 mL of dichloromethane, and turbidity precipitates. Filter through diatomaceous earth and collect the filtrate. After the filtrate is washed with saturated brine, the organic layer is collected, 20 mL of glacial acetic acid is added to the collected filtrate, and dichloromethane and acetonitrile are removed by rotary evaporation to obtain a crude product of compound 14. No purification is required and the next step is directly performed.

[0233] Sodium azide (0.36 g, 5.5 mmol) was dissolved in 10 mL of water and added to the acetic acid solution of 13 prepared in the previous step. The mixture was stirred at 60°C under argon for 3 hours. After the reaction reached the specified time, 200 mL of dichloromethane was added to the reaction solution, and the pH was adjusted to neutral by adding saturated aqueous sodium bicarbonate. The mixture was extracted with saturated brine, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 15 (0.26 g, 30% over two steps) as a red solid. 1 H-NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.50(d,J=8.4Hz,1H),8.0(d,J=8.2Hz,1H),5.76(s,1H),4.76(s,2H); 13 C-NMR (101MHz, DMSO-d6) δ182.1,178.3,164.3,156.7,155.1,141.2,130.9,119.8,112.8.

[0234] Example 46

[0235] Preparation of 7-amino-6-bromoisoquinoline-5,8-dione (16)

[0236] Intermediate 15 (0.35 g, 2 mmol) prepared in Example 5 and N-bromosuccinimide (0.43 g, 2.4 mmol) were weighed and placed in a single-necked flask. 10 mL of anhydrous methanol was added and stirred at room temperature under argon for 5 hours. After the prescribed time, the mixture was filtered and the residue was washed three times with anhydrous methanol to obtain compound 16 (0.44 g, 72.4%). 1 H-NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.52(d,J=8.4Hz,1H),8.2(d,J=8.2Hz,1H),4.82(s,2H); 13 C-NMR (101MHz, DMSO-d6) δ182.1,178.3,164.3,156.7,155.1,141.2,130.9,119.8,107.3.

[0237] Example 47

[0238] Preparation of N-(6-bromo-5,8-dioxo-5,8-dihydroisoquinolin-7-yl)acetamide (17)

[0239] The intermediate 16 (0.25 g, 1 mmol) prepared in Example 46 was weighed and placed in a single-necked flask. 10 mL of acetic anhydride was added and the mixture was uniformly suspended by ultrasound. 3-5 drops of concentrated sulfuric acid were added. Compound 16 was immediately completely dissolved and the reaction turned yellow. The reaction solution was immediately poured into 100 mL of ice water, 100 mL of ethyl acetate was added, and the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. Extraction was performed, and the aqueous layer was extracted twice. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by silica gel column chromatography to obtain a yellow solid 17 (0.25 g, 85.7%). 1 H-NMR (400MHz, CDCl3) δ9.36 (s, 1H), 8.51 (d, J = 8.4Hz, 1H), 8.2 (d, J = 8.2Hz, 1H), 1.91 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ182.1,178.3,171.4,164.3,156.7,155.1,141.2,130.9,119.8,107.3,23.4.

[0240] Example 48

[0241] Preparation of N-(6-bromo-5,8-dioxo-5,8-dihydroisoquinolin-7-yl)acetamide (18a)

[0242] Compound 17 (0.29 g, 1 mmol) prepared in Example 47 and methylamine hydrochloride (0.14 g, 2 mmol) were weighed and placed in a single-necked flask. 20 mL of toluene was added, and triethylamine (0.4 g, 4 mmol) was slowly added. The temperature was raised to 65°C and stirred for 30 minutes. The reaction mixture also turned dark red. After completion of the reaction, the toluene and excess triethylamine were removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 18a (0.1 g, 41%) as a dark red solid. 1 H-NMR (400MHz, CDCl3) δ9.32 (s, 1H), 8.45 (d, J = 8.4Hz, 1H), 8.0 (d, J = 8.2Hz, 1H), 2.78, (s, 3H), 1.91 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ182.1,178.3,171.4,164.3,156.7,155.1,141.2,134.7,130.8,120.0,31.1,23.4.

[0243] Example 49

[0244] Preparation of 1,2-dimethyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S40)

[0245] Compound 18a (0.12 g, 0.5 mmol) prepared in Example 48 was weighed and placed in a single-necked flask. 10 mL of ethanol was added to dissolve the mixture. 1 mL of 2 M aqueous sodium hydroxide solution was added and stirred at room temperature. The reaction solution initially changed from red to purple and then to pale yellow as the reaction proceeded. After completion of the reaction, 100 mL of dichloromethane and 50 mL of saturated brine were added. The pH was adjusted to neutral with 2 M hydrochloric acid. After extraction, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography to yield S40 (69 mg, 61%) as a yellow solid. 1 H-NMR (400MHz, CDCl3) δ9.46 (s, 1H), 9.07 (d, J = 5.1Hz, 1H), 8.00 (d, J = 4.9Hz, 1H), 3.42 (s, 3H), 2.50 (s, 3H); 13 C-NMR (101MHz, CDCl3) δ182.1,178.3,171.4,164.3,156.7,155.1,141.2,134.7,130.8,120.0,31.1,23.4; 13 C-NMR (101MHz, CDCl3) δ178.51,174.75,155.51,154.66,148.83,143.39,138.85,132.21,125.27,118.68,28.3,14.1.

[0246] Example 50

[0247] Preparation of 1-butyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S41)

[0248] The preparation of compound S41 was the same as that of compound S40, except that methylamine hydrochloride was replaced with butylamine hydrochloride (0.22 g, 2 mmol). After purification, a yellow solid, S41 (77 mg, 63%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.47 (s, 1H), 9.08 (d, J = 4.9Hz, 1H), 7.99-7.93 (m, 1H), 4.41 (t, J=7.6Hz,2H),2.63(s,3H),1.92-1.78(m,2H),1.52-1.40(m,2H),1.03(t,J=7.3Hz,3H); 13C NMR (101MHz, CDCl3) δ178.51,174.86,155.54,154.13,148.83,143.29,138.82,132.08,125.26,118.70,45.90,32.39,19.94,13.70,13.49.

[0249] Example 51

[0250] Preparation of 1-isopropyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S42)

[0251] The preparation of compound S42 was the same as that of compound S40, except that methylamine hydrochloride was replaced with isopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S42 (78 mg, 61%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.46 (s, 1H), 9.08 (d, J = 4.9Hz, 1H), 7.99 (d, J = 4.9Hz, 1H), 5.16 (s, 1H), 2.71 (s, 3H), 1.68 (d, J = 6.9Hz, 6H); 13 C NMR (101MHz, CDCl3) δ178.75,174.20,155.59,153.93,148.61,144.20,139.19,132.28,124.91,119.15,50.16,20.86,15.56.

[0252] Example 52

[0253] Preparation of 1-cyclopropyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S43)

[0254] The preparation of compound S43 was the same as that of compound S40, except that methylamine hydrochloride was replaced with cyclopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S43 (77 mg, 60%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.04 (d, J = 5.1Hz, 1H), 7.93 (d, J = 4.9Hz, 1H) ,3.36(dp,J=7.3,4.0Hz,1H),2.67(s,3H),1.47-1.33(m,2H),1.08-1.00(m,2H); 13C NMR (101MHz, DMSO-d6) δ173.81,169.08,151.73,150.81,143.95,138.35,134.27,128.92,120.36,114.13,22.83,10.41,4.79.

[0255] Example 53

[0256] Preparation of 1-cyclopentyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S44)

[0257] The preparation of compound S44 was the same as that of compound S40, except that methylamine hydrochloride was replaced with cyclopentylamine hydrochloride (0.24 g, 2 mmol). After purification, a yellow solid, S44 (86 mg, 61%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.43 (s, 1H), 9.04 (d, J = 5.1Hz, 1H), 7.94 (d, J = 4.9Hz, 1 H),5.07(p,J=9.2Hz,1H),2.66(s,3H),2.18-2.08(m,6H),1.83-1.74(m,2H); 13 C NMR (101MHz, CDCl3) δ173.98,169.55,150.82,149.71,143.87,139.49,134.41,127.64,120.17,114.35,53.75,26.34(×2),20.13(×2),10.60.

[0258] Example 54

[0259] Preparation of 1-cyclohexyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S45)

[0260] The preparation of compound S45 was the same as that of compound S40, except that methylamine hydrochloride was replaced with cyclohexylamine hydrochloride (0.27 g, 2 mmol). After purification, a yellow solid, S45 (89 mg, 60%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.45 (s, 1H), 9.07 (d, J = 4.9Hz, 1H), 7.97 (d, J = 5.0Hz, 1H), 2.70 (s, 3H), 2. 33(bs,2H),2.01(td,J=6.1,3.1Hz,2H),1.90(d,J=12.3Hz,2H),1.84(m,2H),1.58-1.40(m,3H); 13C NMR (101MHz, CDCl3) δ178.73,174.17,155.56,154.10,148.57,144.24,139.27,132.37,124.89,119.12,58.34,30.52,25.98(×2),24.75(×2).

[0261] Example 55

[0262] Preparation of methyl 3-(2-methyl-4,9-dioxo-4,9-dihydro-1H-imidazo[4,5-g]isoquinolin-1-yl)propanoate (S46)

[0263] The preparation of compound S49 was the same as that of compound S43, except that methylamine hydrochloride was replaced with methyl 3-aminopropionate hydrochloride (0.28 g, 2 mmol). After purification, a yellow solid, S46 (70 mg, 47%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.47 (s, 1H), 9.08 (d, J = 4.9Hz, 1H), 7.99-7.93 (m, 1H), 4.43 (t, J = 7.6Hz, 2H), 3.81 (s, 3H), 2.73 (t, J = 7.5Hz, 2H); 13 C NMR (101MHz, CDCl3) δ178.51,174.86,173.5,155.54,154.13,148.83,143.29,138.82,132.08,125.26,118.70,52.13,41.45,36.27,13.49.

[0264] Example 56

[0265] Preparation of 2-methyl-1-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S47)

[0266] The preparation of compound S47 was the same as that of compound S40, except that methylamine hydrochloride was replaced with aniline hydrochloride (0.26 g, 2 mmol). After purification, a yellow solid, S47 (64 mg, 44%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.51 (s, 1H), 9.06 (d, J = 5.1Hz, 1H), 7.84 (d, J = 4.9Hz, 1H), 7.65 (dd, J = 5.1, 2.0Hz, 3H), 7.43-7.35 (m, 2H), 2.47 (s, 3H); 13C NMR (101MHz, CDCl3) δ178.67,173.86,155.67,154.88,148.85,143.24,138.7 5,134.75,133.07,130.35,129.94(×2),126.70(×2),125.20,118.71,13.90.

[0267] Example 57

[0268] Preparation of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S48)

[0269] The preparation of compound S48 was the same as that of compound S40, except that methylamine hydrochloride was replaced with p-anisidine hydrochloride (0.32 g, 2 mmol). After purification, a yellow solid, S48 (72 mg, 45%), was obtained. 1 H NMR(400MHz, CDCl3)δ9.50(s,1H),9.05(d,J=4.9Hz,1H),7.85(d,J=4.9Hz,1H),7 .31-7.30(m,1H),7.29-7.27(m,1H),7.16-7.07(m,2H),3.95(s,3H),2.46(s,3H); 13 C NMR (101MHz, CDCl3) δ178.68,173.93,160.72,155.63,155.24,148.83,143.17,142. 39,138.80,133.17,127.80(×2),127.23,125.22,118.68,115.02(×2),55.69,13.83.

[0270] Example 58

[0271] Preparation of 1-benzyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S49)

[0272] The preparation of compound S49 was the same as that of compound S40, except that methylamine hydrochloride was replaced with benzylamine hydrochloride (0.29 g, 2 mmol). After purification, a yellow solid, S49 (89 mg, 59%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.55(s,1H),9.14(d,J=4.9Hz,1H),8.03(dd,J=4.9,0.9Hz ,1H),7.40-7.28(m,3H),7.13(dd,J=7.7,1.7Hz,2H),5.21(s,2H),2.17(s,3H).13 C NMR (101MHz, CDCl3) δ178.53,174.84,155.71,154.84,148.88,143.38,138.80,1 36.73,131.84,129.10(×2),128.95(×2),127.45,125.29,118.71,47.81,36.72.

[0273] Example 59

[0274] Preparation of 1-(3-hydroxypropyl)-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S50)

[0275] S46 (0.03 g, 0.1 mmol) prepared in Example 55 was weighed and placed in a single-necked flask. 15 mL of anhydrous tetrahydrofuran was added. LiAlH4 (0.038 g, 1 mmol) was added portionwise at 0°C under argon and stirred for 30 minutes. After the reaction, 50 mL of ethyl acetate was slowly added, followed by 10 mL of 2M aqueous NaOH solution, to precipitate a white solid. The organic layer was collected by filtration and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography to yield S53 (21 mg, 79%) as a yellow solid. 1 H-NMR (400MHz, CDCl3) δ9.47 (s, 1H), 9.08 (d, J = 4.9Hz, 1H), 7.99-7.93 (m, 1H), 4 .43(t,J=7.6Hz,2H),3.65(t,J=7.4Hz,2H),2.73(t,J=7.5Hz,2H),1.96(m,2H); 13 C NMR (101MHz, CDCl3) δ178.51,174.86,155.54,154.13,148.83,143.29,138.82,132.08,125.26,118.70,58.19,41.45,33.38,13.49.

[0276] Example 60

[0277] Preparation of 1-(2-dimethylamino)ethyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S51)

[0278] The preparation of compound S51 was the same as that of compound S40, except that methylamine hydrochloride was replaced with N,N-dimethylethylenediamine hydrochloride (0.32 g, 2 mmol). After purification, a yellow solid, S51 (57 mg, 40%), was obtained. 1H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 9.03 (d, J = 4.9Hz, 1H), 7.86 (d, J = 5.1Hz ,1H),4.40(t,J=6.2Hz,2H),2.91(t,J=6.1Hz,2H),2.82(s,6H),2.72(s,3H); 13 C NMR (101MHz, DMSO-d6) δ178.69,174.89,156.07,155.20,147.90,142.67,138.73,132.99,125.64,119.02,58.98,54.41(×2),43.67,12.72.

[0279] Example 61

[0280] Preparation of 1-(3-dimethylamino)propyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S52)

[0281] The preparation of compound S52 was the same as that of compound S40, except that methylamine hydrochloride was replaced with N,N-dimethylpropylenediamine hydrochloride (0.35 g, 2 mmol). After purification, a yellow solid, S52 (58 mg, 39%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.46 (s, 1H), 9.05 (d, J = 4.9Hz, 1H), 7.96 (d, J = 4.9Hz, 1H), 4.45 (t,J=7.3Hz,2H),3.13(t,J=6.9Hz,2H),2.50-2.40(s,6H),2.35(s,3H),1.92(m,2H); 13 C NMR (101MHz, CDCl3) δ174.41,170.70,151.52,150.39,144.79,139.34,134.71,128.08,121.15,114.64,62.87,51.09,49.55,40.09,22.66,9.39.

[0282] Example 62

[0283] Preparation of 2-methyl-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S53)

[0284] The preparation of compound S53 was the same as that of compound S40, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)piperidine hydrochloride (0.4 g, 2 mmol). After purification, a yellow solid, S53 (73 mg, 45%), was obtained. 1H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 9.03 (d, J = 4.9Hz, 1H), 7.86 (d, J = 5.1Hz, 1H), 4.39 (t, J = 6.2Hz ,2H),2.58(t,J=6.1Hz,2H),2.46(s,3H),2.36(s,4H),1.38(t,J=5.6Hz,4H),1.31(q,J=6.0Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ178.69,174.89,156.07,155.20,147.90,142.67,138.7 3,132.99,125.64,119.02,58.46,54.37(×2),43.67,26.14(×2),24.29,12.72.

[0285] Example 63

[0286] Preparation of 2-methyl-1-(3-(piperidin-1-yl)propyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S54)

[0287] The preparation of compound S54 was the same as that of compound S40, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)piperidine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S54 (73 mg, 45%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.43(s,1H),8.86(d,J=4.7Hz,1H),7.90(d,J=4.6Hz,1H),4.48(t,J=7.1Hz,2H),2.32( s,4H),2.67(s,3H),2.58(t,J=6.7Hz,2H),2.01(p,J=6.3Hz,2H)1.38(t,J=5.5Hz,4H),1.31(q,J=5.9Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ178.67,174.85,156.04,155.15,147.93,142.69,138.70,1 32.96,125.65,119.01,56.35,56.33(×2),42.52,30.41,26.10(×2),24.35,12.73.

[0288] Example 64

[0289] Preparation of 2-methyl-1-(2-morpholinoethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S55)

[0290] The preparation of compound S55 was the same as that of compound S40, except that methylamine hydrochloride was replaced with N-(2-aminoethyl)morpholine hydrochloride (0.41 g, 2 mmol). After purification, a yellow solid, S55 (73 mg, 46%), was obtained. 1 H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.89(d,J=4.9Hz,1H),7.81(d,J=4.9Hz,1H ),4.49(t,J=7.1Hz,2H),3.73(t,J=4.5Hz,4H),2.67(s,3H),2.49-2.41(m,6H); 13 C NMR (101MHz, CDCl3) δ174.43,170.71,151.61,150.42,144.80,139.40,134 .75,128.12,121.19,114.65,62.87(×2),51.09,49.55(×2),40.09,10.99.

[0291] Example 65

[0292] Preparation of 2-methyl-1-(3-morpholinopropyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S56)

[0293] The preparation of compound S56 was the same as that of compound S40, except that methylamine hydrochloride was replaced with 1-(3-morpholinopropyl) hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S56 (73 mg, 43%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.48(s,1H),9.08(d,J=4.9Hz,1H),7.95(d,J=4.9Hz,1H),4.49(t,J =7.2Hz,2H),3.73(t,J=4.7Hz,4H),2.67(s,3H),2.50-2.40(m,6H),2.05(p,J=6.6Hz,2H); 13 C NMR(101MHz, CDCl3)δδ174.41,170.70,151.52,150.39,144.79,139.34,134.7 1,128.08,121.15,114.64,62.87(×2),51.09,49.55(×2),40.09,22.66,9.39.

[0294] Example 66

[0295] Preparation of 2-methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S57)

[0296] The preparation of compound S57 was the same as that of compound S40, except that methylamine hydrochloride was replaced with 4-methyl-1-piperazineethylamine hydrochloride (0.5 g, 2 mmol). After purification, a yellow solid, S57 (69 mg, 41%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.46(s,1H),9.07(d,J=4.9Hz,1H),7.94(d,J=4.9Hz,1H),4.46(t,J=7 .2Hz,2H),2.65(s,3H),2.56(s,6H),2.46(t,J=6.6Hz,2H),2.38(s,3H),2.04(p,J=6.7Hz,2H); 13 C NMR (101MHz, CDCl3) δ178.46,174.81,155.55,154.49,148.82,143.39,138.78, 132.15,125.22,118.68,54.87(×2),54.57,52.49,45.65,44.18,27.02,13.46.

[0297] Example 67

[0298] Preparation of 2-methyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S58)

[0299] The preparation of compound S58 was the same as that of compound S40, except that methylamine hydrochloride was replaced with 4-methyl-1-piperazinepropylamine hydrochloride (0.53 g, 2 mmol). After purification, a yellow solid, S58 (69 mg, 39%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),9.05(d,J=4.7Hz,1H),7.93(d,J=4.8Hz,1H),4.43(t,J=7.1Hz,2 H),2.65(s,3H),2.54(s,6H),2.44(t,J=6.6Hz,2H),2.35(s,3H),2.01(p,J=6.7Hz,2H),1.89(m,2H); 13C NMR (101MHz, CDCl3) δ178.43,174.80,155.51,154.45,148.80,143.34,138.80,132 .13,125.21,118.69,54.87(×2),54.57,52.49,45.65,44.18,27.02,21.41,13.46.

[0300] Example 68

[0301] Preparation of 2-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S59)

[0302] The preparation of compound S59 was the same as that of compound S40, except that methylamine hydrochloride was replaced with 1-(aminoethyl)pyrrolidine hydrochloride (0.37 g, 2 mmol). After purification, a yellow solid, S59 (73 mg, 47%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 9.10 (d, J = 4.9Hz, 1H), 7.92 (d, J = 5.0Hz, 1H) ,4.51(t,J=6.7Hz,2H),2.93(bs,2H),2.67(bs,4H),2.58(bs,3H),1.73(bs,4H); 13 C NMR (101MHz, DMSO) δ178.65,174.92,156.11,155.08,147.91,142.72,139 .10,132.91,125.58,119.03,54.94,53.76(×2),44.45,23.65(×2),13.56.

[0303] Example 69

[0304] Preparation of 2-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S60)

[0305] The preparation of compound S60 was the same as that of compound S40, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)pyrrolidine hydrochloride (0.4 g, 2 mmol). After purification, a yellow solid, S60 (75 mg, 44%), was obtained. 1H NMR (400MHz, CDCl3) δ9.48 (s, 1H), 9.08 (d, J = 4.9Hz, 1H), 7.97 (d, J = 4.9Hz, 1H), 4.50 (t,J=7.1Hz,2H),2.66(s,3H),2.51(m,6H),2.06(p,J=6.8Hz,2H),1.86-1.73(m,4H); 13 C NMR (101MHz, CDCl3) δ178.51,174.75,155.51,154.66,148.83,143.39,138.85 ,132.21,125.27,118.68,53.98(×2),52.56,44.31,29.28,23.55(×2),13.34.

[0306] Reaction Scheme V of Compound of Formula I:

[0307] Example 70

[0308] Preparation of 2-isopropyl-1-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S61)

[0309] The intermediate 16 (0.25 g, 1 mmol) prepared in Example 46 was weighed and placed in a single-necked flask. 10 mL of isobutyric anhydride was added and the mixture was uniformly suspended by ultrasound. 3-5 drops of concentrated sulfuric acid were added. Compound 16 was immediately completely dissolved and the reaction turned yellow. The reaction solution was immediately poured into 100 mL of ice water, 100 mL of ethyl acetate was added, and the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. Extraction was performed, and the aqueous layer was extracted twice. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by silica gel column chromatography to obtain a yellow solid 19 (0.27 g, 85.2%).

[0310] Compound 19 (0.32 g, 1 mmol) prepared in the above step and methylamine hydrochloride (0.14 g, 2 mmol) were weighed and placed in a single-necked flask. 20 mL of toluene was added, and triethylamine (0.4 g, 4 mmol) was slowly added. The temperature was raised to 65°C and stirred for 30 minutes. The reaction mixture also turned dark red. After completion of the reaction, the toluene and excess triethylamine were removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography to yield 20a (0.12 g, 44%) as a dark red solid. 1 H-NMR (400MHz, CDCl3) δ9.29 (s, 1H), 8.43 (d, J = 8.2Hz, 1H), 8.0 (d, J = 8.1Hz, 1H), 2.79, (s, 3H), 2.03 (m, 1H), 1.47 (d, J = 6.8Hz, 6H);13 C-NMR (101MHz, CDCl3) δ182.3,178.5,171.5,164.4,156.5,154.9,141.0,134.7,130.7,120.1,31.4,23.2,21.56(×2).

[0311] Compound 20a (0.14 g, 0.5 mmol) was weighed and placed in a single-necked flask. 10 mL of ethanol was added to dissolve the mixture. 1 mL of 2 M aqueous sodium hydroxide solution was added and stirred at room temperature. The reaction solution initially changed from red to purple and then to pale yellow as the reaction proceeded. After completion, 100 mL of dichloromethane and 50 mL of saturated brine were added. The pH was adjusted to neutral with 2 M hydrochloric acid. After extraction, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography to yield S61 (79 mg, 62%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ9.47 (s, 1H), 9.07 (d, J = 5.2Hz, 1H), 7.97 (d, J = 5.0Hz, 1H), 3.75 (s, 3H), 3.31 (m, 1H), 1.47 (d, J = 6.8Hz, 6H); 13 C NMR (101MHz, CDCl3) δ178.88,174.41,162.62,155.58,148.63,144.88,139.31,133.20,125.71,119.20,50.07,27.89,21.56 (×2). 13 C NMR (101MHz, CDCl3) δ178.69,174.98,162.97,155.53,148.86,143.58,138.85,1 31.62,125.32,118.65,56.02,54.60(×2),44.72,26.31,23.68(×2),21.62(×2).

[0312] Example 71

[0313] Preparation of 1-butyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S62)

[0314] The preparation of compound S62 was the same as that of compound S61, except that methylamine hydrochloride was replaced with n-butylamine hydrochloride (0.22 g, 2 mmol). After purification, a yellow solid, S62 (96 mg, 65%), was obtained. 1H NMR (400MHz, CDCl3) δ9.47 (s, 1H), 9.07 (d, J = 5.1Hz, 1H), 7.97 (d, J = 4.9Hz, 1H), 3.60 (t, J = 7. 2Hz,2H),3.31(m,1H),2.05(m,2H),1.43(m,2H),1.47(d,J=6.8Hz,6H),1.01(t,J=6.9Hz,3H); 13 C NMR (101MHz, CDCl3) δ178.89,174.42,162.65,155.57,148.65,144.88,139. 33,133.19,125.72,119.19,48.83,35.21,27.90,21.56(×2),21.02,14.31.

[0315] Example 72

[0316] Preparation of 1-cyclopropyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S63)

[0317] The preparation of compound S63 was the same as that of compound S61, except that methylamine hydrochloride was replaced with cyclopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S63 (90 mg, 64%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.47(s,1H),9.07(d,J=5.1Hz,1H),7.97(d,J=4.9Hz,1H),3.54(m,1H),3.43-3.32(m,1H),1.48(m,8H),1.12-1.03(m,2H); 13 C NMR (101MHz, CDCl3) δ178.71,174.00,164.86,155.49,148.72,143.36,139.11,133.44,125.19,118.81,27.27,27.24,21.33(×2),9.82(×2). 13 C NMR (101MHz, CDCl3) δ183.53,178.67,174.95,162.98,155.53,148.85,143.56,138. 86,131.61,125.33,118.66,56.02,54.60(×2),44.72,26.31,23.68(×2),21.62(×2).

[0318] Example 73

[0319] Preparation of 1-cyclopentyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S64)

[0320] The preparation of compound S64 was the same as that of compound S61, except that methylamine hydrochloride was replaced with cyclopentylamine hydrochloride (0.24 g, 2 mmol). After purification, a yellow solid, S64 (100 mg, 66%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.43 (s, 1H), 9.04 (d, J = 5.1Hz, 1H), 7.94 (d, J = 4.9Hz, 1H), 5.07 (p, J=9.2Hz,1H),3.42(m,1H),2.18-2.08(m,6H),1.83-1.74(m,2H),1.48(d,J=7.1Hz,6H); 13 C NMR (101 MHz, CDCl3); 13 C NMR (101MHz, CDCl3) δ178.92,174.43,162.67,155.56,148.59,144.88,139. 31,133.16,125.73,119.20,50.07,36.2(×2),22.83(×2),27.73,21.56(×2).

[0321] Example 74

[0322] Preparation of 1-cyclohexyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S65)

[0323] The preparation of compound S65 was the same as that of compound S61, except that methylamine hydrochloride was replaced with cyclohexylamine hydrochloride (0.27 g, 2 mmol). After purification, a yellow solid, S65 (100 mg, 62%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.43 (s, 1H), 9.06 (d, J = 4.9Hz, 1H), 7.97 (d, J = 5.0Hz, 1H), 4.89 (m, 1H), 3 .33(m,1H),2.32(bs,2H),2.00(m,2H),1.90(d,J=12.3Hz,2H),1.84(m,2H),1.58-1.40(m,8H); 13C NMR (101MHz, CDCl3) δ178.72,174.16,155.56,154.11,148.57,144.23,139.28, 132.36,124.86,119.10,51.12,32.51(×2),27.73,25.03,24.8(×2),21.45(×2).

[0324] Example 75

[0325] Preparation of methyl 3-(2-isopropyl-4,9-dioxo-4,9-dihydro-1H-imidazo[4,5-g]isoquinolin-1-yl)propanoate (S66)

[0326] The preparation of compound S66 was the same as that of compound S61, except that methylamine hydrochloride was replaced with methyl 3-aminopropionate hydrochloride (0.28 g, 2 mmol). After purification, a yellow solid, S66 (83 mg, 51%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.43(s,1H),9.06(d,J=4.9Hz,1H),7.97(d,J=5.0Hz,1H),4.31(d,J=7.1Hz,2H),3. 65(s,3H),3.32(m,1H),2.62(s,J=7.0Hz,2H),2.00(m,2H),1.90(d,J=12.3Hz,2H),1.47(d,J=6.8Hz,6H); 13 C NMR (101MHz, CDCl3) δ186.21,178.67,174.96,162.99,155.51,148.88,143. 55,138.85,131.61,125.31,118.64,52.10,48.43,36.60,26.31,21.62(×2).

[0327] Example 76

[0328] Preparation of 2-isopropyl-1-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S67)

[0329] The preparation of compound S67 was the same as that of compound S61, except that methylamine hydrochloride was replaced with isopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S67 (86 mg, 61%), was obtained. 1H NMR (400MHz, CDCl3) δ9.42 (s, 1H), 9.05 (d, J = 5.0Hz, 1H), 7.98 (d, J = 5.1Hz, 1H), 4.81 (m, 1H), 3.29 (m, 1H), 1.64 (d, J = 7.0Hz, 6H), 1.46 (d, J = 6.8Hz, 6H); 13 C NMR (101MHz, CDCl3) δ178.68,174.99,163.0,155.53,148.89,143.54,138.86,131.60,125.32,118.63,52.10,26.31,21.94(×2),21.62(×2).

[0330] Example 77

[0331] Preparation of 2-isopropyl-1-(4-methoxyphenyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S68)

[0332] The preparation of compound S68 was the same as that of compound S61, except that methylamine hydrochloride was replaced with p-anisidine hydrochloride (0.32 g, 2 mmol). After purification, a yellow solid, S68 (80 mg, 46%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.51(s,1H),9.05(d,J=4.9Hz,1H),7.84(d,J=4.9Hz,1H),7.31(m ,1H),7.28(m,1H),7.16-7.07(m,2H),3.95(s,3H),2.91,(m,1H),1.46(d,J=6.8Hz,6H); 13 C NMR (101MHz, CDCl3) δ178.67,173.91,160.71,155.62,155.24,148.81,143.16,142.40,13 8.81,133.16,127.79(×2),127.22,125.21,118.69,115.01(×2),55.68,26.31,21.62(×2).

[0333] Example 78

[0334] Preparation of 1-benzyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S69)

[0335] The preparation of compound S69 was the same as that of compound S61, except that methylamine hydrochloride was replaced with benzylamine hydrochloride (0.29 g, 2 mmol). After purification, a yellow solid, S69 (82 mg, 54%), was obtained.1 H NMR (400MHz, CDCl3) δ9.55 (s, 1H), 9.14 (d, J = 4.9Hz, 1H), 8.03 (dd, J = 4.9, 0.9Hz, 1H), 7.40- 7.28(m,3H),7.13(dd,J=7.7,1.7Hz,2H),5.21(s,2H),2.91,(m,1H),1.46(d,J=6.8Hz,6H); 13 C NMR (101MHz, CDCl3) δ178.55,174.84,155.72,154.84,148.88,143.36,138.81,136.77 ,131.84,129.11(×2),128.94(×2),127.45,125.29,118.71,47.81,26.31,21.62(×2).

[0336] Example 79

[0337] Preparation of 2-isopropyl-1-(2-(piperidin-1-yl)ethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S70)

[0338] The preparation of compound S70 was the same as that of compound S61, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)piperidine hydrochloride (0.4 g, 2 mmol). After purification, a yellow solid, S70 (83 mg, 47%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),9.03(d,J=4.9Hz,1H),7.86(d,J=5.1Hz,1H),4.39(t,J=6.2H z,2H),2.58(t,J=6.1Hz,2H),2.61(m,1H),2.36(s,4H),1.40-1.35(m,10H),1.31(q,J=6.0Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ178.69,174.89,156.07,155.20,147.90,142.67,138.73,13 2.99,125.64,119.02,58.46,57.2,54.37(×2),26.43,26.14(×2),21.52(×2),11.73.

[0339] Example 80

[0340] Preparation of 2-isopropyl-1-(3-(piperidin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S71)

[0341] The preparation of compound S71 was the same as that of compound S61, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)piperidine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S71 (81 mg, 44%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.42(s,1H),8.86(d,J=4.7Hz,1H),7.92(d,J=4.6Hz,1H),4.43(t,J=7.1Hz,2H),3.12(m,1H),3.01( t,J=7.1Hz,2H),2.82(bs,4H),2.28(t,J=6.7Hz,2H),1.38(t,J=5.5Hz,4H),1.41(d,J=6.9Hz,6H),1.32(q,J=5.9Hz,2H); 13 C NMR (101MHz, CDCl3) δ178.66,174.84,156.04,155.14,147.95,142.70,138.71,132.97, 125.65,119.01,56.35,56.33(×2),42.52,30.41,26.42,26.10(×2),21.52(×2),12.73.

[0342] Example 81

[0343] Preparation of 2-isopropyl-1-(2-morpholinoethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S72)

[0344] The preparation of compound S72 was the same as that of compound S61, except that methylamine hydrochloride was replaced with N-(2-aminoethyl)morpholine hydrochloride (0.41 g, 2 mmol). After purification, a yellow solid, S72 (74 mg, 42%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.19(s,1H),8.90(d,J=4.9Hz,1H),7.82(d,J=4.9Hz,1H),4.48(t, J=7.1Hz,2H),3.73(t,J=4.4Hz,4H),2.97(m,1H),2.49-2.46(m,6H),1.39(d,J=7.1Hz,6H); 13C NMR(101MHz,DMSO-d6)δ174.42,170.72,151.59,150.44,144.82,139.36,134.64, 128.01,121.11,114.56,62.84(×2),53.14,49.42(×2),40.09,26.25,21.46(×2).

[0345] Example 82

[0346] Preparation of 2-isopropyl-1-(3-morpholinopropyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S73)

[0347] The preparation of compound S73 was the same as that of compound S61, except that methylamine hydrochloride was replaced with N-(3-aminopropyl)morpholine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S73 (77 mg, 42%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.47(s,1H),9.06(d,J=4.9Hz,1H),7.95(d,J=4.9Hz,1H),4.43(t,J=7.2Hz,2H),3 .70(t,J=4.7Hz,4H),2.50-2.40(m,6H),2.05(p,J=6.6Hz,2H),3.22-3.11(m,1H),1.44(d,J=5.3Hz,6H); 13 C NMR(101MHz, CDCl3)δδ174.4o,170.70,151.50,150.40,144.80,139.33,134.71,128 .08,121.15,114.64,62.87(×2),51.09,49.55(×2),40.09,26.29,22.66,21.66(×2).

[0348] Example 83

[0349] Preparation of 2-isopropyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S74)

[0350] The preparation of compound S74 was the same as that of compound S61, except that methylamine hydrochloride was replaced with 3-methyl-1-piperazineethylamine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S74 (72 mg, 39%), was obtained. 1H NMR (400MHz, CDCl3) δ9.44(s,1H),9.04(d,J=4.9Hz,1H),7.91(d,J=4.9Hz,1H),4.49(t,J=6.6Hz,2H),3.2 2-3.11(m,1H),2.72(t,J=6.6Hz,2H),2.57-2.39(m,6H),2.26(s,3H),2.01(s,2H),1.44(d,J=5.3Hz,6H); 13 C NMR (101MHz, CDCl3) δ178.67,175.05,162.98,155.53,148.84,143.49,138.85,131. 72,125.31,118.18,58.29,55.03(×2),53.61(×2),45.99,43.22,26.29,21.66(×2).

[0351] Example 84

[0352] Preparation of 2-isopropyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S75)

[0353] The preparation of compound S75 was the same as that of compound S61, except that methylamine hydrochloride was replaced with 3-methyl-1-piperazinepropylamine hydrochloride (0.53 g, 2 mmol). After purification, a yellow solid, S75 (76 mg, 40%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.44(s,1H),9.04(d,J=4.9Hz,1H),7.91(d,J=4.9Hz,1H),4.49(t,J=6.6Hz,2H),3.22-3.11(m, 1H),2.42(t,J=6.6Hz,2H),2.57-2.39(m,6H),2.32(t,J=6.6Hz,2H),2.26(s,3H),2.01(s,2H),1.44(d,J=5.3Hz,6H); 13 C NMR (101MHz, CDCl3) δ178.67,175.05,162.98,155.53,148.84,143.49,138.85,131.72, 125.31,118.18,58.30,55.02(×2),53.62(×2),45.99,43.22,30.15,26.30,21.66(×2).

[0354] Example 85

[0355] Preparation of 2-isopropyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S76)

[0356] The preparation of compound S76 was the same as that of compound S61, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)pyrrolidine hydrochloride (0.37 g, 2 mmol). After purification, a yellow solid, S76 (73 mg, 43%), was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 9.10 (d, J = 4.9Hz, 1H), 7.92 (d, J = 5.0Hz, 1H) ,4.51(t,J=6.7Hz,2H),2.93(bs,2H),2.67(bs,4H),2.58(bs,3H),1.73(bs,4H); 13 C NMR (101MHz, DMSO) δ178.65,174.92,156.11,155.08,147.91,142.72,139 .10,132.91,125.58,119.03,54.94,53.76(×2),44.45,23.65(×2),13.56.

[0357] Example 86

[0358] Preparation of 2-isopropyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S77)

[0359] The preparation of compound S77 was the same as that of compound S61, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)pyrrolidine hydrochloride (0.40 g, 2 mmol). After purification, a yellow solid, S77 (76 mg, 43%), was obtained. 1 H NMR (400MHz, CDCl3) δ9.48 (s, 1H), 9.08 (d, J = 4.9Hz, 1H), 7.97 (d, J = 4.9Hz, 1H), 4.50 (t,J=7.1Hz,2H),2.66(s,3H),2.51(m,6H),2.06(p,J=6.8Hz,2H),1.86-1.73(m,4H); 13 C NMR (101MHz, CDCl3) δ178.51,174.75,155.51,154.66,148.83,143.39,138.85 ,132.21,125.27,118.68,53.98(×2),52.56,44.31,29.28,23.55(×2),13.34.

[0360] Reaction Scheme VI of Formula I compound:

[0361] Example 87

[0362] Preparation of tert-butyl (6-bromo-5,8-dioxo-5,8-dihydroisoquinolin-7-yl)carbamate (21)

[0363] Intermediate 16 (0.25 g, 1 mmol) prepared in Example 46 and di-tert-butyl dicarbonate (0.44 g, 2 mmol) were weighed into a two-necked flask. p-Dimethylaminopyridine (0.12 g, 1 mmol) was added, and 10 mL of anhydrous THF was added. The mixture was stirred at 0°C for 30 minutes. The reaction solution turned from yellow to red, and the reaction was stopped. The reaction solution was immediately poured into 100 mL of ice water, and 100 mL of ethyl acetate was added. The aqueous layer was extracted twice more. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 0.24 g of a yellow solid, which was compound 21, with a yield of 69.0%. 1 H NMR (400MHz, CDCl3) δ9.48 (s, 1H), 9.08 (d, J = 4.9 Hz, 1H), 7.97 (d, J = 4.9 Hz, 1H), 1.41 (s, 9H).

[0364] Example 88

[0365] Preparation of 1-methyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S78)

[0366] Intermediate 21 (0.35 g, 1 mmol) prepared in Example 87 and methylamine hydrochloride (0.14 g, 2 mmol) were weighed and placed in a single-necked flask. 20 mL of toluene was added, and triethylamine (0.4 g, 4 mmol) was slowly added. The temperature was raised to 65°C and stirred for 30 min. The reaction also turned dark red. After completion, the toluene and excess triethylamine were removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a dark red solid 22a (0.14 g, 45%). Compound 22a (0.10 g, 0.3 mmol) was weighed and placed in a single-necked flask. 15 mL of methanol and 0.5 mL of concentrated hydrochloric acid were added and the mixture was allowed to react at room temperature overnight. The solvent was removed by rotary evaporation under reduced pressure. The mixture was washed with an appropriate amount of ethyl acetate and filtered to obtain a red solid 23a, which was carried on to the next step without purification.

[0367] Compound 23a (0.08 g, 0.4 mmol) prepared in the above step was weighed into a two-necked flask. 15 mL of dichloromethane and triethylamine (0.08 g, 0.8 mmol) were added. Benzoyl chloride (0.067 g, 0.48 mmol) in dichloromethane (5 mL) was slowly added dropwise under an ice bath. The reaction changed from pale yellow to red. Stirring was continued for 30 minutes. The reaction was stopped, and saturated brine (100 mL) and ethyl acetate (100 mL) were added for extraction. The organic layer was collected. The crude product was dried and filtered, and purified by silica gel column chromatography to yield 24a (N-(6-(methylamino)-5,8-dioxy-5,8-dihydroisoquinolin-7-yl)benzamide), 0.063 g, in a 51% yield. 1 H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 9.02 (d, J = 4.9 Hz, 1H), 7.98 (d, J = 4.9 Hz, 1H), 1.41 (s, 9H), 7.92 (m, 2H), 7.59 (m, 2H), 7.50 (m, 1H), 3.41 (s, 3H). Compound S78 was prepared under the same conditions as compound S40 in Example 49 to obtain 66 mg of a yellow solid in a 46% yield. 1 H NMR (400MHz, CDCl3) δ9.52(d,J=0.9Hz,1H),9.11(d,J=4.9Hz,1H),8.00(dd,J=4.9,0.9Hz,1H),7.85-7.75(m,2H),7.59(m,3H),4.21(s,3H); 13 C NMR (101MHz, CDCl3) δ178.54,175.55,155.97,155.63,148.96,143.58,138.8 7,133.14,131.01,129.59(×2),128.97(×2),127.71,125.39,118.68,34.05.

[0368] Example 89

[0369] Preparation of 1-isopropyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S79)

[0370] The preparation of compound S79 was the same as that of compound S78, except that methylamine hydrochloride was replaced with isopropylamine hydrochloride (0.19 g, 2 mmol). After purification, yellow solid S79 (68 mg, 43%) was obtained. 1H NMR (400MHz, CDCl3) δ9.51 (s, 1H), 9.12 (d, J = 4.9Hz, 1H), 8.05 (d, J = 4.9Hz, 1H), 7.67 (m, 2H), 7.60 (m, 3H), 4.94 (m, 1H), 1.71 (d, J = 6.8Hz, 6H); 13 C NMR (101MHz, CDCl3) δ178.87,173.92,156.24,155.67,148.71,145.15,139.48,1 32.99,130.84,129.69(×2),129.13,128.92(×2),125.06,119.29,51.64,20.95.

[0371] Example 90

[0372] Preparation of 1-cyclopropyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S80)

[0373] The preparation of compound S80 was the same as that of compound S78, except that methylamine hydrochloride was replaced with cyclopropylamine hydrochloride (0.19 g, 2 mmol). After purification, yellow solid S80 (71 mg, 45%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),9.04(d,J=4.9Hz,1H),7.93(d,J=4.9Hz,1H ),7.60(m,2H),7.52(m,3H),3.36(m,1H),1.47-1.33(m,2H),1.08-1.00(m,2H); 13 C NMR(101MHz,DMSO-d6)δ178.88,173.92,156.23,155.68,148.72,145.15,13 9.48,132.99,130.84,129.70(×2),129.14,128.93(×2),25.63,5.41,4.79.

[0374] Example 91

[0375] Preparation of 1-benzyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S81)

[0376] The preparation of compound S81 was the same as that of compound S78, except that methylamine hydrochloride was replaced with benzylamine hydrochloride (0.29 g, 2 mmol). After purification, yellow solid S81 (97 mg, 53%) was obtained. 1H NMR (400MHz, CDCl3) δ9.54(d,J=0.9Hz,1H),9.09(d,J=4.9Hz,1H),7.94(dd,J=4.9,0.9Hz,1H),7.74-7.67 (m,2H),7.61-7.55(m,1H),7.54-7.49(m,2H),7.41-7.32(m,3H),7.08(dd,J=7.8,1.9Hz,2H),5.82(s,2H); 13 C NMR (101MHz, CDCl3) δ178.62,175.03,156.44,155.65,148.95,143.95,138.82,135.68,132.70,13 1.13,129.51(×2),129.18(×2),129.03(×2),128.28,127.84,126.08(×2),125.36,118.81,49.98.

[0377] Example 92

[0378] Preparation of 1-(2-(dimethylamino)ethyl)-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S82)

[0379] The preparation of compound S82 was the same as that of compound S78, except that methylamine hydrochloride was replaced with N,N-dimethylethylenediamine hydrochloride (0.32 g, 2 mmol). After purification, yellow solid S82 (58 mg, 41%) was obtained. 1 H NMR(400MHz, CDCl3) δ9.48(s,1H),9.10(d,J=4.9Hz,1H),8.03(d,J=4.9Hz,1H),7. 64(m,2H),7.45(m,3H),4.45(t,J=6.5Hz,2H),2.65(t,J=6.5Hz,2H),2.26(s,6H); 13 C NMR (101MHz, DMSO-d6) δ178.70,174.93,156.09,155.16,147.91,142.73,139.16,132.90,125.62,119.06,58.87,45.88(×2),43.85.

[0380] Example 93

[0381] Preparation of 2-phenyl-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S83)

[0382] The preparation of compound S83 was the same as that of compound S78, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)piperidine hydrochloride (0.4 g, 2 mmol). After purification, yellow solid S83 (73 mg, 45%) was obtained. 1 H NMR (400MHz, CDCl3) δ9.53 (s, 1H), 9.11 (d, J = 4.9Hz, 1H), 8.01 (m, 1H), 7.88-7.79 (m, 2H), 7.64 -7.52(m,3H),4.66(t,J=6.4Hz,2H),2.69(t,J=6.4Hz,2H),2.31(t,J=5.2Hz,4H),1.44(m,6H); 13 C NMR (101MHz, CDCl3) δ178.66,175.22,165.17,156.54,155.61,148.93,143.64,138.97,132.87,130 .81,129.67(×2),128.89(×2),128.39,125.37,118.76,58.90,54.93(×2),44.56,25.90(×2),24.02.

[0383] Example 94

[0384] Preparation of 1-(2-morpholinoethyl)-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S84)

[0385] The preparation of compound S84 was the same as that of compound S78, except that methylamine hydrochloride was replaced with N-(2-aminoethyl)morpholine hydrochloride (0.41 g, 2 mmol). After purification, yellow solid S84 (75 mg, 46%) was obtained. 1 H NMR (400MHz, CDCl3) δ9.48 (s, 1H), 9.11 (d, J = 4.9Hz, 1H), 8.01 (m, 1H), 7.88-7.79 (m, 2 H),7.64-7.52(m,3H),4.46(t,J=7.1Hz,2H),3.72(t,J=4.5Hz,4H),2.49-2.41(m,6H); 13 C NMR (101MHz, CDCl3) δ178.61,175.12,165.12,156.50,155.51,148.88,143.54,138.90,132.88, 130.67,129.61(×2),128.80(×2),128.31,125.21,118.70,62.65(×2),51.01,49.34(×2),40.12.

[0386] Example 95

[0387] Preparation of 1-(2-(4-methylpiperazin-1-yl)ethyl)-2-phenyl-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S85)

[0388] The preparation of compound S85 was the same as that of compound S78, except that methylamine hydrochloride was replaced with N-methyl-4-(2-aminoethyl)piperidine hydrochloride (0.51 g, 2 mmol). After purification, yellow solid S85 (66 mg, 39%) was obtained. 1 H NMR (400MHz, CDCl3) δ9.53 (s, 1H), 9.12 (d, J = 5.2Hz, 1H), 8.00 (d, J = 5.1Hz, 1H), 7.81 (d, J = 7.9Hz, 2H),7.59(bs,3H),4.68(t,J=6.4Hz,2H),2.74(t,J=6.5Hz,2H),2.41(bs,4H),2.31-2.25(m,7H); 13 C NMR (101MHz, CDCl3) δ178.21,175.11,155.49,148.95,143.21,139.49,130.18,129 .64(×2),128.98(×2),125.27,118.78,58.03,54.85(×2),53.14(×2),45.84,44.26.

[0389] Example 96

[0390] Preparation of 2-phenyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S86)

[0391] The preparation of compound S86 was the same as that of compound S78, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)pyrrolidine hydrochloride (0.37 g, 2 mmol). After purification, yellow solid S86 (71 mg, 46%) was obtained. 1 H NMR (400MHz, CDCl3) δ9.53 (s, 1H), 9.12 (d, J = 5.1Hz, 1H), 8.01 (d, J = 4.9Hz, 1H), 7.80 (dd, J = 7.6, 2.2Hz ,2H),7.64-7.52(m,3H),4.68(t,J=6.7Hz,2H),2.89(t,J=6.7Hz,2H),2.45-2.36(m,4H),1.70(m,4H); 13C NMR (101MHz, CDCl3) δ178.68,175.19,156.29,155.62,143.58,148.94,138.93,132.41,130. 80,129.66(×2),128.90(×2),128.36,125.56,118.76,55.86,54.26(×2),45.88,23.61(×2).

[0392] Example 97

[0393] Evaluation of the proliferation inhibitory activity of benzo[g]isoquinoline-5,10-dione derivatives on pancreatic cancer cell lines PANC-1 and MIA-PaCa-2

[0394] (1) Pancreatic cancer cell line information: pancreatic cancer cell lines PANC-1 and MIA-PaCa-2.

[0395] (2) Culture medium and main reagents and consumables: DMEM culture medium (containing 10% FBS and 1% double antibody), EP tubes, Tip heads, centrifuge tubes, polyethylene 96-well plates, etc.

[0396] (3) Experimental methods:

[0397] (a) Pancreatic cancer cells in the logarithmic growth phase were evenly plated into 96-well plates at a cell density of 3000 cells / well in a final volume of 100 μL per well. The cells were cultured in a 37°C, 5% CO2 incubator for 24 h before administration.

[0398] (b) The cells were set up as control group and drug-treated groups (0.0033, 0.01, 0.033, 0.1, 0.33, 1, 3.3, 10 μM), with three replicate wells;

[0399] (c) After 48 hours of culture, 20 μL of 5 g / L MTT solution was added to each well and incubated in the incubator for 4 hours. After the specified time, 100 μL of Tris buffer was added to each well and the cells were incubated in a 37°C incubator overnight.

[0400] (d) After overnight incubation, the absorbance of each well was measured at 570 nm using a microplate reader and the tumor cell inhibition rate was calculated using the following formula: % inhibition rate = [OD(DMSO group) - OD(test sample group)] / [(OD(DMSO group) - OD(blank group)] × 100%.

[0401] (e) Evaluation results of the proliferation inhibitory activity of benzo[g]isoquinoline-5,10-dione derivatives on pancreatic cancer cell lines PANC-1 and MIA-PaCa-2:

[0402] Table 1. Experimental results of the pancreatic cancer cell proliferation inhibitory activity of benzo[g]isoquinoline-5,10-dione derivatives

[0403] The results are shown in the table above. The IC values ​​of the benzo[g]isoquinoline-5,10-dione derivatives involved in the activity evaluation for inhibiting the proliferation of pancreatic cancer Panc-1 and MIA-PaCa-2 cell lines are shown in the table above. 50 Between 0.03 and 5.0 μM, it has good anti-pancreatic cancer proliferation ability.

[0404] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A compound represented by formula I, characterized in that, The compound also includes its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, pharmaceutically acceptable salts or prodrugs; The formula I is the structural formula of a compound, wherein, X is independently selected from Y is independently selected from N and CH; R1 is independently selected from alkoxy, cyano, alkoxycarbonylamino, alkylcarbamoyl, acyloxy, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, alkyl, alkenyl, alkynyl, carbonyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic group, amidino, heteroaryl; R2 is independently selected from hydrogen, hydroxy, alkoxy, cyano, alkoxycarbonylamino, alkylcarbamoyl, acyloxy, carboxyl; substituted or unsubstituted halogen, amino, sulfonyl, alkyl, alkenyl, alkynyl, carbonyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic group, amidino, heteroaryl; The substituents of the substitution are independently selected from halogen, nitro, cyano, amino, alkyl, haloalkyl, hydroxy, hydroxymethyl, hydroxyethyl, aminoethyl, mercapto, carboxyl, aldehyde, ester, aryl, heterocyclic group, arylcarbonyl, cyanoarylcarbonyl, haloalkylarylcarbonyl, heterocyclic enoyl, alkyl mono-substituted acyl, alkyl bis-substituted acyl, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocycliccarbonyloxy, alkoxycarbonyl, cycloalkoxycarbonyl, heterocyclicoxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heterocycliccarbonylamino, aminocarbonyl, alkoxymethanamide, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, carboxyalkylmethylamide.

2. The compound according to claim 1, wherein The structural formula of the said compound is selected from or 3. The compound according to claim 1, characterized in that, The R1 is independently selected from alkoxy, cyano, alkoxycarbonylamino, alkylcarbamoyl, acyloxy, alkoxycarbonyl, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, C1-C 10 alkyl, C1-C 10 alkenyl, C1-C 10 alkynyl, carbonyl, C3-C 10 cycloalkyl, C3-C 10 cycloalkenyl, C6-C 10 aryl, C3-C 10 heterocyclic group, C6-C 10 heteroaryl, formamidine group; R2 is independently selected from alkanamido, alkanoylamino, alkanoyloxy, alkoxycarbonyl; substituted or unsubstituted halogen, amino, sulfonyl, C1-C 10 alkyl, C1-C 10 alkenyl, C1-C 10 alkynyl, carbonyl, C3-C 10 cycloalkyl, C3-C 10 cycloalkenyl, C6-C 10 aryl, C3-C 10 heterocyclic group, C6-C 10 heteroaryl, formamidine group; The substituted substituents are independently selected from halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester group, aminocarbonyl, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, C6-C 10 aryl, C3-C 10 heterocyclic group, C1-C 10 alkyl monosubstituted amino, C1-C 10 alkyl disubstituted amino, C1-C 10 alkoxy, C1-C 10 alkylcarbonyloxy, C3-C 10 cycloalkylcarbonyloxy, C3-C 10 heterocycliccarbonyloxy, C1-C 10 alkoxycarbonyl, C1-C 10 cycloalkoxycarbonyl, C3-C 10 heteroepoxycarbonyl, C1-C 10 alkylcarbonylamino, C3-C 10 cycloalkylcarbonylamino, C3-C 10 heterocycliccarbonylamino, C1-C 10 alkoxymethanamide group, polyhydroxy C1-C 10 alkoxycarbonyl, carboxy C1-C 10 alkoxy, carboxy C1-C 10 alkylformyloxy.

4. The compound according to claim 3, wherein R1 is independently selected from alkoxy, cyano, alkanamido, alkanoylamino, alkanoyloxy, alkoxycarbonyl, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6-C 10 aryl, C3-C6 heterocyclic group, C6-C 10 heteroaryl, N-formamidinyl; R2 is independently selected from alkanamido, alkanoylamino, alkanoyloxy, alkoxycarbonyl; substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6-C 10 aryl, C3-C6 heterocyclic group, C6-C 10 heteroaryl; The substituted substituents are independently selected from halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester group, aminocarbonyl, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, C6-C 10 aryl, C3-C6 heterocyclic group, C1-C6 alkyl monosubstituted amino group, C1-C6 alkyl disubstituted amino group, C1-C6 alkoxy group, C1-C6 alkylcarbonyloxy group, C3-C6 cycloalkylcarbonyloxy group, C3-C6 heterocycliccarbonyloxy group, C1-C6 alkoxycarbonyl group, C1-C6 cycloalkoxycarbonyl group, C3-C6 heterocyclic oxycarbonyl group, C1-C6 alkylcarbonylamino group, C3-C6 cycloalkylcarbonylamino group, C3-C6 heterocycliccarbonylamino group, C1-C6 alkoxymethanamide group, polyhydroxy C1-C6 alkoxycarbonyl group, carboxy C1-C6 alkoxy group, carboxy C1-C6 alkylformyloxy group.

5. The compound according to claim 4, wherein R1 is independently selected from alkoxy, cyano, alkoxycarbonylamino, alkylaminocarbonyl, acyloxy, alkoxycarbonyl, carboxyl; substituted or unsubstituted non-chlorine halogen, amino, sulfonyl, C1-C3 alkyl, C1-C3 alkenyl, C1-C3 alkynyl, carbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6-C 10 aryl, C3-C6 heterocyclic group, C6-C 10 heteroaryl; R2 is independently selected from alkanamido, alkanoyl amino, alkanoyloxy, alkoxycarbonyl, carboxyl; substituted or unsubstituted C1-C3 alkyl, carbonyl, C3-C6 cycloalkyl, C6-C 10 aryl, C3-C6 heterocyclic group; The substituted substituents are independently selected from halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester group, aminocarbonyl, alkyl mercapto, hydroxyalkoxy, sugar residue, sulfo group, phosphate group, C6-C 10 aryl, C3-C6 heterocyclic group, C1-C3 alkyl mono-substituted amino group, C1-C3 alkyl di-substituted amino group, C1-C3 alkoxy group, C1-C3 alkylcarbonyloxy group, C3-C3 cycloalkylcarbonyloxy group, C3-C6 heterocycliccarbonyloxy group, C1-C6 alkoxycarbonyl group, C1-C6 cycloalkoxycarbonyl group, C3-C6 heterocyclic oxycarbonyl group, C1-C6 alkylcarbonylamino group, C3-C6 cycloalkylcarbonylamino group, C3-C6 heterocycliccarbonylamino group, C1-C6 alkoxymethylamide group, polyhydroxy C1-C6 alkoxycarbonyl group, carboxy C1-C6 alkoxy group, carboxy C1-C6 alkylformyloxy group.

6. The compound according to any one of claims 1-5, characterized in that, The compound is selected from any one of the following compounds:

7. A method for preparing the compound according to any one of claims 1-6, characterized in that, The reaction route is selected from at least one of the following six: Reaction Route I: Compound 1 and Compound 2 are reacted through Friedel-Crafts acylation reaction to obtain Compound 3, Compound 3 is reduced by zinc powder and formic acid to obtain Compound 4, Compound 4 undergoes intramolecular Friedel-Crafts acylation under the action of trifluoroacetic anhydride to obtain Compound 5, Compound 5 is then oxidized to obtain Compound S1, and then demethylated by boron tribromide to obtain Compound 6, Compound 6 reacts with trifluoromethanesulfonic anhydride to obtain Compound 7, and finally Compound 7 can undergo various derivatization reactions to obtain the target compounds S3-S30; Reaction Route II: Using reaction route I, Compound 7 reacts with zinc cyanide under palladium catalysis to obtain Compound S2, and Compound S2 is hydrolyzed in the H2O2 / K2CO3 / DMSO system to obtain S31; alternatively, it is hydrolyzed to a carboxylic acid intermediate compound 8 under strong base conditions, and finally esterified or subjected to acid amide condensation to obtain Compound S32 or S33; Reaction Route III: Using reaction route I, Compound 7 reacts with acetamide under palladium catalysis to obtain Compound S5, and Compound S5 is hydrolyzed under acidic conditions to obtain S34; S34 reacts with DMF activated by TAFF to obtain Compound S35; S34 can also be made into diazonium salt compounds 9-11, and then converted to obtain S36, S37 and azide intermediate compound 12; S37 undergoes a coupling reaction to obtain S38; Compound 12 can undergo a Click reaction to obtain S39; Reaction Route IV: In a mixed solvent of acetonitrile and water, 5-hydroxyisoquinoline is oxidized by [bis(trifluoroacetoxy)iodo]benzene to obtain compound 14. Compound 14 reacts with sodium azide in acetic acid solvent to obtain compound 15. Compound 15 reacts with N-bromosuccinimide to quantitatively obtain compound 16. Compound 16 undergoes a solvolysis reaction with acetic anhydride as the solvent under the catalysis of concentrated sulfuric acid to obtain the acetylated intermediate 17. Compound 17 reacts with primary amines to obtain the dark red solid compound 18. Compound 18 undergoes ring closure under basic conditions to obtain a series of compounds S40 - S60; Reaction Route V: Using Reaction Route IV, an acylation reaction is carried out between compound 15 and isobutyric anhydride under the catalysis of sulfuric acid to obtain the intermediate compound 19. Compound 19 reacts with primary amines in toluene to obtain compound 20. Compound 20 is obtained under basic conditions to obtain compounds S61 - S77; Reaction Route VI: Using Reaction Route IV, compound 15 reacts with di-tert-butyl dicarbonate and 4-dimethylaminopyridine in tetrahydrofuran to obtain the intermediate compound 21. Compound 21 reacts with primary amines to obtain the intermediate compound 22. Compound 22 is deprotected under hydrochloric acid acidic conditions to obtain primary amine compound 23. Compound 23 reacts with benzoyl chloride and triethylamine in dichloromethane to obtain the intermediate compound 24. Compound 24 undergoes ring closure under basic conditions to obtain compounds S78 - S86.

8. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 - 6 or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and one or more pharmaceutically acceptable carriers, diluents, excipients.

9. Use of the compound according to any one of claims 1-6 or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 8, in the preparation of a drug for treating infectious diseases, inflammatory diseases and autoimmune diseases, tumors or cardiovascular and cerebrovascular diseases, wherein, The infectious disease does not include the infectious disease caused by Helicobacter pylori infection.

10. The application according to claim 9, wherein The infectious disease includes the infectious disease caused by fungal infection, the infectious disease caused by bacterial infection other than Helicobacter pylori, and the infectious disease caused by viral infection.

11. The application according to claim 9, wherein The tumor is selected from at least one of leukemia, multiple myeloma, lymphoma, lung cancer, head and neck cancer, esophageal cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, breast cancer, cervical cancer, prostate cancer.

12. The application according to claim 9, wherein The inflammatory disease and autoimmune disease are selected from at least one of rheumatoid arthritis, chronic obstructive pulmonary disease, acute lung injury, allergic rhinitis, asthma, lupus erythematosus, psoriasis, multiple sclerosis.

13. The application according to claim 9, characterized in that The cardiovascular and cerebrovascular diseases include coronary heart disease, myocardial infarction, angina pectoris, thrombolytic therapy or percutaneous coronary angioplasty-related acute vessel closure, transient ischemic attack, stroke, intermittent claudication or coronary or peripheral artery bypass grafting, vascular lumen narrowing, restenosis after coronary or venous angioplasty, maintenance of vascular access patency in long-term hemodialysis patients, pulmonary thromboembolism, heart failure caused by anthraquinone drugs.

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