Anti-helicobacter pylori compound and use thereof

Abstract

Disclosed are an anti-Helicobacter pylori compound and use thereof, which relate to the technical field of pharmaceuticals. The compound is a compound represented by formula I and further comprises a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a nitrogen oxide thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. The compound exhibits a good effect in the treatment of Helicobacter pylori infection.

Description

An anti-Helicobacter pylori compound and its application

[0001] The present invention claims priority to the Chinese patent application filed with the Patent Office of China on January 17, 2024, with application number 2024100677877 and invention name “An anti-Helicobacter pylori compound and its application”, the entire contents of which are incorporated by reference into the application. Technical Field

[0002] The present invention relates to the technical field of pharmaceuticals, and in particular to an anti-Helicobacter pylori compound and application thereof. Background Art

[0003] Quinone compounds are widely present in nature and serve as important mediators of electron transfer in organisms through reversible redox reactions. Reported biological activities of quinone compounds include, but are not limited to, antitumor, antibacterial, antifungal, antiviral, anti-AD, 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 hirtus 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. It has less cardiotoxicity and bone marrow suppression than mitoxantrone and has a good effect in the treatment of relapsed and aggressive non-Hodgkin's lymphoma. Some 1- and 3-substituted benzo[g]isoquinoline-5,10-diones have good anti-tuberculosis activity.

[0007] The chemical structures of benzo[g]isoquinoline-5,10-dione, picantron, and 1,3-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 chain 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 on enhancing the bioactivity, improving bioavailability, and reducing the cytotoxicity of the anthraquinone nucleus. However, most structural modifications are focused on positions 1, 3, and 4 of the isoquinoline ring, while modifications to positions 6, 7, 8, and 9 of the benzene ring are rare, resulting in a lack of diversity in benzo[g]isoquinoline-5,10-dione derivatives. Summary of the Invention

[0009] Based on the above analysis, the present invention aims to provide an anti-Helicobacter pylori compound and its application, considering the poor drugability, strong lipid solubility, and low bioavailability of benzo[g]isoquinoline-5,10-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.

[0010] To achieve the above objectives, in one aspect, the present invention provides the use of a compound represented by Formula I in the preparation of an anti-Helicobacter pylori agent, wherein 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 hydroxy, alkoxy, cyano, alkanoyl, alkanoyl, alkanoyloxy, carboxyl; substituted or unsubstituted 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 substituted substituents are independently selected from halogen, nitro, cyano, amino, alkyl, haloalkyl, hydroxyl, hydroxymethyl, hydroxyethyl, aminoethyl, thiol, 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, phosphoric acid, polyhydroxyalkoxycarbonyl, carboxyalkoxy, carboxyalkylformamido.

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

[0016] Preferably, in the compound, R1 is independently selected from hydroxyl, alkoxy, cyano, alkanoyl, alkanoyl, alkanoyl, alkoxyl, carboxyl; 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;

[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 amine, 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, in the compound, R1 is independently selected from hydroxyl, alkoxy, cyano, alkanoyl, alkanoylamino, alkanoylamino, alkanoyloxy, alkoxyacyl, carboxyl; substituted or unsubstituted halogen, amino, sulfonyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbonyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C6-C6 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, in the compound, R1 is independently selected from hydroxyl, alkoxy, cyano, alkanoyl, alkanoylamino, alkanoylamino, 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; 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;

[0023] 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-C3 alkyl monosubstituted amino group, C1-C3 alkyl disubstituted amino group, C1-C3 alkoxy group, C1-C3 alkylcarbonyloxy group, C3-C6 cycloalkylcarbonyloxy group, C 3-C6 heterocyclylcarbonyloxy, C1-C6 alkoxycarbonyl, C1-C6 cycloalkyloxycarbonyl, C3-C6 heterocyclyloxycarbonyl, C1-C6 alkylcarbonylamino, C3-C6 cycloalkylcarbonylamino, C3-C6 heterocyclylcarbonylamino, C1-C6 alkoxyformamido, polyhydroxy C1-C6 alkoxycarbonyl, carboxyl C1-C6 alkoxy, carboxyl C1-C6 alkylformyloxy.

[0024] Further preferably, the compound is selected from any one of the following compounds:

[0025] Preferably, the dosage form of the drug includes injection, tablet, capsule, sustained-release agent, powder, liposome, granule, ointment, cream, emulsion, suspension, lyophilized agent, spray, suppository, aerosol, pill or oral solution.

[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] On the other hand, the present invention provides an anti-Helicobacter pylori 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.

[0039] Preferably, the pharmaceutically acceptable carrier includes at least one of a diluent, an excipient, a filler, a binder, a wetting agent, a lubricant, a disintegrant, an absorption promoter, a surfactant, an adsorption carrier, and a flavoring agent or a sweetener.

[0040] In another aspect, the present invention provides use of the above-mentioned pharmaceutical composition in the preparation of anti-Helicobacter pylori drugs.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] A new anti-Helicobacter pylori compound and its derivatives are proposed, which have high anti-Helicobacter pylori activity, good water solubility and drug-like properties, and can effectively treat and prevent related symptoms of infectious diseases. DETAILED DESCRIPTION

[0048] 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.

[0049] Reaction Scheme I of the compound of formula (I):

[0050] Example 1

[0051] Preparation of 4-(4-methoxybenzoyl)nicotinic acid (3)

[0052] 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.

[0053] Example 2

[0054] Preparation of 4-(4-methoxybenzyl)nicotinic acid (4)

[0055] 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 the reaction was continued 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).

[0056] Example 3

[0057] Preparation of 8-methoxybenzo[g]isoquinolin-10(5H)-one (5)

[0058] Compound 4 (11.0 g, 45.2 mmol) prepared in Example 2 was weighed and placed in a 100 mL pressure tube. 60 mL of trifluoroacetic anhydride was added, 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. An appropriate amount of methanol was added to the mixture, which was then rotary evaporated to remove the methanol, resulting in the precipitation of a red solid. Appropriate amounts of petroleum ether and ethyl acetate were then added to the mixture, and the mixture was slurried. 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).

[0059] Example 4

[0060] Preparation of 8-methoxybenzo[g]isoquinoline-5,10-dione (S2)

[0061] 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 S2 (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); 13C-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.

[0062] Example 5

[0063] Preparation of 8-hydroxybenzo[g]isoquinoline-5,10-dione (S1)

[0064] Weigh S2 (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 S2. 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 S2. 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 residue was washed with a small amount of acetone or methanol and dried to obtain S1 (0.73 g, 81%) as a yellow solid. 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.

[0065] Example 6

[0066] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-trifluoromethanesulfonate (6)

[0067] S1 (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 obtain compound 6 (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.

[0068] Example 7

[0069] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carbonitrile (S3)

[0070] Intermediate 6 (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 reaction 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. The solid, crude S3, was filtered. The filtrate was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (50 mL × 3), then with saturated brine, and finally dried over anhydrous sodium sulfate. The ethyl acetate was removed by rotary evaporation to obtain another portion of crude product. The crude product was purified by slurrying with appropriate amounts of dichloromethane and methanol to obtain a yellow-green solid, S3 (200 mg, 85%). 1 H-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.

[0071] Example 8

[0072] Preparation of 8-ethynylbenzo[g]isoquinoline-5,10-dione (S4)

[0073] The intermediate 6 (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 2-3 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 S4a.

[0074] 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 S4. The crude product was purified by silica gel column chromatography to obtain S4 (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); 13 C-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.

[0075] Example 9

[0076] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)formamide (S5)

[0077] Intermediate 6 (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, and the layers were separated. The aqueous layer was extracted with dichloromethane (5 mL x 3). The organic layer was washed with sodium hydroxide (1 M) 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 S5 (26 mg, 52%) as a yellow solid. 1H-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.

[0078] Example 10

[0079] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)acetamide (S6)

[0080] The preparation of compound S6 was the same as that of compound S5 in Example 9, except that formamide was replaced with acetamide (118 mg, 2.0 mmol, 2.0 equiv). After purification, a yellow solid, S6 (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.

[0081] Example 11

[0082] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzamide (S7)

[0083] The preparation of compound S7 was the same as that of compound S5 in Example 9, except that formamide was replaced with benzamide (48 mg, 0.4 mmol, 2.0 equiv). After purification, a yellow solid, S7 (61 mg, 93%), was obtained. 1H-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.

[0084] Example 12

[0085] Preparation of 4-cyano-N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzamide (S8)

[0086] The preparation of compound S8 was the same as that of compound S5 in Example 9, except that formamide was replaced with 4-cyanobenzamide (58 mg, 0.4 mmol, 2.0 equiv). After purification, a white solid, S8 (53 mg, 75%), was obtained. 1 H-NMR (400MHz, DMSO-d6) δ11.12 (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.

[0087] Example 13

[0088] Preparation of N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)-4-trifluoromethylbenzamide (S9)

[0089] The preparation of compound S9 was the same as that of compound S5 in Example 9, except that formamide was replaced with 4-trifluoromethylbenzamide (74 mg, 0.4 mmol, 2.0 equiv). After purification, a white solid, S9 (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); 13 C-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.

[0090] Example 14

[0091] Preparation of (E)-N-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)-3-(pyridin-3-yl)acrylamide (S10)

[0092] The preparation of compound S10 was the same as that of compound S5 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 S10 (62 mg, 87%) as a yellow solid. 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); 13C-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.

[0093] Example 15

[0094] Preparation of 8-((2-aminoethyl)amino)benzo[g]isoquinoline-5,10-dione (S11)

[0095] Intermediate 6 (71 mg, 0.2 mmol) prepared in Example 6 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 obtain crude product S11a.

[0096] S11a 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, 1M aqueous sodium hydroxide was added to adjust the pH to 13. 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 S11 (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); 13C-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.

[0097] Example 16

[0098] Preparation of 8-anilinobenzo[g]isoquinoline-5,10-dione (S12)

[0099] Intermediate 6 (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(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 S12 (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.

[0100] Example 17

[0101] Preparation of 8-(piperidin-1-yl)benzo[g]isoquinoline-5,10-dione (S13)

[0102] The preparation of compound S13 was the same as that of compound S12 in Example 16, except that aniline was replaced with piperidine (20 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S13 (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); 13 C-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.

[0103] Example 18

[0104] Preparation of 8-(4-(2-hydroxyethyl)piperidin-1-yl)benzo[g]isoquinoline-5,10-dione (S14)

[0105] The preparation of compound S14 was the same as that of compound S12 in Example 16, except that aniline was replaced with 4-piperidineethanol (31 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S14 (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); 13C-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.

[0106] Example 19

[0107] Preparation of 8-(4-morpholinopiperidin-1-yl)benzo[g]isoquinoline-5,10-dione (S15)

[0108] The preparation of compound S15 was the same as that of compound S12 in Example 16, except that aniline was replaced with 4-morpholinopiperidine (41 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S15 (31 mg, 41%), was obtained. 1 H-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.

[0109] Example 20

[0110] Preparation of 8-morpholinobenzo[g]isoquinoline-5,10-dione (S16)

[0111] The preparation of compound S16 was the same as that of compound S12 in Example 16, except that aniline was replaced with morpholine (21 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S16 (21 mg, 36%), was obtained. 1H-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.

[0112] Example 21

[0113] Preparation of (S)-8-(3-methylmorpholinyl)benzo[g]isoquinoline-5,10-dione (S17)

[0114] The preparation of compound S17 was the same as that of compound S12 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, S17 (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.

[0115] Example 22

[0116] Preparation of 8-(4-methylpiperazin-1-yl)benzo[g]isoquinoline-5,10-dione (S18)

[0117] The preparation of compound S18 was the same as that of compound S12 in Example 16, except that aniline was replaced with 4-methylpiperazine (24 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S18 (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); 13 C-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.

[0118] Example 23

[0119] Preparation of 8-(4-phenylpiperazin-1-yl)benzo[g]isoquinoline-5,10-dione (S19)

[0120] The preparation of compound S19 was the same as that of compound S12 in Example 16, except that aniline was replaced with N-phenylpiperazine (39 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S19 (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); 13C-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.

[0121] Example 24

[0122] Preparation of 4-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)piperazine-1-carboxaldehyde (S20)

[0123] The preparation of compound S20 was the same as that of compound S12 in Example 16, except that aniline was replaced with 1-formylpiperazine (27 mg, 0.24 mmol, 1.2 equiv). After purification, a red solid, S20 (38 mg, 59%), was obtained. 1 H-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.

[0124] Example 25

[0125] Preparation of 8-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzo[g]isoquinoline-5,10-dione (S21)

[0126] The preparation of compound S21 was the same as that of compound S12 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, S21 (41 mg, 64%), was obtained. 1H-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.

[0127] Example 26

[0128] Preparation of 8-(4-methoxyphenyl)benzo[g]isoquinoline-5,10-dione (S22)

[0129] Intermediate 6 (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 and reacted 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 S22 (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); 13C-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.

[0130] Example 27

[0131] Preparation of 8-(3,4-dimethoxyphenyl)benzo[g]isoquinoline-5,10-dione (S23)

[0132] The preparation of compound S23 was the same as that of compound S22 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, S24 (51 mg, 74%), was obtained. 1 H-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.

[0133] Example 28

[0134] Preparation of 8-(4-morpholinylphenyl)benzo[g]isoquinoline-5,10-dione (S24)

[0135] The preparation of compound S24 was the same as that of compound S22 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, S24 (44 mg, 59%), was obtained. 1H-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.

[0136] Example 29

[0137] Preparation of 8-([1,1'-biphenyl]-4-yl)benzo[g]isoquinoline-5,10-dione (S25)

[0138] The preparation of compound S25 was the same as that of compound S22 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, S25 (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.

[0139] Example 30

[0140] Preparation of 8-(4-fluorophenyl)benzo[g]isoquinoline-5,10-dione (S26)

[0141] The preparation of compound S26 was the same as that of compound S22 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, S26 (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); 13 C-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).

[0142] Example 31

[0143] Preparation of 4-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzonitrile (S27)

[0144] The preparation of compound S27 was the same as that of compound S22 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, S27 (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); 13C-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.

[0145] Example 32

[0146] Preparation of 2-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)benzonitrile (S28)

[0147] The preparation of compound S28 was the same as that of compound S22 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, S28 (31 mg, 50%), was obtained. 1 H-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.

[0148] Example 33

[0149] Preparation of 8-(4-trifluoromethylphenyl)benzo[g]isoquinoline-5,10-dione (S29)

[0150] The preparation of compound S29 was the same as that of compound S22 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, S29 (40 mg, 57%), was obtained. 1H-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;.

[0151] Example 34

[0152] Preparation of 8-(3,4-bis(trifluoromethyl)phenyl)benzo[g]isoquinoline-5,10-dione (S30)

[0153] The preparation of compound S30 was the same as that of compound S22 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, S30 (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.

[0154] Example 35

[0155] Preparation of (E)-8-phenylvinylbenzo[g]isoquinoline-5,10-dione (S31)

[0156] The preparation of compound S31 was the same as that of compound S22 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, S31 (27 mg, 43%), was obtained. 1 H-NMR (400MHz, CDCl3) δ9.58 (s, 1H), 9.1 1(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), 7.9 2 (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); 13 C-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.

[0157] Reaction Scheme II of Formula I compound:

[0158] Example 36

[0159] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carboxamide (S32)

[0160] Intermediate S3 (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 allowed to react 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 S32 (22 mg, 44%) as a white solid. 1H-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.

[0161] Example 37

[0162] Preparation of N-methyl-5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carboxamide (S33)

[0163] Intermediate S3 (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 allowed to react 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 7, which did not require further purification.

[0164] The intermediate 7 obtained above was placed in a Schlenk reaction tube equipped with a magnetic stirrer. Methylamine hydrochloride (27 mg, 0.4 mmol) and HATU (167 mg, 0.44 mmol) were added, and 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 S33 (18 mg, 34% over two steps) as a white solid. 1H-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.

[0165] Example 38

[0166] Preparation of 5,10-dioxo-5,10-dihydrobenzo[g]isoquinoline-8-carboxylic acid methyl ester (S34)

[0167] Intermediate S3 (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 HCl (2N) was added to slowly adjust the pH to approximately 2. A brown solid precipitated, which was filtered to obtain Intermediate 7, which did not require further purification.

[0168] 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, the layers were separated, and 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 S34 (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); 13C-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.

[0169] Reaction Scheme III of Formula I compound:

[0170] Example 39

[0171] Preparation of 8-aminobenzo[g]isoquinoline-5,10-dione (S35)

[0172] Intermediate S6 (266 mg, 1.0 mmol) prepared in Example 10 was weighed and placed in a 25 mL single-necked flask 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 S35 (200 mg, 89%) as a red solid. 1 H-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.

[0173] Example 40

[0174] Preparation of (E)-N'-(5,10-dioxo-5,10-dihydrobenzo[g]isoquinolin-8-yl)-N,N-dimethylformamidine (S36)

[0175] Intermediate S35 (45 mg, 0.2 mmol) prepared in Example 39 was weighed and placed in a Schlenk reaction tube equipped with a magnetic stirrer. The atmosphere was replaced with argon 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 S36 (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.

[0176] Example 41

[0177] Preparation of 8-fluorobenzo[g]isoquinoline-5,10-dione (S37)

[0178] Intermediate S35 (45 mg, 0.2 mmol) prepared in Example 39 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. A large amount of yellow-brown solid precipitated. Filtration afforded Intermediate 8.

[0179] 8 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 S37 (17 mg, 37% over two steps) as a white solid. 1H-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).

[0180] Example 42

[0181] Preparation of 8-chlorobenzo[g]isoquinoline-5,10-dione (S38)

[0182] Intermediate S35 (45 mg, 0.2 mmol) prepared in Example 39 was weighed and placed in a 25 mL single-necked flask with a magnetic stirrer. 37% HCl (1 mL) was added, the mixture was cooled to 0°C, and 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 CuCl (37 mg, 0.3 mmol) was added dropwise and reacted at 55°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 (14 mg, 29% over two steps) as a white solid. 1 H-NMR (400MHz, CDCl3) δ9.60 (s, 1H), 9.17 (d, J=4.8Hz, 1H), 8.35-8.28 (m, 2H), 8.11 (d, J=4.8Hz, 1H), 7.84 (dd, J=8.0, 2.0Hz, 1H); 13 C-NMR (101MHz, CDCl3) δ181.7, 181.6, 155.9, 149.9, 142.3, 138.3, 134.8, 134.2, 131.3, 129.3, 127.4, 126.0, 119.2.

[0183] Example 43

[0184] Preparation of 8-bromobenzo[g]isoquinoline-5,10-dione (S39)

[0185] Intermediate S35 (45 mg, 0.2 mmol) prepared in Example 39 was weighed and placed in a 25 mL single-necked flask with a magnetic stirrer. 1 mL of 48% HBr was added and 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 S39 (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.

[0186] Example 44

[0187] Preparation of 8-(1-methyl-1H-pyrazol-4-yl)benzo[g]isoquinoline-5,10-dione (S40)

[0188] Intermediate S39 (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 S40 (32 mg, 55%) as a yellow solid.1 H-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.

[0189] Example 45

[0190] Preparation of 8-(1H-1,2,3-triazol-1-yl)benzo[g]isoquinoline-5,10-dione (S41)

[0191] Intermediate S35 (45 mg, 0.2 mmol) prepared in Example 39 was weighed and placed in a 25 mL single-necked flask with a magnetic stirrer. 1 mL of 37% aqueous HCl was added, cooled to 0°C, and 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 1-2 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 11 without further purification.

[0192] 11 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 S41a.

[0193] S41a 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 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 S41 (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.

[0194] Reaction Scheme IV of the compound of formula I:

[0195] Example 46

[0196] Preparation of 7-aminoisoquinoline-5,8-dione (14)

[0197] 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 13. No purification is required and the next step is directly performed.

[0198] 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 14 (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.

[0199] Example 47

[0200] Preparation of 7-amino-6-bromoisoquinoline-5,8-dione (15)

[0201] Intermediate 14 (0.35 g, 2 mmol) prepared in Example 47 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 15 (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.

[0202] Example 48

[0203] Preparation of N-(6-bromo-5,8-dioxo-5,8-dihydroisoquinolin-7-yl)acetamide (16)

[0204] The intermediate 15 (0.25 g, 1 mmol) prepared in Example 48 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 to 5 drops of concentrated sulfuric acid were added. Compound 15 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 16 (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.

[0205] Example 49

[0206] Preparation of N-(6-bromo-5,8-dioxo-5,8-dihydroisoquinolin-7-yl)acetamide (17a)

[0207] Compound 16 (0.29 g, 1 mmol) prepared in Example 49 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 17a (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.

[0208] Example 50

[0209] Preparation of 1,2-dimethyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S42)

[0210] Compound 17a (0.12 g, 0.5 mmol) prepared in Example 49 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 S42 (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.

[0211] Example 51

[0212] Preparation of 1-butyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S43)

[0213] The preparation of compound S43 was the same as that of compound S42, except that methylamine hydrochloride was replaced with butylamine hydrochloride (0.22 g, 2 mmol). After purification, a yellow solid, S43 (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.

[0214] Example 52

[0215] Preparation of 1-isopropyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S44)

[0216] The preparation of compound S44 was the same as that of compound S42, except that methylamine hydrochloride was replaced with isopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S44 (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 CNMR (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.

[0217] Example 53

[0218] Preparation of 1-cyclopropyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S45)

[0219] The preparation of compound S45 was the same as that of compound S42, except that methylamine hydrochloride was replaced with cyclopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S45 (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.

[0220] Example 54

[0221] Preparation of 1-cyclopentyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S46)

[0222] The preparation of compound S46 was the same as that of compound S42, except that methylamine hydrochloride was replaced with cyclopentylamine hydrochloride (0.24 g, 2 mmol). After purification, a yellow solid, S46 (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.

[0223] Example 55

[0224] Preparation of 1-cyclohexyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S47)

[0225] The preparation of compound S47 was the same as that of compound S42, except that methylamine hydrochloride was replaced with cyclohexylamine hydrochloride (0.27 g, 2 mmol). After purification, a yellow solid, S47 (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).

[0226] Example 56

[0227] Preparation of methyl 3-(2-methyl-4,9-dioxo-4,9-dihydro-1H-imidazo[4,5-g]isoquinolin-1-yl)propanoate (S48)

[0228] The preparation of compound S48 was the same as that of compound S42, except that methylamine hydrochloride was replaced with methyl 3-aminopropionate hydrochloride (0.28 g, 2 mmol). After purification, a yellow solid, S48 (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.

[0229] Example 57

[0230] Preparation of 2-methyl-1-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S49)

[0231] The preparation of compound S49 was the same as that of compound S42, except that methylamine hydrochloride was replaced with aniline hydrochloride (0.26 g, 2 mmol). After purification, a yellow solid, S49 (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.

[0232] Example 58

[0233] Preparation of 1-(4-methoxyphenyl)-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S50)

[0234] The preparation of compound S50 was the same as that of compound S42, except that methylamine hydrochloride was replaced with p-anisidine hydrochloride (0.32 g, 2 mmol). After purification, a yellow solid, S50 (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.

[0235] Example 59

[0236] Preparation of 1-benzyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S51)

[0237] The preparation of compound S51 was the same as that of compound S42, except that methylamine hydrochloride was replaced with benzylamine hydrochloride (0.29 g, 2 mmol). After purification, a yellow solid, S51 (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.

[0238] Example 60

[0239] Preparation of 1-(3-hydroxypropyl)-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S52)

[0240] S48 (0.03 g, 0.1 mmol) prepared in Example 56 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 S52 (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.

[0241] Example 61

[0242] Preparation of 1-(2-dimethylamino)ethyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S53)

[0243] The preparation of compound S53 was the same as that of compound S42, except that methylamine hydrochloride was replaced with N,N-dimethylethylenediamine hydrochloride (0.32 g, 2 mmol). After purification, a yellow solid, S53 (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, CD3SOCD3) 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.

[0244] Example 62

[0245] Preparation of 1-(3-dimethylamino)propyl-2-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S54)

[0246] The preparation of compound S54 was the same as that of compound S42, except that methylamine hydrochloride was replaced with N,N-dimethylpropylenediamine hydrochloride (0.35 g, 2 mmol). After purification, a yellow solid, S54 (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.

[0247] Example 63

[0248] Preparation of 2-methyl-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S55)

[0249] The preparation of compound S55 was the same as that of compound S42, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)piperidine hydrochloride (0.4 g, 2 mmol). After purification, a yellow solid, S55 (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, CD3SOCD3) δ178.69,174.89,156.07,155.20,147.90,142.67,138. 73,132.99,125.64,119.02,58.46,54.37(×2),43.67,26.14(×2),24.29,12.72.

[0250] Example 64

[0251] Preparation of 2-methyl-1-(3-(piperidin-1-yl)propyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S56)

[0252] The preparation of compound S56 was the same as that of compound S42, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)piperidine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S56 (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.

[0253] Example 65

[0254] Preparation of 2-methyl-1-(2-morpholinoethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S57)

[0255] The preparation of compound S57 was the same as that of compound S42, except that methylamine hydrochloride was replaced with N-(2-aminoethyl)morpholine hydrochloride (0.41 g, 2 mmol). After purification, a yellow solid, S57 (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.

[0256] Example 66

[0257] Preparation of 2-methyl-1-(3-morpholinopropyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S58)

[0258] The preparation of compound S58 was the same as that of compound S42, except that methylamine hydrochloride was replaced with 1-(3-morpholinopropyl) hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S58 (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.

[0259] Example 67

[0260] Preparation of 2-methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S59)

[0261] The preparation of compound S59 was the same as that of compound S42, except that methylamine hydrochloride was replaced with 4-methyl-1-piperazineethylamine hydrochloride (0.5 g, 2 mmol). After purification, a yellow solid, S59 (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.

[0262] Example 68

[0263] Preparation of 2-methyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S60)

[0264] The preparation of compound S60 was the same as that of compound S42, except that methylamine hydrochloride was replaced with 4-methyl-1-piperazinepropylamine hydrochloride (0.53 g, 2 mmol). After purification, a yellow solid, S60 (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); 13CNMR(101MHz,CDCl3)δ178.43,174.80,155.51,154.45,148.80,143.34,138.80,13 2.13,125.21,118.69,54.87(×2),54.57,52.49,45.65,44.18,27.02,21.41,13.46.

[0265] Example 69

[0266] Preparation of 2-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S61)

[0267] The preparation of compound S61 was the same as that of compound S42, except that methylamine hydrochloride was replaced with 1-(aminoethyl)pyrrolidine hydrochloride (0.37 g, 2 mmol). After purification, a yellow solid, S61 (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.

[0268] Example 70

[0269] Preparation of 2-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S62)

[0270] The preparation of compound S62 was the same as that of compound S42, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)pyrrolidine hydrochloride (0.4 g, 2 mmol). After purification, a yellow solid, S62 (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.

[0271] Reaction Scheme V of Compound of Formula I:

[0272] Example 71

[0273] Preparation of 2-isopropyl-1-methyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S63)

[0274] The intermediate 15 (0.25 g, 1 mmol) prepared in Example 47 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 to 5 drops of concentrated sulfuric acid were added. Compound 15 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 18 (0.27 g, 85.2%).

[0275] Compound 18 (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 19 (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).

[0276] Compound 19 (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 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 S63 (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).

[0277] Example 72

[0278] Preparation of 1-butyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S64)

[0279] The preparation of compound S64 was the same as that of compound S63, except that methylamine hydrochloride was replaced with n-butylamine hydrochloride (0.22 g, 2 mmol). After purification, a yellow solid, S64 (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.

[0280] Example 73

[0281] Preparation of 1-cyclopropyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S65)

[0282] The preparation of compound S65 was the same as that of compound S63, except that methylamine hydrochloride was replaced with cyclopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S65 (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).

[0283] Example 74

[0284] Preparation of 1-cyclopentyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S66)

[0285] The preparation of compound S66 was the same as that of compound S63, except that methylamine hydrochloride was replaced with cyclopentylamine hydrochloride (0.24 g, 2 mmol). After purification, a yellow solid, S66 (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).

[0286] Example 75

[0287] Preparation of 1-cyclohexyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S67)

[0288] The preparation of compound S67 was the same as that of compound S63, except that methylamine hydrochloride was replaced with cyclohexylamine hydrochloride (0.27 g, 2 mmol). After purification, a yellow solid, S67 (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).

[0289] Example 76

[0290] Preparation of methyl 3-(2-isopropyl-4,9-dioxo-4,9-dihydro-1H-imidazo[4,5-g]isoquinolin-1-yl)propanoate (S68)

[0291] The preparation of compound S68 was the same as that of compound S63, except that methylamine hydrochloride was replaced with methyl 3-aminopropionate hydrochloride (0.28 g, 2 mmol). After purification, a yellow solid, S68 (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).

[0292] Example 77

[0293] Preparation of 2-isopropyl-1-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S69)

[0294] The preparation of compound S69 was the same as that of compound S63, except that methylamine hydrochloride was replaced with isopropylamine hydrochloride (0.19 g, 2 mmol). After purification, a yellow solid, S69 (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).

[0295] Example 78

[0296] Preparation of 2-isopropyl-1-(4-methoxyphenyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S70)

[0297] The preparation of compound S70 was the same as that of compound S63, except that methylamine hydrochloride was replaced with p-anisidine hydrochloride (0.32 g, 2 mmol). After purification, a yellow solid, S70 (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).

[0298] Example 79

[0299] Preparation of 1-benzyl-2-isopropyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S71)

[0300] The preparation of compound S71 was the same as that of compound S63, except that methylamine hydrochloride was replaced with benzylamine hydrochloride (0.29 g, 2 mmol). After purification, a yellow solid, S71 (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).

[0301] Example 80

[0302] Preparation of 2-isopropyl-1-(2-(piperidin-1-yl)ethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S72)

[0303] The preparation of compound S72 was the same as that of compound S63, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)piperidine hydrochloride (0.4 g, 2 mmol). After purification, a yellow solid, S72 (83 mg, 47%), was obtained. 1 H NMR (400MHz, CD3SOCD3) 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,CD3SOCD3)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.

[0304] Example 81

[0305] Preparation of 2-isopropyl-1-(3-(piperidin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S73)

[0306] The preparation of compound S73 was the same as that of compound S63, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)piperidine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S73 (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.

[0307] Example 82

[0308] Preparation of 2-isopropyl-1-(2-morpholinoethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S74)

[0309] The preparation of compound S74 was the same as that of compound S63, except that methylamine hydrochloride was replaced with N-(2-aminoethyl)morpholine hydrochloride (0.41 g, 2 mmol). After purification, a yellow solid, S74 (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).

[0310] Example 83

[0311] Preparation of 2-isopropyl-1-(3-morpholinopropyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S75)

[0312] The preparation of compound S75 was the same as that of compound S63, except that methylamine hydrochloride was replaced with N-(3-aminopropyl)morpholine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S75 (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).

[0313] Example 84

[0314] Preparation of 2-isopropyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S76)

[0315] The preparation of compound S76 was the same as that of compound S63, except that methylamine hydrochloride was replaced with 3-methyl-1-piperazineethylamine hydrochloride (0.43 g, 2 mmol). After purification, a yellow solid, S76 (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).

[0316] Example 85

[0317] Preparation of 2-isopropyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S77)

[0318] The preparation of compound S77 was the same as that of compound S63, except that methylamine hydrochloride was replaced with 3-methyl-1-piperazinepropylamine hydrochloride (0.53 g, 2 mmol). After purification, a yellow solid, S77 (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).

[0319] Example 86

[0320] Preparation of 2-isopropyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S78)

[0321] The preparation of compound S78 was the same as that of compound S63, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)pyrrolidine hydrochloride (0.37 g, 2 mmol). After purification, a yellow solid, S78 (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.

[0322] Example 87

[0323] Preparation of 2-isopropyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S79)

[0324] The preparation of compound S79 was the same as that of compound S63, except that methylamine hydrochloride was replaced with 1-(3-aminopropyl)pyrrolidine hydrochloride (0.40 g, 2 mmol). After purification, a yellow solid, S79 (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.

[0325] Reaction Scheme VI of Formula I compound:

[0326] Example 88

[0327] Preparation of tert-butyl (6-bromo-5,8-dioxo-5,8-dihydroisoquinolin-7-yl)carbamate (20)

[0328] Intermediate 15 (0.25 g, 1 mmol) prepared in Example 48 and di-tert-butyl dicarbonate (0.44 g, 2 mmol) were weighed and placed in 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 and extracted. 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 20, with a yield of 69.0%. 1 HNMR (400MHz, CDCl3) δ9.48 (s, 1H), 9.08 (d, J = 4.9Hz, 1H), 7.97 (d, J = 4.9Hz, 1H), 1.41 (s, 9H).

[0329] Example 89

[0330] Preparation of 1-methyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S80)

[0331] Intermediate 20 (0.35 g, 1 mmol) prepared in Example 91 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 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 21a (0.14 g, 45%). Compound 21a (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 22a, which was carried on to the next step without purification.

[0332] Compound 22a (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 23a (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 S80 was prepared under the same conditions as compound S42 in Example 51 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.

[0333] Example 90

[0334] Preparation of 1-isopropyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S81)

[0335] The preparation of compound S81 was the same as that of compound S80, except that methylamine hydrochloride was replaced with isopropylamine hydrochloride (0.19 g, 2 mmol). After purification, yellow solid S81 (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.

[0336] Example 91

[0337] Preparation of 1-cyclopropyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S82)

[0338] The preparation of compound S82 was the same as that of compound S80, except that methylamine hydrochloride was replaced with cyclopropylamine hydrochloride (0.19 g, 2 mmol). After purification, yellow solid S82 (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.

[0339] Example 92

[0340] Preparation of 1-benzyl-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S83)

[0341] The preparation of compound S83 was the same as that of compound S80, except that methylamine hydrochloride was replaced with benzylamine hydrochloride (0.29 g, 2 mmol). After purification, yellow solid S83 (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 CNMR(101MHz, CDCl3)δ178.62,175.03,156.44,155.65,148.95,143.95,138.82,135.68,132.70,1 31.13,129.51(×2),129.18(×2),129.03(×2),128.28,127.84,126.08(×2),125.36,118.81,49.98.

[0342] Example 93

[0343] Preparation of 1-(2-(dimethylamino)ethyl)-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S84)

[0344] The preparation of compound S84 was the same as that of compound S80, except that methylamine hydrochloride was replaced with N,N-dimethylethylenediamine hydrochloride (0.32 g, 2 mmol). After purification, yellow solid S84 (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.

[0345] Example 94

[0346] Preparation of 2-phenyl-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S85)

[0347] The preparation of compound S85 was the same as that of compound S80, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)piperidine hydrochloride (0.4 g, 2 mmol). After purification, yellow solid S85 (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.

[0348] Example 95

[0349] Preparation of 1-(2-morpholinoethyl)-2-phenyl-1H-imidazole[4,5-g]isoquinoline-4,9-dione (S86)

[0350] The preparation of compound S86 was the same as that of compound S80, except that methylamine hydrochloride was replaced with N-(2-aminoethyl)morpholine hydrochloride (0.41 g, 2 mmol). After purification, yellow solid S86 (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.

[0351] Example 96

[0352] Preparation of 1-(2-(4-methylpiperazin-1-yl)ethyl)-2-phenyl-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S87)

[0353] The preparation of compound S87 was the same as that of compound S80, except that methylamine hydrochloride was replaced with N-methyl-4-(2-aminoethyl)piperidine hydrochloride (0.51 g, 2 mmol). After purification, yellow solid S87 (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.

[0354] Example 97

[0355] Preparation of 2-phenyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-g]isoquinoline-4,9-dione (S88)

[0356] The preparation of compound S88 was the same as that of compound S80, except that methylamine hydrochloride was replaced with 1-(2-aminoethyl)pyrrolidine hydrochloride (0.37 g, 2 mmol). After purification, yellow solid S88 (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).

[0357] Example 98

[0358] Evaluation of anti-Helicobacter pylori activity of compounds S1-S88

[0359] (1) Helicobacter pylori strain information: standard strain G27; levofloxacin, clarithromycin and metronidazole multidrug-resistant strain (Hp129).

[0360] (2) Culture medium and main reagents and consumables: Columbia medium, brain heart infusion medium, serum; EP tubes, Tip heads, centrifuge tubes, polyethylene 96-well plates, etc.

[0361] (3) Experimental method: Microdilution method was used to detect the MIC of drugs against Helicobacter pylori (100 μL system); (a) MIC plate preparation: 173.6 μL of culture medium was added to the first well, followed by 6.4 μL of antimicrobial drug, and the mixture was diluted to the seventh well in a doubling ratio; no drug was added to the eighth well, and 90 μL of culture medium was retained as a control. (b) Bacterial suspension preparation: Helicobacter pylori growing in the logarithmic phase on the solid plate was prepared into a bacterial suspension using BHI medium, and the concentration was adjusted to OD600 of 0.3 (1×10 8 CFU / mL), diluted 10 times, 1×10 7 CFU / mL, set aside. (c) Inoculation: Take 10 μL of bacterial solution and add it to wells 1-8 (the bacterial solution concentration in each well is about 1.0×10 6 CFU / mL). The results were determined after 72 hours of incubation. The drug concentrations in wells 1 to 7 were 8, 4, 2, 1, 0.5, 0.25, and 0.125 μg / mL, respectively.

[0362] (4) Result judgment: The lowest drug concentration that completely inhibits bacterial growth in the small well is the MIC. The test is meaningful only when bacteria in the 8th well of the negative control well (i.e., without antibiotics) grow significantly. When a single jump well appears in the microdilution method, the highest drug concentration that inhibits bacterial growth should be recorded. If multiple jump wells appear, the result should not be reported and the test should be repeated. Repeat the test three times for each drug. If the MIC is less than 0.125μg / mL, reset the concentration gradient and repeat the test three times until the MIC is measured.

[0363] The experimental results of MIC (μg / mL) of compounds S1-S89 against Helicobacter pylori are shown in the following table:

[0364] As shown in the table above, the synthesized compounds S1-S88 generally exhibited good anti-H. pylori activity, with MIC values ​​ranging from 0.016 to 8 μg / mL, except for S30. The most active compound was S3, with an MIC of 0.016 μg / mL. Furthermore, S6, S32-S34, and S40 exhibited excellent anti-H. pylori activity.

[0365] 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. Use of the compound shown in Formula I in the preparation of an anti-Helicobacter pylori drug, characterized in that, The compound also includes its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; The formula I is the structural formula of the compound, wherein, X is independently selected from Y is independently selected from N, CH; R1 is independently selected from hydroxy, alkoxy, cyano, alkoxycarbonylamino, alkylcarbamoyl, alkanoyloxy, carboxy; substituted or unsubstituted 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, alkanoyloxy, carboxy; 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, carboxy, aldehyde group, ester group, aryl, heterocyclic group, aroyl, cyanoaroyl, haloalkylaroyl, heterocyclic group alkenyl acyl, alkyl monosubstituted acyl, alkyl disubstituted acyl, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclic group carbonyloxy, alkoxycarbonyl, cycloalkoxycarbonyl, heterocyclic oxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heterocyclic group carbonyloxyamino, aminocarbonyl, alkoxymethylamide group, alkylthio, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, carboxyalkylmethylamide group.

2. The application according to claim 1, wherein The structural formula of the said compound is selected from or 3. The application according to claim 1, wherein In the said compound, the R1 is independently selected from hydroxy, alkoxy, cyano, alkanamido, alkanoylamino, alkanoyloxy, alkoxycarbonyl, carboxyl; 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; 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 application according to claim 3, wherein In the said compound, the R1 is independently selected from, hydroxyl, alkoxy, cyano, alkanamido, alkanoylamino, alkanoyloxy, alkoxycarbonyl, carboxyl; substituted or unsubstituted 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, alkanoyl amino, 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, sulfo group, phospho group, C6-C 10 aryl, C3-C6 heterocyclic group, C1-C6 alkyl mono-substituted amino group, C1-C6 alkyl bis-substituted 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 heterocyclicoxycarbonyl 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 application according to claim 4, wherein In the said compound, the R1 is independently selected from hydroxy, alkoxy, cyano, alkanamido, alkanimidoyl, alkanoyloxy, alkoxycarbonyl, carboxyl; substituted or unsubstituted non-chloro 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, alkanoylamino, 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, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxy, ester, aminocarbonyl, alkylthio, hydroxyalkoxy, sugar residue, sulfo, phospho, C6-C 10 aryl, C3-C6 heterocyclic group, C1-C3 alkyl monosubstituted amino, C1-C3 alkyl disubstituted amino, C1-C3 alkoxy, C1-C3 alkylcarbonyloxy, C3-C3 cycloalkylcarbonyloxy, C3-C6 heterocycliccarbonyloxy, C1-C6 alkoxycarbonyl, C1-C6 cycloalkoxycarbonyl, C3-C6 heterocycloxycarbonyl, C1-C6 alkylcarbonylamino, C3-C6 cycloalkylcarbonylamino, C3-C6 heterocycliccarbonylamino, C1-C6 alkoxymethanamide, polyhydroxy C1-C6 alkoxycarbonyl, carboxy C1-C6 alkoxy, carboxy C1-C6 alkylformyloxy.

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

7. The application according to any one of claims 1-5, characterized in that, The dosage forms of the drug include injections, tablets, capsules, sustained-release agents, powders, liposomes, granules, ointments, creams, emulsions, suspensions, lyophilized products, sprays, suppositories, aerosols, pills or oral liquids.

8. A pharmaceutical composition against Helicobacter pylori, characterized in that, Comprising the compound of formula I or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and one or more pharmaceutically acceptable carriers, wherein the compound of formula I is the compound described in any one of claims 1-6.

9. The pharmaceutical composition according to claim 8, wherein The pharmaceutically acceptable carrier includes at least one of a diluent, an excipient, a filler, a binder, a wetting agent, a lubricant, a disintegrant, an absorption promoter, a surfactant, an adsorption carrier, and a flavoring agent, a sweetening agent.

10. Use of the pharmaceutical composition according to any one of claims 8-9 in the preparation of an anti-Helicobacter pylori drug.

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