2(1H)-quinoxalinone compound, pharmaceutical composition and application thereof

Abstract

The present invention discloses a 2(1H)-quinoxalinone compound, a pharmaceutical composition thereof, and its application, the structure of which is shown in Formula I. The compound exhibits significant inhibitory activity against the MAT2A protein, effectively inhibiting the proliferation of tumor cells lacking the MTAP gene, and exhibiting good selectivity for MTAP wild-type cells. The compound can be used as a highly effective and selective small molecule MAT2A inhibitor for the treatment of cancer, particularly cancers associated with MTAP gene loss.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a 2(1H)-quinoxalinone compound, a pharmaceutical composition and an application thereof. The compound has methionine adenosyltransferase 2A inhibitory activity. Background Art

[0002] Methionine adenosyltransferase 2A (MAT2A), also known as S-adenosylmethionine synthetase, catalyzes the reaction of methionine with ATP to produce S-adenosylmethionine (SAM). SAM is an important intermediate metabolite involved in three key metabolic pathways: transmethylation, transsulfuration, and polyamine synthesis. Therefore, the homeostasis of intracellular SAM is crucial for cell growth, survival, and differentiation.

[0003] Studies have reported that MAT2A is highly expressed in a variety of tumor cells such as colon cancer and liver cancer, and silencing the MAT2A gene can induce tumor cell death (Maria L, T. et al. Polyamine and methionineadenosyltransferase 2A crosstalk in human colon and liver cancer. Experimental Cell Research 2013, 319, 1902-1911). In addition, Majon et al. found that tumor cells with methylthioadenosine phosphorylase (Methylthioadenosine phosphorylase, MTAP) gene deletion were sensitive to MAT2A inhibitors (Majon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A / PRMT5 / RIOK1 axis. Cell Reports 2016, 15, 574-587). MTAP is a key metabolic enzyme in the methionine compensation pathway and is crucial for the homeostasis of intracellular methionine and purine. It is widely expressed in normal tissue cells, but is often deleted in tumor cells. MTAP deficiency promotes tumor proliferation, invasion, and metastasis and is positively correlated with tumor progression and poor prognosis. MTAP deficiency impairs methylthioadenosine metabolism, leading to its accumulation. This increases cellular reliance on SAM production and ultimately enhances cellular sensitivity to MAT2A inhibitors. Therefore, MAT2A inhibitors offer a promising therapeutic approach for cancer patients with MTAP deficiency.

[0004] At present, several patent applications have disclosed MAT2A inhibitors. For example, WO2020123395A1 discloses a series of 2-oxoquinazoline derivatives as MAT2A inhibitors; CN109890822A discloses a pyrazolopyrimidinone MAT2A inhibitor; CN115433211A discloses a pyrazinopyridinone MAT2A inhibitor.

[0005] However, most of the MAT2A inhibitors reported at home and abroad are in the preclinical or clinical phase I research stage, and no MAT2A inhibitors are yet on the market. Therefore, the development of new MAT2A inhibitors has great practical significance and potential application prospects. Summary of the Invention

[0006] Objectives of the invention: One of the objectives of the present invention is to provide a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, metabolite or prodrug thereof:

[0007]

[0008] in,

[0009] X 1 、X 2 、X 3 、X 4 Each independently selected from N or CR a ;

[0010] R a Not present, or selected from H, C1-C6 alkyl;

[0011] R 1 Selected from C6-C 10 Aryl, C3-C6 cycloalkyl, 5-6 membered heterocyclic group or 5-10 membered heteroaryl; wherein, C6-C 10 Aryl, C3-C6 cycloalkyl, 5-6 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted by one or more R 1a Replacement, R 1a is selected from halogen, cyano, hydroxy, C2-C3 alkynyl, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy;

[0012] Among them, R 1a unsubstituted or optionally substituted with one or more R 1b Replacement, R 1b is selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano or hydroxy;

[0013] Ring A and Ring B are each independently selected from an aryl group or a heteroaryl group, wherein Ring A is optionally substituted by 1-5 R 2Substitution; Ring B is optionally substituted with 1-3 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, halogenated C1-C3 alkyl or hydroxyl;

[0014] R 2 is selected from H, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy is optionally substituted with 1-3 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, halogenated C1-C3 alkyl or hydroxy;

[0015] R 3 is selected from H, cyano, C2-C6 alkynyl, halogen, hydroxyl, amino, nitrogen-containing alkyl, oxygen-containing alkyl, sulfur-containing alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, 6-10 membered aryl, C2-C6 alkenyl or C3-C6 cycloalkenyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl or C3-C6 cycloalkenyl is optionally substituted with 1-3 substituents independently selected from halogen, C1-C3 alkyl, cyano or hydroxyl.

[0016] The compound of the general formula I of the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, metabolite or prodrug, preferably a compound having the structure of formula II:

[0017]

[0018] in,

[0019] Dashed lines in the rings represent double or single bonds;

[0020] X 1 、X 2 、X 3 、X 4 Each independently selected from N or CR a ;

[0021] X 1 、X 2 Not N at the same time, and X 3 、X 4 Not all N at the same time;

[0022] R a Not present, or selected from H;

[0023] X 5 、X 6 、X 7 Each independently selected from N, O, S or C, wherein the A ring may be replaced by one or more identical or different R 2 Substituent substitution;

[0024] When X 5 By two R 2 When the group is substituted, the two R 2 The group may, together with the atoms to which it is attached, form a cycloalkyl group, a nitrogen-containing heterocycle, an oxygen-containing heterocycle, or a sulfur-containing heterocycle;

[0025] Or, when X 5 and X 6 Each is an R 2 When the group is substituted, the two R 2 The group may, together with the atoms to which it is attached, form a cycloalkyl group, a nitrogen-containing heterocycle, an oxygen-containing heterocycle, or a sulfur-containing heterocycle;

[0026] Furthermore, the cycloalkyl group is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane;

[0027] Furthermore, the nitrogen-containing heterocycle, oxygen-containing heterocycle or sulfur-containing heterocycle is selected from a 5-8 membered heterocycle;

[0028] Ring A and Ring B are each independently selected from an aryl group or a heteroaryl group, wherein Ring A is optionally substituted by 1-5 R 2 Substitution; Ring B is optionally substituted with 1-3 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, halogenated C1-C3 alkyl or hydroxyl;

[0029] R 1 、R 2 、R 3 As defined in Formula I.

[0030] In some specific preferred embodiments, R 2 is selected from methyl, isopropyl, cyclopentane, ethyl, methoxymethyl, ethylmethoxy, 2-hydroxyprop-2-yl, hydroxymethyl or hydroxyethyl;

[0031] Or, when multiple R 2 If the group is a substituent of the same C atom, then multiple R 2 The group and the C atom to which it is attached together form a cycloalkyl group, wherein the cycloalkyl group is preferably selected from cyclopropane, cyclobutane and cyclopentane;

[0032] Or, when multiple R 2 The groups are not substituents of the same C atom, and multiple R 2 The bond between the group and the C atom to which it is connected together forms a nitrogen-containing heterocyclic ring, and the nitrogen-containing heterocyclic ring is selected from N-methylpiperazinyl, diazepanyl, and N-diazepanyl.

[0033] In certain preferred embodiments,

[0034] Selected from:

[0035]

[0036] In certain more preferred embodiments,

[0037] Selected from:

[0038]

[0039] R 2 is selected from methyl, isopropyl or cyclopentane;

[0040] Or, when multiple R 2 If the groups are substituents of the same atom, then multiple R 2 The group and the atoms to which it is connected together form a cycloalkyl group. More preferably, the cycloalkyl group is cyclopentane.

[0041] In certain more preferred embodiments,

[0042] R 1 is selected from phenyl, naphthyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, furanyl, piperazinyl, piperidinyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazole, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrazinyl, imidazolyl or triazolyl;

[0043] The above groups are optionally replaced by one or more R 1a Replacement, R 1a is selected from halogen, cyano, hydroxy, C2-C3 alkynyl, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy;

[0044] Among them, R 1a Optionally, one or more R 1b Replacement; R 1b is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyano or hydroxy.

[0045] In certain more preferred embodiments,

[0046] R 1 is selected from phenyl, wherein the phenyl is optionally substituted by one or more hydroxyl groups or C1-C6 alkoxy groups, wherein the C1-C6 alkoxy groups are optionally substituted by one or more fluorine groups;

[0047] Furthermore, R 1 Selected from phenyl, wherein the phenyl is substituted by (C1-C2 alkyl)-O-, wherein the C1-C2 alkyl may be substituted by fluorine;

[0048] Furthermore, the R1 Selected from 4-difluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl;

[0049] Furthermore, R 1 Selected from 4-difluoromethoxyphenyl.

[0050] In certain more preferred embodiments,

[0051] R 3 is selected from hydrogen, cyano, ethynyl, 1-propynyl, 2-propynyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitrogen-containing alkyl, oxygen-containing alkyl, sulfur-containing alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, naphthyl, vinyl, propenyl, allyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, and the above groups are optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyano or hydroxyl.

[0052] Furthermore, R 3 Selected from cyclopropane, cyclobutane, methoxy, ethoxy, isopropoxy or 2,2,2-trifluoroethoxy;

[0053] Furthermore, R 3 Selected from cyclopropane.

[0054] In some preferred embodiments, the pharmaceutically acceptable salts include but are not limited to acid addition salts formed by the compound of formula I and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

[0055] The compounds of the general formula I or II of the present invention are preferably the following compounds:

[0056]

[0057]

[0058]

[0059] The compounds of the general formula I described herein may also exist in the form of their salts or solvates, which are converted into compounds of the general formula I in vivo. For example, within the scope of the present invention, the compounds of the present invention may be converted into pharmaceutically acceptable salts according to processes known in the art and used in the form of salts.

[0060] All stereoisomeric forms of the compounds of Formula I of the present invention are included within the scope of the present invention. The compounds of the present invention may exist in specific stereoisomeric forms. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the scope of the present invention.

[0061] As used herein, "prodrug" refers to any covalently bonded carrier that releases the active parent drug when administered to a mammalian patient. Prodrugs can be prepared by modifying functional groups present in a compound in a manner that degrades to the parent compound, either by conventional manipulation or in vivo. Prodrugs include compounds in which, for example, a hydroxyl, amino, sulfhydryl, or carboxyl group attached to any group decomposes to form a free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively, when administered to a mammalian patient. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols, or methylamine and ethylamine derivatives of amine functional groups in the compounds of the invention.

[0062] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated product, metabolite or prodrug thereof and a pharmaceutically acceptable carrier.

[0063] The pharmaceutical compositions of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present invention can be administered alone or in combination with other drugs. Oral compositions can be in any orally acceptable dosage form, including but not limited to tablets, capsules, emulsions, suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.

[0064] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the present invention or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the specific composition employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition employed, the age, sex, weight, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0065] Another object of the present invention is to provide use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, metabolite or prodrug thereof in the preparation of a medicament for treating and / or preventing MAT2A-related diseases.

[0066] The MAT2A-associated disease is selected from mesothelioma, neuroblastoma, rectal cancer, colon cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmacytoma.

[0067] Beneficial effects:

[0068] The compounds of Formula I prepared by the present invention and their pharmaceutically acceptable salts, stereoisomers, solvates, deuterated compounds, metabolites, or prodrugs exhibit significant inhibitory activity against the MAT2A protein, effectively inhibiting the proliferation of tumor cells lacking the MTAP gene, exhibiting good selectivity for MTAP wild-type cells, and exhibiting excellent in vitro and in vivo biological activity. These compounds can be used as highly effective and selective small molecule MAT2A inhibitors for the treatment of cancer, particularly cancers associated with MTAP gene loss.

[0069] Unless otherwise specified, the terms used in the present invention generally have the following meanings.

[0070] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms.

[0071] The term "C1-C6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. C1-C6 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0072] The term "alkoxy" refers to an O-alkyl group. The term "C1-C3 alkoxy" refers to an O-C1-C3 alkyl group.

[0073] The term "C3-C6 cycloalkyl" refers to a cyclic hydrocarbon group having 3 to 6 carbon atoms. 10 Alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0074] The term "halogen" refers to fluorine, chlorine, bromine or iodine. DETAILED DESCRIPTION

[0075] The preparation methods of the compounds of general formula I of the present invention are described below in conjunction with specific examples, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0076] The starting materials and reagents used in the specific embodiments of the present invention are all commercially available. The present invention can be prepared in the form of a salt using a salt-forming method commonly used in the art, for example, by dissolving the compound in hydrochloric acid and ethanol at room temperature to react to form a hydrochloride salt; or by adding benzenesulfonic acid to react to form a benzenesulfonate salt.

[0077] The experimental methods in the examples are conventional methods unless otherwise specified.

[0078] Example 1: Synthesis of 6-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[2,3-b]pyrazin-3(4H)-one (Compound I-1)

[0079]

[0080] Synthesis of intermediate I-1B:

[0081] 2,6-Dichloro-3-nitropyridine (I-1A) (2.00 g, 10.42 mmol) was dissolved in acetonitrile (20 mL), and DIPEA (4.04 g, 31.26 mmol) and 4-difluoromethoxyaniline (1.74 g, 10.94 mmol) were added. The mixture was reacted at 55°C under nitrogen for 8 h. After completion of the reaction, the reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 15 / 1, v / v) to obtain 1.81 g of a red solid, with a yield of 55.0%. 1 H NMR (400MHz, CDCl3) δ (ppm) 10.23 (s, 1H), 8.47 (d, J = 8.6Hz, 1H), 7.73-7.54 (m, 2H), 7.24-7.09 (m, 2H), 6.83 (d, J = 8.6Hz, 1H), 6.52 (t, J = 73.8Hz, 1H).

[0082] Synthesis of intermediate I-1C:

[0083] Intermediate I-1B (1.80 g, 5.70 mmol) was dispersed in 1,4-dioxane (18 mL) and water (3 mL). Potassium phosphate (3.63 g, 17.10 mmol), tricyclohexylphosphine (320 mg, 1.14 mmol), cyclopropylboronic acid (735 mg, 8.55 mmol), and palladium acetate (128 mg, 0.57 mmol) were added sequentially. The mixture was reacted at 105°C under nitrogen for 6 h. After completion of the reaction, the mixture was cooled to room temperature. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25 / 1, v / v) to give 1.83 g of a red solid with a yield of 99.9%. 1 H NMR (300MHz, CDCl3) δ (ppm) 10.28 (s, 1H), 8.39 (d, J = 8.6Hz, 1H), 7.79-7.53 (m, 2H), 7.22-7 .09(m,2H),6.78(d,J=1.0Hz,1H),6.76-6.27(m,1H),2.15-1.99(m,1H),1.20-1.09(m,4H).

[0084] Synthesis of intermediate I-1D:

[0085] Intermediate I-1C (1.83 g, 5.69 mmol) was dissolved in anhydrous ethanol (18 mL). Acetic acid (2.05 g, 34.14 mmol) and iron powder (1.27 g, 22.74 mmol) were added with stirring. The mixture was reacted at 50°C for 2 h under nitrogen. After completion of the reaction, the reaction solution was concentrated to dryness, water (50 mL) was added, and the pH was adjusted to 7-8 with 10% sodium hydroxide solution. Ethyl acetate (50 mL) was added, and the mixture was filtered through Celite. The filter cake was washed with ethyl acetate (50 mL x 2). The filtrate was separated, and the organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.66 g of a brown liquid. The crude product was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.52-7.38 (m, 2H), 7.14-7.02 (m, 2H), 6.95 (d, J = 7. 7Hz,1H),6.70-6.22(m,3H),3.16(s,2H),2.00-1.86(m,1H),1.01-0.82(m,4H).

[0086] Synthesis of intermediate I-1E

[0087] Intermediate I-1D (1.66 g, 5.69 mmol) was dissolved in 1,2-dichloroethane (24 mL) and dichloromethane (6 mL). Triethylamine (5.77 g, 56.90 mmol) was added dropwise to the mixture under ice-cooling. Ethyl oxalyl chloride (3.88 g, 28.47 mmol) was added dropwise. The mixture was allowed to react at room temperature for 1 h. DBU (4.34 g, 28.47 mmol) was then added and the reaction was continued at 85°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (eluent: dichloromethane / ethyl acetate = 2 / 1, v / v) to obtain 447 mg of an off-white solid in a 22.7% yield. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.08 (s, 1H), 7.41 (d, J = 8.0Hz, 1H), 7.38-7.29 (m, 5 H),7.09(d,J=8.0Hz,1H),1.95-1.85(m,1H),0.81-0.67(m,2H),0.50-0.34(m,2H).

[0088] Synthesis of intermediate I-1F:

[0089] Intermediate I-1E (300 mg, 0.87 mmol) was dispersed in acetonitrile (6 mL), and DIPEA (337 mg, 2.61 mmol) and phosphorus oxychloride (400 mg, 2.61 mmol) were added. The mixture was reacted at 100°C for 3 h. After completion of the reaction, the reaction solution was cooled to room temperature and then poured into ice water (100 mL) for quenching. The mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 240 mg of a yellow solid, with a yield of 75.9%. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.99 (d, J = 8.2Hz, 1H), 7.34-7.26 (m, 4H), 7.24 (d, J = 8.1Hz ,1H),6.64(t,J=73.5Hz,1H),2.08-1.95(m,1H),1.03-0.86(m,2H),0.78-0.68(m,2H).

[0090] Synthesis of compound I-1:

[0091] 6-Bromo-1-methyl-1H-benzo[d]imidazole (95 mg, 0.45 mmol) was dissolved in 1,4-dioxane (3 mL), and potassium acetate (88 mg, 0.90 mmol), bis(pinacolato)diboron (137 mg, 0.54 mmol), and Pd(dppf)Cl2·DCM (74 mg, 0.09 mmol) were added. The reaction was carried out at 80°C under nitrogen for 3 h. After the reaction, the reaction solution was cooled to room temperature, and intermediate I-1F (100 mg, 0.275 mmol), 1,4-dioxane (2 mL), water (1 mL), potassium carbonate (115 mg, 0.828 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) were added. The reaction was carried out at 65°C under nitrogen for 2 h. After the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 3, v / v) to obtain 71 mg of a light brown solid, with a yield of 56.2%. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.80 (d, J = 1.2 Hz, 1H), 8.37 ( dd, J = 8.7, 1.5 Hz, 1H), 8.14 ( d, J = 8.1 Hz, 1H), 7.96 ( s, 1H), 7.89 ( d, J = 8 .7Hz,1H),7.34(s,3H),7.25(d,J=8.1Hz,1H),6.64(t,J=73.6Hz,1H),2.10-1.95(m,1H),0.99-0.91(m,2H),0.82-0.69(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 164.52, 156.10, 152.77, 151.13, 151.10, 151.08, 146.23, 143.52, 136.91, 132.47, 130.31, 130.12, 126.41, 123.72, 119.99, 118.74, 118.49, 115.90, 113.32, 112.24, 29.71, 17.61, 11.54. HRMS (ESI): calculated value C 25 H 19 F2N5O2,[M+H] + m / z, 460.1585; found 460.1588.

[0092] Example 2: Synthesis of 6-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-2-(1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrido[2,3-b]pyrazin-3(4H)-one (Compound I-2)

[0093]

[0094] Using 6-bromo-1-isopropyl-1H-benzo[d]imidazole (108 mg, 0.45 mmol) and intermediate I-1F (100 mg, 0.275 mmol) as raw materials, the preparation method was the same as compound I-1 to obtain 90 mg of a yellow solid with a yield of 67.2%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.72 (s, 1H), 8.47 (s, 1H), 8.23-8.14 (m, 2H), 7.76 (d, J = 8.6Hz, 1H), 7.62-7.1 8(m,6H),4.86-4.71(m,1H),2.19-2.05(m,1H),1.57(d,J=6.7Hz,6H),0.96-0.85(m,2H),0.70-0.57(m,2H). 13 CNMR (101 MHz, DMSO-d6) δ (ppm) 163.76, 155.96, 153.30, 150.98, 150.95, 145.78, 144.16, 144.07, 137.19, 133.08, 132.99, 131.08, 130.02, 126.35, 123.51, 119.37, 119.31, 118.49, 116.77, 114.21, 113.15, 47.79, 22.70, 17.53, 11.54. HRMS (ESI): calculated value C 27 H 23 F2N5O2,[M+H] + m / z, 488.1898; found 488.1890.

[0095] Example 3: Synthesis of 6-cyclopropyl-4-(4-(difluoromethoxy)phenyl)-2-(1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-pyrido[2,3-b]pyrazin-3(4H)-one (I-3)

[0096]

[0097] Using 6-bromo-1-cyclopentyl-1H-benzo[d]imidazole (119 mg, 0.45 mmol) and intermediate I-1F (100 mg, 0.275 mmol) as raw materials, the preparation method was the same as compound I-1 to obtain 85 mg of a yellow solid with a yield of 60.2%. 1 H NMR(400MHz, CDCl3)δ(ppm)8.86(d,J=1.7Hz,1H),8.35(dd,J=8.7,1.7Hz,1H),8.14(d,J=8.1Hz,1H),8.07(s,1H),7.89(d,J=8.7Hz,1H),7.34(s,4H ),7.24(d,J=8.1Hz,1H),6.64(t,J=73.6Hz,1H),4.84(p,J=7.0Hz,1H),2. 43-2.25(m,2H),2.13-1.82(m,7H),0.99-0.88(m,2H),0.82-0.69(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 164.45, 156.11, 152.90, 151.11, 145.84, 143.56, 142.32, 136.91, 133.68, 132.50, 130.15, 130.02, 126.42, 123.79, 119.98, 119.93, 118.74, 118.49, 115.91, 113.32, 113.00, 56.89, 32.64, 23.76, 17.61, 11.54. HRMS (ESI): calculated value C 29 H 25 F2N5O2,[M+H] + m / z, 514.2055; found 514.2050.

[0098] Example 4: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[3,4-b]pyrazin-2(1H)-one (I-4)

[0099]

[0100] Synthesis of intermediate I-4B:

[0101] Dissolve 2,4-dichloro-5-nitropyridine (I-4A) (1.5 g, 7.81 mmol) in acetonitrile (20 mL), add DIPEA (2.0 g, 15.62 mmol) and 4-difluoromethoxyaniline (1.2 g, 7.81 mmol). Reaction was carried out at 80°C under nitrogen for 8 h. After completion of the reaction, the reaction solution was cooled to room temperature and then poured into water (150 mL). Stir and crystallize for 20 min. Filter and dry the filter cake under vacuum to obtain 2.28 g of a brown solid (92.3% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 9.61 (s, 1H), 9.12 (s, 1H), 7.36-7.29 (m, 4H), 6.87 (s, 1H), 6.60 (t, J = 73.1Hz, 1H).

[0102] Synthesis of intermediate I-4C:

[0103] The preparation method was the same as compound I-1C using intermediate I-4B (500 mg, 1.58 mmol) and cyclopropylboronic acid (271 mg, 3.16 mmol) as starting materials to give 410 mg of a reddish-brown solid in a yield of 79.0%. 1 H NMR (400MHz, CDCl3) δ (ppm) 9.56 (s, 1H), 9.16 (s, 1H), 7.41-7.16 (m, 4H), 6.74 (s, 1H) ), 6.59 (t, J = 73.3Hz, 1H), 1.90-1.78 (m, 1H), 1.16-1.09 (m, 2H), 1.04-0.96 (m, 2H).

[0104] Synthesis of intermediate I-4D:

[0105] Intermediate I-4C (400 mg, 1.24 mmol) was dissolved in ethanol (4 mL) and water (1 mL). Acetic acid (4 mL) and iron powder (346 mg, 6.20 mmol) were added with stirring. The mixture was reacted at 50°C for 2 h under nitrogen. After completion of the reaction, the reaction solution was concentrated to dryness, water (25 mL) was added, and the pH was adjusted to 7-8 with 10% sodium hydroxide solution. Ethyl acetate (50 mL) was added, and the mixture was filtered through Celite. The filter cake was washed with ethyl acetate (25 mL x 2), and the filtrate was separated. The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 342 mg of a gray solid (94.3% yield). The crude product was used directly in the next step without purification. 1HNMR(400MHz, DMSO-d6)δ(ppm)7.74(s,1H),7.50(s,1H),7.33-6.92(m,5H),6.78(s,1H),4.62(s,2H),1.86-1.70(m,1H),0.85-0.59(m,4H).

[0106] Synthesis of intermediate I-4E

[0107] Intermediate I-4D (200 mg, 0.69 mmol) was dissolved in tetrahydrofuran (4 mL), and triethylamine (349 mg, 3.45 mmol) was added dropwise. Ethyl oxalyl chloride (188 mg, 1.38 mmol) was added dropwise under an ice bath. The mixture was allowed to react at room temperature for 1 h. DBU (210 mg, 1.38 mmol) was then added and the reaction was continued at 75°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (eluent: dichloromethane / methanol = 35 / 1, v / v) to obtain 174 mg of a light yellow solid, with a yield of 73.0%. 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.14(s,1H),8.24(s,1H),7.52-7.41(m,4H) ,7.39(t,J=73.7Hz,1H),6.23(s,1H),1.95-1.86(m,1H),0.85-0.72(m,4H).

[0108] Synthesis of intermediate I-4F

[0109] The intermediate I-4E (150 mg, 0.43 mmol) was used as the starting material and the preparation method was the same as compound I-1F to obtain 144 mg of a white solid with a yield of 91.2%. 1 H NMR (300MHz, CDCl3) δ (ppm) 8.89 (s, 1H), 7.46-7.31 (m, 4H), 6.67 (t, J = 72.9H z,1H),6.47(s,1H),2.01-1.85(m,1H),1.19-1.09(m,2H),1.09-0.97(m,2H).

[0110] Synthesis of compound I-4:

[0111] The preparation method was the same as compound I-1, using 6-bromo-1-methyl-1H-benzo[d]imidazole (95 mg, 0.45 mmol) and intermediate I-4F (100 mg, 0.275 mmol) as starting materials to give 46 mg of an off-white solid with a yield of 36.2%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.95 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 8.23 ​​(d, J = 8.5Hz, 1H), 7.81 (s, 1H),7.67-7.44(m,4H),7.42(s,1H),6.50(s,1H),3.92(s,3H),2.17-2.03(m,1H),1.04-0.88(m,4H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 162.91, 155.09, 153.92, 151.92, 150.91, 147.25, 139.83, 132.51, 130.86, 127.63, 124.02, 120.53, 119.32, 118.80, 116.76, 114.19, 112.74, 106.77, 31.60, 17.45, 10.74. HRMS (ESI): calculated value C 25 H 19 F2N5O2,[M+H] + m / z, 460.1585; found 460.1589.

[0112] Example 5: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-5)

[0113]

[0114] Synthesis of intermediate I-5B:

[0115] Dissolve 2-fluoro-4-bromo-1-nitrobenzene (I-5A) (5.0 g, 22.7 mmol) in DMSO (25 mL), add DIPEA (14.8 g, 11.4 mmol) and 4-difluoromethoxyaniline (4.0 g, 25.1 mmol). Under nitrogen, react at 105°C for 12 h. After completion of the reaction, cool the reaction mixture to room temperature, pour into water (100 mL), and stir for 30 min to allow crystallization. Filter the mixture, wash the filter cake with water (50 mL x 2) and 50% ethanol (50 mL x 2), and dry in vacuo to obtain 7.96 g of a red solid (97.5% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 9.47 (s, 1H), 8.09 (d, J = 9.1Hz, 1H), 7.32-7.22 (m, 5H), 6.92 (dd, J = 9.1, 2.0Hz, 1H), 6.58 (t, J = 73.4Hz, 1H).

[0116] Synthesis of intermediate I-5C:

[0117] Intermediate I-5B (4.0 g, 11.14 mmol) was dissolved in toluene (40 mL) and water (4 mL). Potassium carbonate (4.62 g, 33.42 mmol), tricyclohexylphosphine (625 mg, 2.23 mmol), cyclopropylboronic acid (1.92 g, 22.28 mmol), and palladium acetate (249 mg, 1.11 mmol) were added sequentially. The mixture was reacted at 100°C under nitrogen for 4 h. After completion of the reaction, the mixture was cooled to room temperature. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25 / 1, v / v) to obtain 3.3 g of a reddish-brown solid in a yield of 92.5%. 1 H NMR (400MHz, CDCl3) δ (ppm) 9.52 (s, 1H), 8.12 (d, J = 8.9Hz, 1H), 7.35-7.16 (m, 4H), 6.87 (d, J=1.9Hz,1H),6.76-6.36(m,2H),1.87-1.76(m,1H),1.11-1.01(m,2H),0.80-0.69(m,2H).

[0118] Synthesis of intermediate I-5D:

[0119] Intermediate I-5C (3.3 g, 10.30 mmol) was dissolved in ethanol (33 mL) and acetic acid (33 mL), and iron powder (2.0 g, 36.10 mmol) was added with stirring. The mixture was reacted at 55°C for 2 h under nitrogen. After completion of the reaction, the reaction solution was concentrated to dryness, water (50 mL) was added, and the pH was adjusted to 7-8 with 10% sodium hydroxide solution. Ethyl acetate (50 mL) was added, and the mixture was filtered through Celite. The filter cake was washed with ethyl acetate (50 mL x 2), and the filtrate was separated. The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.10 g of a dark brown liquid. The crude product was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.07-6.98 (m, 2H), 6.86 (d, J = 1.9 Hz, 1H), 6.83-6.68 (m, 4H), 6.43 (t, J =74.7Hz,1H),5.21(s,1H),3.64(s,2H),1.87-1.74(m,1H),0.95-0.82(m,2H),0.65-0.53(m,2H).

[0120] Synthesis of intermediate I-5E:

[0121] Intermediate I-5D (3.10 g, 10.7 mmol) was dissolved in 1,4-dioxane (31 mL), and triethylamine (5.40 g, 53.5 mmol) was added. Ethyl oxalyl chloride (3.65 g, 26.8 mmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 1 h. DBU (3.25 g, 21.4 mmol) was then added and the reaction was continued at 85°C for 1 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and water (50 mL) was added to crystallize and stirred for 1 h. The mixture was filtered, and the filter cake was washed sequentially with water (50 mL) and methyl tert-butyl ether (50 mL), and dried under vacuum to obtain 3.03 g of an off-white solid with a yield of 82.5%. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 12.06 (s, 1H), 7.70-7.15 (m, 5H), 7.12 (d, J = 8.2Hz, 1H), 6.81 (dd, J =8.3,1.8Hz,1H),6.10(d,J=1.8Hz,1H),1.82-1.69(m,1H),0.91-0.74(m,2H),0.49-0.37(m,2H).

[0122] Synthesis of intermediate I-5F:

[0123] Intermediate I-5E (3.0 g, 8.71 mmol) was dispersed in toluene (24 mL), and DMF (2 mL) and SOCl2 (5.2 g, 43.7 mmol) were added. The mixture was allowed to react at 85°C for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature and then poured into ice water (50 mL) for quenching. The mixture was then extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 3.23 g of a white solid in a 98.7% yield. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.71 (d, J = 8.4 Hz, 1H), 7.63-7.22 (m, 5H), 7.01 (dd, J = 8.4, 1 .9Hz,1H),6.33(d,J=1.8Hz,1H),1.97-1.85(m,1H),1.03-0.92(m,2H),0.66-0.56(m,2H).

[0124] Synthesis of compound I-5:

[0125] 6-Bromo-1-methyl-1H-benzo[d]imidazole (583 mg, 2.76 mmol) was dissolved in 1,4-dioxane (3 mL). Potassium acetate (542 mg, 5.52 mmol), bis(pinacolato)diboron (841 mg, 3.31 mmol), and Pd(dppf)Cl2 (202 mg, 0.276 mmol) were added. The mixture was reacted at 80°C under nitrogen for 3 h. After the reaction, the reaction mixture was cooled to room temperature and intermediate I-5F (1.00 g, 2.76 mmol), 1,4-dioxane (10 mL), water (2 mL), potassium carbonate (1.14 g, 8.28 mmol), and Pd(dppf)Cl2 (202 mg, 0.276 mmol) were added. The mixture was reacted at 75°C under nitrogen for 2 h. After the reaction, the reaction mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (50 mL) were added. The mixture was filtered through celite, and the filter cake was washed with ethyl acetate (50 mL x 2). The filtrate was separated, and the organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 3, v / v) to obtain 890 mg of an off-white solid, with a yield of 70.3%. 1 H NMR(400MHz, DMSO-d6)δ(ppm)8.65(d,J=1.6Hz,1H),8.30(s,1H),8.23(dd,J=8.6,1.7Hz,1H),7.85(d,J=8.3Hz,1H),7.74(d,J=8.6Hz,1H), 7.63-7.41(m,5H),7.02(dd,J=8.4,1.8Hz,1H),6.36(d,J=1.8Hz,1H),3.89(s,3H),2.01-1.84(m,1H),1.04-0.92(m,2H),0.70-0.58(m,2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 154.70, 152.34, 151.67, 147.24, 146.89, 145.32, 134.54, 134.40, 133.47, 131.07, 131.01, 130.46, 129.94, 123.37, 120.51, 120.38, 119.34, 119.08, 116.78, 114.21, 112.63, 112.31, 31.24, 16.06, 10.82. HRMS (ESI): calcd. 26 H 20 F2N4O2,[M+H] + m / z, 459.1633; found 459.1620.

[0126] Example 6: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-isopropyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-6)

[0127]

[0128] Using 6-bromo-1-isopropyl-1H-benzo[d]imidazole (66 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as starting materials, the operation method was the same as compound I-5 to obtain 75 mg of a yellow solid with a yield of 55.9%. 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.75(d,J=1.9Hz,1H),8.46(s,1H),8.19(dd,J=8.6,1.6H z,1H),7.85(d,J=8.3Hz,1H),7.75(d,J=8.6Hz,1H),7.64-7.55(m,2H),7.51-7.46(m,2H ),7.34(t,J=73.6Hz,1H),7.01(dd,J=8.4,1.9Hz,1H),6.35(d,J=1.8Hz,1H),4.88-4.69 (m,1H),2.04-1.83(m,1H),1.57(d,J=6.7Hz,6H),1.04-0.92(m,2H),0.72-0.59(m,2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 154.75, 152.36, 151.68, 147.23, 145.62, 143.93, 134.41, 133.49, 132.99, 131.07, 131.01, 130.26, 129.96, 123.34, 120.53, 120.38, 119.33, 116.78, 114.21, 113.01, 112.62, 47.76, 22.71, 16.07, 10.83. HRMS (ESI): calcd. 28 H 24 F2N4O2,[M+H] + m / z, 487.1946; found 487.1940.

[0129] Example 7: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-cyclopentyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-7)

[0130]

[0131] Using 6-bromo-1-cyclopentyl-1H-benzo[d]imidazole (73 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as starting materials, the operation method was the same as compound I-5 to obtain 108 mg of yellow solid in a yield of 76.4%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.77 (s, 1H), 8.43 (s, 1H), 8.20 (d, J = 8.7Hz, 1H), 7.84 (d, J = 8.3Hz, 1H), 7.75 (d, J = 8.7Hz, 1H), 7.67-7.20 (m, 5H),7.01(d,J=8.4Hz,1H),6.34(s,1H),4.89(p,J=7.5Hz,1H),2.30-2.17(m,2H),2.07-1.67(m,7H),1.05-0.88(m,2H),0.71-0.58(m,2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 154.75, 152.24, 151.68, 147.23, 145.68, 144.29, 134.42, 133.54, 133.49, 131.06, 131.01, 130.29, 129.96, 123.39, 120.52, 120.38, 119.33, 116.77, 114.21, 113.15, 112.62, 56.79, 32.31, 23.94, 16.07, 10.83. HRMS (ESI): calcd. 30 H 26 F2N4O2,[M+H] + m / z, 513.2102; found 513.2096.

[0132] Example 8: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-2(1H)-quinoxalinone (I-8)

[0133]

[0134] Using 5'-bromo-2'-methylspiro[cyclopentane-1,3'-indole] (73 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 65 mg of yellow solid with a yield of 46.0%. 1H NMR (400MHz, CDCl3) δ (ppm) 8.42 (d, J = 1.7Hz, 1H), 8.34 (dd, J = 8.2, 1.8Hz, 1H), 7.8 8(d,J=8.3Hz,1H),7.60(d,J=8.2Hz,1H),7.40(q,J=8.9Hz,4H),6.97(dd,J=8.3,1 .9Hz,1H),6.66(t,J=73.2Hz,1H),6.40(d,J=1.9Hz,1H),2.35(s,3H),2.21-2.09( m,2H),2.08-1.96(m,4H),1.96-1.84(m,3H),1.11-0.98(m,2H),0.78-0.63(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 189.70, 155.71, 154.91, 152.75, 151.58, 147.32, 146.89, 133.88, 133.17, 133.02, 131.41, 130.07, 129.50, 122.76, 121.19, 120.68, 119.23, 118.28, 115.68, 113.09, 112.40, 63.95, 35.43, 27.18, 16.32, 16.06, 10.44. HRMS (ESI): calcd. 31 H 27 F2N3O2,[M+H] + m / z, 512.2150; found 512.2143.

[0135] Example 9: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2'-methylspiro[cyclohexane-1,3'-indole]-5'-yl)-2(1H)-quinoxalinone (I-9)

[0136]

[0137] Using 5'-bromo-2'-methylspiro[cyclohexane-1,3'-indole] (77 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 60 mg of yellow solid with a yield of 41.4%. 1H NMR (400MHz, CDCl3) δ (ppm) 8.73 (d, J = 1.8Hz, 1H), 8.34 (dd, J = 8.1, 1.7Hz, 1H), 7. 89(d,J=8.4Hz,1H),7.64(d,J=8.2Hz,1H),7.48-7.35(m,4H),6.97(dd,J=8.4,1.9 Hz,1H),6.67(t,J=73.2Hz,1H),6.40(d,J=1.8Hz,1H),2.35(s,3H),2.13-1.97(m ,3H),1.94-1.75(m,5H),1.57-1.33(m,3H),1.09-0.96(m,2H),0.76-0.62(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 190.09, 156.12, 154.88, 153.19, 151.58, 147.30, 144.21, 133.98, 133.18, 132.15, 131.43, 130.14, 130.09, 129.77, 125.44, 121.12, 120.63, 119.68, 118.29, 115.69, 113.10, 112.41, 58.11, 31.29, 25.37, 21.88, 16.58, 16.06, 10.44. HRMS (ESI): calcd. 32 H 29 F2N3O2,[M+H] + m / z, 526.2306; found 526.2311.

[0138] Example 10: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2,3,3-trimethyl-3H-indol-5-yl)-2(1H)-quinoxalinone (I-10)

[0139]

[0140] Using 5-bromo-2,3,3-trimethyl-3H-indole (66 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 43 mg of yellow solid with a yield of 32.1%. 1H NMR (400MHz, CDCl3) δ (ppm) 8.48 (d, J = 1.4Hz, 1H), 8.40 (dd, J = 8.2, 1.6Hz, 1H), 7.89 (d, J = 8.4Hz, 1H), 7.66 (d, J = 8.2Hz, 1H), 7.47-7.35 (m, 4H), 6.99 (d d,J=8.4,1.8Hz,1H),6.66(t,J=73.2Hz,1H),6.42(d,J=1.7Hz,1H),2.37(s ,3H),1.95-1.82(m,1H),1.38(s,6H),1.10-0.98(m,2H),0.78-0.64(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 190.48, 155.45, 154.94, 152.52, 151.59, 147.40, 145.18, 133.84, 133.16, 132.95, 131.43, 130.04, 129.78, 122.99, 121.23, 120.76, 119.54, 118.28, 115.68, 113.09, 112.40, 53.93, 23.05, 16.06, 15.66, 10.43. HRMS (ESI): calculated value C 29 H 25 F2N3O2,[M+H] + m / z, 486.19931; found 486.19758.

[0141] Example 11: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(benzo[d]oxazol-6-yl)-2(1H)-quinoxalinone (I-11)

[0142]

[0143] Using 6-bromobenzo[d]oxazole (55 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as starting materials, the operation method was the same as compound I-5 to obtain 65 mg of a yellow solid with a yield of 52.9%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.87 (s, 1H), 8.71 (d, J = 1.5Hz, 1H), 8.37 (dd, J = 8.5, 1.6Hz, 1H), 7.89 (dd, J = 23.3, 8.4Hz, 2H), 7.64-7.53 (m, 2H), 7.52-7. 46(m,2H),7.44(t,J=73.6Hz,1H),7.02(dd,J=8.4,1.8Hz,1H),6.36(d,J=1. 9Hz, 1H), 1.94 (tt, J = 8.3, 5.0Hz, 1H), 1.08-0.93 (m, 2H), 0.72-0.56 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 154.79, 154.08, 151.63, 151.40, 149.87, 148.05, 141.66, 133.95, 133.56, 132.98, 131.25, 130.22, 130.02, 126.27, 121.21, 120.87, 119.85, 118.27, 115.68, 113.08, 112.82, 112.47, 16.13, 10.58. HRMS (ESI): calculated value C 25 H 17 F2N3O3,[M+H] + m / z, 446.1316; found 446.1312.

[0144] Example 12: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(benzo[d]thiazol-6-yl)-2(1H)-quinoxalinone (I-12)

[0145]

[0146] Using 6-bromobenzothiazole (59 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 87 mg of yellow solid with a yield of 68.3%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.51 (s, 1H), 9.13 (d, J = 1.7Hz, 1H), 8.45 (dd, J = 8.7, 1.7Hz, 1H), 8.19 (d, J = 8.7Hz, 1H), 7.86 (d, J = 8.4Hz ,1H),7.66-7.23(m,5H),7.03(dd,J=8.5,1.9Hz,1H),6.37(d,J=1.9Hz,1H),2.02-1.88(m,1H),1.06-0.89(m,2H),0.73-0.58(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 156.02, 154.86, 154.26, 151.62, 151.33, 148.08, 133.92, 133.67, 133.21, 132.97, 131.33, 130.23, 130.01, 127.54, 123.81, 122.98, 121.22, 120.89, 118.27, 115.68, 113.08, 112.48, 77.39, 77.07, 76.75, 16.14, 10.60. HRMS (ESI): calculated value C 25 H 17 F2N3O2S,[M+H] + m / z, 462.1088; found 462.1084.

[0147] Example 13: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(imidazo[1,2-a]pyridin-6-yl)-2(1H)-quinoxalinone (I-13)

[0148]

[0149] Using 6-bromo-imidazo[1,2-a]pyridine (54 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 80 mg of yellow solid with a yield of 65.2%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.93 (s, 1H), 8.18 (dd, J = 9.6, 1.5Hz, 1H), 8.13 (s, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.68 (d, J = 9.6Hz, 1H), 7.64-7. 55(m,3H),7.52-7.42(m,3H),7.03(dd,J=8.4,1.5Hz,1H),6.38(d,J=1.3Hz,1H),2.00-1.88(m,1H),1.06-0.92(m,2H),0.71-0.58(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 154.69, 151.67, 148.19, 147.82, 145.19, 134.35, 133.36, 132.82, 131.14, 130.09, 129.90, 129.82, 124.72, 121.39, 121.31, 121.07, 118.22, 116.97, 115.62, 113.82, 113.02, 112.46, 16.16, 10.64. HRMS (ESI): calcd. 25 H 18 F2N4O2,[M+H] + m / z, 445.1476; found 445.1469.

[0150] Example 14: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2(1H)-quinoxalinone (I-14)

[0151]

[0152] Using 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (55 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 96 mg of yellow solid with a yield of 78.1%. 1H NMR(400MHz, CDCl3)δ(ppm)10.23(s,1H),8.71(dd,J=9.5,1.6Hz,1H),8.37(s,1H),7.84(dd,J=23.4,8.9Hz,2H),7.48-7.33(m,4H), 6.99(dd,J=8.4,1.7Hz,1H),6.66(t,J=73.1Hz,1H),6.44(d,J=1.6Hz,1H),1.96-1.82(m,1H),1.10-0.98(m,2H),0.77-0.63(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 155.00, 154.47, 151.76, 151.73, 150.63, 148.85, 147.19, 133.73, 132.62, 131.52, 131.00, 130.24, 130.08, 129.91, 123.06, 121.29, 121.11, 118.23, 115.63, 113.04, 112.52, 16.22, 10.76. HRMS (ESI): calcd. 24 H 17 F2N5O2,[M+H] + m / z, 446.1429; found 446.1428.

[0153] Example 15: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(pyrazolo[1,5-a]pyridin-5-yl)-2(1H)-quinoxalinone (I-15)

[0154]

[0155] Using 5-bromopyrazolo[1,5-a]pyridine (54 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 95 mg of yellow solid with a yield of 77.4%. 1 H NMR (400MHz, CDCl3) δ (ppm) 9.17 (s, 1H), 8.53 (d, J = 7.5Hz, 1H), 7.99 (d, J = 2.1Hz, 1H), 7.96-7.84 (m, 2H), 7.51-7.32 (m, 4H), 7.00 ( dd,J=8.4,1.5Hz,1H),6.89-6.47(m,2H),6.45(d,J=1.3Hz,1H),1.89(tt,J=8.5,5.0Hz,1H),1.14-0.97(m,2H),0.81-0.61(m,2H).13 C NMR (101 MHz, CDCl3) δ (ppm) 154.74, 151.64, 148.87, 148.41, 142.28, 139.48, 133.81, 132.89, 131.12, 130.65, 130.24, 129.98, 127.79, 121.25, 120.95, 120.67, 118.26, 115.66, 113.06, 112.44, 111.39, 99.80, 16.19, 10.67. HRMS (ESI): calculated value C 25 H 18 F2N4O2,[M+H] + m / z, 445.1476; found 445.1475.

[0156] Example 16: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2,3-dihydrobenzofuran-5-yl)-2(1H)-quinoxalinone (I-16)

[0157]

[0158] Intermediate I-5F (100 mg, 0.276 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Potassium carbonate (115 mg, 0.828 mmol), 2,3-dihydro-1-benzofuran-5-ylboronic acid (68 mg, 0.414 mmol), and Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) were added. The mixture was reacted at 80°C for 3 h under nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, v / v) to obtain 88 mg of a yellow solid in a yield of 71.4%. 1H NMR (400MHz, CDCl3) δ (ppm) 8.36 (s, 1H), 8.29 (d, J = 8.5Hz, 1H), 7.85 (d, J = 8.3 Hz,1H),7.39(q,J=8.8Hz,4H),6.96(d,J=7.3Hz,1H),6.88(d,J=8.5Hz,1H),6. 66(t,J=73.3Hz,1H),6.41(d,J=1.3Hz,1H),4.66(t,J=8.7Hz,2H),3.29(t,J= 8.7Hz,2H),1.88(tt,J=8.4,5.0Hz,1H),1.16-0.92(m,2H),0.81-0.58(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 162.29, 154.94, 152.25, 151.51, 146.80, 133.66, 133.24, 131.35, 130.68, 130.08, 129.72, 128.49, 126.96, 126.60, 121.15, 120.64, 118.31, 115.71, 113.12, 112.40, 109.02, 71.91, 29.44, 16.01, 10.37. HRMS (ESI): calcd. 26 H 20 F2N2O3,[M+H] + m / z, 447.1520; found 447.1516.

[0159] Example 17: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-5-yl)-2(1H)-quinoxalinone (I-17)

[0160]

[0161] Using 5-bromo-2-methyl-2H-indazole (58 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 46 mg of yellow solid with a yield of 36.4%. 1H NMR (400MHz, CDCl3) δ (ppm) 9.12 (s, 1H), 8.37 (d, J = 9.2Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.3Hz, 1H), 7.78 (d, J = 9.2Hz, 1H), 7.47-7.34 ( m,4H),7.02-6.94(m,1H),6.66(t,J=73.2Hz,1H),6.43(s,1H),4.25(s,3H),1.97-1.80(m,1H),1.10-0.96(m,2H),0.77-0.64(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 155.01, 152.05, 151.53, 149.47, 147.13, 133.61, 133.27, 131.35, 130.09, 129.96, 129.26, 126.79, 125.81, 124.00, 121.89, 121.16, 120.69, 118.30, 116.86, 115.71, 113.12, 112.38, 40.45, 16.05, 10.42. HRMS (ESI): calculated value C 26 H 20 F2N4O2,[M+H] + m / z, 459.1633; found 459.1637.

[0162] Example 18: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2(1H)-quinoxalinone (I-18)

[0163]

[0164] Using 6-bromo-1,2,4-triazolo[4,3-a]pyridine (55 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 74 mg of yellow solid with a yield of 60.2%. 1H NMR (400MHz, CDCl3) δ (ppm) 10.03 (s, 1H), 8.80 (s, 1H), 8.51 (dd, J = 9.8, 1.5Hz, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.86 (d, J = 9.8Hz, 1H), 7.50-7.34 (m,4H),7.03(dd,J=8.4,1.7Hz,1H),6.69(t,J=73.0Hz,1H),6.48(d,J=1.6Hz,1H),2.01-1.83(m,1H),1.14-1.02(m,2H),0.80-0.63(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 154.60, 151.75, 149.17, 148.89, 146.35, 136.75, 133.50, 132.52, 130.99, 130.31, 129.81, 128.00, 126.89, 123.08, 121.35, 121.27, 118.18, 115.58, 115.26, 112.98, 112.54, 16.27, 10.86. HRMS (ESI): calculated value C 24 H 17 F2N5O2,[M+H] + m / z, 446.1429; found 446.1429.

[0165] Example 19: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2(1H)-quinoxalinone (I-19)

[0166]

[0167] Using 6-bromo-1-methyl-1H-benzotriazole (58 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 76 mg of yellow solid with a yield of 59.9%. 1H NMR (400MHz, CDCl3) δ (ppm) 9.00 (s, 1H), 8.58-8.41 (m, 1H), 8.13 (d, J = 8.9Hz, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.52-7.31 (m, 4H), 7.01 (dd, J =8.4,1.5Hz,1H),6.68(t,J=73.1Hz,1H),6.46(d,J=1.3Hz,1H),4.34(s,3H),2.02-1.80(m,1H),1.27-0.96(m,2H),0.91-0.62(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 154.93, 151.66, 150.64, 148.49, 146.65, 134.62, 133.90, 133.51, 132.92, 131.22, 130.36, 129.94, 125.11, 121.34, 121.00, 119.27, 118.22, 115.62, 113.02, 112.48, 111.71, 34.42, 16.19, 10.68. HRMS (ESI): calculated value C 25 H 19 F2N5O2,[M+H] + m / z, 460.1585; found 460.1586.

[0168] Example 20: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(benzofuran-5-yl)-2(1H)-quinoxalinone (I-20)

[0169]

[0170] Using benzofuran-5-boronic acid (68 mg, 0.414 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-16 to obtain 56 mg of yellow solid with a yield of 45.7%. 1H NMR (400MHz, CDCl3) δ (ppm) 8.78 (s, 1H), 8.38 (d, J = 8.7Hz, 1H), 7.90 (d, J = 8.1Hz, 1H), 7.67 (d, J = 2.0Hz, 1H), 7.60 (d, J = 8.6Hz, 1H), 7.51-7.3 4(m,4H),6.99(d,J=7.4Hz,1H),6.85(s,1H),6.84-6.47(m,1H),6.46- 6.41(m,1H),1.96-1.84(m,1H),1.09-0.99(m,2H),0.76-0.64(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 156.17, 154.92, 152.73, 151.56, 147.32, 145.59, 133.85, 133.18, 131.37, 130.78, 130.09, 130.02, 127.27, 126.14, 123.47, 121.16, 120.69, 118.32, 115.72, 113.13, 112.45, 111.07, 107.31, 16.06, 10.46. HRMS (ESI): calculated value C 26 H 18 F2N2O3,[M+H] + m / z, 445.1364; found 445.1367.

[0171] Example 21: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-21)

[0172]

[0173] Using 6-bromo-2-ethyl-1-methyl-1H-benzimidazole (66 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 55 mg of yellow solid, with a yield of 59.9%. 1H NMR (400MHz, CDCl3) δ (ppm) 8.73 (s, 1H), 8.37 (dd, J = 8.6, 1.5Hz, 1H), 7.90 (d, J = 8 .4Hz,1H),7.82(d,J=8.6Hz,1H),7.50-7.35(m,4H),6.98(dd,J=8.4,1.7Hz,1H), 6.67(t,J=73.2Hz,1H),6.42(d,J=1.6Hz,1H),3.78(s,3H),2.96(q,J=7.5Hz,2H) ,1.98-1.79(m,1H),1.50(t,J=7.5Hz,3H),1.13-0.97(m,2H),0.77-0.60(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 158.11, 155.09, 152.16, 151.56, 147.13, 135.51, 133.70, 133.29, 131.42, 130.07, 129.98, 129.77, 123.57, 121.23, 120.76, 118.68, 118.28, 115.69, 112.37, 111.47, 29.78, 21.03, 16.05, 11.56, 10.39. HRMS (ESI): calculated value C 28 H 24 F2N4O2,[M+H] + m / z, 487.1946; found 487.1939.

[0174] Example 22: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-22)

[0175]

[0176] Using 6-bromo-α,α,1-trimethyl-1H-benzimidazole-2-methanol (80 mg, 0.298 mmol) and intermediate I-5F (108 mg, 0.298 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 90 mg of yellow solid with a yield of 58.5%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.59 (s, 1H), 8.19 (dd, J = 8.6, 1.3Hz, 1H), 7.85 (d, J =8.3Hz,1H),7.67(d,J=8.6Hz,1H),7.58(d,J=8.8Hz,2H),7.48(d,J=8.7Hz,2H), 7.44(t,J=73.7Hz,1H),7.01(d,J=8.4Hz,1H),6.37-6.32(m,1H),5.71(s,1H),4. 05(s,3H),2.02-1.84(m,1H),1.66(s,6H),1.04-0.91(m,2H),0.74-0.56(m,2H). 13 C NMR (101 MHz, DMSO) δ (ppm) 161.06, 154.72, 152.46, 151.66, 147.16, 143.20, 136.73, 134.38, 133.49, 131.08, 131.02, 130.17, 129.93, 123.42, 120.50, 120.36, 119.34, 118.59, 116.78, 114.21, 112.64, 111.86, 70.20, 32.19, 30.21, 16.07, 10.84. HRMS (ESI): calcd. 29 H 26 F2N4O3,[M+H] + m / z, 517.20512; found 517.20185.

[0177] Example 23: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-23)

[0178]

[0179] Using 6-bromo-2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazole (84 mg, 0.331 mmol) and intermediate I-5F (120 mg, 0.331 mmol) as starting materials, the operation was the same as compound I-5 to obtain 77 mg of a yellow solid in a yield of 46.4%. 1HNMR (400MHz, CDCl3) δ (ppm) 8.80 (s, 1H), 8.42 (dd, J = 8.7, 1.3Hz, 1H), 7.91 (d ,J=8.4Hz,1H),7.86(d,J=8.7Hz,1H),7.42(q,J=8.9Hz,4H),7.00(dd,J=8.4, 1.6Hz,1H),6.67(t,J=73.2Hz,1H),6.43(d,J=1.5Hz,1H),4.83(s,2H),3.91( s,3H),3.44(s,3H),2.02-1.81(m,1H),1.16-0.97(m,2H),0.84-0.59(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 155.05, 152.18, 151.98, 151.58, 147.40, 135.90, 133.77, 133.21, 131.40, 130.78, 130.04, 123.93, 121.25, 120.81, 119.42, 118.27, 115.67, 113.08, 112.40, 111.93, 67.15, 58.43, 30.27, 16.08, 10.44. HRMS (ESI): calculated value C 28 H 24 F2N4O3,[M+H] + m / z, 503.1895; found 503.1886.

[0180] Example 24: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-24)

[0181]

[0182] Starting from 6-bromo-2-(2-methoxyethyl)-1-methyl-1H-benzo[d]imidazole (74 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol), the operation was the same as compound I-5 to obtain 82 mg of a yellow solid in a yield of 57.4%. 1HNMR(400MHz,DMSO-d6)δ(ppm)8.57(d,J=1.3Hz,1H),8.18(dd,J=8.6,1.6Hz,1H),7.84(d,J =8.3Hz,1H),7.63(d,J=8.3Hz,1H),7.61-7.55(m,2H),7.53-7.45(m,2H),7.35(t,J=73.7Hz, 1H),7.00(dd,J=8.4,1.7Hz,1H),6.35(d,J=1.6Hz,1H),3.82(t,J=6.7Hz,2H),3.78(s,3H), 3.29(s,3H),3.17(t,J=6.7Hz,2H),1.97-1.86(m,1H),1.02-0.94(m,2H),0.70-0.56(m,2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 155.62, 154.71, 152.46, 151.65, 147.11, 144.18, 135.56, 134.36, 133.49, 131.08, 131.02, 129.90, 129.77, 123.35, 120.50, 120.35, 119.34, 118.02, 116.77, 114.21, 112.62, 111.88, 70.14, 58.52, 30.19, 27.79, 16.06, 10.82. HRMS (ESI): calcd. 29 H 26 F2N4O3,[M+H] + m / z, 517.20512; found 517.20233.

[0183] Example 25: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-25)

[0184]

[0185] Using 6-bromo-1-methyl-1H-benzimidazole-2-ethanol (104 mg, 0.408 mmol) and intermediate I-5F (148 mg, 0.408 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 86 mg of yellow solid with a yield of 41.9%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.57 (s, 1H), 8.18 (d, J = 9.4Hz, 1H), 7.84 (d, J = 8.3Hz, 1H ),7.63(d,J=8.3Hz,1H),7.61-7.54(m,2H),7.53-7.45(m,2H),7.43(t,J=73.7Hz,1H), 7.00(d,J=8.3Hz,1H),6.34(s,1H),4.91(t,J=5.4Hz,1H),3.88(q,J=6.4Hz,2H),3.79( s,3H),3.07(t,J=6.6Hz,2H),2.02-1.84(m,1H),1.08-0.92(m,2H),0.69-0.58(m,2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 156.28, 154.72, 152.50, 151.69, 151.65, 147.08, 144.37, 135.58, 134.36, 133.50, 131.09, 131.03, 129.89, 129.64, 123.27, 120.50, 120.34, 119.34, 118.00, 116.77, 114.21, 112.63, 111.85, 59.78, 31.06, 30.25, 16.06, 10.83. HRMS (ESI): calcd. 28 H 24 F2N4O3,[M+H] + m / z, 503.18497; found 503.18781.

[0186] Example 26: Synthesis of 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-26)

[0187]

[0188] Using 6-bromo-1-methyl-1H-benzo[d]imidazole-2-methanol (120 mg, 0.499 mmol) and intermediate I-5F (181 mg, 0.499 mmol) as starting materials, the operation method was the same as compound I-5 to obtain 96 mg of yellow solid with a yield of 39.4%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.61 (s, 1H), 8.20 (d, J = 8.6Hz, 1H), 7.85 (d, J = 8.3Hz, 1 H),7.68(d,J=8.6Hz,1H),7.58(d,J=8.6Hz,2H),7.48(d,J=8.5Hz,2H),7.44(t,J=73 .7Hz,1H),7.01(d,J=8.2Hz,1H),6.35(s,1H),5.67(t,J=5.6Hz,1H),4.76(d,J=5.6H z, 2H), 3.87 (s, 3H), 2.03-1.84 (m, 1H), 0.98 (d, J = 6.7Hz, 2H), 0.64 (d, J = 3.9Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 156.40, 154.71, 152.40, 151.66, 147.20, 143.88, 135.98, 134.38, 133.48, 131.07, 131.02, 130.32, 129.93, 123.43, 120.50, 120.36, 119.34, 118.71, 116.78, 114.21, 112.63, 112.00, 56.92, 30.41, 16.07, 10.84. HRMS (ESI): calcd. 27 H 22 F2N4O3,[M+H] + m / z, 489.17382; found 489.17184.

[0189] Example 27: Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-7-yl)-7-cyclopropyl-2(1H)-quinoxalinone (I-27)

[0190]

[0191] Using 7-bromo-2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (150 mg, 0.560 mmol) and intermediate I-5F (203 mg, 0.560 mmol) as raw materials, the operation method was the same as compound I-5 to obtain 117 mg of yellow solid with a yield of 40.7%. 1H NMR (400MHz, CDCl3) δ (ppm) 8.72 (d, J = 1.0Hz, 1H), 8.39 (dd, J = 8.6, 1.5Hz, 1H), 7.90 (d ,J=8.4Hz,1H),7.79(d,J=8.6Hz,1H),7.47-7.36(m,4H),6.98(dd,J=8.4,1.7Hz,1H),6 .67(t,J=73.2Hz,1H),6.42(d,J=1.6Hz,1H),4.20(t,J=5.5Hz,2H),3.91(s,2H),3.00( t,J=5.5Hz,2H),2.58(s,3H),1.92-1.84(m,1H),1.09-0.98(m,2H),0.74-0.66(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 155.08, 152.11, 151.56, 151.14, 147.22, 144.82, 133.85, 133.69, 133.24, 131.41, 130.05, 129.99, 129.72, 124.02, 121.24, 120.75, 118.84, 118.27, 115.68, 113.08, 112.40, 111.34, 54.15, 51.52, 45.64, 42.02, 16.06, 10.45. HRMS (ESI): calculated value C 29 H 25 F2N5O2,[M+H] + m / z, 514.20546; found 514.20331.

[0192] Example 28: 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(2,3,4,5-tetrahydrobenzo[4,5]imidazo[1,2-d][1,4]diazepine Synthesis of 2-(9-yl)-2(1H)-quinoxalinone (I-28)

[0193]

[0194] 9-bromo-2,3,4,5-tetrahydrobenzo[4,5]imidazo[1,2-d][1,4]diazepine (73 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) were used as raw materials. The operation method was the same as compound I-5 to obtain 78 mg of yellow-brown solid with a yield of 55.0%. 1H NMR(400MHz, DMSO-d6)δ(ppm)8.56(d,J=1.0Hz,1H),8.22(dd,J=8.6,1.5Hz,1H),7.84( d,J=8.3Hz,1H),7.63(d,J=8.6Hz,1H),7.60-7.55(m,2H),7.51-7.45(m,2H),7.43(t,J =73.8Hz,1H),7.01(dd,J=8.4,1.5Hz,1H),6.35(d,J=1.4Hz,1H),4.13-4.03(m,4H),3. 26-3.18(m,2H),2.89(s,1H),1.97-1.87(m,1H),1.01-0.94(m,2H),0.68-0.60(m,2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 159.59, 154.69, 152.55, 151.64, 147.08, 144.29, 135.75, 134.35, 133.49, 131.10, 131.01, 129.87, 129.75, 123.04, 120.53, 120.44, 119.33, 118.15, 116.77, 114.20, 112.60, 111.52, 49.38, 47.67, 46.40, 34.14, 16.05, 10.77. HRMS (ESI): calcd. 29 H 25 F2N5O2,[M+H] + m / z, 514.20546; found 514.20285.

[0195] Example 29: 7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(3-methyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[1,2-d][1,4]diazepine Synthesis of 2-(9-yl)-2(1H)-quinoxalinone (I-29)

[0196]

[0197] 9-bromo-3-methyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[1,2-d][1,4]diazepine (77 mg, 0.276 mmol) and intermediate I-5F (100 mg, 0.276 mmol) were used as raw materials. The operation method was the same as compound I-5 to obtain 55 mg of yellow-brown solid with a yield of 37.9%. 1HNMR(400MHz,DMSO-d6)δ(ppm)8.57(d,J=0.8Hz,2H),8.17(dd,J=8.6,1.3Hz,1H),7 .84(d,J=8.3Hz,1H),7.62(d,J=8.6Hz,1H),7.58(d,J=8.8Hz,2H),7.48(d,J=8.8Hz, 2H),7.43(t,J=73.7Hz,1H),6.35(d,J=1.5Hz,1H),4.34(d,J=7.2Hz,2H),3.23-3.11 (m,2H),2.78-2.59(m,4H),1.97-1.88(m,1H),1.03-0.91(m,2H),0.72-0.57(m,2H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 158.82, 154.69, 152.53, 151.65, 147.11, 144.20, 135.47, 134.36, 133.48, 131.09, 131.01, 129.88, 129.80, 123.13, 120.50, 120.37, 119.33, 118.22, 116.77, 114.20, 112.63, 111.48, 57.53, 54.67, 46.95, 43.90, 30.10, 16.06, 10.81. HRMS (ESI): calcd. 30 H 27 F2N5O2,[M+H] + m / z, 528.22111; found 528.21893.

[0198] Example 30: Synthesis of 7-cyclopropyl-1-(benzo[d][1,3]dioxol-5-yl)-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-30)

[0199]

[0200] Synthesis of intermediate I-30A:

[0201] Using 2-fluoro-4-bromo-1-nitrobenzene (I-5A) (2.00 g, 9.11 mmol) and 3,4-methylenedioxyaniline (1.37 g, 10.0 mmol) as starting materials, the reaction procedure was the same as for compound I-5B. 3.00 g of a red solid was obtained with a yield of 89.9%. 1H NMR (400MHz, CDCl3) δ (ppm) 9.38 (s, 1H), 8.07 (d, J = 9.1Hz, 1H), 7.17 (d, J = 2.0Hz, 1H), 6.93-6.82 (m, 2H), 6.81-6.71 (m, 2H), 6.07 (s, 2H).

[0202] Synthesis of intermediate I-30B:

[0203] Using intermediate I-30A (2.97 g, 8.81 mmol) and cyclopropylboronic acid (1.51 g, 17.62 mmol) as starting materials, the same procedure as compound I-5C was used to obtain 2.21 g of a reddish-brown solid with a yield of 84.1%. 1 H NMR (400MHz, CDCl3) δ (ppm) 9.45 (s, 1H), 8.10 (d, J = 8.9Hz, 1H), 6.87 (d, J = 8.1Hz, 1H), 6.79 (dd, J = 8.3, 1.9Hz, 3H), 6.76 (dd, J = 8. 2,2.1Hz,2H),6.32(dd,J=9.0,1.8Hz,1H),6.06(s,2H),1.79(ddd,J=13.3,8.4,5.0Hz,1H),1.07-1.00(m,3H),0.78-0.70(m,3H).

[0204] Synthesis of intermediate I-30C:

[0205] Using intermediate I-30B (2.12 g, 7.11 mmol) as starting material, the same procedure as compound I-5D was used to obtain 1.85 g of a dark brown liquid with a yield of 97.0%. 1 H NMR (400MHz, CDCl3) δ (ppm) 6.83 (s, 1H), 6.71 (d, J = 8.2Hz, 3H), 6.42 (d, J = 2.2Hz, 1H), 6.25 ( dd,J=8.3,2.2Hz,1H),5.92(s,2H),1.83-1.75(m,1H),0.91-0.83(m,2H),0.61-0.55(m,2H).

[0206] Synthesis of intermediate I-30D:

[0207] Using intermediate I-30C (1.76 g, 6.56 mmol) as starting material, the same procedure as compound I-5E was used to obtain 1.57 g of off-white solid with a yield of 74.3%. 1H NMR (400MHz, CDCl3) δ (ppm) 11.19 (s, 1H), 7.24 (d, J = 8.3Hz, 1H), 7.03 (d, J = 7.8Hz, 1H), 6.89-6.71 (m, 3H),6.42(s,1H),6.17(s,1H),6.11(s,1H),1.86-1.74(m,1H),1.00-0.86(m,2H),0.62-0.48(m,2H).

[0208] Synthesis of intermediate I-30E:

[0209] Using intermediate I-30D (1.50 g, 4.66 mmol) as starting material, the same procedure as compound I-5F was used to obtain 1.15 g of a white solid with a yield of 72.4%. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.72 (d, J = 8.4Hz, 1H), 7.03 (dd, J = 7.5, 1.0Hz, 1H), 6.96 (dd, J = 8.4, 1.8Hz, 1H), 6.78-6.74 (m, 2 H), 6.53 (d, J = 1.8Hz, 1H), 6.15 (dd, J = 20.2, 1.3Hz, 2H), 1.88 (tt, J = 8.4, 5.0Hz, 1H), 1.09-0.99 (m, 2H), 0.75-0.64 (m, 2H).

[0210] Synthesis of compound I-30:

[0211] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (300 mg, 1.42 mmol) and intermediate I-30E (485 mg, 1.42 mmol), the operation was the same as compound I-5 to obtain 310 mg of off-white solid with a yield of 49.9%. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.87 (s, 1H), 8.43 (dd, J = 8.7, 1.4Hz, 1H), 8.03 (s, 1H), 7.90 (d, J = 8.4Hz, 2H), 7.13-7.04 (m, 1H), 6.99 (dd, J = 8.4, 1.7Hz, 1H),6.88-6.79(m,2H),6.55(d,J=1.6Hz,1H),6.19(d,J=1.2Hz,1H),6.12 (d,J=1.1Hz,1H),2.00-1.84(m,1H),1.11-0.98(m,2H),0.84-0.65(m,2H). 13C NMR (101 MHz, CDCl3) δ (ppm) 155.30, 151.89, 149.20, 148.43, 147.28, 145.10, 134.24, 134.12, 131.37, 130.86, 129.91, 129.67, 123.93, 123.83, 121.69, 120.71, 119.70, 112.63, 112.13, 109.44, 109.07, 102.16, 77.38, 77.07, 76.75, 31.33, 16.10, 10.48. HRMS (ESI): calculated value C 26 H 20 N4O3,[M+H] + m / z, 437.16137; found 437.15995.

[0212] Example 31: Synthesis of 7-cyclopropyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1-(4-(trifluoromethoxy)phenyl)-2(1H)-quinoxalinone (I-31)

[0213]

[0214] Synthesis of intermediate I-31A:

[0215] Using 2-fluoro-4-bromo-1-nitrobenzene (I-5A) (2.00 g, 9.11 mmol) and 4-trifluoromethoxyaniline (1.77 g, 10.0 mmol) as starting materials, the reaction procedure was the same as for compound I-5B to afford 3.05 g of a red solid in a yield of 88.9%. 1 H NMR (400MHz, CDCl3) δ (ppm) 9.48 (s, 1H), 8.10 (d, J = 9.1Hz, 1H), 7.33 (s, 4H), 7.31 (d, J = 2.0Hz, 1H), 6.95 (dd, J = 9.1, 2.0Hz, 1H).

[0216] Synthesis of intermediate I-31B:

[0217] Using intermediate I-31A (2.90 g, 7.69 mmol) and cyclopropylboronic acid (1.32 g, 15.38 mmol) as starting materials, the same procedure as for compound I-5C was used to obtain 2.35 g of a reddish-brown solid in a yield of 90.4%. 1H NMR (400MHz, CDCl3) δ (ppm) 9.52 (s, 1H), 8.12 (d, J = 8.9Hz, 1H), 7.42-7.17 (m, 4H), 6.93 (d, J = 1. 8Hz, 1H), 6.41 (dd, J = 8.9, 1.8Hz, 1H), 1.88-1.77 (m, 1H), 1.11-1.02 (m, 2H), 0.81-0.71 (m, 2H).

[0218] Synthesis of intermediate I-31C:

[0219] Using intermediate I-31B (2.20 g, 6.50 mmol) as starting material, the same procedure as compound I-5D was used to obtain 1.85 g of a dark brown liquid with a yield of 92.5%. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.07 (d, J = 8.3Hz, 2H), 6.87 (d, J = 1.9Hz, 1H), 6.81 (dd, J = 8.1, 2.0Hz, 1H), 6.75 (d, J = 8 .1Hz,1H),6.73-6.67(m,2H),5.26(s,1H),3.65(s,2H),1.86-1.76(m,1H),0.92-0.85(m,2H),0.63-0.55(m,2H).

[0220] Synthesis of intermediate I-31D:

[0221] Using intermediate I-31C (1.72 g, 5.59 mmol) as starting material, the same procedure was followed for compound I-5E to afford 1.18 g of a white solid in a yield of 58.4%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.06 (s, 1H), 7.78-7.44 (m, 4H), 7.13 (d, J = 8.3Hz, 1H), 6.82 (dd, J =8.3,1.7Hz,1H),6.06(d,J=1.7Hz,1H),1.87-1.64(m,1H),0.91-0.73(m,2H),0.51-0.28(m,2H).

[0222] Synthesis of intermediate I-31E:

[0223] Using intermediate I-31D (1.18 g, 3.26 mmol) as starting material, the same procedure was followed for compound I-5F to afford 931 mg of a white solid in a yield of 75.0%. 1H NMR (400MHz, CDCl3) δ (ppm) 7.75 (d, J = 8.4Hz, 1H), 7.51 (d, J = 8.2Hz, 2H), 7.41-7.34 (m, 2H), 6.96 (dd ,J=8.4,1.8Hz,1H),6.41(d,J=1.7Hz,1H),1.92-1.82(m,1H),1.09-1.00(m,2H),0.74-0.64(m,2H).

[0224] Synthesis of compound I-31:

[0225] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (70 mg, 0.33 mmol) and intermediate I-31E (125 mg, 0.33 mmol), the operation was the same as compound I-5 to obtain 74 mg of off-white solid with a yield of 47.0%. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.83 (s, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.04 (s, 1H), 7.99-7.86 (m, 2H), 7.54 (d, J = 8.4Hz, 2H), 7.45 (d, J = 8. 8Hz,2H),7.00(dd,J=8.4,1.6Hz,1H),6.41(d,J=1.5Hz,1H),3.92(s,3H),1.97-1.83(m,1H),1.11-0.99(m,2H),0.77-0.64(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 154.95, 151.95, 149.63, 147.49, 134.56, 133.61, 131.37, 130.62, 130.16, 130.12, 123.73, 122.80, 122.73, 121.72, 120.78, 119.93, 119.86, 119.15, 112.35, 112.02, 31.33, 16.08, 10.51. HRMS (ESI): calculated value C 26 H 19 F3N4O2,[M+H] + m / z, 477.1538; found 477.1535.

[0226] Example 32: Synthesis of 7-cyclopropyl-1-(4-(methoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-32)

[0227]

[0228] Synthesis of intermediate I-32A:

[0229] Using 2-fluoro-4-bromo-1-nitrobenzene (I-5A) (1.00 g, 4.55 mmol) and 4-methoxyaniline (615 mg, 5.00 mmol) as starting materials, the reaction procedure was the same as for compound I-5B to afford 1.24 g of a red solid in a yield of 84.4%. 1 H NMR (300MHz, CDCl3) δ (ppm) 9.44 (s, 1H), 8.08 (d, J = 9.1Hz, 1H), 7.25-7.18 (m, 2H), 7.14(d,J=2.0Hz,1H),7.04-6.97(m,2H),6.84(dd,J=9.1,2.0Hz,1H),3.88(s,3H).

[0230] Synthesis of intermediate I-32B:

[0231] Using intermediate I-32A (1.24 g, 3.84 mmol) and cyclopropylboronic acid (660 mg, 7.68 mmol) as starting materials, the same procedure as compound I-5C was used to obtain 1.05 g of a reddish-brown solid in a yield of 96.3%. 1 H NMR (400MHz, CDCl3) δ (ppm) 9.49 (s, 1H), 8.10 (d, J = 8.9Hz, 1H), 7.25-7.18 (m, 2H), 7.03-6.94 (m, 2H), 6.73 (d, J =1.8Hz,1H),6.31(dd,J=9.0,1.9Hz,1H),3.87(s,3H),1.81-1.73(m,1H),1.05-0.98(m,2H),0.75-0.67(m,2H).

[0232] Synthesis of intermediate I-32C:

[0233] Using intermediate I-32B (1.05 g, 3.69 mmol) as starting material, the same procedure as compound I-5D was used to obtain 937 mg of a dark brown liquid with a yield of 99.8%. 1 H NMR (300MHz, CDCl3) δ (ppm) 6.88-6.76 (m, 5H), 6.76-6.66 (m, 2H), 1.87-1.71 (m, 1H), 0.91-0.80 (m, 2H), 0.61-0.52 (m, 2H).

[0234] Synthesis of intermediate I-32D:

[0235] Using intermediate I-32C (780 mg, 3.07 mmol) as starting material, the same procedure as compound I-5E was used to obtain 610 mg of a white solid with a yield of 64.5%. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 12.04 (s, 1H), 7.36-7.25 (m, 2H), 7.23-7.05 (m, 3H), 6.80 (d, J = 8 .3Hz,1H),6.13(s,1H),3.86(s,3H),1.83-1.65(m,1H),0.91-0.75(m,2H),0.52-0.34(m,2H).

[0236] Synthesis of intermediate I-32E:

[0237] Using intermediate I-32D (583 mg, 1.89 mmol) as starting material, the same procedure as compound I-5F was used to obtain 551 mg of a white solid with a yield of 88.9%. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.72 (d, J = 8.4Hz, 1H), 7.25-7.19 (m, 2H), 7.18-7.11 (m, 2H), 6.96 (dd, J=8.4,1.7Hz,1H),6.47(d,J=1.6Hz,1H),1.90-1.82(m,1H),1.06-0.98(m,2H),0.71-0.63(m,2H).

[0238] Synthesis of compound I-32:

[0239] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (150 mg, 0.71 mmol) and intermediate I-32E (232 mg, 0.71 mmol), the reaction procedure was the same as for compound I-5. 175 mg of a light yellow solid was obtained with a yield of 58.3%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.87(s,1H),8.45-8.38(m,1H),8.00-7.85(m,3H),7.33-7.26(m,2H),7.22-7.14(m,2H),6.99 (dd,J=8.4,1.8Hz,1H),6.49(d,J=1.7Hz,1H),3.95(s,3H),3.90(s,3H),1.95-1.83(m,1H),1.12-0.96(m,2H),0.76-0.62(m,2H). 13C NMR (101 MHz, DMSO) δ (ppm) 159.96, 154.91, 152.10, 147.00, 146.33, 146.02, 145.24, 134.53, 134.42, 131.19, 130.68, 129.71, 128.91, 123.46, 120.50, 118.98, 115.55, 112.61, 112.09, 55.72, 31.20, 16.06, 10.52. HRMS (ESI): calcd. 26 H 22 N4O2,[M+H] + m / z, 423.18210; found 423.18047.

[0240] Example 33: Synthesis of 7-cyclopropyl-1-(3-(methoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-33)

[0241]

[0242] Synthesis of intermediate I-33A:

[0243] Using 2-fluoro-4-bromo-1-nitrobenzene (I-5A) (1.00 g, 4.55 mmol) and 3-methoxyaniline (615 mg, 5.00 mmol) as starting materials, the reaction procedure was the same as for compound I-5B to afford 1.20 g of a red solid in a yield of 81.7%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.51 (s, 1H), 8.09 (d, J = 9.1Hz, 1H), 7.46-7.32 (m, 2H), 6.98-6.74 (m, 4H), 3.86 (s, 3H).

[0244] Synthesis of intermediate I-33B:

[0245] Intermediate I-33A (1.20 g, 3.71 mmol) was used as the starting material and the same procedure was followed as for compound I-5C to afford 960 mg of a red liquid with a yield of 90.9%. 1H NMR(300MHz,Chloroform-d)δ(ppm)9.56(s,1H),8.11(d,J=8.9Hz,1H),7.34(t,J=8.1Hz,1H),7.02(d,J=1.8Hz,1H), 6.93-6.77(m,3H),6.39(dd,J=8.9,1.8Hz,1H),3.85(s,3H),1.88-1.75(m,1H),1.10-1.00(m,2H),0.80-0.69(m,2H).

[0246] Synthesis of intermediate I-33C:

[0247] Using intermediate I-33B (960 mg, 3.69 mmol) as starting material, the same procedure as compound I-5D was used to obtain 680 mg of a dark brown liquid with a yield of 79.2%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.14(t,J=8.1Hz,1H),6.90(d,J=1.8Hz,1H),6.79(dd,J=8.1,1.8Hz,1H),6.73(d,J=8.1Hz,1H),6.4 5-6.35(m,2H),6.34-6.30(m,1H),5.22(s,1H),3.78(s,3H),3.72-3.27(m,2H),1.91-1.71(m,1H),0.99-0.81(m,2H),0.66-0.45(m,2H).

[0248] Synthesis of intermediate I-33D:

[0249] Using intermediate I-33C (680 mg, 2.67 mmol) as starting material, the same procedure as compound I-5E was used to obtain 687 mg of a white solid with a yield of 83.3%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.06 (s, 1H), 7.55 (t, J = 8.1Hz, 1H), 7.18-7.06 (m, 2H), 7.00 (d, J = 2.0Hz, 1H), 6.95 (d, J = 7.8H z,1H),6.80(dd,J=8.3,1.5Hz,1H),6.14-6.03(m,1H),3.80(s,3H),1.82-1.68(m,1H),0.88-0.73(m,2H),0.52-0.27(m,2H).

[0250] Synthesis of intermediate I-33E:

[0251] Using intermediate I-33D (621 mg, 2.01 mmol) as starting material, the same procedure was followed for compound I-5F to afford 514 mg of a white solid in a yield of 78.1%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.73(d,J=8.4Hz,1H),7.56(t,J=8.1Hz,1H),7.18-7.09(m,1H),6.95(dd,J=8.4,1.8Hz,1 H),6.92-6.86(m,1H),6.83(t,J=2.2Hz,1H),6.46(d,J=1.8Hz,1H),1.92-1.80(m,1H),1.07-0.98(m,2H),0.73-0.57(m,2H).

[0252] Synthesis of compound I-33:

[0253] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (200 mg, 0.95 mmol) and intermediate I-33E (310 mg, 0.95 mmol), the reaction procedure was the same as for compound I-5 to give 189 mg of a light yellow solid in a yield of 47.2%. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.87 (s, 1H), 8.42 (d, J = 7.4Hz, 1H), 7.90 (t, J = 9.4Hz, 3H), 7.59 (t, J = 8.1Hz, 1H), 7.15 (dd, J = 8.4, 1.9Hz, 1H), 7.04 -6.94(m,2H),6.90(t,J=2.1Hz,1H),6.48(d,J=1.7Hz,1H),3.91(s,3H) ,3.89(s,3H),1.95-1.84(m,1H),1.07-0.98(m,2H),0.74-0.67(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 161.20, 154.97, 152.02, 147.22, 137.33, 133.84, 131.34, 131.16, 130.81, 129.85, 123.71, 120.64, 120.26, 119.85, 115.51, 113.61, 112.66, 112.20, 55.56, 31.38, 16.06, 10.44. HRMS (ESI): calculated value C 26 H 22 N4O2,[M+H] + m / z, 423.18210; found 423.18043.

[0254] Example 34: Synthesis of 7-cyclopropyl-1-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-34)

[0255]

[0256] Synthesis of intermediate I-34A:

[0257] Using 2-fluoro-4-bromo-1-nitrobenzene (I-5A) (1.00 g, 4.55 mmol) and 6-amino-1,4-benzodioxetine (755 mg, 5.00 mmol) as starting materials, the reaction procedure was the same as for compound I-5B. 1.59 g of a red solid was obtained with a yield of 99.6%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.39 (s, 1H), 8.07 (d, J = 9.1Hz, 1H), 7.21 (d, J = 2.0Hz, 1H), 6.95 (d, J = 8.5Hz, 1H), 6.85 (dd, J = 9.1, 2.0Hz, 1H), 6.81 (d, J = 2.4Hz, 1H), 6.76 (dd, J = 8.5, 2.5Hz, 1H), 4.33 (s, 4H).

[0258] Synthesis of intermediate I-34B:

[0259] Using intermediate I-34A (1.59 g, 4.55 mmol) and cyclopropylboronic acid (781 mg, 9.10 mmol) as starting materials, the same procedure as compound I-5C was used to obtain 1.17 g of a reddish-brown solid with a yield of 82.7%. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 9.46 (s, 1H), 8.09 (d, J = 8.9Hz, 1H), 6.93 (d, J = 8.5Hz, 1H), 6.83 (t, J = 2.1Hz, 2H), 6.77 (dd,J=8.5,2.4Hz,1H),6.31(dd,J=9.0,1.8Hz,1H),4.32(s,4H),1.86-1.74(m,1H),1.10-0.97(m,2H),0.82-0.66(m,2H).

[0260] Synthesis of intermediate I-34C:

[0261] Using intermediate I-34B (1.05 g, 3.36 mmol) as starting material, the same procedure as compound I-5D was used to obtain 910 mg of a dark brown liquid with a yield of 95.9%. 1H NMR (400MHz, Chloroform-d) δ (ppm) 6.84 (s, 1H), 6.79-6.74 (m, 1H), 6.71 (s, 2H), 4.2 9-4.20(m,4H),4.08(s,2H),1.84-1.73(m,1H),0.90-0.80(m,2H),0.62-0.54(m,2H).

[0262] Synthesis of intermediate I-34D:

[0263] Using intermediate I-34C (910 mg, 3.22 mmol) as starting material, the same procedure as compound I-5E was used to obtain 910 mg of a white solid in a yield of 83.9%. 1 H NMR(400MHz, DMSO-d6)δ(ppm)12.02(s,1H),7.09(dd,J=8.4,5.8Hz,2H),6.93(d,J=2.3Hz,1H),6.82(dd,J=8.5,2.4Hz,1H),6 .78(dd,J=8.3,1.7Hz,1H),6.20(d,J=1.5Hz,1H),4.39-4.29(m,4H),1.82-1.71(m,1H),0.87-0.79(m,2H),0.49-0.39(m,2H).

[0264] Synthesis of intermediate I-34E:

[0265] Using intermediate I-34D (844 mg, 2.51 mmol) as starting material, the same procedure as compound I-5F was used to obtain 544 mg of a white solid with a yield of 61.1%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.72(d,J=8.4Hz,1H),7.10(d,J=8.5Hz,1H),6.94(dd,J=8.4,1.7Hz,1H),6.83(d,J=2.4Hz,1H ), 6.76 (dd, J = 8.5, 2.4Hz, 1H), 6.53 (d, J = 1.7Hz, 1H), 4.43-4.33 (m, 4H), 1.94-1.82 (m, 1H), 1.08-0.99 (m, 2H), 0.76-0.63 (m, 2H).

[0266] Synthesis of compound I-34:

[0267] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (200 mg, 0.95 mmol) and intermediate I-34E (336 mg, 0.95 mmol), the reaction procedure was the same as for compound I-5 to give 215 mg of a light yellow solid in a yield of 47.2%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.87 (s, 1H), 8.42 (dd, J = 8.7, 1.4Hz, 1H), 7.9 7(s,1H),7.89(d,J=8.4Hz,2H),7.14(d,J=8.5Hz,1H),6.97(dd,J=8.4,1.7Hz,1H) ,6.90(d,J=2.4Hz,1H),6.83(dd,J=8.5,2.4Hz,1H),6.55(d,J=1.5Hz,1H),4.47-4 .30(m,4H),3.89(s,3H),1.97-1.82(m,1H),1.10-0.97(m,2H),0.86-0.62(m,2H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 155.26, 151.96, 147.14, 145.33, 145.09, 144.76, 144.39, 134.28, 134.09, 131.35, 130.83, 129.84, 129.16, 123.72, 121.05, 120.52, 119.76, 118.81, 117.28, 112.79, 112.12, 64.41, 64.33, 31.26, 16.09, 10.44, 10.42. HRMS (ESI): calculated value C 27 H 22 N4O3,[M+H] + m / z, 451.17702; found 451.17527.

[0268] Example 35: Synthesis of 7-cyclopropyl-1-(4-hydroxyphenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-35)

[0269]

[0270] Synthesis of intermediate I-35A:

[0271] 2-Fluoro-4-bromo-1-nitrobenzene (I-5A) (2.19 g, 10 mmol) was dissolved in DMF (50 mL), and DIPEA (10 mL) and 4-aminophenol (1.64 g, 15 mmol) were added. The reaction was allowed to react at room temperature for 24 h. After completion of the reaction, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1, v / v) to obtain 2.78 g of an orange-red solid, with a yield of 90.3%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.41 (s, 1H), 8.08 (d, J = 9.1Hz, 1H), 7.20-7.15 (m, 2 H), 7.13 (d, J = 2.0Hz, 1H), 6.98-6.92 (m, 2H), 6.85 (dd, J = 9.1, 2.0Hz, 1H), 5.06 (s, 1H).

[0272] Synthesis of intermediate I-35B:

[0273] Intermediate I-35A (2.45 g, 7.93 mmol) and imidazole (1.62 g, 23.8 mmol) were dissolved in THF (20 mL). TBDMSCl (3.0 g, 19.9 mmol) was added under ice-cooling and allowed to react at room temperature for 3 h. After completion of the reaction, saturated NaHCO₃ solution was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 3.19 g of an orange-red solid was obtained, with a yield of 95.1%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.43 (s, 1H), 8.07 (d, J = 9.1Hz, 1H), 7.18-7.10 (m,3H),6.99-6.90(m,2H),6.84(dd,J=9.1,2.0Hz,1H),1.03(s,9H),0.26(s,6H).

[0274] Synthesis of intermediate I-35C:

[0275] Using intermediate I-35B (1.59 g, 3.76 mmol) as starting material, the same procedure as compound I-5C was used to obtain 1.15 g of a reddish-brown solid with a yield of 79.6%. 1H NMR (400MHz, Chloroform-d) δ (ppm) 9.49 (s, 1H), 8.10 (d, J = 8.9Hz, 1H), 7.19-7.10 (m, 2H), 6.98-6.88 (m, 2H), 6.74(d,J=1.7Hz,1H), 6.31(dd,J=9.0,1.8Hz,1H), 1.83-1.71(m,1H), 1.06-0.97(m,11H), 0.75-0.67(m,2H).

[0276] Synthesis of intermediate I-35D:

[0277] Using intermediate I-35C (1.01 g, 2.63 mmol) as starting material, the same procedure as compound I-5D was used to obtain 850 mg of a dark brown liquid with a yield of 91.3%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 6.82 (d, J = 1.8Hz, 1H), 6.79-6.69 (m, 6H), 5.05 (s, 1H), 3. 64(s,1H),1.85-1.72(m,1H),1.01(s,9H),0.90-0.82(m,2H),0.62-0.54(m,2H),0.21(s,6H).

[0278] Synthesis of intermediate I-35E:

[0279] Using intermediate I-35D (850 mg, 2.40 mmol) as starting material, the same procedure as compound I-5E was used to obtain 810 mg of a white solid with a yield of 82.7%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.02 (d, J = 5.7Hz, 1H), 7.25 (d, J = 8.6Hz, 1H), 7.18-7.05 (m, 3H), 6.96 (d, J = 8.6Hz, 1H), 6.82 (dd, J=14.0,8.3Hz,1H),6.08(d,J=45.8Hz,1H),1.79-1.68(m,1H),1.00(s,9H),0.87-0.71(m,2H),0.47-0.33(m,2H),0.28(s,6H).

[0280] Synthesis of intermediate I-35F:

[0281] Using intermediate I-35E (650 mg, 1.59 mmol) as starting material, the same procedure as compound I-5F was used to obtain 410 mg of a white solid in a yield of 60.4%. 1H NMR(400MHz,Chloroform-d)δ(ppm)7.72(d,J=8.4Hz,1H),7.18-7.13(m,2H),7.11-7.04(m,2H),6.97(dd,J=8 .4,1.8Hz,1H),6.44(d,J=1.7Hz,1H),1.91-1.77(m,1H),1.12-0.97(m,11H),0.74-0.58(m,2H),0.30(s,6H).

[0282] Synthesis of intermediate I-35G:

[0283] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (200 mg, 0.95 mmol) and intermediate I-35F (336 mg, 0.95 mmol), the reaction procedure was the same as for compound I-5 to give 215 mg of a light yellow solid in a yield of 47.2%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.84 (d, J = 1.2 Hz, 1H), 8.41 (dd, J = 8.7, 1.6 Hz,1H),7.95(s,1H),7.89(dd,J=8.5,2.6Hz,2H),7.25-7.20(m,2H),7.14-7.0 9(m,2H),7.00(dd,J=8.4,1.8Hz,1H),6.44(d,J=1.7Hz,1H),3.90(s,3H),1.93 -1.82(m,1H),1.06(s,9H),1.05-0.99(m,2H),0.72-0.65(m,2H),0.32(s,6H).

[0284] Synthesis of compound I-35:

[0285] Intermediate I-35H (70 mg, 0.13 mmol) was dissolved in THF (3 mL). 1 mol / L TBAF solution (0.26 mL) was added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane / ethyl acetate = 1 / 1, v / v) to obtain 51 mg of a white solid, with a yield of 93.2%. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.91 (s, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 8.22 (dd, J = 8.6, 1.4 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.29-7.17 (m, 2H), 7.10-6.95 (m, 2H), 6.39 (d, J = 1.5 Hz, 1H), 3.89 (s, 3H), 1.99-1.87 (m, 1H), 1.06-0.93 (m, 2H), 0.70-0.51 (m, 2H). HRMS (ESI): calculated value C 25 H 20 N4O2,[M+H] + m / z, 409.16645; found 409.16448.

[0286] Example 36: Synthesis of 7-cyclobutyl-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-36)

[0287]

[0288] Synthesis of intermediate I-36B:

[0289] 3-Fluoro-4-nitrophenol I-36A (1.5 g, 9.55 mmol) and pyridine (0.76 g, 9.55 mmol) were dissolved in DCM (15 mL). Trifluoromethanesulfonic anhydride (3.3 g, 11.46 mmol) was slowly added under an ice bath and allowed to react for 2 h. After completion of the reaction, saturated NH4Cl solution was added to quench the reaction, and the mixture was extracted with DCM (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2.52 g of a brown liquid (90.4% yield). 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.28-8.21 (m, 1H), 7.37-7.26 (m, 2H).

[0290] Synthesis of intermediate I-36C:

[0291] Intermediate I-36B (2.4 g, 8.3 mmol), cyclobutylboronic acid (995 mg, 9.96 mmol), cesium carbonate (4.1 g, 12.6 mmol), and Pd(dppf)Cl2 (607 mg, 0.83 mmol) were dissolved in toluene (15 mL) and water (7 mL) under nitrogen atmosphere at 95°C for 6 h. After completion of the reaction, water (50 mL) and EA (50 mL) were added for dilution, and the mixture was filtered through Celite. The filtrate was separated, and the aqueous phase was extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25 / 1 to 10 / 1, v / v) to obtain 710 mg of a yellow liquid in a 43.9% yield. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.01(t,J=8.0Hz,1H),7.11(d,J=9.8Hz,2H ),3.71-3.53(m,1H),2.51-2.29(m,2H),2.28-2.03(m,3H),2.00-1.83(m,1H).

[0292] Synthesis of intermediate I-36D:

[0293] Using intermediate I-36C (710 mg, 3.64 mmol) and 4-difluoromethoxyaniline (580 mg, 3.64 mmol) as starting materials, the same procedure as compound I-5B was used to obtain 690 mg of a red solid in a yield of 56.7%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)9.52(s,1H),8.17(d,J=8.8Hz,1H),7.33-7.27(m,2H),7.21(d,J=8.8Hz,2H),6.95(s,1H),6 .69(dd,J=8.8,1.6Hz,1H),6.57(t,J=73.7Hz,1H),3.55-3.39(m,1H),2.40-2.21(m,2H),2.14-1.98(m,3H),1.92-1.79(m,1H).

[0294] Synthesis of intermediate I-36E:

[0295] Using intermediate I-36D (680 mg, 2.03 mmol) as starting material, the same procedure as compound I-5D was used to obtain 510 mg of a dark brown liquid with a yield of 82.4%. 1H NMR(400MHz,Chloroform-d)δ(ppm)7.07-6.96(m,3H),6.92(dd,J=8.0,1.7Hz,1H),6.78(d,J=8.0Hz,1H),6.75-6.69(m,2H), 6.43(t,J=74.7Hz,1H),5.22(s,1H),3.69(s,2H),3.50-3.34(m,1H),2.36-2.23(m,2H),2.14-1.91(m,3H),1.88-1.75(m,1H).

[0296] Synthesis of intermediate I-36F:

[0297] Intermediate I-36E (500 mg, 1.64 mmol) was used as the starting material and the same procedure was followed for compound I-5E to afford 410 mg of a light gray solid in a yield of 69.6%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.09 (s, 1H), 7.45 (q, J = 8.9Hz, 4H), 7.41 (t, J = 73.7Hz, 1H), 7.18 (d, J = 8.2Hz, 1H) ,7.09(d,J=8.2Hz,1H),6.12(s,1H),3.34-3.27(m,1H),2.18-2.09(m,2H),1.91-1.80(m,3H),1.74-1.65(m,1H).

[0298] Synthesis of intermediate I-36G:

[0299] Intermediate I-36F (400 mg, 1.12 mmol) was used as the starting material and the same procedure was followed for compound I-5F to afford 388 mg of a light gray solid in a yield of 92.3%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.80(d,J=8.3Hz,1H),7.44-7.38(m,2H),7.36-7.32(m,2H),7.30(d,J=1.6Hz,1H),6 .67(t,J=73.1Hz,1H),6.45(d,J=1.3Hz,1H),3.57-3.45(m,1H),2.36-2.23(m,2H),2.10-1.96(m,3H),1.88-1.79(m,1H).

[0300] Synthesis of compound I-36

[0301] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (120 mg, 0.57 mmol) and intermediate I-36G (147 mg, 0.57 mmol), the reaction procedure was the same as for compound I-5 to afford 78 mg of a light yellow solid in a yield of 66.5%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.82(s,1H),8.42(dd,J=8.7,1.3Hz,1H),7.97(d,J=8.4Hz,2H),7.89(d,J=8.7Hz,1H),7.49-7.38(m,4H),7.32 (d,J=8.3Hz,1H),6.67(t,J=73.2Hz,1H),6.46(s,1H),3.89(s,3H),3.54( p,J=8.6Hz,1H),2.39-2.24(m,2H),2.15-1.97(m,3H),1.90-1.76(m,1H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 155.09, 152.42, 151.57, 149.08, 145.56, 145.29, 134.35, 133.62, 133.21, 131.53, 130.62, 130.03, 129.96, 123.73, 122.73, 121.23, 119.88, 118.28, 115.68, 113.09, 112.56, 112.04, 40.47, 31.27, 29.72, 18.12. HRMS (ESI): calculated value C 27 H 22 F2N4O2,[M+H] + m / z, 473.17891; found 473.17690.

[0302] Example 37: Synthesis of 1-(4-(difluoromethoxy)phenyl)-7-methoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(1H)-quinoxalinone (I-37)

[0303]

[0304] Synthesis of intermediate I-37A:

[0305] Disperse 3-fluoro-4-nitrophenol I-36A (1.5 g, 9.55 mmol) and potassium carbonate (2.64 g, 19.10 mmol) in acetone (10 mL). Slowly add iodomethane (1.63 g, 11.46 mmol) and allow to react overnight at room temperature. After completion, quench the reaction with water (50 mL) and extract with EA (50 mL x 3). The combined organic phases are washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A brown solid (1.49 g) is obtained, yielding 91.2%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.20-7.99 (m, 1H), 6.85-6.66 (m, 2H), 3.92 (s, 3H).

[0306] Synthesis of intermediate I-37B:

[0307] Using intermediate I-37A (1.4 g, 8.18 mmol) and 4-difluoromethoxyaniline (1.3 g, 8.18 mmol) as starting materials, the same procedure as for compound I-5B was used to obtain 1.32 g of an orange solid with a yield of 52.0%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)9.71(s,1H),8.22(d,J=9.5Hz,1H),7.32(d,J=8.8Hz,2H),7.24- 7.19 (m, 2H), 6.56 (t, J = 73.6Hz, 1H), 6.48 (d, J = 2.6Hz, 1H), 6.38 (dd, J = 9.5, 2.6Hz, 1H), 3.77 (s, 3H).

[0308] Synthesis of intermediate I-37C:

[0309] Using intermediate I-37B (1.32 g, 4.25 mmol) as starting material, the same procedure as compound I-5D was used to obtain 1.19 g of a dark brown liquid with a yield of 99.8%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.06-6.99 (m, 2H), 6.88-6.82 (m, 2H), 6.79 (d, J = 8.6Hz, 1H), 6. 75(d,J=2.7Hz,1H),6.58(dd,J=8.6,2.7Hz,1H),6.44(t,J=74.6Hz,1H),5.30(s,2H),3.74(s,3H).

[0310] Synthesis of intermediate I-37D:

[0311] Using intermediate I-37C (1.1 g, 3.92 mmol) as starting material, the same procedure as compound I-5E was used to obtain 978 mg of a light gray solid with a yield of 74.5%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.02 (s, 1H), 7.51-7.44 (m, 2H), 7.42 (d, J = 8.9Hz, 2H), 7.40 (t, J = 7 3.7Hz, 1H), 7.17 (d, J = 8.8Hz, 1H), 6.81 (dd, J = 8.8, 2.6Hz, 1H), 5.79 (d, J = 2.6Hz, 1H), 3.59 (s, 3H).

[0312] Synthesis of intermediate I-37E:

[0313] Using intermediate I-37D (950 mg, 2.84 mmol) as starting material, the same procedure as compound I-5F was used to obtain 854 mg of a light gray solid in a yield of 85.2%. 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.79(d,J=8.9Hz,1H),7.43-7.31(m,4H),6.96 (dd, J=8.9, 2.6Hz, 1H), 6.66 (t, J=73.0Hz, 1H), 6.11 (d, J=2.6Hz, 1H), 3.76 (s, 3H).

[0314] Synthesis of compound I-37:

[0315] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (120 mg, 0.57 mmol) and intermediate I-37F (200 mg, 0.57 mmol), the reaction procedure was the same as for compound I-5 to afford 113 mg of a light yellow solid in a yield of 44.2%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.78(s,1H),8.39(dd,J=8.7,1.2Hz,1H),8.01-7.78(m,3H),7.47-7.35( m, 4H), 6.99 (dd, J = 8.9, 2.5Hz, 1H), 6.65 (t, J = 73.2Hz, 1H), 6.13 (d, J = 2.5Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H). 13C NMR (101 MHz, CDCl3) δ (ppm) 161.00, 155.14, 151.60, 150.27, 145.10, 135.34, 133.25, 131.52, 130.75, 129.95, 128.14, 123.58, 121.35, 119.79, 118.23, 115.64, 113.04, 111.78, 111.44, 99.31, 55.71, 31.26. HRMS (ESI): calculated value C 24 H 18 F2N4O2,[M+H] + m / z, 449.14252; found 449.14040.

[0316] Example 38: Synthesis of 1-(4-(difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)quinoxalin-2(1H)-one (I-38)

[0317]

[0318] Synthesis of intermediate I-38A:

[0319] Using 3-fluoro-4-nitrophenol I-36A (1.5 g, 9.55 mmol) and iodoethane (1.79 g, 11.46 mmol) as starting materials, the reaction procedure was the same as for compound I-37A. 1.52 g of a brown solid was obtained with a yield of 86.0%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.10 (t, J = 8.9 Hz, 1H), 6.92-6.33 (m, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H).

[0320] Synthesis of intermediate I-38B:

[0321] Using intermediate I-38A (1.4 g, 7.56 mmol) and 4-difluoromethoxyaniline (1.2 g, 7.56 mmol) as starting materials, the operation was the same as compound I-5B to obtain 1.38 g of an orange solid with a yield of 56.0%. 1H NMR (400MHz, Chloroform-d) δ (ppm) 9.70 (s, 1H), 8.21 (d, J = 9.5Hz, 1H), 7.34-7.29 (m, 2H), 7.25-7.17 (m, 2H ), 6.78-6.37 (m, 1H), 6.47 (d, J = 2.5Hz, 1H), 6.41-6.33 (m, 1H), 3.98 (q, J = 7.0Hz, 2H), 1.40 (t, J = 7.0Hz, 3H).

[0322] Synthesis of intermediate I-38C:

[0323] Using intermediate I-38B (1.3 g, 4.0 mmol) as starting material, the same operation as compound I-5D was used to obtain 1.09 g of a dark brown liquid with a yield of 92.4%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.07-6.99 (m, 2H), 6.86-6.80 (m, 2H), 6.77 (d, J = 8.6Hz, 1H), 6.74 (d, J = 2.7Hz, 1H), 6.58 (dd, J = 8.6, 2.7Hz, 1H), 6.44 (t, J = 74.6Hz, 1H), 3.95 (q, J = 7.0Hz, 2H), 3.61 (s, 2H), 1.38 (t, J = 7.0Hz, 3H).

[0324] Synthesis of intermediate I-38D:

[0325] Using intermediate I-38C (1.0 g, 3.4 mmol) as starting material, the same procedure was followed for compound I-5E to afford 1.04 mg of a light gray solid in a yield of 87.9%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.02 (s, 1H), 7.55-7.31 (m, 4H), 7.40 (t, J = 73.7Hz, 1H), 7.15 (d, J = 8.8H z, 1H), 6.80 (dd, J = 8.8, 2.6Hz, 1H), 5.78 (d, J = 2.5Hz, 1H), 3.83 (q, J = 6.9Hz, 2H), 1.21 (t, J = 6.9Hz, 3H).

[0326] Synthesis of intermediate I-38E:

[0327] Using intermediate I-38D (950 mg, 2.73 mmol) as starting material, the same procedure as compound I-5F was used to obtain 775 mg of a light gray solid with a yield of 77.5%. 1H NMR(300MHz,Chloroform-d)δ(ppm)7.78(d,J=8.9Hz,1H),7.44-7.30(m,4H),6.94(dd,J=8.9,2.6H z, 1H), 6.66 (t, J = 73.1Hz, 1H), 6.10 (d, J = 2.6Hz, 1H), 3.96 (q, J = 7.0Hz, 2H), 1.39 (t, J = 7.0Hz, 3H).

[0328] Synthesis of compound I-38:

[0329] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (120 mg, 0.57 mmol) and intermediate I-38E (209 mg, 0.57 mmol), the reaction procedure was the same as for compound I-5 to afford 149 mg of a light yellow solid in a yield of 56.5%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.79(s,1H),8.39(dd,J=8.7,1.5Hz,1H),8.00-7.85(m,3H),7.41(t,J=2.9Hz,4H),6.97(d d,J=8.9,2.6Hz,1H),6.66(t,J=73.2Hz,1H),6.11(d,J=2.5Hz,1H),3.98(q,J=7.0Hz,2H),3.89(s,3H),1.40(t,J=7.0Hz,3H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 160.40, 155.15, 151.60, 150.12, 145.16, 135.35, 134.38, 133.27, 131.47, 130.77, 129.97, 128.04, 123.55, 121.31, 119.78, 118.26, 115.66, 113.06, 111.76, 111.75, 99.85, 64.09, 31.25, 14.59. HRMS (ESI): calculated value C 25 H 20 F2N4O3,[M+H] + m / z, 463.15817; found 463.15662.

[0330] Example 39: Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-isopropyl-quinoxaline-2(1H)-one (I-39)

[0331]

[0332] Synthesis of intermediate I-39A:

[0333] 3-Fluoro-4-nitrophenol I-36A (1.5 g, 9.55 mmol), triphenylphosphine (3.76 g, 14.33 mmol), and isopropanol (861 mg, 14.33 mmol) were dispersed in THF (30 mL). DIAD (2.90 g, 14.33 mmol) was slowly added under nitrogen and ice-cooled. The mixture was allowed to react overnight at room temperature. After completion, the reaction was quenched with water (100 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1, v / v) to obtain 1.84 g of a light yellow liquid, with a yield of 96.8%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.09 (t, J = 9.2 Hz, 1H), 6.91-6.56 (m, 2H), 4.76-4.52 (m, 1H), 1.40 (d, J = 6.1 Hz, 6H).

[0334] Synthesis of intermediate I-39B:

[0335] Using intermediate I-39A (1.0 g, 5.02 mmol) and 4-difluoromethoxyaniline (800 mg, 5.02 mmol) as starting materials, the same procedure as compound I-5B was used to obtain 1.27 g of a red solid with a yield of 74.8%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.67 (s, 1H), 8.20 (d, J = 9.5Hz, 1H), 7.39-7.15 (m, 4H), 6.56 (t, J = 73 .6Hz, 1H), 6.45 (d, J = 2.6Hz, 1H), 6.35 (dd, J = 9.5, 2.6Hz, 1H), 4.56-4.43 (m, 1H), 1.32 (d, J = 6.1Hz, 6H).

[0336] Synthesis of intermediate I-39C:

[0337] Using intermediate I-39B (1.2 g, 3.55 mmol) as starting material, the same procedure as compound I-5D was used to obtain 910 mg of a dark brown liquid with a yield of 83.2%. 1H NMR(400MHz,Chloroform-d)δ(ppm)7.06-7.00(m,2H),6.84-6.79(m,2H),6.79-6.71(m,2H),6.59(dd,J=8 .5, 2.7Hz, 1H), 6.44 (t, J = 74.6Hz, 1H), 5.32 (s, 1H), 4.47-4.29 (m, 1H), 3.12 (s, 2H), 1.30 (d, J = 6.1Hz, 6H).

[0338] Synthesis of intermediate I-39D:

[0339] Using intermediate I-39C (890 mg, 2.89 mmol) as starting material, the same procedure as compound I-5E was used to obtain 811 mg of a light gray solid in a yield of 77.5%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.98 (s, 1H), 7.50-7.40 (m, 4H), 7.39 (t, J = 73.8Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.5Hz, 1H), 5.75 (d, J = 2.5Hz, 1H), 4.44-4.25 (m, 1H), 1.14 (d, J = 6.0Hz, 6H).

[0340] Synthesis of intermediate I-39E:

[0341] Using intermediate I-39D (800 mg, 2.21 mmol) as starting material, the same procedure was followed for compound I-5F to afford 810 mg of a light gray solid in a yield of 96.3%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.77 (d, J = 8.9 Hz, 1H), 7.43-7.30 (m, 4H), 6.93 (dd, J = 9.0, 2. 5Hz, 1H), 6.66 (t, J = 73.1Hz, 1H), 6.08 (d, J = 2.5Hz, 1H), 4.54-4.43 (m, 1H), 1.30 (d, J = 6.1Hz, 6H).

[0342] Synthesis of compound I-39:

[0343] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (120 mg, 0.57 mmol) and intermediate I-39E (220 mg, 0.57 mmol), the reaction procedure was the same as for compound I-5 to afford 145 mg of a light yellow solid in a yield of 53.4%. 1H NMR (400MHz, Chloroform-d) δ (ppm) 8.78 (s, 1H), 8.38 (d, J = 8.5Hz, 1H), 8.01-7.77 (m, 4H), 7.40 (t, J = 5.7Hz, 4H), 6. 96 (d, J = 8.9 Hz, 1H), 6.66 (t, J = 73.2 Hz, 1H), 6.10 (s, 1H), 4.52 (p, J = 5.9 Hz, 1H), 3.88 (s, 3H), 1.32 (d, J = 6.0 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 159.38, 155.16, 151.57, 150.10, 145.24, 145.08, 135.44, 134.33, 133.29, 131.46, 130.77, 129.97, 127.91, 123.53, 121.33, 119.81, 118.26, 115.66, 113.06, 112.30, 111.74, 101.21, 70.58, 31.25, 21.83. HRMS (ESI): calculated value C 26 H 22 F2N4O3,[M+H] + m / z, 477.17382; found 477.17212.

[0344] Example 40: Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(2,2,2-trifluoroethoxy)-2(1H)-quinoxalinone (I-40)

[0345]

[0346] Synthesis of intermediate I-40A:

[0347] 3-Fluoro-4-nitrophenol I-36A (1.5 g, 9.55 mmol) was dissolved in DMF (20 mL). NaH (575 mg, 14.33 mmol, 60% content) was added under ice-cooling and stirred for 30 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (2.5 g, 10.51 mmol) was then slowly added. The reaction mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was poured into ice water (100 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1, v / v) to obtain 1.59 g of a yellow liquid, with a yield of 69.6%. 1H NMR (400MHz, Chloroform-d) δ (ppm) 8.35-7.96 (m, 1H), 7.00-6.75 (m, 2H), 4.48 (q, J = 7.8Hz, 2H).

[0348] Synthesis of intermediate I-40B:

[0349] Using intermediate I-40A (1.0 g, 4.20 mmol) and 4-difluoromethoxyaniline (668 mg, 4.20 mmol) as starting materials, the same procedure as compound I-5B was used to obtain 1.05 g of a red solid in a yield of 66.4%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.65 (s, 1H), 8.27 (d, J = 9.5Hz, 1H), 7.50-7.15 (m, 4 H), 6.79-6.37 (m, 1H), 6.52 (d, J = 2.6Hz, 1H), 6.44-6.37 (m, 1H), 4.31 (q, J = 7.9Hz, 2H).

[0350] Synthesis of intermediate I-40C:

[0351] Using intermediate I-40B (1.0 g, 2.64 mmol) as starting material, the same procedure as compound I-5D was used to obtain 604 mg of a dark brown liquid with a yield of 65.6%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.09-7.02(m,2H),6.87-6.74(m,4H),6.61(dd,J=8 .6, 2.8Hz, 1H), 6.45 (t, J = 74.4Hz, 1H), 5.33 (s, 1H), 4.27 (q, J = 8.3Hz, 2H), 3.45 (s, 2H).

[0352] Synthesis of intermediate I-40D:

[0353] Using intermediate I-40C (550 mg, 1.58 mmol) as starting material, the same procedure as compound I-5E was used to obtain 602 mg of a light gray solid with a yield of 95.1%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.06 (s, 1H), 7.50-7.40 (m, 4H), 7.39 (t, J = 73.7Hz, 1H), 7.19 (d, J=8.8Hz, 1H), 6.94 (dd, J=8.8, 2.6Hz, 1H), 5.90 (d, J=2.6Hz, 1H), 4.63 (q, J=8.9Hz, 2H).

[0354] Synthesis of intermediate I-40E

[0355] Using intermediate I-40D (550 mg, 1.37 mmol) as starting material, the same procedure as compound I-5F was used to obtain 509 mg of a light gray solid with a yield of 88.5%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.85(d,J=8.9Hz,1H),7.44-7.39(m,2H),7.37-7.30(m,2H), 6.97 (dd, J=8.9, 2.7Hz, 1H), 6.67 (t, J=73.0Hz, 1H), 6.21 (d, J=2.6Hz, 1H), 4.31 (q, J=7.9Hz, 2H).

[0356] Synthesis of compound I-40:

[0357] Starting from 6-bromo-1-methyl-1H-benzo[d]imidazole (120 mg, 0.57 mmol) and intermediate I-40E (215 mg, 0.57 mmol), the reaction procedure was the same as for compound I-5 to afford 127 mg of a light yellow solid in a yield of 48.1%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.80(s,1H),8.40(dd,J=8.6,1.2Hz,1H),8.00(d,J=8.9Hz,2H),7.89(d,J=8.7Hz,1H),7.5 0-7.36(m,4H),6.99(dd,J=8.9,2.6Hz,1H),6.67(t,J=73.1Hz,1H),6.21(d,J=2.6Hz,1H),4.33(q,J=7.9Hz,2H),3.90(s,3H). 13 C NMR (101 MHz, CDCl3) δ (ppm) 158.20, 154.97, 151.76, 151.49, 145.33, 135.27, 132.84, 131.81, 130.43, 129.89, 128.99, 124.30, 123.65, 121.54, 121.44, 119.87, 118.20, 115.60, 113.00, 112.01, 111.06, 101.00, 66.36, 66.00, 65.64, 65.28, 31.29. HRMS (ESI): calculated for C 25 H 17 F5N4O3,[M+H] + m / z, 517.12991; found 517.12807.

[0358] Example 41: Determination of the activity of the compounds of the present invention on MAT2A enzyme

[0359] The human recombinant protein MAT2A used in the experiment was purchased from BPS Bioscience; ATP was purchased from Invitrogen; L-methionine was purchased from Dalian Meilun; Kinase-Glo Max reagent was purchased from Promega; all other reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.; 384-reaction microplates were purchased from PerkinElmer; the multifunctional microplate reader was a product of Tecan, model: Spark Cyto; and the experimental water was distilled water produced by Sinopharm Group.

[0360] Compound preparation: The compound was centrifuged at 12000 g for 5 min and DMSO was added to prepare 10 -2 M stock solution, vortex evenly, sonicate for 10 minutes before use, and store at -20°C. The final DMSO concentration in the system during testing was 1%.

[0361] Experimental method: (1) Enzymatic reaction: Add 2 μL of compound and 4 μL of enzyme buffer (Tris buffer: 50 mM Tris, 50 mM KCl, 15 mM MgCl2, 0.3 mM EDTA, 0.05% BSA pH 8.0) to a 384-well plate, incubate at room temperature in the dark for 10 min, then add 2 μL of mixed substrate (containing 320 μM L-Methionine and 320 μM ATP) and incubate at 37°C for 60 min; (2) Detection reaction: Add 8 μL of Kinase-Glo solution to each well and incubate at 37°C for 15 min; (3) Plate reading: The luminescence signal is read by a multifunctional microplate reader (Tecan Spark Cyto); (4) The inhibition rate of the compound on MAT2A is calculated by the following formula, and the IC value of the compound on MAT2A enzyme activity inhibition is calculated using Graphpadprism software. 50 In this experiment, AGI-24512 and AGI-41998 from Agios were used as positive control drugs.

[0362] The calculation formula of the inhibition rate of the test compound on MAT2A enzyme activity is:

[0363] Inhibition rate (%) = (fluorescence value of compound well - fluorescence value of enzyme control well) / (fluorescence value of ATP well - fluorescence value of enzyme control well) × 100%

[0364] The inhibitory activity of the compounds of the present invention on MAT2A enzyme was determined according to the above experimental method. The results are shown in Table 1:

[0365] Table 1 IC inhibition of MAT2A enzyme activity by compounds 50

[0366] Test compound <![CDATA[MAT2AIC 50 (nM)]]> Test compound <![CDATA[MAT2A IC 50 (nM)]]> I-1 23.1±2.7 I-22 131.4±15.3 I-2 54.8±4.1 I-23 136.8±21.2 I-3 106.1±28.2 I-24 202.4±23.4 I-4 613.2±116.0 I-25 117.9±7.6 I-5 49.0±8.8 I-26 368.0±37.2 I-6 138.0±37.6 I-27 163.7±10.3 I-7 252.7±25.0 I-28 152.0±26.5 I-8 309.0±30.1 I-29 159.7±20.6 I-9 471.4±81.0 I-30 >1000 I-10 89.2±10.9 I-31 201.8±4.2 I-11 98.5±4.3 I-32 642.6±28.2 I-12 174.3±52.2 I-33 >1000 I-13 63.9±8.1 I-34 589.4±22.8 I-14 115.4±17.7 I-35 264.3±6.6 I-15 81.4±0.8 I-36 228.3±2.0 I-16 76.3±28.1 I-37 94.3±10.0 I-17 79.2±15.8 I-38 106.5±0.8 I-18 103.3±29.8 I-39 203.1±18.7 I-19 28.9±2.5 I-40 284.1±4.0 I-20 87.5±23.9 AGI-24512 139.0±4.5 I-21 154.5±16.5 AGI-41998 56.1±3.2

[0367] Example 42: Determination of the selectivity of the compounds of the present invention for inhibiting proliferation of constructed MTAP wild-type and deletion cells

[0368] The reagents used in the experiment, such as sulforhodamine B and cell culture-related culture media, were purchased from Dalian Meilun Biotechnology Co., Ltd.; other conventional reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.; the experimental water was distilled water produced by Sinopharm Group; and the full-wavelength microplate reader used for plate reading was a product of Molecular Devices, model: SpectraMax 190.

[0369] Cell lines: The constructed MTAP wild-type (B16F10 MTAP WT) and MTAP deletion (B16F10 MTAP KO) cells were derived from the Yantai New Drug Creation Shandong Provincial Laboratory. The cell lines were constructed based on CRISPR / Cas9 gene editing technology (reference for construction method: Yuanwu Ma et al. Genome modification by CRISPR / Cas9, FEBS J 2014, 281(23):5186-5193.). The parental cell line B16F10 was purchased from ATCC.

[0370] Experimental method: The cell growth inhibition test adopts the SRB method. The specific steps are as follows: 200 cells / well in the logarithmic growth phase are seeded into a 96-well culture plate, 100 μL per well, and cultured in a 37°C, 5% CO2 incubator overnight. Then, different concentrations of drugs are added to act for 96 hours, and three replicate wells are set for each concentration, and DMSO wells with corresponding concentrations are set as controls; continue to culture until the end of the action, discard the supernatant, add 100 μL TCA fixative to each well and store at 4°C for 1 hour. Wash with tap water 5 times and dry in an oven; add 100 μL of SRB to each well, place at room temperature for 20 minutes, wash 5 times with 1% glacial acetic acid, and dry; add 100 μL Tris to each well for re-dissolution, and measure the optical density (OD value) at a wavelength of 560 nm with a SpectraMax190 enzyme reader. The inhibition rate of the compound on cell proliferation is calculated by the following formula:

[0371] Inhibition rate (%) = (OD 对照孔 -OD 给药孔 ) / OD 对照孔 ×100%

[0372] IC 50 The values ​​were calculated using the four-parameter fitting method using the enzyme reader software.

[0373] The effects of the compounds of the present invention on the proliferation of constructed B16F10 MTAP WT and B16F10 MTAPKO cells were determined according to the above experimental method. The results showed that the compounds of the present invention can selectively inhibit B16F10 MTAP-deficient cells (Table 2).

[0374] Table 2 Inhibitory activity and selectivity of compounds against constructed MTAP wild-type and deletion cell proliferation

[0375]

[0376] Note: *SI: IC value of compound on B16F10 MTAP WT cells 50 IC of compounds on B16F10 MTAP KO cells 50

[0377] Example 43: Pharmacokinetic study of the compound of the present invention in SD rats

[0378] Experimental animals: Male SD rats (6-8 weeks, 180-200 g), 3 for each dosage form, were purchased from Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.

[0379] Test sample preparation:

[0380] (1) Accurately weigh an appropriate amount of the test compound, add 10% NMP, 10% HS, and 80% normal saline (all percentages by volume) in sequence, and mix thoroughly by ultrasonication to obtain a dosing solution with a test compound concentration of 0.5 mg / mL for intravenous administration.

[0381] (2) Accurately weigh an appropriate amount of the test compound, add 5% DMSO, 25% PEG400, 2% Tween 80, and 68% saline in sequence, and mix thoroughly by ultrasonication to obtain a dosing solution with a test sample concentration of 1 mg / mL for oral administration by gavage.

[0382] Dosage: Weigh the rats before administration and calculate the dosage based on their body weight.

[0383] Blood collection time points: 0.033h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 14h, and 24h after administration.

[0384] Sample Collection and Processing: At each time point, 150 μL of blood was collected from the eye socket and anticoagulated with sodium heparin. Blood samples were centrifuged at 4000 rpm for 10 minutes, and the supernatant plasma was collected. At each time point, 20 μL of plasma was added to 180 μL of acetonitrile, vortexed, and centrifuged at 18,000 g for 10 minutes. The supernatant was collected and subjected to LC-MS / MS quantitative analysis. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin software.

[0385] The pharmacokinetic properties of compounds I-2 and I-5 of the present invention in SD rats were determined according to the above experimental method. The results showed that the compounds of the present invention exhibited excellent pharmacokinetic properties in rats (Table 3).

[0386] Table 3 Pharmacokinetic parameters of the compounds in SD rats

[0387]

[0388] Note: iv: intravenous injection; po: oral administration; CL: apparent clearance; T 1 / 2 : Half-life; AUC 0-t : area under the drug-time curve from the start of drug administration to the last point (24 h); C max : peak concentration; F: relative bioavailability.

[0389] Example 44: Pharmacokinetic Study of Compounds in ICR Mice

[0390] Experimental animals: Male ICR mice (6-8 weeks, 18-22 g), 3 for each formulation, purchased from Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.

[0391] Test sample preparation:

[0392] (1) Accurately weigh an appropriate amount of the test compound, add 10% NMP, 10% HS, and 80% normal saline (all percentages by volume) in sequence, and mix thoroughly by ultrasonication to obtain a dosing solution with a test compound concentration of 0.2 mg / mL for intravenous administration.

[0393] (2) Accurately weigh an appropriate amount of the test compound, add 5% DMSO, 25% PEG400, 2% Tween 80, and 68% saline in sequence, and vortex or sonicate to mix thoroughly to obtain a dosing solution with a test compound concentration of 0.6 mg / mL for oral administration by gavage.

[0394] Dosage method: Weigh the mice before administration and calculate the dosage based on their body weight.

[0395] Blood collection time points: 0.033h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 14h, 24h, 36h after administration.

[0396] Sample Collection and Processing: 30 μL of blood was collected from the orbital cavity at each time point and anticoagulated with sodium heparin. Blood samples were centrifuged at 4000 rpm for 10 minutes, and the supernatant plasma was collected. At each time point, 20 μL of plasma was added to 180 μL of acetonitrile, vortexed, and centrifuged at 18,000 g for 10 minutes. The supernatant was collected and subjected to LC-MS / MS quantitative analysis. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin software.

[0397] The pharmacokinetic properties of the compound I-5 of the present invention were determined in ICR mice according to the above experimental method. The results showed that the compound of the present invention exhibited excellent pharmacokinetic properties in mice (Table 4).

[0398] Table 4 Pharmacokinetic parameters of compounds in ICR mice

[0399]

[0400] As described above, although the present invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the present invention itself. Various changes may be made to it in form and detail without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A 2(1H)-quinoxalinone compound or a pharmaceutically acceptable salt thereof, characterized in that Selected from: ； ； ； ； ； ； ； ； ； ； ； 。 2. The compound according to claim 1, characterized in that: The pharmaceutically acceptable salts include acid addition salts formed between the compound of claim 1 and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

3. A pharmaceutical composition, characterized in that: The invention comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. Use of the compound according to claim 1 in the preparation of a medicament for treating and / or preventing MAT2A-related diseases.

5. The use according to claim 4, characterized in that: The MAT2A-related disease is selected from melanoma.

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