Azaindole compound as well as preparation method and application thereof

Abstract

The invention relates to an azaindole compound as well as a preparation method and application thereof. The compound has a structure as shown in a formula I. The invention also relates to a preparation method of the compound with the structure shown in the formula I and a pharmaceutical composition. The invention also provides application of the compound in preparation of drugs for reducing uric acid.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis and pharmaceutical application technology. Specifically, this invention relates to an azaindole compound, its preparation method or a pharmaceutical combination containing the same, and its uses in medicine. Background Technology

[0002] In recent years, the number of patients with hyperuricemia and gout has been rapidly increasing, and the patient population is showing a trend towards younger ages. The overall prevalence of hyperuricemia and gout in my country is relatively high, and the number of patients is expected to continue to rise in the future, making the disease burden a pressing concern. Hyperuricemia can induce gout, uric acid nephropathy, and other diseases, and is prone to complications including hypertension. Currently, uric acid-lowering drugs are mainly divided into three categories: drugs that inhibit uric acid production (such as allopurinol and febuxostat), drugs that promote uric acid excretion (such as benzbromarone and probenecid), and drugs that promote uric acid breakdown (such as previcurase and raburicase). However, existing treatments still have significant limitations in terms of safety, efficacy, and patient compliance during long-term treatment. For example, allopurinol is prone to causing hypersensitivity reactions in the Chinese population, febuxostat may increase the risk of cardiovascular events, and benzbromarone has a certain potential to cause liver damage. Therefore, developing new uric acid-lowering drugs that combine good safety and significant efficacy is an urgent clinical need for patients with hyperuricemia and gout. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a method for preparing azaindole compounds. This invention also provides the activity screening results of the above compounds as uric acid-lowering drugs and their applications.

[0004] The technical solution of the present invention is as follows:

[0005] I. Azaindole compounds

[0006] The azaindole compounds of the present invention, or pharmaceutically acceptable salts thereof, have the structure shown in general formula I:

[0007]

[0008] X, Y, Z are carbon or nitrogen atoms; R1 is cyclopropyl or bromine; R2 is an alkane or a substituted alkane, wherein the substituent is a C1-C5 alkane.

[0009] According to a preferred embodiment of the present invention, R2 is respectively .

[0010] According to the present invention, the azaindole compound is one of the following:

[0011] Table 1. Structural formulas of compounds 1-48

[0012]

[0013]

[0014] II. Preparation methods of azaindole compounds

[0015] The method for preparing the azaindole compounds of the present invention is one of the following methods:

[0016] (1) Synthesis of compounds 1-24:

[0017] Taking cycloI-0 as an example, 1-bromo-4-methylnaphthalene is first used as the starting material. Under the catalysis of benzoyl peroxide, it reacts with N-bromosuccinimide in n-hexane to generate 1-1, namely 1-bromo-4-(bromomethyl)naphthalene. In acetonitrile, intermediate 1-1 reacts with I-0 (7-chloro-6-azaindole) under the catalysis of cesium carbonate to generate intermediate 2A-I, namely 1-(4-bromonaphth-1-yl)methyl-7-chloro-azaindole. Intermediate 2A-I undergoes a Suzuki coupling reaction with cyclopropylboronic acid and tricyclohexylphosphine under alkaline conditions (potassium phosphate) in a palladium acetate catalytic system to successfully prepare intermediate 3A-I, namely 7-chloro-1-((4-bromonaphthyl) ... -Cyclopropylnaphth-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine; intermediate 3A-I reacts with thiourea in n-butanol under high temperature to generate intermediate 4A-I, namely 1-((4-cyclopropylnaphth-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-7-thiol; 4A-I undergoes nucleophilic substitution reaction with esters of different substituents in N,N-dimethylformamide solution under the action of potassium carbonate to give esterified products 5a-eI; subsequently, 5a-eI is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to give target products 1~5; the synthesis steps of other rings are the same as those of ring I-0 to obtain target products 6~24;

[0018]

[0019] Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70°C; (ii) 7-chloro-6-azaindole / 4-chloroimidazole[4,5-C]pyridine / 7-chloro-1H-pyrazolo[3,4-C]pyridine / 4-chloropyrrolo[2,3-D]pyrimidine / 6-chloropurine, cesium carbonate, acetonitrile, 70°C; (iii) cyclopropylboronic acid, potassium phosphate, palladium acetate, tricyclohexylphosphine, toluene / water (20:1), nitrogen, 100°C; (iv) thiourea, n-butanol, 130°C; (v) potassium carbonate, N,N-dimethylformamide, room temperature; (vi) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature;

[0020] (2) Synthesis of compounds 25-44:

[0021] Taking ring I-0 as an example, 7-chloro-1H-pyrrolo[2,3-c]pyridine is first used as the starting material. It reacts with thiourea in n-butanol under high temperature to generate intermediate 6A-I, namely 1H-pyrrolo[2,3-c]pyridine-7-thiol. 6A-I undergoes nucleophilic substitution reaction with esters of different substituents in N,N-dimethylformamide solution under the action of potassium carbonate to obtain esterified product 7a-eI. Under the catalysis of cesium carbonate, it reacts with 1-1 to generate intermediate 8a-eI. Intermediate 8a-eI is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain target products 25-29. The synthesis steps of other rings are the same as those of ring I-0 to obtain target products 30-44.

[0022]

[0023] Reagents and conditions: (i) thiourea, n-butanol, 130°C; (ii) 1-bromo-4-(bromomethyl)naphthalene, cesium carbonate, acetonitrile, 70°C; (iii) potassium carbonate, N,N-dimethylformamide, room temperature; (iv) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature.

[0024] (3) Synthesis of compounds 45-48:

[0025] First, using 6-mercaptopurine as the starting material, a nucleophilic substitution reaction was carried out with esters of different substituents in anhydrous ethanol solution under the action of potassium carbonate to obtain the esterified product 9a-eV; then, 9a-eV reacted with 1-1 under the catalysis of cesium carbonate to generate the intermediate 10a-eV; then, 10a-eV was hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain the target product 45-48.

[0026]

[0027] Reagents and conditions: (i) Potassium carbonate, anhydrous ethanol, room temperature; (ii) 1-bromo-4-(bromomethyl)naphthalene, cesium carbonate, acetonitrile, 70°C; (iii) Lithium hydroxide, tetrahydrofuran, methanol, water, room temperature.

[0028] The room temperature mentioned in this invention refers to 20~30℃.

[0029] III. Applications of Azaindole Compounds

[0030] This invention discloses the screening results of azinondole compounds for lowering uric acid activity and their first application in the preparation of uric acid-lowering drugs. Experiments demonstrate that the azinondole compounds of this invention can be used as uric acid-lowering drugs. Specifically, these compounds can be used to prepare uric acid-lowering drugs. This invention also provides the application of the above compounds in the preparation of uric acid-lowering drugs.

[0031] Uric acid-lowering activity of the target compound:

[0032] Forty-eight compounds were synthesized according to the above method (the structural formulas of the compounds are shown in Table 1), and their uric acid-lowering activity was screened. Their uric acid-lowering activity data are listed in Tables 2 and 3, with Lesinurad as the positive drug.

[0033] As shown in Tables 2 and 3, 44 compounds exhibited uric acid-lowering activity, which was stronger than or comparable to the positive control drug Lesinurad. Among them, the representative compounds 12, 21, 22, 29, 33, 35, 47, and 48 all showed a reduction rate of over 80% in serum uric acid in animal activity tests, demonstrating excellent uric acid-lowering activity and can be considered as candidate drugs for uric acid-lowering.

[0034] Therefore, the azaindole compounds in this invention are a novel class of compounds with uric acid-lowering activity, which can be used as candidate drugs for lowering uric acid and for preparing uric acid-lowering drugs.

[0035] A uric acid-lowering pharmaceutical composition comprising the azaindole compound of the present invention and one or more pharmaceutically acceptable carriers or excipients. Detailed Implementation

[0036] The following examples are helpful in understanding the present invention, but should not limit the scope of the invention. In the following examples, all target compounds are numbered the same as in Table 1.

[0037] (1) Synthetic routes for compounds 1-24:

[0038]

[0039] Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70°C; (ii) 7-chloro-6-azaindole / 4-chloroimidazole[4,5-C]pyridine / 7-chloro-1H-pyrazolo[3,4-C]pyridine / 4-chloropyrrolo[2,3-D]pyrimidine / 6-chloropurine, cesium carbonate, acetonitrile, 70°C; (iii) cyclopropylboronic acid, potassium phosphate, palladium acetate, tricyclohexylphosphine, toluene / water (20:1), nitrogen, 100°C; (iv) thiourea, n-butanol, 130°C; (v) potassium carbonate, N,N-dimethylformamide, room temperature; (vi) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature.

[0040] Preparation of compound 1-1

[0041] N-bromosuccinimide (4.00 g, 27.12 mmol) and benzoyl peroxide (0.16 g, 0.45 mmol) were mixed in a 250 mL round-bottom flask, and 100 mL of n-hexane was added. Then, 1-bromo-4-methylnaphthalene (5.00 g, 22.62 mmol) was added dropwise to the flask, and the mixture was heated to 70 °C and reacted for 12 h. The reaction was monitored by TLC until complete, and then heating was stopped. After the reaction mixture cooled to room temperature, the filter cake was collected. The filter cake was placed in a 250 mL beaker, and 150 mL of saturated NaHCO3 aqueous solution was added to the beaker. After stirring for 10 min, the mixture was filtered, and the filter cake was collected. The above operation was repeated twice, and the last time the mixture was washed with 100 mL of water and filtered again. Collect the filter cake and place it in a 100 mL flask. Add 50 mL of n-hexane and heat to reflux for 1 h. After heating, stop the heating, cool to room temperature, filter, and vacuum dry to obtain a pale yellow powder with a yield of 50.4% and a melting point of 102–104 °C. ESI-MS: m / z 301.24 [M + 2 + H] + C 11 H8Br2[297.90].

[0042] Preparation of compound 2A-I

[0043] Taking 2A-I as an example, 1-bromo-4-(bromomethyl)naphthalene (5.80 g, 26.32 mmol) was added to a 250 mL round-bottom flask, followed by approximately 50 mL of acetonitrile to dissolve it. Cesium carbonate (8.50 g, 26.32 mmol) was then added to the flask, followed by 7-chloro-6-azaindole (2.00 g, 13.16 mmol) dissolved in 50 mL of acetonitrile, which was slowly added dropwise to the flask. The mixture was heated to 70 °C, and solids continuously precipitated during stirring. After 12 h, TLC monitoring was performed. After the reaction was complete, the mixture was filtered, and the filter cake was collected. The filter cake was placed in a 250 mL beaker, and 150 mL of water was added to the beaker. After stirring for 10 min, the mixture was filtered, and the filter cake was collected. This process was repeated twice. Finally, the filter cake was placed in a 100 mL flask, 50 mL of anhydrous ethanol was added, and the mixture was heated to 80 °C and stirred for 1 h. Heating was then stopped, and the mixture was cooled to room temperature and filtered. The filter cake was then vacuum dried to obtain a yellow solid with a yield of 62.0%. ESI-MS: m / z 371.96 [M+H] + C 18 H 12 BrClN2[369.99]. The preparation method of compound 2A-II-V is the same as that of 2A-I.

[0044] Preparation of compound 2A-II

[0045] The procedure was the same as for 2A-I, except that 1-1 (2.32 g, 7.81 mmol) was reacted with 4-chloroimidazole [4,5-C]pyridine (1.00 g, 6.51 mmol), yielding a yellow solid in 54.0% yield. ESI-MS: m / z 372.96 [M + H]. + C 17 H 11 BrClN3 [370.98].

[0046] Preparation of compound 2A-III

[0047] The procedure was the same as for 2A-I, except that 1-1 (5.80 g, 19.53 mmol) reacted with 7-chloro-1H-pyrazolo[3,4-C]pyridine (2.00 g, 13.02 mmol), producing a yellow solid in 25.0% yield. ESI-MS: m / z 372.02 [M + H] + C 17 H 11 BrClN3 [370.98].

[0048] Preparation of compound 2A-IV

[0049] The procedure was the same as for 2A-I, except that 1-1 (14.55 g, 48.84 mmol) reacted with 4-chloropyrrolo[2,3-D]pyrimidine (5 g, 32.56 mmol), producing a yellow solid in 62.1% yield. ESI-MS: m / z 372.10 [M + H] + C 17 H 11 BrClN3 [370.98].

[0050] Preparation of compound 2A-V

[0051] The procedure was the same as for 2A-I, except that 1-1 (5.70 g, 19.40 mmol) reacted with 6-chloropurine (2.00 g, 12.90 mmol). The product was a white solid, yield 52.1%, ESI-MS: m / z 373.96 [M + H]. + C 17 H 11 BrClN3 [371.98].

[0052] Preparation of compound 3A-I

[0053] Taking 3A-I as an example, the raw materials cyclopropylboronic acid (0.52 g, 6.09 mmol), potassium phosphate (3.00 g, 14.18 mmol), 1-((4-bromonaphthyl-1-yl)methyl)-7-chloro-1H-pyrrolo[2,3-c]pyridine (1.50 g, 4.05 mmol), tricyclohexylphosphine (0.23 g, 0.82 mmol) and palladium acetate (0.09 g, 0.41 mmol) were dissolved in 20 mL of toluene and water (toluene:water = 20:1). After reacting at a constant temperature of 100 °C for 10 h under nitrogen protection, insoluble impurities were removed by diatomaceous earth filtration, and toluene was removed by vacuum distillation. The solution was dissolved in 20 mL of ethyl acetate, washed with saturated NaCl solution (20 mL × 3 times), dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure and then purified by rapid column chromatography (ethyl acetate:petroleum ether = 1:5). Yield 82.1%, ESI-MS: m / z 333.89 [M + H] + 335.88 [M + 2 + H] + C 21 H 17 ClN2[332.10]. The preparation method of compound 3A-II-V is the same as that of 3A-I.

[0054] Preparation of compound 3A-II

[0055] The procedure was the same as 3A-I, except that the starting materials cyclopropylboronic acid (0.48 g, 5.66 mmol), potassium phosphate (2.80 g, 13.20 mmol), tricyclohexylphosphine (0.21 g, 0.75 mmol), and palladium acetate (0.08 g, 0.35 mmol) reacted with 7-chloro-1-((4-cyclopropylnaphthyl-1-yl)methyl)-1H-pyrazolo[3,4-c]pyridine (1.40 g, 3.77 mmol). The reaction yielded a white solid, 96.0% yield, ESI-MS: m / z 334.10 [M + H]. + 336.25 [M + 2 + H] + C 20 H 16 ClN3[333.10].

[0056] Preparation of compound 3A-III

[0057] The procedure was the same as 3A-I, except that the starting materials cyclopropylboronic acid (0.45 g, 5.25 mmol), potassium phosphate (2.60 g, 12.25 mmol), tricyclohexylphosphine (0.20 g, 0.70 mmol), and palladium acetate (0.08 g, 0.35 mmol) reacted with 7-chloro-1-((4-cyclopropylnaphthyl-1-yl)methyl)-1H-pyrazolo[3,4-c]pyridine (1.30 g, 3.50 mmol) to produce a yellow solid in 43.1% yield. ESI-MS: m / z 334.14 [M + H] + 336.22 [M + 2 + H] + C 20 H 16 ClN3[333.10].

[0058] Preparation of compound 3A-IV

[0059] The procedure was the same as 3A-I, except that the starting materials cyclopropylboronic acid (0.70 g, 8.09 mmol), potassium phosphate (4.01 g, 18.90 mmol), tricyclohexylphosphine (0.31 g, 1.08 mmol), and palladium acetate (0.12 g, 0.54 mmol) reacted with 4-chloro-5-((4-cyclopropylnaphth-1-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine (1.50 g, 5.40 mmol). The product was a white solid, yield 65.2%, ESI-MS: m / z 334.25 [M + H]. + C 20 H 16 ClN3[333.10].

[0060] Preparation of compound 3A-V

[0061] The procedure was the same as 3A-I, except that the starting materials cyclopropylboronic acid (0.86 g, 10.00 mmol), potassium phosphate (5.00 g, 23.50 mmol), tricyclohexylphosphine (0.37 g, 1.34 mmol), and palladium acetate (0.15 g, 0.67 mmol) reacted with 6-chloro-7-((4-cyclopropylnaphth-1-yl)methyl)-7H-purine (2.50 g, 6.72 mmol). The product was a white solid, yield 47.8%, ESI-MS: m / z 335.14 [M + H]. + C 19 H 15 ClN4[334.10].

[0062] Preparation of compound 4A-I

[0063] Taking 4A-I as an example, thiourea (1.36 g, 17.80 mmol) and 3A-I (1.18 g, 3.56 mmol) were weighed and 20 mL of n-butanol was added. The mixture was stirred at 130 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 20 mL of 1 mol / L sodium hydroxide solution was added. The mixture was stirred at room temperature for 2 h. Subsequently, the pH was adjusted to 2-3 with 1 mol / L hydrochloric acid solution, at which point a large amount of yellow solid precipitated out of the solution. The filter cake was obtained by filtering through a funnel and washed with plenty of water (50 mL × 3 times). The filter cake was collected and dried in a vacuum drying oven to finally obtain the yellow solid 4A-I, with a yield of 65.1%. ESI-MS: m / z 332.89 [M + H] + 334.88 [M + 2 + H] + C 21 H 18 N2S [330.12]. Compound 4A-II-V was prepared using the same method as 4A-I.

[0064] Preparation of compound 4A-II

[0065] The procedure was the same as for 4A-I, except that thiourea (1.30 g, 18.00 mmol) reacted with 3A-II (1.20 g, 3.60 mmol). The product was a yellow solid, yield 58.3%, ESI-MS: m / z 332.23 [M + H]. + C 20 H 17 N3S [331.11].

[0066] Preparation of compound 4A-III

[0067] The procedure was the same as for 4A-I, except that thiourea (1.25 g, 16.50 mmol) reacted with 3A-III (1.10 g, 3.30 mmol). The product was a yellow solid, yield 63.6%, ESI-MS: m / z 332.20 [M + H]. + C 20 H 17 N3S [331.11].

[0068] Preparation of compound 4A-IV

[0069] The procedure was the same as for 4A-I, except that thiourea (1.36 g, 16.50 mmol) reacted with 3A-IV (1.10 g, 3.30 mmol). The product was a yellow solid, yield 77.7%, ESI-MS: m / z 332.25 [M + H]. + C 20 H 17 N3S [331.11].

[0070] Preparation of compound 4A-V

[0071] The procedure was the same as for 4A-I, except that thiourea (1.36 g, 17.80 mmol) reacted with 3A-V (1.18 g, 3.56 mmol). The product was a yellow solid, yield 27.5%, ESI-MS: m / z 333.23 [M + H]. + C 19 H 16 N4S [332.11].

[0072] Preparation of compound 5a-I

[0073] Weigh 0.20 g (0.61 mmol) of 4A-I and 0.13 g (0.91 mmol) of potassium carbonate and dissolve them in 10 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.14 g, 0.91 mmol). Stir the reaction mixture at room temperature for 10 h. After the reaction is terminated, add 30 mL of water to the reaction system, followed by 30 mL of ethyl acetate for extraction. Repeat this process three times. After extraction and separation, wash with saturated NaCl solution (20 mL × 3 times). Transfer the organic phase to a dry container, add an appropriate amount of anhydrous sodium sulfate for dehydration and drying, concentrate under reduced pressure, and purify by column chromatography to obtain a white solid (ethyl acetate (EA): petroleum ether (PE) = 1:2), yield 50.0%, ESI-MS: m / z 403.34 [M + H] + C 24 H 22 N2O2S [402.14].

[0074] Preparation of compound 5b-I

[0075] The procedure was the same as for 5a-I, except that 4A-I (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromopropionate (0.15 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 89.5%. ESI-MS: m / z 417.31 [M + H] + C 25 H 24 N2O2S [416.15].

[0076] Preparation of compound 5c-I

[0077] The procedure was the same as for 5a-I, except that 4A-I (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromo-2-methylpropionate (0.16 g, 0.91 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 53.8%. ESI-MS: m / z 431.25 [M + H] + C 26 H 26 N2O2S [430.17].

[0078] Preparation of compound 5d-I

[0079] The procedure was the same as for 5a-I, except that 4A-I (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 3-bromopropionate (0.15 g, 0.91 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 32.0%. ESI-MS: m / z 418.25 [M + H] + C 25 H 24 N2O2S [416.15].

[0080] Preparation of compound 5e-I

[0081] The procedure was the same as for 5a-I, except that 4A-I (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 4-bromobutyrate (0.15 g, 0.91 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 87.0%. ESI-MS: m / z 431.29 [M + H] + C 26 H 26 N2O2S [430.17].

[0082] Preparation of compound 5a-II

[0083] Weigh 4A-II (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) and dissolve them in 10 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.14 g, 0.91 mmol). Stir the reaction mixture at room temperature for 10 h. After the reaction is terminated, add 30 mL of water to the reaction system, followed by 30 mL of ethyl acetate for extraction. Repeat this process three times. After extraction and separation, wash with saturated NaCl solution (20 mL × 3 times). Transfer the organic phase to a dry container, add an appropriate amount of anhydrous sodium sulfate for dehydration and drying, concentrate under reduced pressure, and purify by column chromatography to obtain a white solid (ethyl acetate (EA): petroleum ether (PE) = 1:2), yield 41.7%, ESI-MS: m / z 404.14 [M + H] + C 24 H 22 N2O2S [403.14].

[0084] Preparation of compound 5b-II

[0085] The procedure was the same as for 5a-I, except that 4A-II (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The mixture was activated at room temperature for 15 min, then methyl 2-bromopropionate (0.15 g, 0.91 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 32.0%. ESI-MS: m / z 418.31 [M + H] + C 24 H 23 N3O2S [417.15].

[0086] Preparation of compound 5c-II

[0087] The procedure was the same as for 5a-I, except that 4A-II (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromo-2-methylpropionate (0.16 g, 0.91 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 23.1%. ESI-MS: m / z 432.10 [M+ H] + C 25 H 25 N3O2S [431.17].

[0088] Preparation of compound 5d-II

[0089] The procedure was the same as for 5a-I, except that 4A-II (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 3-bromopropionate (0.15 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 44.0%. ESI-MS: m / z 418.40 [M + H] + C 24 H 23 N3O2S [417.15].

[0090] Preparation of compound 5e-II

[0091] The procedure was the same as for 5a-I, except that 4A-II (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 4-bromobutyrate (0.16 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 38.5%. ESI-MS: m / z 432.19 [M + H] + C 25 H 25 N3O2S [431.17].

[0092] Preparation of compound 5a-III

[0093] Weigh 0.20 g (0.61 mmol) of 4A-III and 0.13 g (0.91 mmol) of potassium carbonate and dissolve them in 10 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.14 g, 0.91 mmol). Stir the reaction mixture at room temperature for 10 h. After the reaction is terminated, add 30 mL of water to the reaction system, followed by extraction with 30 mL of ethyl acetate. Repeat this process three times. After separation of the extract, wash with saturated NaCl solution (20 mL × 3 times). Transfer the organic phase to a dry container, add an appropriate amount of anhydrous sodium sulfate for dehydration and drying, concentrate under reduced pressure, and purify by column chromatography to obtain a white solid (ethyl acetate:petroleum ether = 1:2), yield 45.8%, ESI-MS: m / z 404.25 [M + H]. + C 24 H 22 N2O2S[403.14].

[0094] Preparation of compound 5b-III

[0095] The procedure was the same as for 5a-I, except that 4A-III (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromopropionate (0.15 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 52.0% yield. ESI-MS: m / z 418.11 [M + H] + C 24 H 23 N3O2S [417.15].

[0096] Preparation of compound 5c-III

[0097] The procedure was the same as for 5a-I, except that 4A-III (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The mixture was activated at room temperature for 15 min, then methyl 2-bromo-2-methylpropionate (0.16 g, 0.91 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 30.8%. ESI-MS: m / z 432.16 [M+ H] + C 25 H 25 N3O2S [431.17].

[0098] Preparation of compound 5d-III

[0099] The procedure was the same as for 5a-I, except that 4A-III (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 3-bromopropionate (0.15 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 44.0%. ESI-MS: m / z 418.10 [M + H] + C 24 H 23 N3O2S [417.15].

[0100] Preparation of compound 5e-III

[0101] The procedure was the same as for 5a-I, except that 4A-III (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 4-bromobutyrate (0.16 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 46.2%. ESI-MS: m / z 432.16 [M + H] + C 25 H 25 N3O2S [431.17].

[0102] Preparation of compound 5a-IV

[0103] Weigh 0.20 g (0.61 mmol) of 4A-IV and 0.13 g (0.91 mmol) of potassium carbonate and dissolve them in 10 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.14 g, 0.91 mmol). Stir the reaction mixture at room temperature for 10 h. After the reaction is terminated, add 30 mL of water to the reaction system, followed by 30 mL of ethyl acetate for extraction. Repeat this process three times. After separation of the extract, wash with saturated NaCl solution (20 mL × 3 times). Transfer the organic phase to a dry container, add an appropriate amount of anhydrous sodium sulfate for dehydration and drying, concentrate under reduced pressure, and purify by column chromatography to obtain a white solid (ethyl acetate:petroleum ether = 1:2), yield 88.0%, ESI-MS: m / z 404.25 [M + H]. + C 24 H 22 N2O2S[403.14].

[0104] Preparation of compound 5b-IV

[0105] The procedure was the same as for 5a-IV, except that 4A-IV (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromopropionate (0.15 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 60.0% yield. ESI-MS: m / z 418.11 [M + H] + C 24 H 23 N3O2S [417.15].

[0106] Preparation of compound 5c-IV

[0107] The procedure was the same as for 5a-IV, except that 4A-IV (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromo-2-methylpropionate (0.16 g, 0.91 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 53.8%. ESI-MS: m / z 432.11 [M+ H] + C 25 H 25 N3O2S [431.17].

[0108] Preparation of compound 5d-IV

[0109] The procedure was the same as for 5a-IV, except that 4A-IV (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 3-bromopropionate (0.15 g, 0.91 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 20.0% yield. ESI-MS: m / z 418.48 [M + H] + C 24 H 23 N3O2S [417.15].

[0110] Preparation of compound 5e-IV

[0111] The procedure was the same as for 5a-IV, except that 4A-IV (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 4-bromobutyrate (0.15 g, 0.91 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 48.0%. ESI-MS: m / z 432.39 [M + H] + C 25 H 25 N3O2S [431.17].

[0112] Preparation of compound 5a-V

[0113] Weigh 0.20 g (0.61 mmol) of 4A-V and 0.13 g (0.91 mmol) of potassium carbonate and dissolve them in 10 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.14 g, 0.91 mmol). Stir the reaction mixture at room temperature for 10 h. After the reaction is terminated, add 30 mL of water to the reaction system, followed by extraction with 30 mL of ethyl acetate. Repeat this process three times. After separation of the extract, wash with saturated NaCl solution (20 mL × 3 times). Transfer the organic phase to a dry container, add an appropriate amount of anhydrous sodium sulfate for dehydration and drying, concentrate under reduced pressure, and purify by column chromatography to obtain a white solid (ethyl acetate:petroleum ether = 1:2), yield 44.4%, ESI-MS: m / z 405.15 [M + H]. + C 22 H 20 N4O2S[404.13].

[0114] Preparation of compound 5b-V

[0115] The procedure was the same as for 5a-V, except that 4A-V (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The mixture was activated at room temperature for 15 min, then methyl 2-bromopropionate (0.15 g, 0.91 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 84.0%. ESI-MS: m / z 419.14 [M + H] + C 23 H 22 N4O2S [418.15].

[0116] Preparation of compound 5c-V

[0117] The procedure was the same as for 5a-V, except that 4A-V (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The mixture was activated at room temperature for 15 min, then methyl 2-bromo-2-methylpropionate (0.16 g, 0.91 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 64.0%. ESI-MS: m / z 433.01 [M + H] + C 24 H 24 N4O2S [432.16].

[0118] Preparation of compound 5e-V

[0119] The procedure was the same as for 5a-V, except that 4A-V (0.20 g, 0.61 mmol) and potassium carbonate (0.13 g, 0.91 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The mixture was activated at room temperature for 15 min, then methyl 4-bromobutyrate (0.15 g, 0.91 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 76.0%. ESI-MS: m / z 433.09 [M + H] + C 24 H 24 N4O2S [432.16].

[0120] (2) Synthetic routes of compounds 25-44

[0121]

[0122] Reagents and conditions: (i) thiourea, n-butanol, 130°C; (ii) 1-bromo-4-(bromomethyl)naphthalene, cesium carbonate, acetonitrile, 70°C; (iii) potassium carbonate, N,N-dimethylformamide, room temperature; (iv) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature.

[0123] Preparation of compound 6A-I

[0124] Taking 6A-I as an example, thiourea (6.24 g, 81.92 mmol) and 7-chloro-6-azaindole (5.00 g, 32.77 mmol) were weighed and added to 150 mL of n-butanol. The mixture was stirred at 130 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 100 mL of 1 mol / L sodium hydroxide solution was added. The mixture was stirred at room temperature for 2 h. Subsequently, the pH was adjusted to 2-3 with 1 mol / L hydrochloric acid solution, at which point a large amount of yellow solid precipitated in the solution. The filter cake was obtained by filtering through a funnel, washed with plenty of water (50 mL × 3 times), and then dried in a vacuum drying oven to finally obtain a yellow solid with a yield of 20.0%. ESI-MS: m / z 151.03 [M+ H] + C7H6N2S [150.03]. Compound 6A-II-Ⅳ was prepared using the same method as 6A-I.

[0125] Preparation of compound 6A-II

[0126] The procedure was the same as for 6A-I, except that thiourea (2.50 g, 32.60 mmol) was reacted with 4-chloroimidazole [4,5-C]pyridine (2.00 g, 13.00 mmol). The product was a yellow solid, yield 61.2%, ESI-MS: m / z 152.02 [M + H]. + , C6H5N3S[151.02].

[0127] Preparation of compound 6A-III

[0128] The procedure was the same as for 6A-I, except that thiourea (2.50 g, 32.60 mmol) was reacted with 7-chloro-1H-pyrazolo[3,4-C]pyridine (2.00 g, 13.00 mmol). The product was a white solid, yield 50.0%, ESI-MS: m / z 152.02 [M + H]. + ,C6H5N3S [151.02].

[0129] Preparation of compound 6A-IV

[0130] The procedure was the same as for 6A-I, except that thiourea (1.36 g, 16.50 mmol) was reacted with 4-chloropyrrolo[2,3-D]pyrimidine (1.10 g, 3.30 mmol). The product was a yellow solid, yield 70.0%, ESI-MS: m / z 152.12 [M + H]. + C 20 H 17 N3S [151.02].

[0131] Preparation of compound 7a-I

[0132] Weigh 0.30 g (2.00 mmol) of 6A-I and 0.41 g (3.00 mmol) of potassium carbonate and dissolve them in 15 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.46 g, 3.00 mmol). Stir the reaction mixture at room temperature for 2 h. After the reaction is terminated, add 30 mL of water to the reaction system, followed by extraction with 30 mL of ethyl acetate. Repeat this process three times. After separation of the extract, wash with saturated NaCl solution (20 mL × 3 times). Transfer the organic phase to a dry container, add an appropriate amount of anhydrous sodium sulfate for dehydration and drying, concentrate under reduced pressure, and purify by column chromatography to obtain a yellow solid (ethyl acetate:petroleum ether = 1:2), yield 61.4%, ESI-MS: m / z 223.04 [M + H]. + C 10 H 10 N2O2S [222.05].

[0133] Preparation of compound 7b-I

[0134] The procedure was the same as for 7a-I, except that 6A-I (0.30 g, 2.00 mmol) and potassium carbonate (0.41 g, 3.00 mmol) were dissolved in 15 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromopropionate (0.50 g, 3.00 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 68.1%. ESI-MS: m / z 237.16 [M + H] + C 11 H 12 N2O2S [236.06].

[0135] Preparation of compound 7c-I

[0136] The procedure was the same as for 7a-I, except that 6A-I (0.30 g, 2.00 mmol) and potassium carbonate (0.41 g, 3.00 mmol) were dissolved in 10 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromo-2-methylpropionate (0.54 g, 3.00 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 62.0% [M+H], ESI-MS: m / z 251.05. + C 12 H 14 N2O2S [250.08].

[0137] Preparation of compound 7d-I

[0138] The procedure was the same as for 7a-I, except that 6A-I (0.30 g, 2.00 mmol) and potassium carbonate (0.41 g, 3.00 mmol) were dissolved in 15 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 3-bromopropionate (0.50 g, 3.00 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 66.0% yield. ESI-MS: m / z 237.11 [M + H] + C 11 H 12 N2O2S [236.06].

[0139] Preparation of compound 7e-I

[0140] The procedure was the same as for 7a-I, except that 6A-I (0.30 g, 2.00 mmol) and potassium carbonate (0.41 g, 3.00 mmol) were dissolved in 15 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 4-bromobutyrate (0.54 g, 3.00 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 66.0% yield. ESI-MS: m / z 251.29 [M + H] + C 12 H 14 N2O2S [250.08].

[0141] Preparation of compound 7a-II

[0142] Weigh 6A-II (0.30 g, 1.98 mmol) and potassium carbonate (0.54 g, 3.96 mmol) and dissolve them in 20 mL of anhydrous ethanol. Activate at room temperature for 30 min, then add methyl 2-bromoacetate (0.30 g, 2.97 mmol). Stir the reaction mixture at room temperature for 10 h. After the reaction is terminated, dissolve the solid in 20 mL of ethyl acetate, wash with saturated NaCl solution (20 mL × 3 times), dry to anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure and purify using rapid column chromatography (ethyl acetate:petroleum ether = 1:2). A yellow solid is given in 45.5% yield. ESI-MS: m / z 224.04 [M + H] + C 10 H 10 N2O2S [223.04].

[0143] Preparation of compound 7b-II

[0144] The procedure was the same as for 7a-II, except that 6A-II (0.30 g, 1.98 mmol) and potassium carbonate (0.40 g, 2.98 mmol) were dissolved in 20 mL of anhydrous ethanol, activated at room temperature for 30 min, and then methyl 2-bromopropionate (0.36 g, 1.98 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 21.3%. ESI-MS: m / z 238.06 [M + H] + C 10 H 11 N3O2S [237.06].

[0145] Preparation of compound 7c-II

[0146] The procedure was the same as for 7a-II, except that 6A-II (0.50 g, 3.31 mmol) and potassium carbonate (0.90 g, 6.62 mmol) were dissolved in 20 mL of anhydrous ethanol, activated at room temperature for 30 min, and then methyl 2-bromo-2-methylpropionate (0.59 g, 3.31 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 45.8%. ESI-MS: m / z 252.08 [M + H] + C 11 H 13 N3O2S [251.07].

[0147] Preparation of compound 7d-II

[0148] The procedure was the same as for 7a-II, except that 6A-II (0.50 g, 3.29 mmol) and potassium carbonate (0.90 g, 6.58 mmol) were dissolved in 20 mL of anhydrous ethanol, activated at room temperature for 30 min, and then methyl 3-bromopropionate (0.55 g, 3.29 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 10.3% yield. ESI-MS: m / z 238.11 [M + H] + C 10 H 11 N3O2S [237.06].

[0149] Preparation of compound 7e-II

[0150] The procedure was the same as for 7a-II, except that 6A-II (0.30 g, 2.00 mmol) and potassium carbonate (0.41 g, 3.00 mmol) were dissolved in 20 mL of anhydrous ethanol, activated at room temperature for 30 min, and then methyl 4-bromobutyrate (0.36 g, 2.00 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 42.0% yield. ESI-MS: m / z 252.19 [M + H] + C 11 H 13 N3O2S [251.07].

[0151] Preparation of compound 7a-Ⅲ

[0152] Weigh 6A-III (0.30 g, 1.98 mmol) and potassium carbonate (0.22 g, 3.96 mmol) and dissolve them in 20 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.45 g, 2.98 mmol). Stir the reaction mixture at room temperature for 2 h. After the reaction is terminated, dissolve the solid in 20 mL of ethyl acetate, wash with saturated NaCl solution (20 mL × 3 times), dry to anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure and purify using rapid column chromatography (ethyl acetate:petroleum ether = 1:2). A white solid was given in 86.3% yield. ESI-MS: m / z 224.11 [M+ H] + , C9H9N3O2S[223.04].

[0153] Preparation of compound 7b-Ⅲ

[0154] The procedure was the same as for 7a-Ⅲ, except that 6A-Ⅲ (0.30 g, 1.98 mmol) and potassium carbonate (0.41 g, 2.98 mmol) were dissolved in 20 mL of N,N-dimethylformamide. The mixture was activated at room temperature for 15 min, then methyl 2-bromopropionate (0.50 g, 2.98 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 76.6%. ESI-MS: m / z 238.30 [M + H] + C 10 H 11 N3O2S [237.06].

[0155] Preparation of compound 7c-Ⅲ

[0156] The procedure was the same as for 7a-Ⅲ, except that 6A-Ⅲ (0.50 g, 3.31 mmol) and potassium carbonate (0.37 g, 6.62 mmol) were dissolved in 20 mL of N,N-dimethylformamide. The mixture was activated at room temperature for 15 min, then methyl 2-bromo-2-methylpropionate (0.59 g, 3.31 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 50.6%. ESI-MS: m / z 252.07 [M+ H] + C 11 H 13 N3O2S [251.07].

[0157] Preparation of compound 7d-III

[0158] The procedure was the same as for 7a-Ⅲ, except that 6A-Ⅲ (0.50 g, 3.31 mmol) and potassium carbonate (0.68 g, 3.97 mmol) were dissolved in 20 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 3-bromopropionate (0.66 g, 3.97 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 31.8%. ESI-MS: m / z 238.06 [M + H] + C 10 H 11 N3O2S [237.06].

[0159] Preparation of compound 7e-Ⅲ

[0160] The procedure was the same as for 7a-Ⅲ, except that 6A-Ⅲ (0.30 g, 1.98 mmol) and potassium carbonate (0.42 g, 2.98 mmol) were dissolved in 20 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 4-bromobutyrate (0.54 g, 2.98 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 62.0% yield. ESI-MS: m / z 252.07 [M + H] + C 11 H 13 N3O2S [251.07].

[0161] Preparation of compound 7a-Ⅳ

[0162] Weigh 0.30 g (1.98 mmol) of 6A-Ⅳ and 0.41 g (2.98 mmol) of potassium carbonate and dissolve them in 20 mL of N,N-dimethylformamide. Activate at room temperature for 15 min, then add methyl 2-bromoacetate (0.45 g, 2.98 mmol). Stir the reaction mixture at room temperature for 2 h. After the reaction is terminated, dissolve the solid in 20 mL of ethyl acetate, wash with saturated NaCl solution (20 mL × 3 times), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure and purify using rapid column chromatography (ethyl acetate:petroleum ether = 1:2). A white solid was given in 88.6% yield. ESI-MS: m / z 224.01 [M+ H] + , C9H9N3O2S [223.04].

[0163] Preparation of compound 7b-Ⅳ

[0164] The procedure was the same as for 7a-Ⅳ, except that 6A-Ⅳ (0.50 g, 3.31 mmol) and potassium carbonate (0.69 g, 4.96 mmol) were dissolved in 20 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromopropionate (0.82 g, 4.96 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 60.3%. ESI-MS: m / z 238.11 [M + H] + C 10 H 11 N3O2S [237.06].

[0165] Preparation of compound 7c-Ⅳ

[0166] The procedure was the same as for 7a-Ⅳ, except that 6A-Ⅳ (0.50 g, 3.31 mmol) and potassium carbonate (0.69 g, 5.00 mmol) were dissolved in 20 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 2-bromo-2-methylpropionate (0.91 g, 5.00 mmol) was added and reacted at room temperature. A white solid was obtained, yielding 92.6%. ESI-MS: m / z 252.05 [M+ H] + C 11 H 13 N3O2S [251.07].

[0167] Preparation of compound 7d-Ⅳ

[0168] The procedure was the same as for 7a-Ⅳ, except that 6A-Ⅳ (0.30 g, 1.98 mmol) and potassium carbonate (0.41 g, 2.97 mmol) were dissolved in 20 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 3-bromopropionate (0.40 g, 2.97 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 25.0%. ESI-MS: m / z 238.16 [M + H] + C 10 H 11 N3O2S [237.06].

[0169] Preparation of compound 7e-Ⅳ

[0170] The procedure was the same as for 7a-Ⅳ, except that 6A-Ⅳ (0.50 g, 3.31 mmol) and potassium carbonate (0.69 g, 4.97 mmol) were dissolved in 20 mL of N,N-dimethylformamide, activated at room temperature for 15 min, and then methyl 4-bromobutyrate (0.72 g, 3.97 mmol) was added. The reaction was carried out at room temperature, yielding a white solid with a yield of 74.7%. ESI-MS: m / z 252.36 [M + H] + C 11 H 13 N3O2S [251.07].

[0171] Preparation of compound 8a-I

[0172] Taking 8a-I as an example, 1-bromo-4-(bromomethyl)naphthalene (0.44 g, 1.48 mmol) was added to a 50 mL round-bottom flask, followed by approximately 10 mL of acetonitrile to dissolve it. Cesium carbonate (0.64 g, 1.97 mmol) was then added to the flask, followed by 7a-I (0.22 g, 0.98 mmol) dissolved in 5 mL of acetonitrile, which was slowly added dropwise to the flask. The mixture was heated to 75 °C, and TLC was monitored after 12 h. After the reaction was complete, the mixture was filtered, and the filter cake was collected. The filter cake was placed in a 50 mL beaker, and 20 mL of water was added to the beaker. The mixture was stirred for 10 min, filtered, and the filter cake was collected. This process was repeated twice. Finally, the filter cake was placed in a 50 mL flask, 20 mL of anhydrous ethanol was added, and the mixture was heated to 80 °C and stirred for 1 h. Heating was then stopped, and the mixture was cooled to room temperature and filtered. The filter cake was then vacuum dried to obtain a yellow solid with a yield of 41.9%. ESI-MS: m / z 441.15 [M + H] + C 21 H 17 BrN2O2S [440.02]. Compound 8a-II-V was prepared by the same method as 8a-I.

[0173] Preparation of compound 8b-I

[0174] The procedure was the same as for 8a-I, except that 7b-I (0.29 g, 1.23 mmol) was reacted with 1-bromo-4-(bromomethyl)naphthalene (0.55 g, 1.84 mmol). The product was a yellow solid, yield 66.1%, ESI-MS: m / z 455.02 [M + H]. + C 22 H 19 BrN2O2S[454.04].

[0175] Preparation of compound 8c-I

[0176] The procedure was the same as for 8a-I, except that 7c-I (0.21 g, 0.84 mmol) was reacted with 1-bromo-4-(bromomethyl)naphthalene (0.38 g, 1.26 mmol). The product was a white solid, yield 69.2%, ESI-MS: m / z 469.10 [M + H]. + C 23 H 21 BrN2O2S[468.05].

[0177] Preparation of compound 8d-I

[0178] The procedure was the same as for 8a-I, except that 7d-I (0.25 g, 1.06 mmol) was reacted with 1-bromo-4-(bromomethyl)naphthalene (0.47 g, 1.59 mmol). The product was a white solid, yield 66.7%, ESI-MS: m / z 455.10 [M + H]. + C 22 H 19 BrN2O2S[454.04].

[0179] Preparation of compound 8e-I

[0180] The procedure was the same as for 8a-I, except that 7d-I (0.33 g, 1.32 mmol) was reacted with 1-bromo-4-(bromomethyl)naphthalene (0.59 g, 1.98 mmol). The product was a white solid, yield 45.9%, ESI-MS: m / z 469.05 [M + H]. + C 22 H 19 BrN2O2S[468.05].

[0181] Preparation of compound 8a-II

[0182] The procedure was the same as for 8a-I, except that 7a-II (0.59 g, 2.64 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.94 g, 3.17 mmol) were reacted. The product was a white solid, yield 37.0%, ESI-MS: m / z 442.03 [M + H]. + C 20 H 16 BrN3O2S[441.01].

[0183] Preparation of compound 8b-II

[0184] The procedure was the same as for 8a-I, except that 7b-II (0.42 g, 1.77 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.63 g, 2.12 mmol) were reacted. The product was a white solid, yield 40.5%, ESI-MS: m / z 456.00 [M + H]. + C 21 H 18 BrN3O2S[455.03].

[0185] Preparation of compound 8c-II

[0186] The procedure was the same as for 8a-I, except that 7c-II (0.38 g, 1.70 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.61 g, 2.04 mmol) were reacted. The product was a white solid, yield 61.5%, ESI-MS: m / z 470.10 [M + H]. + C 22 H 20 BrN3O2S[469.03].

[0187] Preparation of compound 8d-II

[0188] The procedure was the same as for 8a-I, except that 7d-II (0.19 g, 0.76 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.27 g, 0.91 mmol) were reacted. The product was a white solid, yield 63.8%, ESI-MS: m / z 456.07 [M + H]. + C 21 H 18 BrN3O2S[455.03].

[0189] Preparation of compound 8e-II

[0190] The procedure was the same as for 8a-I, except that 7e-II (0.19 g, 0.76 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.18 g, 0.81 mmol) were reacted. The product was a white solid, yield 63.8%, ESI-MS: m / z 469.05 [M + H]. + C 22 H 20 BrN3O2S[470.05].

[0191] Preparation of compound 8a-Ⅲ

[0192] The procedure was the same as for 8a-I, except that 7a-III (0.38 g, 1.69 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.76 g, 2.54 mmol) were reacted. The product was a pale yellow solid, yield 90.6%, ESI-MS: m / z 442.02 [M + H]. + C 20 H 16 BrN3O2S[441.01].

[0193] Preparation of compound 8b-Ⅲ

[0194] The procedure was the same as for 8a-I, except that 7b-III (0.36 g, 1.52 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.68 g, 2.27 mmol) were reacted. The product was a yellow solid, yield 54.4%, ESI-MS: m / z 456.8 [M + H]. + C 21 H 18 BrN3O2S[455.03].

[0195] Preparation of compound 8c-Ⅲ

[0196] The procedure was the same as for 8a-I, except that 7c-III (0.42 g, 1.72 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.61 g, 2.07 mmol) were reacted. The product was a white solid, yield 15.6%, ESI-MS: m / z 470.08 [M + H]. + C 22 H 20 BrN3O2S[469.05].

[0197] Preparation of compound 8d-III

[0198] The procedure was the same as for 8a-I, except that 7d-III (0.42 g, 1.72 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.61 g, 2.07 mmol) were reacted. The product was a white solid, yield 65.0%, ESI-MS: m / z 456.03 [M + H]. + C 21 H 18 BrN3O2S[455.03].

[0199] Preparation of compound 8e-III

[0200] The procedure was the same as for 8a-I, except that 7e-III (0.42 g, 1.72 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.61 g, 2.07 mmol) were reacted. The product was a pale yellow solid, yield 22.6%, ESI-MS: m / z 470.14 [M + H]. + C 22 H 20 BrN3O2S[469.05].

[0201] Preparation of compound 8a-Ⅳ

[0202] The procedure was the same as for 8a-I, except that 7a-Ⅳ (0.39 g, 2.54 mmol) and 1-bromo-4-(bromomethyl)naphthalene (1.13 g, 3.81 mmol) were reacted. The product was a white solid, yield 35.5%, ESI-MS: m / z 442.25 [M + H]. + C 20 H 16 BrN3O2S[441.01].

[0203] Preparation of compound 8b-Ⅳ

[0204] The procedure was the same as for 8a-I, except that 7b-Ⅳ (0.46 g, 1.93 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.86 g, 2.89 mmol) were reacted. The product was a pale yellow solid, yield 60.7%, ESI-MS: m / z 458.07 [M + 2 + H]. + C 21 H 18 BrN3O2S [455.03].

[0205] Preparation of compound 8c-Ⅳ

[0206] The procedure was the same as for 8a-I, except that 7c-Ⅳ (0.21 g, 0.83 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.37 g, 1.25 mmol) were reacted. The product was a white solid, yield 15.6%, ESI-MS: m / z 470.00 [M + H]. + C 22 H 20 BrN3O2S[469.05].

[0207] Preparation of compound 8d-Ⅳ

[0208] The procedure was the same as for 8a-I, except that 8d-Ⅳ (0.20 g, 0.84 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.38 g, 1.27 mmol) were reacted. The product was a white solid, yield 71.1%, ESI-MS: m / z 456.35 [M + H]. + C 21 H 18 BrN3O2S[455.03].

[0209] Preparation of compound 8e-Ⅳ

[0210] The procedure was the same as for 8a-I, except that 8d-Ⅳ (0.62 g, 2.47 mmol) and 1-bromo-4-(bromomethyl)naphthalene (1.10 g, 3.71 mmol) were reacted. The product was a pale yellow solid, yield 50.4%, ESI-MS: m / z 472.07 [M + 2 + H]. + C 22 H 20 BrN3O2S [469.05].

[0211] (3) Synthetic routes of compounds 45-48

[0212]

[0213] Reagents and conditions: (i) Potassium carbonate, anhydrous ethanol, room temperature; (ii) 1-bromo-4-(bromomethyl)naphthalene, cesium carbonate, acetonitrile, 70°C; (iii) Lithium hydroxide, tetrahydrofuran, methanol, water, room temperature.

[0214] Preparation of compound 9a-V

[0215] Weigh 1-2 (0.30 g, 1.97 mmol) and potassium carbonate (0.39 g, 3.00 mmol) and dissolve them in 15 mL of anhydrous ethanol. Activate at room temperature for 30 min, then add methyl 2-bromoacetate (0.30 g, 1.97 mmol). Stir the reaction mixture at room temperature for 2 h. After evaporating the organic solvent, dissolve the solid in 20 mL of DCM, wash with saturated NaCl aqueous solution (20 mL × 3), collect the organic phase, dry it with anhydrous sodium sulfate, and purify by column chromatography to give a white solid (ethyl acetate:petroleum ether = 1:1), yield 40.0%, ESI-MS: m / z 225.04 [M + H] + , C8H8N4O2S [224.04].

[0216] Preparation of compound 9b-V

[0217] The procedure was the same as for 9a-V, except that 1-2 (0.30 g, 1.97 mmol) and potassium carbonate (0.41 g, 3.00 mmol) were dissolved in 15 mL of anhydrous ethanol, activated at room temperature for 30 min, and then methyl 2-bromopropionate (0.33 g, 1.97 mmol) was added. The reaction was carried out at room temperature, yielding a white solid in 62.5% yield. ESI-MS: m / z 239.10 [M + H] + C9H 10 N4O2S[238.05].

[0218] Preparation of compound 9c-V

[0219] The procedure was the same as for 9a-V, except that 1-2 (0.50 g, 3.29 mmol) and potassium carbonate (0.45 g, 3.29 mmol) were dissolved in 10 mL of anhydrous ethanol. The mixture was activated at room temperature for 30 min, then methyl 2-bromo-2-methylpropionate (0.59 g, 3.29 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 50.6%. ESI-MS: m / z 253.05 [M + H] + C 10 H 12 N4O2S [252.07].

[0220] Preparation of compound 9e-V

[0221] The procedure was the same as for 9a-V, except that 1-2 (0.50 g, 3.29 mmol) and potassium carbonate (0.45 g, 3.29 mmol) were dissolved in 15 mL of anhydrous ethanol. The mixture was activated at room temperature for 30 min, then methyl 3-bromopropionate (0.59 g, 3.29 mmol) was added, and the reaction was carried out at room temperature. A white solid was obtained, yielding 48.2%. ESI-MS: m / z 253.01 [M + H]+, C 10 H 12 N4O2S[252.07].

[0222] Preparation of compound 10a-V

[0223] Taking 10a-V as an example, 1-bromo-4-(bromomethyl)naphthalene (0.78 g, 2.62 mmol) was added to a 100 mL round-bottom flask, followed by approximately 15 mL of acetonitrile to dissolve it. Cesium carbonate (1.42 g, 1.97 mmol) was then added to the flask, followed by 9a-V (0.49 g, 2.18 mmol) dissolved in 25 mL of acetonitrile, which was slowly added dropwise to the flask. The mixture was heated to 75 °C, and TLC was monitored after 12 h. After the reaction was complete, the mixture was filtered, and the filter cake was collected. The filter cake was placed in a 100 mL beaker, and 20 mL of water was added to the beaker. After stirring for 10 min, the mixture was filtered, and the filter cake was collected. This process was repeated twice. Finally, the filter cake was placed in a 50 mL flask, 20 mL of anhydrous ethanol was added, and the mixture was heated to 80 °C and stirred for 1 h. Heating was then stopped, and the mixture was cooled to room temperature and filtered. The filter cake was then vacuum dried to obtain a white solid with a yield of 71.9%. ESI-MS: m / z 443.25 [M + H] + C 19 H 15 BrN4O2S [442.01]. The preparation method of compound 10b-dV is the same as that of 10a-V.

[0224] Preparation of compound 10b-V

[0225] The procedure was the same as for 10a-V, except that 9b-V (0.49 g, 2.05 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.74 g, 2.47 mmol) were reacted. The product was a white solid, yield 35.5%, ESI-MS: m / z 457.11 [M + H]. + C 20 H 17 BrN4O2S[456.03].

[0226] Preparation of compound 10c-V

[0227] The procedure was the same as for 10a-V, except that 9c-V (0.23 g, 0.91 mmol) and 1-bromo-4-(bromomethyl)naphthalene (0.32 g, 1.09 mmol) were reacted. The product was a white solid, yield 29.3%, ESI-MS: m / z 471.06 [M + H]. + C 21 H 19 BrN4O2S[470.04].

[0228] Preparation of compound 10e-V

[0229] The procedure was the same as for 10a-V, except that 10e-V (0.39 g, 1.54 mmol) was reacted with 1-bromo-4-(bromomethyl)naphthalene (0.55 g, 1.86 mmol). The product was a white solid, yield 28.9%, ESI-MS: m / z 471.23 [M + H]. + C 21 H 19 BrN4O2S [470.04].

[0230] Example 1. Preparation of Compound 1

[0231] Weigh 0.12 g (0.30 mmol) of 5a-I and dissolve it in 10 mL of tetrahydrofuran. Dissolve 0.07 g (3.00 mmol) of lithium hydroxide in 5 mL of water and slowly add it to the above solution, followed by 6 mL of anhydrous methanol. Stir the mixture at room temperature for 2 h. After the reaction is complete, remove the organic solvent from the reaction system by vacuum distillation. Then, add 15 mL of water quantitatively to the concentrated residue and acidify dropwise with 1 mol / L hydrochloric acid solution until the pH of the system reaches 2-3. A large amount of solid is observed to gradually precipitate in the reaction system. Filter and collect the solid, then vacuum dry it to obtain a white solid with a yield of 80.4% and a melting point of 131-133°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 6.8, 3.1 Hz, 1H,Naph-H), 8.21 (dd, J = 6.6, 3.1 Hz, 1H, Naph-H), 8.02 (d, J = 5.5 Hz, 1H,Indo-H), 7.71 – 7.67 (m, 2H, Naph-H × 2), 7.64 (d, J = 3.3 Hz, 1H, Naph-H), 7.47 (dd, J = 6.5, 4.2 Hz, 1H, Naph-H), 7.08 (d, J = 7.5 Hz, 1H, Indo-H), 6.68 (d, J = 3.1 Hz, 1H, Indo-H), 6.32 (d, J = 5.5 Hz, 2H, CH2), 6.18 – 6.14 (m, 1H, Indo-H), 3.94 (s, 2H, CH2), 2.37 (dd, J = 10.3, 4.8 Hz, 1H, CH), 1.04– 1.00 (m, 2H, CH2), 0.66 (td, J = 6.0, 4.1 Hz, 2H, CH2). ESI-MS: 389.13 m / z[M + H] + , C 23 H 20 N2O2S [388.12].

[0232] Example 2. Preparation of Compound 2

[0233] The procedure was the same as in Example 1, except that 5b-I (0.34 g, 0.82 mmol) reacted with lithium hydroxide (0.20 g, 8.20 mmol). The product was a white solid, yield 36.4%, melting point: 140-142°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.51 – 8.46 (m, 1H, Naph-H), 8.23 ​​– 8.15 (m, 1H, Naph-H), 8.05 (d, J = 5.4Hz, 1H, Indo-H), 7.72 – 7.59 (m, 3H, Naph-H × 2, Indo-H), 7.49 (d, J = 5.5Hz, 1H, Naph-H), 7.08 (d, J = 7.4 Hz, 1H, Naph-H), 6.68 (d, J = 3.0 Hz, 1H, Indo-H), 6.28 (s, 2H, CH2), 6.15 (d, J = 7.4 Hz, 1H, Indo-H), 4.53 (q, J =7.2 Hz, 1H, CH), 2.37 (td, J = 10.2, 6.1 Hz, 1H,CH), 1.27 (d, J = 7.2 Hz, 3H,CH3), 1.02 (dd, J = 8.2, 2.6 Hz, 2H, CH2), 0.72 – 0.60 (m, 2H, CH2). ESI-MS:m / z 403.17 [M+H] + C 24 H 22 N2O2S [402.14].

[0234] Example 3. Preparation of Compound 3

[0235] The procedure was the same as in Example 1, except that 5c-I (0.14 g, 0.33 mmol) reacted with lithium hydroxide (0.07 g, 3.30 mmol). The product was a white solid, yield 50.0%, melting point: 138-140°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.52 – 8.44 (m, 1H, Naph-H), 8.25 – 8.17 (m, 1H, Naph-H), 8.07 (d, J = 5.5Hz, 1H, Naph-H), 7.80 (s, 1H, Indo-H), 7.68 (dt, J = 6.9, 3.5 Hz, 2H, Naph-H× 2), 7.61 (d, J = 5.5 Hz, 1H, Naph-H), 7.05 (d, J = 7.4 Hz, 1H, Indo-H), 6.75 (d, J = 3.1 Hz, 1H, Indo-H), 6.31 (s, 2H, CH2), 6.03 (d, J = ESI-MS: m / z 417.22 [M+H] + C 25 H 24 N2O2S [416.16].

[0236] Example 4. Preparation of Compound 4

[0237] The procedure was the same as in Example 1, except that 5d-I (0.14 g, 0.33 mmol) reacted with lithium hydroxide (0.07 g, 3.30 mmol). The product was a white solid, yield 51.9%, melting point: 150-153°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.47 (dd, J = 6.9, 3.1 Hz, 1H, Naph-H), 8.22 – 8.16 (m, 1H, Naph-H), 8.04 (d, J = 5.4 Hz, 1H, Indo-H), 7.71 – 7.64 (m, 2H, Naph-H × 2), 7.58 (d, J =3.0 Hz, 1H, Naph-H), 7.41 (d, J = 5.4 Hz, 1H, Naph-H), 7.06 (d, J = 7.4 Hz,1H, Indo-H), 6.63 (d, J = 3.0 Hz, 1H, Indo-H), 6.29 (s, 2H, CH2), 6.10 (d, J= 7.4 Hz, 1H, Indo-H), 3.14 (t, J = 7.0 Hz, 2H, CH2), 2.41 – 2.33 (m, 1H,CH), 2.11 (t, J = 7.4 Hz, 2H,CH2), 1.67 (p, J = 7.5 Hz, 2H, CH2), 1.04 – 0.96(m, 2H, CH2), 0.64 (t, J = 5.3 Hz, 2H, CH2). ESI-MS: m / z 403.12 [M+H] + C 25 H 24 N2O2S [402.14].

[0238] Example 5. Preparation of Compound 5

[0239] The procedure was the same as in Example 1, except that 5e-I (0.40 g, 0.93 mmol) reacted with lithium hydroxide (0.23 g, 9.30 mmol). The product was a white solid, yield 26.3%, melting point: 138-141°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.47 (dd, J = 6.9, 3.1 Hz, 1H, Naph-H), 8.22 – 8.16 (m, 1H, Naph-H), 8.04 (d, J = 5.4 Hz, 1H, Indo-H), 7.71 – 7.64 (m, 2H, Naph-H × 2), 7.58 (d, J =3.0 Hz, 1H, Naph-H), 7.41 (d, J = 5.4 Hz, 1H, Naph-H), 7.06 (d, J = 7.4 Hz,1H, Indo-H), 6.63 (d, J = 3.0 Hz, 1H, Indo-H), 6.29 (s, 2H, CH2), 6.10 (d, J= 7.4 Hz, 1H, Indo-H), 3.14 (t, J = 7.0 Hz, 2H, CH2), 2.41 – 2.33 (m, 1H,CH), 2.11 (t, J = 7.4 Hz, 2H, CH2), 1.67 (p, J = 7.5 Hz, 2H, CH2), 1.04 – 0.96(m, 2H, CH2), 0.64 (t, J = 5.3 Hz, 2H, CH2). ESI-MS: m / z 417.35 [M+H] + C 25 H 24 N2O2S [416.16].

[0240] Example 6. Preparation of Compound 6

[0241] The procedure was the same as in Example 1, except that 5a-II (0.10 g, 0.26 mmol) was reacted with lithium hydroxide (0.06 g, 2.60 mmol). The product was a white solid, yield 83.3%, melting point: 135-137°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.48 (d, J = 6.4 Hz, 2H, Naph-H × 2), 8.18 (d, J = 9.7 Hz, 1H, Pyridine-H), 8.13 (d, J = 5.7 Hz, 1H, Imidazole-H), 7.71 – 7.58 (m, 2H, Naph-H × 2),7.34 (d, J = 5.7 Hz, 1H, Naph-H), 7.20 (d, J = 7.5 Hz, 1H, Imidazole-H), 6.99(d, J = 7.5 Hz, 1H, Naph-H), 6.02 (s, 2H, CH2), 4.08 (s, 2H, CH2), 2.38 (s,1H, CH), 1.09 – 0.99 (m, 2H, CH2), 0.69 (d, J = 3.4 Hz, 2H, CH2). ESI-MS: m / z390.14 [M+H] + C 22 H 19 N3O2S [389.12].

[0242] Example 7. Preparation of Compound 7

[0243] The procedure was the same as in Example 1, except that 5b-II (0.08 g, 0.19 mmol) reacted with lithium hydroxide (0.05 g, 1.90 mmol). The product was a white solid, yield 77.9%, melting point: 150-152°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.48 (d, J = 12.2 Hz, 2H, Naph-H × 2), 8.21 – 8.14 (m, 2H, Naph-H,Pyridine-H), 7.65 (dq, J = 6.0, 3.7 Hz, 2H, Imidazole-H × 2), 7.37 (d, J =5.7 Hz, 1H, Naph-H), 7.20 (d, J = 7.3 Hz, 1H, Naph-H), 7.01 (d, J = 7.4 Hz,1H, Naph-H), 6.02 (s, 2H, CH2), 4.76 (q, J = 7.2 Hz, 1H, CH), 2.39 (dt, J =8.5, 3.1 Hz, 1H, CH), 1.54 (d, J = 7.2 Hz, 3H, CH3), 1.08 – 0.99 (m, 2H, CH2), 0.69 (td, J = 5.9, 4.0 Hz, 2H, CH2). ESI-MS: m / z 402.12 [M+H] + C 23 H 21 N3O2S [403.14].

[0244] Example 8. Preparation of Compound 8

[0245] The procedure was the same as in Example 1, except that 5c-II (0.06 g, 0.14 mmol) reacted with lithium hydroxide (0.03 g, 1.40 mmol). The product was a white solid, yield 70.0%, melting point: 143-145°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.48 (d, J = 10.5 Hz, 2H, Naph-H × 2), 8.22 – 8.16 (m, 1H, Pyridine-H), 8.09 (d, J = 5.7 Hz, 1H, Naph-H), 7.68 – 7.60 (m, 2H, Naph-H × 2), 7.35 (d,J = 5.7 Hz, 1H, Naph-H), 7.21 (d, J = 7.3 Hz, 1H, Imidazole-H), 7.03 (d, J =7.4 Hz, 1H, Imidazole-H), 6.01 (s, 2H, CH2), 2.39 (td, J = 8.5, 4.3 Hz, 1H,CH), 1.65 (s, 6H, CH3 × 2), 1.07 – 1.01 (m, 2H, CH2), 0.70 (t, J = 5.1 Hz,2H, CH2). ESI-MS: m / z 418.25 [M+H] + C 24 H 23 N3O2S [417.15].

[0246] Example 9. Preparation of Compound 9

[0247] The procedure was the same as in Example 1, except that 5d-II (0.11 g, 0.26 mmol) was reacted with lithium hydroxide (0.06 g, 2.60 mmol). The product was a white solid, yield 80.0%, melting point: 148-150°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.52 – 8.39 (m, 2H, Naph-H × 2), 8.17 (dt, J = 12.3, 6.7 Hz, 2H, Pyridine-H, Naph-H), 7.65 (dq, J = 6.1, 3.3 Hz, 2H, Naph-H × 2), 7.20 (d, J = 7.4 Hz,1H, Imidazole-H), 7.07 – 6.94 (m, 1H, Imidazole-H), 6.00 (d, J = 15.3 Hz, 2H,CH2), 3.45 (t, J = 7.0 Hz, 2H, CH2), 2.70 (t, J = 7.1 Hz, 1H, CH2), 2.40 (s,2H, CH2), 1.08 – 1.01 (m, 2H, CH2), 0.72 – 0.66 (m, 2H, CH2). ESI-MS: m / z404.14 [M+H] + C 23 H 21 N3O2S [403.14].

[0248] Example 10. Preparation of Compound 10

[0249] The procedure was the same as in Example 1, except that 5e-II (0.10 g, 0.23 mmol) reacted with lithium hydroxide (0.05 g, 2.30 mmol). The product was a white solid, yield 83.3%, melting point: 142-144°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.54 – 8.42 (m, 2H, Naph-H × 2), 8.18 (t, J = 6.7 Hz, 2H, Pyridine-H,Naph-H), 7.70 – 7.56 (m, 2H, Naph-H × 2), 7.38 (d, J = 5.8 Hz, 1H, Naph-H), 7.20 (d, J = 7.4 Hz, 1H, Imidazole-H), 7.02 (d, J = 7.4 Hz, 1H, Imidazole-H), 6.02 (s, 2H, CH2), 3.32 (d, J = 7.2 Hz, 2H, CH2), 2.38 (t, J = 7.4 Hz, 3H, CH,CH2), 1.91 (p, J = 7.4 Hz, 2H, CH2), 1.04 (d, J = 8.0 Hz, 2H, CH2), 0.68 (t, J= 5.3 Hz, 2H, CH2). ESI-MS: m / z 418.15 [M+H] + C 24 H 23 N3O2S [417.15].

[0250] Example 11. Preparation of Compound 11

[0251] The procedure was the same as in Example 1, except that 5a-III (0.11 g, 0.27 mmol) reacted with lithium hydroxide (0.07 g, 2.70 mmol). The product was a white solid, yield 72.7%, melting point: 145-147°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.47 (d, J = 8.7 Hz, 2H, Naph-H × 2), 8.20 (dd, J = 7.2, 2.4 Hz, 1H, Pyridine-H), 7.86 (d, J = 6.0 Hz, 1H, Naph-H), 7.65 – 7.57 (m, 2H, Naph-H ×2), 7.34 (d, J = 6.0 Hz, 1H, Naph-H), 7.31 – 7.26 (m, 2H, Pyrazole-H × 2), 6.19 (s, 2H, CH2), 4.07 (s, 2H, CH2), 2.42 (tt, J = 8.5, 5.3 Hz, 1H, CH), 1.09– 1.03 (m, 2H, CH2), 0.72 (dt, J = 6.0, 3.0 Hz, 2H, CH2). ESI-MS: m / z 390.16[M+H] + C 22 H 19 N3O2S [389.12].

[0252] Example 12. Preparation of Compound 12

[0253] The procedure was the same as in Example 1, except that 5b-III (0.08 g, 0.19 mmol) reacted with lithium hydroxide (0.05 g, 1.90 mmol). The product was a white solid, yield 80.0%, melting point: 133-136°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.50 – 8.44 (m, 2H, Naph-H × 2), 8.20 (dd, J = 6.4, 2.0 Hz, 1H, Pyridine-H), 7.87 (d, J = 5.9 Hz, 1H, Pyrazole-H), 7.61 (ddt, J = 9.7, 6.9, 3.4 Hz,2H, Naph-H × 2), 7.36 (d, J = 6.0 Hz, 1H, Pyrazole-H), 7.33 – 7.26 (m, 2H,Naph-H × 2), 6.18 (s, 2H, CH2), 4.72 (q, J = 7.2 Hz, 1H, CH), 2.41 (td, J =8.4, 4.3 Hz, 1H, CH), 1.54 (d, J = 7.2 Hz, 3H, CH3), 1.08 – 1.04 (m, 2H, CH2), 0.72 (dt, J = 6.1, 3.1 Hz, 2H, CH2). ESI-MS: m / z 404.16 [M+H] + C 23 H 21 N3O2S [403.14].

[0254] Example 13. Preparation of Compound 13

[0255] The procedure was the same as in Example 1, except that 5c-III (0.08 g, 0.19 mmol) reacted with lithium hydroxide (0.05 g, 1.90 mmol). The product was a white solid, yield 57.1%, melting point: 110-112°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.48 – 8.46 (m, 2H, Naph-H × 2), 8.22 – 8.16 (m, 1H, Pyridine-H), 7.79 (d,J = 6.0 Hz, 1H, Pyrazole-H), 7.61 (ddd, J = 7.2, 4.6, 1.8 Hz, 2H, Naph-H ×2), 7.34 – 7.26 (m, 3H, Pyrazole-H, Naph-H × 2), 6.16 (s, 2H, CH2), 2.42(td, J = 5.5, 2.7 Hz, 1H, CH), 1.66 (s, 6H, CH3 × 2), 1.08 – 1.05 (m, 2H,CH2), 0.72 (dt, J = 6.0, 3.0 Hz, 2H, CH2). ESI-MS: m / z 418.27 [M+H] + C 24 H 23 N3O2S [417.15].

[0256] Example 14. Preparation of Compound 14

[0257] The procedure was the same as in Example 1, except that 5d-III (0.11 g, 0.26 mmol) was reacted with lithium hydroxide (0.06 g, 2.60 mmol). The product was a white solid, yield 75.5%, melting point: 120-123°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.47 (d, J = 8.1 Hz, 1H, Naph-H), 8.30 (d, J = 4.4 Hz, 1H, Pyridine-H), 8.17 (d, J = 8.0 Hz, 1H, Naph-H), 7.62 (q, J = 7.4 Hz, 2H, Naph-H × 2), 7.55(d, J = 7.1 Hz, 1H, Pyrazole-H), 7.30 (q, J = 7.6 Hz, 2H, Naph-H × 2), 6.96(d, J = 7.2 Hz, 1H, Pyrazole-H), 6.09 (s, 2H, CH2), 4.69 (t, J = 7.3 Hz, ESI-MS: m / z 404.14 [M+H] + C 23 H 21 N3O2S [403.14].

[0258] Example 15. Preparation of Compound 15

[0259] The procedure was the same as in Example 1, except that 5e-III (0.12 g, 0.25 mmol) reacted with lithium hydroxide (0.06 g, 2.55 mmol). The product was a white solid, yield 43.1%, melting point: 124-127°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.47 (q, J = 2.6 Hz, 2H, Naph-H × 2), 8.22 – 8.17 (m, 1H, Pyridine-H),7.88 (d, J = 5.9 Hz, 1H, Naph-H), 7.61 (p, J = 6.3 Hz, 2H, Naph-H × 2), 7.35– 7.24 (m, 3H, Pyrazole-H × 2, Naph-H), 6.17 (s, 2H, CH2), 3.29 (t, J = 7.1Hz, 2H, CH2), 2.44 – 2.34 (m, 3H, CH3), 1.91 (p, J = 7.3 Hz, 2H, CH2), 1.06 (dt, J = 8.7, 3.1 Hz, 2H, CH2), 0.72 (dt, J = 6.1, 3.1 Hz, 2H, CH2). ESI-MS: m / z 418.15 [M+H] + C 24 H 23 N3O2S [417.15].

[0260] Example 16. Preparation of Compound 16

[0261] The procedure was the same as in Example 1, except that 5a-Ⅳ (0.22 g, 0.55 mmol) reacted with lithium hydroxide (0.13 g, 5.50 mmol). The product was a white solid, yield 42.9%, melting point: 130-132°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.63 (s, 1H, Naph-H), 8.52 – 8.46 (m, 1H, Pyrimidine-H), 8.24 – 8.17 (m,1H, Naph-H), 7.87 (d, J = 3.2 Hz, 1H, Naph-H), 7.72 – 7.66 (m, 2H, Naph-H ×2), 7.10 (d, J = 7.5 Hz, 1H, Pyrrole-H), 6.74 (d, J = 3.2 Hz, 1H, Naph-H), 6.23 (s, 2H, CH2), 6.18 (d, J = 7.5 Hz, 1H, Pyrrole-H), 4.01 (s, 2H, CH2), 2.38 (td, J = 8.5, 4.3 Hz, 1H, CH), 1.02 (dt, J = 8.5, 3.1 Hz, 2H, CH2), 0.66 (dt, J = 6.1, 3.1 Hz, 2H, CH2). ESI-MS: m / z 390.09 [M+H] + C 22 H 19 N3O2S [389.12].

[0262] Example 17. Preparation of Compound 17

[0263] The procedure was the same as in Example 1, except that 5b-Ⅳ (0.18 g, 0.43 mmol) reacted with lithium hydroxide (0.10 g, 4.30 mmol). The product was a white solid, yield 42.9%, melting point: 129-131°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.62 (d, J = 2.7 Hz, 1H, Naph-H), 8.48 (dd, J = 6.3, 3.6 Hz, 1H, Pyrimidine-H), 8.20 – 8.09 (m, 1H, Naph-H), 7.79 – 7.60 (m, 3H, Naph-H × 2,Pyrrole-H), 7.10 (dd, J = 7.5, 2.6 Hz, 1H, Naph-H), 6.69 (d, J = 3.1 Hz, 1H,Naph-H), 6.27 – 6.14 (m, 3H, Pyrrole-H, CH2), 4.65 (qd, J = 7.2, 2.6 Hz, 1H,CH), 2.37 (dt, J = 13.1, 6.3 Hz, 1H, CH), 1.39 (dd, J = 7.2, 2.6 Hz, 3H,CH3), 1.02 (dt, J = 8.5, 3.0 Hz, 2H, CH2), 0.66 (dq, J = 5.7, 3.4 Hz, 2H,CH2). ESI-MS: m / z 404.14 [M+H] + C 23 H 21 N3O2S [403.14].

[0264] Example 18. Preparation of Compound 18

[0265] The procedure was the same as in Example 1, except that 5c-Ⅳ (0.18 g, 0.43 mmol) reacted with lithium hydroxide (0.10 g, 4.30 mmol). The product was a white solid, yield 64.7%, melting point: 116-119°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 12.63 (s, 1H, COOH), 8.57 (s, 1H, Naph-H), 8.52 – 8.46 (m, 1H, Pyrimidine-H), 8.17 (dt, J = 8.0, 2.6 Hz, 1H, Naph-H), 7.80 (d, J = 3.3 Hz, 1H, Naph-H), 7.72 – 7.65 (m, 2H, Naph-H × 2), 7.11 (d, J = 7.5 Hz, 1H, Pyrrole-H), 6.71 (d, J = 3.3 Hz, 1H, Naph-H), 6.27 (d, J = 7.5 Hz, 1H, Pyrrole-H), 6.19 (s,2H, CH2), 2.44 – 2.36 (m, 1H, CH), 1.46 (s, 6H, CH3 × 2), 1.07 – 0.99 (m, 2H,CH2), 0.70 – 0.62 (m, 2H, CH2). ESI-MS: m / z 418.77 [M+H] + C 24 H 23 N3O2S [417.15].

[0266] Example 19. Preparation of Compound 19

[0267] The procedure was the same as in Example 1, except that 5d-IV (0.08 g, 0.20 mmol) reacted with lithium hydroxide (0.05 g, 2.00 mmol). The product was a white solid, yield 62.5%, melting point: 128-130°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.58 (s, 1H, Naph-H), 8.48 – 8.43 (m, 1H, Naph-H), 8.19 – 8.13 (m, 1H, Indo-H), 7.71 – 7.57 (m, 4H, Naph-H × 2, Pyrrole-H, Pyrimidine-H), 7.11 (d,J = 7.4 Hz, 1H, Naph-H), 6.70 (s, 2H, CH2), 6.59 (d, J = 3.1 Hz, 1H, Pyrrole-H), 6.34 (d, J = 7.4 Hz, 1H, Naph-H), 4.67 (t, J = 6.9 Hz, 2H, CH2), 2.84 (t,J = 7.0 Hz, 2H, CH2), 2.35 (td, J = 8.4, 4.2 Hz, 1H,CH), 1.41 – 1.16 (m, 2H,CH2), 1.01 (dt, J = 8.7, 3.1 Hz, 2H, CH2), 0.66 (h, J = 4.0 Hz, 2H, CH2). ESI-MS: m / z 402.20 [MH] - C 23 H 21 N3O2S [403.14].

[0268] Example 20. Preparation of Compound 20

[0269] The procedure was the same as in Example 1, except that 5e-Ⅳ (0.08 g, 0.20 mmol) reacted with lithium hydroxide (0.05 g, 2.00 mmol). The product was a white solid, yield 52.6%, melting point: 133-135°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.68 (s, 1H, Naph-H), 8.54 – 8.45 (m, 1H, Naph-H), 8.21 – 8.14 (m, 1H, Pyrimidine-H), 7.84 (d, J = 3.2 Hz, 1H, Naph-H), 7.71 – 7.64 (m, 2H, Naph-H× 2), 7.09 (d, J = 7.4 Hz, 1H, Naph-H), 6.72 (d, J = 3.2 Hz, 1H, Pyrrole-H), 6.22 (s, 2H, CH2), 6.19 (d, J = 7.5 Hz, 1H, Pyrrole-H), 3.24 (t, J = 7.1 Hz,2H, CH2), 2.38 (td, J = 8.5, 4.3 Hz, 1H, CH), 2.17 (t, J = 7.4 Hz, 2H, CH2), 1.76 (p, J = 7.3 Hz, 2H, CH2), 1.05 – 0.98 (m, 2H, CH2), 0.71 – 0.62 (m, 2H,CH2). ESI-MS: m / z 418.65 [M+H] + C 24 H 23 N3O2S [417.15].

[0270] Example 21. Preparation of Compound 21

[0271] The procedure was the same as in Example 1, except that 5a-V (0.03 g, 0.07 mmol) was reacted with lithium hydroxide (0.02 g, 0.70 mmol). The product was a white solid, yield 71.4%, melting point: 140-143°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.73 (s, 1H, Naph-H), 8.53 (s, 1H, Naph-H), 8.47 (d, J = 7.9 Hz, 1H, Purine-H), 8.25 (d, J = 7.8 Hz, 1H, Purine-H), 7.63 (p, J = 6.7 Hz, 2H, Naph-H × 2), 7.20 (d, J = 7.3 Hz, 1H, Naph-H ), 7.10 (d, J = 7.4 Hz, 1H, Naph-H), 5.93 (s, 2H, CH2), 4.18 (s, 2H, CH2), 2.42 – 2.36 (m, 1H, CH), 1.04 (d, J =8.1 Hz, 2H, CH2), 0.68 (d, J = 5.3 Hz, 2H, CH2). ESI-MS: m / z 418.65 [M+H] + C 21 H 18 N4O2S [390.12].

[0272] Example 22. Preparation of Compound 22

[0273] The procedure was the same as in Example 1, except that 5b-V (0.21 g, 0.50 mmol) was reacted with lithium hydroxide (0.12 g, 5.00 mmol). The product was a white solid, yield 48.3%, melting point: 142-144°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.73 (s, 1H, Naph-H), 8.53 (s, 1H, Naph-H), 8.46 (d, J = 8.1 Hz, 1H, Purine-H), 8.25 (d, J = 7.7 Hz, 1H, Purine-H), 7.63 (q, J = 6.4 Hz, 2H, Naph-H × 2), 7.20 (d, J = 7.3 Hz, 1H, Naph-H), 7.11 (d, J = 7.4 Hz, 1H, Naph-H), 5.93 (s, 2H, CH2), 4.82 (q, J = 7.2 Hz, 1H, CH), 2.38 (q, J = 5.0 Hz, 1H,CH), 1.59 (d, J = 7.3 Hz, 3H, CH3), 1.04 (d, J = 8.2 Hz, 2H, CH2), 0.68 (d, J= 5.3 Hz, 2H, CH2). ESI-MS: m / z 405.07 [M+H] + C 22 H 20 N4O2S [404.13].

[0274] Example 23. Preparation of compound 23

[0275] The procedure was the same as in Example 1, except that 5c-V (0.17 g, 0.39 mmol) reacted with lithium hydroxide (0.09 g, 3.93 mmol). The product was a white solid, yield 87.5%, melting point: 160-162°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.46 (s, 1H, Naph-H), 8.17 (d, J = 7.5 Hz, 1H, Naph-H), 8.09 (d, J = 5.7Hz, 1H, Purine-H), 7.64 (q, J = 5.7 Hz, 2H, Naph-H × 2), 7.33 (d, J = 5.8Hz, 1H, Purine-H), 7.20 (d, J = 7.3 Hz, 1H, Naph-H), 7.05 (d, J = 7.4 Hz, 1H,Naph-H), 5.99 (s, 2H, CH2), 2.38 (q, J = 7.0 Hz, 1H, CH), 1.64 (s, 6H, CH3 ×2), 1.04 (q, J = 6.5 Hz, 2H, CH2), 0.69 (t, J = 5.3 Hz, 2H, CH2). ESI-MS: m / z419.18 [M+H] + C 23 H 22 N4O2S [418.15].

[0276] Example 24. Preparation of compound 24

[0277] The procedure was the same as in Example 1, except that 5e-V (0.21 g, 0.49 mmol) reacted with lithium hydroxide (0.09 g, 4.90 mmol). The product was a white solid, yield 78.8%, melting point: 139-141°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 12.15 (s, 1H, COOH), 8.44 (s, 1H, Naph-H), 8.16 (dd, J = 17.3, 6.6 Hz, 2H, Naph-H × 2), 7.63 (h, J = 6.0 Hz, 2H, Naph-H × 2), 7.31 (d, J = 5.7 Hz, 1H, Purine-H), 7.20 (d, J = 7.3 Hz, 1H, Naph-H), 7.01 (d, J = 7.4 Hz, 1H, Purine-H), 6.00 (s, 2H, CH2), 3.29 (t, J = 7.1 Hz, 2H, CH2), 2.38 (q, J = 7.6 Hz, 3H,CH2, CH), 1.91 (dd, J = 8.7, 5.7 Hz, 2H, CH2), 1.03 (p, J = 4.7 Hz, 2H, CH2), 0.68 (q, J = 5.2 Hz, 2H, CH2). ESI-MS: m / z 419.22 [M+H] + C 23 H 22 N4O2S [418.15].

[0278] Example 25. Preparation of compound 25

[0279] The procedure was the same as in Example 1, except that 8a-I (0.21 g, 0.48 mmol) reacted with lithium hydroxide (0.11 g, 4.80 mmol). The product was a white solid, yield 60.0%, melting point: 133-136°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 12.69 (s, 1H, COOH), 8.35 – 8.29 (m, 1H, Naph-H), 8.28 – 8.22 (m, 1H, Naph-H), 8.01 (d, J = 5.5 Hz, 1H, Indo-H), 7.80 (p, J = 5.9 Hz, 2H, Naph-H × 2), 7.72 (dd, J = 14.9, 5.4 Hz, 2H, Naph-H × 2), 7.44 (d, J = 5.5 Hz, 1H, Indo-H), 6.70 (d, J = 3.0 Hz, 1H, Indo-H), 6.33 (s, 2H, CH2), 6.10 (d, J = 7.8 Hz, 1H, Indo-H), 3.91 (s, 2H, CH2). ESI-MS: m / z 425.07 [MH] - C 20 H 15 BrN2O2S[426.00].

[0280] Example 26. Preparation of Compound 26

[0281] The procedure was the same as in Example 1, except that 8b-I (0.33 g, 0.72 mmol) reacted with lithium hydroxide (0.17 g, 7.20 mmol). The product was a white solid, yield 76.1%, melting point: 150-152°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 11.81 (s, 1H, COOH), 8.15 (dt, J = 14.2, 9.1 Hz, 3H, Naph-H × 3), 7.82 (d,J = 7.7 Hz, 1H, Indo-H), 7.63 (dd, J = 17.4, 9.6 Hz, 2H, Naph-H × 2), 7.50 (d, J = 11.0 Hz, 2H, Indo-H × 2), 7.37 (s, 1H, Naph-H), 6.60 (s, 1H, Indo-H), 4.10 – 3.83 (m, 3H, CH, CH2), 1.45 (s, 3H, CH3). ESI-MS: m / z 441.25 [M+H] + C 21 H 17 BrN2O2S [440.02].

[0282] Example 27. Preparation of Compound 27

[0283] The procedure was the same as in Example 1, except that 8c-I (0.27 g, 0.57 mmol) reacted with lithium hydroxide (0.10 g, 5.77 mmol). The product was a white solid, yield 53.8%, melting point: 155-157°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.25 (t, J = 5.1 Hz, 2H, Naph-H × 2), 8.08 (d, J = 5.5 Hz, 1H, Naph-H),7.88 – 7.75 (m, 3H, Indo-H, Naph-H × 2), 7.71 (d, J = 7.8 Hz, 1H, Indo-H), 7.62 (d, J = 5.5 Hz, 1H, Naph-H), 6.78 (d, J = 3.0 Hz, 1H, Indo-H), 6.34 (s, 2H, CH2), 6.03 (d, J = 7.8 Hz, 1H, Indo-H), 1.08 (s, 6H, CH3× 2). ESI-MS: m / z 455.12 [M+H] + C 22 H 19 BrN2O2S [454.04].

[0284] Example 28. Preparation of compound 28

[0285] The procedure was the same as in Example 1, except that 8d-I (0.32 g, 0.70 mmol) reacted with lithium hydroxide (0.17 g, 7.00 mmol). The product was a white solid, yield 64.5%, melting point: 140-143°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.76 (s, 1H, Naph-H), 8.61 (s, 1H, Naph-H), 8.39 – 8.30 (m, 1H, Naph-H), 8.26 – 8.17 (m, 1H, Naph-H), 7.85 (d, J = 7.8 Hz, 1H, Indo-H), 7.74 (ddt, J =10.5, 7.8, 4.2 Hz, 2H, Naph-H × 2), 7.12 (d, J = 7.8 Hz, 1H, Indo-H), 6.00(s, 2H, CH2), 3.40 (d, J = 14.3 Hz, 2H, CH2), 2.42 (t, J = 7.3 Hz, 2H, CH2),1.98 (p, J = 7.3 Hz, 2H, CH2). ESI-MS: m / z 441.37 [M+H] + C 21 H 17 BrN2O2S[440.02].

[0286] Example 29. Preparation of compound 29

[0287] The procedure was the same as in Example 1, except that 8e-I (0.28 g, 0.60 mmol) reacted with lithium hydroxide (0.14 g, 6.00 mmol). The product was a white solid, yield 77.7%, melting point: 135-138°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.34 – 8.21 (m, 2H, Naph-H × 2), 8.05 (d, J = 5.4 Hz, 1H, Indo-H), 7.83 –7.75 (m, 2H, Naph-H × 2), 7.74 – 7.63 (m, 2H, Naph-H × 2), 7.42 (d, J = 5.4Hz, 1H, Indo-H), 6.67 (d, J = 3.0 Hz, 1H, Indo-H), 6.32 (s, 2H, CH2), 6.14 –6.04 (m, 1H, Indo-H), 3.13 (t, J = 7.1 Hz, 2H,CH 2,), 2.11 (t, J = 7.4 Hz, 2H,CH2), 1.66 (p, J = 7.3 Hz, 2H, CH2). ESI-MS: m / z 455.02 [M+H] + C 22 H 19 BrN2O2S[454.04].

[0288] Example 30. Preparation of compound 30

[0289] The procedure was the same as in Example 1, except that 8a-II (0.12 g, 0.27 mmol) was reacted with lithium hydroxide (0.06 g, 2.72 mmol). The product was a white solid, yield 69.0%, melting point: 140-144°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.51 (s, 1H, Naph-H), 8.25 (ddd, J = 9.4, 6.7, 3.1 Hz, 2H, Naph-H × 2), 8.14 (d, J = 5.7 Hz, 1H, Naph-H), 7.84 (d, J = 7.7 Hz, 1H, Pyridine-H), 7.76(ddd, J = 6.8, 4.0, 1.8 Hz, 2H, Imidazole-H, Naph-H ), 7.34 (d, J = 5.7 Hz,1H, Imidazole-H), 6.92 (d, J = 7.8 Hz, 1H, Naph-H), 6.08 (s, 2H, CH2), 4.09(s, 2H, CH2). ESI-MS: m / z 428.10 [M+H] + C 19 H 14 BrN3O2S [427.00].

[0290] Example 31. Preparation of compound 31

[0291] The procedure was the same as in Example 1, except that 8b-II (0.12 g, 0.27 mmol) reacted with lithium hydroxide (0.06 g, 2.72 mmol). The product was a white solid, yield 51.7%, melting point: 138-140°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.52 (d, J = 9.4 Hz, 1H, Naph-H ), 8.27 – 8.22 (m, 2H, Naph-H × 2), 7.83 (t, J = 9.2 Hz, 2H, Imidazole-H, Naph-H ), 7.78 – 7.70 1.55 (d, J = 7.3 Hz, 3H,CH3). ESI-MS: m / z 442.00 [M+H] + C 20 H 16 BrN3O2S [441.01].

[0292] Example 32. Preparation of compound 32

[0293] The procedure was the same as in Example 1, except that 8c-II (0.48 g, 1.05 mmol) reacted with lithium hydroxide (0.25 g, 10.50 mmol). The product was a white solid, yield 32.6%, melting point: 142-144°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H, Naph-H), 8.25 (t, J = 9.4 Hz, 2H, Naph-H × 2), 8.10 (d, J = 5.7 Hz, 1H, Naph-H), 7.85 (d, J = 7.7 Hz, 1H, 1.66 (s, 6H, CH3 × 2). ESI-MS:m / z 442.00 [M+H] + C 21 H 18 BrN3O2S [441.01].

[0294] Example 33. Preparation of compound 33

[0295] The procedure was the same as in Example 1, except that 8d-II (0.23 g, 0.50 mmol) was reacted with lithium hydroxide (0.12 g, 5.00 mmol). The product was a white solid, yield 54.5%, melting point: 143-146°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.33 – 8.26 (m, 3H, Naph-H × 2, Pyridine-H), 8.20 (d, J = 8.1 Hz, 1H, Naph-H), 7.82 (d, J = 7.8 Hz, 1H, Naph-H), 7.71 (p, J = 7.1 Hz, 2H, Naph-H ×2), 7.62 (d, J = 7.7 Hz, 1H, Imidazole-H), 7.54 (d, J = 5.7 Hz, 1H, Imidazole-H), 5.08 (s, 2H, CH2), 4.46 (t, J = 6.6 Hz, 2H, CH2), 2.82 (t, J =6.6 Hz, 2H, CH2). ESI-MS: m / z 442.03 [M+H] + C 20 H 16 BrN3O2S [441.01].

[0296] Example 34. Preparation of compound 34

[0297] The procedure was the same as in Example 1, except that 8e-II (0.13 g, 0.27 mmol) reacted with lithium hydroxide (0.06 g, 2.70 mmol). The product was a white solid, yield 71.4%, melting point: 147-149°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 12.10 (s, 1H, COOH), 8.47 (s, 1H, Naph-H), 8.25 (ddd, J = 12.0, 6.3, 2.3Hz, 3H, Naph-H × 2, Pyridine-H), 8.16 (d, J = 5.6 Hz, 1H, Naph-H), 7.78 –7.71 (m, 2H, Naph-H × 2), 7.33 (d, J = 5.7 Hz, 1H, Imidazole-H), 6.95 (d, J= 7.8 Hz, 1H, Imidazole-H), 6.06 (s, 2H, CH2), 3.16 (t, J = 7.1 Hz, 2H, CH2),2.38 (t, J = 7.4 Hz, 2H, CH2), 1.92 (p, J = 7.2 Hz, 2H, CH2). ESI-MS: m / z456.03 [M+H] + C 21 H 18 BrN3O2S [455.03].

[0298] Example 35. Preparation of compound 35

[0299] The procedure was the same as in Example 1, except that 8a-III (0.39 g, 0.83 mmol) reacted with lithium hydroxide (0.20 g, 8.30 mmol). The product was a white solid, yield 52.0%, melting point: 110-113°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.37 (d, J = 6.3 Hz, 2H, Naph-H × 2), 8.27 – 8.20 (m, 1H, Pyridine-H),8.12 (d, J = 5.6 Hz, 1H, Naph-H), 7.83 – 7.77 (m, 2H, Naph-H × 2 ), 7.74 (d,J = 7.8 Hz, 1H, Naph-H), 7.61 (d, J = 5.6 Hz, 1H, Pyridine-H), 6.50 (s, 2H,CH2), 6.25 (d, J = 7.8 Hz, 1H, Pyrazole-H), 4.02 (s, 2H, CH2). ESI-MS: m / z428.00 [M+H] + C 19H 14 BrN3O2S [427.00].

[0300] Example 36. Preparation of compound 36

[0301] The procedure was the same as in Example 1, except that 8b-III (0.09 g, 0.19 mmol) reacted with lithium hydroxide (0.05 g, 1.90 mmol). The product was a white solid, yield 68.9%, melting point: 145-148°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.35 (d, J = 11.3 Hz, 2H, Naph-H × 2), 8.26 – 8.21 (m, 1H, Pyridine-H),8.15 (d, J = 5.6 Hz, 1H, Naph-H), 7.79 (dt, J = 6.3, 2.6 Hz, 2H, Naph-H ×2), 7.75 (d, J = 7.9 Hz, 1H, Naph-H), 7.64 (d, J = 5.6 Hz, 1H, Pyridine-H), 6.47 (s, 2H, CH2), 6.28 (d, J = 7.8 Hz, 1H, Pyrazole-H), 4.66 (t, J = 7.3 Hz,1H, CH), 1.41 (d, J = 7.2 Hz, 3H, CH3). ESI-MS: m / z 443.21 [M+H] + C 20 H 16 BrN3O2S[442.09].

[0302] Example 37. Preparation of compound 37

[0303] The procedure was the same as in Example 1, except that 8c-III (0.12 g, 0.25 mmol) reacted with lithium hydroxide (0.06 g, 2.50 mmol). The product was a white solid, yield 51.7%, melting point: 152-155°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 12.69 (s, 1H, COOH), 8.35 (d, J = 12.6 Hz, 2H, Naph-H × 2), 8.27 – 8.21(m, 1H, Pyridine;oH), 8.11 (d, J = 5.5 Hz, 1H, 1.43 (s, 6H, CH3 × 2). ESI-MS: m / z 456.30 [M+H] + C 21 H 18 BrN3O2S [455.03].

[0304] Example 38. Preparation of compound 38

[0305] The procedure was the same as in Example 1, except that 8d-III (0.26 g, 0.57 mmol) reacted with lithium hydroxide (0.13 g, 5.70 mmol). The product was a white solid, yield 51.8%, melting point: 134-137°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.31 (dd, J = 8.4, 1.6 Hz, 1H, Naph-H), 8.24 – 8.17 (m, 3H, Naph-H × 2, Pyridine-H), 7.87 – 7.81 (m, 1H, Pyridine-H), 7.76 – 7.63 (m, 3H, Naph-H ×2, Pyrazole-H), 7.56 (dd, J = 5.5, 2.1 Hz, 1H, Naph-H), 5.17 (d, J = 2.1 Hz,2H, CH2), 4.84 (t, J = 7.0 Hz, 2H, CH2), 2.81 (t, J = 7.0 Hz, 2H, CH2). ESI-MS: m / z 442.03 [M+H] + C 20 H 16 BrN3O2S [441.03].

[0306] Example 39. Preparation of compound 39

[0307] The procedure was the same as in Example 1, except that 8e-III (0.26 g, 0.57 mmol) reacted with lithium hydroxide (0.13 g, 5.70 mmol). The product was a white solid, yield 86.2%, melting point: 130-132°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.33 (d, J = 9.9 Hz, 2H, Naph-H × 2), 8.24 – 8.19 (m, 1H, Pyridine-H),8.14 (d, J = 5.6 Hz, 1H, Naph-H), 7.77 (dt, J = 6.1, 2.2 Hz, 2H, Naph-H ×2), 7.70 (d, J = 7.8 Hz, 1H, Naph-H), 7.60 (d, J = 5.6 Hz, 1H, Pyridine-H), 6.47 (s, 2H, CH2), 6.22 (d, J = 7.8 Hz, 1H, Pyrazole-H), 3.22 (d, J = 14.2Hz, 2H, CH2), 2.20 (t, J = 7.4 Hz, 2H, CH2), 1.74 (p, J = 7.3 Hz, 2H, CH2).ESI-MS: m / z 456.30 [M+H] + C 20 H 16 BrN3O2S [455.03].

[0308] Example 40. Preparation of Compound 40

[0309] The procedure was the same as in Example 1, except that 8a-Ⅳ (0.11 g, 0.25 mmol) reacted with lithium hydroxide (0.06 g, 2.50 mmol). The product was a white solid, yield 84.9%, melting point: 146-148°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 8.64 (s, 1H, Naph-H), 8.33 – 8.23 ​​(m, 2H, Naph-H × 2), 7.93 (d, J = 3.2Hz, 1H, Pyrimidine-H), 7.83 – 7.78 (m, 2H, Naph-H × 2), 7.75 (d, J = 7.8 Hz, 1H, Naph-H), 6.77 (d, J = 3.2 Hz, 1H, Pyrrole-H), 6.26 (s, 2H, CH2), 6.18 (d,J = 7.8 Hz, 1H, Pyrrole-H), 4.00 (s, 2H, CH2). ESI-MS: m / z 426.00 [MH] - C 19 H 14 BrN3O2S [427.00].

[0310] Example 41. Preparation of compound 41

[0311] The procedure was the same as in Example 1, except that 8b-Ⅳ (0.3 g, 0.64 mmol) reacted with lithium hydroxide (0.15 g, 6.40 mmol). The product was a white solid, yield 68.9%, melting point: 149-152°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.67 (s, 1H, Naph-H), 8.33 – 8.20 (m, 3H, Naph-H × 2, Pyrimidine-H), 7.91 (d, J = 3.2 Hz, 1H, Naph-H), 7.82 – 7.78 (m, 2H, Naph-H × 2), 7.75 (d, J =7.7 Hz, 1H, Pyrrole-H), 6.77 (d, J = 3.2 Hz, 1H, Pyrrole-H), 6.22 (d, J =14.5 Hz, 3H, CH3), 4.72 (q, J = 7.2 Hz, 1H, CH), 1.39 (d, J = 7.3 Hz, 3H,CH3). ESI-MS: m / z 442.00 [M+H] + C 20 H 16 BrN3O2S [441.00].

[0312] Example 42. Preparation of compound 42

[0313] The procedure was the same as in Example 1, except that 8c-Ⅳ (0.17 g, 0.37 mmol) reacted with lithium hydroxide (0.09 g, 3.73 mmol). The product was a white solid, yield 68.9%, melting point: 143-146°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.39 – 8.30 (m, 2H, Naph-H × 2), 8.27 – 8.21 (m, 1H, Pyrimidine-H), 8.11(d, J = 5.6 Hz, 1H, Naph-H), 7.83 – 7.71 (m, 3H, Pyrrole-H, Naph-H × 2), 7.66 (d, J = 5.6 Hz, 1H, Naph-H ), 6.48 (s, 2H, CH2), 6.28 (d, J = 7.8 Hz, 1H, Pyrrole-H), 1.43 (s, 6H, CH3 × 2). ESI-MS: m / z 456.02 [M+H] + C 21 H 18 BrN3O2S[455.03].

[0314] Example 43. Preparation of compound 43

[0315] The procedure was the same as in Example 1, except that 8d-IV (0.08 g, 0.18 mmol) reacted with lithium hydroxide (0.04 g, 1.80 mmol). The product was a white solid, yield 50.0%, melting point: 144-149°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6)δ 12.35 (s, 1H, COOH), 8.34 – 8.29 (m, 1H, Naph-H), 8.21 (dd, J = 8.9, 2.9Hz, 3H, Naph-H × 2, Pyrimidine-H), 7.84 (d, J = 7.7 Hz, 1H, Naph-H), 7.77 –7.64 (m, 3H, Pyrrole-H × 2, Naph-H), 7.57 (d, J = 5.6 Hz, 1H, Naph-H), 5.17(s, 2H, CH2), 4.84 (t, J = 7.0 Hz, 2H, CH2), 2.82 (t, J = 7.0 Hz, 2H, CH2).ESI-MS: m / z 442.05 [M+H] + C 20 H 16 BrN3O2S [441.01].

[0316] Example 44. Preparation of compound 44

[0317] The procedure was the same as in Example 1, except that 8d-IV (0.39 g, 0.83 mmol) reacted with lithium hydroxide (0.20 g, 8.30 mmol). The product was a white solid, yield 34.5%, melting point: 132-134°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.67 (s, 1H, Naph-H), 8.29 – 8.23 ​​(m, 2H, Pyrimidine, Naph-H ), 7.90 (d, J= 3.2 Hz, 1H, Naph-H), 7.82 – 7.76 (m, 2H, Naph-H), 7.73 (d, J = 7.8 Hz, 1H, Naph-H), 6.75 (d, J = 3.1 Hz, 1H, Pyrrole-H), 6.24 (s, 2H, CH2), 6.16 (d, J =7.8 Hz, 1H, Pyrrole-H), 3.22 (d, J = 7.1 Hz, 2H, CH2), 2.17 (t, J = 7.4 Hz, 2H, CH2), 1.75 (p, J = 7.3 Hz, 2H, CH2). ESI-MS: m / z 454.03 [MH] - C 20 H16 BrN3O2S [455.03].

[0318] Example 45. Preparation of compound 45

[0319] The procedure was the same as in Example 1, except that 10a-V (0.09 g, 0.20 mmol) was reacted with lithium hydroxide (0.05 g, 2.04 mmol). The product was a pale yellow solid with a yield of 95.4% and a melting point of 125-127°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H, COOH), 8.73 (s, 1H, Naph-H), 8.60 (s, 1H, Naph-H), 8.33 (d, J = 7.9 Hz, 1H, Naph-H), 8.23 ​​(d, J = 8.0 Hz, 1H, Naph-H), 7.85 (d,J = 7.7 Hz, 1H, Purine-H), 7.74 (p, J = 6.8 Hz, 2H, Naph-H × 2), 7.08 (d, J= 7.8 Hz, 1H, Purine-H), 6.00 (s, 2H, CH2), 4.19 (s, 2H, CH2). ESI-MS: m / z428.99 [M+H] + C 18 H 13 BrN4O2S [427.99].

[0320] Example 46. Preparation of Compound 46

[0321] The procedure was the same as in Example 1, except that 10b-V (0.33 g, 0.72 mmol) was reacted with lithium hydroxide (0.17 g, 7.20 mmol). The product was a white solid, yield 16.1%, melting point: 129-131°C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H, Naph-H), 8.59 (s, 1H, Naph-H), 8.34 (dd, J = 7.5, 2.0Hz, 1H, Purine-H), 8.25 – 8.18 (m, 1H, Naph-H), 7.84 (d, J = 7.8 Hz, 1H, Naph-H), 7.74 (ddd, J = 7.8, 5.8, 1.6 Hz, 2H, Naph-H × 2), 7.10 (d, J = 7.7Hz, 1H, Purine-H), 5.99 (s, 2H, CH2), 4.84 (q, J = 7.3 Hz, 1H, CH), 1.60 (d,J = 7.3 Hz, 3H, CH3). ESI-MS: m / z 443.10 [M+H] + C 18 H 13 BrN4O2S [442.01].

[0322] Example 47. Preparation of Compound 47

[0323] The procedure was the same as in Example 1, except that 10c-V (0.21 g, 0.45 mmol) was reacted with lithium hydroxide (0.10 g, 4.50 mmol). The product was a white solid, yield 60.0%, melting point: 137-139°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H, Naph-H), 8.57 (s, 1H, Naph-H), 8.37 – 8.32 (m, 1H, Naph-H), 8.27 – 8.19 (m, 1H, Naph-H), 7.85 (d, J = 7.8 Hz, 1H, Purine-H), 7.75 (q, J = 6.7 Hz, 2H, Naph-H × 2), 7.09 (d, J = 7.8 Hz, 1H, Purine-H), 5.98 (s, 2H, CH2), 1.72 (s, 6H, CH3 × 2). ESI-MS: m / z 457.12 [M+H] + C 20 H 17 BrN4O2S [456.03].

[0324] Example 48. Preparation of compound 48

[0325] The procedure was the same as in Example 1, except that 10e-V (0.20 g, 0.42 mmol) was reacted with lithium hydroxide (0.10 g, 4.20 mmol). The product was a white solid, yield 52.6%, melting point: 150-153°C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H, Naph-H), 8.61 (s, 1H, Naph-H), 8.39 – 8.30 (m, 1H, Naph-H), 8.26 – 8.17 (m, 1H, Naph-H), 7.85 (d, J = 7.8 Hz, 1H, Purine-H), 7.74 (ddt, J = 10.5, 7.8, 4.2 Hz, 2H, Naph-H × 2), 7.12 (d, J = 7.8 Hz, 1H, Purine-H), 6.00 (s, 2H, CH2), 3.40 (d, J = 14.3 Hz, 2H, CH2), 2.42 (t, J = 7.3Hz, 2H, CH2), 1.98 (p, J = 7.3 Hz, 2H, CH2). ESI-MS: m / z 457.03 [M+H] + C 20 H 17 BrN4O2S [456.03].

[0326] Example 49. In vivo uric acid-lowering activity assay of the target compound

[0327] Test materials and methods:

[0328] (1) Experimental animals: Adult male Kunming mice weighing about 20 g were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0329] (2) Modeling drugs: hypoxanthine, potassium oxonate, sodium carboxymethylcellulose (CMC-Na).

[0330] (3) Positive control drug: Lesinurad

[0331] (4) Testing instruments: Acon uric acid meter and uric acid test strips

[0332] (5) Experimental principle: A mouse model of acute hyperuricemia was established by subcutaneous injection of potassium oxonate combined with gavage administration of hypoxanthine. Then, 2 mg / kg of positive control drug and test compound were given. By measuring the change of serum uric acid level in mice after 4 h, compounds with excellent in vivo activity were screened.

[0333] (6) Sample preparation:

[0334] First, weigh 0.5 g of CMC-Na and place it in a 250 mL flask. Add 100 mL of distilled water and heat at 100℃ for 2 h. After the solution becomes clear, stop heating and let it cool before use.

[0335] Preparation of 60 mg / mL hypoxanthine suspension: Add 1.2 g hypoxanthine to 20 mL of 0.5% CMC-Na solution, mix thoroughly under sonication, and set aside for use. The intragastric administration volume of hypoxanthine to Kunming mice is 0.2 mL, corresponding to an animal dose of 600 mg / kg.

[0336] Preparation of 40 mg / mL potassium oxonate suspension: Add 0.8 g potassium oxonate to 12 mL of distilled water and 8 mL of CMC-Na solution, mix thoroughly under sonication, and set aside for use. The subcutaneous injection volume of potassium oxonate in Kunming mice is 0.2 mL, corresponding to an animal dose of 400 mg / kg.

[0337] Preparation of 0.2 mg / mL Recinard or test compound solution: Weigh 1 mg of Recinard or test compound, dissolve in 100 μl DMSO, then add 4.9 mL of 0.5% CMC-Na solution and mix well. The corresponding animal dosage is 2 mg / kg, 0.2 mL / animal administered by gavage.

[0338] Preparation of blank solution for gavage: Mix 3 mL of 0.5% CMC-Na solution with 1 mL of distilled water, vortex and sonicate, and mix thoroughly before use.

[0339] Preparation of blank solution for subcutaneous injection: Mix 3 mL of distilled water, 0.88 mL of 0.5% CMC-Na solution, and 0.12 mL of DMSO, vortex and sonicate until homogeneous, and set aside for use. Before use, prepare an appropriate concentration of the test compound using DMSO and CMC-Na.

[0340] (7) Test method:

[0341] Mice were randomly divided into four groups after acclimatizing for one week. For the first 12 hours of the experiment, mice were fasted but allowed free access to water. The experimental group received 0.2 mL of hypoxanthine suspension (60 mg / mL) by gavage, 0.2 mL of potassium oxonate suspension (40 mg / mL) subcutaneously, and 0.2 mL of a compound solution (0.2 mg / mL) by gavage. The control group received 0.2 mL of hypoxanthine suspension (60 mg / mL) by gavage, 0.2 mL of potassium oxonate suspension (40 mg / mL) subcutaneously, and 0.2 mL of Recinard solution (0.2 mg / mL) by gavage. The model group received 0.2 mL of hypoxanthine suspension (60 mg / mL) by gavage, 0.2 mL of potassium oxonate suspension (40 mg / mL) subcutaneously, and 0.2 mL of a blank solution by gavage. The blank control group received 0.4 mL of a blank solution by gavage and 0.2 mL of a blank solution subcutaneously. Four hours later, the mice were anesthetized, their eyeballs were removed to collect blood, and they were euthanized by spinal cord dislocation. Serum was separated, and the serum uric acid concentration was measured.

[0342] The rate of decrease in serum uric acid concentration (DR)% = (model value - experimental value) / (model value - blank value) × 100%. The higher the rate of decrease, the better the activity.

[0343] Table 2. Uric acid-lowering activity of compounds 1-24

[0344]

[0345] The structures of compounds 1-24 are shown in Table 1 (1-24);

[0346] Table 3. Structures and uric acid-lowering activities of compounds 25–48

[0347]

[0348] The structures of compounds 25–48 are shown in Table 1. (Where: Ⅰ indicates a SUA value less than 400 μmol / L; Ⅱ indicates a SUA value between 400 and 600 μmol / L; Ⅲ indicates a SUA value between 600 and 800 μmol / L; Ⅳ indicates a SUA value greater than 800 μmol / L; A indicates a DR value greater than 80%; B indicates a DR value between 65% and 80%; C indicates a DR value between 45% and 65%; D indicates a DR value less than 45%.)

[0349] Conclusion: As shown in Tables 2 and 3, 44 compounds exhibited uric acid-lowering activity, which was stronger than or comparable to the positive control drug Lesinurad. Among them, the representative compounds 12, 21, 22, 29, 33, 35, 47, and 48 all showed a reduction rate of over 80% in serum uric acid in animal activity tests, demonstrating excellent uric acid-lowering activity and can be considered as candidate drugs for uric acid-lowering.

Claims

1. Azaindole compounds, or pharmaceutically acceptable salts thereof, having the structure shown in general formula I: in, X, Y, Z are carbon or nitrogen atoms; R1 is cyclopropyl or bromine; R2 is an alkane or a substituted alkane, wherein the substituent is a C1-C5 alkane.

2. The azaindole compound as described in claim 1, characterized in that, The R2 mentioned above are respectively .

3. The azaindole compound as described in claim 2, characterized in that, It is one of the following compounds: 。 4. The method for preparing aza-indole compounds as described in claim 3, characterized in that, One of the following methods: (1) Synthesis of compounds 1-24: Taking cycloI-0 as an example, 1-bromo-4-methylnaphthalene is first used as the starting material. Under the catalysis of benzoyl peroxide, it reacts with N-bromosuccinimide in n-hexane to generate 1-1, i.e., 1-bromo-4-(bromomethyl)naphthalene. In acetonitrile, intermediate 1-1 reacts with I-0 under the catalysis of cesium carbonate to generate intermediate 2A-I, i.e., 1-(4-bromonaphth-1-yl)methyl-7-chloro-azaindole. Intermediate 2A-I undergoes a Suzuki coupling reaction with cyclopropylboronic acid and tricyclohexylphosphine under alkaline conditions in a palladium acetate catalytic system to successfully prepare intermediate 3A-I, i.e., 7-chloro-1-((4-cyclopropylnaphth-1-yl)methyl-7-chloro ... 1-((4-cyclopropylnaphthyl-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine; intermediate 3A-I reacts with thiourea in n-butanol under high temperature to generate intermediate 4A-I, namely 1-((4-cyclopropylnaphthyl-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-7-thiol; 4A-I undergoes nucleophilic substitution reaction with esters of different substituents in N,N-dimethylformamide solution under the action of potassium carbonate to give esterified products 5a-eI; subsequently, 5a-eI is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to give target products 1-5; the synthesis steps of other rings are the same as those of ring I-0 to obtain target products 6-24; Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70°C; (ii) 7-chloro-6-azaindole / 4-chloroimidazole[4,5-C]pyridine / 7-chloro-1H-pyrazolo[3,4-C]pyridine / 4-chloropyrrolo[2,3-D]pyrimidine / 6-chloropurine, cesium carbonate, acetonitrile, 70°C; (iii) cyclopropylboronic acid, potassium phosphate, palladium acetate, tricyclohexylphosphine, toluene / water (20:1), nitrogen, 100°C; (iv) thiourea, n-butanol, 130°C; (v) potassium carbonate, N,N-dimethylformamide, room temperature; (vi) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (2) Synthesis of compounds 25-44: Taking ring I-0 as an example, 7-chloro-1H-pyrrolo[2,3-c]pyridine is first used as the starting material and reacted with thiourea in n-butanol under high temperature to generate intermediate 6A-I, namely 1H-pyrrolo[2,3-c]pyridine-7-thiol; 6A-I undergoes nucleophilic substitution reaction with esters of different substituents in N,N-dimethylformamide solution under the action of potassium carbonate to obtain esterified product 7a-eI. Under the catalysis of cesium carbonate, it reacts with 1-1 to generate intermediate 8a-eI; intermediate 8a-eI is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain target products 25-29; the synthesis steps of other rings are the same as those of ring I-0 to obtain target products 30-44. Reagents and conditions: (i) thiourea, n-butanol, 130℃; (ii) 1-bromo-4-(bromomethyl)naphthalene, cesium carbonate, acetonitrile, 70℃; (iii) potassium carbonate, N,N-dimethylformamide, room temperature; (iv) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (3) Synthesis of compounds 45-48: First, using 6-mercaptopurine as the starting material, a nucleophilic substitution reaction was carried out with esters of different substituents in anhydrous ethanol solution under the action of potassium carbonate to obtain the esterified product 9a-eV; then, 9a-eV reacted with 1-1 under the catalysis of cesium carbonate to generate the intermediate 10a-eV; then, 10a-eV was hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain the target product 45-48; Reagents and conditions: (i) Potassium carbonate, anhydrous ethanol, room temperature; (ii) 1-bromo-4-(bromomethyl)naphthalene, cesium carbonate, acetonitrile, 70°C; (iii) Lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; The room temperature mentioned refers to 20~30℃.

5. The use of the azaindole compounds according to any one of claims 1-3 in the preparation of uric acid-lowering drugs.

6. A uric acid-lowering pharmaceutical composition comprising a azidoindole compound as described in any one of claims 1-3 and one or more pharmaceutically acceptable carriers or excipients.

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