CN114478522B - A kind of pyridoimidazole derivatives and its preparation method and application - Google Patents

Abstract

The invention relates to a pyridoimidazole derivative, a preparation method and application thereof. The compound has the structure shown in formula I or II. The present invention also relates to a preparation method and a pharmaceutical composition containing the compound of formula I or formula II. The present invention also provides the application of the above compound in the preparation of uric acid-lowering medicine.

Description

A pyridimidazole derivative and its preparation method and application

Technical Field

The present invention relates to the field of drugs for treating hyperuricemia and gout, and in particular to a pyridoimidazole compound for treating hyperuricemia and gout, a preparation method thereof, or a drug combination containing the same, and the use thereof in medicine.

Background Art

Hyperuricemia (HUA) refers to the fasting blood uric acid level on two different days under a normal purine diet: male blood uric acid>420μmol/L, female blood uric acid>360μmol/L. Gout refers to a crystal-related arthropathy caused by monosodium urate (MSU) deposition with a blood uric acid concentration exceeding 6.8mg/dL. It is directly related to hyperuricemia caused by purine metabolism disorders or reduced uric acid excretion, specifically acute characteristic arthritis and chronic tophi. Gout and hyperuricemia are both related to the level of uric acid in the human body. A normal adult produces about 750mg of uric acid per day, of which 1/3 is decomposed and metabolized by the intestines and 2/3 is excreted by the kidneys, thereby maintaining the stability of uric acid levels in the body. Currently, there are two main types of drugs for the treatment of gout: one is xanthine oxidase inhibitors that inhibit uric acid production, and the other is URAT1 inhibitors that promote uric acid excretion. Uric acid transporter 1 (URAT1) is located on the brush border of human renal proximal tubular epithelial cells and mainly mediates the reabsorption of uric acid in the kidney. Increased URAT1 activity or gene expression caused by its gene mutation is one of the important pathogenesis of hyperuricemia. Lesinurad is a URAT1 inhibitor used to treat hyperuricemia and gout. It was withdrawn from the market due to its high therapeutic dose and serious toxic side effects. Therefore, further structural modification is expected to obtain a new uric acid-lowering drug with better activity and safety and independent intellectual property rights.

Summary of the invention

In view of the deficiencies in the prior art, the present invention provides a pyridimidazole derivative and a preparation method thereof. The present invention also provides the activity screening results of the above-mentioned compounds as uric acid-lowering drugs and their applications.

The technical solution of the present invention is as follows:

1. Pyridoimidazole derivatives

The pyridoimidazole derivatives of the present invention, or pharmaceutically acceptable salts thereof, have the structure shown in the following general formula I or II:

Wherein, Ar is 1-cyclopropyl-4-naphthalene or 1-bromo-4-naphthalene; when X is a nitrogen atom, Y is a carbon atom or when X is a carbon atom, Y is a nitrogen atom; R is an alkane or a substituted alkane, and the substituent is a C1-C10 alkane.

Preferably according to the present invention, R is methylene, ethyl, propyl, isopropyl, tert-butyl or cyclobutyl.

According to the present invention, the pyridoimidazole derivative is one of the following:

Table 1. Structural formula of compound 9-44

2. Preparation method of pyridimidazole derivatives

The preparation method of the pyridoimidazole derivatives of the present invention is one of the following methods:

(1) Synthesis of Compound 9-20:

In the presence of benzoyl peroxide (BPO), 1a was treated with N-bromosuccinimide (NBS) in n-hexane to give intermediate 2a, which was reacted with potassium phthalimide to give 3a; 3a was reacted with 80% hydrazine hydrate to give 4a via Gabriel synthesis, and then 4a was converted to 5a via Suzuki coupling reaction in a 25:1 v/v toluene/water mixture; 5a and 2-nitro-3-pyridyl trifluoromethanesulfonate (1b) or 4-chloro-3-pyridyl trifluoromethanesulfonate (1c) were reacted with 4-chloro-3-pyridyl trifluoromethanesulfonate (1d) to give 5a. -nitropyridine (1c) is subjected to coupling reaction to obtain intermediate 6a or 6b; in the presence of Pd/C, 7a or 7b is obtained by hydrogenation reduction, and then 1,1'-thiocarbonyldiimidazole (TCDI) is used for cyclization to obtain key intermediate 8a or 8b; compound 9-14 is obtained by nucleophilic substitution reaction and lithium hydroxide hydrolysis; the preparation method of compound 15-20 is similar to compound 9-14, except that in step V, 4-chloro-3-nitropyridine (1c) is used as the starting material;

Route 1:

Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, nitrogen, n-hexane, 70°C; (ii) potassium phthalimide, N,N-dimethylformamide, 100°C, nitrogen; (iii) 80% hydrazine hydrate, ethanol, 80°C; (iv) cyclopropylboric acid, potassium phosphate, tetrakis(triphenylphosphine)palladium, toluene, water, nitrogen, 100°C; (v-a) 2-nitro-3-pyridyltriazine Fluoromethanesulfonate, triethylamine, acetonitrile, 90°C; (v-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (vi) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (vii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (viii) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (ix) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.

R is methylene, ethyl, propyl, isopropyl, tert-butyl or cyclobutyl.

(2) Synthesis of Compounds 21-32

4a is treated with 2-nitro-3-pyridyl trifluoromethanesulfonate (1b) or 4-chloro-3-nitropyridine (1c) to obtain 5b or 5c through a coupling reaction; then, it is subjected to hydrogenation reduction in the presence of stannous chloride to obtain 6c or 6d, which is cyclized with 1,1'-thiocarbonyldiimidazole (TCDI) to obtain the key intermediate 7c or 7d, and then subjected to nucleophilic substitution and hydrolysis to obtain the target compounds 21-26; the preparation method of compounds 27-32 is similar to that of compounds 21-26, except that the starting material of step I is 4-chloro-3-nitropyridine (1c);

Route 2:

Reagents and conditions: (i-a) 2-nitro-3-pyridyl trifluoromethanesulfonate, triethylamine, acetonitrile, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (ii) stannous chloride, ethanol, nitrogen, room temperature; (iii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.

R is methylene, ethyl, propyl, isopropyl, tert-butyl or cyclobutyl.

(3) Synthesis of Compounds 33-44

The starting material 4-cyclopropyl-1-naphthylamine (1d) is treated with 2-nitro-3-pyridyl trifluoromethanesulfonate (1b) or 4-chloro-3-nitropyridine (1c) to obtain intermediate 2b or 2c through coupling reaction; then, it is subjected to hydrogenation reduction in the presence of palladium carbon to obtain 3b or 3c, which is cyclized with N,N'-carbonyldiimidazole (CDI) to obtain 4b or 4c, and then subjected to nucleophilic substitution and hydrolysis to obtain compounds 33-38; the preparation method of compounds 39-44 is similar to that of compounds 33-38, except that the starting material is 4-chloro-3-nitropyridine (1c);

Route 3:

Reagents and conditions: (i-a) 2-nitro-3-pyridyl trifluoromethanesulfonate, palladium acetate, 4,5-bis(diphenylphosphino-9,9-dimethylxanthene), cesium carbonate, nitrogen, 1,4-dioxane, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (ii) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (iii) N,N'-carbonyldiimidazole (CDI), triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.

R is methylene, ethyl, propyl, isopropyl, tert-butyl or cyclobutyl.

The room temperature described in the present invention refers to 20-30°C.

3. Application of pyridimidazole derivatives

The present invention discloses the results of screening the uric acid lowering activity of pyridoimidazole derivatives and their first application in preparing uric acid lowering drugs. Experiments prove that the pyridoimidazole derivatives of the present invention can be used as uric acid lowering drugs. Specifically, they can be used as uric acid lowering compounds for preparing uric acid lowering drugs. The present invention also provides the application of the above compounds in preparing uric acid lowering drugs.

Uric acid-lowering activity of target compounds:

36 compounds synthesized according to the above method (the structural formulas of the compounds are shown in Table 1) were screened for uric acid lowering activity. Their uric acid lowering activity data are listed in Table 2. Lesinurad was selected as a positive drug.

It can be seen from Tables 2 and 3 that 29 compounds all showed good anti-uric acid lowering activity, and the uric acid lowering activity was stronger than that of the positive control drug Lesinurad. Among them, representative compounds 13, 23, 33, 35, 36, 38 and 39, in the in vivo activity test of animals, had a blood uric acid reduction rate of more than 80%, showing excellent uric acid lowering activity, and can be used as a drug for preparing uric acid lowering.

Therefore, the pyridoimidazole derivatives of the present invention are a series of novel compounds with blood uric acid lowering activity, which can be used as candidate drugs for lowering uric acid and used for preparing drugs for lowering uric acid.

A uric acid-lowering pharmaceutical composition comprises the pyridoimidazole derivatives of the present invention and one or more pharmaceutically acceptable carriers or excipients.

DETAILED DESCRIPTION

The following examples are helpful for understanding the present invention, but they cannot limit the content of the present invention. In the following examples, the numbers of all target compounds are the same as those in Table 1.

Synthesis route of compound 9-20:

Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, nitrogen, n-hexane, 70°C; (ii) potassium phthalimide, N,N-dimethylformamide, 100°C, nitrogen; (iii) 80% hydrazine hydrate, ethanol, 80°C; (iv) cyclopropylboric acid, potassium phosphate, tetrakis(triphenylphosphine)palladium, toluene, water, nitrogen, 100°C; (v-a) 2-nitro-3-pyridyltriazine Fluoromethanesulfonate, triethylamine, acetonitrile, 90°C; (v-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (vi) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (vii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (viii) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (ix) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.

R is methylene, ethyl, propyl, isopropyl, tert-butyl or cyclobutyl.

Preparation of compound 2a

Commercially available compound 1a (2 g, 9.05 mmol), BPO (44.11 mg, 0.18 mmol) and NBS (1.93 g, 10.86 mmol) were added to n-hexane (50 mL) and refluxed under nitrogen for 36 h (monitored by TLC). The reaction mixture was cooled to room temperature under stirring, and the precipitate was collected by vacuum filtration. The precipitate was washed with saturated sodium bicarbonate aqueous solution (100 mL×2), water (100 mL×2) and n-hexane (100 mL) in sequence to give crude product 2a as a white solid. Yield: 75.0%. Melting point: 103-105°C. ESI-MS: m/z 300.88 [M+H] ⁺ .C ₁₁ H ₈ Br ₂ (Exact Mass: 297.90).

Preparation of compound 3a

Compound 2a (1 g, 3.36 mmol) and potassium phthalimide (0.62 g, 3.33 mmol) were dissolved in DMF (10 mL), and the mixture was stirred at 100 ° C under nitrogen atmosphere until the reaction was completed as monitored by TLC. After cooling to room temperature, the reaction mixture was poured into ice water (50 mL) and extracted with dichloromethane (20 mL×3). The combined organic solution was washed with saturated aqueous sodium chloride solution (20 mL×3) and dried over anhydrous sodium sulfate. After filtration, the organic phase was evaporated under reduced pressure to obtain a crude product, which was recrystallized from ethanol to obtain compound 3a as a white solid. Yield: 66.6%. Melting point: 165-168 ° C. ESI-MS: m/z 367.74 [M+H] ⁺ .C ₁₉ H ₁₂ BrNO ₂ (Exact Mass: 365.00).

Preparation of compound 4a

Compound 3a (1 g, 2.73 mmol) and 80% hydrazine hydrate (0.34 g, 5.46 mmol) were dissolved in ethanol (25 mL) and refluxed at 80 ° C for 12 hours (monitored by TLC). After cooling for about 10 minutes, 1M sodium hydroxide aqueous solution (10 mL) was added to the reaction mixture, and then the mixture was concentrated under reduced pressure to half of its original volume. It was poured into ice water (100 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with 5% sodium hydroxide (10 mL×2) and 5% brine (20 mL), dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator to obtain a residue, which was purified by column chromatography to obtain compound 4a, a yellow oil. Yield: 84.0%. ESI-MS: m/z 236.38 [M+H] ⁺ .C ₁₁ H ₁₀ BrN (Exact Mass: 234.99).

Preparation of compound 5a

A mixture of compound 4a (2.0 g, 9.0 mmol), cyclopropylboronic acid (1 g, 11.60 mmol), potassium phosphate (6.40 g, 30.0 mmol) and tetrakis(triphenylphosphine)palladium (0.70 g, 0.6 mmol) was added to a mixed solvent of toluene (50 mL) and water (2 mL), and the reaction system was reacted at 100 ° C for 12 h under a nitrogen atmosphere. TLC monitored the completion of the reaction. When the reaction mixture was cooled to room temperature, the reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. After filtration, the organic phase was evaporated under reduced pressure to obtain a crude product 5a as a brown oil. Yield: 52.4%. ESI-MS: m/z 198.62 [M+H] ⁺ .C ₁₄ H ₁₅ N (Exact Mass: 197.12).

Preparation of compound 6a

Compound 5a (2 g, 10.14 mmol) was dissolved in 50 mL of acetonitrile, and then 2-nitro-3-pyridyl trifluoromethanesulfonate (1b) (3.3 g, 12.12 mmol) and triethylamine (0.5 g, 5.07 mmol) were added to the solution. The mixture was stirred at 50 ° C overnight (monitored by TLC) under a nitrogen atmosphere and then filtered. The filter residue was recrystallized from ethyl acetate to obtain compound 6a as a yellow solid. Yield: 73.2%. Melting point: 141-143 ° C. ESI-MS: m/z 320.56 [M+H] ⁺ .C ₁₉ H ₁₇ N ₃ O ₂ (ExactMass: 319.13).

Preparation of compound 7a

Compound 6a (1 g, 3.13 mmol) was dissolved in 30 mL of tetrahydrofuran, and 10% palladium on carbon (0.2 g) was added to the solution. The mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure. Compound 7a was purified by flash column chromatography as a light yellow solid. Yield: 76.2%. Melting point: 162-164°C. ESI-MS: m/z 290.02 [M+H] ⁺ .C ₁₉ H ₁₉ N ₃ (Exact Mass: 289.16).

Preparation of compound 8a

Compound 7a (1 g, 3.46 mmol), 1,1'-thiocarbonyldiimidazole (1 g, 5.53 mmol) and triethylamine (0.1 mL) were dissolved in 50 mL of acetonitrile. The solution was reacted at 90 °C for 5 hours, then cooled to room temperature and filtered. The solid was recrystallized from ethyl acetate to obtain compound 8a as a white solid. Yield: 47.6%. Melting point: 156-159 °C. ESI-MS: m/z 330.09

[M–H] ^– .C ₁₉ H ₁₇ N ₃ O ₂ (Exact Mass: 331.11).

Preparation of compounds 9a-14a

Compound 8a (0.20 g, 0.60 mmol) was dissolved in DMF (10 mL), potassium carbonate (0.13 g, 0.90 mmol) was added, and then the appropriate substituted ester (1.1 equivalents) was added and the mixture was stirred at room temperature for 4 hours (TLC monitoring). DMF was evaporated under reduced pressure and extracted with ethyl acetate (30 mL×3). The organic solution was washed with saturated aqueous sodium chloride solution (3×10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by column chromatography to obtain compounds 9a-14a. Compound 9a, white solid, yield: 79.8%, melting point: 130-133°C, ESI-MS: m/z 404.11 [M+H] ⁺ .C ₂₃ H ₂₁ N ₃ O ₂ S (Exact Mass: 403.14). Compound 10a, white solid, yield: 79.8%, melting point: 139-142°C, ESI-MS: m/z 418.29 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₂ S (Exact Mass: 417.15). Compound 11a, white solid, yield: 68.0%, melting point: 151-152°C, ESI-MS: m/z 432.03 [M+H] ⁺ .C ₂₅ H ₂₅ N ₃ O ₂ S (Exact Mass: 431.17). Compound 12a, white solid, yield: 75.5%, melting point: 177-179°C, ESI-MS: m/z 418.17 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₂ S (Exact Mass: 417.15). Compound 13a, light yellow oil, yield: 60.0%, melting point: 150-153°C, ESI-MS: m/z 432.01 [M+H] ⁺ .C ₂₅ H ₂₅ N ₃ O ₂ S (Exact Mass: 431.17). Compound 14a, white solid, yield: 79.8%, melting point: 130-133°C, ESI-MS: m/z 458.19 [M+H] ⁺ .C ₂₇ H ₂₇ N ₃ O ₂ S (Exact Mass: 457.18).

Preparation of Compounds 9-14

Compound 9a-14a was dissolved in a mixture of 5 mL of tetrahydrofuran and 5 mL of ethanol. Lithium hydroxide (0.1 g, 4.13 mmol) was dissolved in a small amount of water and added dropwise to the above solution, and then the mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added to the residue, and 1 M HCl solution was added dropwise to adjust the pH to 3-4. The product was collected by filtration and recrystallized from ethanol to obtain the target compound 9-14.

Example 1. Preparation of Compound 9

Recrystallized from ethyl acetate to a yellow solid with a yield of 82.6% and a melting point of 60-63°C. Spectral data of compound 9: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (t, 1H, Pyr-H), 8.39 (d, J = 4.9 Hz, 1H, Pyr-H), 8.21 (t, 1H, Naph-H), 7.87 (d, J = 8.1 Hz, 1H, Naph-H), 7.70 (d, J = 6.6 Hz, 1H, Pyr-H), 7.67 (t, J = 3.8 Hz, 1H, Naph-H), 7.21 (q, J = 5.0 Hz, 1H, Naph-H), 7.11 (d, J = 7.5 Hz, 1H, Naph-H), 6.52 (d, J = 7.5 Hz, 1H, Naph-H), 5.95 (s, 2H, CH _{2 13 C NMR ​} ^​ _​ )δ172.66,155.83,154.79,142.97,139.61,133.63,130.62,129.82,129.42,126.90,126.74,125.47,123.99,123.19,123.13,119.39,117.99,4 5.89, 45.24, 18.73, 13.29, 7.10. HR-MS: m/z 388.1127[MH] ^- .C ₂₂ H ₁₉ N ₃ O ₂ S (Exact Mass: 389.12).

Example 2. Preparation of Compound 10

Recrystallized from ethyl acetate to give a white solid, yield: 86.1%, melting point: 80-83°C. Spectral data of compound 10: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.49 (q, 1H, Pyr-H), 8.32 (d, J = 3.3Hz, 1H, Pyr-H), 8.24–8.17 (m, 1H, Naph-H), 7.75 (d, J = 8.1Hz, 1H, Pyr-H), 7.69 (d, J = 7.0 Hz,1H,Naph-H),7.66(t,J＝3.8Hz,1H,Naph-H),7.13(d,J＝4.6Hz,1H,Naph-H),7.11(d,J＝4.8Hz,1H,Naph-H),6.57(d,J＝7.5Hz,1H,Naph-H),5.93(s,2H,CH _{2 13 C NMR ​} ^​ )δ169.68,163.63,156.07,155.77,143.87,139.60,133.63,130.72,129.53,129.50,126.89,126.68,125.47,124.03,123.49,123.14,118.07,1 17.67, 45.75, 35.23, 19.03, 13.29, 7.10. HR-MS: m/z 402.1282[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₂ S (Exact Mass: 403.14).

Example 3. Preparation of Compound 11

Recrystallized from ethyl acetate to give a white solid, yield: 80%, melting point: 60-63°C. Spectral data of compound 11: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (t, 1H, Pyr-H), 8.40 (d, J = 4.8 Hz, 1H, Pyr-H), 8.22 (t, 1H, Naph-H), 7.85 (d, J = 7.9 Hz, 1H, Naph-H), 7.70 (s, 1H, Pyr-H), 7.68 (d, J = 5.0 Hz, 1H, Naph-H), 7.21 (q, J = 4.8 Hz, 1H, Naph-H), 7.09 (d, J = 7.5 Hz, 1H, Naph-H), 6.39 (d, J = 7.5 Hz, 1H, Naph-H), 5.98 (s, 2H, CH ₂ ), 2.42–2.33 (m, 1H, CH), 1.72 (s, 6H, CH ₃ × 2), 1.03 (q, 2H, CH ₂ ), 0.66 (q, J＝4.8Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ174.33,155.06,153.95,143.69,139.47,133.60,130.53,129.85,128.97,126.89,126.89,126.74,126.74,125.47,123.97,123.13,122.77,1 19.43, 118.30, 54.32, 45.90, 26.79, 13.26, 7.08. HR-MS: m/z416.1438[MH] ^- .C ₂₄ H ₂₃ N ₃ O ₂ S (Exact Mass: 417.15).

Example 4. Preparation of Compound 12

Recrystallized from ethyl acetate to give a white solid, yield: 83.1%, melting point: 145-148°C. Spectral data of compound 12: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (t, 1H, Pyr-H), 8.29 (t, J = 10.4 Hz, 1H, Pyr-H), 8.15 (q, 1H, Naph-H), 7.67 (d, J = 5.1 Hz, 1H, Naph-H), 7.65 (d, J = 4.9 Hz, 1H, Pyr-H), 7.44 (q, 1H, Naph-H), 7.17 (q, 1H, Naph-H), 7.08 (q, 1H, Naph-H), 6.83 (q, 1H, Naph-H), 5.97 (d, 2H, CH ₂ ), 4.81 (s, 4H, CH ₂ ×2), 2.41–2.34 (m, 1H, CH), 1.03 (d, J＝8.6Hz, 2H, CH ₂ ), 0.67 (d, J＝5.5Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ172.39,170.92,145.63,144.92,143.44,139.36,133.67,130.99,129.42,129.19,126.77,126.58,126.48,125.43,124.31,124.28,123.12,1 18.49,117.41,45.38,32.24,13.29,7.08.HR-MS: m/z 438.1048[M+Cl] ^- .C ₂₃ H ₂₁ N ₃ O ₂ S (Exact Mass: 403.14).

Example 5. Preparation of Compound 13

Recrystallized from ethyl acetate to a yellow solid, yield: 79%, melting point: 60-63°C. Spectral data of compound 13: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.48 (q, J＝5.8Hz, 1H, Pyr-H), 8.36 (t, 1H, Pyr-H), 8.26–8.17 (m, 1H, Naph-H), 7.93 (d, J＝8.1Hz, 1H, Naph-H), 7.68 (d, J＝3.8 Hz,1H,Pyr-H),7.66(t,1H,Naph-H),7.27–7.16(m,1H,Naph-H),7.12(q,J＝7.4Hz,1H,Naph-H),6.61(q,1H,Naph-H),6.00(d,2H,CH ₂ ),3.70(s,2H,CH _{2 13 C NMR ​} ^​ _​ )δ174.20,171.00,145.21,143.38,141.82,139.59,133.63,130.64,130.45,129.37,126.87,126.72,125.49,123.96,123.13,119.85,119.10,1 17.80, 45.87, 32.83, 31.75, 24.87, 13.27, 7.11. HR-MS: m/z 452.1205 [MH] ^- .C ₂₄ H ₂₃ N ₃ O ₂ S (Exact Mass: 417.15).

Example 6. Preparation of Compound 14

Recrystallized from ethyl acetate to give a white solid, yield: 67%, melting point: 230-235°C. Spectral data of compound 14: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (t, 1H, Pyr-H), 8.30 (t, 1H, Pyr-H), 8.15 (d, J=5.0 Hz, 1H, Naph-H), 7.67 (d, J=6.0 Hz, 1H, Naph-H), 7.64 (t, J=3.8 Hz, 1H, Pyr-H), 7.40 (d, J=8.1 Hz, 1H, Naph-H), 7.15 (d, J=7.3 Hz, 1H, Naph-H), 7.07 (q, J=5.0 Hz, 1H, Naph-H), 6.85 (d, J=7.3 Hz, 1H, Naph-H), 5.97 (s, 2H, CH ₂ ), 3.38 (s, 6H, CH ₂ ×3),2.37(t,J＝5.3Hz,1H,CH),1.05–1.00(m,2H,CH ₂ ),0.68(q,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ170.97,145.75,144.06,143.45,139.35,133.68,131.00,129.46,126.76,126.56,126.48,125.43,124.33,124.28,123.13,123.13,118.44,1 17.34, 45.79, 45.39, 33.03, 29.72, 16.94, 13.29, 7.08. HR-MS: m/z 428.1438 [MH] ^- .C ₂₅ H ₂₃ N ₃ O ₂ S (Exact Mass: 429.15).

Preparation of compound 6b

4-Chloro-3-nitropyridine (1c) (1g, 6.33mmol), compound 5a (1.5g, 7.6mmol) and sodium bicarbonate (1.6g, 18.9mmol) were dissolved in 50mL of ethanol, and the solution was refluxed at 60°C for 10 hours, and then cooled to room temperature. Dichloromethane (30ml) was added, and the mixture was washed with saturated sodium chloride (3×10mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound 6b was obtained by flash column chromatography as a yellow solid with a yield of 73.0% and a melting point of 143-146°C. ESI-MS: m/z 320.54 [M+H] ⁺ .C ₁₉ H ₁₇ N ₃ O ₂ (Exact Mass: 319.13).

Preparation of compound 7b

The synthesis method of compound 7b is similar to that of compound 7a. White solid, yield: 76.2%, melting point: 192-195°C. ESI-MS: m/z 290.13 [M+H] ⁺ .C ₁₉ H ₁₉ N ₃ (Exact Mass: 289.16).

Preparation of compound 8b

The synthesis method of compound 8b is similar to that of compound 8a. Yellow solid, yield: 52.6%, melting point: 130-134°C. ESI-MS: m/z 330.77 [M+H] ⁺ .C ₁₉ H ₁₇ N ₃ O ₂ (Exact Mass: 331.11).

Preparation of compounds 9b-14b

The synthesis method of compounds 9b-14b is similar to that of compounds 9a-14a, except that compound 8b is reacted with a suitable substituted ester. Compound 9b, white solid, yield: 80.0%, melting point: 142-145°C, ESI-MS: m/z 404.96 [M+H] ⁺ .C ₂₃ H ₂₁ N ₃ O ₂ S (Exact Mass: 403.14). Compound 10b, white solid, yield: 79.0%, melting point: 120-122°C, ESI-MS: m/z 419.11 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₂ S (Exact Mass: 417.15). Compound 11b, white solid, yield: 83.0%, melting point: 130-133°C. ESI-MS: m/z 432.81 [M+H] ⁺ .

C ₂₅ H ₂₅ N ₃ O ₂ S (Exact Mass: 431.17). Compound 12b, colorless oil, yield 67.5%, melting point: 147-150°C, ESI-MS: m/z 418.98 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₂ S (Exact Mass: 417.15). Compound 13b, colorless oil, yield 84.0%, melting point: 160-163°C, ESI-MS: m/z 432.55 [M+H] ⁺ .C ₂₅ H ₂₅ N ₃ O ₂ S (Exact Mass: 431.17). Compound 14b, colorless oil, yield 59.0%, melting point: 130-133°C, ESI-MS: m/z

458.65[M+H] ⁺ .C ₂₇ H ₂₇ N ₃ O ₂ S (Exact Mass: 457.18).

Preparation of Compounds 15-20

The synthesis of compounds 15-20 was similar to the synthesis described for the preparation of compounds 9-14.

Example 7. Preparation of Compound 15

Recrystallized from ethyl acetate to give a white solid, yield: 80%, melting point: 95-100°C. Spectral data of compound 15: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.88(s, 1H, Pyr-H),8.48(d, J＝7.5 Hz, 1H, Pyr-H),8.23(s, 1H, Naph-H),8.21(s, 1H, Naph-H),7.68(s, 1H, Pyr-H),7.67(d, J＝3.7 Hz, 1H, Naph-H),7.42(d, J＝5.7 Hz, 1H, Naph-H),7.12(d, J＝7.5 Hz, 1H, Naph-H),6.57–6.47(m, 1H, Naph-H),5.93(s, 2H, CH ₂ ),4.21(s, 2H, CH ₂ ¹³ C NMR 39.65,133.64,130.71,129.38,126.90,126.71,125.48,124.01,123.45,123.13,123.09,105.93,45.66,35.10,13.29,7.11.HR- _{MS :} m/ _z 388.1125[MH] ^- .C ₂₂ H ₁₉ N ₃ O ₂ S(ExactMass:389.12).

Example 8. Preparation of Compound 16

Recrystallized from ethyl acetate to a yellow solid, yield: 78%, melting point: 60-63°C. Spectral data of compound 16: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H, Pyr-H), 8.49 (q, 1H, Pyr-H), 8.24 (d, J = 5.5 Hz, 1H, Naph-H), 8.21 (q, 1H, Naph-H), 7.69 (t, 1H, Pyr-H), 7.67 (t, J = 2.1 Hz, 1H, Naph-H), 7.43 (d, J = 5.6 Hz, 1H, Naph-H), 7.11 (d, J = 7.5 Hz, 1H, Naph-H), 6.46 (d, J = 7.3 Hz, 1H, Naph-H), 5.93 (s, 2H, CH _{2 13 C NMR} ^​ _​ )δ172.75,153.95,141.87,141.65,140.66,140.33,139.59,133.63,130.63,129.47,126.89,126.72,125.48,123.97,123.14,123.10,123.10,1 06.07, 45.67, 45.43, 18.85, 13.28, 7.09. HR-MS: m/z 402.1282[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₂ S (Exact Mass: 403.14).

Example 9. Preparation of Compound 17

Recrystallized from ethyl acetate to give a white solid, yield: 84%, melting point: 65-68°C. Spectral data of compound 17: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.96(s,1H,Pyr-H),8.49(t,1H,Pyr-H),8.26(d,J＝5.6Hz,1H,Naph-H),8.22(t,1H,Naph-H),7.70(s,1H,Pyr-H),7.68(d,J＝5.0Hz,1H,Naph-H),7.45(d,J＝5.6Hz,1H,Naph-H),7.09(d,J＝7.5Hz,1H,Naph-H),6.34(d,J＝7.5Hz,1H,Naph-H),5.97(s,2H,CH ₂ ),2.41–2.33(m,1H,CH ),1.69(s,6H,CH _{( 3} 60,130.52,129.83,126.90,126.75,125.47,123.95,123.13,122.69,106.40,54.28,45.78,26.75,26.49,13.26,7.08.HR-MS: _{m /} z 416.1438[ ^MH ] ^- .C ₂₄ H ₂₃ N ₃ O ₂ S (Exact Mass: 417.15).

Example 10. Preparation of Compound 18

Recrystallized from ethyl acetate to give a white solid, yield: 80%, melting point: 248-251°C. Spectral data of compound 18: ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.28 (s, 1H, Pyr-H), 8.54 (d, J = 6.4Hz, 1H, Pyr-H), 8.49 (t, 1H, Naph-H), 8.25 (t, 1H, Naph-H), 7.73 (d, J = 6.4Hz, 1H, Pyr-H), 7 .70(d,J＝3.3Hz,1H,Naph-H),7.68(d,J＝3.3Hz,1H,Naph-H),7.09(d,J＝7.5Hz,1H,Naph-H),6.71(d,J＝7.6Hz,1H,Naph-H),6.09(s,2H,CH ₂ ),4.64(t,J＝7.0Hz,2H , CH ₂ ),2.92(t,J＝7.0Hz,2H,CH ₂ ),2.40–2.35(m,1H,CH),1.03(t,2H,CH ₂ ),0.67(d,J＝3.5Hz,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ173.79,172.55,142.15,139.48,137.57,133.67,131.00,130.73,128.32,126.89,126.72,125.83,125.47,124.14,123.25,123.11,123.03,1 06.88, 46.71, 42.01, 31.71, 13.29, 7.09. HR-MS: m/z402.1284[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₂ S (Exact Mass: 403.14).

Example 11. Preparation of Compound 19

Recrystallized from ethyl acetate to give a white solid, yield: 80%, melting point: 180-183°C. Spectral data of compound 19: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.91 (s, 1H, Pyr-H), 8.49 (q, 1H, Pyr-H), 8.22 (d, J = 5.5Hz, 1H, Naph-H), 8.19 (s, 1H, Naph-H), 7.68 (d, J = 3.9Hz, 1H, Pyr-H), 7 .66(d,J＝6.6Hz,1H,Naph-H),7.41(d,J＝5.5Hz,1H,Naph-H),7.11(d,J＝7.5Hz,1H,Naph-H),6.43(d,J＝7.5Hz,1H,Naph-H),5.91(d,2H,CH ₂ ),3.40(d,J＝7.1Hz,2H , CH ₂ ),2.37(t,J＝3.8Hz,1H,CH),2.34(d,J＝7.3Hz,2H,CH ₂ ),2.01–1.92(m,2H,CH ₂ ),1.05–1.00(m,2H,CH ₂ ),0.67(q,2H,CH ₂ ). ¹³ CNMR(100MHz,DMSO-d ₆ )δ174.31,155.09,141.81,140.75,140.18,139.54,133.64,130.66,129.53,129.20,126.85,126.71,126.71,125.49,123.95,123.15,123.00,1 05.89, 45.54, 32.86, 31.65, 24.84, 13.27, 7.10. HR-MS: m/z 416.1437[MH] ^- .C ₂₄ H ₂₃ N ₃ O ₂ S (ExactMass: 417.15).

Example 12. Preparation of Compound 20

Recrystallized from ethyl acetate to give a white solid, yield: 61%, melting point: 60-63°C. Spectral data of compound 20: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H, Pyr-H), 8.49 (d, J = 9.8 Hz, 1H, Pyr-H), 8.22 (s, 1H, Naph-H), 8.21 (s, 1H, Naph-H), 7.68 (d, J = 4.0 Hz, 1H, Pyr-H), 7.67 (s, 1H, Naph-H), 7.39 (d, J = 5.5 Hz, 1H, Naph-H), 7.11 (d, 1H, Naph-H), 6.46 (d, 1H, Naph-H), 5.94 (s, 2H, CH ₂ ), 3.41 (s, 6H, CH ₂ ×3), 2.39 (d, J = 5.3Hz, 1H, CH), 1.03 (d, J = 10.5Hz, 2H, CH ₂ ), 0.67 (d, J = 3.8Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ153.48,141.93,141.02,140.83,140.75,139.51,133.62,130.60,129.77,129.76,126.88,126.72,125.47,123.99,123.14,123.06,123.02,1 06.16, 45.81, 32.74, 21.56, 16.90, 13.28, 7.08, 7.08. HR-MS: m/z 428.1438 [MH] ^- .C ₂₅ H ₂₃ N ₃ O ₂ S (Exact Mass: 429.15).

Synthesis route of compound 21-32:

Reagents and conditions: (i-a) 2-nitro-3-pyridyl trifluoromethanesulfonate, triethylamine, acetonitrile, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (ii) stannous chloride, ethanol, nitrogen, room temperature; (iii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.

R is methylene, ethyl, propyl, isopropyl, tert-butyl or cyclobutyl.

Preparation of compound 5b

The synthesis of compound 5b is similar to that described for compound 6a, except that the starting compound 4a is reacted with 2-nitro-3-pyridyl trifluoromethanesulfonate (1b). Yellow solid, yield: 60.6%, melting point: 144-147°C. ESI-MS: m/z 358.1950 [M+H] ⁺ .C ₁₆ H ₁₂ BrN ₃ O ₂ (Exact Mass: 357.01).

Preparation of compound 6c

Compound 5b (1 g, 2.80 mmol) was dissolved in ethanol (30 mL) and stannous chloride (3.16 g) was added to the solution. The mixture was stirred at room temperature overnight and the reaction was completed by TLC monitoring. Sodium hydroxide was added to adjust the pH to 9-10 and stirring was continued for 1 hour. Then the mixture was filtered under reduced pressure, extracted with ethyl acetate and concentrated. The residue was recrystallized from EA to obtain compound 6c as a white solid with a yield of 76.0% and a melting point of 192-193°C. ESI-MS: m/z 328.21 [M+H] ⁺ .C ₁₆ H ₁₄ BrN ₃ (Exact Mass: 327.03).

Preparation of compound 7c

The synthesis method of compound 7c is similar to the method described for compound 8a. Compound 7c, yellow solid, yield: 70.9%, melting point: 246-248°C. ESI-MS: m/z 370.26 [M+H] ⁺ .C ₁₇ H ₁₂ BrN ₃ S (Exact Mass: 368.99).

Preparation of compounds 8c-13c

The synthesis method of compounds 8c-13c is similar to the synthesis method described in compounds 9a-14a. Compound 8c, white solid, yield: 84.8%, melting point: 132-135°C, ESI-MS: m/z 442.96 [M+H] ⁺ .C ₂₀ H ₁₆ BrN ₃ O ₂ S (ExactMass: 441.01). Compound 9c, white solid, yield: 76.6%, melting point: 124-127°C, ESI-MS: m/z

456.36 [M+H] ⁺ .C ₂₁ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 455.03). Compound 10c, white solid, yield: 81.6%, melting point: 130-132°C, ESI-MS: m/z 470.39 [M+H] ⁺ .C ₂₂ H ₂₀ BrN ₃ O ₂ S (Exact Mass: 469.05). Compound 11c, white solid, yield: 80.0%, melting point: 135-138°C, ESI-MS: m/z 456.36 [M+H] ⁺ .C ₂₁ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 455.03). Compound 12c, white solid, yield: 77.7%, melting point: 140-143°C, ESI-MS: m/z 471.01 [M+H] ⁺ .C ₂₂ H ₂₀ BrN ₃ O ₂ S (Exact Mass: 469.05). Compound 13c, white solid, yield: 62.1%, melting point: 139-141°C, ESI-MS: m/z 496.43 [M+H] ⁺ .

C ₂₄ H ₂₂ BrN ₃ O ₂ S (Exact Mass: 495.06).

Preparation of Compounds 21-26

The synthesis of compounds 21-26 was similar to the synthesis described for the preparation of compounds 9-14.

Example 13. Preparation of Compound 21

Recrystallized from ethyl acetate to a yellow solid with a yield of 80.1% and a melting point of 71-74°C. Spectral data of compound 21: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.34 (d, J = 4.9 Hz, 1H, Pyr-H), 8.31 (t, 1H, Pyr-H), 8.25 (t, 1H, Naph-H), 7.81 (s, 1H, Naph-H), 7.80 (s, 1H, Naph-H), 7.78 (s, 1H, Naph-H), 7.76 (d, J = 4.0Hz, 1H, Naph-H), 7.15 (q, J = 4.8Hz, 1H, Pyr-H), 6.57 (d, J = 7.7Hz, 1H, Naph-H), 5.98 (s, 2H, CH ₂ ), 4.22 (s, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ169.61,156.12,155.80,143.98,132.20,132.20,131.88,131.66,130.12,129.44,128.64,128.21,127.69,124.47,122.35,118.06,117.76,4 5.45, 35.49. HR-MS: m/z 425.9917 [MH] ^- .C ₁₉ H ₁₄ BrN ₃ O ₂ S (Exact Mass: 427.00).

Example 14. Preparation of Compound 22

Recrystallized from ethyl acetate to give a white solid, yield: 77.1%, melting point: 62-65°C. Spectral data of compound 22: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.37 (d, J = 4.8Hz, 1H, Pyr-H), 8.29 (t, 1H, Pyr-H), 8.25 (t, 1H, Naph-H), 7.83 (d, J = 9.8Hz, 1H, Naph-H), 7.80 (d, J = 2.2Hz, 1H, Naph-H),7.78(d,J＝5.4Hz,1H,Naph-H),7.75(s,1H,Naph-H),7.17(dd,J＝8.1,4.8Hz,1H,Pyr-H),6.49(d,J＝7.8Hz,1H,Naph-H),5.98(s,2H,CH ₂ ¹³ C NMR .19,128.67,128.19,127.69,124.43,124.14,122.29,118.30,117.99,45.52,45.47,18.88.HR-MS:m/z 440.0074[ _MH ] ^- .C _{20 H 16} BrN ₃ O ₂ S(Exact Mass:441.01).

Example 15. Preparation of Compound 23

Recrystallized from ethyl acetate to give a white solid with a yield of 84.0% and a melting point of 79-82°C. Spectral data of compound 23: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J = 4.8 Hz, 1H, Pyr-H), 8.30 (q, J = 3.3 Hz, 1H, Py rH), 8.25 (q, 1H, Naph-H), 7.84 (d, J = 8.1 Hz, 1H, Naph-H), 7.81 (t, J = 2.2 Hz, 1H, Naph-H), 7.79 (t, J = 3.7 Hz, 1H, Naph-H), 7.74 (d, J = 7.7 Hz, 1H, Naph-H), 7.19 (q, J = 4.8 Hz, 1H, Pyr-H), 6.38 (d, J = 7.8 Hz, 1H, Naph-H), 6.02 (s, 2H, CH ₂ ¹³ _C NMR 9,124.40,123.78,122.18,118.70,118.37,54.60,45.53,26.84,26.84.HR-MS: m/z 454.0231[MH] ^- .C ₂₁ H ₁₈ BrN _{3 O 2 S} (Exact Mass: 455.03).

Example 16. Preparation of Compound 24

Recrystallized from ethyl acetate to give a white solid, yield: 83.0%, melting point: 225-228°C. Spectral data of compound 24: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.37 (t, 1H, Pyr-H), 8.24 (t, 1H, Pyr-H), 8.17 (t, J = 4.9Hz, 1H, Naph-H), 7.80 (d, J = 6.1Hz, 1H, Naph-H), 7.78 (s, 1H, Naph-H), 7.76(d,J＝5.7Hz,1H,Naph-H),7.51–7.27(m,1H,Naph-H),7.18–7.07(m,1H,Pyr-H),6.88–6.47(m,1H,Naph-H),5.97(d,2H,CH ₂ ),3.18(s,2H,CH ₂ ),1.23(s, 2H,CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ171.09,145.98,143.54,132.17,132.10,131.70,130.07,128.52,128.08,127.68,126.47,125.14,124.66,122.09,1 19.23, 118.46, 117.27, 45.06, 34.68, 32.57. HR-MS: m/z440.0074[MH] ^- .C ₂₀ H ₁₆ BrN ₃ O ₂ S (Exact Mass: 441.01).

Example 17. Preparation of Compound 25

Recrystallized from ethyl acetate to a yellow solid, yield: 79.0%, melting point: 60-63°C. Spectral data of compound 25: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.36(d, J＝4.6 Hz, 1H, Pyr-H),8.29(d, J＝9.7 Hz, 1H, Pyr-H),8.25(t, 1H, Naph-H),7.84(d, J＝6.4 Hz, 1H, Naph-H),7.79(d, J＝6.8 Hz, 1H, Naph-H),7.77(d, J＝3.7 Hz, 1H, Naph-H),7.75(d, J＝3.7 Hz, 1H, Naph-H),7.22–7.13(m, 1H, Pyr-H),6.58(q, 1H, Naph-H),6.01(d, 2H, CH ₂ ), 3.41 (t, J＝7.2Hz, 2H, CH ₂ ), 2.36 (q, J＝7.6Hz, 2H, CH ₂ ), 2.15–1.95 (m, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ173.25, 170.98, 145.70, 143.60, 132.16, 13 2.04,131.70,130.07,128.52,128.10,127.68,126.42,125.13,124.64,122.11,118.58,117.37,54.41,46.01,45.06,32.69.HR-MS:m/z 454.0234[MH] ^- .C ₂₁ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 455.03).

Example 18. Preparation of Compound 26

Recrystallized from ethyl acetate to give a white solid, yield: 67.0%, melting point: 230-233°C. Spectral data of compound 26: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.67 (s, 1H, COOH), 8.38 (q, J = 3.4 Hz, 1H, Pyr-H), 8.23 (q, 1H, Pyr-H), 8.18 (d, J = 5.0 Hz, 1H, Naph-H), 7.80 (s, 1H, Naph-H), 7.78 (s, 1H, Naph-H), 7.76 (d, J = 3.4 Hz, 1H, Naph-H), 7.49 (d, J = 7.9 Hz, 1H, Naph-H), 7.11 (q, J = 5.0 Hz, 1H, Pyr-H), 6.83 (d, J = 7.8 Hz, 1H, Naph-H), 6.00 (s, 2H, CH ₂ ),3.67(s,6H,CH ₂ ×3). ¹³ C NMR (100MHz, DMSO-d ₆ )δ173.20,170.97,145.70,143.60,132.16,132.04,131.70,130.07,128.52,128.10,127.68,126.42, 125.13,124.64,122.11,118.59,117.38,54.46,47.24,45.06,32.69,17.13. HR-MS: m/z466.0230[MH] ^- .C ₂₂ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 467.03).

Preparation of compound 5c

The synthesis method of compound 5c is similar to that described for compound 6b. Compound 5c, yellow solid, yield: 69.8%, melting point: 116-118°C. ESI-MS: m/z 358.19 [M+H] ⁺ .C ₁₆ H ₁₂ BrN ₃ O ₂ (Exact Mass: 357.01).

Preparation of compound 6d

The synthesis method of compound 6d is similar to that described for compound 6c. Compound 6d, white solid, yield: 73.5%, melting point: 144-147°C. ESI-MS: m/z 328.21 [M+H] ⁺ .C ₁₆ H ₁₄ BrN ₃ (Exact Mass: 327.03).

Preparation of compound 7d

The synthesis method of compound 7d is similar to the method described for compound 8a. Compound 7d, yellow solid, yield: 69.9%, melting point: 143-144°C. ESI-MS: m/z 370.26 [M+H] ⁺ .C ₁₇ H ₁₂ BrN ₃ S (Exact Mass: 368.99).

Preparation of compounds 8d-13d

The synthesis method of compounds 8d-13d is similar to the synthesis method described in compounds 9a-14a. Compound 8d, white solid, yield: 80.7%, melting point: 135-138°C, ESI-MS: m/z 444.03 [M+H] ⁺ .C ₂₀ H ₁₆ BrN ₃ O ₂ S (Exact Mass: 441.01). Compound 9d, white solid, yield: 63.8%, melting point: 134-137°C, ESI-MS: m/z 458.11 [M+H] ⁺ .C ₂₁ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 455.03). Compound 10d, white solid, yield: 82.7%, melting point: 130-131°C, ESI-MS: m/z 472.21 [M+H] ⁺ .C ₂₂ H ₂₀ BrN ₃ O ₂ S (Exact Mass: 469.05). Compound 11d, white solid, yield: 61.7%, melting point: 154-156°C, ESI-MS: m/z 456.87 [M+H] ⁺ .C ₂₁ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 455.03). Compound 12d, white solid, yield: 50.5%, melting point: 177-179°C, ESI-MS: m/z 470.88 [M+H] ⁺ .C ₂₂ H ₂₀ BrN ₃ O ₂ S (Exact Mass: 469.05). Compound 13d, white solid, yield: 64.0%, melting point: 165-168°C, ESI-MS: m/z 496.8221 [M+H] ⁺ .C ₂₄ H ₂₂ BrN ₃ O ₂ S (Exact Mass: 495.06).

Preparation of Compounds 27-32

The synthesis of compounds 27-32 was similar to that described for the preparation of compounds 9-14.

Example 19. Preparation of Compound 27

Recrystallized from ethyl acetate to give a white solid, yield: 83.0%, melting point: 128-131°C. Spectral data of compound 27: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.88 (s, 1H, Pyr-H), 8.31 (d, J = 9.8Hz, 1H, Pyr-H), 8.25 (d, J = 2.6Hz, 1H, Naph-H), 8.23 (s, 1H, Naph-H), 7.78 (s, 2H, Naph-H) ,7.76(s,1H,Pyr-H),7.46(d,J＝5.6Hz,1H,Naph-H),6.53(d,J＝7.8Hz,1H,Naph-H),5.98(s,2H,CH ₂ ),4.16(s,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ169.49,155.37,141.84,141.80,140.66,140.14,132.12,131.86,131.66,130.11,128.65,128.22,127.70,124.45,124.34,122.35,105.83,4 5.32,36.44. HR-MS: m/z 425.9917[MH] ^- .C ₁₉ H ₁₄ BrN ₃ O ₂ S (Exact Mass: 427.00).

Example 20. Preparation of Compound 28

Recrystallized from ethyl acetate to a yellow solid, yield: 87.4%, melting point: 115-118°C. Spectral data of compound 28: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 1H, Pyr-H), 8.30 (s, 1H, Pyr-H), 8.27 (d, J = 5.7 Hz, 1H, Naph-H), 8.24 (s, 1H, Naph-H), 7.80 (d, J = 5.6 Hz, 1H, Naph-H), 7.77 (s, 1H, Naph-H), 7.75 (s, 1H, Pyr-H), 7.50 (d, J = 5.5 Hz, 1H, Naph-H), 6.46 (d, J = 7.7 Hz, 1H, Naph-H), 5.98 (s, 2H, CH ₂ ¹³ C NMR .66,130.12,128.69,128.22,127.71,124.42,124.08,122.35,106.04,45.44,45.38,18.81.HR-MS:m/z 440.0074[ _MH ] ^- .C _{20 H 16} BrN ₃ O ₂ S(Exact Mass:441.01).

Example 21. Preparation of Compound 29

Recrystallized from ethyl acetate to a yellow solid, yield: 86.2%, melting point: 135-138°C. Spectral data of compound 29: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.95 (s, 1H, Pyr-H), 8.31 (t, 1H, Pyr-H), 8.26 (s, 1H, Naph-H), 8.25 (s, 1H, Naph-H), 7.80 (d, J=3.9 Hz, 1H, Naph-H), 7.78 (t, 1H, Naph-H), 7.74 (s, 1H, Pyr-H), 7.73 (s, 1H, Naph-H), 6.33 (d, J=7.8 Hz, 1H, Naph-H), 6.01 (s, 2H, CH ₂ ), 1.70 (s, 6H, CH ₃ ×2). ¹³ C NMR (100 MHz, DMSO-d ₆ )δ174.57,163.94,153.46,142.08,140.96,140.80,140.73,132.62,131.67,131.60,130.06,128.67,128.20,127.68,124.39,123.66,122.15,1 06.19, 45.44, 27.17, 27.16. HR-MS: m/z 454.0234 [MH] ^- .C ₂₁ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 455.03).

Example 22. Preparation of Compound 30

Recrystallized from ethyl acetate to a yellow solid, yield: 81.1%, melting point: 78-81°C. Spectral data of compound 30: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.93 (s, 1H, Pyr-H), 8.30 (s, 1H, Pyr-H), 8.28 (s, 1H, Naph-H), 8.25 (d, J = 8.9Hz, 1H, Naph-H), 7.80 (d, J = 6.7Hz, 1H, Naph-H), 7.77(s,1H,Naph-H),7.75(s,1H,Pyr-H),7.50(d,J＝5.5Hz,1H,Naph-H),6.47(d,J＝8.1Hz,1H,Naph-H),5.98(s,2H,CH ₂ ),4.72–4.42(m,2H,CH ₂ ¹³ C NMR 28.22, 127.71, 124.43, _{124.07, 122.34, 106.05, 45.43, 45.38, 18.81. HR-MS: m/z440.0074[MH] - .C 20 H 16 Br N 3 O 2 S} ⁽ _{Exact Mass : 441.01} ).

Example 23. Preparation of Compound 31

Recrystallized from ethyl acetate to a yellow solid, yield: 77.0%, melting point: 80-83°C. Spectral data of compound 31: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H, Pyr-H), 8.38 (q, J=3.2 Hz, 1H, Pyr-H), 8.24 (d, J=2.4 Hz, 1H, Naph-H), 8.22 (d, J=5.5 Hz, 1H, Naph-H), 7.79 (s, 1H, Naph-H), 7.77 (s, 1H, Naph-H), 7.75 (d, J=7.9 Hz, 1H, Pyr-H), 7.19 (d, J=5.5 Hz, 1H, Naph-H), 6.78 (d, J=7.7 Hz, 1H, Naph-H), 5.99 (s, 2H, CH ₂ ), 3.37 (s, 6H, CH ₂ ×3). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ171.38,143.35,138.80,132.13,131.94,131.70,130.05,129.32,128.55,128.11,127.75,127.69,124.90,124.63,122.12, 105.72,45.18,40.42,40.21,39.79,39.59.HR-MS: m/z 454.0235[MH] ^- .C ₂₁ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 455.03).

Example 24. Preparation of Compound 32

Recrystallized from ethyl acetate to a yellow solid, yield: 67.0%, melting point: 80-83°C. Spectral data of compound 32: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H, Pyr-H), 8.29 (q, J = 6.6, 3.1 Hz, 1H, Pyr-H), 8.26 (d, J = 2.9 Hz, 1H, Naph-H), 8.24 (d, J = 4.8 Hz, 1H, Naph-H), 7.79 (d, J = 3.3 Hz, 1H, Naph-H), 7.77 (d, J = 4.0 Hz, 1H, Naph-H), 7.75 (d, J = 3.5 Hz, 1H, Pyr-H), 7.48 (d, J = 5.5 Hz, 1H, NaphH), 6.45 (d, J = 7.8 Hz, 1H, Naph-H), 5.96 (s, 2H, CH ₂ ), 3.39 (t, J = 7.2Hz, 2H, CH ₂ ), 2.34 (t, J = 7.4Hz, 2H, CH ₂ ), 1.96 (q, J = 7.3Hz, 2H, CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ174.34,155.04,141.91,141.78,140.75,140.25,132.20,131.81,131.66,130.13,128.67,128.18,127.72,124.39,124.00,122.28,105.85,4 5.26, 32.94, 31.73, 24.87, 24.87. HR-MS: m/z466.0235[MH] ^- .C ₂₂ H ₁₈ BrN ₃ O ₂ S (Exact Mass: 467.03).

Synthetic routes of compounds 33-44

Reagents and conditions: (i-a) 2-nitro-3-pyridyl trifluoromethanesulfonate, palladium acetate, 4,5-bis(diphenylphosphino-9,9-dimethylxanthene), cesium carbonate, nitrogen, 1,4-dioxane, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (ii) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (iii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.

R is methylene, ethyl, propyl, isopropyl, tert-butyl or cyclobutyl.

Preparation of compound 2b

Palladium acetate (0.007 g, 0.032 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.036 g, 0.063 mmol) were dissolved in 2 mL of 1,4-dioxane and stirred for 30 minutes. 2-Nitro-3-pyridyl trifluoromethanesulfonate (1b) (0.17 g, 0.63 mmol), 4-cyclopropyl-1-naphthylamine (1d) (0.13 g, 0.76 mmol) and cesium carbonate (0.41 g, 1.26 mmol) were dissolved in 10 mL of 1,4-dioxane. The two solutions were mixed and refluxed at 90 ° C for 12 hours under a nitrogen atmosphere. The reaction was monitored by TLC. After cooling to room temperature, 30 mL of dichloromethane and saturated sodium chloride aqueous solution (3×10 mL) were added for extraction. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The product was purified by flash column chromatography to obtain compound 2b. Yellow solid, yield: 69.5%, melting point: 76-79° C. ESI-MS: m/z 306.4 [M+H] ⁺ .C ₁₈ H ₁₅ N ₃ O ₂ (Exact Mass: 305.12).

Preparation of compound 3b

The synthesis method of compound 3b is similar to that of compound 7a, except that the starting material is compound 2b. Compound 3b, light yellow solid, yield: 73.0%, melting point: 143-146°C. ESI-MS: m/z 276.44 [M+H] ⁺ .C ₁₉ H ₁₇ N ₃ O ₂ (Exact Mass: 275.14).

Preparation of compound 4b

Compound 3b (1 g, 3.60 mmol), N,N'-carbonyldiimidazole (CDI) (0.94 g, 5.80 mmol) and triethylamine (0.4 mL) were dissolved in 30 mL of acetonitrile. The solution was refluxed at 90 °C for 10 h, then cooled to room temperature and the solvent was evaporated under reduced pressure. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated after washing with 30 mL of dichloromethane and saturated aqueous sodium chloride solution (3 × 10 mL). Compound 4b was obtained by flash column chromatography. White solid, yield: 57.2%, melting point: 149-150 °C. ESI-MS: m/z 300.28 [M–H] ^– .C ₁₉ H ₁₅ N ₃ O (Exact Mass: 301.12).

Preparation of compounds 5e-10e

The synthesis method of compounds 5e-10e is similar to the synthesis method described in compounds 9a-14a. Compound 5e, white solid, yield: 87.5%, melting point: 184-185°C, ESI-MS: m/z 374.24 [M+H] ⁺ .C ₂₂ H ₁₉ N ₃ O ₃ (Exact Mass: 373.14). Compound 6e, white solid, yield: 81.6%, melting point: 173-176°C, ESI-MS: m/z 388.41 [M+H] ⁺ .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16). Compound 7e, white solid, yield: 88.4%, melting point: 152-155°C, ESI-MS: m/z 402.1 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₃ (Exact Mass: 401.17). Compound 8e, transparent oil, yield: 64.8%, melting point: 154-156°C, ESI-MS: m/z 388.6 [M+H] ⁺ .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16). Compound 9e, transparent oil, yield: 60.6%, melting point: 177-179°C, ESI-MS: m/z 402.8 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₃ (Exact Mass: 401.17). Compound 10e, white solid, yield: 47.5%, melting point: 188-190°C, ESI-MS: m/z 428.3 [M+H] ⁺ .C ₂₆ H ₂₅ N ₃ O ₃ (Exact Mass: 427.19).

Preparation of Compounds 33-38

The synthesis of compounds 33-38 was similar to the synthesis described for the preparation of compounds 9-14.

Example 25. Preparation of Compound 33

Recrystallized from ethyl acetate to give a white solid, yield: 77.8%, melting point: 190-193°C. Spectral data of compound 33: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.56(t, J＝8.4 Hz, 1H, Pyr-H),8.05(t, J＝5.1 Hz, 1H, Naph-H),7.70(t, 1H, Naph-H),7.59(d, J＝7.6 Hz, 1H, Pyr-H),7.54(d, J＝6.5 Hz, 1H, Naph-H),7.52(s, 1H, Naph-H),7.43(d, J＝7.6 Hz, 1H, Naph-H),7.00(q, 1H, Pyr-H),6.93(t, J＝8.5 Hz, 1H, Naph-H),4.65–4.56(m, 2H, CH ₂ ¹³ C NMR ,130.01,128.47,127.51,127.22,126.97,126.46,125.66,125.45,123.52,118.05,114.96,42.28,13.40,7.60,7.32.HR- _MS : _m /z 358.1197[MH] ^- . _{C 21} H ₁₇ N ₃ O ₃ (ExactMass:359.13).

Example 26. Preparation of Compound 34

Recrystallized from ethyl acetate to a red solid, yield: 60.0%, melting point: 100-103°C. Spectral data of compound 34: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.58(d,J＝5.7Hz,1H,Pyr-H),8.55(d,J＝7.7Hz,1H,Naph-H),8.16(d,J＝5.3Hz,1H,Naph-H),7.70(t,J＝7.6Hz,1H,Pyr-H),7.60(d,J＝7.6Hz,1H,Naph-H),7.55( t,1H,Naph-H),7.45(t,1H,Naph-H),7.38(t,1H,Pyr-H),6.64(d,J＝5.3Hz,1H,Naph-H),5.31(t,J＝7.2Hz,1H,CH),2.58–2.52(m,1H,CH),1.77(q,J＝3.6Hz,3H, CH ₃ ),1.15(d,J＝8.7Hz,2H,CH ₂ ),0.88–0.81(m,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ171.76,148.14,141.12,135.66,131.74,129.94,128.83,128.35,126.79,126.21,125.28,124.12,123.49,119.46,118.10,115.24,113.33,13.40,13.22,13.03,7.02,6.49.HR-MS:m/z 372.1354[MH] ^- .C ₂₂ H ₁₉ N ₃ O ₃ (Exact Mass:373.14).

Example 27. Preparation of Compound 35

Recrystallized from ethyl acetate to a yellow solid, yield: 78.8%, melting point: 180-183°C. Spectral data of compound 35: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 8.6 Hz, 1H, Pyr-H), 7.99 (d, J = 3.9 Hz, 1H, Naph-H), 7.69 (d, J = 7.7 Hz, 1H, Naph-H), 7.57 (s, 1H, Pyr-H), 7.54 (d, J = 6.7 Hz, 1H, Naph-H), 7.49 (d, J = 8.3 Hz, 1H, Naph-H), 7.41 (d, J = 7.6 Hz, 1H, Naph-H), 6.92 (q, J = 5.0 Hz, 1H, Pyr-H), 6.79 (d, J = 9.1 Hz, 1H, Naph-H), 3.38 (s, 6H, CH ₃ ×2),2.51(s,1H,CH),1.14(d,J＝8.4Hz,2H,CH ₂ ),0.89–0.76(m,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ154.12,144.82,141.18,141.03,134.31,130.13,129.80,129.00,128.77,127.42,127.11,127.00,126.57,125.41,123.52,123.05,117.28,114.44,13.38,7.59,7.59,7.28,7.27.HR-MS:m/z 386.1509[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16).

Example 28. Preparation of Compound 36

Recrystallized from ethyl acetate to a yellow solid with a yield of 57.2%, melting point: 68-71°C. Spectral data of compound 36: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 8.4 Hz, 1H, Pyr-H), 8.08 (t, J = 5.0 Hz, 1H, Naph-H), 7.69 (t, 1H, Naph-H), 7.57 (t, 1H, Pyr-H), 7.55 (d, J = 4.2 Hz, 1H, Naph-H), 7.53 (s, 1H, Naph-H), 7.42 (d, J = 7.6 Hz, 1H, Naph-H), 7.04–6.95 (m, 1H, Pyr-H), 6.86 (t, 1H, Naph-H), 4.23 (t, 2H, CH ₂ ),3.45(q,J＝7.2Hz,1H,CH),2.85(t,J＝7.6Hz,2H,CH ₂ ),1.14(t,J＝8.6Hz,2H,CH ₂ ),0.89–0.77(m,2H,CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ172.91,153.78,152.91,144.32,143.65,141.45,141.09,134.31,130.08,128.52,127.49,127.20,127.01,125.41,123.49,117.87,114.94,3 6.55, 33.05, 13.39, 7.59, 7.33. HR-MS: m/z 372.1354 [MH] ^- .C ₂₂ H ₁₉ N ₃ O ₃ (Exact Mass: 373.14).

Example 29. Preparation of Compound 37

Recrystallized from ethyl acetate to a yellow solid, yield: 65.5%, melting point: 58-61°C. Spectral data of compound 37: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.56(d, J＝8.6 Hz, 1H, Pyr-H),8.07(d, J＝5.0 Hz, 1H, Naph-H),7.72–7.69(m, 1H, Naph-H),7.60(d, J＝7.6 Hz, 1H, Pyr-H),7.55(s, 1H, Naph-H),7.54(s, 1H, Naph-H),7.42(d, J＝7.6 Hz, 1H, Naph-H),6.99(q, J＝5.3 Hz, 1H, Pyr-H),6.88(d, J＝7.8 Hz, 1H, Naph-H),4.05(t, J＝6.9 Hz, 2H, CH _{2 13 C NMR ​} ^​ _​ )δ174.37,153.19,143.88,141.41,141.06,134.30,130.10,129.00,128.59,127.50,127.17,127.08,126.43,125.41,123.57,123.50,117.80,1 14.90, 31.50, 23.82, 13.40, 7.59, 7.32. HR-MS: m/z386.1509[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16).

Example 30. Preparation of Compound 38

Recrystallized from ethyl acetate to a white solid, yield: 46.0%, melting point: 180-183°C. Spectral data of compound 38: ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.94(s,1H,COOH),8.55(d,J＝8.6Hz,1H,Pyr-H),8.00(d,J＝5.0Hz,1H,Naph-H),7.69(d,J＝6.5Hz,1H,Naph-H),7.56(d,J＝7.5Hz,1H,Pyr-H),7.52(d,J＝7.7Hz ,1H,Naph-H),7.49(d,J＝8.1Hz,1H,Naph-H),7.41(d,J＝7.6Hz,1H,Naph-H),6.93(q,J＝5.3Hz,1H,Pyr-H),6.81(d,J＝6.5Hz,1H,Naph-H),3.35(s,6H,CH ₂ ×3),2.58–2.51(m,1H,CH),1.18–1.10(m,2H,CH ₂ ),0.90–0.76(m,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ153.82,144.38,141.26,141.09,134.31,130.12,129.88,129.01,128.64,127.75,127.46,127.13,127.03,126.48,125.42,123.50,123.00,1 17.47,114.61,13.38,7.60,7.60,7.28,7.28.HR-MS: m/z398.1514[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 399.16).

Preparation of compound 2c

The synthesis method of compound 2c is similar to that of compound 6b, except that the starting material is compound 1d. Compound 2c, yellow solid, yield: 56.6%, melting point: 116-118°C. ESI-MS: m/z 306.4 [M+H] ⁺ .C ₁₈ H ₁₅ N ₃ O ₂ (Exact Mass: 305.11).

Preparation of compound 3c

The synthesis method of compound 3c is similar to that of compound 7a, except that the starting material is compound 2c. Compound 3c, yellow solid, yield: 76.2%, melting point: 192-193°C. ESI-MS: m/z 276.4 [M+H] ⁺ .C ₁₈ H ₁₇ N ₃ (Exact Mass: 275.14).

Preparation of compound 4c

The synthesis method of compound 4c is similar to that of compound 4b, white solid, yield: 60.9%, melting point: 159-161°C. ESI-MS: m/z 300.88 [M–H] ^– .C ₁₉ H ₁₅ N ₃ O (Exact Mass: 301.12).

Preparation of compounds 5f-10f

The synthesis method of compounds 5f-10f is similar to the synthesis method described in compounds 9a-14a. Compound 5f, white solid, yield: 82.2%, melting point: 123-125°C, Melting point: 123-125°C. ESI-MS: m/z 374.7 [M+H] ⁺ .C ₂₂ H ₁₉ N ₃ O ₃ (Exact Mass: 373.14). Compound 6f, white solid, yield: 84.5%, melting point: 136-137°C, ESI-MS: m/z 388.3 [M+H] ⁺ .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16). Compound 7f, light yellow oil, yield: 88.2%, melting point: 142-145°C, ESI-MS: m/z 402.6 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₃ (Exact Mass: 401.17). Compound 8f, light yellow oil, yield: 70.0%, melting point: 151-154°C, ESI-MS: m/z 388.1 [M+H] ⁺ .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16). Compound 9f, white solid, yield: 53.9%, melting point: 152-155°C, ESI-MS: m/z 402.4 [M+H] ⁺ .C ₂₄ H ₂₃ N ₃ O ₃ (Exact Mass: 401.17). Compound 10f, white solid, yield: 55.0%, melting point: 164-167°C, ESI-MS: m/z 428.4 [M+H] ⁺ .C ₂₆ H ₂₅ N ₃ O ₃ (Exact Mass: 427.19).

Preparation of Compounds 39-44

The synthesis of compounds 39-44 was similar to that described for the preparation of compounds 9-14.

Example 31. Preparation of Compound 39

Recrystallized from ethyl acetate to a yellow solid, yield: 72.5%, melting point: 120-123°C. Spectral data of compound 39: ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.54 (d, 1H, COOH), 8.54 (s, 1H, Pyr-H), 8.37 (d, J = 4.9Hz, 1H, Pyr-H), 8.15 (d, J = 5.3Hz, 1H, Naph-H), 8.10 (d, J = 5.3Hz, 1H, Na ph-H),7.70(d,J＝6.8Hz,1H,Naph-H),7.67(s,1H,Naph-H),7.57(s,1H,Pyr-H),7.55(s,1H,Naph-H),7.45(s,1H,Naph-H),6.59(q,2H,CH ₂ ),4.74(d,J＝8.6Hz,2H , CH ₂ ),2.54(q,1H,CH),1.14(d,J＝8.3Hz,2H,CH ₂ ),0.88–0.83(m,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ169.71,154.02,143.42,142.95,141.77,141.50,138.17,136.92,134.29,130.23,127.54,127.19,126.99,125.46,123.49,123.31,104.21,43.60,13.39,7.62,7.31.HR-MS:m/z 358.1197[MH] ^- .C ₂₁ H ₁₇ N ₃ O ₃ (Exact Mass: 359.13).

Example 32. Preparation of Compound 40

Recrystallized from ethyl acetate to a yellow solid, yield: 76.9%, melting point: 245-248°C. Spectral data of compound 40: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.58(s,1H,Pyr-H),8.56(t,1H,Pyr-H),8.16(d,J＝5.3Hz,1H,Naph-H),7.70(t,J＝7.9Hz,1H,Naph-H),7.60(d,J＝7.6Hz,1H,Naph-H),7.55(t,1H,Naph-H),7.4 5(t,1H,Pyr-H),7.38(t,1H,Naph-H),6.64(d,J＝5.3Hz,1H,Naph-H),5.31(t,J＝7.2Hz,1H,CH),2.60–2.52(m,1H,CH),1.78(q,J＝3.7Hz,3H,CH ₃ ),1.14(d,J＝8.8 Hz,2H,CH ₂ ),0.87–0.79(m,2H,CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ )δ171.87,152.86,143.30,141.83,137.05,134.34,130.42,129.80,128.17,127.59,127.28, 127.06,125.50,123.48,123.29,122.94,104.36,51.19,15.66,13.40,7.60,7.39.HR-MS: m/z 372.1354[MH] ^- .C ₂₂ H ₁₉ N ₃ O ₃ (Exact Mass: 373.14).

Example 33. Preparation of Compound 41

Recrystallized from ethyl acetate to a yellow solid with a yield of 92.0% and a melting point of 110-113°C. Spectral data of compound 41: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.57 (s, 1H, COOH), 8.56 (d, J = 8.4 Hz, 1H, Pyr-H), 8.37 (d, 1H, Pyr-H), 8.10 (t, J = 5.3 Hz, 1H, Naph-H), 7.69 (t, J = 7.1 Hz, 1H, Naph-H), 7.57 (s, 1H, Naph-H), 7.54 (d, J = 7.9 Hz, 1H, Naph-H), 7.45 (d, J = 8.2 Hz, 1H, Pyr-H), 7.42 (d, J = 7.6 Hz, 1H, CH, Naph-H), 6.55 (d, J = 5.3 Hz, 1H, Naph-H), 3.39 (s, 6H, CH ₃ ×2),2.54(t,J＝8.2Hz,1H,CH),1.14(t,2H,CH ₂ ),0.88–0.79(m,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ154.02,142.95,141.49,138.15,134.29,130.25,129.97,128.47,127.54,127.19,126.99,126.82,125.46,125.37,123.49,123.39,123.31,1 04.21,13.39,7.62,7.62,7.31,7.31.HR-MS: m/z386.1507[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16).

Example 34. Preparation of Compound 42

Recrystallized from ethyl acetate to give a white solid with a yield of 88.4% and a melting point of 105-108°C. Spectral data of compound 42: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H, Pyr-H), 8.56 (d, J = 8.4 Hz, 1H, Pyr-H), 8.14 (d, J = 5.3 Hz, 1H, Naph-H), 7.69 (t, J = 7.2 Hz, 1H, Naph-H), 7.57 (d, J = 7.7 Hz, 1H, Naph-H), 7.54 (d, J = 7.0 Hz, 1H, Naph-H), 7.45 (d, J = 8.3 Hz, 1H, Pyr-H), 7.43 (d, J = 7.6 Hz, 1H, Naph-H), 6.59 (d, J = 5.3 Hz, 1H, Naph-H), 4.24 (t, J = 7.0 Hz, 2H, CH ₂ ),2.82(t,J＝6.9Hz,2H,CH ₂ ),2.55(q,1H,CH),1.14(d,J＝8.4Hz,2H,CH ₂ ),0.88–0.80(m,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ172.88,153.06,143.22,141.69,136.93,134.30,130.13,129.91,128.37,127.58,127.25,127.25,126.99,125.46,123.47,123.37,104.16,3 7.93, 33.04, 13.40, 7.61, 7.36. HR-MS: m/z 372.1354 [MH] ^- .C ₂₂ H ₁₉ N ₃ O ₃ (Exact Mass: 373.14).

Example 35. Preparation of Compound 43

Recrystallized from ethyl acetate to a yellow solid with a yield of 66.1% and a melting point of 150-153°C. Spectral data of compound 43: ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.18(s,1H,COOH),8.61(s,1H,Pyr-H),8.56(d,J＝8.6Hz,1H,Pyr-H),8.15(d,J＝5.3Hz,1H,Naph-H),7.69(t,J＝7.7Hz,1H,Naph-H),7.59(d,J＝7.5Hz,1H,Naph-H ),7.54(d,J＝7.0Hz,1H,Naph-H),7.47(d,J＝8.6Hz,1H,Pyr-H),7.43(d,J＝7.7Hz,1H,Naph-H),6.60(d,J＝5.3Hz,1H,Naph-H),4.04(q,J＝7.0Hz,2H,CH _{2 13 C NMR ​} ^​ _​ )δ174.39,153.22,143.28,141.64,136.97,134.28,129.94,129.63,128.45,127.59,127.46,127.22,127.04,125.46,123.48,123.37,104.22,3 1.22, 23.77, 13.40, 7.62, 7.62, 7.35. HR-MS: m/z 386.1507[MH] ^- .C ₂₃ H ₂₁ N ₃ O ₃ (Exact Mass: 387.16).

Example 36. Preparation of Compound 44

Recrystallized from ethyl acetate to a yellow solid with a yield of 77.0% and a melting point of 70-73°C. Spectral data of compound 44: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.54 (d, 1H, COOH), 8.56 (d, J = 8.6 Hz, 1H, Pyr-H), 8.37 (s, 1H, Pyr-H), 8.10 (d, J = 5.3 Hz, 1H, Naph-H), 7.70 (d, J = 8.3 Hz, 1H, Naph-H), 7.67 (s, 1H, Naph-H), 7.58 (s, 1H, Naph-H), 7.56 (s, 1H, Pyr-H), 7.44 (d, J = 4.0 Hz, 1H, Naph-H), 6.56 (t, J = 5.4 Hz, 1H, Naph-H), 3.50 (q, 2H, CH ₂ ),2.54(t,1H,CH),1.15(d,2H,CH ₂ ),1.13(t,2H,CH ₂ ),0.92–0.84(m,2H,CH ₂ ),0.80(q,2H,CH ₂ ). ¹³ C NMR(100MHz,DMSO-d ₆ )δ154.00,142.82,141.52,138.28,134.29,130.04,129.95,128.43,127.55,127.19,127.09,127.00,126.83,125.46,123.49,123.39,123.31,1 04.24, 37.24, 34.68, 13.40, 7.63, 7.62, 7.31. HR-MS: m/z398.1509[MH] ^- .C ₂₄ H ₂₁ N ₃ O ₃ (Exact Mass: 399.16).

Example 17. In vivo uric acid-lowering activity test of target compounds

Test Materials and Methods:

(1) Experimental animals: Male Kunming mice, provided by the Experimental Animal Center of Shandong University.

(2) Sample treatment: Before use, the test compound was prepared with DMSO and CMC-Na to an appropriate concentration.

(3) Modeling drugs: hypoxanthine and potassium oxalate.

(4) Positive control drug: Lesinurad.

(5) Test method: Each group was gavaged with 0.2 mL of hypoxanthine and subcutaneously injected with 0.2 mL of potassium oxonate. After gavage with 0.2 mL of drug, the timing was started. The eyeballs were removed and blood was collected 4 hours after administration. After 30 minutes of coagulation, the blood was centrifuged and the supernatant serum was collected. The uric acid concentration in the serum was tested with a uric acid meter.

Table 2. Structures and uric acid-lowering activities of compounds 9 to 32

Table 3. Structures and uric acid-lowering activities of compounds 33-44

Conclusion: It can be seen from Tables 2 and 3 that 29 compounds showed uric acid-lowering activity, and the uric acid-lowering activity was better than or equivalent to that of the positive control drug Lesinurad. Among them, representative compounds 13, 23, 33, 35, 36, 38 and 39 had a blood uric acid reduction rate of more than 80% in the in vivo activity test in animals, showing excellent uric acid-lowering activity and can be used as candidate uric acid-lowering drugs.

Claims (4)

1. The pyridoimidazole derivative 23 or a pharmaceutically acceptable salt thereof is characterized by having the structure shown below:

2. the method for preparing the pyridoimidazole derivative 23 according to claim 1, wherein the method comprises the following steps:

compound 1a was treated with 2-nitro-3-pyridyltrifluoromethane sulfonate, and 2b was obtained by coupling reaction; then, hydrogenation reduction is carried out in the presence of stannous chloride to obtain 3c, the 3c is cyclized with 1,1' -thiocarbonyldiimidazole to obtain a key intermediate 3c, and nucleophilic substitution and hydrolysis reaction are carried out to obtain a target compound 23;

route one:

reagents and conditions (i) 2-nitro-3-pyridyltrifluoromethane sulfonate, triethylamine, acetonitrile, 90 ℃; (ii) stannous chloride, ethanol, nitrogen, room temperature; (iii) 1,1' -thiocarbonyldiimidazole, triethylamine, acetonitrile, 90 ℃; (iv) Esters, potassium carbonate, N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.

3. The use of a pyridoimidazole derivative 23 according to claim 1 for the manufacture of a medicament for reducing uric acid.

4. A uric acid lowering pharmaceutical composition comprising the pyridoimidazole derivative 23 of claim 1 and one or more pharmaceutically acceptable carriers or excipients.