CN114478522B - Pyridoimidazole derivative and preparation method and application thereof - Google Patents

Pyridoimidazole derivative and preparation method and application thereof Download PDF

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CN114478522B
CN114478522B CN202210098964.9A CN202210098964A CN114478522B CN 114478522 B CN114478522 B CN 114478522B CN 202210098964 A CN202210098964 A CN 202210098964A CN 114478522 B CN114478522 B CN 114478522B
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展鹏
刘新泳
赵彤
章健
梁瑞鹏
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Abstract

The invention relates to a pyridoimidazole derivativeA preparation method and application thereof. The compound has a structure shown in a formula I or II. The invention also relates to a preparation method of the compound containing the structure shown in the formula I or the formula II and a pharmaceutical composition. The invention also provides application of the compound in preparing uric acid reducing medicines.

Description

Pyridoimidazole derivative and preparation method and application thereof
Technical Field
The invention relates to the field of related medicaments for treating hyperuricemia and gout. In particular, the invention relates to a pyridoimidazole compound for treating hyperuricemia and gout, a preparation method thereof or a pharmaceutical composition containing the same, and application thereof in medicine.
Background
Hyperuricemia (HUA) refers to fasting blood uric acid levels twice a day, not under normal purine dietary conditions: male blood uric acid >420 mu mol/L, and female blood uric acid >360 mu mol/L. Gout refers to a concentration of blood uric acid exceeding 6.8mg/dL, a crystal-related arthropathy caused by the deposition of monosodium urate (MSU), and is directly related to hyperuricemia caused by purine metabolic disorder or uric acid excretion reduction, in particular to acute characteristic arthritis and chronic tophus diseases. Gout and hyperuricemia are both associated with uric acid levels in humans. Normal adults produce approximately 750mg of uric acid daily, 1/3 of which is catabolized by the intestinal tract and 2/3 of which is excreted by the kidneys, thus maintaining stable uric acid levels in the body. The current drugs for treating gout are mainly of two types: one class is xanthine oxidase inhibitors that inhibit uric acid production, and the other class is URAT1 inhibitors that promote uric acid excretion. Uric acid transporter 1 (URAT 1) is located on the brush border of human kidney proximal tubular epithelial cells, and mainly mediates uric acid reabsorption in the kidney, and increased URAT1 activity or increased gene expression due to gene mutation is one of the important pathogenesis of hyperuricemia. Lesinurad is a URAT1 inhibitor for the treatment of hyperuricemia and gout, and has been withdrawn from the market due to its large therapeutic dose and serious toxic side effects. Therefore, the novel uric acid reducing drug with better activity and safety and independent intellectual property is hopeful to be obtained by further structural modification.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a pyridoimidazole derivative and a preparation method thereof, and also provides an activity screening result of the compound as a uric acid reducing drug and application thereof.
The technical scheme of the invention is as follows:
1. pyridoimidazole derivatives
The pyridoimidazole derivative or the pharmaceutically acceptable salt thereof has a 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 alkane or substituted alkane, and the substituent is C1-C10 alkane.
According to the invention, R is preferably methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
According to a further preferred embodiment of the invention, the pyridoimidazole derivative is one of the following:
TABLE 1 structural formulas of Compounds 9-44
2. Process for preparing pyridoimidazole derivatives
The preparation method of the pyridoimidazole derivative is one of the following methods:
(1) Synthesis of Compounds 9-20:
treating 1a with N-bromosuccinimide (NBS) in N-hexane in the presence of Benzoyl Peroxide (BPO) to give intermediate 2a, and reacting it with potassium phthalimide to give 3a;3a and 80% hydrazine hydrate are synthesized by Gabriel to obtain 4a, and then Suzuki coupling reaction is carried out in a toluene/water mixture of 25:1v/v to convert the 4a into 5a; obtaining an intermediate 6a or 6b through a coupling reaction between 5a and 2-nitro-3-pyridinyl trifluoro methane sulfonate (1 b) or 4-chloro-3-nitropyridine (1 c); hydrogenation reduction in the presence of Pd/C to give 7a or 7b, followed by cyclization with 1,1' -Thiocarbonyldiimidazole (TCDI) to give key intermediate 8a or 8b; obtaining compounds 9-14 through nucleophilic substitution reaction and lithium hydroxide hydrolysis; the preparation method of the compound 15-20 is similar to the compound 9-14, except that in the step V, 4-chloro-3-nitropyridine (1 c) is taken as a starting material;
route one:
reagents and conditions of (i) N-bromosuccinimide, benzoyl peroxide, nitrogen, N-hexane, 70 ℃; (ii) Potassium phthalimide, N-dimethylformamide, nitrogen at 100 ℃; (iii) 80% hydrazine hydrate, ethanol, 80 ℃; (iv) Cyclopropyl boric acid, potassium phosphate, tetrakis (triphenylphosphine) palladium, toluene, water, nitrogen, 100 ℃; (v-a) 2-nitro-3-pyridyltrifluoromethane sulfonate, triethylamine, acetonitrile, 90 ℃; (v-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60 ℃; (vi) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (vii) 1,1' -thiocarbonyldiimidazole, triethylamine, acetonitrile, 90 ℃; (viii) Esters, potassium carbonate, N-dimethylformamide, room temperature; (ix) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.
R is methylene, ethyl, propyl, isopropyl, tertiary butyl or cyclobutyl.
(2) Synthesis of Compounds 21-32
4a is treated with 2-nitro-3-pyridyltrifluoromethane sulfonate (1 b) or 4-chloro-3-nitropyridine (1 c) to obtain 5b or 5c through coupling reaction; then, hydrogenation reduction is carried out in the presence of stannous chloride to obtain 6c or 6d, the stannous chloride is cyclized with 1,1' -Thiocarbonyldiimidazole (TCDI) to obtain a key intermediate 7c or 7d, and nucleophilic substitution and hydrolysis reaction are carried out to obtain a target compound 21-26; compounds 27-32 are prepared similarly to compounds 21-26 except that the starting material for step I is 4-chloro-3-nitropyridine (1 c);
route two:
reagents and conditions (i-a) 2-nitro-3-pyridyltrifluoromethane sulfonate, triethylamine, acetonitrile, 90 ℃; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60 ℃; (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.
R is methylene, ethyl, propyl, isopropyl, tertiary butyl or cyclobutyl.
(3) Synthesis of Compounds 33-44
The starting material 4-cyclopropyl-1-naphthylamine (1 d) is treated with 2-nitro-3-pyridyltrifluoromethane sulfonate (1 b) or 4-chloro-3-nitropyridine (1 c), and intermediate 2b or 2c is obtained through coupling reaction; then, hydrogenation reduction is carried out in the presence of palladium carbon to obtain 3b or 3c, the 3b or 3c is cyclized with N, N' -Carbonyl Diimidazole (CDI) to obtain 4b or 4c, and nucleophilic substitution and hydrolysis are carried out to obtain a compound 33-38; compounds 39-44 were prepared similarly to compounds 33-38, except that the starting material was 4-chloro-3-nitropyridine (1 c);
route three:
reagents and conditions (i-a) 2-nitro-3-pyridyltrifluoromethane sulfonate, palladium acetate, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, cesium carbonate, nitrogen, 1, 4-dioxane, 90 ℃; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60 ℃; (ii) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (iii) N, N' -Carbonyldiimidazole (CDI), triethylamine, acetonitrile, 90 ℃; (iv) Esters, potassium carbonate, N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.
R is methylene, ethyl, propyl, isopropyl, tertiary butyl or cyclobutyl.
The room temperature of the invention is 20-30 ℃.
3. Application of pyridoimidazole derivative
The invention discloses a screening result of the activity of pyridoimidazole derivatives in reducing blood uric acid and the first application of the screening result in preparing uric acid reducing medicines. Experiments prove that the pyridoimidazole derivative can be applied to medicines for reducing blood uric acid. In particular, can be used as a blood uric acid reducing compound for preparing uric acid reducing medicines. The invention also provides application of the compound in preparing uric acid reducing medicines.
Uric acid lowering activity of the target compound:
the uric acid-lowering activity of 36 compounds synthesized according to the above method (the structural formula of the compounds is shown in Table 1) were screened, and their uric acid-lowering activity data are shown in Table 2, with Lesinurad as a positive drug.
From tables 2 and 3, it can be seen that 29 compounds all exhibit better anti-uric acid-lowering activity, and the uric acid-lowering activity is stronger than that of the positive control drug Lesinurad. Wherein, the representative compounds 13, 23, 33, 35, 36, 38 and 39 have the blood uric acid reduction rate exceeding 80 percent in the animal body activity test, show excellent uric acid reduction activity and can be used for preparing uric acid reduction medicines.
Therefore, the pyridoimidazole derivatives are a series of compounds with novel structures and blood uric acid reducing activity, can be used as candidate medicines for reducing uric acid and are used for preparing medicines for reducing uric acid.
A uric acid reducing pharmaceutical composition comprising a pyridoimidazole derivative of the invention and one or more pharmaceutically acceptable carriers or excipients.
Detailed Description
The present invention will be further understood by the following examples, in which all target compounds are numbered the same as in table 1, but the content of the present invention is not limited thereto.
Synthetic route for compounds 9-20:
reagents and conditions of (i) N-bromosuccinimide, benzoyl peroxide, nitrogen, N-hexane, 70 ℃; (ii) Potassium phthalimide, N-dimethylformamide, nitrogen at 100 ℃; (iii) 80% hydrazine hydrate, ethanol, 80 ℃; (iv) Cyclopropyl boric acid, potassium phosphate, tetrakis (triphenylphosphine) palladium, toluene, water, nitrogen, 100 ℃; (v-a) 2-nitro-3-pyridyltrifluoromethane sulfonate, triethylamine, acetonitrile, 90 ℃; (v-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60 ℃; (vi) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (vii) 1,1' -thiocarbonyldiimidazole, triethylamine, acetonitrile, 90 ℃; (viii) Esters, potassium carbonate, N-dimethylformamide, room temperature; (ix) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.
R is methylene, ethyl, propyl, isopropyl, tertiary butyl or cyclobutyl.
Preparation of Compound 2a
Commercial 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 36h (monitored by TLC). The reaction mixture was cooled to room temperature with stirring, and the precipitate was collected by vacuum filtration. The precipitate was washed successively with saturated aqueous sodium bicarbonate (100 mL. Times.2), water (100 mL. Times.2) and n-hexane (100 mL) to give crude product 2a as a white solid. Yield: 75.0%. Melting point: 103-105 ℃. 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 stirred under nitrogen at 100deg.C until TLC monitoring was complete. 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 solutions were washed with saturated aqueous sodium chloride (20 mL. Times.3) and dried over anhydrous sodium sulfate. After filtration, the organic phase was evaporated under reduced pressure to give a crude product, which was recrystallized from ethanol to give compound 3a as a white solid. Yield: 66.6%. Melting point: 165-168 ℃. 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 ℃ for 12 hours (monitored by TLC). About 10 minutes of cooling, 1M aqueous sodium hydroxide (10 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to half its original volume. It was poured into ice water (100 mL) and extracted with dichloromethane (3X 20 mL). The combined organic layers were washed with 5% sodium hydroxide (10 ml×2) and 5% brine (20 mL), dried over anhydrous sodium sulfate, evaporated on a rotary evaporator to give a residue which was purified by column chromatography to give compound 4a as 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 then the reaction system was reacted at 100℃for 12h under nitrogen atmosphere, and TLC was monitored for completion of the reaction. When the reaction mixture was cooled to room temperature, the reaction mixture was poured into 100mL of water and extracted with ethyl acetate (20 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate and filtered. After filtration, the mixture was evaporated under reduced pressureThe organic phase was taken up to give 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 50mL of acetonitrile, then 2-nitro-3-pyridyltrifluoromethane sulfonate (1 b) (3.3 g,12.12 mmol) and triethylamine (0.5 g,5.07 mmol) were added to the solution, and the mixture was stirred under nitrogen at 50℃overnight (monitored by TLC) and then filtered. The residue was recrystallized from ethyl acetate to give compound 6a as a yellow solid. Yield: 73.2%. Melting point: 141-143 ℃. ESI-MS: m/z 320.56[ M+H ]] + .C 19 H 17 N 3 O 2 (Exact Mass:319.13)。
Preparation of Compound 7a
Compound 6a (1 g,3.13 mmol) was dissolved in 30mL tetrahydrofuran and 10% palladium on carbon (0.2 g) was added to the solution. The mixture was stirred at room temperature under hydrogen atmosphere for 6 hours, and then filtered. The filtrate was concentrated under reduced pressure. Purification by flash column chromatography gave compound 7a as a pale yellow solid. Yield: 76.2%. Melting point: 162-164 ℃. ESI-MS: M/z290.02[ M+H ]] + .C 19 H 19 N 3 (Exact Mass:289.16).
Preparation of Compound 8a
Compound 7a (1 g,3.46 mmol), 1' -thiocarbonyldiimidazole (1 g,5.53 mmol) and triethylamine (0.1 mL) were dissolved in 50mL acetonitrile. The solution was reacted at 90℃for 5 hours, then cooled to room temperature and filtered. The solid was recrystallized from ethyl acetate to give compound 8a as a white solid. Yield: 47.6%. Melting point: 156-159 ℃. 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, then the appropriate substituted ester (1.1-fold equivalent) was added and the mixture stirred at room temperature for 4 hours (TLC monitoring). DMF was evaporated under reduced pressure and acetic acid was usedEthyl ester (30 ml×3) extraction. The organic solution was washed with saturated aqueous sodium chloride (3X 10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by column chromatography to give compounds 9a-14a. Compound 9a, white solid, yield: 79.8%, melting point: 130-133 ℃, 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 ℃, 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 ℃, 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 ℃, ESI-MS: m/z 418.17[ M+H ]] + .C 24 H 23 N 3 O 2 S (Exact Mass: 417.15). Compound 13a, pale yellow oil, yield: 60.0%, melting point: 150-153 ℃, 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 ℃, 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
Compounds 9a-14a were dissolved in a mixture of 5mL tetrahydrofuran and 5mL 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 the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. To the residue was added 10mL of water and 1M HCl solution was added dropwise to adjust the pH to 3-4. The product was collected by filtration and recrystallized from ethanol to give the objective compounds 9-14.
Example 1 preparation of Compound 9
Recrystallisation from ethyl acetate as a yellow solid gave a yield of 82.6%, melting point: 60-63 ℃. Spectroscopic data for compound 9: 1 H NMR(400MHz,DMSO-d 6 )δ8.49(t,1H,Pyr-H),8.39(d,J＝4.9Hz,1H,Pyr-H),8.21(t,1H,Naph-H),7.87(d,J＝8.1Hz,1H,Naph-H),7.70(d,J＝6.6Hz,1H,Pyr-H),7.67(t,J＝3.8Hz,1H,Naph-H),7.21(q,J＝5.0Hz,1H,Naph-H),7.11(d,J＝7.5Hz,1H,Naph-H),6.52(d,J＝7.5Hz,1H,Naph-H),5.95(s,2H,CH 2 ),2.43–2.33(m,1H,CH),1.63(d,J＝7.3Hz,2H,CH 2 ),CH 2 ,1.06–1.00(m,2H,CH 2 ),0.69–0.64(m,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ172.66,155.83,154.79,142.97,139.61,133.63,130.62,129.82,129.42,126.90,126.74,125.47,123.99,123.19,123.13,119.39,117.99,45.89,45.24,18.73,13.29,7.10.HR-MS:m/z 388.1127[M-H] - .C 22 H 19 N 3 O 2 S(Exact Mass:389.12)。
EXAMPLE 2 preparation of Compound 10
Recrystallisation from ethyl acetate as a white solid, yield: 86.1%, melting point: 80-83 ℃. Spectroscopic data for 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＝7.0Hz,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 ),4.22(s,3H,CH 3 ),3.44(q,J＝7.0Hz,1H,CH),2.41–2.34(m,1H,CH),1.05–0.99(m,2H,CH 2 ),0.68(q,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ169.68,163.63,156.07,155.77,143.87,139.60,133.63,130.72,129.53,129.50,126.89,126.68,125.47,124.03,123.49,123.14,118.07,117.67,45.75,35.23,19.03,13.29,7.10.HR-MS:m/z 402.1282[M-H] - .C 23 H 21 N 3 O 2 S(Exact Mass:403.14)。
EXAMPLE 3 preparation of Compound 11
Recrystallisation from ethyl acetate as a white solid, yield: 80%, melting point: 60-63 ℃. Spectroscopic data for compound 11: 1 H NMR(400MHz,DMSO-d 6 )δ8.49(t,1H,Pyr-H),8.40(d,J＝4.8Hz,1H,Pyr-H),8.22(t,1H,Naph-H),7.85(d,J＝7.9Hz,1H,Naph-H),7.70(s,1H,Pyr-H),7.68(d,J＝5.0Hz,1H,Naph-H),7.21(q,J＝4.8Hz,1H,Naph-H),7.09(d,J＝7.5Hz,1H,Naph-H),6.39(d,J＝7.5Hz,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 )δ174.33,155.06,153.95,143.69,139.47,133.60,130.53,129.85,128.97,126.89,126.89,126.74,126.74,125.47,123.97,123.13,122.77,119.43,118.30,54.32,45.90,26.79,13.26,7.08.HR-MS:m/z 416.1438[M-H] - .C 24 H 23 N 3 O 2 S(Exact Mass:417.15)。
EXAMPLE 4 preparation of Compound 12
Recrystallisation from ethyl acetate as a white solid, yield: 83.1%, melting point: 145-148 ℃. Spectroscopic data for compound 12: 1 H NMR(400MHz,DMSO-d 6 )δ8.47(t,1H,Pyr-H),8.29(t,J＝10.4Hz,1H,Pyr-H),8.15(q,1H,Naph-H),7.67(d,J＝5.1Hz,1H,Naph-H),7.65(d,J＝4.9Hz,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 )δ172.39,170.92,145.63,144.92,143.44,139.36,133.67,130.99,129.42,129.19,126.77,126.58,126.48,125.43,124.31,124.28,123.12,118.49,117.41,45.38,32.24,13.29,7.08.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
Recrystallisation from ethyl acetate as a yellow solid, yield: 79%, melting point: 60-63 ℃. Spectroscopic data for 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＝3.8Hz,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 ),2.39(s,1H,CH),2.35(q,2H,CH 2 ),2.15–1.95(m,2H,CH 2 ),1.05–1.00(m,2H,CH 2 ),0.66(d,J＝3.4Hz,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ174.20,171.00,145.21,143.38,141.82,139.59,133.63,130.64,130.45,129.37,126.87,126.72,125.49,123.96,123.13,119.85,119.10,117.80,45.87,32.83,31.75,24.87,13.27,7.11.HR-MS:m/z 452.1205[M-H] - .C 24 H 23 N 3 O 2 S(Exact Mass:417.15)。
EXAMPLE 6 preparation of Compound 14
Recrystallisation from ethyl acetate as a white solid, yield: 67%, melting point: 230-235 ℃. Spectroscopic data for compound 14: 1 H NMR(400MHz,DMSO-d 6 )δ8.47(t,1H,Pyr-H),8.30(t,1H,Pyr-H),8.15(d,J＝5.0Hz,1H,Naph-H),7.67(d,J＝6.0Hz,1H,Naph-H),7.64(t,J＝3.8Hz,1H,Pyr-H),7.40(d,J＝8.1Hz,1H,Naph-H),7.15(d,J＝7.3Hz,1H,Naph-H),7.07(q,J＝5.0Hz,1H,Naph-H),6.85(d,J＝7.3Hz,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 )δ170.97,145.75,144.06,143.45,139.35,133.68,131.00,129.46,126.76,126.56,126.48,125.43,124.33,124.28,123.13,123.13,118.44,117.34,45.79,45.39,33.03,29.72,16.94,13.29,7.08.HR-MS:m/z 428.1438[M-H] - .C 25 H 23 N 3 O 2 S(Exact Mass:429.15)。
preparation of Compound 6b
4-chloro-3-nitropyridine (1 c) (1 g,6.33 mmol), compound 5a (1.5 g,7.6 mmol) and sodium bicarbonate (1.6 g,18.9 mmol) were dissolved in 50mL of ethanol and the solution was refluxed at 60℃for 10 hours, then cooled to room temperature. Dichloromethane (30 mL) was added and the mixture was washed with saturated sodium chloride (3×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 6b was obtained by flash column chromatography as yellow solid, yield: 73.0%, melting point: :143-146 ℃. 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 of compound 7b was similar to that of compound 7 a. White solid, yield: 76.2%, melting point: 192-195 ℃. ESI-MS: m/z 290.13[ M+H ]] + .C 19 H 19 N 3 (Exact Mass:289.16)。
Preparation of Compound 8b
The synthesis of compound 8b was similar to that of compound 8 a. Yellow solid, yield: 52.6%, melting point: 130-134 ℃. 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 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 ℃, ESI-MS: M/z404.96[ 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 ℃, 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 ℃. 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, 67.5% yield, melting point: 147-150 ℃, 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, 84.0% yield, melting point: 160-163 deg.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, 59.0% yield, melting point: 130-133 ℃, 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 that described for the preparation of compounds 9-14.
EXAMPLE 7 preparation of Compound 15
Recrystallisation from ethyl acetate as a white solid, yield: 80%, melting point: 95-100 ℃. Spectroscopic data for compound 15: 1 H NMR(400MHz,DMSO-d 6 )δ8.88(s,1H,Pyr-H),8.48(d,J＝7.5Hz,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＝3.7Hz,1H,Naph-H),7.42(d,J＝5.7Hz,1H,Naph-H),7.12(d,J＝7.5Hz,1H,Naph-H),6.57–6.47(m,1H,Naph-H),5.93(s,2H,CH 2 ),4.21(s,2H,CH 2 ),2.38(s,1H,CH),1.03(d,J＝10.3Hz,2H,CH 2 ),0.67(d,J＝5.5Hz,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ169.71,154.91,141.91,141.79,140.58,140.16,139.65,133.64,130.71,129.38,126.90,126.71,125.48,124.01,123.45,123.13,123.09,105.93,45.66,35.10,13.29,7.11.HR-MS:m/z 388.1125[M-H] - .C 22 H 19 N 3 O 2 S(Exact Mass:389.12)。
EXAMPLE 8 preparation of Compound 16
Recrystallisation from ethyl acetate as a yellow solid, yield: 78%, melting point: 60-63 ℃. Spectroscopic data for compound 16: 1 H NMR(400MHz,DMSO-d 6 )δ8.92(s,1H,Pyr-H),8.49(q,1H,Pyr-H),8.24(d,J＝5.5Hz,1H,Naph-H),8.21(q,1H,Naph-H),7.69(t,1H,Pyr-H),7.67(t,J＝2.1Hz,1H,Naph-H),7.43(d,J＝5.6Hz,1H,Naph-H),7.11(d,J＝7.5Hz,1H,Naph-H),6.46(d,J＝7.3Hz,1H,Naph-H),5.93(s,2H,CH 2 ),4.67(q,J＝7.2Hz,1H,CH),2.40–2.35(m,1H,CH),1.61(d,J＝7.2Hz,3H,CH 3 ),1.02(q,J＝2.0Hz,2H,CH 2 ),0.67(q,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ172.75,153.95,141.87,141.65,140.66,140.33,139.59,133.63,130.63,129.47,126.89,126.72,125.48,123.97,123.14,123.10,123.10,106.07,45.67,45.43,18.85,13.28,7.09.HR-MS:m/z 402.1282[M-H] - .C 23 H 21 N 3 O 2 S(Exact Mass:403.14)。
EXAMPLE 9 preparation of Compound 17
Recrystallisation from ethyl acetate as a white solid, yield: 84%, melting point: 65-68 ℃. Spectroscopic data for compound 17: 1 H NMR(400MHz,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 ×2),1.02(q,J＝6.1Hz,2H,CH 2 ),0.66(q,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ174.40,152.33,141.98,140.96,140.90,140.72,140.72,139.48,133.60,130.52,129.83,126.90,126.75,125.47,123.95,123.13,122.69,106.40,54.28,45.78,26.75,26.49,13.26,7.08.HR-MS:m/z 416.1438[M-H] - .C 24 H 23 N 3 O 2 S(Exact Mass:417.15)。
EXAMPLE 10 preparation of Compound 18
Recrystallisation from ethyl acetate as a white solid, yield: 80%, melting point: 248-251 ℃. Spectroscopic data for 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 )δ173.79,172.55,142.15,139.48,137.57,133.67,131.00,130.73,128.32,126.89,126.72,125.83,125.47,124.14,123.25,123.11,123.03,106.88,46.71,42.01,31.71,13.29,7.09.HR-MS:m/z402.1284[M-H] - .C 23 H 21 N 3 O 2 S(Exact Mass:403.14)。
EXAMPLE 11 preparation of Compound 19
Recrystallisation from ethyl acetate as a white solid, yield: 80%, melting point: 180-183 ℃. Compound 19Spectral data: 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 )δ174.31,155.09,141.81,140.75,140.18,139.54,133.64,130.66,129.53,129.20,126.85,126.71,126.71,125.49,123.95,123.15,123.00,105.89,45.54,32.86,31.65,24.84,13.27,7.10.HR-MS:m/z 416.1437[M-H] - .C 24 H 23 N 3 O 2 S(Exact Mass:417.15)。
EXAMPLE 12 preparation of Compound 20
Recrystallisation from ethyl acetate as a white solid, yield: 61%, melting point: 60-63 ℃. Spectroscopic data for compound 20: 1 H NMR(400MHz,DMSO-d 6 )δ8.88(s,1H,Pyr-H),8.49(d,J＝9.8Hz,1H,Pyr-H),8.22(s,1H,Naph-H),8.21(s,1H,Naph-H),7.68(d,J＝4.0Hz,1H,Pyr-H),7.67(s,1H,Naph-H),7.39(d,J＝5.5Hz,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 )δ153.48,141.93,141.02,140.83,140.75,139.51,133.62,130.60,129.77,129.76,126.88,126.72,125.47,123.99,123.14,123.06,123.02,106.16,45.81,32.74,21.56,16.90,13.28,7.08,7.08.HR-MS:m/z 428.1438[M-H] - .C 25 H 23 N 3 O 2 S(Exact Mass:429.15)。
synthetic route to compounds 21-32:
reagents and conditions (i-a) 2-nitro-3-pyridyltrifluoromethane sulfonate, triethylamine, acetonitrile, 90 ℃; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60 ℃; (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.
R is methylene, ethyl, propyl, isopropyl, tertiary butyl or cyclobutyl.
Preparation of Compound 5b
The synthesis of compound 5b was similar to that described for compound 6 a. Except that starting compound 4a was reacted with 2-nitro-3-pyridyltrifluoromethane sulfonate (1 b). Yellow solid, yield: 60.6%, melting point: 144-147 ℃. ESI-MS: M/z358.1950[ 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 TLC monitored the reaction was complete. Sodium hydroxide is added to adjust the pH to 9-10, and stirring is continued for 1 hour. Then filtered under reduced pressure, extracted with ethyl acetate and concentrated. The residue was recrystallized from EA to give compound 6c as a white solid, yield: 76.0%, melting point: 192-193 ℃. ESI-MS: m/z 328.21[ M+H ]] + .C 16 H 14 BrN 3 (Exact Mass:327.03).
Preparation of Compound 7c
The synthesis of compound 7c was similar to that described for compound 8 a. Compound 7c, yellow solid, yield: 70.9%, melting point: 246-248 ℃. ESI-MS: m/z 370.26[ M+H ]] + .C 17 H 12 BrN 3 S(Exact Mass:368.99)。
Preparation of Compounds 8c-13c
Chemical combinationThe synthesis of compounds 8c-13c was similar to that described for compounds 9a-14a. Compound 8c, white solid, yield: 84.8%, melting point: 132-135 ℃, ESI-MS: m/z 442.96[ M+H ]] + .C 20 H 16 BrN 3 O 2 S (Exact Mass: 441.01). Compound 9c, white solid, yield: 76.6%, melting point: 124-127 ℃, 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 ℃, 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: ESI-MS at 135-138℃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 ℃, 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 ℃, 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 that described for the preparation of compounds 9-14.
EXAMPLE 13 preparation of Compound 21
Recrystallisation from ethyl acetate as a yellow solid gave 80.1% yield, melting point: 71-74 ℃. Spectroscopic data for compound 21: 1 H NMR(400MHz,DMSO-d 6 )δ8.34(d,J＝4.9Hz,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 )δ169.61,156.12,155.80,143.98,132.20,132.20,131.88,131.66,130.12,129.44,128.64,128.21,127.69,124.47,122.35,118.06,117.76,45.45,35.49.HR-MS:m/z 425.9917[M-H] - .C 19 H 14 BrN 3 O 2 S(Exact Mass:427.00)。
EXAMPLE 14 preparation of Compound 22
Recrystallisation from ethyl acetate as a white solid, yield: 77.1%, melting point: 62-65 ℃. Spectroscopic data for 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 ),4.70(q,J＝7.2Hz,1H,CH),1.63(d,J＝7.2Hz,3H,CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ172.74,155.77,154.97,144.21,132.27,131.79,131.65,130.13,129.19,128.67,128.19,127.69,124.43,124.14,122.29,118.30,117.99,45.52,45.47,18.88.HR-MS:m/z 440.0074[M-H] - .C 20 H 16 BrN 3 O 2 S(Exact Mass:441.01)。
EXAMPLE 15 preparation of Compound 23
Recrystallisation from ethyl acetate to a white solid gave a yield of 84.0%, melting point: 79-82 ℃. Spectroscopic data for compound 23: 1 H NMR(400MHz,DMSO-d 6 )δ8.40(d,J＝4.8Hz,1H,Pyr-H),8.30(q,J＝3.3Hz,1H,Py r-H),8.25(q,1H,Naph-H),7.84(d,J＝8.1Hz,1H,Naph-H),7.81(t,J＝2.2Hz,1H,Naph-H),7.79(t,J＝3.7Hz,1H,Naph-H),7.74(d,J＝7.7Hz,1H,Naph-H),7.19(q,J＝4.8Hz,1H,Pyr-H),6.38(d,J＝7.8Hz,1H,Naph-H),6.02(s,2H,CH 2 ),1.72(s,6H,CH 3 ×2). 13 C NMR(100MHz,DMSO-d 6 )δ174.40,155.74,153.33,144.58,132.62,131.69,131.62,130.11,128.67,128.53,128.19,127.69,124.40,123.78,122.18,118.70,118.37,54.60,45.53,26.84,26.84.HR-MS:m/z 454.0231[M-H] - .C 21 H 18 BrN 3 O 2 S(Exact Mass:455.03)。
EXAMPLE 16 preparation of Compound 24
Recrystallisation from ethyl acetate as a white solid, yield: 83.0%, melting point: 225-228 ℃. Spectroscopic data for 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 )δ171.09,145.98,143.54,132.17,132.10,131.70,130.07,128.52,128.08,127.68,126.47,125.14,124.66,122.09,119.23,118.46,117.27,45.06,34.68,32.57.HR-MS:m/z 440.0074[M-H] - .C 20 H 16 BrN 3 O 2 S(Exact Mass:441.01)。
EXAMPLE 17 preparation of Compound 25
Recrystallisation from ethyl acetate as a yellow solid, yield: 79.0%, melting point: 60-63 ℃. Spectroscopic data for compound 25: 1 H NMR(400MHz,DMSO-d 6 )δ8.36(d,J＝4.6Hz,1H,Pyr-H),8.29(d,J＝9.7Hz,1H,Pyr-H),8.25(t,1H,Naph-H),7.84(d,J＝6.4Hz,1H,Naph-H),7.79(d,J＝6.8Hz,1H,Naph-H),7.77(d,J＝3.7Hz,1H,Naph-H),7.75(d,J＝3.7Hz,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 )δ173.25,170.98,145.70,143.60,132.16,132.04,131.70,130.07,128.52,128.10,127.68,126.42,125.13,124.64,122.11,118.58,117.37,54.41,46.01,45.06,32.69.HR-MS:m/z 454.0234[M-H] - .C 21 H 18 BrN 3 O 2 S(Exact Mass:455.03)。
EXAMPLE 18 preparation of Compound 26
Recrystallisation from ethyl acetate as a white solid, yield: 67.0%, melting point: 230-233 ℃. Spectroscopic data for compound 26: 1 H NMR(400MHz,DMSO-d 6 )δ13.67(s,1H,COOH),8.38(q,J＝3.4Hz,1H,Pyr-H),8.23(q,1H,Pyr-H),8.18(d,J＝5.0Hz,1H,Naph-H),7.80(s,1H,Naph-H),7.78(s,1H,Naph-H),7.76(d,J＝3.4Hz,1H,Naph-H),7.49(d,J＝7.9Hz,1H,Naph-H),7.11(q,J＝5.0Hz,1H,Pyr-H),6.83(d,J＝7.8Hz,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[M-H] - .C 22 H 18 BrN 3 O 2 S(Exact Mass:467.03)。
preparation of Compound 5c
The synthesis of compound 5c was similar to that described for compound 6 b. Compound 5c, yellow solid, yield: 69.8%, melting point: 116-118 ℃. ESI-MS: m/z358.19 [ M+H ]] + .C 16 H 12 BrN 3 O 2 (Exact Mass:357.01)。
Preparation of Compound 6d
Compounds of formula (I)The synthesis of 6d is similar to that described for compound 6 c. Compound 6d, white solid, yield: 73.5%, melting point: 144-147 ℃. ESI-MS: m/z 328.21[ M+H ]] + .C 16 H 14 BrN 3 (Exact Mass:327.03).
Preparation of Compound 7d
The synthesis of compound 7d was similar to that described for compound 8 a. Compound 7d, yellow solid, yield: 69.9%, melting point: 143-144 ℃. 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 of compounds 8d-13d was similar to that described for compounds 9a-14a. Compound 8d, white solid, yield: 80.7%, melting point: ESI-MS: m/z 444.03[ M+H ] at 135-138 ℃] + .C 20 H 16 BrN 3 O 2 S (Exact Mass: 441.01). Compound 9d, white solid, yield: 63.8%, melting point: 134-137 deg.C, ESI-MS: M/z458.11[ 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 ℃, 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 ℃, 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 ℃, 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 ℃, 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
Recrystallisation from ethyl acetate as a white solid, yield: 83.0%, melting point: 128-131 ℃. Spectroscopic data for 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 )δ169.49,155.37,141.84,141.80,140.66,140.14,132.12,131.86,131.66,130.11,128.65,128.22,127.70,124.45,124.34,122.35,105.83,45.32,36.44.HR-MS:m/z 425.9917[M-H] - .C 19 H 14 BrN 3 O 2 S(Exact Mass:427.00)。
EXAMPLE 20 preparation of Compound 28
Recrystallisation from ethyl acetate as a yellow solid, yield: 87.4%, melting point: 115-118 ℃. Spectroscopic data for compound 28: 1 H NMR(400MHz,DMSO-d 6 )δ8.93(s,1H,Pyr-H),8.30(s,1H,Pyr-H),8.27(d,J＝5.7Hz,1H,Naph-H),8.24(s,1H,Naph-H),7.80(d,J＝5.6Hz,1H,Naph-H),7.77(s,1H,Naph-H),7.75(s,1H,Pyr-H),7.50(d,J＝5.5Hz,1H,Naph-H),6.46(d,J＝7.7Hz,1H,Naph-H),5.98(s,2H,CH 2 ),4.67(q,J＝7.2Hz,1H,CH),1.61(d,J＝7.3Hz,3H,CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ172.69,153.83,142.02,141.60,140.65,140.41,132.13,131.79,131.66,130.12,128.69,128.22,127.71,124.42,124.08,122.35,106.04,45.44,45.38,18.81.HR-MS:m/z 440.0074[M-H] - .C 20 H 16 BrN 3 O 2 S(Exact Mass:441.01)。
EXAMPLE 21 preparation of Compound 29
Recrystallisation from ethyl acetate as a yellow solid, yield: 86.2%, melting point: 135-138 ℃. Spectroscopic data for compound 29: 1 H NMR(400MHz,DMSO-d 6 )δ8.95(s,1H,Pyr-H),8.31(t,1H,Pyr-H),8.26(s,1H,Nap h-H),8.25(s,1H,Naph-H),7.80(d,J＝3.9Hz,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＝7.8Hz,1H,Naph-H),6.01(s,2H,CH 2 ),1.70(s,6H,CH 3 ×2). 13 C NMR(100MHz,DMSO-d 6 )δ174.57,163.94,153.46,142.08,140.96,140.80,140.73,132.62,131.67,131.60,130.06,128.67,128.20,127.68,124.39,123.66,122.15,106.19,45.44,27.17,27.16.HR-MS:m/z 454.0234[M-H] - .C 21 H 18 BrN 3 O 2 S(Exact Mass:455.03)。
EXAMPLE 22 preparation of Compound 30
Recrystallisation from ethyl acetate as a yellow solid, yield: 81.1%, melting point: 78-81 ℃. Spectroscopic data for 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 ),1.61(d,J＝7.2Hz,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ172.71,153.85,142.01,141.61,140.64,140.40,132.12,131.78,131.65,130.12,128.69,128.22,127.71,124.43,124.07,122.34,106.05,45.43,45.38,18.81.HR-MS:m/z 440.0074[M-H] - .C 20 H 16 Br N 3 O 2 S(Exact Mass:441.01)。
EXAMPLE 23 preparation of Compound 31
Recrystallisation from ethyl acetate as a yellow solid, yield: 77.0%, melting point: 80-83 ℃. Spectroscopic data for compound 31: 1 H NMR(400MHz,DMSO-d 6 )δ8.52(s,1H,Pyr-H),8.38(q,J＝3.2Hz,1H,Pyr-H),8.24(d,J＝2.4Hz,1H,Naph-H),8.22(d,J＝5.5Hz,1H,Naph-H),7.79(s,1H,Naph-H),7.77(s,1H,Na ph-H),7.75(d,J＝7.9Hz,1H,Pyr-H),7.19(d,J＝5.5Hz,1H,Naph-H),6.78(d,J＝7.7Hz,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[M-H] - .C 21 H 18 BrN 3 O 2 S(Exact Mass:455.03).
EXAMPLE 24 preparation of Compound 32
Recrystallisation from ethyl acetate as a yellow solid, yield: 67.0%, melting point: 80-83 ℃. Spectroscopic data for compound 32: 1 H NMR(400MHz,DMSO-d 6 )δ8.92(s,1H,Pyr-H),8.29(q,J＝6.6,3.1Hz,1H,Pyr-H),8.26(d,J＝2.9Hz,1H,Naph-H),8.24(d,J＝4.8Hz,1H,Naph-H),7.79(d,J＝3.3Hz,1H,Naph-H),7.77(d,J＝4.0Hz,1H,Naph-H),7.75(d,J＝3.5Hz,1H,Pyr-H),7.48(d,J＝5.5Hz,1H,Nap h-H),6.45(d,J＝7.8Hz,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 )δ174.34,155.04,141.91,141.78,140.75,140.25,132.20,131.81,131.66,130.13,128.67,128.18,127.72,124.39,124.00,122.28,105.85,45.26,32.94,31.73,24.87,24.87.HR-MS:m/z 466.0235[M-H] - .C 22 H 18 BrN 3 O 2 S(Exact Mass:467.03)。
synthetic route to Compounds 33-44
Reagents and conditions (i-a) 2-nitro-3-pyridyltrifluoromethane sulfonate, palladium acetate, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, cesium carbonate, nitrogen, 1, 4-dioxane, 90 ℃; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60 ℃; (ii) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (iii) 1,1' -thiocarbonyldiimidazole, triethylamine, acetonitrile, 90 ℃; (iv) Esters, potassium carbonate, N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.
R is methylene, ethyl, propyl, isopropyl, tertiary butyl or cyclobutyl.
Preparation of Compound 2b
Palladium acetate (0.0070 g,0.032 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.036 g,0.063 mmol) were dissolved in 2mL of 1, 4-dioxane and stirred for 30 minutes. 2-nitro-3-pyridyltrifluoromethane sulfonate (1 b) (0.17 g,0.63 mmol), 4-cyclopropyl-1-naphthylamine (1 d) (0.13 g,0.76 mmol) and cesium carbonate (0.41 g,1.26 mmol) were dissolved in 10mL of 1, 4-dioxane. The two solutions were mixed and refluxed for 12 hours at 90 ℃ under nitrogen atmosphere. After the reaction was completed by TLC and cooled to room temperature, 30mL of methylene chloride and a saturated aqueous solution of sodium chloride (3X 10 mL) were added and extracted. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The product was purified by flash column chromatography to give compound 2b. Yellow solid, yield: 69.5%, melting point: 76-79 ℃. 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 of compound 3b was similar to that of compound 7a, except that the starting material was compound 2b. Compound 3b, pale yellow solid, yield: 73.0%, melting point: 143-146 ℃. 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' -Carbonyldiimidazole (CDI) (0.94 g,5.80 mmol) and triethylamine (0.4 mL) were dissolved in 30mL acetonitrile. The solution was refluxed at 90 ℃ for 10 hours, then cooled to room temperature and the solvent evaporated under reduced pressure. The organic layer was separated by washing with 30mL of methylene chloride and saturated aqueous sodium chloride (3X 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave compound 4b. White solid, yield: 57.2%, melting point: 149-150 ℃. 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 of compounds 5e-10e was similar to that described for compounds 9a-14a. Compound 5e, white solid, yield: 87.5%, melting point: 184-185 ℃, 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 ℃, 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 ℃, 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 ℃, 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 ℃, 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 ℃, 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 that described for the preparation of compounds 9-14.
EXAMPLE 25 preparation of Compound 33
Recrystallisation from ethyl acetate as a white solid, yield: 77.8%, melting point: 190-193 ℃. Spectroscopic data for compound 33: 1 H NMR(400MHz,DMSO-d 6 )δ8.56(t,J＝8.4Hz,1H,Pyr-H),8.05(t,J＝5.1Hz,1H,Naph-H),7.70(t,1H,Naph-H),7.59(d,J＝7.6Hz,1H,Pyr-H),7.54(d,J＝6.5Hz,1H,Naph-H),7.52(s,1H,Naph-H),7.43(d,J＝7.6Hz,1H,Naph-H),7.00(q,1H,Pyr-H),6.93(t,J＝8.5Hz,1H,Naph-H),4.65–4.56(m,2H,CH 2 ),2.57–2.51(m,1H,CH),1.14(d,J＝8.4Hz,2H,CH 2 ),0.90–0.75(m,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ169.73,153.33,143.85,141.52,141.15,134.37,130.01,128.47,127.51,127.22,126.97,126.46,125.66,125.45,123.52,118.05,114.96,42.28,13.40,7.60,7.32.HR-MS:m/z 358.1197[M-H] - .C 21 H 17 N 3 O 3 (Exact Mass:359.13)。
EXAMPLE 26 preparation of Compound 34
Recrystallisation from ethyl acetate as a red solid, yield: 60.0%, melting point: 100-103 ℃. Spectroscopic data for compound 34: 1 H NMR(400MHz,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[M-H] - .C 22 H 19 N 3 O 3 (Exact Mass:373.14)。
EXAMPLE 27 preparation of Compound 35
Recrystallisation from ethyl acetate as a yellow solid, yield: 78.8%, melting point: 180-183 ℃. Spectroscopic data for compound 35: 1 H NMR(400MHz,DMSO-d 6 )δ8.55(d,J＝8.6Hz,1H,Pyr-H),7.99(d,J＝3.9Hz,1H,Naph-H),7.69(d,J＝7.7Hz,1H,Naph-H),7.57(s,1H,Pyr-H),7.54(d,J＝6.7Hz,1H,Naph-H),7.49(d,J＝8.3Hz,1H,Naph-H),7.41(d,J＝7.6Hz,1H,Naph-H),6.92(q,J＝5.0Hz,1H,Pyr-H),6.79(d,J＝9.1Hz,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[M-H] - .C 23 H 21 N 3 O 3 (Exact Mass:387.16)。
EXAMPLE 28 preparation of Compound 36
Recrystallisation from ethyl acetate as a yellow solid gave a yield of 57.2%, melting point: 68-71 ℃. Spectroscopic data for compound 36: 1 H NMR(400MHz,DMSO-d 6 )δ8.55(d,J＝8.4Hz,1H,Pyr-H),8.08(t,J＝5.0Hz,1H,Naph-H),7.69(t,1H,Naph-H),7.57(t,1H,Pyr-H),7.55(d,J＝4.2Hz,1H,Naph-H),7.53(s,1H,Naph-H),7.42(d,J＝7.6Hz,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 )δ172.91,153.78,152.91,144.32,143.65,141.45,141.09,134.31,130.08,128.52,127.49,127.20,127.01,125.41,123.49,117.87,114.94,36.55,33.05,13.39,7.59,7.33.HR-MS:m/z 372.1354[M-H] - .C 22 H 19 N 3 O 3 (Exact Mass:373.14)。
EXAMPLE 29 preparation of Compound 37
Recrystallisation from ethyl acetate as a yellow solid, yield: 65.5%, melting point: 58-61 ℃. Spectroscopic data for compound 37: 1 H NMR(400MHz,DMSO-d 6 )δ8.56(d,J＝8.6Hz,1H,Pyr-H),8.07(d,J＝5.0Hz,1H,Na ph-H),7.72–7.69(m,1H,Naph-H),7.60(d,J＝7.6Hz,1H,Pyr-H),7.55(s,1H,Naph-H),7.54(s,1H,Naph-H),7.42(d,J＝7.6Hz,1H,Naph-H),6.99(q,J＝5.3Hz,1H,Pyr-H),6.88(d,J＝7.8Hz,1H,Naph-H),4.05(t,J＝6.9Hz,2H,CH 2 ),3.37(s,1H,CH),2.39(t,J＝7.3Hz,2H,CH 2 ),2.07(t,J＝7.0Hz,2H,CH 2 ),1.14(q,2H,CH 2 ),0.89–0.78(m,2H,CH 2 ). 13 C NMR(100MHz,DMS O-d 6 )δ174.37,153.19,143.88,141.41,141.06,134.30,130.10,129.00,128.59,127.50,127.17,127.08,126.43,125.41,123.57,123.50,117.80,114.90,31.50,23.82,13.40,7.59,7.32.HR-MS:m/z386.1509[M-H] - .C 23 H 21 N 3 O 3 (Exact Mass:387.16)。
EXAMPLE 30 preparation of Compound 38
Recrystallisation from ethyl acetate as a white solid, yield: 46.0%, melting point: 180-183 ℃. Spectroscopic data for Compound 38： 1 H NMR(400MHz,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 )δ153.82,144.38,141.26,141.09,134.31,130.12,129.88,129.01,128.64,127.75,127.46,127.13,127.03,126.48,125.42,123.50,123.00,117.47,114.61,13.38,7.60,7.60,7.28,7.28.HR-MS:m/z398.1514[M-H] - .C 23 H 21 N 3 O 3 (Exact Mass:399.16)。
Preparation of Compound 2c
The synthesis of compound 2c was similar to that of compound 6b, except that the starting material was compound 1d. Compound 2c, yellow solid, yield: 56.6%, melting point: 116-118 ℃. 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 of compound 3c was similar to that of compound 7a, except that the starting material was compound 2c. Compound 3c, yellow solid, yield: 76.2%, melting point: 192-193 ℃. ESI-MS: m/z 276.4[ M+H ]] + .C 18 H 17 N 3 (Exact Mass:275.14)。
Preparation of Compound 4c
The synthesis of compound 4c was similar to that of compound 4b, a white solid, yield: 60.9%, melting point: 159-161 ℃. 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 of compounds 5f-10f was similar to that described for compounds 9a-14a. Compound 5f, white solid, yield: 82.2%, melting point:123-125 ℃, melting Point, 123-125%℃.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 deg.C, ESI-MS: m/z 388.3[ M+H ]] + .C 23 H 21 N 3 O 3 (Exact Mass: 387.16). Compound 7f, pale yellow oil, yield: 88.2%, melting point: 142-145 ℃, ESI-MS: m/z 402.6[ M+H ]] + .C 24 H 23 N 3 O 3 (Exact Mass: 401.17). Compound 8f, pale yellow oil, yield: 70.0%, melting point: 151-154 ℃, 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 ℃, 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 ℃, 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
Recrystallisation from ethyl acetate as a yellow solid, yield: 72.5%, melting point: 120-123 ℃. Spectroscopic data for 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,Naph-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[M-H] - .C 21 H 17 N 3 O 3 (Exact Mass:359.13)。
EXAMPLE 32 preparation of Compound 40
Recrystallisation from ethyl acetate as a yellow solid, yield: 76.9%, melting point: 245-248 ℃. Spectroscopic data for compound 40: 1 H NMR(400MHz,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),7.45(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＝8.8Hz,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[M-H] - .C 22 H 19 N 3 O 3 (Exact Mass:373.14)。
EXAMPLE 33 preparation of Compound 41
Recrystallisation from ethyl acetate as a yellow solid produced 92.0% yield, melting point: 110-113 ℃. Spectroscopic data for compound 41: 1 H NMR(400MHz,DMSO-d 6 )δ11.57(s,1H,COOH),8.56(d,J＝8.4Hz,1H,Pyr-H),8.37(d,1H,Pyr-H),8.10(t,J＝5.3Hz,1H,Naph-H),7.69(t,J＝7.1Hz,1H,Naph-H),7.57(s,1H,Na ph-H),7.54(d,J＝7.9Hz,1H,Naph-H),7.45(d,J＝8.2Hz,1H,Pyr-H),7.42(d,J＝7.6Hz,1H,CH,Naph-H),6.55(d,J＝5.3Hz,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 )δ154.02,142.95,141.49,138.15,134.29,130.25,129.97,128.47,127.54,127.19,126.99,126.82,125.46,125.37,123.49,123.39,123.31,104.21,13.39,7.62,7.62,7.31,7.31.HR-MS:m/z 386.1507[M-H] - .C 23 H 21 N 3 O 3 (Exact Mass:387.16)。
EXAMPLE 34 preparation of Compound 42
Recrystallisation from ethyl acetate to a white solid gave 88.4% yield, melting point: 105-108 ℃. Spectroscopic data for compound 42: 1 H NMR(400MHz,DMSO-d 6 )δ8.64(s,1H,Pyr-H),8.56(d,J＝8.4Hz,1H,Pyr-H),8.14(d,J＝5.3Hz,1H,Naph-H),7.69(t,J＝7.2Hz,1H,Naph-H),7.57(d,J＝7.7Hz,1H,Naph-H),7.54(d,J＝7.0Hz,1H,Naph-H),7.45(d,J＝8.3Hz,1H,Pyr-H),7.43(d,J＝7.6Hz,1H,Naph-H),6.59(d,J＝5.3Hz,1H,Naph-H),4.24(t,J＝7.0Hz,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 )δ172.88,153.06,143.22,141.69,136.93,134.30,130.13,129.91,128.37,127.58,127.25,127.25,126.99,125.46,123.47,123.37,104.16,37.93,33.04,13.40,7.61,7.36.HR-MS:m/z 372.1354[M-H] - .C 22 H 19 N 3 O 3 (Exact Mass:373.14)。
EXAMPLE 35 preparation of Compound 43
Recrystallisation from ethyl acetate as a yellow solid gave 66.1% yield, melting point: 150-153 ℃. Spectroscopic data for compound 43: 1 H NMR(400MHz,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 ),2.54(t,J＝5.3Hz,1H,CH),2.41(t,J＝7.3Hz,2H,CH 2 ),2.03(t,2H,CH 2 ),1.14(d,J＝8.4Hz,2H,CH 2 ),0.88–0.79(m,2H,CH 2 ). 13 C NMR(100MHz,DMSO-d 6 )δ174.39,153.22,143.28,141.64,136.97,134.28,129.94,129.63,128.45,127.59,127.46,127.22,127.04,125.46,123.48,123.37,104.22,31.22,23.77,13.40,7.62,7.62,7.35.HR-MS:m/z 386.1507[M-H] - .C 23 H 21 N 3 O 3 (Exact Mass:387.16)。
EXAMPLE 36 preparation of Compound 44
Recrystallisation from ethyl acetate as a yellow solid produced 77.0% yield, melting point: 70-73 ℃. Spectroscopic data for compound 44: 1 H NMR(400MHz,DMSO-d 6 )δ11.54(d,1H,COOH),8.56(d,J＝8.6Hz,1H,Pyr-H),8.37(s,1H,Pyr-H),8.10(d,J＝5.3Hz,1H,Naph-H),7.70(d,J＝8.3Hz,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＝4.0Hz,1H,Naph-H),6.56(t,J＝5.4Hz,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 )δ154.00,142.82,141.52,138.28,134.29,130.04,129.95,128.43,127.55,127.19,127.09,127.00,126.83,125.46,123.49,123.39,123.31,104.24,37.24,34.68,13.40,7.63,7.62,7.31.HR-MS:m/z 398.1509[M-H] - .C 24 H 21 N 3 O 3 (Exact Mass:399.16)。
EXAMPLE 17 in vivo uric acid lowering Activity assay of target Compounds
Test materials and methods:
(1) Experimental animals: male Kunming mice, supplied by the Shandong university laboratory animal center.
(2) Sample treatment: the test compounds were formulated with DMSO and CMC-Na at appropriate concentrations immediately prior to use.
(3) And (3) molding medicine: hypoxanthine and potassium oxazinate.
(4) Positive control drug: lesinurad.
(5) The testing method comprises the following steps: each group of gastric hypoxanthine is 0.2mL, potassium oxazinate is 0.2mL is subcutaneously injected, gastric lavage medicine is 0.2mL and begins timing, eyeballs are taken out for blood after 4 hours of administration, blood coagulation is carried out for 30 minutes, and supernatant serum is taken out. Uric acid concentration in serum was measured with a uric acid meter.
TABLE 2 Structure of Compounds 9 to 32 and uric acid-lowering Activity
TABLE 3 Structure of Compounds 33 to 44 and uric acid-lowering Activity
Conclusion: as can be seen from tables 2 and 3, 29 compounds exhibit uric acid lowering activity, which is superior or equivalent to that of the positive control drug Lesinurad, wherein the compounds 13, 23, 33, 35, 36, 38 and 39 are represented, and in vivo activity tests of animals, the decrease rate of haematuric acid exceeds 80%, and the compounds exhibit excellent uric acid lowering activity and can be used as uric acid lowering candidate 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.
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