One or more embodiments of the present disclosure will now be described in detail with reference to the following examples. However, these examples are for illustrative purposes only and are not intended to limit the scope of the one or more embodiments of the present disclosure.
Example 1: Synthesis of N-(1-azoniabicyclo[2.2.2]octan-3-yl)-6-oxo-1-phenyl-3-pyridinecarboxamide
Example 1-1: Synthesis of dimethyl 4-(methoxymethylene)-2-pentanedioate
52 mL (0.73 mmol) of acetyl chloride was slowly dropwise added into a mixed solution of 500 mL of methanol and 50 g (0.36 mol) of coumalic acid at about 0℃ for about 10 minutes while stirring. The resulting reaction solution was stirred under reflux for about 10 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. The residue was extracted three times with water and ethyl acetate, and an organic solvent phase was purified at a reduced pressure using column chromatography (hexane:ethyl acetate=1:5), thereby obtaining a target compound (Actual yield: 38 g, Percent yield: 53 %).
(Major/minor ratio = 5.8:1)
1H-NMR(CDCl3,200MHz,major)δ7.64(s,1H),7.58(d,1H),6.62(d,1H),4.02(s,3H),3.73(m,6H)
1H-NMR(CDCl3,200MHz,minor)δ8.87(s,1H),8.31(d,1H),6.34(d,1H),3.89(s,3H),3.73(m,6H)
Example 1-2: Synthesis of methyl 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylate
After 1.06 g (5.2 mmol) of dimethyl 4-(methoxymethylene)-2-pentanedioate was dissolved in 10 mL of DMF, 510 mg (5.5 mmol) of aniline was added to the solution. Afterward, the resulting reaction solution was stirred under reflux at about 150℃ for 10 hours. After termination of the reaction was determined by liquid chromatography, the reaction solution was diluted with ethyl acetate and was then washed using brine, followed by drying using magnesium sulfate, and filtration. After distillation under reduced pressure, the resulting product was purified using column chromatography (hexane:ethyl acetate=1:2) to obtain a target compound (Actual yield: 750 mg, Yield ratio: 63%).
1H-NMR(CDCl3,200MHz)δ8.25(s,1H),7.93(d,1H),7.50(m,3H),7.39(m,2H),6.64(d,1H),3.87(s,3H)
Example 1-3: Synthesis of 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylic acid
After 750 mg (3.27 mmol) of methyl 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylate was dissolved in 9 mL of methanol and 3 mL of water, 235 mg (9.81 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50℃ for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by addition of aqueous HCl to titrate a pH of the reaction product to pH 2. After filtration of the resulting solid compound (Actual yield: 470 mg, Percent yield: 67 %), the resulting compound was used without purification.
1H-NMR(DMSO-d6,200MHz)δ8.18(s,1H),7.88(d,1H),7.49(m,5H),6.54(d,2H)
Example 1-4: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-phenyl-3-pyridinecarboxamide
N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-phenyl-3-pyridinecarboxamide was synthesized using one of the following methods.
Method 1: After 300 mg (1.39 mmol) of 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylic acid was dissolved in 10 mL of tetrahydrofuran and 1 mL of DMF, 415 mg (2.08 mmol) of 3-aminoquinuclidine dihydrochloride and 538 mg (4.17 mmol) of diethylisopropylamide were added to the solution. After the reaction solution was stirred at room temperature for about 30 minutes, 635 mg (1.67 mmol) of O-(benzotriazole-1-yl)-N,N,N’,N’-tetramethyluroniumhexafluorophosphate(HATU)wasaddedtothereactionsolution,whichwasthenstirredatroomtemperatureforabout24hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by extraction three times with chloroform and an aqueous NaOH solution (pH 12) and purification using liquid chromatography (chloroform:methanol:ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 281 mg, Percent yield: 63%).
Method 2: After dissolution of 300 mg (1.39 mmol) of 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylic acid in 10 mL of dichloromethane, 530 mg (4.17 mmol) of oxalyl chloride was added to the solution, and a catalytic amount of DMF was then added thereto. After being stirred at room temperature for about 2 hours, the solvent was removed in vacuo. After addition of 415 mg (2.08 mmol) of quinuclidine dihydrochloride to 10 mL of acetonitrile, 898 mg (6.95 mmol) of diethylisopropylamide was added to the solution. This reaction solution was stirred at room temperature for about 24 hours. After addition of the reaction mixture distilled under reduced pressure to acetonitrile, the 3-aminoquinuclidine dihydrochloride reaction solution was slowly added thereto, followed by stirring at room temperature for about 15 hours and the solvent was removed in vacuo. The resulting compound was extracted three times with chloroform and an aqueous NaOH solution (pH=12), and was then purified using liquid chromatography (chloroform: methanol: ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 360 mg, Percent yield: 80 %).
Method 3: After 300 mg (1.39 mmol) of 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylic acid was dissolved in 10 mL of acetonitrile, 415 mg (2.08 mmol) of 3-aminoquinuclidine dihydrochloride and 718 mg (5.56 mmol) of diethylisopropylamide were added to the solution. Afterward, 207 mg (1.53 mmol) of 1-hydroxylbenzotriazole (HOBt) and 266 mg (1.39 mmol) of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC) were added to the reaction solution. This reaction solution was stirred at room temperature for about 24 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and then extracted three times with chloroform and an aqueous NaOH solution (pH=12), followed by purification using liquid chromatography (chloroform: methanol: ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 317 mg, Percent yield: 70%).
1H-NMR(CDCl3,200MHz)δ8.11(s,1H),7.75(d,1H),7.40(m,4H),6.65(d,1H),6.26(br,1H),4.15(m,1H),3.39(m,1H),2,89(m,4H),2,53(m,1H),2.06(m,1H),1.53(m,4H)
Example 2: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-chlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-chloroaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ7.97(s,1H),7.84(d,1H),7.42(m,4H),7.14(br,d,1H),6.54(d,1H),4.06(m,1H),3.25(m,1H),2,77(m,4H),2.56(m,1H),1.92(m,1H),1.65(m,3H),1.45(m,1H)
Example 3: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-chlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 3-chloroaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.11(s,1H),7.83(d,1H),7.29(m,4H),6.94(br,d,1H),6.56(d,1H),4.09(m,1H),3.32(m,1H),2,77(m,5H),2.01(m,1H),1.72(m,3H),1.59(m,1H)
Example 4: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-chlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-chloroaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.20(s,1H),7.84(d,1H),7.42(d,2H),7.25(d,2H),7.04(br,d,1H),6.50(d,1H),4.13(m,1H),3.23(m,1H),2,59(m,5H),2.01(m,1H),1.67(m,3H),1.40(m,1H)
Example 5: Synthesis of N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(4-chlorophenyl)-6-oxopyridine-3-carboxamide
6-Oxo-1-(4-chlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 4-chloroaniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(4-chlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3R-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 2.
1H-NMR(CDCl3,200MHz)δ8.20(s,1H),7.84(d,1H),7.42(d,2H),7.25(d,2H),7.04(br,d,1H),6.50(d,1H),4.13(m,1H),3.23(m,1H),2,59(m,5H),2.01(m,1H),1.67(m,3H),1.40(m,1H)
Example 6: Synthesis of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(4-chlorophenyl)-6-oxopyridine-3-carboxamide
6-Oxo-1-(4-chlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 4-chloroaniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(4-chlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3S-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 2.
1H-NMR(CDCl3,200MHz)δ8.20(s,1H),7.84(d,1H),7.42(d,2H),7.25(d,2H),7.04(br,d,1H),6.50(d,1H),4.13(m,1H),3.23(m,1H),2,59(m,5H),2.01(m,1H),1.67(m,3H),1.40(m,1H)
Example 7: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-fluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-fluoroaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.11(s,1H),7.74(d,1H),7.31(m,4H),6.50(d,1H),6.35(br,d,1H),4.11(m,1H),3.38(m,1H),2,86(m,4H),2.61(m,1H),2.03(m,1H),1.74(m,3H),1.55(m,1H)
Example 8: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-fluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-fluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.01(m,1H),7.72(m,1H),7.43(m,1H),7.32(m,3H),6.64(d,1H),6.12(br,1H),4.03(m,1H),3.40(m,1H),2.81(m,4H),2.59(m,1H),2.02(m,1H),1.83(m,3H),1.58(m,1H)
Example 9: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-fluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3-fluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.08(s,1H),7.69(d,1H),7.51(m,1H),7.15(m,3H),6.67(d,1H),6.17(br,1H),4.15(m,1H),3.44(m,1H),2.95(m,4H),2.67(d,1H),2.05(m,1H),1.68(m,3H),1.43(m,1H)
Example 10: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-bromophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-bromoaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.08(s,1H),7.75(d,1H),7.60(d,2H),7.21(d,2H),6.71(br,d,1H),6.55(d,1H),4.09(m,1H),3.32(m,1H),2,80(m,4H),2.55(m,1H),1.97(m,1H),1.69(m,3H),1.50(m,1H)
Example 11: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.98(s,1H),7.86(d,1H),7.27(m,2H), 7.21 (m, 1H), 7.14 (m, 1H), 7.02 (br,d, 1H), 6.45 (d, 1H), 3.95 (m, 1H), 3.17 (m, 1H), 2,74 (m, 4H), 2.49 (m, 1H), 2.17 (s, 3H), 1.84 (m, 1H), 1.58 (m, 3H), 1.29 (m, 1H)
Example 12: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-methylaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.11(s,1H),7.77(d,1H),7.27(m,4H),6.65(br,d,1H),6.57(d,1H),4.09(m,1H),3.34(m,1H),2,89(m,5H),2.48(s,3H),2.01(m,1H),1.72(m,3H),1.52(m,1H)
Example 13: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.07(s,1H),7.78(d,1H),7.39(m,1H),7.25(m,1H),7.15(m,2H),6.62(d,1H),6.37(br,1H),4.08(m,1H),3.40(m,1H),2.83(m,4H),2.59(m,1H),2.40(s,3H),2.20(m,1H),1.63(m,3H),1.42(m,1H)
Example 14: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-ethylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-ethylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.08(s,1H),7.69(m,1H),7.27(m,4H),6.64(m,1H),6.04(br,1H),4.12(m,1H),3.44(m,1H),2.87(m,4H),2.71(m,2H),2.60(m,1H),2.05(m,1H),1.70(m,3H),1.53(m,1H),1.28(t,3H)
Example 15: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(4-propylphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-propylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.08(s,1H),7,67(d,1H),7.31(m,4H),6.65(d,1H),5.95(br,1H),4.10(m,1H),3.46(m,1H),2.86(m,4H),2.65(m,2H),2.52(m,1H), 2.01 (m, 1H), 1.72 (m, 5H), 1.55 (m, 1H), 1.02 (t, 3H)
Example 16: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-propan-2-ylphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-isopropylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(s,1H),7.85(d,1H),7.46(m,2H), 7.29 (m, 1H), 7.08 (m, 1H), 6.87 (br,d, 1H), 6.54 (d, 1H), 4.06 (m, 1H), 3.39 (m, 1H), 2,80 (m, 4H), 2.67 (m, 1H), 2.56 (m, 1H), 1.94 (m, 1H), 1.67 (m, 3H), 1.41 (m, 1H), 1.17 (d, 6H)
Example 17: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(4-propan-2-ylphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-isopropylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.08(s,1H),7.68(m,1H),7.37(m,2H),7.30(m,2H),6.66(m,1H),5.99(br,1H),4.10(m,1H),3.42(m,1H),2.99(m,1H),2.89(m,3H),2.55(m,1H),2.00(m,1H),1.72(m,3H),1.53(m,1H),1.28(m,6H)
Example 18: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-cyclohexylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-cyclohexylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.07(s,1H),7.68(d,1H),7.34(d,2H),7.30(d,2H),6.65(d,1H),6.01(br,1H),4.12(m,1H),3.43(m,1H),2.87(m,4H),2.58(m,2H),2.02(m,1H),1.90(m,4H),1.79(m,1H),1.73(m,3H),1.54(m,1H),1.47(m,4H),1.28(m,1H)
Example 19: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.09(s,1H),7.75(d,1H),7.25(d,2H),6.95(d,2H),6.73(br,d,1H),6.53(d,1H),4.05(m,1H),3.83(s,3H),3.30(m,1H),2,61(m,5H),1.95(m,1H),1.70(m,3H),1.46(m,1H)
Example 20: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-methoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.98(s,1H),7.78(d,1H),7.48(t,1H),7.24(s,1H),7.13(t,2H),6.72(d,1H),6.12(br,1H),4.11(m,1H),3.87(s,3H),3.78(m,1H),2.85(m,4H),2.53(m,1H),2.05(m,1H),1.82(m,3H),1.52(m,1H)
Example 21: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-methoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.83(d,1H),7.34(m,2H),7.21(d,1H),6.96(d,1H),6.81(d,2H),6.48(d,1H),4.12(m,1H),3.67(s,3H),3.25(m,1H),2.71(m,4H),2.57(m,1H),1.94(m,1H),1.66(m,3H),1.43(m,1H)
Example 22: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[4-(trifluoromethyl)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-trifluoromethylaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.09(s,1H),7.83(d,1H),7.79(d,2H),7.66(d,2H),6.67(br,d,1H),6.64(d,1H),4.12(m,1H),3.34(m,1H),2,84(m,4H),2.52(m,1H),2.03(m,1H),1.74(m,3H),1.51(m,1H)
Example 23: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-trifluoromethoxyaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.09(s,1H),7.73(d,1H),7.40(m,4H),6.65(d,1H),6.25(br,d,1H),4.11(m,1H),3.41(m,1H),2,87(m,4H),2.58(m,1H),2.03(m,1H),1.73(m,3H),1.57(m,1H)
Example 24: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[2-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-trifluoromethoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.99(s,1H),7.72(m,1H),7.58(m,1H),7.44(m,3H),6.67(m,1H),6.09(br,1H),4.13(m,1H),3.43(m,1H),2.92(m,4H),2.62(m,1H),2.03(m,1H),1.73(m,3H),1.64(m,1H)
Example 25: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4-dichlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2,4-dichloroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.96(s,1H),7.87(d,1H),7.54(s,1H),7.36(d,1H),7.22(d,1H),7.02(br,d,1H),6.49(d,1H),4.01(m,1H),3.23(m,1H),2,77(m,4H),2.54(m,1H),1.89(m,1H),1.63(m,3H),1.37(m,1H)
Example 26: Synthesis of N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4-dichlorophenyl)-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(2,4-dichlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 2,4-dichloroaniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(2,4-dichlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3R-quinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 2.
1H-NMR(CDCl3,500MHz)δ7.96(s,1H),7.87(d,1H),7.54(s,1H),7.36(d,1H),7.22(d,1H),7.02(br,d,1H),6.49(d,1H),4.01(m,1H),3.23(m,1H),2,77(m,4H),2.54(m,1H),1.89(m,1H),1.63(m,3H),1.37(m,1H)
Example 27: Synthesis of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4-dichlorophenyl)-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(2,4-dichlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 2,4-dichloroaniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(2,4-dichlorophenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3S-quinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 2.
1H-NMR(CDCl3,500MHz)δ7.96(s,1H),7.87(d,1H),7.54(s,1H),7.36(d,1H),7.22(d,1H),7.02(br,d,1H),6.49(d,1H),4.01(m,1H),3.23(m,1H),2,77(m,4H),2.54(m,1H),1.89(m,1H),1.63(m,3H),1.37(m,1H)
Example 28: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-chloro-4-methoxyphenyl)-6-oxo-3- pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 3-chloro-4-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.07(s,1H),7.70(d,1H),7.41(m,1H),7.26(m,1H),7.03(d,1H),6.64(d,1H),6.23(br,d,1H),4.05(m,1H),3.97(s,3H),3.42(m,1H),2,87(m,4H),2.59(m,1H),2.04(m,1H),1.80(m,3H),1.56(m,1H)
Example 29: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-chloro-4-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-chloro-4-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.97(s,1H),7.87(d,1H),7.27(s,1H),7.20(m,2H),7.00(br,d,1H),6.45(d,1H),3.98(m,1H),3.18(m,1H),2,72(m,4H),2.53(m,1H),2.03(s,3H),1.86(m,1H),1.60(m,3H),1.35(m,1H)
Example 30: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,5-difluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2,5-difluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(m,1H),7.75(d,1H),7.17(m,3H),6.65(d,1H),6.25(br,1H),4.11(m,1H),3.41(m,1H),2.85(m,4H),2.66(m,1H),2.04(m,1H),1.84(m,3H),1.63(m,1H)
Example 31: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3,5-dichlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3,5-dichloroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.03(s,1H),7.70(d,1H),7.47(s,1H),7.32(s,2H),6.71(d,1H),6.07(br,1H),4.10(m,1H),3.43(m,1H),2.85(m,4H),2.56(m,1H),2.02(m,1H),1.71(m,3H),1.46(m,1H)
Example 32: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4-dimethylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2,4-dimethylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.96(s,1H),7.81(d,1H),7.18(m,3H),6.63(d,1H),6.10(br,1H),4.13(m,1H),3.47(m,1H),3.05(m,1H),2.95(m,4H),2.38(s,3H),2.12(s,3H),1.97(m,1H),1.51(m,3H),1.40(m,1H)
Example 33: N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-chloro-4-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-chloro-4-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(d,1H),7.91(m,1H),7.37(s,1H),7.18(m,2H),7.02(br,1H),6.64(m,1H),4.21(m,1H),3.23(m,1H),2.95(m,5H),2.40(s,3H),2.12(m,1H),1.85(m,3H),1.49(m,1H)
Example 34: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4-difluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2,4-difluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.03(s,1H),7.76(m,1H),7.34(m,1H),7.05(m,2H),6.65(d,1H),6.51(br,1H),4.12(m,1H),3.49(m,1H),3.22(m,1H),2.83(m,4H),2.02(m,1H),1.78(m,3H),1.62(m,1H)
Example 35: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-chloro-5-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 1-chloro-5-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.95(m,1H),7.79(d,1H),7.43(d,1H),7.22(s,1H),7.16(s,1H),6.67(d,1H),6.32(br,1H),4.15(m,1H),3.41(m,1H),2.85(m,4H),2.73(d,1H),2.37(s,3H),2.05(m,1H),1.72(m,3H),1.48(m,1H)
Example 36: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-tert-butyl-2-chlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-tert-butyl-2-chloroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.94(m,1H),7.82(d,1H),7.54(d,1H),7.33(d,1H),7.23(t,1H),6.61(d,1H),6.57(br,1H),4.07(m,1H),3.29(m,1H),2.84(m,4H),2.60(m,1H),1.87(m,1H),1.68(m,3H),1.40(m,1H),1.34(s,9H)
Example 37: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-chloro-4-fluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-chloro-4-fluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.09(s,1H),7.91(d,1H),7.73(m,2H),7.33(m,1H),6.67(d,1H),6.11(br,1H),4.10(m,1H),3.39(m,1H),2.81(m,4H),2.56(m,1H),1.72(m,4H),1.49(m,1H)
Example 38: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-chloro-2-fluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-2-fluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.98(s,1H),7.72(d,1H),7.31(m,3H),6.62(d,1H),6.14(br,1H),4.09(m,1H),3.47(m,1H),3.36(m,1H),2.86(m,3H),2.56(m,1H),2.07(s,1H),1.72(m,3H),1.53(m,1H)
Example 39: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3,4-dimethoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3,4-dimethoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.10(s,1H),7.73(d,1H),6.91(m,3H),6.57(d,1H),6.33(br,1H),4.10(d,1H),3.95(m,3H),3.91(m,3H),3.37(m,1H),2.81(m,4H),2.55(m,1H),2.04(m,1H),1.68(m,3H),1.49(m,1H)
Example 40: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3,4-dichlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3,4-dichloroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.07(s,1H),7.74(d,1H),7.55(m,2H),7.23(m,1H),6.59(m,1H),6.42(br,1H),4.12(m,1H),3.38(m,1H),2.83(m,4H),2.63(m,1H),2.03(m,1H),1.73(m,2H),1.49(m,1H)
Example 41: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3,4-difluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3,4-difluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.08(s,1H),7.72(d,1H),7.32(m,2H),7.16(m,1H),6.65(d,1H),6.29(br,1H),4.10(m,1H),3.40(m,1H),2.87(m,4H),2.53(m,1H),1.98(m,1H),1.67(m,3H),1.48(m,1H)
Example 42: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-chloro-3-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-3-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(s,1H),7.62(d,1H),7.42(d,1H),7.28(s,1H),7.18(m,1H),6.63(d,1H),6.01(br,1H),4.06(m,1H),3.42(m,1H),2.80(m,4H),2.59(m,1H),2.42(s,3H),1.97(m,1H),1.63(m,3H),1.48(m,1H)
Example 43: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3,5-difluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3,5-difluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.45(m,1H),8.42(s,1H),8.15(m,1H),7.10(m,2H),6.86(m,1H),6.59(d,1H),4.57(m,1H),4.17(m,1H),3.99(m,1H),3.52(m,1H),3.29(m,2H),3.11(m,1H),2.50(m,1H),2.48(m,1H),2.08(m,2H),1.83(m,1H)
Example 44: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-fluoro-2-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-fluoro-2-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.94(s,1H),7.71(d,1H),7.16(m,1H),7.05(m,2H),6.65(d,1H),6.05(br,1H),4.09(m,1H),3.42(m,1H),2.88(m,4H),2.56(m,1H),2.14(s,3H),1.67(m,4H),1.52(m,1H)
Example 45: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,5-dimethoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2,5-dimethoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.06(s,1H),7.74(d,1H),6.57(d,1H),6.52(d,1H),6.50(m,2H),4.08(m,1H),3.79(s,6H),3.37(m,1H),2.95(m,4H),2.60(m,1H),1.98(m,1H),1.66(m,3H),1.48(m,1H)
Example 46: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,3-dichlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2,3-dichloroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.99(s,1H),7.80(d,1H),7.61(d,1H),7.38(m,2H),6.63(d,1H),6.29(br,1H),4.08(m,1H),3.42(m,1H),2.85(m,5H),2.08(m,1H),1.82(m,3H),1.59(m,1H)
Example 47: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-chloro-2-methoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3-chloro-2-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.97(s,1H),7.81(d,1H),7.52(d,1H),7.21(m,2H),6.72(d,1H),6.21(br,1H),4.14(m,1H),3.84(s,3H),3.41(m,1H),2.98(m,4H),2.68(m,1H),2.03(s,1H),1.68(m,3H),1.45(m,1H)
Example 48: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-fluoro-4-methoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3-fluoro-4-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.09(s,1H),7.69(d,1H),7.03(m,3H),6.60(d,1H),6.21(br,1H),4.09(m,1H),3.92(s,3H),3.40(m,1H),2.94(m,4H),2.60(m,1H),2.01(m,1H),1.85(m,3H),1.49(m,1H)
Example 49: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4-dimethoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2,4-dimethoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.95(s,1H),7.72(d,1H),7.18(m,1H),6.61(m,3H),6.17(br,1H),4.12(m,1H),3.85(s,3H),3.79(s,3H),3.42(m,1H),2.92(m,4H),2.60(m,1H),1.90(m,1H),1.73(m,3H),1.41(m,1H)
Example 50: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-chloro-4-fluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3-chloro-4-fluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(s,1H),7.68(d,1H),7.51(d,1H),7.37(m,2H),6.63(d,1H),6.02(br,1H),4.05(m,1H),3.42(m,1H),2.85(m,4H),2.58(m,1H),2.02(m,1H),1.72(m,3H),1.56(m,1H)
Example 51: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-chloro-3-methoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-3-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.03(s,1H),7.77(d,1H),7.62(d,1H),6.97(m,2H),6.60(d,1H),6.42(br,1H),4.18(m,1H),3.89(s,3H),3.41(m,1H),2.87(m,5H),2.18(m,1H),1.80(m,3H),1.58(m,1H)
Example 52: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-methoxy-5-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-methoxy-5-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(s,1H),7.81(d,1H),7.23(m,1H),7.12(s,1H),6.79(d,1H),6.63(br,1H),6.60(d,1H),4.20(m,1H),3.78(s,3H),3.72(m,1H),3.20(m,1H),2.88(m,4H),2.38(s,3H),2.18(s,1H),1.82(m,3H),1.59(m,1H)
Example 53: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-chloro-2-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-2-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.01(s,1H),7.81(d,1H),7.37(m,2H),7.14(d,1H),6.78(d,1H),6.48(br,1H),4.15(m,1H),3.49(m,1H),3.05(m,1H),2.89(m,4H),2.17(s,3H),2.10(m,1H),1.80(m,3H),1.63(m,1H)
Example 54: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methoxy-2-methylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-methoxy-2-methylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.01(s,1H),7.85(d,1H),7.06(d,1H),6.79(m,3H),6.58(d,1H),4.20(m,1H),3.79(s,3H),3.44(m,1H),3.05(m,1H),2.90(m,4H),2.09(s,3H),2.07(m,1H),1.81(m,3H),1.59(m,1H)
Example 55: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-3-(trifluoromethyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.07(s,1H),7.72(m,3H),7.53(m,1H),6.65(d,1H),6.09(br,1H),4.13(m,1H),3.48(m,1H),2.89(m,4H),2.57(m,1H),2.01(m,1H),1.78(m,2H),1.69(m,1H),1.43(m,1H)
Example 56: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-methoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 5-chloro-2-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.91(s,1H),7.70(d,1H),7.42(d,1H),7.26(s,1H),7.00(d,1H),6.61(d,1H),6.06(br,1H),4.10(m,1H),3.80(s,3H),3.37(m,1H),2.88(m,4H),2.57(m,1H),1.98(m,1H),1.67(m,3H),1.42(m,1H)
Example 57: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-chloro-4-(trifluoromethoxy)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-chloro-4-(trifluoromethoxy)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.95(s,1H),7.82(d,1H),7.47(s,1H),7.41(d,1H),7.30(d,1H),6.63(d,1H),6.50(br,d,1H),4.11(m,1H),3.36(m,1H),2,87(m,4H),2.62(m,1H),2.00(m,1H),1.71(m,3H),1.50(m,1H)
Example 58: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-chloro-3-fluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-3-fluorophenylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.09(s,1H),7.73(d,1H),7.51(t,1H),7.25(m,1H),7.15(d,1H),6.62(d,1H),6.29(br,1H),4.13(m,1H),3.47(m,1H),2.86(m,4H),2.65(d,1H),2.02(m,1H),1.95(m,1H),1.71(m,2H),1.54(m,1H)
Example 59: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4,5-trimethoxyphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2,4,5-trimethoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.09(s,1H),7.69(d,1H),6.65(d,1H),6.56(s,2H),6.07(br,1H),4.11(m,1H),3.87(m,9H),3.43(m,1H),2.82(m,4H),2.59(m,1H),2.01(m,1H),1.69(m,3H),1.54(m,1H)
Example 60: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4,5-trichlorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2,4,5-trichloroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.93(s,1H),7.78(d,1H),7.69(s,1H),7.49(s,1H),6.68(d,1H),6.22(br,1H),4.13(m,1H),3.42(m,1H),2.88(m,4H),2.67(m,1H),1.78(m,3H),1.65(m,1H),1.47(m,1H)
Example 61: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3,4,5-trifluorophenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 3,4,5-trifluoroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.07(s,1H),7.78(d,1H),7.18(m,2H),6.58(m,2H),4.09(m,1H),3.67(m,1H),3.40(m,1H),2.83(m,3H),2.57(m,1H),1.99(m,1H),1.68(m,3H),1.51(m,1H)
Example 62: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(3-phenylphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 3-phenylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.78(s,1H),7.63(d,1H),7.45(m,3H),7.22(m,6H),6.57(br,d,1H),6.28(d,1H),3.90(m,1H),3.19(m,1H),2,71(m,4H),2.42(m,1H),1.80(m,1H),1.57(m,3H),1.30(m,1H)
Example 63: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-phenylmethoxyphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-phenylmethoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.03(s,1H),7.80(d,1H),7.23(m,7H),7.02(m,2H),6.92(br,d,1H),6.44(d,1H),5.04(s,2H),4.01(m,1H),3.24(m,1H),2,75(m,4H),2.55(m,1H),1.89(m,1H),1.63(m,3H),1.33(m,1H)
Example 64: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-phenylphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-phenylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.78(s,1H),7.63(d,1H),7.44(m,3H),7.20(m,6H),6.57(br,d,1H),6.28(d,1H),3.90(m,1H),3.19(m,1H),2,76(m,4H),2.41(m,1H),1.80(m,1H),1.57(m,3H),1.30(m,1H)
Example 65: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-phenylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-phenylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.16(s,1H),7.72(m,3H),7.62(m,2H),7.49(m,4H),7.42(m,1H),6.67(m,1H),6.14(br,1H),4.12(m,1H),3.42(m,1H),2.86(m,4H),2.58(m,1H),2.02(m,1H),1.72(m,1H),1.53(m,1H)
Example 66: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-methoxy-5-phenylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-methoxy-5-phenylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(s,1H),7.71(m,2H),7.57(m,2H),7.51(m,1H),7.48(m,2H),7.35(m,1H),7.14(m,1H),6.67(m,1H),6.02(br,1H),4.12(m,1H),3.88(s,3H),3.45(m,1H),2.85(m,4H),2.58(m,1H),2.02(m,1H),1.73(m,3H),1.56(m,1H)
Example 67: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-chlorophenyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-(4-chlorophenyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.15(s,1H),7.69(m,3H),7.56(m,2H),7.45(m,4H),6.68(m,1H),6.03(br,1H),4.13(m,1H),3.43(m,1H),2.86(m,4H),2.56(m,1H),2.03(m,1H),1.73(m,1H),1.56(m,1H)
Example 68: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-methoxyphenyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-(4-methoxyphenyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.15(s,1H),7.70(m,3H),7.57(m,2H),7.45(m,2H),7.03(m,2H),6.70(m,1H),6.03(br,1H),4.13(m,1H),3.89(s,3H),3.45(m,1H),2.84(m,4H),2.58(m,1H),2.02(m,1H),1.74(m,3H),1.65(m,1H)
Example 69: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-methylphenyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-(4-methylphenyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.15(s,1H),7.71(m,3H),7.53(m,2H),7.46(m,2H),7.31(m,2H),6.69(m,1H),6.60(br,1H),4.13(m,1H),3.43(m,1H),2.84(m,4H),2.56(m,1H),2.43(s,3H),2.03(m,1H),1.73(m,3H),1.57(m,1H)
Example 70: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-chloro-4-phenylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-chloro-4-phenylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.65(s,1H),8.39(m,1H),8.34(m,1H),7.74(m,1H),7.59(m,3H),7.48(m,3H),7.41(m,1H),6.68(d,1H),4.06(m,1H),3.48(m,1H),3.13(m,4H),2.51(m,1H),2.05(m,1H),1.77(m,3H),1.51(m,1H)
Example 71: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-chlorophenoxy)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-(4-chlorophenoxy)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.15(s,1H),7.78(d,1H),7.45(m,3H),7.10(m,2H),7.04(m,3H),6.68(d,1H),6.38(br,1H),4,17(m,1H),3.42(m,1H),3.08(m,1H),2.88(m,4H),2.09(m,1H),1.78(m,3H),1.64(m,1H)
Example 72: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-methylphenoxy)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-(4-methylphenoxy)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.15(s,1H),7.73(m,1H),7.32(m,2H),7.22(m,1H),7.08(m,3H),7.02(m,2H),6.63(d,1H),6.58(br,1H),4.15(m,1H),3.42(m,1H),3.01(m,1H),2.91(m,3H),2.72(m,1H),2.36(s,3H),2.04(m,1H),1.74(m,3H),1.55(m,1H)
Example 73: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(4-phenoxyphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-phenoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.14(s,1H),8.85(d,1H),7.34(m,3H),7.15(m,2H),7.14(br,s,1H),7.01(m,4H),6.46(d,1H),4.04(m,1H),3.23(m,1H), 2.76 (m, 4H), 2.64 (m, 1H), 1.93 (m, 1H), 1.64 (m, 3H), 1.37 (m, 1H)
Example 74: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-phenoxyphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-phenoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.06(s,1H),7.75(d,1H),7.35(m,1H),7.27(m,3H),7.15(m,1H),7.08(m,1H),6.95(m3H),6.64(br,1H),6.42(d,1H),4.02(m,1H),3.23(m,1H),2.75(m,4H),2.53(m,1H),1.91(m,1H),1.62(m,3H),1.35(m,1H)
Example 75: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-ethynylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-ethynyl aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.09(s,1H),7.80(d,1H),7.53(d,2H),7.26(d,2H),6.95(br,d,1H),6.49(d,1H),4.04(m,1H),3.26(m,1H),3.18(s,1H),2,76(m,4H),2.60(m,1H),1.93(s,3H),1.86(m,1H),1.64(m,3H),1.41(m,1H)
Example 76: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-(methylthio)aniline was used as a starting material.
1H-NMR(CDCl3,200MHz)δ8.06(s,1H),7.80(d,1H),7.13(m,4H),7.05(br,d,1H),6.43(d,1H),4.03(m,1H),3.23(m,1H),2,74(m,4H),2.54(m,1H),2.46(s,3H),1.90(m,1H),1.63(m,3H),1.38(m,1H)
Example 77: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-(methylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.94(s,1H),7.86(d,1H),7.42(m,1H),7.33(m,1H),7.23(m,1H),7.13(m,1H),7.11(br,d,1H),6.49(d,1H),3.99(m,1H),3.20(m,1H),2,75(m,4H),2.53(m,1H),2.37(s,3H),1.89(m,1H),1.63(m,3H),1.33(m,1H)
Example 78: Synthesis of N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 2-(methylthio)aniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3R-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 1.
1H-NMR(CDCl3,500MHz)δ7.94(s,1H),7.86(d,1H),7.42(m,1H),7.33(m,1H),7.23(m,1H),7.13(m,1H),7.11(br,d,1H),6.49(d,1H),3.99(m,1H),3.20(m,1H),2,75(m,4H),2.53(m,1H),2.37(s,3H),1.89(m,1H),1.63(m,3H),1.33(m,1H)
Example 79: Synthesis of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(2-(methylthio)phenyl)-1,6-dehydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 2-(methylthio)aniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3S-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 1.
1H-NMR(CDCl3,500MHz)δ7.94(s,1H),7.86(d,1H),7.42(m,1H),7.33(m,1H),7.23(m,1H),7.13(m,1H),7.11(br,d,1H),6.49(d,1H),3.99(m,1H),3.20(m,1H),2,75(m,4H),2.53(m,1H),2.37(s,3H),1.89(m,1H),1.63(m,3H),1.33(m,1H)
Example 80: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(ethylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(ethylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.95(s,1H),7.84(m,1H),7.43(m,2H),7.32(m,1H),7.23(m,1H),6.65(br,1H),6.59(d,1H),4.12(m,1H),3.35(m,1H),2.92(m,1H),2.87(m,5H),2.67(m,1H),2.01(m,1H),1.72(m,3H),1.53(m,1H),1.29(t,3H)
Example 81: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[2-(propan-2-ylthio)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(propan-2-ylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.95(s,1H),7.84(d,1H),7.56(m,1H),7.41(m, 1H), 7.34 (m, 1H), 7.22 (m, 1H), 6.72 (br, 1H), 6.55 (d, 1H), 4.04 (m, 1H), 3.34 (m, 2H), 2.81 (m, 4H), 2.51 (m, 1H), 1.94 (m, 1H), 1.67 (m, 3H), 1.40 (m, 1H), 1.23 (m, 6H)
Example 82: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[2-(phenylmethylthio)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(phenylmethylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.79(m,3H),7.45(m,1H),7.37(m,3H),7.23(m,4H),6.66(d,1H),6.32(br,1H),4.18(m,1H),4.06(s,2H),3.47(m,1H),3.06(m,1H),2.89(m,4H),2.08(m,1H),1.78(m,3H),1.56(m,1H)
Example 83: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(methylthio)-5-(trifluoromethyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(methylthio)-5-(trifluoromethyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.93(s,1H),7.89(d,1H),7.78(m,1H),7.50(m,1H),7.43(m,1H),6.67(m,1H),6.15(br,1H),4.13(m,1H),3.41(m,1H),2.94(m,1H),2.89(m,3H),2.83(m,1H),2.47(s,3H),2.03(m,1H),1.72(m,3H),1.54(m,1H)
Example 84: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-methoxy-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-methoxy-2-(methylthio)phenylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.97(s,1H),7.74(m,1H),7.18(m,1H),6.87(m,1H),6.79(m,1H),6.69(d,1H),6.10(br,1H),4.05(m,1H),3.88(s,3H),3.42(m,1H),2.87(m,4H),2.65(m,1H),2.42(s,3H),2.05(m,1H),1.73(m,3H),1.58(m,1H)
Example 85: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(ethylthio)-4-methoxyphenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(ethylthio)-4-methoxyaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.95(s,1H),7.75(d,1H),7.23(d,1H),7.01(s,1H),6.87(d,1H),6.69(d,1H),6.03(br,1H),4.13(m,1H),3.97(s,3H),3.49(m,1H),2.92(m,4H),2.83(m,2H),2.61(m,1H),2.04(m,1H),1.73(m,3H),1.56(m,1H),1.33(t,3H)
Example 86: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-chloro-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-2-(methylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.94(s,1H),7.86(d,1H),7.26(s,1H),7.21(d,1H),7.10(d,1H),6.88(br,d,1H),6.55(d,1H),4.05(m,1H),3.28(m,1H),2.79(m,4H),2.62(m,1H),2.41(s,3H),1.95(m,1H),1.68(m,3H),1.42(m,1H)
Example 87: Synthesis of N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[4-chloro-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(4-chloro-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 4-chloro-2-(methylthio)aniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(4-chloro-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3R-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 1.
1H-NMR(CDCl3,500MHz)δ7.94(s,1H),7.86(d,1H),7.26(s,1H),7.21(d,1H),7.10(d,1H),6.88(br,d,1H),6.55(d,1H),4.05(m,1H),3.28(m,1H),2.79(m,4H),2.62(m,1H),2.41(s,3H),1.95(m,1H),1.68(m,3H),1.42(m,1H)
Example 88: Synthesis of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[4-chloro-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(4-chloro-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 4-chloro-2-(methylthio)aniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(4-chloro-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3S-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 1.
1H-NMR(CDCl3,500MHz)δ7.94(s,1H),7.86(d,1H),7.26(s,1H),7.21(d,1H),7.10(d,1H),6.88(br,d,1H),6.55(d,1H),4.05(m,1H),3.28(m,1H),2.79(m,4H),2.62(m,1H),2.41(s,3H),1.95(m,1H),1.68(m,3H),1.42(m,1H)
Example 89: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-methyl-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-methyl-2-(methylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.93(s,1H),7.81(d,1H),7.16(s,1H),7.07(s,2H),6.58(m,2H),4.08(m,1H),3.36(m,1H),2.84(m,4H),2.64(s,3H),2.61(s,3H),1.97(m,1H),1.73(m,3H),1.53(m,1H)
Example 90: Synthesis of N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[4-methyl-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(4-methyl-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 4-methyl-2-(methylthio)aniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(4-methyl-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3R-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 1.
1H-NMR(CDCl3,500MHz)δ7.93(s,1H),7.81(d,1H),7.16(s,1H),7.07(s,2H),6.58(m,2H),4.08(m,1H),3.36(m,1H),2.84(m,4H),2.64(s,3H),2.61(s,3H),1.97(m,1H),1.73(m,3H),1.53(m,1H)
Example 91: Synthesis of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[4-methyl-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
6-Oxo-1-(4-methyl-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid was synthesized in the same manner as in Example 1-2 and Example 1-3, except that 4-chloro-2-(methylthio)aniline was used as a starting material. A target compound was obtained from the synthesized 6-oxo-1-(4-methyl-2-(methylthio)phenyl)-1,6-dihydro-3-pyridinecarboxylic acid and 3S-aminoquinuclidine dihydrochloride in the same manner as in Example 1-4 and Method 1.
1H-NMR(CDCl3,500MHz)δ7.93(s,1H),7.81(d,1H),7.16(s,1H),7.07(s,2H),6.58(m,2H),4.08(m,1H),3.36(m,1H),2.84(m,4H),2.64(s,3H),2.61(s,3H),1.97(m,1H),1.73(m,3H),1.53(m,1H)
Example 92: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-tert-butyl-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-tert-butyl-2-(methylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.98(s,1H),7.92(m,1H),7.40(m,1H),7.32(m,1H),7.16(m,1H),6.90(br,1H),6.61(d,1H),4.27(m,1H),3.46(m,1H),3.22(m,1H),2.98(m,4H),2.41(s,3H),2.13(s,1H),1.95(m,3H),1.62(m,1H),1.35(s,9H)
Example 93: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-chloro-2-(propan-2-ylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-2-(propan-2-ylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.93(s,1H),7.82(d,1H),7.51(m,1H),7.32(m,1H),7.22(m,1H),6.68(d,1H),6.38(br,1H),4.19(m,1H),3.45(m,2H),3.09(m,1H),2.91(m,4H),2.09(m,1H),1.81(m,3H),1.76(m,1H),1.28(m,6H)
Example 94: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(methylthio)-4-propylphenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(methylthio)-4-propylaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.92(s,1H),7.90(m,1H),7.18(m,1H),7.07(m,3H),6.57(br,1H),4.29(m,1H),3.53(m,1H),3.23(m,1H),3.02(m,4H),2.63(m,2H),2.39(s,3H),2.18(m,1H),1.97(m,1H),1.86(m,2H),1.68(m,3H),0.99(t,3H)
Example 95: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[2-(phenylthio)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-(phenylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.92(m,1H),7.83(d,1H),7.30(m,9H),6.75(br,s,1H),6.55(d,1H),4.08(m,1H),3.30(m,1H),2.81(m,4H),2.67(m,1H),1.99(m,1H),1.70(m,3H),1.44(m,1H)
Example 96: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(methylthio)-4-propan-2-ylphenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(methylthio)-4-propan-2-yl aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.03(m,2H),7.32(br,1H),7.23(s,1H),7.12(m,2H),6.61(d,1H),4.28(m,1H),3.42(m,1H),3.37(m,1H),3.23(m,1H),2.96(m,4H),2.41(s,3H),2.19(m,1H),2.06(m,1H),1.85(m,2H),1.59(m,1H),1.29(m,6H)
Example 97: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-chloro-2-(ethylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-2-(ethylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.03(d,1H),7.97(d,1H),7.36(s,1H),7.21(m,1H),7.20(br,1H),7.16(m,1H),6.59(d,1H),4.28(m,1H),3.42(m,1H),3.28(m,1H),3.16(m,1H),2.98(m,5H),2.16(m,1H),1.97(m,1H),1.85(m,2H),1.58(m,1H),1.29(t,3H)
Example 98: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-ethyl-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-ethyl-2-(methylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.91(s,1H),7.73(m,1H),7.30(m,1H),7.18(m,2H),6.64(d,1H),6.10(br,1H),4.12(m,1H),3.42(m,1H),2.89(m,4H),2.73(m,3H),2.40(s,3H),2.03(m,1H),1.70(m,3H),1.47(m,1H),1.23(t,3H)
Example 99: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-cyclohexyl-2-(methylthio)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-cyclohexyl-2-(methylthio)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.90(s,1H),7.75(d,1H),7.22(s,1H),7.14(m,2H),6.64(d,1H),6.18(br,1H),4.10(m,1H),3.41(m,1H),2.92(m,4H),2.57(m,2H),2.41(s,3H),2.01(m,1H),1.92(m,4H),1.77(m,4H),1.52(m,5H),1.28(m,1H)
Example 100: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-methylsulfonylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-methylsulfonyl aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.10(m,1H),7.94(s,1H),7.85(d,1H),7.77(m,1H),7.69(m,1H),7.37(m,1H),6.67(br,d,1H),6.53(d,1H),3.94(m,1H),3.22(m,1H),3.07(s,3H),2.74(m,4H),2.49(m,1H),1.88(m,1H),1.61(m,3H),1.36(m,1H)
Example 101: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methylsulfonylphenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 4-methylsulfonyl aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.16(s,1H),8.11(d,2H),7.77(d,1H),7.66(d,2H),6.69(d,1H),6.35(br,d,1H),4.15(m,1H),3.12(m,1H),3.07(s,3H),2.86(m,4H),2.62(m,1H),1.87(m,1H),1.56(m,3H),1.34(m,1H)
Example 102: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1-naphthalenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 1-aminonaphthalene was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.01(m,3H),7.85(d,1H),7.60(m,3H),7.41(m,2H),6.71(d,1H),6.28(br,1H),4.07(m,1H),3.40(m,1H),2.83(m,4H),2.58(m,1H),1.98(m,1H),1.68(m,3H),1.46(m,1H)
Example 103: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2-naphthalenyl)-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-aminonaphthalene was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.22(s,1H),7.87(m,5H),7.56(m,2H),7.42(m,1H),6.60(m,2H),4.13(m,1H),3.35(m,1H),2.88(m,4H),2.69(m,1H)2.02(m,1H),1.76(m,3H),1.47(m,1H)
Example 104: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[2-(2-thiazolyl)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 2-(2-thiazolyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.03(m,2H),7.78(d,1H),7.67(d,1H),7.53(m,2H),7.27(d,1H),7.20(m,1H),7.09(br,d,1H),6.34(d,1H),3.92(m,1H),3.17(m,1H),2.69(m,4H),2.47(m,1H),1.80(m,1H),1.56(m,3H),1.25(m,1H)
Example 105: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-chloro-2-(2-thiazolyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-chloro-2-(2-thiazolyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.12(s,1H),8.00(d,1H),7.80(m,2H),7.52(m,1H),7.37(d,1H),7.28(d,1H),6.56(br,1H),6.52(d,1H),4.06(m,1H),3.33(m,1H),2.82(m,4H),2.57(m,1H),1.95(m,1H),1.68(m,3H),1.47(m,1H)
Example 106: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(5-methyl-2-thiazolyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(5-methyl-2-thiazolyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.02(s,2H),7.80(m,1H),7.56(m,2H),7.39(s,1H),7.29(d,1H),6.61(br,1H),6.53(d,1H),4.07(m,1H),3.33(m,1H),2.83(m,4H),2.66(m,1H),2.42(s,3H),1.98(m,1H),1.68(m,3H),1.45(m,1H)
Example 107: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(1,3-benzothiazole-2-yl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(1,3-benzothiazole-2-yl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.19(s,1H),8.07(m,1H),7.91(m,2H),7.81(m,1H),7.79(m,2H),7.47(m,2H),7.40(m,1H),6.62(m,1H),6.14(br,1H),4.13(m,1H),3.42(m,1H),2.87(m,4H),2.62(m,1H),2.06(m,1H),1.72(m,3H),1.55(m,1H)
Example 108: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(5-methyl-2-thiophenyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 4-(5-methyl-2-thiophenyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.13(s,1H),7.73(d,1H),7.68(d,2H),7.36(d,2H),7.17(d,1H),6.68(d,1H),6.77(d,1H),6.17(br,1H),4.14(m,1H),3.46(m,1H),2.88(m,4H),2.63(m,1H),2.54(m,3H),2.04(m,1H),1.78(m,3H),1.58(m,1H)
Example 109: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-chloro-4-(5-methyl-2-thiophenyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-chloro-4-(5-methyl-2-thiophenyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.07(s,1H),7.91(m,1H),7.87(s,1H),7.56(m,1H),7.35(m,1H),7.18(m,1H),6.84(m,2H),6.65(d,1H),4.23(m,1H),3.46(m,1H),3.21(m,1H),2.93(m,4H),2.58(m,3H),2.08(m,1H),1.75(m,3H),1.58(m,1H)
Example 110: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiophene-2-ylphenyl)-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(thiophene-2-yl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ7.93(s,1H),7.92(m,1H),7.71(m,1H),7.54(m,2H),7.46(m,1H),6.99(m,2H),6.62(m,1H),6.60(m,1H),6.52(br,1H),4.21(m,1H),3.40(m,1H),3.20(m,1H),2.93(m,4H),2.12(m,1H),1.92(m,3H),1.62(m,1H)
Example 111: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[2-(5-methyl-2-thiophenyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 1, except that 2-(5-methyl-2-thiophenyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.54(m,1H),8.49(m,1H),8.23(m,1H),7.63(m,1H),7.47(m,1H),7.44(m,1H),7.35(m,2H),6.76(m,1H),6.60(m,1H),4.54(m,1H),4.22(m,1H),4.04(m,1H),3.36(m,1H),3.16(m,3H),2.45(m,1H),2.41(s,3H),2.05(m,3H),1.76(m,1H)
Example 112: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[3-(2-methyl-4-thiazolyl)phenyl]-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 2, except that 3-(2-methyl-4-thiazolyl)aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.14(s,1H),7.95(m,2H),7.72(m,1H),7.58(m,1H),7.44(s,1H),7.35(m,1H),6.68(d,1H),6.15(br,1H),4.13(m,1H),3.45(m,1H),2.92(m,4H),2.78(s,3H),2.57(m,1H),2.03(m,1H),1.72(m,3H),1.54(m,1H)
Example 113: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-dimethylaminophenyl]-6-oxo-3-pyridinecarboxamide
Example 113-1: Synthesis of methyl 1-(4-dimethylaminophenyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate
After 1.24 g (6.1 mmol) of dimethyl 4-(methoxymethylene)2-pentenedioate obtained in Example 1-1 was dissolved in 10 mL of DMF, 830 g (6.1 mmol) of 4-dimethylaminoaniline was added to the solution. Afterward, the resulting reaction solution was stirred under reflex at about 50℃ for about 3 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then washed using brine, followed by drying using magnesium sulfate and filtration. After distillation under reduced pressure, the resulting product was purified using column chromatography (hexane:ethyl acetate=1:1) to obtain a target compound (Actual yield: 357 mg, Yield ratio: 21%).
Example 113-2: Synthesis of 1-(4-dimethylaminophenyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid
After 357 mg (1.31 mmol) of methyl 1-(4-dimethylaminophenyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate was dissolved in 12 mL of methanol and 4 mL of water, 94 mg (3.93 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50℃ for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, and aqueous HCl was then added to the reaction solution to titrate until a neutral solution was obtained. The resulting solid compound was filtrated and used in Example 113-3 without an additional purification process.
Example 113-3: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-dimethylaminophenyl]-6-oxo-3-pyridinecarboxamide
After 300 mg (1.18 mmol) of 1-(4-dimethylaminophenyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid was dissolved in 20 mL of tetrahydrofuran and 2 mL of DMF, 391 mg (1.96 mmol) of 3-aminoquinuclidine dihydrochloride and 460 mg (3.54 mmol) of diethylisopropylamide were added to the solution. After the reaction solution was stirred at room temperature for about 30 minutes, 600 g (1.57 mmol) of O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate(HATU) was added to the reaction solution. This reaction solution was stirred at room temperature for about 20 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by extraction three times with chloroform and an aqueous NaOH solution (pH 12) and purification using liquid chromatography (chloroform:methanol:ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 158 mg, Percent yield: 31 %).
1H-NMR(CDCl3,500MHz)δ8.11(s,1H),7.78(d,1H),7.13(d,2H),6.84(br,1H),6.68(d,2H),6.53(d,1H),4.10(m,1H),3.35(m,1H),2.98(s,6H),3.16(m,1H),2.82(m,4H),2.68(m,1H),1.99(m,1H),1.72(m,3H),1.46(m,1H)
Example 114: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-{4-[(methyl-propl-2-ylnyl-amino)-methyl]-phenyl}-6-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 1 and Method 113, except that 1-{4-[(methyl-prop-2-ylnyl-amino)-methyl]-phenyl}aniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.11(s,1H),7.79(d,1H),7.45(d,2H),7.27(d,2H),6.75(br,d,1H),6.56(d,1H),4.08(m,1H),3.61(s,2H),3.34(m,3H),2,84(m,4H),2.62(m,1H),2.35(s,3H),2,29(s,1H),2.21(s,1H),1.97(m,1H),1.60(m,3H),1.45(m,1H)
Example 115: Synthesis of (1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-phenyl-3-pyridinecarboxylate
Example 115-1: Synthesis of 6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carbonyl chloride
After 197 mg (0.91 mmol) of 6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid obtained in Example 1-3 was dissolved in 10 mL of toluene, 217 mg (1.82 mmol) of thionyl chloridethionyl chloride was added to the solution. Afterward, the resulting reaction solution was stirred under reflux at about 100℃ for 2 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then used in Example 115-2 without an additional purification process.
Example 115-2: Synthesis of (1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-phenyl-3-pyridinecarboxylate
After dissolution of the mixed solution of 6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carbonyl chloride obtained in Example 115-1 in 5 mL of pyridine, 231 mg (1.82 mmol) of 3-hydroxyquinuclidine was added thereto. Afterward, the resulting reaction solution was stirred at room temperature for about 3 days. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. Without an additional purification process, the resulting compound was extracted three times with water and chloroform, and the organic phase was purified using liquid chromatography (chloroform: methanol: ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 65 mg, Percent yield: 20 %).
1H-NMR(CDCl3,500MHz)δ8.23(s,1H),7.94(d,1H),7.50(m3H),7.40(d,2H),6.66(d,1H),5.01(m,1H),3.33(m,1H),2.83(m,5H),2.12(m,1H),1.87(m,1H),1.74(m,1H),1.63(m,1H),1.48(m,1H)
Example 116: Synthesis of (1-azabicyclo[2.2.2]octan-3-yl)-1-(2,4-dichlorophenyl)-6-oxo-3-pyridinecarboxylate
A target compound was obtained in the same manner as in Example 115, except that 2,4-dichloroaniline was used as a starting material.
1H-NMR(CDCl3,500MHz)δ8.01(s,1H),7.95(d,1H),7.59(s,1H),7.40(m,1H),7.32(m,1H),6.64(d,1H),4.99(m,1H),3.29(m,1H),2.78(m,5H),2.09(m,1H),1.85(m,1H),1.71(m,1H),1.60(m,1H),1.45(m,1H)
Example 117: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-2-oxo-1-phenyl-3-pyridinecarboxamide
Example 117: Synthesis of 2-hydroxynicotinic acid
1.5 g (10.6 mmol) of 2-fluoronicotinic acid was dissolved in 42 mL of 6N HCl and was then stirred under reflux for about 1 hour. Afterward, the resulting reaction product was cooled to room temperature and was then filtrated to obtain a solid compound. The resulting solid compound was used in Example 117-2 without an additional purification process.
Example 117-2: Synthesis of methyl 2-hydroxy nicotinate
After 1 g (7.19 mmol) of 2-hydroxynicotinic acid was dissolved in 20 mL of methylene chloride, 3.4 g (28.8 mmol) of thionyl chloride was added thereto. Afterward, the resulting reaction solution was stirred at about 75℃ for 3 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. This compound was dissolved in methanol and was then stirred at room temperature for about 2 hours. The compound was extracted three times with water and dichloromethane, and an organic solvent phase was purified using column chromatography (hexane:ethyl acetate=1:1) to obtain a target compound (Actual yield: 480 mg, Percent yield: 53 %).
Example 117-3: Synthesis of methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate
After 480 mg (3.8 mmol) of methyl 2-hydroxy nicotinate, 0.56 mL (7.6 mmol) of pyridine, and 634 mg (4.1 mmol) of acetate were mixed together, 10 mL of methylene chloride was added thereto. 775 mg (7.6 mmol) of phenylboronic acid was added to the mixed solution and was then stirred at room temperature for about 12 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. The resulting mixed solution was extracted three times with an aqueous ammonium chloride solution and dichloromethane, and an organic solvent phase was purified using column chromatography (hexane:ethyl acetate=1:2) to obtain a target compound (Actual yield: 430 mg, Percent yield: 49 %).
Example 117-4: Synthesis of 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid
A target compound was obtained using methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate in the same manner as in Example 1-3.
Example 117-5: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-2-oxo-1-phenyl-3-pyridinecarboxamide
A target compound was obtained using 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid in the same manner as in Example 1-4 and Method 2.
1H-NMR(CDCl3,200MHz)δ10.01(br,1H),8.51(d,1H),7.47(m,6H),6.50(t,1H),4.07(m,1H),3.29(m,1H),2.78(m,4H),2.59(m,1H),1.94(m,1H),1.65(m,3H),1.41(m,1H)
Example 118: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methoxyphenyl)-2-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 117, except that 4-methoxyphenylboronic acid was used as a starting material.
1H-NMR(CDCl3,500MHz)δ10.00(br,1H),8.57(d,1H),7.53(d,1H),7.26(d,2H),7.00(d,2H),6.47(t,1H),4.08(m,1H),3.82(s,3H),3.32(m,1H),2.78(m,4H),2.57(m,1H),1.93(m,1H),1.64(m,3H),1.40(m,1H)
Example 119: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-chlorophenyl)-2-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 117, except that 4-chlorophenylboronic acid was used as a starting material.
1H-NMR(CDCl3,200MHz)δ9.80(br,1H),8.46(d,1H),7.43(m,3H),7.24(d,2H),6.41(t,1H),3.94(m,1H),3.20(m,1H),2.67(m,4H),2.49(m,1H),1.81(m,1H),1.52(m,3H),1.27(m,1H)
Example 120: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-2-oxo-1-[4-(trifluoromethyl)phenyl]-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 117, except that 4-trifluoromethylphenylboronic acid was used as a starting material.
1H-NMR(CDCl3,200MHz)δ9.90(br,1H),8.64(d,1H),7.83(d,2H),7.54(m,3H),6.56(t,1H),4.11(m,1H),3.34(m,1H),2.78(m,4H),2.59(m,1H),1.94(m,1H),1.66(m,3H),1.42(m,1H)
Example 121: Synthesis of N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-tert-butylphenyl)-2-oxo-3-pyridinecarboxamide
A target compound was obtained in the same manner as in Example 117, except that 4-tert-butylphenylboronic acid was used as a starting material.
1H-NMR(CDCl3,200MHz)δ10.01(br,1H),8.63(d,1H),7.55(m,3H),7.30(d,2H),6.51(t,1H),4.18(m,1H),3.38(m,1H),2.82(m,4H),2.61(m,1H),1.99(m,1H),1.68(m,3H),1.43(m,1H)
Example 122: Measurement of human α7 nicotinic acetylcholine receptor (nAChR)’s activity
Activity of heteromeric α7 nAChR was measured via FlexStation-Ca2+ influx assay. In the present example, in consideration of α7 nAChR being Ca2+-permeable non-selective cationic channels, changes intracellular Ca2+ concentration were measured using a fluorescent dye Calcium-3 (available from Molecular Devices) and FlexStation Ⅱ instrument (available from Molecular Devices).
Human CHRNA7 (NM_000746) cDNA ORF clone (C/N RC221382; Origene) and Human RIC (NM_024557) cDNA ORF clone (C/N RC205179; Origene) were subcloned into pcDNA2.1/Zeo(+) vector (available from Invitrogen, Co.) to construct HEK293T/17 cells (ATCC, CRL-11268) transfected with human α7 nAChR. Afterward, the cells were suspended in growth media (consisted of Dulbecco’s Modified Eagle’s Media (DMEM, available from Invitrogen), a 10% heat-inactivated fetal bovine serum (FBS, available from Invitrogen), 300 μg/ml Geneticin (available from Invitrogen), 250 μg/ml Zeocin (available from Invitrogen), and 1x penicillin/streptomycin (available from Invitrogen)), followed by plating onto a Ф150 mm plate. Twenty-four hours prior to the start of the assay, grown cells in the suspension were collected, followed by centrifugation and further suspension at a concentration of 5 x 105 cells/mL in growth media. This cell suspension was dispensed to each well of a 96-well black plate (5 x 104 cells/well) with a poly-D-lysine-coated transparent bottom (available from Biocoat, BD). The plate with the cells were incubated at about 37℃ in 5% CO2 for about 24 hours.
On the day of the assay, after removal of the growth media, the cells were washed once with an assay buffer (7 mM Tris-Cl, 20 mM HEPES, 20 mM NaCl, 5 mM KCl, 0.8 mM MgSO4, 4 mM CaCl2,120 mM NMDG, 5 mM D-glucose, pH 7.4), followed by addition of about 100 ul per well of a Calcium-3 dye diluted with the assay buffer, and storage at room temperature for about 1 hour. A test compound (10 mM stock in 100% dimethyl sulfoxide (DMSO)) was diluted with the assay buffer to various concentrations, from the highest at about 40 μM to be lower by 1/3, and PNU-120596 (available from Sigma) for amplifying Ca2+ permeability signaling was diluted to about 30 μM with the assay buffer. Epibatidine (available from Sigma) in a final concentration of about 1 μM was used as a positive control group.
To measure changes in intracellular Ca2+ concentration, after the plate was stored at room temperature for about 1 hour and the test compound dilution plate were put into FlexStation Ⅱ equipment, fluorescence of the cells were measured for about 30 seconds prior to addition of drugs (the compounds), followed by addition of PNU-120596 and measurement of changes in fluorescence for about 120 seconds. After the cells were exposed to the test compound, changes in fluorescence for about 90 seconds were measured (excitation at 485 nm /emission at 525 nm). The largest fluorescence value at each concentration was recorded, and an EC50 of the test compound was determined using non-linear regression analysis with relative fluorescence values relative to the positive control group.
The results were represented as EC50 values. For those compounds lacking dependency on concentration, relative fluorescence values were read at a concentration with the highest fluorescence value among the compounds tested. This test was performed one time or more. Efficacies of the compounds synthesized in some examples were tested using the same method as above, and the results are shown in Tables 1 and 2 below. In Table 1, + denotes an EC50 of 1000 nM or greater, ++ denotes an EC50 of from 500nM to 1000 nM, +++ denotes an EC50 of from 100 nM to about 500 nM, and ++++ denotes an EC50 of 100 nM or less.
Table 1
Example | EC50 of human α7nAChR(nM) |
1 | + |
2 | ++++ |
4 | + |
5 | + |
6 | + |
7 | ++ |
11 | + |
12 | ++ |
14 | ++ |
15 | ++ |
17 | ++ |
18 | ++ |
20 | ++ |
25 | ++ |
26 | +++ |
27 | + |
29 | + |
32 | + |
33 | +++ |
36 | +++ |
38 | +++ |
46 | +++ |
49 | +++ |
56 | ++ |
57 | +++ |
60 | ++ |
63 | + |
65 | +++ |
67 | ++ |
69 | +++ |
70 | +++ |
71 | +++ |
72 | +++ |
73 | ++ |
74 | +++ |
76 | +++ |
77 | ++++ |
78 | ++++ |
79 | +++ |
80 | ++++ |
81 | +++ |
82 | +++ |
83 | ++ |
84 | ++++ |
85 | ++++ |
86 | ++++ |
87 | ++++ |
88 | +++ |
89 | ++++ |
90 | ++++ |
91 | +++ |
93 | +++ |
94 | ++++ |
95 | ++++ |
96 | ++++ |
97 | ++++ |
98 | ++++ |
99 | +++ |
101 | +++ |
102 | +++ |
104 | +++ |
105 | ++ |
106 | ++ |
107 | ++++ |
108 | +++ |
109 | +++ |
110 | +++ |
111 | +++ |
113 | ++ |
115 | + |
+; 1000 nM or greater, ++; from 500 nm to 1000 nM, +++; from 100 mM to 500 nM, ++++; 100 nM or less
Example 123: Novel object recognition test (NORT) on mice administered with pyridone derivative compound-containing composition
A NORT, which was first introduced by Ennaceur and Delacour, is a cognitive memory test for measuring whether rats are able to remember objects with which they have had previous experience based on the nature of rats, i.e., preference to explore novel objects [Ennaceur A and Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats.1; Behavioral data. Behavioral Brain Res. 31;47-59]. This NOR test is a popular experimental method for measuring changes in memory of objects in rodents administered with either an amnesia-inducing drug or other general drugs, by which memory recovery efficacy of a test drug in the rodents administered with the amnesia-inducing drug is explored. In the present example, the test was performed in accord with the description of Bevins and Besheer [Bevins, R.A.& Besheer, J. Object recognition in rats and mice; a one-trial non-matching-to-sample learning task to study 'recognition memory'. Nat Protoc. 2006;1(3);1306-11. (2006)]. Male ICR mice (available from Orient Bio Inc., Korea) weighing from about 20 g to about 32 g were orally administered a test compound dissolved in a 30% PEG at doses of 0.03~3 mg/kg and 10 ml/kg body weight. 30 minutes after the administration, MK-801 (available from Sigma) dissolved in saline was subcutaneously administered at doses of 0.1 mg/kg and 10 ml/kg body weight to induce amnesia. About 30 minutes after the administration of MK-801, the mice were allowed to explore a rectangular stainless steel pillar or a circular plastic pillar which was previously placed in a box for about 5 minutes. About 24 hours after the exploration, one of the two objects previously presented was replaced with a new one (i.e., to include one rectangular stainless steel pillar and one circular plastic pillar), the times they took to explore were measured for about 5 minutes. A recognition index (RI) was defined as:
[(Exploration time for novel object in test compound group/ Exploration time for all objects in test compound group)/(Exploration time for novel object in MK801 group/ Exploration time for all objects in MK801 group) x 100].
Table 2 below presents relative RIs of the compounds at a minimal dose resulting in half maximal activation (EC50).
Table 2
Example | NORT Relative RI (%)@MED |
4 | 116.2% @3po |
5 | 115.8% @0.1ip |
25 | 115.6% @3po |
26 | 116.4% @1po |
27 | 114.1% @1po |
33 | 112.1% @1po |
65 | 110.7% @1ip |
77 | 122.1% @0.1ip |
84 | 119.7% @0.3po |
86 | 115.2% @0.3po |
89 | 113.8% @0.03po |
91 | 118.2% @3po |
104 | 114.8% @3po |
105 | 116.2% @0.3po |
109 | 112.6% @3po |