# Patent

## Title
N-substituted pyrazolo [3,4-D] pyrimidine ketone compound, and preparation process and use thereof

## Abstract

Disclosed are an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound of formula (I), and a preparation process and use thereof as a phosphodiesterase IX (PDEIX) inhibitor:




    
    
        wherein
        R′ is selected from isopropyl, cyclopentyl, cyclohexyl, isobutyl, and o-chlorophenyl;
        when R′′═CH3, R represents benzyl; and
        when R′′═H, R is selected from 3-methylpyridine, 1-phenylethyl, 1-(4-chlorophenyl)ethyl,
    
    






D- or L-configured CHCH3CONHR′′′, D- or L-configured CH2CONHR′′′, D- or L-configured CH2CH2CONHR′′′; wherein R1 is selected from hydrogen, chlorine, methoxy, methyl, trifluoromethyl, dimethoxy, methylenedioxy, and dichlorine, and R2 is selected from hydrogen, methoxy, ethoxy, isopropoxy, methyl, dimethoxy, and 2-methyl-4-methoxy, and wherein R′′′ is p-methoxyphenyl.

## Background
TECHNICAL FIELD
The present invention relates to a phosphodiesterase IX (PDEIX) inhibitor, and in particular, relates to a novel N-substituted pyrazolo [3,4-d] pyrimidine ketone compound, and a preparation process and use thereof.
BACKGROUND
Phosphodiesterase (PDE) denotes a species of proteases, and is capable of selectively degrading the second massagers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in human bodies to the corresponding adenosine monophosphates to exert important physiological functions. Till now, 11 families of phosphodiesterases have been reported, wherein the phosphodiesterase IX (PDEIX) is capable of hydrolyzing the cGMP with a high specificity, and is widely distributed in human bodies (J Bio Chem, 1998, 273(25) 15559-15564). A PDEIX inhibitor is capable of inhibiting the enzymolysis effect on the cGMP by the PDEIX, and thus improving the cGMP level. In this way, the effects of NO and insulin are magnified, and the effects of dilating arteries are exerted, metabolization is speeded up, and atherosclerosis is resisted (WO03037432). Researches show that the cGMP plays an important role on the improvement of the cognitive ability of the human being. These characteristics render the phosphodiesterase IX to be a new target spot for the treatment of diabetes, obesity and cardiovascular diseases, and for the improvement of attention, cognitive abilities, learning and memory.
In 2005, Frank Wunder (Mol Pharmacol, 2005, 68: 1775-1781) reported the first PDEIX selective inhibitor BAY 73-6691. This discovery promotes people's commitments on research into the PDEIX selective inhibitor. The phosphodiesterase IX inhibitors discovered in recent years have better phosphodiesterase IX and achieve better pharmacological activity. International Patents WO2003037899, WO2004096811, and WO2012020022 have disclosed a pyrazole pyrimidine ketone-parented PDEIX inhibitor and a process for preparing the same; WO2004113306 has disclosed a cyano pyrimidine ketone-parented PDEIX inhibitor and a process for preparing the same; WO2004096811 and WO2012040230 have disclosed an imidazole trinitrogen heterocyclic ketone-parented PDEIX inhibitor and a process for preparing the same; WO2012004900 has disclosed a thienopyrimidine-parented PDEIX inhibitor and a process for preparing the same; WO2012033101 and WO201203314 have disclosed an imidazo quinoline ketone-parented PDEIX inhibitor and a process for preparing the same; and WO2004096811 has disclosed a PDEIX inhibitor using other ketone compounds as a matrix and a process for preparing the same, wherein the ketone compounds comprise imidazolyl pyrimidine ketone, oxazole pyrimidine ketone, and thiazole pyrimidine ketone. In 2011, our research group disclosed a 6-position-N-substituted pyrazolo pyrimidine ketone-parented PDEIX inhibitor having better inhibition activity and a preparation process thereof (CN102260266A).
SUMMARY
The present invention is directed to providing a high activity and high selectivity novel phosphodiesterase IX inhibitor, and providing an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound, and a preparation method and use thereof.
The present invention is implemented by the following technical solutions:
The present invention provides an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound of formula (I):




wherein
R′ is selected from isopropyl, cyclopentyl, cyclohexyl, and isobutyl;
when R′′═CH3, R represents benzyl; and
when R′′═H, R is selected from 3-methylpyridine, 1-phenylethyl, 1-(4-chlorophenyl)ethyl,




wherein R1 is selected from hydrogen, chlorine, methoxy, methyl, trifluoromethyl, dimethoxy, methylenedioxy, and dichlorine, and R2 is selected from hydrogen, methoxy, ethoxy, isopropoxy, methyl, dimethoxy, and 2-methyl-4-methoxy.
Preferably, when R′′═H, the compound is selected from compounds of formulas (II), (III), (IV), and (V):




wherein
R′ is selected from isopropyl, cyclopentyl, cyclohexyl, and isobutyl;
R1 in formula (II) is selected from hydrogen, methyl, methoxy, 2,4-dimethoxy, 3,4-methylenedioxy, chlorine, 2,4-dichlorine, and trifluoromethyl;
R2 in formula (III) is selected from hydrogen, methyl, methoxy, ethoxy, isopropoxy, 2-methyl-4-methoxy, and 2,5-dimethoxy; and
R3 in formula (IV) is selected from hydrogen and chlorine.
The present invention provides an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound of formula (VI):




wherein
R′ is selected from isopropyl or cyclopentyl, cyclohexyl, isobutyl, and o-chlorophenyl;
when R′′═CH3, R represents benzyl; and
when R′′═H, R is selected from D- or L-configured CHCH3CONHR′′′, D- or L-configured CH2CONHR′′′, D- or L-configured CH2CH2CONHR′′′, wherein R′′′ is p-methoxyphenyl.
Preferably, the N-substituted pyrazolo [3,4-d] pyrimidine ketone compound according to the present invention is selected from compounds of formulas (VII), (VIII), (IX), (X), and (XI):




The present invention provides a process for the preparation of an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound, comprising the following steps:
(1) reacting using 2,4,6-trichloro-5-pyrimidinecarbaldehyde and hydrazine having a substituent group as starting materials, triethylamine as a base, and ethanol as a solvent at temperature −78° C. to obtain a compound A, wherein a molar ratio of 2,4,6-trichloro-5-pyrimidinecarbaldehyde to hydrazine to triethylamine is 1:1-1.1:2-3, and 2,4,6-trichloro-5-pyrimidinecarbaldehyde has a concentration of 0.05 to 1.0 mol/L;




(2) hydrolyzing the compound A under a basic condition to obtain a compound B, wherein the basic condition comprises sodium hydroxide and potassium hydroxide, a molar ration of A to a base is 1:10-40, and A has a concentration of 0.05 to 0.5 mol/L; and




(3) reacting the compound B with an amine compound in the presence of triethylamine as a base to obtain a target compound I, wherein a molar ratio of B to triethylamine to the amino compound is 1:1.3:1.2-3, and B has a concentration of 0.05 to 0.5 mol/L.




The N-substituted pyrazolo [3,4-d] pyrimidine ketone compound according to the present invention has a better inhibition effect on a phosphodiesterase IX, and may be used as a selective inhibitor of the phosphodiesterase.
The N-substituted pyrazolo [3,4-d] pyrimidine ketone compound according to the present invention may be used for the treatment of diabetes, obesity and cardiovascular diseases, and for the improvement of attention, cognitive abilities, learning and memory.
The preparation method according to the present invention has the advantages of quickness, convenience, low cost, and the like.


DETAILED DESCRIPTION
The present invention is hereinafter described in detail, but is not limited to the following description.
I. Instruments and Medicaments
The nuclear magnetic resonance spectrum (NMR) in the present invention is tested by the instrument AVANCE 400 manufactured by Bruker in Germany, and a solvent residual peak is used as an internal standard; the mass spectrum is tested by the instrument LCMS-2010A (ESI source) manufactured by Shimadzu Corporation in Japan; the chemical reagents are purchased from Guangzhou Ai Er Lu Chemicals Company, J&K Corporation, Alfar-Aser Corporation, Aladdin Chemical Regents Corporation, and so on; and the silica gel for column chromatography is purchased from Qingdao Haiyang Chemical Co., Ltd.
Example 1
Synthesis of Compound M-1 of Formula (M-1)




2,4,6-trichloro-5-pyrimidinecarbaldehyde (424 mg, 2 mmol), isopropylhydrazine hydrochloride (221 mg, 2 mmol), triethylamine (505 mg, 5 mmol) were reacted in ethanol (40 ml) at temperature −78° C. for 2 hours; the temperature was raised to room temperature, and the mixture was further reacted for 8 hours; the solvent was removed by rotatary evaporation, and the reaction product was extracted using ethyl acetate and dried by anhydrous sodium sulfate; the solvent was evaporated by reducing the pressure and the reaction product was separated and purified through rapid column chromatography; finally 323 mg white solids were obtained, and the yield was 70%.
MS (ESI+): m/z: 231 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 5.16 (hept, J=6.8 Hz, 1H), 1.57 (d, J=6.7 Hz, 6H).
Example 2
Synthesis of Compound M-2 of Formula (M-2)




At 60° C., compound M-1 (231 mg, 1 mmol) obtained in Example 1 was added into 20 ml 1 mol/L NaOH aqueous solution, and stirred for 1 hour for reaction. After the reaction, the pH was adjusted to 5 to 6 using glacial acetic acid, and white solids then precipitated; the reaction product was subjected to sucking filtration, washing, and drying; finally, 162 mg white solids were obtained, and the yield was 76%.
MS (ESI−): m/z: 211 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 5.01 (hept, J=6.7 Hz, 1H), 1.54 (d, J=6.7 Hz, 6H).
Example 3
Synthesis of Compound M-3 of Formula (M-3)




The synthesis method was the same as that for the method for the synthesis of compound M-1 in Example 1. 2,4,6-trichloro-5-pyrimidinecarbaldehyde (424 mg, 2 mmol), cyclopentylhydrazine hydrochloride (300 mg, 2.2 mmol), triethylamine (404 mg, 4 mmol) were reacted in ethanol (2 ml); the reaction product was separated and purified; finally, 374 mg white solids were obtained, and the yield was 73%.
MS (ESI+): m/z: 231 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 5.36-5.26 (m, 1H), 2.25-2.07 (m, 4H), 2.05-1.94 (m, 2H), 1.82-1.71 (m, 2H).
Example 4
Synthesis of Compound M-4 of Formula (M-4)




The synthesis method was the same as that for the method for the synthesis of compound M-2 in Example 2. Compound M-3 (257 mg, 1 mmol) and 2 ml 5 mol/L NaOH aqueous solution were reacted; finally, 410 mg white solids were obtained, and the yield was 86%.
MS (ESI−): m/z: 237 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 5.15 (p, J=7.5 Hz, 1H), 2.20-2.04 (m, 4H), 2.02-1.91 (m, 2H), 1.72 (ddd, J=11.2, 7.8, 3.2 Hz, 2H).
Example 5
Synthesis of Compound M-5 of Formula (M-5)




The synthesis method was the same as that for the method for the synthesis of compound M-1 in Example 1. 2,4,6-trichloro-5-pyrimidinecarbaldehyde (424 mg, 2 mmol), cyclohexylhydrazine hydrochloride (301 mg, 2 mmol), triethylamine (606 mg, 6 mmol) were reacted in ethanol (10 ml); the reaction product was separated and purified; finally, 690 mg white solids were obtained, and the yield was 64%.
MS (ESI+): m/z: 271 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 4.81-4.70 (m, 1H), 2.05-1.90 (m, 6H), 1.81-1.72 (m, 1H), 1.58-1.46 (m, 2H), 1.38-1.26 (m, 1H).
Example 6
Synthesis of Compound M-6 of Formula (M-6)




The synthesis method was the same as that for the method for the synthesis of compound M-2 in Example 2. Compound M-5 (271 mg, 1 mmol) and 5 ml 2 mol/L NaOH aqueous solution were reacted; finally, 318 mg white solids were obtained, and the yield was 63%.
MS (ESI−): m/z: 251 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 13.13 (brs, 1H), 8.06 (s, 1H), 4.55-4.39 (m, 1H), 1.91-1.79 (m, 6H), 1.68 (d, J=12.6 Hz, 1H), 1.53-1.38 (m, 2H), 1.24 (ddd, J=12.8, 9.5, 3.2 Hz, 1H).
Example 7
Synthesis of Compound M-7




The synthesis method was the same as that for the method for the synthesis of compound M-1 in Example 1. 2,4,6-trichloro-5-pyrimidinecarbaldehyde (424 mg, 2 mmol), isobutylhydrazine hydrochloride (249 mg, 2 mmol), triethylamine (505 mg, 5 mmol) were reacted in ethanol (25 ml); the reaction product was separated and purified; finally, 378 mg white solids were obtained, and the yield was 77%.
MS (ESI+): m/z: 231 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 4.26 (d, J=7.3 Hz, 2H), 2.38 (dp, J=13.8, 6.9 Hz, 1H), 0.93 (d, J=6.7 Hz, 6H).
Example 8
Synthesis of Compound M-8




The synthesis method was the same as that for the method for the synthesis of compound M-2 in Example 2. Compound M-7 (245 mg, 1 mmol) and 10 ml 4 mol/L NaOH aqueous solution were reacted; finally, 350 mg white solids were obtained, and the yield was 77%.
MS (ESI−): m/z: 225 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 12.45 (brs, 1H), 8.11 (s, 1H), 4.13 (d, J=7.4 Hz, 2H), 2.33 (dp, J=13.8, 6.9 Hz, 1H), 0.92 (d, J=6.7 Hz, 6H).
Example 9
Synthesis of Compound M-9
The synthesis method was the same as that for the method for the synthesis of compound M-1 in Example 1. The reaction product was separated and purified, and finally, brown solids were obtained (180 mg, 30%).




MS (ESI+): m/z: 298 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.55-7.46 (m, 2H), 7.42-7.29 (m, 2H).
Example 10
Synthesis of Compound M-10
The synthesis method was the same as that for the method for the synthesis of compound M-2 in Example 2. Finally, white solids were obtained (168 mg, 60%).




MS (ESI−): m/z: 279 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 12.45 (brs, 1H), 8.11 (s, 1H), 7.53-7.45 (m, 2H), 7.41-7.29 (m, 2H).
Example 11
Synthesis of Compound M-11-D




D-alanine (890 mg, 10 mmol), di-tert-butyl dicarbonate (2616 mg, 12 mmol), and triethylamine (1515 mg, 15 mmol) were reacted in a mixed solution of water and 1,4-dioxane at room temperature for 8 hours; the solvent is removed by rotatary evaporation, and the reaction product was extracted using ethyl acetate and dried by anhydrous sodium sulfate; the solvent was evaporated by reducing the pressure; finally a light yellow thick crude product was obtained; the obtained crude product was directly put into the next reaction instead of being further purified. A DMF solution of p-methoxyaniline (1230 mg, 10 mmol) and 1-methylimidazole (820 mg, 10 mmol) were added; and at 0° C., dethyl chlorophosphate (1725 mg, 10 mmol) was dropwise added to a three-necked flask. After the dropwise adding, the reaction temperature was naturally raised to the room temperature. The reaction was stopped after the substances were sufficiently reacted. Subsequently, a saturated NaHCO3 aqueous solution was added until no bubbles were generated, and then solids precipitated. The reaction product was filtered, and then watered using a small amount of water and dried. Finally, white solids were obtained. The obtained white solids were dissolved in 30 ml methanol, and under an ice bath condition, an HCL gas was given to the solution. The reaction was stopped after the substances were sufficiently reacted. The obtained crude product was separated and purified via column chromatography (DCM:MeOH=15:1), and finally a colorless oil-like substance was obtained (400 mg, 21%).
MS (ESI+): m/z: 195 ([M+H]+); 1H NMR (300 MHz, DMSO) δ 7.54 (d, J=8.9 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H), 3.70 (s, 3H), 3.42 (dd, J=13.7, 6.8 Hz, 1H), 2.83 (s, 2H), 1.22 (d, J=6.9 Hz, 3H).
Example 12
Synthesis of Compound M-11-L




L-alanine was used as the starting material, and the synthesis method was the same as that for the method for the synthesis of compound M-11-D in Example 11. The reaction product was separated and purified, and finally, a colorless oil-like substance was obtained (420 mg, 22%).
MS (ESI+): m/z: 195 ([M+H]+); 1H NMR (300 MHz, CDCl3) δ 9.31 (brs, 1H), 7.48-7.41 (m, 2H), 6.84-6.77 (m, 2H), 3.74 (s, 3H), 3.54 (q, J=7.0 Hz, 1H), 1.80 (s, 2H), 1.37 (d, J=7.0 Hz, 3H).
Example 13
Synthesis of Compound M-12




Glycine was used as the starting material, and the synthesis method was the same as that for the method for the synthesis of compound M-11-D in Example 11. The reaction product was separated and purified, and finally, a colorless oil-like substance was obtained (380 mg, 21%).
MS (ESI+): m/z: 181 ([M+H]+); 1H NMR (300 MHz, DMSO) δ 9.81 (brs, 1H), 7.52 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.9 Hz, 2H), 3.70 (s, 3H), 3.24 (s, 2H), 2.67 (brs, 2H).
Example 14
Synthesis of Compound M-13




The synthesis method was the same as that for the method for the synthesis of compound M-11-D in Example 11. The reaction product was separated and purified, and finally, a colorless oil-like substance was obtained (400 mg, 21%).
MS (ESI+): m/z: 195 ([M+H]+); 1H NMR (300 MHz, DMSO) δ 9.90 (brs, 1H), 7.47 (d, J=8.2 Hz, 2H), 6.83 (d, J=8.1 Hz, 2H), 3.69 (s, 3H), 2.83 (s, 2H), 2.37 (s, 2H).
Example 15
Synthesis of Compound WYQ-1




Compound M-2 (64 mg, 0.3 mmol) obtained in Example 2, 4-chlorobenzylamine (51 mg, 0.36 mmol), triethylamine (40 mg, 0.4 mmol), and isopropanol (2 ml) were added into a reaction tube, and were reacted at 100° C. for 1 hour after the tube was sealed. After the reaction, the solvent was removed by rotatary evaporation. The reaction product was separated and purified via column chromatography (CH2Cl2:MeOH=20:1), and finally, light yellow solids were obtained (83 mg, 87%).
MS (ESI+): m/z: 318 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 10.97 (brs, 1H), 7.52 (s, 1H), 7.34-7.27 (m, 4H), 6.89 (t, J=5.1 Hz, 1H), 4.85 (hept, J=6.7 Hz, 1H), 4.62 (d, J=5.2 Hz, 2H), 1.49 (d, J=6.7 Hz, 6H).
Example 16
Synthesis of Compound WYQ-2




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 3-chlorobenzylamine (51 mg, 0.36 mmol), and isopropanol (6 ml) were reacted. The reaction product was separated and purified, and finally light yellow solids (90 mg, 94%) were obtained.
MS (ESI+): m/z: 318 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.27 (d, J=2.5 Hz, 2H), 6.85 (t, J=5.6 Hz, 1H), 4.92-4.81 (m, 1H), 4.63 (d, J=5.7 Hz, 2H), 1.49 (d, J=6.7 Hz, 6H).
Example 17
Synthesis of Compound WYQ-3




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2-chlorobenzylamine (51 mg, 0.36 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (80 mg, 84%) were obtained.
MS (ESI+): m/z: 318 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 10.87 (brs, 1H), 7.53 (s, 1H), 7.53-7.49 (m, 1H), 7.41-7.36 (m, 1H), 7.25-7.21 (m, 2H), 7.08 (s, 1H), 4.89 (hept, J=6.7 Hz, 1H), 4.76 (d, J=5.8 Hz, 2H), 1.49 (d, J=6.7 Hz, 6H).
Example 18
Synthesis of Compound WYQ-4




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 4-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (85 mg, 90%) were obtained.
MS (ESI+): m/z: 314 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 10.82 (brs, 1H), 7.33 (s, 1H), 7.33-7.30 (m, 2H), 6.92-6.85 (m, 3H), 4.89 (hept, J=6.7 Hz, 1H), 4.58 (d, J=5.2 Hz, 2H), 3.80 (s, 3H), 1.50 (d, J=6.7 Hz, 6H).
Example 19
Synthesis of Compound WYQ-5




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 3-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally light yellow solids (87 mg, 92%) were obtained.
MS (ESI+): m/z: 314 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 10.91 (brs, 1H), 7.39 (s, 1H), 7.32-7.28 (m, 1H), 7.03-6.95 (m, 3H), 6.87 (dd, J=8.2, 2.2 Hz, 1H), 4.90 (hept, J=6.7 Hz, 1H), 4.65 (d, J=5.3 Hz, 2H), 3.79 (s, 3H), 1.51 (d, J=6.7 Hz, 6H).
Example 20
Synthesis of Compound WYQ-6




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally light yellow solids (89 mg, 95%) were obtained.
MS (ESI+): m/z: 314 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 10.98 (brs, 1H), 7.63 (s, 1H), 7.39 (dd, J=7.4, 1.6 Hz, 1H), 7.30-7.25 (m, 1H), 6.91 (ddd, J=8.2, 7.4, 3.4 Hz, 2H), 6.76 (s, 1H), 4.92 (hept, J=6.7 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 3.83 (s, 3H), 1.52 (d, J=6.7 Hz, 6H).
Example 21
Synthesis of Compound WYQ-7




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 4-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (6 ml) were reacted. The reaction product was separated and purified, and finally light yellow solids (81 mg, 91%) were obtained.
MS (ESI−): m/z: 296 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.84 (brs, 1H), 7.36-7.27 (m, 3H), 7.15 (d, J=7.3 Hz, 2H), 6.89 (s, 1H), 4.89 (dt, J=12.5, 6.1 Hz, 1H), 4.61 (s, 2H), 2.35 (s, 3H), 1.50 (d, J=6.5 Hz, 6H).
Example 22
Synthesis of Compound WYQ-8




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2,4-dimethoxybenzylamine (100 mg, 0.6 mmol), and isopropanol (0.6 ml) were reacted. The reaction product was separated and purified, and finally light yellow solids (86 mg, 83%) were obtained.
MS (ESI−): m/z: 342 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.93 (brs, 1H), 7.63 (s, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.48-6.40 (m, 2H), 4.92 (hept, J=6.7 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 3.79 (d, J=1.9 Hz, 6H), 1.52 (d, J=6.7 Hz, 6H).
Example 23
Synthesis of Compound WYQ-9




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 3,4-methylenedioxybenzylamine (68 mg, 0.45 mmol), and isopropanol (6 ml) were reacted. The reaction product was separated and purified, and finally light yellow solids (96 mg, 98%) were obtained.
MS (ESI−): m/z: 326 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.90 (brs, 1H), 7.45 (s, 1H), 6.91 (brs, 1H), 6.89-6.83 (m, 2H), 6.77 (d, J=7.9 Hz, 1H), 5.94 (s, 2H), 4.89 (hept, J=6.7 Hz, 1H), 4.55 (d, J=4.4 Hz, 2H), 1.50 (d, J=6.7 Hz, 6H).
Example 24
Synthesis of Compound WYQ-10




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), α-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally light yellow solids (83 mg, 93%) were obtained.
MS (ESI−): m/z: 296 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.70 (brs, 1H), 7.59 (s, 1H), 7.45 (d, J=7.3 Hz, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.31-7.27 (m, 1H), 7.21 (d, J=6.9 Hz, 1H), 5.26 (p, J=6.6 Hz, 1H), 4.91-4.79 (m, 1H), 1.67 (d, J=6.9 Hz, 3H), 1.49 (dd, J=21.9, 6.7 Hz, 6H).
Example 25
Synthesis of Compound WYQ-11




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 3-pyridinebenzylamine (65 mg, 0.6 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (80 mg, 92%) were obtained.
MS (ESI−): m/z: 283 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.97 (brs, 1H), 8.65 (s, 1H), 8.49 (dd, J=4.7, 1.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.55 (s, 1H), 7.23 (dd, J=7.8, 4.9 Hz, 1H), 6.92 (t, J=5.7 Hz, 1H), 4.88-4.76 (m, 1H), 4.63 (d, J=5.6 Hz, 2H), 1.45 (d, J=6.7 Hz, 6H).
Example 26
Synthesis of Compound WYQ-12




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), α-methylbenzylamine (48 mg, 0.45 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (82 mg, 96%) were obtained.
MS (ESI−): m/z: 282 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.93 (brs, 1H), 7.42-7.27 (m, 6H), 7.01 (d, J=8.3 Hz, 1H), 4.88 (hept, J=6.7 Hz, 1H), 4.66 (d, J=3.8 Hz, 2H), 1.49 (d, J=6.7 Hz, 6H).
Example 27
Synthesis of Compound WYQ-13




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 4-methoxybenzenamine (111 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (78 mg, 87%) were obtained.
MS (ESI−): m/z: 298 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.61 (brs, 1H), 8.85 (brs, 1H), 7.88 (s, 1H), 7.58 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 4.95-4.86 (m, 1H), 3.83 (s, 3H), 1.53 (d, J=6.7 Hz, 6H).
Example 28
Synthesis of Compound WYQ-14




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 3-methoxybenzenamine (111 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (57 mg, 63%) were obtained.
MS (ESI−): m/z: 298 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.35 (brs, 1H), 8.91 (brs, 1H), 7.85 (s, 1H), 7.53 (t, J=2.2 Hz, 1H), 7.25 (t, J=8.1 Hz, 1H), 7.05 (ddd, J=8.1, 2.0, 0.7 Hz, 1H), 6.64 (ddd, J=8.3, 2.5, 0.7 Hz, 1H), 4.80 (hept, J=6.7 Hz, 1H), 3.78 (s, 3H), 1.45 (d, J=6.7 Hz, 6H).
Example 29
Synthesis of Compound WYQ-15




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2-methoxybenzenamine (111 mg, 0.9 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (40 mg, 44%) were obtained.
MS (ESI−): m/z: 298 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 11.06 (brs, 1H), 8.55 (brs, 1H), 8.46 (dd, J=7.8, 1.7 Hz, 1H), 7.85 (s, 1H), 7.14-6.96 (m, 3H), 4.91-4.74 (m, 1H), 3.91 (s, 3H), 1.45 (d, J=6.7 Hz, 6H).
Example 30
Synthesis of Compound WYQ-16




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 4-ethoxybenzenamine (123 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (89 mg, 95%) were obtained.
MS (ESI−): m/z: 312 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.62 (brs, 1H), 8.80 (brs, 1H), 7.87 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 4.89 (hept, J=6.7 Hz, 1H), 4.05 (q, J=7.0 Hz, 2H), 1.52 (d, J=6.7 Hz, 6H), 1.43 (t, J=7.0 Hz, 3H).
Example 31
Synthesis of Compound WYQ-17




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 4-isopropoxybenzenamine (136 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (87 mg, 89%) were obtained.
MS (ESI−): m/z: 326 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.29 (brs, 1H), 8.67 (brs, 1H), 7.82 (s, 1H), 7.52 (d, J=9.0 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 4.78 (hept, J=6.7 Hz, 1H), 4.55 (hept, J=6.0 Hz, 1H), 1.41 (d, J=6.7 Hz, 6H), 1.25 (d, J=6.0 Hz, 6H).
Example 32
Synthesis of Compound WYQ-18




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2,5-dimethoxybenzenamine (138 mg, 0.9 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (30 mg, 30%) were obtained.
MS (ESI−): m/z: 328 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 11.11 (brs, 1H), 8.59 (brs, 1H), 8.26 (d, J=3.0 Hz, 1H), 7.85 (s, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.59 (dd, J=8.9, 3.1 Hz, 1H), 4.81 (hept, J=6.7 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 1.47 (d, J=6.7 Hz, 6H).
Example 33
Synthesis of Compound WYQ-19




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2-methyl-4-methoxybenzenamine (123 mg, 0.9 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (77 mg, 80%) were obtained.
MS (ESI−): m/z: 312 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.41 (brs, 1H), 7.80 (brs, 1H), 7.76 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.84-6.76 (m, 2H), 4.79 (hept, J=6.6 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H), 1.46 (d, J=6.7 Hz, 6H).
Example 34
Synthesis of Compound WYQ-20




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2-methylbenzenamine (96 mg, 0.9 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (22 mg, 26%) were obtained.
MS (ESI−): m/z: 282 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.76 (brs, 1H), 8.12 (brs, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.24 (t, J=7.7 Hz, 2H), 7.09-7.03 (m, 1H), 4.70 (hept, J=6.7 Hz, 1H), 2.28 (s, 3H), 1.39 (d, J=6.7 Hz, 6H).
Example 35
Synthesis of Compound WYQ-21




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 2,4-dichlorobenzylamine (132 mg, 0.75 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (80 mg, 75%) were obtained.
MS (ESI−): m/z: 350 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 11.03 (brs, 1H), 7.70 (s, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.2, 1.9 Hz, 1H), 6.97 (brs, 1H), 4.86 (dt, J=13.3, 6.7 Hz, 1H), 4.70 (d, J=4.0 Hz, 2H), 1.49 (d, J=6.7 Hz, 6H).
Example 36
Synthesis of Compound WYQ-22




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 1-(4-chlorphenyl)ethylamine (93 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (69 mg, 69%) were obtained.
MS (ESI−): m/z: 330 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.70 (brs, 1H), 7.65 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.30-7.26 (m, 2H), 7.14 (d, J=7.0 Hz, 1H), 5.18 (p, J=6.9 Hz, 1H), 4.77 (dt, J=13.5, 6.7 Hz, 1H), 1.61 (d, J=7.0 Hz, 3H), 1.48 (d, J=6.7 Hz, 3H), 1.41 (d, J=6.7 Hz, 3H).
Example 37
Synthesis of Compound WYQ-23




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), 4-trifluoromethylbenzylamine (105 mg, 0.6 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (100 mg, 95%) were obtained.
MS (ESI−): m/z: 350 ([M−H]−); 1H NMR (500 MHz, DMSO) δ 10.62 (brs, 1H), 7.73 (s, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H), 7.09 (t, J=5.6 Hz, 1H), 4.68 (dt, J=13.4, 6.7 Hz, 1H), 4.61 (d, J=5.8 Hz, 2H), 1.32 (d, J=6.7 Hz, 6H).
Example 38
Synthesis of Compound WYQ-24




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 15. Compound M-2 (64 mg, 0.3 mmol), N-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (72 mg, 80%) were obtained.
MS (ESI−): m/z: 296 ([M−H]−); 1H NMR (500 MHz, DMSO) δ 10.66 (brs, 1H), 7.75 (s, 1H), 7.36-7.32 (m, 2H), 7.27 (dd, J=14.0, 7.2 Hz, 3H), 4.82 (s, 2H), 4.74 (dt, J=13.4, 6.7 Hz, 1H), 3.08 (s, 3H), 1.37 (d, J=6.7 Hz, 6H).
Example 39
Synthesis of Compound WYQ-25




Compound M-4 (71 mg, 0.3 mmol) obtained in Example 4, 4-chlorobenzylamine (85 mg, 0.6 mmol), triethylamine (40 mg, 0.4 mmol), and isopropanol (1 ml) were added into a reaction tube, and were reacted at 100° C. for 1 hour after the tube was sealed. After the reaction, the solvent was removed by rotatary evaporation. The reaction product was separated and purified via column chromatography (CH2Cl2:MeOH=20:1), and finally, white solids were obtained (81 mg, 79%).
MS (ESI−): m/z: 342 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 11.00 (brs, 1H), 7.52 (s, 1H), 7.33-7.27 (m, 4H), 6.86 (brs, 1H), 4.99 (p, J=7.5 Hz, 1H), 4.62 (s, 2H), 2.06 (dd, J=12.7, 6.9 Hz, 4H), 1.99-1.87 (m, 2H), 1.74-1.62 (m, 2H).
Example 40
Synthesis of Compound WYQ-26




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 3-chlorobenzylamine (85 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (84 mg, 82%) were obtained.
MS (ESI−): m/z: 342 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 11.02 (brs, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.26 (s, 3H), 6.93 (s, 1H), 5.00 (p, J=7.1 Hz, 1H), 4.63 (s, 2H), 2.08 (s, 4H), 1.94 (s, 2H), 1.70 (d, J=4.3 Hz, 2H).
Example 41
Synthesis of Compound WYQ-27




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2-chlorobenzylamine (85 mg, 0.6 mmol), and isopropanol (6 ml) were reacted. The reaction product was separated and purified, and finally white solids (81 mg, 79%) were obtained.
MS (ESI−): m/z: 342 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.54 (brs, 1H), 7.73 (s, 1H), 7.49-7.43 (m, 2H), 7.35-7.26 (m, 2H), 7.03 (t, J=5.8 Hz, 1H), 4.88 (p, J=7.6 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 1.97-1.83 (m, 4H), 1.82-1.73 (m, 2H), 1.59 (dt, J=8.4, 3.8 Hz, 2H).
Example 42
Synthesis of Compound WYQ-28




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 4-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (81 mg, 80%) were obtained.
MS (ESI−): m/z: 338 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.86 (brs, 1H), 7.36 (s, 1H), 7.31 (d, J=8.6 Hz, 2H), 6.89-6.85 (m, 2H), 5.02 (p, J=7.6 Hz, 1H), 4.58 (d, J=4.1 Hz, 2H), 3.80 (s, 3H), 2.13-2.02 (m, 4H), 2.00-1.90 (m, 2H), 1.69 (dd, J=10.3, 5.6 Hz, 2H).
Example 43
Synthesis of Compound WYQ-29




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 3-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (86 mg, 84%) were obtained.
MS (ESI−): m/z: 338 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.92 (brs, 1H), 7.39 (s, 1H), 7.29-7.24 (m, 1H), 6.99-6.94 (m, 2H), 6.84 (dd, J=8.2, 2.0 Hz, 1H), 5.01 (p, J=7.6 Hz, 1H), 4.63 (d, J=4.9 Hz, 2H), 3.76 (s, 3H), 2.11-2.02 (m, 4H), 1.98-1.88 (m, 2H), 1.74-1.64 (m, 2H).
Example 44
Synthesis of Compound WYQ-30




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (100 mg, 98%) were obtained.
MS (ESI−): m/z: 338 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.98 (brs, 1H), 7.60 (s, 1H), 7.39 (dd, J=7.4, 1.6 Hz, 1H), 7.30-7.24 (m, 1H), 6.94-6.86 (m, 2H), 6.76 (t, J=5.2 Hz, 1H), 5.05 (p, J=7.6 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 3.83 (s, 3H), 2.14-2.06 (m, 4H), 1.99-1.91 (m, 2H), 1.72 (dd, J=7.3, 4.6 Hz, 2H).
Example 45
Synthesis of Compound WYQ-31




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 4-methylbenzylamine (109 mg, 0.9 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (70 mg, 72%) were obtained.
MS (ESI−): m/z: 322 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.89 (brs, 1H), 7.35 (s, 1H), 7.28 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.8 Hz, 2H), 6.89 (brs, 1H), 5.02 (p, J=7.5 Hz, 1H), 4.60 (s, 2H), 2.34 (s, 3H), 2.07 (dd, J=7.1, 5.5 Hz, 4H), 1.94 (dd, J=9.3, 5.7 Hz, 2H), 1.75-1.64 (m, 2H).
Example 46
Synthesis of Compound WYQ-32




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2,5-dimethoxybenzylamine (100 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (91 mg, 82%) were obtained.
MS (ESI−): m/z: 368 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.93 (brs, 1H), 7.62 (s, 1H), 7.29 (d, J=8.2 Hz, 1H), 6.66 (brs, 1H), 6.47-6.40 (m, 2H), 5.06 (p, J=7.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 3.79 (d, J=1.9 Hz, 6H), 2.14-2.07 (m, 4H), 2.01-1.93 (m, 2H), 1.76-1.68 (m, 2H).
Example 47
Synthesis of Compound WYQ-33




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 3,4-methylenedioxybenzylamine (68 mg, 0.45 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (86 mg, 81%) were obtained.
MS (ESI−): m/z: 352 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.85 (brs, 1H), 7.39 (s, 1H), 6.91-6.82 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 5.94 (s, 2H), 5.02 (p, J=7.6 Hz, 1H), 4.55 (d, J=3.0 Hz, 2H), 2.08 (dt, J=7.1, 6.3 Hz, 4H), 1.94 (dd, J=9.2, 5.9 Hz, 2H), 1.69 (dd, J=10.3, 5.6 Hz, 2H).
Example 48
Synthesis of Compound WYQ-34




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), α-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (0.6 ml) were reacted. The reaction product was separated and purified, and finally white solids (78 mg, 80%) were obtained.
MS (ESI−): m/z: 322 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.70 (brs, 1H), 7.58 (s, 1H), 7.45-7.39 (m, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.29-7.24 (m, 1H), 7.13 (d, J=7.0 Hz, 1H), 5.25 (p, J=6.8 Hz, 1H), 4.96 (p, J=7.6 Hz, 1H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.97-1.88 (m, 2H), 1.75-1.67 (m, 2H), 1.65 (d, J=6.9 Hz, 3H).
Example 49
Synthesis of Compound WYQ-35




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 3-pyridinebenzylamine (65 mg, 0.6 mmol), and isopropanol (0.8 ml) were reacted. The reaction product was separated and purified, and finally white solids (77 mg, 83%) were obtained.
MS (ESI−): m/z: 309 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 11.02 (brs, 1H), 8.69 (s, 1H), 8.54 (d, J=3.8 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.58 (s, 1H), 7.28 (d, J=7.0 Hz, 1H), 6.92 (t, J=5.5 Hz, 1H), 5.00 (p, J=7.4 Hz, 1H), 4.68 (d, J=5.3 Hz, 2H), 2.07 (d, J=3.8 Hz, 4H), 1.94 (s, 2H), 1.70 (d, J=4.5 Hz, 2H).
Example 50
Synthesis of Compound WYQ-36




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), benzylamine (64 mg, 0.6 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (82 mg, 88%) were obtained.
MS (ESI−): m/z: 308 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.93 (brs, 1H), 7.42-7.27 (m, 6H), 5.01 (p, J=7.6 Hz, 1H), 4.66 (d, J=4.9 Hz, 2H), 2.13-2.01 (m, 4H), 1.99-1.88 (m, 2H), 1.74-1.63 (m, 2H).
Example 51
Synthesis of Compound WYQ-37




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 4-methoxybenzenamine (111 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (65 mg, 67%) were obtained.
MS (ESI−): m/z: 324 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.30 (brs, 1H), 8.69 (brs, 1H), 7.82 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 5.00-4.89 (m, 1H), 3.75 (s, 3H), 2.10-1.91 (m, 4H), 1.90-1.79 (m, 2H), 1.66 (dt, J=8.8, 4.0 Hz, 2H).
Example 52
Synthesis of Compound WYQ-38




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 3-methoxybenzenamine (111 mg, 0.9 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (40 mg, 41%) were obtained.
MS (ESI−): m/z: 324 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.75 (brs, 1H), 8.98 (brs, 1H), 7.92 (s, 1H), 7.55 (t, J=2.1 Hz, 1H), 7.30-7.25 (m, 1H), 7.12 (dd, J=8.0, 1.2 Hz, 1H), 6.69 (dd, J=8.1, 2.1 Hz, 1H), 5.05 (p, J=7.5 Hz, 1H), 3.84 (s, 3H), 2.13 (dt, J=7.1, 3.7 Hz, 4H), 1.96 (dd, J=10.1, 5.9 Hz, 2H), 1.77-1.65 (m, 2H).
Example 53
Synthesis of Compound WYQ-39




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2-methoxybenzenamine (111 mg, 0.9 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (40 mg, 41%) were obtained.
MS (ESI−): m/z: 324 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 11.06 (brs, 1H), 8.55 br (s, 1H), 8.46 (dd, J=7.8, 1.7 Hz, 1H), 7.85 (s, 1H), 7.12-6.97 (m, 3H), 5.04-4.94 (m, 1H), 3.90 (s, 3H), 2.14-1.93 (m, 4H), 1.93-1.81 (m, 2H), 1.73-1.60 (m, 2H).
Example 54
Synthesis of Compound WYQ-40




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 4-ethoxybenzenamine (123 mg, 0.9 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (70 mg, 70%) were obtained.
MS (ESI−): m/z: 338 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.56 (brs, 1H), 8.75 (brs, 1H), 7.85 (s, 1H), 7.56-7.50 (m, 2H), 6.95-6.89 (m, 2H), 5.01 (p, J=7.5 Hz, 1H), 4.05 (q, J=7.0 Hz, 2H), 2.11 (ddd, J=7.4, 6.4, 2.6 Hz, 4H), 2.00-1.89 (m, 2H), 1.76-1.66 (m, 2H), 1.43 (t, J=7.0 Hz, 3H).
Example 55
Synthesis of Compound WYQ-41




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 4-isopropoxybenzenamine (136 mg, 0.9 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (75 mg, 71%) were obtained.
MS (ESI−): m/z: 352 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.54 (brs, 1H), 8.71 (brs, 1H), 7.87 (s, 1H), 7.54 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 5.02 (p, J=7.4 Hz, 1H), 4.53 (hept, J=6.0 Hz, 1H), 2.12 (d, J=5.4 Hz, 4H), 1.94 (d, J=6.4 Hz, 2H), 1.76-1.64 (m, 2H), 1.36 (d, J=6.0 Hz, 6H).
Example 56
Synthesis of Compound WYQ-42




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2,5-dimethoxybenzenamine (138 mg, 0.9 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (27 mg, 27%) were obtained.
MS (ESI−): m/z: 354 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 11.09 (brs, 1H), 8.58 (brs, 1H), 8.27 (d, J=3.0 Hz, 1H), 7.84 (s, 1H), 6.98 (d, J=8.9 Hz, 1H), 6.58 (dd, J=8.9, 3.1 Hz, 1H), 4.97 (p, J=7.3 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 2.12-1.96 (m, 4H), 1.91-1.80 (m, 2H), 1.70-1.60 (m, 2H).
Example 57
Synthesis of Compound WYQ-43




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2-methyl-4-methoxybenzenamine (123 mg, 0.9 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (77 mg, 75%) were obtained.
MS (ESI−): m/z: 338 ([M−H]−); 1H NMR (500 MHz, DMSO) δ 10.55 (brs, 1H), 8.04 (brs, 1H), 7.78 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.80 (dd, J=8.8, 2.8 Hz, 1H), 4.80 (dt, J=14.6, 7.4 Hz, 1H), 3.27 (s, 3H), 2.22 (s, 3H), 1.99-1.88 (m, 4H), 1.79 (dd, J=12.8, 9.6 Hz, 2H), 1.63-1.53 (m, 2H).
Example 58
Synthesis of Compound WYQ-44




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2-methylbenzenamine (96 mg, 0.9 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (14 mg, 15%) were obtained.
MS (ESI−): m/z: 308 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.79 (brs, 1H), 8.15 (brs, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.82 (s, 1H), 7.23 (t, J=7.8 Hz, 2H), 7.06 (dd, J=11.1, 3.7 Hz, 1H), 4.90-4.79 (m, 1H), 2.26 (s, 3H), 1.96 (dtd, J=18.8, 12.6, 6.1 Hz, 4H), 1.79 (dd, J=9.0, 5.7 Hz, 2H), 1.59 (dd, J=9.8, 5.3 Hz, 2H).
Example 59
Synthesis of Compound WYQ-45




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 2,4-dichlorobenzylamine (106 mg, 0.6 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (75 mg, 66%) were obtained.
MS (ESI−): m/z: 376 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.61 (brs, 1H), 7.73 (s, 1H), 7.62 (d, J=2.1 Hz, 1H), 7.42 (dt, J=8.3, 5.2 Hz, 2H), 7.08 (t, J=5.7 Hz, 1H), 4.93-4.77 (m, 1H), 4.57 (d, J=5.8 Hz, 2H), 1.98-1.71 (m, 6H), 1.65-1.54 (m, 2H).
Example 60
Synthesis of Compound WYQ-46




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 1-(4-chlorphenyl)ethylamine (93 mg, 0.6 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (49 mg, 46%) were obtained.
MS (ESI−): m/z: 356 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.72 (brs, 1H), 7.64 (s, 1H), 7.36-7.32 (m, 2H), 7.30-7.26 (m, 2H), 7.07 (d, J=7.1 Hz, 1H), 5.18 (p, J=6.9 Hz, 1H), 4.90 (p, J=7.5 Hz, 1H), 2.09-2.03 (m, 2H), 1.97 (dd, J=8.6, 5.2 Hz, 2H), 1.90 (ddd, J=14.2, 9.4, 4.1 Hz, 2H), 1.73-1.65 (m, 2H), 1.61 (d, J=7.0 Hz, 3H).
Example 61
Synthesis of Compound WYQ-47




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), 4-trifluoromethylbenzylamine (105 mg, 0.6 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (92 mg, 81%) were obtained.
MS (ESI−): m/z: 376 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.65 (brs, 1H), 7.73 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.10 (t, J=5.8 Hz, 1H), 4.89-4.79 (m, 1H), 4.61 (d, J=5.8 Hz, 2H), 1.96-1.73 (m, 6H), 1.63-1.53 (m, 2H).
Example 62
Synthesis of Compound WYQ-48




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. Compound M-4 (71 mg, 0.3 mmol), N-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (45 mg, 46%) were obtained.
MS (ESI−): m/z: 322 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 7.76 (s, 1H), 7.39-7.23 (m, 5H), 4.96-4.86 (m, 1H), 4.82 (s, 2H), 3.08 (s, 3H), 2.03-1.76 (m, 6H), 1.60 (dd, J=9.9, 5.3 Hz, 2H).
Example 63
Synthesis of Compound WYQ-49




Compound M-6 (76 mg, 0.3 mmol) obtained in Example 6, 4-chlorobenzylamine (85 mg, 0.6 mmol), triethylamine (40 mg, 0.4 mmol), and isopropanol (6 ml) were added into a reaction tube, and were reacted at 100° C. for 1 hour after the tube was sealed. After the reaction, the solvent was removed by rotatary evaporation. The reaction product was separated and purified via column chromatography (CH2Cl2:MeOH=20:1), and finally, white solids were obtained (76 mg, 71%).
MS (ESI−): m/z: 356 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 11.04 (brs, 1H), 7.52 (s, 1H), 7.31 (q, J=8.5 Hz, 4H), 6.87 (brs, 1H), 4.62 (d, J=4.4 Hz, 2H), 4.46-4.36 (m, 1H), 1.97-1.69 (m, 7H), 1.49-1.27 (m, 3H).
Example 64
Synthesis of Compound WYQ-50




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 3-chlorobenzylamine (85 mg, 0.6 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (82 mg, 77%) were obtained.
MS (ESI−): m/z: 356 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.61 (brs, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 7.37-7.32 (m, 2H), 7.32-7.26 (m, 1H), 7.08 (t, J=5.8 Hz, 1H), 4.48 (d, J=5.9 Hz, 2H), 4.35-4.25 (m, 1H), 1.83-1.63 (m, 7H), 1.41-1.16 (m, 3H).
Example 65
Synthesis of Compound WYQ-51




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 2-chlorobenzylamine (85 mg, 0.6 mmol), and isopropanol (6 ml) were reacted. The reaction product was separated and purified, and finally white solids (75 mg, 70%) were obtained.
MS (ESI−): m/z: 356 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.15 (brs, 1H), 7.70 (s, 1H), 7.52-7.41 (m, 2H), 7.32-7.24 (m, 2H), 7.09 (t, J=5.7 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 4.36-4.21 (m, 1H), 1.81-1.61 (m, 7H), 1.41-1.14 (m, 3H).
Example 66
Synthesis of Compound WYQ-52




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 4-methoxybenzylamine (50 mg, 0.36 mmol), and isopropanol (0.6 ml) were reacted. The reaction product was separated and purified, and finally white solids (76 mg, 72%) were obtained.
MS (ESI−): m/z: 352 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.95 (brs, 1H), 7.44 (s, 1H), 7.32 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 4.58 (d, J=3.1 Hz, 2H), 4.51-4.40 (m, 1H), 3.80 (s, 3H), 2.02-1.68 (m, 7H), 1.49-1.25 (m, 3H).
Example 67
Synthesis of Compound WYQ-53




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 3-methoxybenzylamine (50 mg, 0.36 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (78 mg, 74%) were obtained.
MS (ESI−): m/z: 352 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.46 (brs, 1H), 7.72 (s, 1H), 7.24 (dd, J=11.6, 4.3 Hz, 1H), 6.97 (d, J=1.4 Hz, 2H), 6.85-6.79 (m, 1H), 4.47 (d, J=5.7 Hz, 2H), 4.33 (ddd, J=15.2, 10.0, 5.2 Hz, 1H), 3.73 (s, 3H), 1.88-1.60 (m, 7H), 1.45-1.13 (m, 3H).
Example 68
Synthesis of Compound WYQ-54




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 2-methoxybenzylamine (50 mg, 0.36 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (77 mg, 73%) were obtained.
MS (ESI−): m/z: 352 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.95 (brs, 1H), 7.62 (s, 1H), 7.41 (dd, J=7.4, 1.6 Hz, 1H), 7.30-7.24 (m, 1H), 6.90 (ddd, J=8.2, 6.7, 2.9 Hz, 2H), 4.63 (d, J=5.7 Hz, 2H), 4.55-4.43 (m, 1H), 3.83 (s, 3H), 2.03-1.69 (m, 7H), 1.54-1.28 (m, 3H).
Example 69
Synthesis of Compound WYQ-55




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 4-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (78 mg, 77%) were obtained.
MS (ESI−): m/z: 336 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.86 (s, 1H), 7.34 (s, 1H), 7.29 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 4.60 (d, J=4.8 Hz, 2H), 4.52-4.38 (m, 1H), 2.34 (s, 3H), 2.02-1.68 (m, 7H), 1.48-1.26 (m, 3H).
Example 70
Synthesis of Compound WYQ-56




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 2,5-dimethoxybenzylamine (100 mg, 0.6 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (85 mg, 74%) were obtained.
MS (ESI−): m/z: 382 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.89 (brs, 1H), 7.62 (s, 1H), 7.31 (d, J=8.2 Hz, 1H), 6.81 (s, 1H), 6.51-6.34 (m, 2H), 4.55 (d, J=5.2 Hz, 2H), 4.48 (dd, J=14.6, 7.0 Hz, 1H), 3.78 (s, 6H), 2.01-1.73 (m, 7H), 1.37 (dd, J=44.9, 32.2 Hz, 3H).
Example 71
Synthesis of Compound WYQ-57




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 3,4-methylenedioxybenzylamine (68 mg, 0.45 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (82 mg, 74%) were obtained.
MS (ESI−): m/z: 366 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.44 (brs, 1H), 7.71 (s, 1H), 6.98 (d, J=1.1 Hz, 1H), 6.93-6.82 (m, 2H), 6.85 (brs, 1H), 5.97 (s, 2H), 4.39 (d, J=5.7 Hz, 2H), 4.37-4.28 (m, 1H), 1.86-1.62 (m, 7H), 1.45-1.17 (m, 3H).
Example 72
Synthesis of Compound WYQ-58




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), α-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (72 mg, 71%) were obtained.
MS (ESI−): m/z: 336 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.70 (brs, 1H), 7.60 (s, 1H), 7.47-7.41 (m, 2H), 7.35 (dd, J=10.2, 4.7 Hz, 2H), 7.28-7.23 (m, 1H), 7.21 (d, J=6.7 Hz, 1H), 5.21 (p, J=6.8 Hz, 1H), 4.44-4.32 (m, 1H), 2.01-1.74 (m, 7H), 1.66 (d, J=6.9 Hz, 3H), 1.50-1.28 (m, 3H).
Example 73
Synthesis of Compound WYQ-59




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 3-pyridinebenzylamine (65 mg, 0.6 mmol), and isopropanol (6 ml) were reacted. The reaction product was separated and purified, and finally white solids (61 mg, 63%) were obtained.
MS (ESI−): m/z: 323 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 11.04 (brs, 1H), 8.69 (s, 1H), 8.53 (d, J=4.0 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.55 (s, 1H), 6.84 (t, J=5.7 Hz, 1H), 4.66 (d, J=5.6 Hz, 2H), 4.46-4.33 (m, 1H), 1.84 (p, J=12.6 Hz, 7H), 1.37 (ddd, J=61.4, 19.9, 11.1 Hz, 3H).
Example 74
Synthesis of Compound WYQ-60




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), benzylamine (64 mg, 0.6 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (69 mg, 71%) were obtained.
MS (ESI−): m/z: 322 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.97 (brs, 1H), 7.45-7.30 (m, 6H), 6.95 (brs, 1H), 4.68 (d, J=4.6 Hz, 2H), 4.53-4.40 (m, 1H), 2.01-1.72 (m, 7H), 1.52-1.31 (m, 3H).
Example 75
Synthesis of Compound WYQ-61




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 4-methoxybenzenamine (111 mg, 0.9 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (76 mg, 74%) were obtained.
MS (ESI−): m/z: 338 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.52 (brs, 1H), 8.67 (s, 1H), 7.86 (s, 1H), 7.60-7.52 (m, 2H), 6.94 (d, J=9.0 Hz, 2H), 4.51-4.39 (m, 1H), 3.84 (s, 3H), 2.01-1.72 (m, 7H), 1.48-1.27 (m, 3H).
Example 76
Synthesis of Compound WYQ-62




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 4-ethoxybenzenamine (123 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (74 mg, 70%) were obtained.
MS (ESI−): m/z: 352 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.56 (brs, 1H), 8.75 (brs, 1H), 7.84 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 4.49-4.37 (m, 1H), 4.05 (q, J=7.0 Hz, 2H), 2.01-1.72 (m, 7H), 1.45 (d, J=7.0 Hz, 3H), 1.47-1.25 (m, 3H).
Example 77
Synthesis of Compound WYQ-63




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 4-isopropoxybenzenamine (136 mg, 0.9 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (84 mg, 76%) were obtained.
MS (ESI−): m/z: 366 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.47 (brs, 1H), 8.62 (brs, 1H), 7.87 (s, 1H), 7.54 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 4.54 (dt, J=12.1, 6.1 Hz, 1H), 4.50-4.40 (m, 1H), 2.02-1.73 (m, 17H), 1.36 (d, J=6.1 Hz, 6H), 1.47-1.26 (m, 3H).
Example 78
Synthesis of Compound WYQ-64




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 2,4-dichlorobenzylamine (106 mg, 0.6 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (90 mg, 77%) were obtained.
MS (ESI−): m/z: 390 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.59 (brs, 1H), 7.71 (s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 2.1 Hz, 1H), 7.12 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.32-4.20 (m, 1H), 1.80-1.62 (m, 7H), 1.35 (dd, J=9.2, 3.3 Hz, 2H), 1.16 (d, J=13.8 Hz, 1H).
Example 79
Synthesis of Compound WYQ-65




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 1-(4-chlorphenyl)ethylamine (93 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (63 mg, 57%) were obtained.
MS (ESI−): m/z: 370 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.76 (brs, 1H), 7.67 (s, 1H), 7.36-7.32 (m, 2H), 7.30-7.26 (m, 2H), 6.98 (d, J=6.6 Hz, 1H), 5.12 (p, J=6.8 Hz, 1H), 4.30 (tt, J=9.5, 4.6 Hz, 1H), 1.93-1.76 (m, 7H), 1.61 (d, J=7.0 Hz, 3H), 1.44-1.27 (m, 3H).
Example 80
Synthesis of Compound WYQ-66




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), 4-trifluoromethylbenzylamine (105 mg, 0.6 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (40 mg, 34%) were obtained.
MS (ESI−): m/z: 390 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.68 (brs, 1H), 7.70 (s, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.13 (t, J=5.7 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 4.28-4.15 (m, 1H), 1.81-1.61 (m, 7H), 1.35-1.12 (m, 3H).
Example 81
Synthesis of Compound WYQ-67




The synthesis method was the same as that for the method for the synthesis of compound WYQ-49 in Example 63. Compound M-6 (76 mg, 0.3 mmol), N-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (62 mg, 61%) were obtained.
MS (ESI−): m/z: 336 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.29 (brs, 1H), 7.80 (s, 1H), 7.36-7.27 (m, 5H), 4.86 (s, 2H), 4.43 (dt, J=15.6, 8.7 Hz, 1H), 3.20 (s, 3H), 1.99-1.68 (m, 7H), 1.46-1.26 (m, 3H).
Example 82
Synthesis of Compound WYQ-68




Compound M-8 (68 mg, 0.3 mmol) obtained in Example 8, 4-chlorobenzylamine (85 mg, 0.6 mmol), triethylamine (40 mg, 0.4 mmol), and isopropanol (4 ml) were added into a reaction tube, and were reacted at 100° C. for 1 hour after the tube was sealed. After the reaction, the solvent was removed by rotatary evaporation. The reaction product was separated and purified via column chromatography (CH2Cl2:MeOH=20:1), and finally, white solids were obtained (66 mg, 66%).
MS (ESI−): m/z: 330 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.59 (brs, 1H), 7.74 (s, 1H), 7.41-7.33 (m, 4H), 7.03 (t, J=5.7 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 3.85 (d, J=7.1 Hz, 2H), 2.07 (dp, J=13.6, 6.8 Hz, 1H), 0.76 (d, J=6.7 Hz, 6H).
Example 83
Synthesis of Compound WYQ-69




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 3-chlorobenzylamine (85 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (70 mg, 70%) were obtained.
MS (ESI−): m/z: 330 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.62 (brs, 1H), 7.74 (s, 1H), 7.46-7.41 (m, 1H), 7.35-7.27 (m, 3H), 7.07 (t, J=5.8 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 3.86 (d, J=7.2 Hz, 2H), 2.09 (dp, J=13.7, 6.8 Hz, 1H), 0.76 (d, J=6.7 Hz, 6H).
Example 84
Synthesis of Compound WYQ-70




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 2-chlorobenzylamine (85 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (64 mg, 64%) were obtained.
MS (ESI−): m/z: 330 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.53 (brs, 1H), 7.74 (s, 1H), 7.45 (ddd, J=7.2, 4.1, 2.7 Hz, 2H), 7.32-7.25 (m, 2H), 7.08 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.9 Hz, 2H), 3.86 (d, J=7.1 Hz, 2H), 2.06 (dp, J=13.7, 6.8 Hz, 1H), 0.74 (d, J=6.7 Hz, 6H).
Example 85
Synthesis of Compound WYQ-71




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 4-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (74 mg, 75%) were obtained.
MS (ESI−): m/z: 326 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.89 (brs, 1H), 7.37 (s, 1H), 7.34-7.29 (m, 2H), 6.91-6.85 (m, 2H), 6.79 (brs, 1H), 4.57 (d, J=5.1 Hz, 2H), 4.00 (d, J=7.2 Hz, 2H), 3.80 (s, 3H), 2.28 (dp, J=13.7, 6.8 Hz, 1H), 0.91 (d, J=6.7 Hz, 6H).
Example 86
Synthesis of Compound WYQ-72




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 3-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (66 mg, 67%) were obtained.
MS (ESI−): m/z: 326 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.91 (brs, 1H), 7.34 (s, 1H), 7.30-7.25 (m, 1H), 7.00-6.92 (m, 2H), 6.85 (dd, J=8.2, 2.0 Hz, 1H), 4.62 (d, J=4.9 Hz, 2H), 3.99 (d, J=7.3 Hz, 2H), 3.77 (s, 3H), 2.27 (dp, J=13.7, 6.8 Hz, 1H), 0.89 (d, J=6.7 Hz, 6H).
Example 87
Synthesis of Compound WYQ-73




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 2-methoxybenzylamine (83 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (71 mg, 72%) were obtained.
MS (ESI−): m/z: 326 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.91 (brs, 1H), 7.54 (s, 1H), 7.40 (dd, J=7.4, 1.6 Hz, 1H), 7.32-7.26 (m, 1H), 6.91 (ddd, J=8.2, 6.6, 2.9 Hz, 2H), 4.63 (d, J=5.7 Hz, 2H), 4.03 (d, J=7.3 Hz, 2H), 3.83 (s, 3H), 2.31 (dp, J=13.7, 6.9 Hz, 1H), 0.93 (d, J=6.7 Hz, 6H).
Example 88
Synthesis of Compound WYQ-74




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 4-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (3 ml) were reacted. The reaction product was separated and purified, and finally white solids (70 mg, 75%) were obtained.
MS (ESI−): m/z: 310 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.45 (brs, 1H), 7.74 (s, 1H), 7.26 (d, J=7.9 Hz, 2H), 7.12 (d, J=7.8 Hz, 2H), 6.93 (t, J=5.5 Hz, 1H), 4.45 (d, J=5.7 Hz, 2H), 3.88 (d, J=7.1 Hz, 2H), 2.26 (s, 3H), 2.12 (dp, J=13.6, 6.8 Hz, 1H), 0.80 (d, J=6.7 Hz, 6H).
Example 89
Synthesis of Compound WYQ-75




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 2,5-dimethoxybenzylamine (100 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (74 mg, 69%) were obtained.
MS (ESI−): m/z: 356 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.92 (brs, 1H), 7.63 (s, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.72 (brs, 1H), 6.49-6.39 (m, 2H), 4.55 (d, J=5.8 Hz, 2H), 4.03 (d, J=7.2 Hz, 2H), 3.80 (d, J=5.1 Hz, 6H), 2.31 (dp, J=13.6, 6.8 Hz, 1H), 0.94 (d, J=6.7 Hz, 6H).
Example 90
Synthesis of Compound WYQ-76




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 3,4-methylenedioxybenzylamine (68 mg, 0.45 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (73 mg, 72%) were obtained.
MS (ESI−): m/z: 3406 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.45 (brs, 1H), 7.74 (s, 1H), 6.96 (s, 1H), 6.91 (t, J=5.5 Hz, 1H), 6.88-6.82 (m, 2H), 5.97 (s, 2H), 4.40 (d, J=5.8 Hz, 2H), 3.90 (d, J=7.1 Hz, 2H), 2.13 (dp, J=13.6, 6.8 Hz, 1H), 0.81 (d, J=6.7 Hz, 6H).
Example 91
Synthesis of Compound WYQ-77




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), α-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (6 ml) were reacted. The reaction product was separated and purified, and finally white solids (52 mg, 54%) were obtained.
MS (ESI−): m/z: 310 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.66 (brs, H), 7.48 (s, H), 7.43-7.39 (m, 2H), 7.36-7.29 (m, 2H), 7.29-7.21 (m, 1H), 7.16 (d, J=6.9 Hz, 1H), 5.20 (p, J=6.8 Hz, 1H), 4.00-3.88 (m, 2H), 2.28-2.11 (m, 1H), 1.64 (d, J=6.9 Hz, 3H), 0.85 (dd, J=28.4, 6.7 Hz, 6H).
Example 92
Synthesis of Compound WYQ-78




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 3-pyridinebenzylamine (65 mg, 0.6 mmol), and isopropanol (0.6 ml) were reacted. The reaction product was separated and purified, and finally white solids (54 mg, 60%) were obtained.
MS (ESI−): m/z: 297 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.64 (brs, 1H), 8.61 (d, J=1.5 Hz, 1H), 8.45 (dd, J=4.7, 1.3 Hz, 1H), 7.77 (m, 1H), 7.74 (s, 1H), 7.34 (dd, J=7.8, 4.8 Hz, 1H), 7.09 (t, J=5.7 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 3.86 (d, J=7.1 Hz, 2H), 2.07 (dp, J=13.7, 6.9 Hz, 1H), 0.76 (d, J=6.7 Hz, 6H).
Example 93
Synthesis of Compound WYQ-79




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), benzylamine (64 mg, 0.6 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (58 mg, 65%) were obtained.
MS (ESI−): m/z: 296 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.50 (brs, 1H), 7.75 (s, 1H), 7.40-7.30 (m, 4H), 7.25 (ddd, J=7.1, 3.8, 1.4 Hz, 1H), 7.00 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 3.88 (d, J=7.1 Hz, 2H), 2.11 (dp, J=13.7, 6.8 Hz, 1H), 0.79 (d, J=6.7 Hz, 6H).
Example 94
Synthesis of Compound WYQ-80




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 4-methoxy (111 mg, 0.9 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (75 mg, 80%) were obtained.
MS (ESI−): m/z: 312 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.90 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.2 Hz, 2H), 4.04 (d, J=6.8 Hz, 2H), 3.84 (s, 3H), 2.36-2.28 (m, 1H), 0.96 (d, J=6.6 Hz, 6H).
Example 95
Synthesis of Compound WYQ-81




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 4-ethoxy (123 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (60 mg, 60%) were obtained.
MS (ESI−): m/z: 326 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.60 (brs, 1H), 8.69 (brs, 1H), 7.86 (s, 1H), 7.55 (d, J=8.9 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 4.09-3.97 (m, 4H), 2.31 (dp, J=13.4, 6.7 Hz, 1H), 1.44 (t, J=7.0 Hz, 3H), 0.95 (d, J=6.7 Hz, 6H).
Example 96
Synthesis of Compound WYQ-82




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 4-isopropoxy (136 mg, 0.9 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (70 mg, 68%) were obtained.
MS (ESI−): m/z: 340 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.51 (brs, 1H), 8.69 (brs, 1H), 7.89 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 4.54 (dt, J=12.0, 6.0 Hz, 1H), 4.03 (d, J=7.1 Hz, 2H), 2.32 (dt, J=13.6, 6.8 Hz, 1H), 1.36 (d, J=6.0 Hz, 6H), 0.95 (d, J=6.6 Hz, 6H).
Example 97
Synthesis of Compound WYQ-83




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 2,4-dichlorobenzylamine (132 mg, 0.75 mmol), and isopropanol (1 ml) were reacted. The reaction product was separated and purified, and finally white solids (74 mg, 67%) were obtained.
MS (ESI−): m/z: 364 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.46 (brs, 1H), 7.74 (s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.38 (dd, J=8.3, 2.1 Hz, 1H), 7.13 (t, J=5.8 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H), 3.84 (d, J=7.1 Hz, 2H), 2.03 (dp, J=13.7, 6.8 Hz, 1H), 0.73 (d, J=6.7 Hz, 6H).
Example 98
Synthesis of Compound WYQ-84




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 1-(4-chlorphenyl)ethylamine (93 mg, 0.6 mmol), and isopropanol (2 ml) were reacted. The reaction product was separated and purified, and finally white solids (61 mg, 58%) were obtained.
MS (ESI−): m/z: 344 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.79 (brs, 1H), 7.65 (s, 1H), 7.31 (td, J=8.6, 6.5 Hz, 4H), 6.88 (d, J=6.7 Hz, 1H), 5.13 (p, J=6.8 Hz, 1H), 3.96-3.85 (m, 2H), 2.21-2.10 (m, 1H), 1.61 (d, J=7.0 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.7 Hz, 3H).
Example 99
Synthesis of Compound WYQ-85




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), 4-trifluoromethylbenzylamine (105 mg, 0.6 mmol), and isopropanol (5 ml) were reacted. The reaction product was separated and purified, and finally white solids (59 mg, 54%) were obtained.
MS (ESI−): m/z: 364 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.73 (brs, 1H), 7.74 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.16 (t, J=5.6 Hz, 1H), 4.58 (d, J=5.8 Hz, 2H), 3.80 (d, J=7.2 Hz, 2H), 1.98 (dt, J=13.6, 6.8 Hz, 1H), 0.67 (d, J=6.7 Hz, 6H).
Example 100
Synthesis of Compound WYQ-86




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. Compound M-8 (68 mg, 0.3 mmol), N-methylbenzylamine (73 mg, 0.6 mmol), and isopropanol (4 ml) were reacted. The reaction product was separated and purified, and finally white solids (39 mg, 42%) were obtained.
MS (ESI−): m/z: 310 ([M−H]−)1H NMR (400 MHz, DMSO) δ 7.78 (s, 1H), 7.37-7.22 (m, 5H), 4.80 (s, 2H), 3.88 (d, J=7.1 Hz, 2H), 3.08 (s, 3H), 2.11 (dp, J=13.6, 6.8 Hz, 1H), 0.79 (d, J=6.7 Hz, 6H).
Example 101
Synthesis of Compound WYQ-87-D




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 1. The reaction product was separated and purified, and finally, white solids were obtained (55 mg, 50%).
MS (ESI−): m/z: 369 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.41 (d, J=8.9 Hz, 2H), 6.83 (d, J=8.9 Hz, 2H), 4.85-4.78 (m, 2H), 4.70-4.62 (m, 1H), 3.77 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.45 (dd, J=14.9, 6.7 Hz, 6H).
Example 102
Synthesis of Compound WYQ-87-L




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 1. The reaction product was separated and purified, and finally, white solids were obtained (50 mg, 45%).
MS (ESI−): m/z: 369 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.44 (brs, 1H), 10.08 (s, 1H), 7.75 (s, 1H), 7.54-7.48 (m, 2H), 6.92 (d, J=6.9 Hz, 1H), 6.91-6.86 (m, 2H), 4.77-4.69 (m, 1H), 4.59 (p, J=6.8 Hz, 1H), 3.72 (s, 3H), 1.44 (d, J=6.9 Hz, 3H), 1.38 (d, J=6.7 Hz, 3H), 1.31 (d, J=6.7 Hz, 3H).
Example 103
Synthesis of Compound WYQ-88




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 1. The reaction product was separated and purified, and finally, white solids were obtained (39 mg, 37%)
MS (ESI−): m/z: 355 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 10.02 (s, 1H), 7.75 (s, 1H), 7.49 (d, J=9.0 Hz, 2H), 6.88 m, 3H), 4.78-4.67 (m, 1H), 4.14 (d, J=5.1 Hz, 2H), 3.72 (s, 3H), 1.36 (d, J=6.7 Hz, 6H).
Example 104
Synthesis of Compound WYQ-89




The synthesis method was the same as that for the method for the synthesis of compound WYQ-1 in Example 1. The reaction product was separated and purified, and finally, white solids were obtained (50 mg, 45%).
MS (ESI−): m/z: 369 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.56 (s, 1H), 7.66 (s, 1H), 7.46 (d, J=8.8 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 6.58 (s, 1H), 4.80 (dt, J=13.1, 6.6 Hz, 1H), 3.70 (d, J=1.0 Hz, 3H), 3.58 (s, 2H), 2.59 (t, J=5.3 Hz, 2H), 1.41 (dd, J=6.6, 1.1 Hz, 6H).
Example 105
Synthesis of Compound WYQ-90-D




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. The reaction product was separated and purified, and finally, white solids were obtained (45 mg, 38%).
MS (ESI−): m/z: 395 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.1 Hz, 2H), 4.86-4.77 (m, 1H), 4.46 (q, J=6.9 Hz, 1H), 3.68 (s, 3H), 1.92 (dd, J=8.4, 5.0 Hz, 2H), 1.75 (t, J=7.2 Hz, 4H), 1.62-1.45 (m, 2H), 1.40 (d, J=7.0 Hz, 3H).
Example 106
Synthesis of Compound WYQ-90-L




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. The reaction product was separated and purified, and finally, white solids were obtained (49 mg, 42%).
MS (ESI−): m/z: 395 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 10.08 (s, 1H), 7.75 (s, 1H), 7.55-7.49 (m, 2H), 6.93-6.86 (m, 3H), 4.88 (p, J=7.3 Hz, 1H), 4.56 (p, J=6.8 Hz, 1H), 3.72 (s, 3H), 2.02-1.92 (m, 2H), 1.88-1.77 (m, 4H), 1.63-1.51 (m, 2H), 1.44 (d, J=6.9 Hz, 3H).
Example 107
Synthesis of Compound WYQ-91




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. The reaction product was separated and purified, and finally, white solids were obtained (39 mg, 34%).
MS (ESI−): m/z: 381 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 7.76 (s, 1H), 7.50 (d, J=9.0 Hz, 2H), 6.92-6.84 (m, 3H), 4.89 (p, J=7.4 Hz, 1H), 4.13 (d, J=5.1 Hz, 2H), 3.72 (s, 3H), 1.99-1.87 (m, 4H), 1.87-1.75 (m, 2H), 1.65-1.52 (m, 2H).
Example 108
Synthesis of Compound WYQ-92




The synthesis method was the same as that for the method for the synthesis of compound WYQ-25 in Example 39. The reaction product was separated and purified, and finally, white solids were obtained (43 mg, 37%).
MS (ESI−): m/z: 395 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 8.98 (s, 1H), 7.67 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 6.65 (d, J=8.8 Hz, 2H), 6.49 (s, 1H), 4.86 (p, J=7.5 Hz, 1H), 3.67-3.61 (m, 2H), 3.61 (s, 3H), 2.54 (t, J=5.8 Hz, 2H), 1.97-1.84 (m, 4H), 1.83-1.73 (m, 2H), 1.58-1.47 (m, 2H).
Example 109
Synthesis of Compound WYQ-93-D




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. The reaction product was separated and purified, and finally, white solids were obtained (43 mg, 37%).
MS (ESI−): m/z: 383 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.51-7.44 (m, 2H), 6.88-6.82 (m, 2H), 4.47 (q, J=6.9 Hz, 1H), 3.92-3.74 (m, 2H), 3.68 (s, 3H), 2.05 (dp, J=13.6, 6.8 Hz, 1H), 1.40 (d, J=7.0 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H), 0.63 (d, J=6.7 Hz, 3H).
Example 110
Synthesis of Compound WYQ-94-D




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. The reaction product was separated and purified, and finally, white solids were obtained (50 mg, 38%).
MS (ESI−): m/z: 437 ([M−H]−); 1H NMR (300 MHz, CDCl3) δ 10.59 (brs, 1H), 8.17 (brs, 1H), 8.12 (s, 1H), 7.53-7.45 (m, 2H), 7.41-7.29 (m, 2H), 7.09 (d, J=8.9 Hz, 2H), 7.00 (d, J=5.0 Hz, 1H), 6.77 (d, J=8.9 Hz, 2H), 4.50 (p, J=6.8 Hz, 1H), 3.76 (s, 3H), 1.49 (d, J=6.9 Hz, 3H).
Example 111
Synthesis of Compound WYQ-95




The synthesis method was the same as that for the method for the synthesis of compound WYQ-68 in Example 82. The reaction product was separated and purified, and finally, white solids were obtained (43 mg, 34%).
MS (ESI−): m/z: 423 ([M−H]−); 1H NMR (400 MHz, DMSO) δ 10.87 (brs, 1H), 9.93 (s, 1H), 8.05 (s, 1H), 7.66-7.62 (m, 1H), 7.55-7.49 (m, 2H), 7.47-7.38 (m, 3H), 7.01 (brs, 1H), 6.92-6.85 (m, 2H), 3.98 (d, J=4.7 Hz, 2H), 3.72 (s, 3H).
Inhibition activities of all the N-substituted pyrazolo [3,4-d] pyrimidine ketone compounds according to the present invention to the phosphodiesterase IX are tested. The IC50 value is the concentration of the inhibitor when the inhibition rate reaches 50%. The test results are listed in the following table.














Compound
IC50 (nM)



















WYQ-1
19



WYQ-2
47



WYQ-3
50



WYQ-4
121



WYQ-5
140



WYQ-6
83



WYQ-7
42



WYQ-8
70



WYQ-9
40



WYQ-10
111



WYQ-11
114



WYQ-12
78



WYQ-13
690



WYQ-14
162



WYQ-15
400



WYQ-16
607



WYQ-17
584



WYQ-18
319



WYQ-19
695



WYQ-20
235



WYQ-21
25



WYQ-22
23



WYQ-23
120



WYQ-24
105



WYQ-25
4



WYQ-26
20



WYQ-27
14



WYQ-28
20



WYQ-29
52



WYQ-30
25



WYQ-31
14



WYQ-32
15



WYQ-33
29



WYQ-34
39



WYQ-35
33



WYQ-36
17



WYQ-37
84



WYQ-38
98



WYQ-39
148



WYQ-40
380



WYQ-41
292



WYQ-42
179



WYQ-43
253



WYQ-44
125



WYQ-45
8



WYQ-46
6



WYQ-47
40



WYQ-48
20



WYQ-49
23



WYQ-50
18



WYQ-51
28



WYQ-52
39



WYQ-53
28



WYQ-54
39



WYQ-55
43



WYQ-56
36



WYQ-57
29



WYQ-58
54



WYQ-59
26



WYQ-60
19



WYQ-61
193



WYQ-62
908



WYQ-63
303



WYQ-64
76



WYQ-65
79



WYQ-66
163



WYQ-67
58



WYQ-68
15



WYQ-69
17



WYQ-70
19



WYQ-71
46



WYQ-72
25



WYQ-73
44



WYQ-74
53



WYQ-75
43



WYQ-76
32



WYQ-77
80



WYQ-78
45



WYQ-79
12



WYQ-80
1055



WYQ-81
743



WYQ-82
560



WYQ-83
21



WYQ-84
47



WYQ-85
121



WYQ-86
37



WYQ-87-D
1



WYQ-87-L
303



WYQ-88
26



WYQ-89
26



WYQ-90-D 
0.6



WYQ-90-L
3



WYQ-91
6



WYQ-92
6



WYQ-93-D
18



WYQ-94-D
6



WYQ-95
52










As seen from the above test results, the N-substituted pyrazolo [3,4-d] pyrimidine ketone compound according to the present invention achieves an inhibition effect on the phosphodiesterase IX, and may be used as an inhibitor of the phosphodiesterase IX and have a wide application prospect.

## Claims

1. A compound of formula (I):



wherein
R′ is selected from the group consisting of isopropyl, cyclopentyl, cyclohexyl, and isobutyl; and
when R′′═CH3, R represents benzyl; and
when R′′═H, R is selected from the group consisting of L-configured CHCH3CONHR′′′, D-configured CHCH3CONHR′′′, L-configured CH2CONHR′′′, D-configured CH2CONHR′′′, L-configured CH2CH2CONHR′′′, D-configured CH2CH2CONHR′′′, 3-methylpyridine, 1-phenylethyl, 1-(4-chlorophenyl)ethyl,




wherein R′′′ is p-methoxyphenyl,
R1 is selected from the group consisting of hydrogen, chlorine, methoxy, methyl, trifluoromethyl, dimethoxy, methylenedioxy, and dichlorine, and
R2 is selected from the group consisting of hydrogen, methoxy, ethoxy, isopropoxy, methyl, dimethoxy, and 2-methyl-4-methoxy.

2. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds of formulas (II), (III), (IV), (V), (VII), (VIII), (IX), and (X):



wherein
R′ is selected from the group consisting of isopropyl, cyclopentyl, cyclohexyl, and isobutyl;
R1 in formula (II) is selected from the group consisting of hydrogen, methyl, methoxy, 2,4-dimethoxy, 3,4-methylenedioxy, chlorine, 2,4-dichlorine, and trifluoromethyl;
R2 in formula (III) is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, isopropoxy, 2-methyl-4-methoxy, and 2,5-dimethoxy; and
R3 in formula (IV) is selected from the group consisting of hydrogen and chlorine.

3. A process for the preparation of an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound as defined in claim 1, comprising the following steps:
(1) reacting using 2,4,6-trichloro-5-pyrimidinecarbaldehyde and hydrazine as starting materials, triethylamine as a base, and ethanol as a solvent at temperature −78° C. to obtain a compound A, wherein a molar ratio of 2,4,6-trichloro-5-pyrimidinecarbaldehyde to hydrazine to triethylamine is 1:1-1.1:2-3, and 2,4,6-trichloro-5-pyrimidinecarbaldehyde has a concentration of 0.05 to 1.0 mol/L,




(2) hydrolyzing the compound A under a basic condition to obtain a compound B, wherein a molar ratio of the compound A to a base is 1:10-40, and the compound A has a concentration of 0.05 to 0.5 mol/L,





and
(3) reacting the compound B with an amine compound in the presence of triethylamine as a base to obtain a target compound I, wherein a molar ratio of the compound B to triethylamine to the amine compound is 1:1.3:1.2-3, and the compound B has a concentration of 0.05 to 0.5 mol/L,

4. The process for the preparation of an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound according to claim 3, wherein the base in step (2) is selected from sodium hydroxide and potassium hydroxide.

5. The process for the preparation of an N-substituted pyrazolo [3,4-d] pyrimidine ketone compound according to claim 3, wherein step (3) is performed based on heating-based tube sealing.