Selective Butyrylcholinesterase Inhibitor or Pharmaceutically Acceptable Salt Thereof, Preparation Method and Use Thereof

Abstract

The present invention discloses a selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and use thereof. The treatment efficacy of Alzheimer’s disease, especially moderate to severe Alzheimer’s disease, is tested through butyrylcholinesterase inhibitory activity, selectivity screening and toxicity to nerve cells as a carrier, and it is found that it has good target activity in vitro, extremely high selectivity and drug safety, can be used as a lead substance for further development of the treatment of Alzheimer’s disease by selectively inhibiting butyrylcholinesterase.

Claims

1. A selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof, ##STR00083## wherein n is an integer from 0 to 3; R.sub.1 represents ##STR00084## or thiophene, furan, pyrrole, pyridine, thiazole, imidazole or cyclohexane substituted with R.sub.4; wherein R.sub.3 represents hydroxyl, C.sub.1-C.sub.4 carboxyl, C.sub.1-C.sub.4 aldehyde group, halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with halogen, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxycarbonyl, C.sub.1-C.sub.4 acyl, cyano, nitro or -NR.sub.5R.sub.6, where R.sub.5 and R.sub.6 represent hydrogen or C.sub.1-C.sub.3 alkyl respectively; R.sub.4 represents hydrogen or C.sub.1-C.sub.4 alkyl; R.sub.2 represents hydrogen or -CH.sub.2N(R.sub.7).sub.2, where R.sub.7 is C.sub.1-C.sub.3 alkyl.

2. The selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1: wherein n is 0 or 1; R.sub.1 represents ##STR00085## or thiophene, furan, pyrrole, pyridine, thiazole, imidazole or cyclohexane substituted with R.sub.4; wherein R.sub.3 represents hydrogen or substituted hydroxyl, carboxyl, aldehyde group, fluorine, chlorine, bromine, iodine, methyl, isopropyl, trifluoromethyl, methoxy, methoxycarbonyl, acetyl, cyano, nitro or -NR.sub.5R.sub.6, where R.sub.5 and R.sub.6 represent hydrogen or methyl respectively; R.sub.4 represents hydrogen; R.sub.2 represents hydrogen or —CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2N(C.sub.2H.sub.5).sub.2, or —CH.sub.2N(C.sub.3H.sub.7).sub.2.

3. The selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1: wherein n is 0 or 1; R.sub.1 represents fluorine, phenyl mono- or poly-substituted with methyl, unsubstituted or methyl-substituted thiophene, furan, pyrrole, pyridine, thiazole, imidazole or cyclohexane; R.sub.2 represents —CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2N(C.sub.2H.sub.5).sub.2, or —CH.sub.2N(C.sub.3H.sub.7).sub.2.

4. The selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof is any one of the following: ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## .

5. The selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the selective butyrylcholinesterase inhibitor is hydrochloride, maleate or citrate.

6. A pharmaceutical composition containing a therapeutically effective amount of one or more selective butyrylcholinesterase inhibitors having a general formula (I) or a pharmaceutically acceptable salt thereof according to claims 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, the pharmaceutical composition further containing a pharmaceutically acceptable auxiliary material.

8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a tablet, capsule, powder, syrup, liquid, suspension or injection.

9. The selective butyrylcholinesterase inhibitor having a general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the selective butyrylcholinesterase inhibitor is prepared by a preparation method that comprises: taking 3-aminobenzoic acid as a starting material, forming a corresponding amide intermediate ##STR00124## with an aromatic acid having a different ring system and different substituents, and then reacting with an intermediate ##STR00125## to prepare the selective butyrylcholinesterase inhibitor having general formula (I) or a pharmaceutically acceptable salt thereof; wherein the reaction scheme is as follows: ##STR00126## .

10. A method for treating Alzheimer’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of one or more selective butyrylcholinesterase inhibitors or a pharmaceutically acceptable salt thereof of claim 1.

Description

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Synthesis Of 3-(Thiophen-2-Carboxamido)Benzoic Acid (Intermediate 1)

[0030] 3-aminobenzoic acid (1 g, 7.29 mmol) was placed in an eggplant-shaped flask and dissolved with tetrahydrofuran (10 mL). Triethylamine (0.89 g, 8.75 mmol) was added and a solution ofthiophene-2-formyl chloride (1.28 g, 8.75 mmol) in tetrahydrofuran was added dropwise under an ice bath. After completion of the dropwise addition, the mixture was stirred at normal temperature for 2 hours. After completion of the reaction, the tetrahydrofuran was removed under reduced pressure, dichloromethane was added, the mixture was filtered with suction, the filter cake was washed twice with dichloromethane, and dried to obtain 3-(thiophen-2-carboxamido)benzoic acid (1.7 g, yield 94.44%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d6): δ 13.04 (s, 1H, OH), 10.42 (s, 1H, NH), 8.35 (t, J= 1.5 Hz, 1H, ArH), 8.07 (dd, J.sub.1 = 1 Hz, J.sub.2 = 4 Hz, 1H, ArH), 8.03 (dd, J.sub.1 = 1 Hz, J.sub.2 = 8 Hz, 1H, ArH), 7.89 (dd, J.sub.1 = 1 Hz, J.sub.2 = 4.5 Hz, 1H, ArH), 7.68 (d, J= 8 Hz, 1H, ArH), 7.49 (t, J= 4 Hz, 1H, ArH), 7.24 (t, J= 4.5 Hz, 1H, ArH). MS (ESI): calcd. for C.sub.12H.sub.9NO.sub.3S[M+H].sup.+248.0303 found 248.0720.

Synthesis Ofn-(2-(Aminomethyl)Benzyl)-N-Ethylethylamine (Intermediate 2)

[0031] 2-cyanobenzyl bromide (750 mg, 3.47 mmol) was placed in an eggplant-shaped flask and dissolved with acetonitrile (10 mL). Potassium carbonate (500 mg, 3.62 mmol) was added, a solution of diethylamine (256 mg, 3.5 mmol) in acetonitrile (2 mL) was added dropwise under stirring. After completion of the dropwise addition, the mixture was stirred at normal temperature overnight. After completion of the reaction, suction filtration was performed with diatomaceous earth, and the solvent was removed under reduced pressure to obtain a crude product. The solution of the obtained crude product in anhydrous ether (5 mL) was added dropwise to a suspension of lithium aluminum hydride (0.3 g, 8 mmol) in anhydrous ether (10 mL) under an ice bath. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, 20% sodium hydroxide solution (5 mL) was added dropwise to the reaction flask under an ice bath, and extracted with ether (10 mL each) for three times. The combined organic phase was dried with anhydrous sodium sulfate and separated by silica gel column chromatography to obtain the intermediate N-(2-(aminomethyl)benzyl)-N-ethylethylamine (460 mg, yield 62.50%). .sup.1H NMR (500 MHz, CDCl3): δ 7.28 (dd, J.sub.1 =1.5 Hz, J.sub.2 = 7.5 Hz, 2H, ArH), 7.25 (td, J.sub.1 = 7.5 Hz, J.sub.2 = 1.5 Hz, 2H, ArH), 3.84 (s, 2H, CH.sub.2), 3.60 (s, 2H, CH.sub.2), 2.52 (q, J= 7 Hz, 4H, CH.sub.2), 1.06 (t, J= 7 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.12H.sub.20N.sub.2 [M+H].sup.+ 193.1626 found 193.0690.

Synthesis ofn-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-Carboxamide

[0032] 3-(thiophen-2-carboxamido)benzoic acid (250 mg, 1.01 mmol) was placed in an eggplant-shaped flask and dissolved with dichloromethane (5 mL). After that, 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (480 mg, 1.26 mmol) and N,N-diisopropylethylamine (163 mg, 1.26 mmol) were stirred at room temperature for 1 hour for activation. After completion of the activation, a solution of N-(2-(aminomethyl)benzyl)-N-ethylethylamine (194 mg, 1.01 mmol) in dichloromethane (2 mL) was added dropwise, and reacted at room temperature for 18 hours. The reaction solution was washed once with deionized water, once with a saturated sodium bicarbonate solution, and once with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide (162 mg, yield 46.30%). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.47 (s, 1H, NH), 8.53 (s, 1H, ArH), 8.16 (d, J= 7.5 Hz, 1H, ArH), 7.95 (s, 1H, ArH), 7.77 (d, J= 3.0 Hz, 1H, ArH), 7.56 (dd, J.sub.1= 5.0 Hz, J.sub.2 = 1.0 Hz, 1H, ArH), 7.37 (dt, J.sub.1 = 15.5 Hz, J.sub.2 = 7.5 Hz, 4H, ArH), 7.25 (dd, J.sub.1= 10.0 Hz, J.sub.2 = 4.0 Hz, 2H), 7.14 (dd, J.sub.1 = 5.0 Hz, J.sub.2 = 4.0 Hz, 1H), 4.61 (d, J= 5.0 Hz, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.60 (q, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (t, J= 7.0 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.24H.sub.27N.sub.3O.sub.2S[M+H].sup.+ 422.1824 found 422.2450.

Example 2

Synthesis Ofn,N-Dimethyl-1-(2-Nitrophenyl)Methylamine (Intermediate 3)

[0033] 2-nitrobenzaldehyde (1.00 g, 6.62 mmol) was placed in an eggplant-shaped flask and dissolved with dichloroethane (95 mL). Dimethylamine (447 mg, 9.93 mmol) and zinc chloride (0.90 g, 6.62 mmol) were added. After stirring for 3 hours at room temperature, sodium cyanoborohydride (624 mg, 9.93 mmol) was added. After stirring at room temperature for 18 hours, a saturated sodium bicarbonate solution (40 mL) was added and the stirring was continued for one hour. The mixture was extracted with dichloromethane (100 mL), the organic phase was combined and washed twice with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain N,N-dimethyl-1-(2- nitrophenyl)methylamine (940 mg, yield 79.10%). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.85 (d, J= 8.0 Hz, 1H, ArH), 7.63 (d, J= 7.5 Hz, 1H, ArH), 7.57 (t, J= 7.5 Hz, 1H, ArH), 7.41 (t, J= 8.0 Hz, 1H, ArH), 3.73 (s, 2H, CH.sub.2), 2.25 (s, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.11H.sub.16N.sub.2O.sub.2 [M+H].sup.+ 209.1212 found 209.2458.

Synthesis of 2-((Dimethylamino)Methyl)Aniline (Intermediate 4)

[0034] N,N-dimethyl-1-(2-nitrophenyl)methylamine (405 mg, 2.25 mmol) was placed in an eggplant-shaped flask and dissolved with absolute ethanol (45 mL). Ammonium formate (0.99 g, 15.75 mmol) and 10% palladium on carbon (177 mg, 0.17 mmol) were added. The mixture was stirred at room temperature for one hour, and suction filtration was performed with diatomaceous earth. The solvent was removed via rotary evaporation, and then the residue was dissolved in dichloromethane (30 mL), and washed with deionized water for three times. The organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography to obtain 2-((dimethylamino)methyl)aniline (212 mg, yield 63.10%). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 6.93 (d, J= 8.0 Hz, 1H, ArH), 6.74 (d, J= 7.5 Hz, 1H, ArH), 6.68 (t, J= 7.5 Hz, 1H, ArH), 6.53 (t, J= 8.0 Hz, 1H, ArH), 3.66 (s, 2H, CH.sub.2), 2.16 (s, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.11H.sub.18N.sub.2 [M+H].sup.+ 179.1470 found 179.3024.

Synthesis Ofn-(3-((2-((Dimethylamino)Methyl)Phenyl)Carbamoyl)Phenyl)Thiophene-2-Carboxamide

[0035] 3-(thiophen-2-carboxamido)benzoic acid (250 mg, 1.01 mmol) was placed in an eggplant-shaped flask and dissolved with dichloromethane (5 mL). After that, 2-(7-oxobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (480 mg, 1.26 mmol) and N,N-diisopropylethylamine (163 mg, 1.26 mmol) were added and stirred at room temperature for 1 hour for activation. After activation, a solution of N-(2-(aminomethyl)benzyl)-N-ethylethylamine (167 mg, 1.11 mmol) in dichloromethane (2 mL) was added dropwise, and reacted at room temperature for 18 hours. The reaction solution was washed once with deionized water, once with a saturated sodium bicarbonate solution and once with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain N-(3-((2-((dimethylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide (207 mg, yield 54.11%). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 11.92 (s, 1H, CONH), 8.44 (d, J= 8.1 Hz, 1H, ArH), 8.30 (s, 1H, ArH), 8.15 (s, 1H, ArH), 8.08 (dd, J.sub.1= 8.1, J.sub.2 = 1.4 Hz, 1H, ArH), 7.71 (dd, J.sub.1 = 3.7, J.sub.2 = 0.9 Hz, 1H, ArH), 7.63 (d, J= 7.8 Hz, 1H, ArH), 7.55 (dd, J.sub.1 = 5.0, J.sub.2 =0.9 Hz, 1H, ArH), 7.47 (t, J= 7.8 Hz, 1H, ArH), 7.34 (m, 1H, ArH), 7.14 (d, J= 6.7 Hz, 1H, ArH), 7.09 (dd, J.sub.1 = 5.0, J.sub.2 = 3.7 Hz, 1H, ArH), 7.05 (td, J.sub.1 = 7.4, J.sub.2 = 0.9 Hz, 1H, ArH), 3.60 (s, 2H, CH.sub.2), 2.36 (s, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.21H.sub.21N.sub.3O.sub.2S[M+H].sup.+ 379.1354 found 379.3057.

Example 3

[0036] Synthesis of N-(3-((2-((diethylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide:

[0037] With reference to the synthesis method of Example 2, the intermediate 4 in Example 2 was replaced with 2-((diethylamino)methyl)aniline to obtain a yellow oily liquid compound, namely N-(3-((2-((diethylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide (Compound 3). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 8.41 (d, J= 8.0 Hz, 1H, ArH), 8.19 (d, J= 8.0 Hz, 1H, ArH), 8.14 (s, 1H, ArH), 8.01 (d, J= 1.5 Hz, 1H, ArH), 7.71 (m, 1H, ArH), 7.64 (d, J= 8.0 Hz, 1H, ArH), 7.57 (d, J= 5.0 Hz, 1H, ArH), 7.48 (t, J= 7.8 Hz, 1H, ArH), 7.33 (t, J= 7.8 Hz, 1H, ArH), 7.15 (m, 2H, ArH), 7.06 (t, J= 7.4 Hz, 1H, ArH), 3.73 (s, 2H, CH.sub.2), 2.65 (q, J= 7.1 Hz, 4H, CH.sub.2), 1.05 (t, J= 7.1 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.23H.sub.25N.sub.3O.sub.2S[M+H].sup.+ 408.1667 found 408.2413.

Example 4

[0038] Synthesis of N-(3-((2-((dipropylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide:

[0039] With reference to the synthesis method of Example 2, the intermediate 4 in Example 2 was replaced with 2-((dipropylamino)methyl)aniline to obtain a yellow oily liquid compound, namely N-(3-((2-((dipropylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide (Compound 4). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 11.71 (s, 1H, CONH), 8.41 (d, J= 8.0 Hz, 1H, ArH), 8.18 (d, J= 8.0 Hz, 1H, ArH), 8.02 (s, 1H, ArH), 7.99 (s, 1H, ArH), 7.69 (d, J= 3.0 Hz, 1H, ArH), 7.63 (d, J= 7.5 Hz, 1H, ArH), 7.58 (dd, J= 5.0, 1.0 Hz, 1H, ArH), 7.48 (m, 1H, ArH), 7.34 (m, 2H, ArH), 7.14 (t, J= 4.3 Hz, 1H, ArH), 7.06 (t, J= 7.5 Hz, 1H, ArH), 3.74 (s, 2H, CH.sub.2), 2.49 (m, 4H, CH.sub.2), 1.50 (m, 4H, CH.sub.2), 0.81 (t, J= 7.3 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.25H.sub.29N.sub.3O.sub.2S[M+H].sup.+ 436.1980 found 436.4032.

Example 5

[0040] Synthesis of N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-pyrrole-2-carboxamide:

[0041] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(pyrazole-2-carboxamido)benzoic acid to obtain a pale yellow solid compound, namely N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-pyrrole-2-carboxamide (Compound 5). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1HNMR (300 MHz, DMSO-d6): δ 11.30 (s, 1H, ArH), 9.86 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 Hz, 1H, ArH)7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.56 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 7.45 (t, J= 7.5 Hz, 1H, ArH), 7.44(dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37(q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 6.42 (t, J= 7.5 Hz, 1H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.56 (d, J= 8.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 405.2212 found 405.0745.

Example 6

[0042] Synthesis of N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)furan-2-carboxamide:

[0043] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(furan-2-carboxamido)benzoic acid to obtain a yellow oily liquid compound, namely N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)furan-2-carboxamide (Compound 6). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.40 (s, 1H, CONH), 8.22 (s, 1H, ArH), 8.07 (dd, J.sub.1 = 8.0, J.sub.2 =1.0 Hz, 1H, ArH), 7.88 (s, 1H, ArH), 7.54 (d, J= 1.0 Hz, 1H, ArH), 7.49 (d, J= 7.4 Hz, 1H, ArH), 7.45 (d, J= 7.8 Hz, 1H, ArH), 7.38 (t, J= 7.8 Hz, 1H, ArH), 7.32 (m, 1H, ArH), 7.27 (dd, J.sub.1 = 7.4, J.sub.2 = 1.9 Hz, 2H, ArH), 6.58 (dd, J.sub.1 = 3.5, J.sub.2 = 1.9 Hz, 1H, ArH), 4.68 (d, J= 4.8 Hz, 2H, CH.sub.2), 3.67 (s, 2H, CH.sub.2), 2.61 (dd, J= 14.0, 7.0 Hz, 4H, CH.sub.2), 1.03 (t, J= 7.0 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.24H.sub.27N.sub.3O.sub.3 [M+H].sup.+ 406.2052 found 406.2413.

Example 7

[0044] Synthesis of N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-pyridineamide:

[0045] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(pyridine-2-carboxamido)benzoic acid to obtain a pale yellow solid compound, namely N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-pyridineamide (Compound 7). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 9.86 (s, 1H, NHCO), 8.77 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 8.74 (s, 1H, NHCO), 8.37 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 8.02 (q, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.93 (q, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, NHCO) 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, J.sub.3= 1.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 8.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 417.2212 found 417.3052.

Example 8

[0046] Synthesis of N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-thiazole-2-carboxamide:

[0047] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(thiazol-2-carboxamido)benzoic acid to obtain a pale yellow solid compound, namely N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-thiazole-2-carboxamide (Compound 8). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ10.81 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.19 (d, J= 7.5 Hz, 1H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.81 (d, J= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 8.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 423.1776 found 423.5935.

Example 9

[0048] Synthesis of N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-imidazole-2-carboxamide:

[0049] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(imidazole-2-carboxamido)benzoic acid to obtain a pale yellow solid compound, namely N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-imidazole-2-carboxamide (Compound 9). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.81 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.63 (s, 1H, CHNHCH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.18 (d, J= 7.5 Hz, 1H, ArH), 6.84 (d, J= 7.5 Hz, 1H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 8.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 406.2165 found 406.0414.

Example 10

[0050] Synthesis of 3-(cyclohexanecarboxamido)-N-(2-((diethylamino)methyl)benzyl)benzamide:

[0051] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(cyclohexane-2-carboxamido)benzoic acid to obtain a pale yellow solid compound, namely 3-(cyclohexanecarboxamido)-N-(2-((diethylamino)methyl)benzyl)benzamide (Compound 10). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.78 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH),4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.70 (dd, J.sub.1= 7.0 Hz, J.sub.2= 7.1 Hz, 4H, CH.sub.2), 1.48 (t, J= 7.1 H, 4H, CH.sub.2), 1.45 (t, J= 7.1 H, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 422.2729 found 422.0368.

Example 11

[0052] Synthesis of 3-benzamido-N-(2-((diethylamino)methyl)benzyl)benzamide:

[0053] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(phenyl-2-carboxamido)benzoic acid to obtain a pale yellow solid compound, namely 3-benzamido-N-(2-((diethylamino)methyl)benzyl)benzamide (Compound 11). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.4 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.96 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.62 (m, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, J.sub.4= 7.5 Hz 2H, ArH), 7.54 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 416.2260 found 416.9463.

Example 12

[0054] Synthesis of N-(2-((diethylamino)methyl)benzyl)-3-(4-hydroxybenzamido)benzamide:

[0055] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(hydroxyphenyl-2-carboxamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((diethylamino)methyl)benzyl)-3-(4-hydroxybenzamido)benzamide (Compound 12). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 9.68 (s, 1H, OH), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.76 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 6.88 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 432.2209 found 432.9846.

Example 13

[0056] Synthesis of 4-((3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)carbamoyl)benzoic acid:

[0057] With reference to the synthesis method of Example 1, the Intermediate 1 in Example 1 was replaced with 3-(-carboxybenzamido)benzoic acid to obtain a pale yellow solid compound, namely 4-((3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)carbamoyl)benzoic acid (Compound 13). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 12.71 (s, 1H, COOH), 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.21 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 8.06 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 460.2158 found 460.4872.

Example 14

[0058] Synthesis of N-(2-((diethylamino)methyl)benzyl)-3-(4-formanilide)benzamide:

[0059] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-formylbenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((diethylamino)methyl)benzyl)-3-(4-formanilide)benzamide (Compound 14). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 9.89 (s, 1H, CHO), 8.74 (s, 1H, NHCO), 8.19 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 8.03 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 444.2209 found 444.3533.

Example 15

[0060] Synthesis of N-(2-((diethylamino)methyl)benzyl)-3-(4-fluorobenzamido)benzamide:

[0061] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-fluorobenzamide)benzoic acid to obtain a yellow oily liquid compound, namely N-(2-((diethylamino)methyl)benzyl)-3-(4-fluorobenzamido)benzamide (Compound 15). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDCl.sub.3): δ 9.47 (s, 1H, CONH), 8.49 (s, 1H, ArH), 8.16 (d, J= 7.2 Hz, 1H, ArH), 7.95 (t, J= 7.2 Hz, 3H, ArH), 7.40 (dt, J.sub.1 = 17.6, J.sub.2 = 7.8 Hz, 3H, ArH), 7.25 (m, 2H, ArH), 7.17 (t, J= 8.5 Hz, 2H, ArH), 4.58 (d, J= 4.7 Hz, 2H, CH.sub.2), 3.70 (s, 2H, CH.sub.2), 2.64 (q, J= 6.8 Hz, 4H, CH.sub.2), 1.05 (t, J= 6.8 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.26H.sub.28FN.sub.3O.sub.2 [M+H].sup.+ 434.2166 found 434.5021.

Example 16

[0062] Synthesis of N-(3-((2-(diethylamino)methyl)benzyl)carbamoyl)phenyl)-3,4-difluorobenzamide:

[0063] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(3,4-difluorobenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(3-((2-(diethylamino)methyl)benzyl)carbamoyl)phenyl)-3,4-difluorobenzamide (Compound 16). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.89 (q, J.sub.1= 1.5 Hz, J.sub.2= 5.0 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.59 (q, J.sub.1= 1.5 Hz, J.sub.2= 5.0 Hz, J.sub.3= 8.0 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.36 (q, J.sub.1= 5.0 Hz, J.sub.2= 7.5 Hz, J.sub.3= 8.0 Hz, 1H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 452.2071 found 452.9844.

Example 17

[0064] Synthesis of N-(2-((diethylamino)methyl)benzyl)-3-(3-fluorobenzamido)benzamide:

[0065] Referring to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(3-fluorobenzamide)benzoic acid to obtain a yellow oily liquid compound, namely N-(2-((diethylamino)methyl)benzyl)-3-(3-fluorobenzamido)benzamide (Compound 17). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDC1.sub.3): δ 9.54 (s, 1H, CONH), 8.47 (s, 1H, ArH), 8.19 (d, J= 7.0 Hz, 1H, ArH), 7.95 (t, J= 7.0 Hz, 3H, ArH), 7.38 (dt, J.sub.1 = 17.5, J.sub.2 = 8.0 Hz, 3H, ArH), 7.25 (m, 2H, ArH), 7.20 (t, J= 8.5 Hz, 2H, ArH), 4.44 (d, J= 4.7 Hz, 2H, CH.sub.2), 3.65 (s, 2H, CH.sub.2), 2.62 (q, J= 6.8 Hz, 4H, CH.sub.2), 1.05 (t, J= 6.8 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.26H.sub.28FN.sub.3O.sub.2 [M+H].sup.+ 434.2166 found 434.5022.

Example 18

[0066] Synthesis of N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-2-fluorobenzamide:

[0067] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(2-fluorobenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-2-fluorobenzamide (Compound 18). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.14 (q, J.sub.1= 1.5 Hz, J.sub.2= 5.0 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.51 (m, J.sub.1= 1.5 Hz, J.sub.2= 5.0 Hz, J.sub.3= 7.5 Hz, J.sub.4= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.29 (q, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.15 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 434.2166 found 434.8462.

Example 19

[0068] Synthesis of 3-(4-chlorobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide:

[0069] Referring to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(2-chlorobenzamido)benzoic acid to obtain a pale yellow solid compound, namely 3-(4-chlorobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide (Compound 19). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.90 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.55 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).HR-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 450.1870 found 450.3457.

Example 20

[0070] Synthesis of 3-(4-bromobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide:

[0071] Referring to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(2-bromobenzamido)benzoic acid to obtain a pale yellow solid compound, namely 3-(4-bromobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide (Compound 20). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.84 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.70 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2[M+H.sup.+] 494.1365 found 494.6042.

Example 21

[0072] Synthesis of 3-(4-iodobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide:

[0073] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(2-iodobenzamido)benzoic acid to obtain a pale yellow solid compound, namely 3-(4-iodobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide (Compound 21). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.95 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.76 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 542.1226 found 542.5073.

Example 22

[0074] Synthesis of N-(2-((diethylamino)methyl)benzyl)-3-(4-methylbenzamido)benzamide:

[0075] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-methylbenzamido)benzoic acid to obtain a yellow oily liquid compound, namely N-(2-((diethylamino)methyl)benzyl)-3-(4-methylbenzamido)benzamide (Compound 22). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, DMSO):δ 10.48 (s, 1H, CONH), 9.62 (s, 1H, CONH), 8.31 (s, 1H, ArH), 7.85 (d, J= 7.5 Hz, 1H, ArH), 7.60 (d, J= 7.5 Hz, 1H, ArH), 7.56 (d, J= 8.0 Hz, 1H, ArH), 7.50 (m, 2H, ArH), 7.46 (d, J= 9.0 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.32 (d, J= 8.0 Hz, 2H, ArH), 4.53 (d, J= 5.7 Hz, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.51 (q, J= 7.0 Hz, 4H, CH.sub.2), 2.39 (s, 3H, CH.sub.3), 1.31 (t, J= 7.0 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.27H.sub.3IN.sub.3O.sub.2 [M+H].sup.+ 430.2416 found 430.3461.

Example 23

[0076] Synthesis of N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-3,4-dimethylbenzamide:

[0077] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(3,4-dimethylbenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-3,4-dimethylbenzamide (Compound 23). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH),7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.76 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.74 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.39 (d, J= 7.5 Hz, 1H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 444.2573 found 444.4592.

Example 24

[0078] Synthesis of N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-isopropylbenzamide)benzamide:

[0079] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-isopropylbenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-isopropylbenzamide)benzamide (Compound 24). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH),7.89 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.50 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 5.0 (t, J= 6.98 Hz, 1H, CH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 12H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 458.2729 found 458.4982.

Example 25

[0080] Synthesis of N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-trifluoromethylbenzamide)benzamide:

[0081] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-trifluoromethylbenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-trifluoromethylbenzamide)benzamide (Compound 25). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.82 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.65 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 484.2134 found 484.2134.

Example 26

[0082] Synthesis of N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-methoxybenzamide)benzamide:

[0083] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-methoxybenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-methoxybenzamide)benzamide (Compound 26). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.96 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.08 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.81 (s, 3H, CH.sub.3), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 446.2365 found 446.2365.

Example 27

[0084] Synthesis of N-(2-((2-((diethylamino)methyl)benzyl)-3-(3-methoxybenzamide)benzamide:

[0085] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(3-methoxybenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((2-((diethylamino)methyl)benzyl)-3-(3-methoxybenzamide)benzamide (Compound 27). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.71 (t, J= 7.5 H, 1H, ArH), 7.63 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.19 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 6.77 (t, J= 1.5 H, 1H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 446.2365 found 446.6379.

Example 28

[0086] Synthesis of N-(2-((2-((diethylamino)methyl)benzyl)-3-(2-methoxybenzamide)benzamide:

[0087] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(2-methoxybenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((2-((diethylamino)methyl)benzyl)-3-(2-methoxybenzamide)benzamide (Compound 28). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.71 (t, J= 7.5 H, 1H, ArH), 7.64 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.57 (q, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.23 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 7.11 (q, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 4.47 (s, 2H, CH.sub.2), 3.93 (s, 3H, CH.sub.3), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 446.2365 found 446.5206.

Example 29

[0088] Synthesis of methyl 4-((3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)carbamoyl)benzoate:

[0089] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 is replaced with 3-(4-(methoxycarbonyl)benzamido)benzoic acid to obtain a pale yellow solid compound, namely methyl 4-((3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)carbamoyl)benzoate (Compound 29). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 8.11 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.90 (dd, J.sub.1= 1.5 Hz, J.sub.2)= 7.5 Hz, 2H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.89 (s, 3H, CH.sub.3), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 474.2315 found 474.3004.

Example 30

[0090] Synthesis of 3-(4-acetylbenzoyl)-N-(2-((diethylamino)methyl)benzyl)benzamide:

[0091] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-acetylbenzamido)benzoic acid to obtain a pale yellow solid compound, namely 3-(4-acetylbenzyl)-N-(2-((diethylamino)methyl)benzyl)benzamide (Compound 30). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 8.11 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 8.08 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 458.2365 found 458.5092.

Example 31

[0092] Synthesis of 3-(4-cyanobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide:

[0093] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-cyanobenzamido)benzoic acid to obtain a yellow oily liquid compound, namely 3-(4-cyanobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide (Compound 31). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDC1.sub.3):<δ 9.84 (s, 1H, CONH), 9.66 (s, 1H, CONH), 8.31 (d, J= 7.8 Hz, 1H, ArH), 8.16 (s, 1H, ArH), 8.08 (d, J= 8.2 Hz, 2H, ArH), 7.72 (d, J= 8.2 Hz, 2H, ArH), 7.37 (t, J= 7.8 Hz, 1H, ArH), 7.31 (d, J= 7.8 Hz, 1H, ArH), 7.24 (td, J.sub.1 = 8.8, J.sub.2 = 4.9 Hz, 3H, ArH), 7.15 (m, 1H, ArH), 4.36 (d, J= 5.0 Hz, 2H, CH.sub.2), 3.61 (s, 2H, CH.sub.2), 2.57 (q, J= 7.1 Hz, 4H, CH.sub.2), 0.99 (t, J= 7.1 Hz, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.27H.sub.28N.sub.4O.sub.2 [M+H].sup.+ 440.2212 found 440.3541.

Example 32

[0094] Synthesis of N-(2-((diethylamino)methyl)benzyl)-3-)4-nitrobenzamido)benzamide:

[0095] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-nitrobenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((diethylamino)methyl)benzyl)-3-)4-nitrobenzamido)benzamide (Compound 32). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.39 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 8.21 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 8.13 (t, J = 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 461.2111 found 461.4013.

Example 33

[0096] Synthesis of N-(2-((diethylamino)methyl)benzyl)-3-)4-aminobenzamido)benzamide:

[0097] With reference to the synthesis method of Example 1, the intermediate 1 in Example 1 was replaced with 3-(4-aminobenzamido)benzoic acid to obtain a pale yellow solid compound, namely N-(2-((diethylamino)methyl)benzyl)-3-)4-aminobenzamido)benzamide (Compound 33). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H, NHCO), 8.74 (s, 1H, NHCO), 8.13 (t, J= 1.5 H, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.54 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.45 (t, J= 1.5 H, 1H, ArH), 7.43 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 7.37 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 6.54 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 2H, ArH), 5.48 (s, 2H, NH.sub.2)4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.54 (d, J= 7.0 Hz, 4H, CH.sub.2), 1.02 (d, J= 8.0 Hz, 6H, CH.sub.3). R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 431.2369 found 431.3065. R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 461.2111 found 461.4013.

Example 34

[0098] Synthesis of N-(3-((2-((dimethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide:

[0099] With reference to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced with 1-2-(aminomethyl)phenyl)-N,N-dimethylmethylamine to obtain a yellow oily liquid compound, namely N -(3-((2-((dimethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide (Compound 34). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDC1.sub.3):<δ 9.94 (s, 1H, CONH), 8.84 (s, 1H, CONH), 8.09 (d, J= 8.0 Hz, 1H, ArH), 8.05 (s, 1H, ArH), 7.82 (d, J= 3.5 Hz, 1H, ArH), 7.55 (d, J= 4.5 Hz, 1H, ArH), 7.37 (d, J= 4.5 Hz, 1H, ArH), 7.34 (dd, J.sub.1 = 8.0, J.sub.2 =3.5 Hz, 2H, ArH), 7.26 (m, 2H, ArH), 7.22 (m, 1H, ArH), 7.12 (t, J= 4.5 Hz, 1H, ArH), 4.59 (d, J= 4.5 Hz, 2H, CH.sub.2), 3.50 (s, 2H, CH.sub.2), 2.28 (s, 6H, CH.sub.3). MS (ESI): calcd. for C.sub.22H.sub.23N.sub.3O.sub.2S[M+H].sup.+ 394.1511 found 394.4213.

Example 35

[0100] Synthesis of N-(3-((2-((dipropylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide:

[0101] With reference to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced with 1-2-(aminomethyl)phenyl)-N,N-dipropylmethylamine to obtain a yellow oily liquid compound, namely N -(3-((2-((dipropylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide (Compound 35). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, CDC1.sub.3):<δ 9.22 (s, 1H, CONH), 8.50 (s, 1H, CONH), 8.13 (d, J= 7.5 Hz, 1H, ArH), 7.96 (s, 1H, ArH), 7.77 (d, J= 3.5 Hz, 1H, ArH), 7.56 (d, J = 5.0 Hz, 1H, ArH), 7.41 (q, J= 8.0 Hz, 2H, ArH), 7.37 (t, J = 8.0 Hz, 1H, ArH), 7.30 (m, 1H, ArH), 7.25 (t, J= 8.0 Hz, 2H, ArH), 7.13(t, J= 4.0 Hz, 1H, ArH), 4.62 (s, 2H, CH.sub.2), 3.69 (s, 2H, CH.sub.2), 2.48 (t, J= 7.5 Hz, 4H, CH.sub.2), 1.49 (tt, J= 15.0, 7.5 Hz, 4H, CH.sub.2), 0.80 (t, J= 7.5 Hz, 6H, CH.sub.3).MS (ESI): calcd. for C.sub.26H.sub.3IN.sub.3O.sub.2S[M+H.sup.]+ 450.2137 found 450.4125.

Example 36

[0102] Synthesis of N-(3-(benzylamino)phenyl)thiophene-2-carboxamide:

[0103] With reference to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced with benzylamine to obtain a white solid compound, namely N-(3-(benzylamino)phenyl)thiophene-2-carboxamide (Compound 36 ). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (500 MHz, DMSO):δ 10.39 (s, 1H, CONH), 9.05 (t, J= 5.5 Hz, 1H, CONH), 8.21 (s, 1H, ArH), 8.07 (m, 1H, ArH), 7.95 (dd, J.sub.1 = 8.0, J.sub.2 = 1.0 Hz, 1H, ArH), 7.88 (d, J = 5.0 Hz, 1H, ArH), 7.64 (d, J = 7.5 Hz, 1H, ArH), 7.46 (t, J = 8.0 Hz, 1H, ArH), 7.34 (s, 2H, ArH), 7.34 (s, 2H, ArH), 7.25 (m, J = 9.0, 2H, ArH), 4.50 (d, J = 6.0 Hz, 2H, CH.sub.2).MS (ESI): calcd. for C.sub.19H.sub.16N.sub.2O.sub.2S[M+H].sup.+ 337.0932 found 337.1254.

Example 37

[0104] Synthesis of N-(3-((3-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide:

[0105] With reference to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced with N-(3-(aminomethyl)benzyl)-N-ethylethylamine to obtain a pale yellow solid compound, namely N-(3-((3-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide (Compound 37). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.20 (s, 1H, NHCO), 8.92 (s, 1H, NHCO), 8.30 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 7.98 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.59 (t, J = 7.5 H, 1 Hz, ArH), 7.45 (t, J = 7.5 Hz, 1H, ArH), 7.31 (t, J = 1.5 H, 1 Hz, ArH), 7.28 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 2H, ArH), 7.20 (t, J = 7.5 H, 1 Hz, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.56 (d, J = 8.0 Hz, 4H, CH.sub.2), 1.02 (d, J = 8.0 Hz, 6H, CH.sub.3). R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 422.1824 found 422.2948.

Example 38

[0106] Synthesis of N-(3-((4-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide:

[0107] With reference to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced with N-(4-(aminomethyl)benzyl)-N-ethylethylamine to obtain a pale yellow solid compound, namely N-(3-((4-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide (Compound 37). There was one spot under TLC detection, there was a dark spot under ultraviolet light at 254 nm, and there was no fluorescence under 365 nm. .sup.1H NMR (300 MHz, DMSO-d6): δ 10.20 (s, 1H, NHCO), 8.92 (s, 1H, NHCO), 8.30 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 8.13 (t, J= 1.5 H, 1H, ArH), 7.98 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 1H, ArH), 7.91 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.79 (q, J.sub.1= 1.5 Hz, J.sub.2= 1.5 Hz, J.sub.3= 7.5 Hz, 1H, ArH), 7.45 (t, J= 7.5 Hz, 1H, ArH), 7.27 (dd, J.sub.1= 1.5 Hz, J.sub.2= 7.5 Hz, 4H, ArH), 7.20 (t, J= 7.5 H, 1 Hz, ArH), 4.47 (s, 2H, CH.sub.2), 3.66 (s, 2H, CH.sub.2), 2.56 (d, J= 8.0 Hz, 4H, CH.sub.2), 1.02 (d, J = 8.0 Hz, 6H, CH.sub.3).R-MS (ESI): calcd. for C.sub.24H.sub.28N.sub.4O.sub.2 [M+H.sup.+] 422.1824 found 422.7979.

[0108] The following are the pharmacodynamic tests and results of some compounds of the present invention:

[0109] Determination of cholinesterase inhibitory activity:

[0110] Drugs and reagents: Test compounds, AChE (E.C.3.1.1.7, Type VI-S, selected from electric eel), BuChE (E.C.3.1.1.8, selected from horse serum), 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), acetylthiocholine (ATC) iodide and butyrylthiocholine (BTC) iodide were all purchased from Sigma; the positive control tacrine hydrochloride (9-amino-1,2,3,4-tetrahydroacridine hydrochloride hydrate) was purchased from BioTrend.

[0111] Instrument: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.

[0112] Experimental method:

[0113] Formulation of buffer: 13.6 g of potassium dihydrogen phosphate was dissolved in 1 L of water, and pH was adjusted with potassium hydroxide to reach pH = 8 ± 0.1. The solution was stored at 4° C. for later use.

[0114] Formulation of 0.01 M DTNB solution: 0.396 g of DTNB and 0.15 g of sodium bicarbonate were dissolved in 100 mL of water to prepare a 0.01 M DTNB solution, which was stored at -30° C. for later use.

[0115] Formulation of 0.075 M ATC and BTC solutions: 0.217 g of ATC was dissolved in 10 mL of water to prepare a 0.075 M ATC solution, which was stored at -30° C. for later use; 0.237 g of BTC was dissolved in 10 mL of water to prepare a 0.075 M BTC solution, which was stored at -30° C. for later use.

[0116] Formulation of AChE and BuChE solutions: 5,000 units of AChE were dissloved in 1 mL of 1% gel solution, and then diluted to 100 mL with water to prepare a AChE solution with a concentration of 5 units/mL, which was stored at -30° C. for later use; 5,000 units of BuChE were dissloved in 1 mL of 1% gel solution, and then diluted to 100 mL with water to prepare a BuChE solution with a concentration of 5 units/mL, which was stored at -30° C. for later use.

[0117] Formulation of test substance solution: The test compound was dissolved in ethanol to obtain a solution with a concentration of 10.sup.-3 M (ethanol would not affect the test results), and then diluted with water to prepare solutions with concentrations of 10.sup.-4, 10.sup.-5, 10.sup.-6, 10.sup.-7, 10.sup.-8, 10.sup.-9, and 10.sup.-10 M, respectively.

[0118] Before the start of the experiment, all the solutions as used were warmed to room temperature, and the AChE and BuChE solutions were diluted 1-fold with water to prepare an enzyme solution with a concentration of 2.5 units/mL. The background UV absorbance was measured with a blank buffer (3 mL) as a subtraction value. Firstly, 100 .Math.L of test compound solution, 100 .Math.L of DTNB solution, and 100 .Math.L of enzyme solution were added to 3 mL of buffer. After adding 20 .Math.L of ATC or BTC solution to trigger the reaction, the time was recorded immediately and the test solution was mixted quickly and uniformly at the same time. After 2 minutes, the UV absorbance was measured at a wavelength of 412 nm. The blank control group was measured with an equal volume of water instead of the test substance solution. All tests were performed three times in parallel. The UV absorption value of the blank control group was taken as 100%, the absorbance (OD value) of the test compound at each concentration was recorded, and GraphPad Prism™ (GraphPad Software, San Diego, CA, USA) software was used to analyze the results in a non-linear regression analysis model to calculate the corresponding IC.sub.50 values, as shown in Table 1.

TABLE-US-00001 Test results of each compound on eqBuChE and hBuChE Compound Strcutural formula IC.sub.50 (nM) ± SEM eqBuChE hBuChE N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)thiophene-2-carboxamide [00045] 0.13± 0.01 0.42 ± 0.07 N-(3-((2-((dimethylamino)methyl)phenyl)carba moyl)phenyl)thiophene-2-carboxamide [00046] 1906.00± 983.00 ND N-(3-((2-((diethylamino)methyl)phenyl)carbamo yl)phenyl)thiophene-2-carboxamide [00047] 480.80 ± 109.55 ND N-(3-((2-((dipropylamino)methyl)phenyl)carbam oyl)phenyl)thiophene-2-carboxamide [00048] 122.200± 284.7 ND N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)-pyrrole-2-carboxamide [00049] 0.87 ± 0.03 2.99 ± 0.67 N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)furan-2-carboxamide [00050] 0.79± 0.09 0.63 ± 0.13 N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)-pyridine-2-carboxamide [00051] 0.34± 0.02 0.78 ± 0.63 N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)-thiazole-2-carboxamide [00052] 0.75 ± 0.14 1.88 ± 0.52 N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)-imidazole-2-carboxamide [00053] 0.52± 0.10 1.91 ± 0.24 3-(cyclohexanecarboxamido)-N-(2-((diethylamino)methyl)benzyl)benzami de [00054] 121.98± 15.39 ND 3-benzamido-N-(2-((diethylamino)methyl)benzyl)benzami de [00055] 0.48 ± 0.07 0.99 ± 0.18 N-(2-((diethylamino)methyl)benzyl)-3-(4-hydroxybenzamido)benzamide [00056] 0.79 ± 0.19 2.45 ± 0.37 4-((3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)carbamoyl)benzoic acid [00057] 0.76 ± 0.09 3.40 ± 0.31 N-(2-((diethylamino)methyl)benzyl)-3-(4-formanilide)benzamide [00058] 0.89± 0.63 2.09 ± 0.99 N-(2-((diethylamino)methyl)benzyl)-3-(4-fluorobenzamido)benzamide [00059] 0.15± 0.06 1.44± 1.66 N-(3-((2-(diethylamino)methyl)benzyl)carbamoy l)phenyl)-3,4-difluorobenzamide [00060] 0.30 ± 0.07 0.57± 0.10 N-(2-((diethylamino)methyl)benzyl)-3-(3-fluorobenzamido)benzamide [00061] 4.55±0.74 25.19±19.07 N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)-2-fluorobenzamide [00062] 3.50± 1.10 17.36± 1.98 3-(4-chlorobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzami de [00063] 0.34 ± 0.21 0.83± 0.39 3-(4-bromobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzami de [00064] 0.98± 0.62 1.91± 0.59 3-(4-iodobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzami de [00065] 1.59 ± 0.26 3.33 ± 1.62 N-(2-((diethylamino)methyl)benzyl)-3-(4-methylbenzamido)benzamide [00066] 0.98± 0.21 1.54± 0.56 N-(3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)-3,4-dimethylbenzamide [00067] 0.80 ± 0.24 1.53 ± 0.55 N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-isopropylbenzamide)benzamide [00068] 0.58 ± 0.67 2.08± 0.73 N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-trifluoromethylbenzamide)benzamide [00069] 0.38± 0.10 1.41± 0.01 N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-methoxybenzamide)benzamide [00070] 0.55 ± 0.09 1.04± 0.52 N-(2-((2-((diethylamino)methyl)benzyl)-3-(3-methoxybenzamide)benzamide [00071] 4.91 ±1.35 12.85±6.01 N-(2-((2-((diethylamino)methyl)benzyl)-3-(2-methoxybenzamide)benzamide [00072] 5.28±1.21 19.98± 2.06 Methyl 4-((3-((2-((diethylamino)methyl)benzyl)carbamo yl)phenyl)carbamoyl)benzoate [00073] 2.48 ± 0.26 9.06± 0.74 3-(4-acetylbenzoyl)-N-(2-((diethylamino)methyl)benzyl)benzami de [00074] 6.63± 0.66 23.98± 1.52 3-(4-cyanobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzami de [00075] 15.78±2.84 16.54±15.11 N-(2-((diethylamino)methyl)benzyl)-3-)4-nitrobenzamido)benzamide [00076] 22.65 ± 0.98 30.90 ± 3.26 N-(2-((diethylamino)methyl)benzyl)-3-)4-aminobenzamido)benzamide [00077] 1.56± 0.67 7.99± 2.53 N-(3-((2-((dimethylamino)methyl)benzyl)carba moyl)phenyl)thiophene-2-carboxamide [00078] 0.29± 0.05 0.75 ± 0.27 N-(3-((2-((dipropylamino)methyl)benzyl)carbam oyl)phenyl)thiophene-2-carboxamide [00079] 0.45± 0.04 0.89± 0.67 N-(3-(benzylamino)phenyl)thiophene-2-carboxamide [00080] 27.23%.sup.a ND N-(3-((3-((diethylamino)methyl)benzyl)carbamo yl)phenyl)thiophene-2-carboxamide [00081] 12.56± 0.86 32.87 ±15.66 N-(3-((4-((diethylamino)methyl)benzyl)carbamo yl)phenyl)thiophene-2-carboxamide [00082] 24.68± 10.63 75.05±22.87 .sup.a represents the inhibition rate of the compound on the target at a concentration of 10 .Math.M

[0119] The 38 compounds in Table 1 all show better inhibitory activity on BuChE (the best compound is compound 1, and its BuChE inhibitory activity is 0.13±0.01 nM), and all have no inhibitory activity on AChE at a concentration of 10 .Math.M (the inhibition rate at a concentration of 10 .Math.M is less than 10%), indicating that this series of compounds have extremely high selectivity. In a healthy brain, the activity of AChE is dominant (80%), while BuChE appears to only play a supporting role. However, in progressive AD, the levels of AChE in the brain gradually decrease to 55-67% of normal level, while the levels of BuChE increase to 120% of normal level. This suggests that in the middle and late stages of severe AD, BuChE replaces the dominating role of AChE and becomes the main metabolic enzyme for hydrolyzing Ach, which deserves more attention. However, selective BuChE inhibitors show weak peripheral cholinergic side effects during the treatment process and have stronger drug safety. Therefore, the development of selective BuChE inhibitors is of great significance. The compound involved in the present invention has good inhibitory activity and extremely high selectivity to BuChE, and is expected to have a good curative effect on AD.

[0120] Toxicity test in PC-12 nerve cell:

[0121] Drugs and reagents: Test compounds, DMEM medium (01-050-1A) purchased from Biological Industries, FBS fetal bovine serum (04-001-1A) purchased from Biological Industries, MTT thiazolyl blue reagent (KGT525500) purchased from KeyGEN BioTECH.

[0122] Instrument: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.

[0123] Experimental method: About 3×10.sup.3 PC-12 cells were evenly mixed in 0.1 mL of DMEM medium containing 10% FBS, and plated on a 96-well bottom plate, and incubated overnight at 37° C. in an environment containing 5% CO.sub.2. The 20 .Math.M and 50 .Math.M compounds diluted in 0.1 mL of DMEM medium were treated on the cells for 24 hours. Then MTT reagent was added to the well plate, and the plate was incubated at 37° C. for 2 to 4 hours. The color reaction was measured at 492 nm using a spectrophotometer (Thermo, multiskan FC). The cell survival rate (SR%) corresponding to the compound represented by formula (I) was calculated, as shown in Table 2.

TABLE-US-00002 Survival rate test results of each compound on PC-12 neural cell line Compound 20 .Math.M SR(%).sup.a 50 .Math.M SR(%).sup.b N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide 97.36 84.34 N-(3-((2-((dimethylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide 94.30 91.45 N-(3-((2-((diethylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide 95.23 89.64 N-(3-((2-((dipropylamino)methyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide 87.24 79.48 N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-pyrrole-2-carboxamide 97.53 92.47 N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)furan-2-carboxamide 95.37 81.46 N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-pyridine-2-carboxamide 92.36 75.46 N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-thiazole-2-carboxamide 93.57 89.42 N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-imidazole-2-carboxamide 80.36 70.74 3-(cyclohexanecarboxamido)-N-(2-((diethylamino)methyl)benzyl)benzamide 90.23 83.22 3-benzamido-N-(2-((diethylamino)methyl)benzyl)benzamide 96.30 83.4 N-(2-((diethylamino)methyl)benzyl)-3-(4-hydroxybenzamido)benzamide 91.46 89.64 4-((3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)carbamoyl)benzoic acid 91.46 75.25 N-(2-((diethylamino)methyl)benzyl)-3-(4-formanilide)benzamide 86.34 81.34 N-(2-((diethylamino)methyl)benzyl)-3-(4-fluorobenzamido)benzamide 93.57 84.35 N-(3-((2-(diethylamino)methyl)benzyl)carbamoyl)phenyl)-3,4-difluorobenzamide 95.72 89.53 N-(2-((diethylamino)methyl)benzyl)-3-(3-fluorobenzamido)benzamide 98.40 89.75 N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-2-fluorobenzamide 80.26 73.56 3-(4-chlorobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide 90.43 79.24 3-(4-bromobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide 94.00 85.21 3-(4-iodobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide 94.40 89.63 N-(2-((diethylamino)methyl)benzyl)-3-(4-methylbenzamido)benzamide 93.35 89.42 N-(3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)-3,4-dimethylbenzamide 85.05 80.72 N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-isopropylbenzamide)benzamide 97.02 86.21 N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-trifluoromethylbenzamide)benzamide 97.58 91.57 N-(2-((2-((diethylamino)methyl)benzyl)-3-(4-methoxybenzamide)benzamide 97.20 82.25 N-(2-((2-((diethylamino)methyl)benzyl)-3-(3-methoxybenzamide)benzamide 91.23 83.60 N-(2-((2-((diethylamino)methyl)benzyl)-3-(2-methoxybenzamide)benzamide 95.42 85.46 Methyl 4-((3-((2-((diethylamino)methyl)benzyl)carbamoyl)phenyl)carbamoyl)benzoate 99.42 93.32 3-(4-acetylbenzoyl)-N-(2-((diethylamino)methyl)benzyl)benzamide 91.86 72.56 3-(4-cyanobenzamido)-N-(2-((diethylamino)methyl)benzyl)benzamide 94.67 91.59 N-(2-((diethylamino)methyl)benzyl)-3-)4-nitrobenzamido)benzamide 97.42 84.65 N-(2-((diethylamino)methyl)benzyl)-3-)4-aminobenzamido)benzamide 90.21 74.62 N-(3-((2-((dimethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide 96.10 94.5 N-(3-((2-((dipropylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide 92.58 84.86 N-(3-(benzylamino)phenyl)thiophene-2-carboxamide 89.57 77.42 N-(3-((3-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide 92.05 82.03 N-(3-((4-((diethylamino)methyl)benzyl)carbamoyl)phenyl)thiophene-2-carboxamide 93.67 84.23 .sup.a Cell survival rate (SR%) after treatment with 20 .Math.M compound for 24 h .sup.b Cell survival rate (SR%) after treatment with 50 .Math.M compound for 24 h

[0124] The 38 compounds in Table 1 are less toxic to PC-12 nerve cells at the two concentrations of 20 .Math.M and 50 .Math.M, indicating that they have good drug safety in vitro and lay a foundation for its subsequent development as selective BuChE inhibitors for the treatment of AD.