2-phenyl-benzo nitrogen-containing heterocyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a 2-phenyl-benzo nitrogen-containing heterocyclic compound as well as a preparation method and application thereof, and relates to the technical field of medicinal chemistry, the structural formula of the 2-phenyl-benzo nitrogen-containing heterocyclic compound is as shown in a formula I and a formula II: # imgabs0 #. The 2-phenyl-benzo nitrogen-containing heterocyclic compound disclosed by the invention shows certain inhibitory activity on 17 beta-HSD10; wherein the compound 34 has the best inhibitory activity, has a treatment effect on scopolamine-induced mouse cognitive impairment, is relatively low in toxicity, and is expected to be applied to preparation of medicines for treating AD (Alzheimer's disease).

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a 2-phenyl-benzo nitrogen-containing heterocyclic compound and a preparation method and application thereof. Background Art

[0002] Alzheimer's disease (AD) is a fatal neurodegenerative disease that mainly manifests in memory, behavioral function, and reasoning. Studies have found that 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) interacts with Aβ peptides. Overexpression in AD brains further disrupts the homeostasis of neurosteroid metabolism and may change the levels of neuroprotective steroids in different brain regions, such as 17β-estradiol (E2) and isoproterenol (ALLOP). These two neurosteroids have significant effects on mitochondrial function, bioenergetics, antioxidant processes, and the accumulation of AD-related pathological markers (Aβ and hyperphosphorylated tau protein). A large amount of data shows that inhibiting the activity of 17β-HSD10 enzyme can restore the disrupted homeostasis of E2 and ALLOP neurosteroids and has a therapeutic effect on AD. Therefore, the discovery of effective and selective small molecule 17β-HSD10 inhibitors for the treatment of AD can be used as a new strategy for the treatment of AD. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a 2-phenyl-benzo nitrogen-containing heterocyclic compound and a preparation method thereof. The compound can be used as a new type of 17β-HSD10 inhibitor, among which compound 34 has an activity equivalent to that of the positive control 17β-HSD10-IN-1 and has low toxicity, and is expected to be used in the preparation of drugs for the treatment of AD.

[0005] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0006] The first object of the present invention is to provide a 2-phenyl-benzo nitrogen-containing heterocyclic compound, the structural formula of which is shown in Formula I and II:

[0007]

[0008] Wherein, R1, R2, and R3 are each independently selected from any one of hydrogen, alkyl, alkoxy, and halogen; R4 is selected from any one of halogen, alkyl, nitro, ester, amino, urea and its derivatives, amide and its derivatives; X1 and X2 are each independently selected from any one of nitrogen, hydrogen, oxygen, and nitrogen methyl.

[0009] Furthermore, the 2-phenyl-benzo nitrogen-containing heterocyclic compound includes the following specific compounds 1 to 45:

[0010]

[0011]

[0012] The second object of the present invention is to provide a method for preparing the 2-phenyl-benzo nitrogen-containing heterocyclic compound, comprising the following steps:

[0013] (1) 3,5-dimethyl-1,2-phenylenediamine reacts with a benzaldehyde derivative to give compound 1-7;

[0014]

[0015] 1: R 1 =F, R 2 =H2:R 1 =Cl, R 2 =H 3:R 1 =methyl, R 2 =H 4:R 1 =nitryl, R 2 =H5:R 1 =H, R 2 =nitryl 6: R 1 =carboxyl, R 2 =H 7:R 1 =methyl acetate, R 2 =H

[0016] (2) Compound 4 undergoes nitro reduction reaction to obtain compound 8;

[0017]

[0018] (3) Compound 8 undergoes a condensation reaction with an isocyanate derivative to obtain compound 9-17;

[0019]

[0020] 9: R 3 =ethyl 10: R 3 =n-butyl 11: R 3 =4-methylphenyl 12: R 3 =4-chlorophenyl

[0021] 13: R 3 =4-bromophenyl 14:R 3 =4-methoxyphenyl

[0022] 15: R 3=4-trifluoromethoxyphenyl 16:R 3 =4-chloro-3-trifluoromethylphenyl

[0023] 17: R 3 =3-trifluoromethylphenyl

[0024] (4) Compound 8 undergoes an amide condensation reaction with a carboxylic acid derivative to obtain compound 18-33;

[0025]

[0026] 18: R 4 =phenyl19:R 4 =cresyl 20:R 4 =ethylphenyl 21:R 4 =propylphenyl 22: R 4 =butylbenzenly

[0027] 23: R 4 =styryl 24: R 4 =4-pyridyl 25: R 4 =3-pyridyl 27: R 4 =cyclohexyl

[0028] 28: r 4 =4,4-difluorocyclohexyl 29: R 4 =4-methylcyclohexyl 30: R 4 =4-isopropyl-cyclohexyl

[0029] 31: r 4 =4-tetrahydropyranyl 32: R 4 =(3R,5R,7R)-adamantane-l-yl

[0030] 33: R 4 =(1r,3R,5S,7r)-3,5-dimethyladamantan-l-yl

[0031] (5) Compound 8 undergoes methylation reaction with iodomethane to obtain intermediate M1;

[0032] (6) Intermediate M1 undergoes reduction reaction to obtain intermediate M2;

[0033] (7) Intermediate M2 undergoes amide condensation reaction with a carboxylic acid derivative to obtain compounds 34-35;

[0034]

[0035] (8) 2,4-Dimethylaniline reacts with p-nitrobenzoic acid to undergo an amide condensation reaction to obtain intermediate M3;

[0036] (9) Intermediate M3 undergoes a ring-closing reaction catalyzed by metal to obtain intermediate M4;

[0037] (10) Intermediate M4 undergoes nitro reduction reaction to obtain intermediate M5;

[0038] (11) Intermediate M5 undergoes amide condensation reaction with a carboxylic acid derivative to give compounds 36-37;

[0039]

[0040] 36: R 6 =cyclohexyl 37:R 6 =4,4-difluorocyclohexyl

[0041] (12) 4,6-Dimethyl-2-nitroaniline reacts with methyl iodide to give intermediate M6;

[0042] (13) Intermediate M6 undergoes nitro reduction reaction to obtain intermediate M7;

[0043] (14) Intermediate M7 undergoes a ring-closing reaction with p-nitrobenzaldehyde to obtain intermediate M8;

[0044] (15) Intermediate M8 undergoes nitro reduction reaction to obtain intermediate M9;

[0045] (16) Intermediate M9 undergoes amide condensation reaction with a carboxylic acid derivative to give compounds 38-39;

[0046]

[0047] 38: R 7 =cyclohexyl 39:R 7 =4,4-difluorocyclohexyl

[0048] (17) The phenylenediamine derivative undergoes an amide condensation reaction with p-nitrobenzaldehyde to obtain intermediate M10-13;

[0049] (18) Intermediate M10-13 undergoes methylation reaction with methyl iodide to obtain intermediate M14-17;

[0050] (19) Intermediate M14-17 undergoes reduction reaction to obtain intermediate M18-21;

[0051] (20) Intermediate M18-21 undergoes amide condensation reaction with a carboxylic acid derivative to give compound 39-4;

[0052]

[0053] 40: R 8 =cyclohexyl, R 9 =H, R 10 =H 41:R 8 =cyclohexyl, R 9 =H, R 10 =Cl 42:R 8 =cyclohexyl, R 9 =methyl, R 10 =methyl

[0054] 43: R 8 =cyclohexyl, R 9 =Cl, R 10 =Cl 44:R 8 =4,4-difluorocyclohexyl, R 9 =H, R 10 =H

[0055] 45: R 8 =4,4-difluorocyclohexyl, R 9 =H, R 10 =Cl

[0056] The third object of the present invention is to provide a pharmaceutical composition comprising the 2-phenyl-benzo nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof.

[0057] The fourth object of the present invention is to provide the use of the 2-phenyl-benzo nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof in the preparation of a 17β-HSD10 inhibitor.

[0058] The fifth object of the present invention is to provide the use of the 2-phenyl-benzo nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating Alzheimer's disease.

[0059] The beneficial effects of the present invention are:

[0060] (1) The 2-phenyl-benzo nitrogen-containing heterocyclic compound of the present invention can be used for the study of signal transduction pathways involved in 17β-HSD10 and the activity evaluation of novel 17β-HSD10 inhibitors;

[0061] (2) The 2-phenyl-benzo nitrogen-containing heterocyclic compounds of the present invention were screened for 17β-HSD10 activity. The results showed that these compounds exhibited certain inhibitory activity against 17β-HSD10, among which compound 13 had the best inhibitory activity and low toxicity;

[0062] (3) In vivo activity screening was performed on compound 13 of the present invention, and the results showed that it had a therapeutic effect on scopolamine-induced cognitive dysfunction in mice and had low toxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 The crystal structures of intermediate M9 (A) and compound 34 (B);

[0064] Figure 2 The Morris water maze test results of compound 34. DETAILED DESCRIPTION

[0065] In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further described below in conjunction with specific embodiments and diagrams.

[0066] Example 1

[0067] Synthesis of 2-(4-fluorophenyl)-4,6-dimethyl-1H-benzo[d]imidazole (Compound 1):

[0068] 3,5-dimethyl-1,2-phenylenediamine (2g, 14.68mmol) and 4-fluorobenzaldehyde (2g, 16.15mmol) were added to a flask, 20mL DMF was added, and then AcOH (1.76g, 29.37mmol) was added, and the mixture was heated in an oil bath at 85°C for 6h. After the reaction, 200mL of saturated brine was added for washing, and the mixture was extracted with ethyl acetate. The organic phase was taken, dried with anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 3:1, v / v) to obtain a light yellow solid with a yield of 58.67%. 1 H NMR (400MHz, DMSO-d6) δ12.58 (d, J=83.0Hz, 1H), 8.48-8.00 (m, 2H), 7.39 (t, J= 8.9Hz,2H),7.28-7.00(m,1H),6.83(s,1H),2.51(q,J=1.8Hz,3H),2.38(s,3H). 13C NMR (101MHz, DMSO) δ164.55,162.10,132.10,129.05,127.57,127.54,116.44,116 .22,40.55,40.39,40.34,40.18,40.13,39.93,39.72,39.51,39.30,21.76,17.17.

[0069] Example 2

[0070] Synthesis of 2-(4-chlorophenyl)-4,6-dimethyl-1H-benzo[d]imidazole (Compound 2):

[0071] The synthesis steps are the same as those of Example 1, except that 4-chlorobenzaldehyde is used to replace 4-fluorobenzaldehyde. 1 H NMR (400MHz, DMSO-d6) δ12.65 (d, J=84.4Hz, 1H), 8.30-8.07 (m, 2H), 7.62 (dd, J=8.5,6.1Hz,2H),7.13(s,1H),6.83(s,1H),2.52-2.49(m,3H),2.39(s,3H). 13 C NMR(101MHz,DMSO)δ149.25,141.81,134.52,129.78,129.40,128.40,124.21,109 .03,40.56,40.35,40.14,39.93,39.82,39.72,39.60,39.51,39.30,21.78,17.09.

[0072] Example 3

[0073] Synthesis of 4,6-dimethyl-2-(p-tolyl)-1H-benzo[d]imidazole (Compound 3):

[0074] The synthesis steps are the same as those of Example 1, except that 4-methylbenzaldehyde is used to replace 4-fluorobenzaldehyde. 1 H NMR (400MHz, DMSO-d6) δ12.45(d,J=81.8Hz,1H),8.04(dd,J=28.1,8.2Hz,2H),7.31(dd,J=8.1,3. 7Hz,2H),7.13(d,J=54.7Hz,1H),6.77(d,J=4.0Hz,1H),2.47(d,J=2.0Hz,3H),2.41-2.26(m,6H). 13C NMR (101MHz, DMSO) δ151.62,150.47,144.37,141.83,139.68,139.52,135.22,133.10,131.88,130.91,129.89,129.80,128.23,128.20,128.13 ,126.98,126.64,124.99,123.93,121.07,116.34,108.88,40.57,40.36 ,40.15,39.94,39.73,39.52,39.31,21.84,21.69,21.42,17.57,17.11.

[0075] Example 4

[0076] Synthesis of 4,6-dimethyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Compound 4):

[0077] The synthesis steps are the same as those in Example 1, except that 4-nitrobenzaldehyde is used to replace 4-fluorobenzaldehyde. 1 H NMR(400MHz,DMSO-d6)δ12.95(d,J=88.6Hz,1H),8.51-8.38(m,4H),7.25(d,J=59.5Hz, 1H), 6.89 (d, J = 11.7Hz, 1H), 3.36 (s, 4H), 2.55 (d, J = 8.8Hz, 3H), 2.40 (d, J = 9.3Hz, 3H). 13 C NMR(101MHz,DMSO)δ149.13,148.07,147.88,144.43,142.07,136.78,136.76,1 35.60,133.53,133.49,131.86,130.57,129.00,127.86,127.74,127.51,126.24 ,124.71,124.69,124.61,124.54,124.38,121.73,116.88,109.29,40.56,40.36,40.15,40.04,39.94,39.73,39.52,39.31,21.88,21.67,21.53,17.53,17.04.

[0078] Example 5

[0079] Synthesis of 4,6-dimethyl-2-(3-nitrophenyl)-1H-benzo[d]imidazole (Compound 5):

[0080] The synthesis steps are the same as those of Example 1, except that 4-fluorobenzaldehyde is replaced by 3-nitrobenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ12.96(d,J=82.3Hz,1H),9.25-8.86(m,1H),8.59(d,J=7.9Hz,1H),8.31(s ,1H),7.92-7.78(m,1H),7.24(d,J=55.8Hz,1H),6.88(d,J=10.3Hz,1H),2.56(s,3H),2.41(s,3H). 13 CNMR(101MHz,DMSO)δ148.75,132.87,132.44,130.99,124.31,121.08,40.56,40.35,40.14,39.93,39.72,39.52,39.31,21.77,17.26.

[0081] Example 6

[0082] Synthesis of methyl 4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoate (Compound 6):

[0083] The synthesis steps were the same as in Example 1, except that 4-fluorobenzaldehyde was replaced by methyl 4-formylbenzoate. 1 H NMR (400MHz, DMSO-d6) δ12.80(d,J=85.2Hz,1H),8.33(dd,J=29.9,8.5Hz,2H),8.12(dd,J=8.6,2.4Hz ,2H),7.23(d,J=58.2Hz,1H),6.87(d,J=9.3Hz,1H),3.90(d,J=1.2Hz,3H),2.55(s,3H),2.40(s,3H). 13 C NMR (101MHz, DMSO) δ166.32,150.16,149.06,144.38,141.95,135.44,135 .09,133.36,132.91,131.50,130.42,130.29,130.23,130.12,128.72,12 7.12,126.78,125.79,124.41,121.53,116.71,109.17,52.72,40.55,40. 40,40.35,40.14,39.93,39.72,39.51,39.30,21.86,21.68,17.54,17.07.

[0084] Example 7

[0085] Synthesis of methyl 2-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)acetate (Compound 7):

[0086] The synthesis steps were the same as in Example 1, except that 4-fluorobenzaldehyde was replaced by methyl 2-(4-formylphenyl)acetate. 1 HNMR (400MHz, DMSO-d6) δ12.54(d,J=82.7Hz,1H),8.22-8.06(m,2H),7.43(dd,J=8.2,3.5Hz,2H),7.18(d,J =55.4Hz,1H),6.82(d,J=5.5Hz,1H),3.78(d,J=2.0Hz,2H),3.64(s,3H),2.53(s,3H),2.38(d,J=8.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ171.92,150.19,141.87,136.23,135.29,132.11,130.34,130.24 ,129.57,129.36,128.28,127.01,126.73,126.38,124.06,108.95,52.26,21.78,17.12.

[0087] Example 8

[0088] Synthesis of 4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)aniline (Compound 8):

[0089] Compound 4 (200 mg, 748.26 μmol) and NH4Cl (800.47 mg, 14.97 mmol) were added to a flask, and then 5 mL of methanol and 5 mL of water were added, and zinc powder (489.21 mg, 7.48 mmol) was added in small amounts and several times, and the mixture was reacted at room temperature for 4 h. After the reaction was completed, 10 mL of ethyl acetate was added and stirred, filtered through diatomaceous earth, separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 1:1, v / v) to obtain a yellow solid with a yield of 56.31%. 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),7.85(d,J=8.1Hz,2H),7.07(s,1H),6.74(s,1H),6.66(d,J=8.2Hz,2H),5.55(s,2H),2.49(s,3H),2.36(s,3H). 13 C NMR (101MHz, DMSO-d6) δ150.72,130.62,128.13,123.72,118.16,113.95,21.76,17.31.

[0090] Example 9

[0091] Synthesis of 1-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-ethylurea (Compound 9):

[0092] Compound 8 (100 mg, 421.40 μmol) and DMAP (15.44 mg, 126.42 μmol) were added to a flask, and then 3 mL of DMF and DIPEA (73.40 mmL, 421.40 μmol) were added. After stirring, ethane isocyanate (44.93 mg, 632.10 μmol) was added. The reaction was carried out at room temperature for 6 h. After the reaction was completed, 30 mL of water was added to quench, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 2:1, v / v) to obtain a light yellow solid with a yield of 36.93%. 1 H NMR (400MHz, DMSO-d6) δ12.35(d,J=82.0Hz,1H),8.70(s,1H),7.99(d,J=8.4Hz,2H),7.61-7.48(m,2H),7.07(s,1H ),6.78(s,1H),6.22(s,1H),3.13(dd,J=7.2,5.6Hz,2H),2.51(d,J=1.8Hz,3H),2.38(s,3H),1.07(t,J=7.2Hz,3H). 13 CNMR(101MHz,DMSO)δ155.38,152.84,140.91,130.43,130.16,129.85,124.70,123.48,122.41, 118.75,117.82,114.68,60.23,40.56,40.40,40.35,40.15,39.94,39.73,39.52,39.31,15.91.

[0093] Example 10

[0094] Synthesis of 1-butyl-3-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)urea (Compound 10):

[0095] The synthesis steps are the same as those of Example 9, except that 1-isocyanatopropane is used to replace isocyanatoethane. 1H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.67(s,1H),8.02(d,J=8.3Hz,2H),7.58-7.49(m,2H),7.12(s,1H),6.79(s,1H),6.24(t,J =5.7Hz,1H),3.15-3.06(m,2H),2.51(d,J=2.0Hz,3H),2.37(s,3H),1.49-1.39(m,2H),1.36-1.26(m,2H),0.91(t,J=7.3Hz,3H). 13 C NMR (101MHz, DMSO) δ155.44,142.40,127.52,123.41,117.76,40.61,40.56,40.40,40.3 5,40.19,40.14,39.93,39.73,39.52,39.31,39.17,32.31,21.78,20.00,17.31,14.18.

[0096] Embodiment 11

[0097] Synthesis of 1-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-(p-tolyl)urea (Compound 11):

[0098] The synthesis steps were the same as those of Example 9, except that 1-isocyanato-4-methylbenzene was used to replace isocyanatoethane. 1 H NMR (400MHz, DMSO-d6) δ12.41(d,J=73.1Hz,1H),8.88(s,1H),8.66(s,1H),8.08(d,J=8.3Hz,2H),7.60(d,J= 8.4Hz,2H),7.37(d,J=8.0Hz,2H),7.10(d,J=8.2Hz,3H),6.79(s,1H),2.52(s,3H),2.38(s,3H),2.25(s,3H). 13 C NMR(101MHz,DMSO)δ152.86,141.55,137.41,131.31,129.69,127.59,124.24,1 18.84,118.36,40.56,40.35,40.14,39.93,39.72,39.52,39.31,21.79,20.82.

[0099] Example 12

[0100] Synthesis of 1-(4-chlorophenyl)-3-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)urea (Compound 12):

[0101] The synthesis steps were the same as those in Example 9, except that 1-chloro-4-isocyanatobenzene was used to replace isocyanatoethane. 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),8.95(d,J=19.5Hz,2H),8.06(d,J=8.4Hz,2H),7.61(d,J=8.8Hz,2H), 7.52(d,J=8.9Hz,2H),7.35(d,J=8.8Hz,2H),7.09(s,1H),6.80(s,1H),2.52(d,J=1.9Hz,3H),2.38(s,3H). 13 C NMR (101MHz, DMSO) δ152.75,139.02,129.14,125.98,124.52,120.30,118.58,40.56,40.35,40.14,39.94,39.73,39.52,39.31,21.80.

[0102] Example 13

[0103] Synthesis of 1-(4-bromophenyl)-3-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)urea (Compound 13):

[0104] The synthesis steps were the same as those of Example 9, except that 1-bromo-4-isocyanatobenzene was used to replace isocyanatoethane. 1 H NMR (400MHz, DMSO-d6) δ12.42(d,J=81.6Hz,1H),8.95(d,J=19.3Hz,2H),8.17-8.04(m,2H),7.65- 7.57(m,2H),7.47(s,4H),7.15(d,J=51.5Hz,1H),6.80(s,1H),2.52(d,J=1.7Hz,3H),2.38(s,3H). 13 C NMR (101MHz, DMSO) δ152.71,141.25,139.45,132.03,124.53,120.69,118. 57,113.86,40.57,40.41,40.36,40.15,39.94,39.73,39.52,39.31,21.79.

[0105] Embodiment 14

[0106] Synthesis of 1-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-(4-methoxyphenyl)urea (Compound 14):

[0107] The synthesis steps were the same as those of Example 9, except that 1-isocyanato-4-methoxybenzene was used to replace isocyanatoethane. 1 HNMR (400MHz, DMSO-d6) δ12.40(d,J=81.4Hz,1H),8.84(s,1H),8.58(s,1H),8.05(d,J=8.5Hz,2H),7.60(d,J=8.7Hz,2H) ,7.43-7.32(m,2H),7.15(d,J=50.6Hz,1H),6.95-6.84(m,2H),6.79(s,1H),3.73(s,3H),2.56-2.51(m,3H),2.38(s,3H). 13 C NMR(101MHz,DMSO)δ155.03,153.01,141.66,132.97,127.52,124.14,120.59,118.32, 114.46,55.62,40.56,40.41,40.35,40.15,39.94,39.82,39.73,39.52,39.31,21.79.

[0108] Embodiment 15

[0109] Synthesis of 1-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (Compound 15):

[0110] The synthesis steps were the same as those of Example 9, except that 1-isocyanato-4-trifluoromethoxybenzene was used to replace isocyanatoethane. 1 H NMR(400MHz,DMSO-d6)δ12.42(d,J=80.4Hz,1H),8.99(s,2H),8.20-8.01(m,2H),7.73- 7.51(m,4H),7.31(d,J=8.4Hz,2H),7.10(s,1H),6.80(s,1H),2.52(s,3H),2.38(s,3H). 13 C NMR(101MHz,DMSO)δ152.79,143.15,141.25,139.33,127.57,124.54,122.27,1 21.93,119.96,118.58,40.56,40.35,40.15,39.94,39.73,39.52,39.31,21.78.

[0111] Example 16

[0112] Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)urea (Compound 16):

[0113] The synthesis steps were the same as those of Example 9, except that 1-chloro-4-isocyanato-2-trifluoromethylbenzene was used to replace isocyanatoethane. 1 HNMR (400MHz, DMSO-d6) δ12.59(s,1H),9.26(d,J=60.8Hz,2H),8.23(d,J=2.3Hz,1H),8.18(d,J =8.3Hz,2H),7.82-7.60(m,4H),7.27-7.10(m,1H),6.89-6.84(m,1H),2.59(s,3H),2.44(s,3H). 13 C NMR (101MHz, DMSO) δ162.77,152.74,140.96,139.68,132.49,127.59,127.34,127.04,124.79,124.65,124.30,123.63,122.93,121.9 3,118.86,117.32,117.27,60.23,40.56,40.40,40.35,40.14,39.93,39.72,39.51,39.30,36.23,31.21,21.77,21.22,17.30,14.53.

[0114] Embodiment 17

[0115] Synthesis of 1-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (Compound 17):

[0116] The synthesis steps were the same as those of Example 9, except that 1-isocyanato-3-trifluoromethylbenzene was used to replace isocyanatoethane. 1 HNMR(400MHz,DMSO-d6)δ12.42(d,J=81.4Hz,1H),9.10(d,J=36.8Hz,2H),8.24-7.99(m,3H),7.74-7.43 (m,4H),7.34(d,J=7.6Hz,1H),7.16(d,J=52.7Hz,1H),6.80(s,1H),2.52(s,3H),2.38(d,J=6.1Hz,3H). 13C NMR (101MHz, DMSO) δ170.83,152.84,141.08,140.91,130.43,130.16,129.85,127.52,126.04,124.70,123.34 ,122.41,118.74,114.68,60.23,40.56,40.41,40.35,40.15,39.94,39.73,39.52,39.31,21.78,21.23,14.54.

[0117] Embodiment 18

[0118] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)benzamide (Compound 18):

[0119] Compound 8 (100 mg, 421.40 μmol) and HATU (169.75 mg, 463.54 μmol) were added to a flask, and then 3 mL of DMF and DIPEA (80.74 mmL, 463.54 μmol) were added. After stirring for 30 min, benzoic acid (83.01 mg, 505.68 μmol) was added. The reaction was allowed to react at room temperature for 6 h. After the reaction was completed, 30 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 2:1, v / v) to obtain a light yellow solid with a yield of 50.05%. 1 H NMR (400MHz, DMSO-d6) δ12.48(d,J=82.5Hz,1H),10.46(s,1H),8.17(dd,J=28.3,8.4Hz,2H),8.06-7.90(m,4H) ,7.66-7.51(m,3H),7.17(d,J=53.5Hz,1H),6.82(d,J=3.5Hz,1H),2.53(d,J=4.7Hz,3H),2.38(d,J=7.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ171.13,151.40,150.71,141.59,140.87,135.09,131.52,129.25,128.82,128.73,127.49,12 6.45,125.42,124.37,121.10,119.39,40.56,40.35,40.14,39.93,39.73,39.52,39.31,38.47,31.21,21.78,17.30.

[0120] Embodiment 19

[0121] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-phenylacetamide (Compound 19):

[0122] The synthesis steps were the same as in Example 18, with 2-phenylacetic acid replacing benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ12.45(d,J=82.3Hz,1H),10.41(s,1H),8.11(dd,J=28.4,8.6Hz,2H),7.76(d,J=8.5Hz,2H),7.35(d ,J=6.6Hz,4H),7.26(s,1H),7.15(d,J=53.5Hz,1H),6.80(s,1H),3.68(s,2H),2.51(d,J=1.9Hz,3H),2.37(d,J=7.6Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ172.36,140.98,131.51,127.49,125.30,124.36,119.33,56.49,21.78,19.03,17.29,15.11,7.87.

[0123] Embodiment 20

[0124] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-3-phenylpropanamide (Compound 20):

[0125] The synthesis procedure was the same as in Example 18, with 3-phenylpropionic acid replacing benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),10.16(s,1H),8.10(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),7.28(d,J=2.4 Hz,4H),7.23-7.11(m,2H),6.81(s,1H),2.94(t,J=7.7Hz,2H),2.68(t,J=7.7Hz,2H),2.52(s,3H),2.38(s,3H). 13 C NMR (101MHz, DMSO) δ169.83,136.31,129.61,128.82,127.07,125.73,119.51,43.84,40.56,40.36,40.15,39.94,39.73,39.61,39.52,39.31.

[0126] Embodiment 21

[0127] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-phenylbutanamide (Compound 21):

[0128] The synthesis steps were the same as in Example 18, with 4-phenylbutyric acid replacing benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ12.43(d,J=82.2Hz,1H),10.12(s,1H),8.10(dd,J=28.2,8.6Hz,2H),7.75(d,J=8.4Hz,2H),7.31(t,J= 7.5Hz,2H),7.25-7.17(m,3H),7.14-6.67(m,2H),2.64(t,J=7.6Hz,2H),2.52(s,3H),2.37(d,J=8.2Hz,5H),1.98-1.86(m,2H). 13 C NMR (101MHz, DMSO) δ166.19,140.82,135.24,132.22,128.93,128.19,127.31,126. 10,120.67,56.49,40.54,40.33,40.12,39.91,39.70,39.50,39.29,21.79,19.03.

[0129] Embodiment 22

[0130] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cinnamamide (Compound 22):

[0131] The synthesis procedure was the same as in Example 18, with 5-phenylpentanoic acid replacing benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ12.44(d,J=81.4Hz,1H),10.12(s,1H),8.07(d,J=9.1Hz,2H),7.79-7.71(m,2H),7.27( d,J=7.4Hz,2H),7.23-7.04(m,4H),6.80(s,1H),2.62(s,2H),2.51(d,J=2.0Hz,3H),2.38(s,5H),1.63(s,4H). 13C NMR (101MHz, DMSO) δ175.03,141.13,127.38,125.33,119.41,56.49,45.37,40.56,40.4 0,40.35,40.14,39.93,39.72,39.52,39.31,29.58,25.86,25.69,21.77,19.03,17.29.

[0132] Embodiment 23

[0133] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cinnamamide (Compound 23):

[0134] The synthesis steps were the same as in Example 18, except that cinnamic acid was used to replace benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),10.47(s,1H),8.15(d,J=8.3Hz,2H),7.87(d,J=8.8Hz,2H),7.71 -7.58(m,3H),7.45(dd,J=10.3,7.2Hz,3H),7.16(s,1H),6.92-6.79(m,2H),2.53(s,3H),2.38(s,3H). 13 C NMR(101MHz,DMSO)δ164.16,141.01,140.87,135.10,130.39,129.54,128.28,127.55,1 25.86,122.51,119.65,40.57,40.41,40.36,40.15,39.94,39.73,39.52,39.31,21.79,

[0135] Embodiment 24

[0136] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)isonicotinamide (Compound 24):

[0137] The synthesis steps were the same as in Example 18, with isonicotinic acid replacing benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ12.53 (d, J = 83.1Hz, 1H), 10.72 (s, 1H), 8.87-8.76 (m, 2H), 8.27-8. 12(m,2H),8.01-7.87(m,4H),7.12(s,1H),6.82(s,1H),2.53(s,3H),2.39(d,J=4.4Hz,3H). 13C NMR (101MHz, DMSO) δ164.65,151.56,151.10,150.79,150.39,142.20,140.51,140.08,135.10,132.06,129.32,127.59,125.88 ,124.81,123.22,122.08,121.18,120.84,40.61,40.56,40.40,40.35,40.14,39.94,39.73,39.52,39.31,21.76,17.28,0.56.

[0138] Embodiment 25

[0139] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)nicotinamide (Compound 25):

[0140] The synthesis steps were the same as in Example 18, with nicotinic acid replacing benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ12.52(d,J=83.0Hz,1H),10.67(s,1H),9.19-9.10(m,1H),8.79(dd,J=4.8,1.7Hz,1H),8.33(dt,J=8.0,2.0Hz,1H),8 .19(dd,J=27.7,8.3Hz,2H),8.02-7.90(m,2H),7.60(ddd,J=7.9,4.9,0.9Hz,1H),7.26-7.09(m,1H),6.82(s,1H),2.53(s,3H),2.39(s,3H). 13 C NMR (101MHz, DMSO) δ164.69,152.71,150.59,149.21,140.51,136.00,131.63,130.93,127.41,126.31,124.45 ,124.01,120.70,56.49,40.57,40.41,40.35,40.20,40.15,39.94,39.73,39.52,39.31,21.79,19.03,17.30.

[0141] Embodiment 26

[0142] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclopropanecarboxamide (Compound 26):

[0143] The synthesis procedure was the same as in Example 18, with cyclopropanecarboxylic acid replacing benzoic acid. 1H NMR (400MHz, DMSO-d6) δ12.48(s,1H),10.42(s,1H),8.10(d,J=8.3Hz,2H),7.76(d,J=8.3Hz,2H),7. 15(s,1H),6.80(s,1H),2.52(s,3H),2.38(s,3H),1.82(td,J=7.5,3.9Hz,1H),0.84(t,J=5.5Hz,4H). 13 C NMR (101MHz, DMSO) δ171.91,142.52,140.91,128.77,128.73,127.40,126.15,125.48,119 .37,40.56,40.35,40.14,39.93,39.72,39.52,39.31,36.78,35.39,31.14,25.22,21.78.

[0144] Embodiment 27

[0145] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 27):

[0146] The synthesis procedure was the same as in Example 18, with cyclohexanecarboxylic acid replacing benzoic acid. 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),8.09(d,J=8.4Hz,2H),7.76(d,J=8.5Hz,2H),7.15(s,1H),6.81(s,1H) ,2.52(s,3H),2.38(s,4H),1.88-1.72(m,4H),1.67(d,J=11.1Hz,1H),1.50-1.37(m,2H),1.35-1.14(m,3H). 13 C NMR (101MHz, DMSO) δ171.69,150.31,142.13,141.87,140.87,135.23,131.78,128.83,128.80,128.02,127.63,127.27,126.30,125.4 9,123.91,119.45,119.34,108.83,40.56,40.41,40.35,40.14,39.93,39.73,39.52,39.31,36.28,35.08,27.18,21.84,17.57,17.13.

[0147] Embodiment 28

[0148] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 28):

[0149] The synthesis procedure was the same as in Example 18, except that 4,4-difluorocyclohexane-1-carboxylic acid was used to replace benzoic acid. 1 H NMR(400MHz,DMSO-d6)δ12.45(d,J=81.2Hz,1H),10.21(s,1H),8.23-8.02(m,2H),7.86-7.66(m,2 H),7.15(d,J=51.1Hz,1H),6.80(s,1H),2.51(s,4H),2.38(s,3H),2.10(s,2H),2.02-1.63(m,6H). 13 C NMR(101MHz,DMSO)δ173.61,150.25,144.40,141.85,140.90,140.77,135.23 ,133.10,131.82,130.90,128.03,127.62,127.26,125.65,124.93,119.60,11 9.49,116.25,108.83,42.47,40.55,40.39,40.34,40.13,39.92,39.71,39.50,39.30,32.90,32.67,32.43,26.07,25.98,21.83,21.69,17.55,17.11,0.56.

[0150] Embodiment 29

[0151] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-methylcyclohexane-1-carboxamide (Compound 29):

[0152] The synthesis procedure was the same as in Example 18, with 4-methylcyclohexane-1-carboxylic acid replacing benzoic acid. 1H NMR (400MHz, DMSO-d6) δ12.44(d,J=82.5Hz,1H),10.03(d,J=26.9Hz,1H),8.10(dd, J=28.6,8.4Hz,2H),7.76(dd,J=8.9,2.5Hz,2H),7.15(d,J=52.6Hz,1H),6.80(s,1H ),2.52(d,J=1.7Hz,3H),2.47(d,J=4.1Hz,1H),2.37(d,J=6.9Hz,3H),1.82(s,4H), 1.62-1.40(m,5H),1.40-1.19(m,1H),0.94(d,J=6.9Hz,2H),0.89(d,J=6.5Hz,1H). 13 C NMR (101MHz, DMSO) δ175.09,174.94,141.15,141.10,127.35,125.39,125.33,119.48,119.42,45.15,43.08,40.55,40 .34,40.13,39.92,39.71,39.62,39.50,39.29,34.44,32.06,31.09,29.54,28.82,25.51,23.02,21.77,19.90,17.29.

[0153] Embodiment 30

[0154] Synthesis of (1r,4r)-N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-4-isopropylcyclohexane-1-carboxamide (Compound 30):

[0155] The synthesis procedure was the same as in Example 18, except that benzoic acid was replaced by (1r,4r)-4-isopropylcyclohexane-1-carboxylic acid. 1 HNMR (400MHz, DMSO-d6) δ12.44(d,J=80.1Hz,1H),10.05(s,1H),8.08(s,2H),7.81-7.72(m,2H),7.15(d,J=43.7Hz,1H),6.80(s,1H),2.51(s,3H) ),2.37(s,3H),2.34-2.24(m,1H),1.89(dd,J=13.6,3.5Hz,2H),1.81-1 .73(m,2H),1.50-1.37(m,3H),1.09-0.95(m,3H),0.87(d,J=6.7Hz,6H). 13C NMR(101MHz,DMSO)δ175.06,141.09,127.37,125.39,119.42,45.57,43.24,40.61,4 0.55,40.35,40.14,39.93,39.72,39.51,39.30,32.81,29.70,28.97,21.78,20.12.

[0156] Embodiment 31

[0157] Synthesis of N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide (Compound 31):

[0158] The synthesis procedure was the same as in Example 18, except that benzoic acid was replaced by tetrahydro-2H-pyran-4-carboxylic acid. 1 H NMR (400MHz, DMSO-d6) δ12.46(d,J=73.0Hz,1H),10.14(s,1H),8.10(d,J=8.2Hz,2H),7.87-7.68(m,2H),7.12(s,1H),6.80(s,1H),3.9 8-3.80(m,2H),3.40(d,J=3.2Hz,1H),3.34(d,J=3.6Hz,1H),2.62(dd,J=10.5,5.0Hz,1H),2.51(s,3H),2.38(s,3H),1.82-1.53(m,4H). 13 CNMR(101MHz,DMSO)δ173.73,140.93,127.41,125.54,119.52,66.83,42.27, 40.53,40.32,40.11,39.90,39.69,39.59,39.49,39.28,29.28,21.77,17.29.

[0159] Embodiment 32

[0160] Synthesis of (3r,5r,7r)-N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)adamantane-1-carboxamide (Compound 32):

[0161] The synthesis procedure was the same as in Example 18, except that benzoic acid was replaced by (3r,5r,7r)-adamantane-1-carboxylic acid. 1H NMR (400MHz, DMSO-d6) δ12.44(d,J=80.9Hz,1H),9.35(s,1H),8.20-8.02(m,2H),7.90-7.78(m,2H),7.15(d,J=51 .3Hz,1H),6.80(s,1H),2.51(s,3H),2.38(s,3H),2.08-2.01(m,3H),1.94(d,J=2.9Hz,6H),1.72(t,J=3.2Hz,6H). 13 C NMR (101MHz, DMSO) δ176.64,141.06,131.45,127.13,125.48,124.32,120.41,60.24,41.51,40. 55,40.34,40.13,39.93,39.72,39.51,39.30,38.68,36.46,28.13,21.77,21.22,17.29,14.54.

[0162] Embodiment 33

[0163] Synthesis of (1r,3R,5S,7r)-N-(4-(4,6-dimethyl-1H-benzo[d]imidazol-2-yl)phenyl)-3,5-dimethyladamantane-1-carboxamide (Compound 33):

[0164] The synthesis steps were the same as in Example 18, except that benzoic acid was replaced by (1r,3R,5S,7r)-3,5-dimethyladamantane-1-carboxylic acid. 1 HNMR (400MHz, DMSO-d6) δ12.44(d,J=81.6Hz,1H),9.36(s,1H),8.16-8.03(m,2H),7.83(dd,J=8.8,1.6Hz,2H),7.23-7.07(m,1H),6.80(t,J=2.4Hz,1 H),2.52(s,3H),2.37(d,J=7.5Hz,3H),2.12(p,J=3.2Hz,1H),1.80-1.71(m ,2H),1.56(q,J=12.2Hz,4H),1.43-1.29(m,4H),1.17(s,2H),0.86(s,6H). 13CNMR(101MHz,DMSO)δ176.37,141.04,127.01,125.53,120.41,50.61,44.85,43.46,42.70, 40.56,40.41,40.35,40.14,39.93,39.73,39.52,39.31,37.35,31.25,30.90,29.33,21.79.

[0165] Embodiment 34

[0166] Synthesis of 1,4,6-trimethyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M1):

[0167] Compound 4 (200 mg, 748.26 μmol) was added to a flask, and then 4 mL of DMF was added, followed by NaH (35.91 mg, 1.50 mmol) under ice bath conditions, and potassium iodide (93.16 mml, 1.50 mmol) was added after 15 min, and the mixture was reacted at 0°C for 3 min and then transferred to room temperature. After the reaction was completed, 30 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 2:1, v / v) to obtain a yellow solid with a yield of 48.46%.

[0168] Synthesis of 4-(1,4,6-trimethyl-1H-benzo[d]imidazol-2-yl)aniline (Intermediate M2):

[0169] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M1.

[0170] Synthesis of N-(4-(1,4,6-trimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 34):

[0171] The synthesis steps were the same as those of Example 18, except that cyclohexanecarboxylic acid was used to replace benzoic acid, and intermediate M2 was used to replace compound 8. 1 HNMR(400MHz,DMSO-d6)δ10.07(s,1H),7.78(q,J=8.5Hz,4H),7.17(s,1H),6.87(s,1H),3.80(s,3H),2.42(s ,6H),1.80(dd,J=24.1,12.4Hz,4H),1.67(d,J=11.6Hz,1H),1.44(q,J=12.2,11.7Hz,2H),1.36-1.00(m,4H). 13CNMR(101MHz,DMSO)δ175.11,152.12,140.94,140.43,136.87,131.78,130.17,128.26,125.13,124.20,119.1 7,108.09,45.41,40.56,40.35,40.14,39.93,39.73,39.52,39.31,32.14,29.58,25.86,25.70,21.94,16.87.

[0172] Embodiment 35

[0173] 4,4-difluoro-N-(4-(1,4,6-trimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexane-1-carboxamide (Synthesis of Compound 35):

[0174] The synthesis steps were the same as those of Example 18, except that 4,4-difluorocyclohexane-1-carboxylic acid was used to replace benzoic acid, and intermediate M2 was used to replace compound 8. 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.78(d,J=4.4Hz,4H),7.18(s,1H),6.87(s,1H) ,3.80(s,3H),2.69(s,1H),2.42(s,3H),2.33(s,1H),2.12(s,3H),2.02-1.64(m,8H). 13 C NMR (101MHz, DMSO) δ173.68,152.05,140.67,140.43,136.88,131.82,130.20,128.28,125.39,124.21,119.31,108.10, 42.51,40.55,40.35,40.14,39.93,39.72,39.51,39.30,32.92,32.69,32.45,32.14,26.80,26.08,25.99,21.94,16.86.

[0175] Embodiment 36

[0176] Synthesis of N-(2,4-dimethylphenyl)-4-nitrobenzamide (Intermediate M3):

[0177] The synthesis steps were the same as those of Example 18, except that p-nitrobenzoic acid was used to replace benzoic acid, and 2,4-dimethylaniline was used to replace compound 8.

[0178] Synthesis of 4,6-dimethyl-2-(4-nitrophenyl)benzo[d]oxazole (Intermediate M4):

[0179] Take Pd(OAc)2 (8.31 mg, 37.00 μmol), intermediate M4 (100 mg, 369.98 μmol), glacial acetic acid (1.6 mL), N,N-dimethylformamide (0.4 mL), potassium peroxodisulfate (150.01 mg, 554.96 μmol) and TfOH (32.74 μL, 369.98 μmol) and put them into a 50 mL sealed tube. Heat the reaction mixture in a 100 ° C oil bath for 24 h. Filter the reaction mixture through diatomaceous earth. Concentrate the filtrate under vacuum, and silica gel column chromatography (petroleum ether / ethyl acetate=10:1, v / v) to obtain a white solid with a yield of 32%.

[0180] Synthesis of 4-(4,6-dimethylbenzo[d]oxazol-2-yl)aniline (Intermediate M5):

[0181] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M4.

[0182] Synthesis of N-(4-(4,6-dimethylbenzo[d]oxazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 36):

[0183] The synthesis steps were the same as those of Example 18, except that p-cyclohexanecarboxylic acid was used to replace benzoic acid, and intermediate M5 was used to replace compound 8. 1 HNMR (400MHz, DMSO-d6) δ10.19(s,1H),8.09(d,J=8.8Hz,2H),7.83(d,J=8.8Hz,2H),7.36(d,J=1.5Hz,1H),7.03(s,1H),2.52(s, 3H),2.42(s,3H),2.36(dt,J=11.5,3.4Hz,1H),1.87-1.71(m,4H),1.66(d,J=11.1Hz,1H),1.49-1.37(m,2H),1.34-1.14(m,3H). 13 C NMR (101MHz, DMSO) δ175.25,161.49,150.56,142.90,139.17,135.13,129.26,128.32,126.78,121.29,119.54,1 08.47,45.40,40.57,40.36,40.15,39.94,39.73,39.53,39.32,29.53,25.83,25.66,21.73,21.71,16.68,16.65.

[0184] Embodiment 37

[0185] Synthesis of N-(4-(4,6-dimethylbenzo[d]oxazol-2-yl)phenyl)-4,4-difluorocyclohexane-1-carboxamide (Compound 37):

[0186] The synthesis steps were the same as those of Example 18, except that 4,4-difluorocyclohexane-1-carboxylic acid was used to replace benzoic acid, and intermediate M5 was used to replace compound 8. 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.11(d,J=8.8Hz,2H),7.87-7.80(m,2H),7.36(d,J=1.5Hz,1 H),7.03(s,1H),2.53(s,4H),2.42(s,3H),2.18-2.06(m,2H),2.00-1.78(m,4H),1.77-1.65(m,2H). 13 C NMR (101MHz, DMSO) δ173.83,173.81,161.44,150.57,142.62,139.16,135.18,129.30,128.35,126.80,121.54,119.68,1 08.49,42.51,40.57,40.41,40.36,40.15,39.95,39.74,39.53,39.32,32.88,32.64,32.41,26.03,25.93,21.72,16.66.

[0187] Embodiment 38

[0188] Synthesis of N,2,4-trimethyl-6-nitroaniline (Intermediate M6):

[0189] The synthesis procedure was the same as that for the preparation of intermediate M1 in Example 34, with 2,4-dimethyl-6-nitroaniline replacing compound 4.

[0190] Synthesis of N1,4,6-trimethyl-1,2-phenylenediamine (Intermediate M7):

[0191] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M6.

[0192] Synthesis of 1,5,7-trimethyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M8):

[0193] The synthesis steps were the same as in Example 1, except that the intermediate M7 was used to replace 3,5-dimethyl-1,2-phenylenediamine.

[0194] Synthesis of 2-(4-azidophenyl)-1,5,7-trimethyl-1H-benzo[d]imidazole (Intermediate M9):

[0195] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M8.

[0196] Synthesis of N-(4-(1,5,7-trimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 38):

[0197] The synthesis steps were the same as those of Example 18, except that cyclohexanecarboxylic acid was used to replace benzoic acid, and intermediate M9 was used to replace compound 8. 1 HNMR(400MHz,DMSO-d6)δ10.06(s,1H),7.79(d,J=8.3Hz,2H),7.66(d,J=8.3Hz,2H),7.24(s,1H),6.81(s,1H),3.97(s,3H),2 .70(s,3H),2.42-2.36(m,1H),2.36(s,3H),1.89-1.72(m,4H),1.67(d,J=10.9Hz,1H),1.49-1.37(m,2H),1.36-1.13(m,4H). 13 C NMR(101MHz,DMSO)δ175.12,154.05,143.86,141.03,133.63,131.08,130.50,126.5 3,124.99,121.72,119.15,117.12,45.41,34.50,29.58,25.86,25.69,21.45,18.68.

[0198] Embodiment 39

[0199] Synthesis of 4,4-difluoro-N-(4-(1,5,7-trimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexane-1-carboxamide (Compound 39):

[0200] The synthesis steps were the same as those of Example 18, except that 4,4-difluorocyclohexane-1-carboxylic acid was used to replace benzoic acid, and intermediate M9 was used to replace compound 8. 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.85-7.75(m,2H),7.74-7.62(m,2H),7.24(s,1H),6.81(s,1 H),3.97(s,3H),2.70(s,3H),2.60-2.52(m,1H),2.36(s,3H),2.19-2.06(m,2H),2.02-1.64(m,6H). 13C NMR (101MHz, DMSO) δ173.71,173.68,153.97,143.81,140.76,133.62,131.12,130.56,126.57,126.52,125.21,124.13,121.75,119.27,117.11 ,56.49,42.51,40.56,40.41,40.35,40.14,39.93,39.73,39.61,39.52 ,39.31,34.50,32.92,32.68,32.45,26.08,25.99,21.45,19.03,18.68.

[0201] Embodiment 40

[0202] Synthesis of 2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M10):

[0203] The synthesis steps are the same as those of Example 1, except that benzene-1,2-diamine is used to replace 3,5-dimethyl-1,2-phenylenediamine.

[0204] Synthesis of 1-methyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M14):

[0205] The synthesis procedure was the same as that for the preparation of intermediate M1 in Example 34, replacing compound 4 with intermediate M10.

[0206] Synthesis of 4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (Intermediate M18):

[0207] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M14.

[0208] Synthesis of N-(4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 40):

[0209] The synthesis steps were the same as those of Example 18, except that cyclohexanecarboxylic acid was used to replace benzoic acid, and intermediate M18 was used to replace compound 8. 1 HNMR(400MHz, DMSO-d6)δ10.08(s,1H),7.87-7.72(m,4H),7.62(dd,J=24.3,7.8Hz,2H),7.25(dt,J=19.0,7.2Hz,2H),3. 87(s,3H),2.38(tt,J=11.8,3.7Hz,1H),1.93-1.72(m,4H),1.67(d,J=11.6Hz,1H),1.51-1.37(m,2H),1.37-1.15(m,4H). 13C NMR(101MHz,DMSO)δ175.16,153.37,142.94,141.21,137.07,130.28,124.81 ,122.59,122.29,119.24,119.21,110.88,45.42,32.16,29.58,25.86,25.69.

[0210] Embodiment 41

[0211] Synthesis of 6-chloro-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M11):

[0212] The synthesis steps are the same as those in Example 1, except that 4-chloro-1,2-phenylenediamine is used to replace 3,5-dimethyl-1,2-phenylenediamine.

[0213] Synthesis of 6-chloro-1-methyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M15):

[0214] The synthesis procedure was the same as that for the preparation of intermediate M1 in Example 34, replacing compound 4 with intermediate M11.

[0215] Synthesis of 4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (Intermediate M19):

[0216] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M15.

[0217] Synthesis of N-(4-(6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 41):

[0218] The synthesis steps were the same as those of Example 18, except that cyclohexanecarboxylic acid was used to replace benzoic acid, and intermediate M19 was used to replace compound 8. 1 HNMR (400MHz, DMSO-d6) δ10.11(s,1H),7.85-7.74(m,5H),7.65(d,J=8.5Hz,1H),7.24(dt,J=8.6,1.5Hz,1H),3.86(s,3H),2.37(td,J=9 .8,8.0,5.8Hz,1H),1.90-1.73(m,4H),1.66(d,J=11.3Hz,1H),1.43(qd,J=12.1,2.9Hz,2H),1.26(dddt,J=24.8,17.0,13.0,6.4Hz,3H). 13C NMR(101MHz,DMSO-d6)δ175.21,154.48,141.64,141.42,137.86,130.33,27.0 9,124.29,122.62,120.45,119.23,111.06,45.41,32.43,29.57,25.85,25.68.

[0219] Embodiment 42

[0220] Synthesis of 5,6-dimethyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M12):

[0221] The synthesis steps are the same as those in Example 1, except that 4,5-dimethyl-1,2-phenylenediamine is used to replace 3,5-dimethyl-1,2-phenylenediamine.

[0222] Synthesis of 1,5,6-trimethyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M16):

[0223] The synthesis procedure was the same as that for the preparation of intermediate M1 in Example 34, replacing compound 4 with intermediate M12.

[0224] Synthesis of 4-(1,5,6-trimethyl-1H-benzo[d]imidazol-2-yl)aniline (Intermediate M20):

[0225] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M16.

[0226] Synthesis of N-(4-(1,5,6-trimethyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 42):

[0227] The synthesis steps were the same as those of Example 18, except that cyclohexanecarboxylic acid was used to replace benzoic acid, and intermediate M20 was used to replace compound 8. 1 HNMR(400MHz,DMSO-d6)δ10.07(s,1H),7.84-7.71(m,4H),7.38(d,J=24.9Hz,2H),3.81(s,3H),2.34(d,J =15.7Hz,7H),1.88-1.73(m,4H),1.67(d,J=11.0Hz,1H),1.43(qd,J=12.1,2.8Hz,2H),1.35-1.14(m,3H). 13C NMR(101MHz,DMSO)δ175.10,152.45,141.57,140.97,135.68,131.21,130.51,130.1 0,125.08,119.34,119.18,110.88,45.41,32.10,29.59,25.86,25.70,20.63,20.40.

[0228] Embodiment 43

[0229] Synthesis of 5,6-dichloro-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M13):

[0230] The synthesis steps are the same as those of Example 1, except that 4,5-dichloro-1,2-phenylenediamine is used to replace 3,5-dimethyl-1,2-phenylenediamine.

[0231] Synthesis of 5,6-dichloro-1-methyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole (Intermediate M17):

[0232] The synthesis procedure was the same as that for the preparation of intermediate M1 in Example 34, replacing compound 4 with intermediate M13.

[0233] Synthesis of 4-(5,6-dichloro-1-methyl-1H-benzo[d]imidazol-2-yl)aniline (Intermediate M21):

[0234] The synthesis steps were the same as in Example 8, except that compound 4 was replaced by intermediate M17.

[0235] Synthesis of N-(4-(5,6-dichloro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexanecarboxamide (Compound 43):

[0236] The synthesis steps were the same as those of Example 18, except that cyclohexanecarboxylic acid was used to replace benzoic acid, and intermediate M21 was used to replace compound 8. 1 HNMR(400MHz,DMSO-d6)δ10.11(s,1H),8.03(s,1H),7.93(s,1H),7.81(s,4H),3.88(s,3H),2.37(tt, J=11.9,3.7Hz,1H),1.87-1.73(m,4H),1.67(d,J=11.6Hz,1H),1.49-1.37(m,2H),1.36-1.13(m,4H). 13C NMR(101MHz,DMSO)δ175.22,155.75,142.40,141.67,136.73,130.41,124.95 ,124.79,123.87,120.26,119.21,112.84,45.42,32.68,29.56,25.84,25.68.

[0237] Embodiment 44

[0238] Synthesis of 4,4-difluoro-N-(4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexane-1-carboxamide (Compound 44):

[0239] The synthesis steps were the same as those of Example 18, except that 4,4-difluorocyclohexane-1-carboxylic acid was used to replace benzoic acid, and intermediate M18 was used to replace compound 8. 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),7.81(s,4H),7.69-7.57(m,2H),7.26(ddd,J=11.8,7.6,1.3Hz,2H),3.88(s,3H),2.54(s,1H),2.19

[0240] -2.06(m,2H),2.01-1.79(m,4H),1.78-1.65(m,2H). 13 C NMR (101MHz, DMSO) δ173.73,173.71,153.29,142.89,140.95,137.05,130.33,125.03,122.63,122.33,119.33,119.2 4,110.91,42.52,40.57,40.41,40.36,40.15,39.94,39.73,39.52,39.31,32.92,32.68,32.45,32.17,26.08,25.98.

[0241] Embodiment 45

[0242] Synthesis of N-(4-(6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-4,4-difluorocyclohexane-1-carboxamide (Compound 45):

[0243] The synthesis steps were the same as those of Example 18, except that 4,4-difluorocyclohexane-1-carboxylic acid was used to replace benzoic acid, and intermediate M19 was used to replace compound 8. 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),7.81(s,4H),7.78(d,J=2.1Hz,1H),7.66(d,J=8.6Hz,1H),7.25(dd,J=8.5 ,2.1Hz,1H),3.87(s,3H),2.55(d,J=11.1Hz,1H),2.12(d,J=10.1Hz,2H),2.00-1.79(m,4H),1.77-1.65(m,2H). 13 C NMR (101MHz, DMSO) δ173.76,173.74,154.42,141.66,141.15,137.87,130.37,127.09,124.56,122.62,120.48,11 9.33,111.09,42.52,40.57,40.41,40.36,40.15,39.94,39.73,39.52,39.31,32.91,32.68,32.44,26.07,25.97.

[0244] Embodiment 46

[0245] Crystal structure analysis of intermediate M8 and compound 35:

[0246] Intermediate M8 and compound 35 were determined by X-ray crystallography ( Figure 1 ).

[0247] Intermediate M8:C 16 H 15 N3O2, orthorhombic system, space group: p212121; a=7.1923(7), b=12.7507(11), c=15.1600(14) α=90, β=90, γ=90(°), V=1390.3(2)nm 3 ,T=223.0K,Z=4,Dc=1.344g / cm 3 ,F(000)=592,Reflections collected=9310(R int =0.0342),Indep.reflns=2441,Refns obs.[I>2σ(I)]=2232,Data / restr. / paras=2441 / 0 / 194,Goodness-of-fit on F 2=1.059,R1,wR2(all data)=0.0365 / 0.0842,R1,wR2[I>2σ(I)]=0.0325 / 0.0813,Large peak / hole CCDC.No:2385735.

[0248] Compound 35: C 23 H 25 F2N3O(H2O), triclinic system, space group: P-1; a=7.1699(13), b=10.430(2), c=15.039(3) α=80.809(8), β=89.290(7), γ=78.757(8)(°), V=1088.7(4)nm 3 ,T=223K,Z=2,Dc=1.267g / cm 3 ,F(000)=2440,Reflections collected=28915(R int =0.0737),Indep.reflns=4943,Refns obs.[I>2σ(I)]=3532,Data / restr. / paras=4943 / 0 / 277,Goodness-of-fit on F 2 =1.035,R1,wR2(all data)=0.0711 / 0.1373,R1,wR2[I>2σ(I)]=0.0479 / 0.1155,Large peak / hole CCDC.No:2385734.

[0249] Embodiment 47

[0250] The inhibitory effects of compounds 1 to 45 on 17β-HSD10 were evaluated, and the safety of compounds 1 to 45 was evaluated by the CCK8 method, and compound 17β-HSD10-IN-1 was selected as a positive control. All experiments were repeated three times, and the mean ± standard deviation was taken.

[0251] Compound safety screening methods:

[0252] HepaRG cells in the proliferation stage were cultured at 1×10 4The cells were seeded in a 96-well plate at a density of 10 cells / mL and incubated in a 37°C, 5% CO2 incubator for 24 h to reach about 60% confluence. The cells were treated with different concentrations of the compound (0.8 μM, 4 μM, 20 μM, and 100 μM) for 24 h, followed by the addition of 2 μL of MTT solution (5 mg / mL, Sigma-Aldrich) and incubation for 4 h. The supernatant was discarded. The absorbance was measured at 492 nm using a microplate reader. At least three independent experiments were performed to determine the IC 50 Value, IC 50 Values ​​are mean ± SD. All experimental data were analyzed using GraphPad Prism software.

[0253] Compound activity screening method:

[0254] 1) Add 2 μL Lipofectamine 2000 and 50 μL opti-MEM to the EP tube, pipette gently, and react at room temperature for 5 min; take a new EP tube and add 0.8 μL DNA and 50 μL opti-MEM; mix the liquids in the two EP tubes, pipette gently, and react at room temperature for 20 min; then add 400 μL opti-MEM, pipette gently to mix, and obtain the transfection reagent.

[0255] 2) When the fusion degree of 293T cells of the 4th to 5th generation after recovery is 85-95%, digest them with 0.25% trypsin and inoculate them into a new 12-well plate, and culture them in a 37°C, 5% CO2 incubator with high-glucose DMEM culture medium containing 10% FBS for 24 hours; discard the original culture medium in the culture plate, wash it with 1×PBS, add 500μL transfection reagent, and place it in the incubator for transfection for 4 hours; discard the transfection reagent in the culture plate, wash it with 1×PBS, and add 1mL DMEM culture medium containing 10% FBS to each well. Add complete culture medium containing 5μM target compound and incubate for 30 minutes. Discard the culture medium, add 100μL PBS, and measure the absorbance using a microplate reader with an excitation wavelength of 435nm and an emission wavelength of 520nm. At least two independent experiments were performed to determine IR (fluorescence intensity of drug-treated group-fluorescence intensity of blank group / fluorescence intensity of transfected group-percentage of fluorescence intensity of blank group), and IR values ​​are mean ± standard deviation. All experimental data were analyzed using GraphPad Prism software.

[0256] Table 1 Inhibitory activity of compounds 1 to 45 on 17β-HSD10 and toxicity to HepaRG cells

[0257]

[0258]

[0259] As can be seen from Table 1, most compounds showed good inhibitory activity against 17β-HSD10, especially compound 34, whose inhibitory activity against 17β-HSD10 was comparable to that of the positive control 17β-HSD10-IN-1, and the cytotoxicity of compound 34 was lower than that of the positive control 17β-HSD10-IN-1.

[0260] Embodiment 48

[0261] In order to evaluate the in vivo activity of compound 34, the present invention conducted a Morris water maze experiment using a scopolamine-induced mouse cognitive dysfunction model to evaluate the behavioral changes of the mice.

[0262] Eight-week-old male Kunming mice weighing 18 to 22 g were placed in the environment for one week to adapt to the environment. The mice were randomly divided into five groups: (1) control group (0.5% sodium carboxymethylcellulose solution); (2) model group; (3) high-dose test group (compound 34, 20 mg / kg); (4) low-dose test group (compound 34, 10 mg / kg); (5) positive control group (donepezil, 10 mg / kg). Except for the control group that only received saline injection, the other groups received intraperitoneal injection of scopolamine hydrobromide to establish the Alzheimer's disease model (10 consecutive days, 1 dose per day). On the 5th day, the mice were trained in the water maze experiment and received oral gavage and intraperitoneal injection of modeling drugs until the test on the 10th day. The water maze apparatus mainly consists of a circular pool (diameter 150 cm × height 60 cm), an escape platform (diameter 10 cm), a data acquisition system, and an analysis system. The circular pool can be divided into four quadrants, and the escape platform is always located in the center of the third quadrant. At the beginning of the experiment, water was added to the pool until the water level was 1 cm above the escape platform, and titanium dioxide powder (0.25 g / L) was added to make the water opaque. During the training phase, mice were placed facing the inner wall and randomly introduced into the swimming pool from each of the four quadrants. If a mouse found the escape platform within 1 min, it was allowed to rest on the platform for 15 s; if unsuccessful, it was gently guided to the platform to rest for 15 s. Training was continued for five consecutive days, and then the exploration experiment was carried out from the sixth day. In the exploration experiment, mice were placed in the pool from the first quadrant and given 1 min to find the platform, during which their movement trajectory and the time required to locate the platform were observed, recorded and analyzed.

[0263] from Figure 1It can be seen that compared with the blank control group, mice injected with scopolamine (3 mg / kg) showed obvious memory deficits, manifested as disordered movement patterns and difficulty in platform positioning, indicating that the mouse cognitive dysfunction model was successfully established. The positive control group treated with donepezil can simplify the movement trajectory of mice and shorten the time required to reach the platform. The mice in the experimental group treated with a low dose of compound 34 (10 mg / kg) showed behavioral improvements; the behavioral improvements of the mice in the experimental group treated with a high dose of compound 34 (20 mg / kg) were even slightly higher than those in the donepezil positive control group. In addition, no changes in the body weight of the treated mice were observed, indicating that compound 34 has good safety.

[0264] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A 2-phenyl-benzo nitrogen-containing heterocyclic compound, characterized in that: The structural formula of the 2-phenyl-benzo nitrogen-containing heterocyclic compound is shown in Formula I and Formula II: Wherein, R1, R2, and R3 are each independently selected from any one of hydrogen, alkyl, alkoxy, and halogen; R4 is selected from any one of halogen, alkyl, nitro, ester, amino, urea and its derivatives, amide and its derivatives; X1 and X2 are each independently selected from any one of nitrogen, hydrogen, oxygen, and nitrogen methyl.

2. The method for preparing the 2-phenyl-benzo nitrogen-containing heterocyclic compound according to claim 1, characterized in that: The preparation method comprises the following steps: (1) 3,5-dimethyl-1,2-phenylenediamine reacts with a benzaldehyde derivative to give compound 1-7; (2) Compound 4 undergoes nitro reduction reaction to obtain compound 8; (3) Compound 8 undergoes a condensation reaction with an isocyanate derivative to obtain compound 9-17; (4) Compound 8 undergoes an amide condensation reaction with a carboxylic acid derivative to obtain compound 18-33; (5) Compound 8 undergoes methylation reaction with iodomethane to obtain intermediate M1; (6) Intermediate M1 undergoes reduction reaction to obtain intermediate M2; (7) Intermediate M2 undergoes amide condensation reaction with a carboxylic acid derivative to obtain compounds 34-35; (8) 2,4-Dimethylaniline reacts with p-nitrobenzoic acid to undergo an amide condensation reaction to obtain intermediate M3; (9) Intermediate M3 undergoes a ring-closing reaction catalyzed by metal to obtain intermediate M4; (10) Intermediate M4 undergoes nitro reduction reaction to obtain intermediate M5; (11) Intermediate M5 undergoes amide condensation reaction with a carboxylic acid derivative to give compounds 36-37; (12) 4,6-Dimethyl-2-nitroaniline reacts with methyl iodide to give intermediate M6; (13) Intermediate M6 undergoes nitro reduction reaction to obtain intermediate M7; (14) Intermediate M7 undergoes a ring-closing reaction with p-nitrobenzaldehyde to obtain intermediate M8; (15) Intermediate M8 undergoes nitro reduction reaction to obtain intermediate M9; (16) Intermediate M9 undergoes amide condensation reaction with a carboxylic acid derivative to give compounds 38-39; (17) The phenylenediamine derivative undergoes an amide condensation reaction with p-nitrobenzaldehyde to obtain intermediate M10-13; (18) Intermediate M10-13 undergoes methylation reaction with methyl iodide to obtain intermediate M14-17; (19) Intermediate M14-17 undergoes reduction reaction to obtain intermediate M18-21; (20) Intermediate M18-21 undergoes amide condensation reaction with a carboxylic acid derivative to give compound 40-45; 3. A pharmaceutical composition comprising the 2-phenyl-benzo nitrogen-containing heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. Use of the 2-phenyl-benzo nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a 17β-HSD10 inhibitor.

5. Use of the 2-phenyl-benzo nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating Alzheimer's disease.

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