Preparation and use of new anticancer drug TNBG-d compound

Abstract

The present invention belongs to the field of chemical medicine. Provided in the present invention are the preparation and use of a new anticancer drug TNBG-D compound. In the present invention, the structure of the anticancer drug TNBG is simplified, i.e., by deleting a D ring (benzene ring), to obtain a series of compounds represented by formula I or salts or stereoisomers thereof. The anticancer drug TNBG-D compound of the present invention and a formulation prepared therefrom with a suitable excipient or auxiliary ingredient have good inhibitory effects on solid tumor cells such as liver cancer, lung cancer and breast cancer, and non-solid tumor cells such as hematologic tumors, possess the potential for treating both solid and non-solid tumors, and have broad prospects for research and application.

Description

Preparation and application of a novel anticancer drug, TNBG-D compound. Technical Field

[0001] This invention belongs to the field of chemical medicine and relates to the preparation and application of a novel anticancer drug, TNBG-D compound. Background Technology

[0002] Studies in tumor metabolomics and antitumor drugs have shown that tumor lipid metabolism involves many intracellular processes, including cell growth, proliferation, differentiation, survival, and membrane homeostasis, playing a crucial role in tumor metabolism. On one hand, due to the specific biosynthetic needs of tumor cells, cutting off the lipid raw materials and energy supply required for tumor cell growth will induce a "lipid starvation" state, achieving an antitumor effect. Examples include acetyl-CoA carboxylase inhibitors (ND-654), fatty acid synthase inhibitors (orlistat, TVB-2640), carnitine palmitoyltransferase 1 inhibitors (etomoxicillin), and monoacylglycerol lipase (MAGL) inhibitors such as JZL184. On the other hand, excessive lipid accumulation within tumor cells, i.e., lipotoxicity, not only affects basic cellular processes but also induces tumor cell apoptosis or death. Therefore, since metabolic alterations in tumor cells may lead to dependence on specific metabolic cascades, utilizing tumor metabolic characteristics to interfere with tumor lipid metabolism may become a novel strategy for cancer prevention and treatment, and this will be of great significance.

[0003] Our earlier Chinese invention patent CN95111450.6 disclosed a novel azasteroid compound, Tetrazanbigen (TNBG), with the structure shown below:

[0004] TNBG is a molecularly targeted antitumor drug based on lipotoxicity. Its structure is that of a novel isoquinoline-containing azasteroid compound, exhibiting good in vitro and in vivo antitumor activity and no cross-resistance with other commonly used antitumor drugs. TNBG's mechanism of action involves activating SCAP (Sterol Regulated Element Binding Protein-1), SREBP-1, and PPARγ (Peroxisome Proliferator-Activated Receptors-1), inhibiting the lipid transport MTTP (Microsomal Triglyceride Transfer Protein), causing lipid accumulation in tumor cells, leading to lipotoxic cell death. TNBG has a significant inhibitory effect on most tumor cells, especially liver and lung cancer cells, and exhibits some selectivity. However, due to its high lipid solubility and poor water solubility, TNBG's absorption, blood concentration, and tissue concentration are affected, limiting its drug development potential.

[0005] In summary, based on the characteristics of tumor cell lipid metabolism and the structure of the anticancer drug TNBG, a "reducing rigidity and increasing flexibility" approach can be adopted to improve the water solubility of TNBG and enhance its antitumor activity. Therefore, designing and developing novel compounds with reduced D rings (TNBG-D) of the anticancer drug TNBG will be of great importance and significance. Summary of the Invention

[0006] This invention uses the anticancer drug TNBG as a lead compound and innovatively obtains a series of novel TNBG-D compounds with good drug-like properties that can be used for antitumor treatment by adopting a "reducing rigidity and increasing flexibility" strategy, namely by deleting the D ring (benzene ring, i.e. TNBG-D) in the TNBG parent structure.

[0007] One object of the present invention is to provide a method for preparing and using the novel anticancer drug TNBG-D compound represented by Formula I.

[0008] Another object of the present invention is to provide a method for preparing the novel anticancer drug TNBG-D compound of Formula I, or its salt, or its stereoisomer.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] In a first aspect, the present invention provides an anticancer drug TNBG-D compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0011] in,

[0012] R1-R5 are selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, amino, carboxyl, formula II or formula III, etc.

[0013] n1 is an integer selected from 1 to 8, with the sign... Represents a single bond or a double bond;

[0014] R6 and R7 are selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, or cyclobutyl; and methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, or cyclobutyl with substituents.

[0015] n2 is an integer selected from 1 to 8, with the sign... Represents a single bond or a double bond;

[0016] n3 is an integer selected from 1 to 2, with the sign... Represents a single bond or a double bond;

[0017] X is selected from oxygen, nitrogen, or carbon, etc.;

[0018] R8 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, amino or carboxyl, etc.;

[0019] In some preferred embodiments, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is used. The substituted amino group in R5 is typically dimethylamino, diethylamino, etc.; the substituted six-membered heterocycle in R2 is typically morpholine, piperidine, N-methylpiperazine, etc.; and the benzoyl group is typically p-methoxybenzoyl, p-chlorobenzoyl, etc.

[0020] This invention provides a synthetic route for the anticancer drug TNBG-D compound represented by Formula I, as follows:

[0021] The synthesis of the anticancer drug TNBG-D compound shown in Formula I has the following characteristics:

[0022] The synthesis proceeded through cyclization, chlorination, and cyclization to obtain key intermediate 4, which was then converted into target compound I via substitution (d1) or amide condensation (d2).

[0023] The cyclization reaction is the reaction of the starting material with diethyl oxalate under acidic conditions (dilute hydrochloric acid); the chlorination reaction is the conversion of hydroxyl groups into chlorine atoms using phosphorus oxychloride; the cyclization reaction is the formation of a four-membered ring key intermediate 4 with 2-aminomethylpiperidine under alkaline conditions (potassium carbonate); the substitution reaction is the substitution of hydrogen on the secondary amine under strongly alkaline conditions (NaH (60%)) to obtain target products I-1 to I-40; the amide condensation reaction is the condensation reaction under alkaline conditions (DIEA) using HATU as a condensing agent to obtain target products I-41 to I-46.

[0024] Secondly, the present invention provides the following representative compounds or pharmaceutically acceptable salts or stereoisomers thereof:

[0025] Thirdly, the present invention provides the use of the compound of Formula I or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for treating and / or preventing cancer-beneficial diseases.

[0026] The prepared anticancer drug is a drug for treating solid tumors and non-solid tumors, characterized in that: preferably, the solid tumors include liver cancer, lung cancer, breast cancer, etc., and the non-solid tumors include hematologic malignancies, etc.

[0027] A drug is a formulation prepared by using a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as the active ingredient, and in combination with suitable excipients or auxiliary ingredients. Attached Figure Description

[0028] Figure 1 is a schematic diagram of the general structure of this invention patent. Detailed Implementation

[0029] Unless otherwise stated, all reagents and instruments used in this invention are commercially available, and all chemical reagents are AR grade, requiring no further purification. The invention will now be further described in detail with reference to the embodiments, but is not limited to these embodiments.

[0030] The structures of the compounds in the following examples were determined primarily by nuclear magnetic resonance (NMR) or high-resolution mass spectrometry (HRMS). NMR measurements were performed using a Bruker AV-600 NMR spectrometer (USA) with deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as internal standard; HRMS measurements were performed using a Waters G2-S QTOF-MS mass spectrometer (USA); melting point data were collected using a WRS-2C melting point apparatus (Shanghai, China).

[0031] Firstly, the synthesis of compounds of formula I:

[0032] Example 1: Synthesis of key intermediate 4a-4k

[0033] The synthetic route for the key intermediate 4a-4k is as follows:

[0034] The reagents and conditions a are: diethyl oxalate, dilute hydrochloric acid, and 90°C;

[0035] The reagents and conditions b are: phosphorus oxychloride, N,N-dimethylformamide, and 90℃;

[0036] The reagents and conditions for c are: 2-aminomethylpiperidine, N,N-dimethylformamide, and 90℃;

[0037] The specific preparation method is as follows:

[0038] (1) Preparation of 6-fluoro-(2,3-dihydroxyquinoxaline) (compound 2a)

[0039] In a clean, round-bottomed flask, 4-fluoro-1,2-phenylenediamine (2.0 g, 15.9 mmol, 1 eq), diethyl oxalate (3.5 g, 23.8 mmol, 1.5 eq), and 15 mL of 4 mol / L hydrochloric acid were added sequentially. The mixture was refluxed at 90 °C for 2 h, and the reaction was monitored by TLC until complete. After cooling to room temperature, 50 mL of water was added, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with water, and dried to give 2.3 g of a brownish-yellow solid (compound 2a), yield 80.4%, mp > 300 °C.

[0040] (2) Preparation of 6-chloro-(2,3-dihydroxyquinoxaline) (compound 2b)

[0041] In a clean, round-bottomed flask, 4-chloro-1,2-phenylenediamine (5.0 g, 35.1 mmol, 1 eq), diethyl oxalate (7.7 g, 52.6 mmol, 1.5 eq), and 50 mL of 4 mol / L hydrochloric acid were added sequentially. The mixture was refluxed at 90 °C for 2 h, and the reaction was monitored by TLC until complete. After cooling to room temperature, 100 mL of water was added, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with water, and dried to give 6.6 g of a pale pink solid (compound 2b), yield 95.8%, mp > 300 °C. 1 H NMR (600MHz, DMSO-d6) δ11.98(s,1H),11.96(s,1H),7.14-7.09(m,3H). 13 C NMR(151MHz,DMSO-d6)δ155.48,155.28,127.36,127.02,125.24,123.12,117.04,114.90.ESI-HRMS:m / z calcd.for C8H5ClN2O2NaCl[M+Na] +218.9937; found 218.9937.

[0042] (3) The preparation method of compound 2c-2k is the same as that in "Example 1-(1)".

[0043] (4) Preparation of 2,3-dichloro-6-fluoro-quinoxaline (compound 3a)

[0044] In a clean, round-bottomed flask, compound 2a (2.3 g, 12.7 mmol, 1 eq), 10 mL of N,N-dimethylformamide, and phosphorus oxychloride (3.6 mL, 38.3 mmol, 1.5 eq) were added sequentially. The mixture was refluxed at 90 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in ice water, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with water, and dried to obtain 2.2 g of a purple solid (compound 3a), with a yield of 79.4%.

[0045] (5) Preparation of 2,3,6-trichloroquinoxaline (compound 3b)

[0046] In a clean, round-bottomed flask, compound 2b (6.6 g, 33.6 mmol, 1 eq), 80 mL of N,N-dimethylformamide, and phosphorus oxychloride (9.4 mL, 100.4 mmol, 1.5 eq) were added sequentially. The mixture was refluxed at 90 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution was quenched in ice water, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with water, and dried to give 7.5 g of a white solid (compound 3b), yield 95.7%, mp 145.4–146.8 °C. 1 H NMR (600MHz, Chloroform-d) δ8.02(d,J=2.3Hz,1H),7.97(d,J=8.9Hz,1H),7.75(dd,J=9.0,2.3Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ146.64,145.69,140.82,139.08,137.32,132.30,129.36,127.24.ESI-HRMS:m / z calcd.for C8H4Cl3N2[M+H] + 232.9440; found 232.9431.

[0047] (6) The preparation method of compound 3c-3k is the same as that in “Example 1-(4)”.

[0048] (7) Preparation of 9-fluoro-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4a)

[0049] Take a clean, round-bottomed flask and add compound 3a (2.2 g, 4.6 mmol, 1 eq), 15 mL of N,N-dimethylformamide, anhydrous potassium carbonate (1.91 g, 13.8 mmol, 3 eq), and 2-aminomethylpiperidine (0.79 g, 6.9 mmol, 1.5 eq) sequentially. Stir thoroughly and reflux at 90 °C until the reaction is complete, as monitored by TLC. Add 100 mL of water to the reaction mixture, stir, and a large amount of solid precipitates. Filter and dry the solid. Extract the filtrate with ethyl acetate (2 x 100 mL). Combine the organic phases, wash with 100 mL of saturated NaCl solution, dry under reduced pressure, concentrate, and purify by column chromatography (mobile phase: V). PE :V EA =5:1), concentrated to give 1.5 g of yellow solid (compound 4a), yield 57.8%, mp 244.4-245.0℃. 1 H NMR(600MHz,Chloroform-d)δ7.50(dd,J=8.9,5.9Hz,1H),7.07(dd,J=10.0,2.8Hz,1H),7.03-6.97(m,1H),6.16(s,1H) ,4.89-4.82(m,1H),3.57-3.53(m,1H),3.41-3.35(m,2H),2.75-2.69(m,1H),1.93-1.86(m,2H),1.84-1.80(m,1H),1.61 -1.48(m,2H),1.42-1.35(m,1H). 13 C NMR(151MHz,Chloroform-d)δ161.04,159.44,144.42,143.65(d,J=1.9Hz),137.39(d,J=12.5Hz),134.46(d,J=1.0Hz) ,126.72(d,J=9.9Hz),112.87,112.71,108.89,108.75,52.83,45.42,44.33,30.03,24.47,23.32.HRMS(ESI):m / z[M+H] + Calcd for C 14 H 16 N4F:259.1359; Found:259.1361.

[0050] (8) Preparation of 9-chloro-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4b)

[0051] In a clean, round-bottomed flask, dissolve compound 3b (7.1 g, 30.3 mmol, 1 eq) in 150 mL of N,N-dimethylformamide. Then, add anhydrous potassium carbonate (12.6 g, 91.0 mmol, 3 eq) and 2-aminomethylpiperidine (5.2 g, 45.6 mmol, 1.5 eq) sequentially. Stir thoroughly and reflux at 90 °C until the reaction is complete, as monitored by TLC. After cooling to room temperature, add 300 mL of water, precipitating a large amount of solid. Filter and dry. Remove isomers by repeated stirring with ethyl acetate (5 x 20 mL) at room temperature. Then, precipitate with dichloromethane and methanol (V... DCM / V MeOH =3:2) recrystallized at 90°C and left at room temperature to precipitate colorless crystals (compound 4b), 3.4 g, yield 40.8%, mp 235.5-238.0°C. 1 H NMR(600MHz,Chloroform-d)δ7.46(d,J=8.7Hz,1H),7.40(d,J=2.4Hz,1H),7.1 9(dd,J=8.7,2.4Hz,1H),5.96(s,1H),4.91-4.86(m,1H),3.57-3.52(m,1H),3.4 2-3.36(m,2H),2.73(td,J=13.0,3.0Hz,1H),1.94-1.90(m,1H),1.89-1.85(m,1 H),1.84-1.80(m,1H),1.62-1.55(m,1H),1.55-1.47(m,1H),1.43-1.36(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.16,144.08,137.25,136.28,129.68,126.58,124.84,123.44,52.91,45.34,44.31,30.05,24.46,23.30.ESI-HRMS:m / z calcd.for C 14 H 16 ClN4[M+H] + 275.1063; found 275.1067.

[0052] (9) Preparation of 9-bromo-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4c)

[0053] Same preparation method as in “Example 1-(7)”. Yellow solid (compound 4c), 1.6 g, yield 50%, mp 229.8-231.0 °C. 1H NMR(600MHz,Chloroform-d)δ7.57(d,J=2.2Hz,1H),7.40(d,J=8.6Hz,1H),7.33(dd,J=8.7,2.2Hz,1H),5.80(s,1H),4.92-4.86(m,1H) ,3.57-3.52(m,1H),3.41-3.36(m,2H),2.76-2.70(m,1H),1.93-1.87(m,2H),1.84-1.80(m,1H),1.60-1.49(m,2H),1.44-1.36(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.12(d,J=7.2Hz),137.77,136.76,127.50,126.8 7,126.67,117.42,52.93,45.32,44.30,30.05,24.46,23.31.HRMS(ESI):m / z[M+H] + Calcd for C 14 H 16 N4Br:319.0558; Found:319.0561.

[0054] (10) Preparation of 9-trifluoromethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4d)

[0055] Same preparation method as in “Example 1-(7)”. Yellow solid (compound 4d), 2.2 g, yield 71%, mp 244.8-247 °C. 1 H NMR(600MHz,Chloroform-d)δ7.68(d,J=2.1Hz,1H),7.60(dd,J=8.5,1.0Hz,1H),7.44(dd,J=8.5,2.1Hz,1H),6.08(s,1H),5.00-4.93(m,1H),3.58(dd,J =11.2,3.5Hz,1H),3.47-3.42(m,1H),3.42-3.37(m,1H),2.80-2.74(m,1H), 1.95-1.88(m,2H),1.86-1.82(m,1H),1.61-1.50(m,2H),1.46-1.39(m,1H). 13C NMR(151MHz,Chloroform-d)δ145.03,144.47,139.89,135.99,126.03(d,J=5.3Hz),121.74(q, J=4.0Hz),120.48(q,J=3.4Hz),53.05,45.10,44.36,30.08,24.44,23.29.HRMS(ESI):m / z[M+H] + Calcd for C 15 H 16 N4F3:309.1327; Found:309.1331.

[0056] (11) Preparation of 9-methoxy-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4e)

[0057] Same preparation method as in “Example 1-(7)”. Yellow solid (compound 4e), 2.0 g, yield 73.7%, mp 208.8-210.2 °C. 1 H NMR(600MHz,Chloroform-d)δ7.48(d,J=8.8Hz,1H),6.94-6.89(m,2H),5.63(s,1H),4.86-4.41(m,1H),3.85(s,3H),3.52(dd,J=11.3,3.5Hz,1H),3. 41-3.36(m,1H),3.36-3.31(m,1H),2.73-2.67(m,1H),1.92-1.85(m,2H), 1.82-1.77(m,1H),1.62-1.54(m,1H),1.53-1.45(m,1H),1.41-133(m,1H). 13 C NMR(151MHz,Chloroform-d)δ157.36,144.07,142.90,137.58,132.57,126.51,114 .65,105.10,55.49,52.89,45.66,44.37,30.02,24.52,23.38.HRMS(ESI):m / z[M+H] + Calcd for C 15 H 19 N4O:271.1559; Found:271.1566.

[0058] (12) Preparation of methyl 2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-9-carboxylate (compound 4f)

[0059] Same preparation method as in “Example 1-(7)”. Yellow solid (compound 4f), 2.3 g, yield 76.7%, mp 260.9-262.4 °C. 1 H NMR(600MHz,Chloroform-d)δ8.28(d,J=1.9Hz,1H),7.90(dd,J=8.5,2.0Hz,1H),7.42(d,J=8.5Hz,1H),6.10(s,1H),4.94-4.88(m,1H),3.93(s ,3H),3.58(d,J=7.8Hz,1H),3.43-3.39(m,2H),2.78-2.73(m,1H),1.95 -1.88(m,2H),1.85-1.82(m,1H),1.62-1.51(m,2H),1.44-1.38(m,1H). 13 C NMR(151MHz,Chloroform-d)δ167.42,144.82,144.46,140.15,137.07,127.99,125.77, 125.31,124.01,52.79,51.97,45.34,44.38,30.04,24.40,23.28.HRMS(ESI):m / z[M+H] + Calcd for C 16 H 19 N4O2:299.1508; Found:299.1514.

[0060] (13) Preparation of ethyl 2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-9-carboxylate (compound 4 g)

[0061] Same preparation method as in “Example 1-(7)”. White solid (4 g of compound), 1.5 g, yield 47.8%, mp 209.8-211.5 °C. 1H NMR(600MHz,Chloroform-d)δ8.28(d,J=1.9Hz,1H),7.91(dd,J=8.4,2.0Hz,1H),7.39(d,J=8.4Hz,1H),6.76(s,1H),4.94-4.87(m,1H),4.39(q,J=7.1Hz, 2H),3.61-3.56(m,1H),3.43-3.38(m,2H),2.78-2.72(m,1H),1.94-1.87(m,2 H),1.86-1.80(m,1H),1.62-1.50(m,2H),1.41(d,J=7.1Hz,3H),1.40(s,1H). 13 C NMR(151MHz,Chloroform-d)δ166.94,145.04,144.51,140.14,136.94,127.88,125.99,125 .33,123.76,60.74,52.71,45.26,44.39,30.05,24.39,23.25,14.43.HRMS(ESI):m / z[M+H] + Calcd for C 17 H 21 N4O2:313.1665; Found:313.1669.

[0062] (14) Preparation of 2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4h)

[0063] Same preparation method as in “Example 1-(7)”. White solid (compound 4h), 1.8 g, yield 74.6%, mp 200.5-202.3℃. 1 H NMR(600MHz,Chloroform-d)δ7.59-7.54(m,1H),7.46-7.37(m,1H),7.29-7.22(m,2H),6.76-6.51(m,1H),4.96-4.89(m,1H),3.58-3.49(m,1H), 3.41-3.33(m,2H),2.75-2.68(m,1H),1.91-1.84(m,2H),1.81-1.77(m,1 H),1.62-1.54(m,4.3,3.0Hz,1H),1.53-1.45(m,1H),1.41-1.33(m,1H). 13C NMR(151MHz,Chloroform-d)δ144.17,137.77,136.78,125.68,124.69,124.30,124.06,52.99,45.35,44.33,30.09,24.53,23.38.HRMS(ESI):m / z[M+H] + Calcd for C 14 H 17 N4:241.1453; Found:241.1456.

[0064] (15) Preparation of 9,10-difluoro-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4i)

[0065] Same preparation method as in “Example 1-(7)”. Yellow solid (compound 4i), 2.2 g, yield 79.3%, mp 235.9-238.6 °C. 1 H NMR(600MHz,Chloroform-d)δ7.30(dd,J=11.6,8.3Hz,1H),7.16(dd,J=11.4,8.2Hz,1H),5.81(s,1H),4.89-4.82(m,1H),3.57- 3.50(m,1H),3.41-3.36(m,2H),2.75-2.69(m,1H),1.93-1.84(m,2H),1.84-1.79(m,1H),1.61-1.49(m,2H),1.43-1.36(m,1H). 13 C NMR(151MHz,Chloroform-d)δ149.16,147.66,144.10,143.86,112.00,111.88,110.54,52.94,45.30,44.27,30.03,24.44,23.29.HRMS(ESI):m / z[M+H] + Calcd for C 14 H 15 N4F2:277.1265; Found:277.1267.

[0066] (16) Preparation of 9,10-dichloro-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4j)

[0067] Same preparation method as in “Example 1-(7)”. Pink solid (compound 4j), 2.2 g, yield 90.6%, mp 243.6-245.2 °C. 1 H NMR(600MHz,Chloroform-d)δ7.63(s,1H),7.50(s,1H),5.59(s,1H),4.91-4.85(m,1H),3.58-3.53(m,1H),3.45-3.35(m,2H) ,2.73(td,J=12.9,3.2Hz,1H),1.95-1.91(m,1H),1.90-1.86(m,1H),1.85-1.81(m,1H),1.62-1.49(m,2H),1.44-1.37(m,1H). 13 C NMR (151MHz, Chloroform-d) δ144.42,144.12,137.21,136.00,127.70,127.64,126.22,125.03,52.98,45.23,44.30,30.04,24.40,23.26.

[0068] (17) Preparation of 9,10-dimethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (compound 4k)

[0069] Same preparation method as in “Example 1-(7)”. Yellow solid (compound 4k), 2.4 g, yield 89.1%, mp 272.6-278.2 °C. 1 H NMR(600MHz,Chloroform-d)δ7.35(s,1H),7.21(s,1H),5.53(s,1H),4.92-4.86(m,1H),3.54-3.47(m,1H),3.39-3.3 4(m,2H),2.75-2.67(m,1H),2.33(s,6H),1.91-1.83(m,2H),1.82-1.77(m,1H),1.60-1.47(m,2H),1.42-1.35(m,1H). 13 C NMR(151MHz,Chloroform-d)δ134.88,134.88,133.71,125.62,124.27,53.13,44.30,44.30,30.06,24.57,23.44,19.85,19.74.HRMS(ESI):m / z[M+H] + Calcd for C 16 H 21N4:269.1766; Found:269.1771.

[0070] (18) Preparation of 6-phenethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-9-ol (compound 4l)

[0071] In a clean round-bottom flask, compound 4e (7.0 g, 0.026 mol, 1 eq) and 80 mL of 40% hydrobromic acid solution were added sequentially. The mixture was refluxed at 130 °C for 6 h, and the reaction was monitored by TLC until completion. The hydrobromic acid reaction solution was concentrated, and the pH was adjusted to 7-8 with saturated sodium hydroxide solution. After the solid precipitated, it was filtered, dried, and recrystallized from methanol to give 6.0 g of brown solid (compound 4l), with a yield of 90.4% and mp 220.1-221.5 °C. 1 H NMR(600MHz, DMSO-d6)δ9.20(s,1H),7.41(d,J=3.3Hz,1H),7.23(d,J=8.5Hz,1H),6.71-6.63(m,2H),4.64-4.55(m,1H),3.43(dt,J=11.4,3.2Hz ,1H),3.26-3.13(m,2H),2.60(td,J=12.7,3.1Hz,1H),1.84-1.70(m,3H) ,1.44(td,J=12.0,11.1,2.9Hz,2H),1.24(qd,J=11.9,10.4,6.2Hz,1H). 13 C NMR(151MHz,DMSO)δ155.00,144.53,142.54,138.83,131.10,126.25,114.00,107.89,52.75,45.00,44.39,29.76,24.49,23.36.HRMS(ESI,m / z):Calcd for C 14 H 17 N4O[M+H] + 257.1402; found 257.1401.

[0072] Example 2: Synthesis of Compound I

[0073] The synthetic route for compound I is as follows:

[0074] Reagents and conditions d1 (compounds I-1 to I-36): various basic or neutral halogenated side chains, sodium hydride (60%), N,N-dimethylformamide, 45℃;

[0075] The reagents and conditions for d2 were (compounds I-37 to I-42): p-chlorobenzoic acid / p-methoxybenzoic acid, HATU, DIEA, N,N-dimethylformamide, 60℃ to room temperature.

[0076] The specific preparation method is as follows:

[0077] (1) Preparation of 2-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-ethylamine (I-1)

[0078] Take a clean, round-bottomed flask and add compound 4b (0.20 g, 0.73 mmol, 1 eq) and 12 mL of N,N-dimethylformamide sequentially. Then, add sodium hydride (0.12 g, 2.90 mmol, 4 eq) under ice bath conditions and activate for 0.5 h. Add N,N-dimethylaminoethyl bromide hydrobromide (0.20 g, 0.87 mmol, 1.2 eq) and reflux at 45 °C until the reaction is complete as monitored by TLC. Quench the reaction solution dropwise with stirring under ice bath conditions. Filter to remove insoluble matter, retain the filtrate, and extract sequentially with dichloromethane (3 x 20 mL) and water (2 x 50 mL). Wash with 50 mL of saturated brine, dry to anhydrous sodium sulfate, concentrate, and purify by column chromatography (V). DCM / V MeOH =30:1), concentrated under reduced pressure to give a white solid (I-1), 40 mg, yield 16.0%, mp 102.5-103.3℃. 1 H NMR(600MHz,Chloroform-d)δ7.47(d,J=2.4Hz,1H),7.42(d,J=8.6Hz,1H),7.14(dd,J=8.6,2.4Hz,1 H),4.84-4.79(m,1H),3.88-3.82(m,1H),3.76-3.70(m,1H),3.50-3.45(m,1H),3.44-3.39(m,1H),3 .36-3.30(m,1H),2.67(td,J=13.0,3.1Hz,1H),2.64-2.54(m,2H),2.37-2.27(s,6H),1.92-1.88(m, 1H),1.88-1.83(m,1H),1.83-1.78(m,1H),1.61-1.52(m,1H),1.52-1.44(m,1H),1.38-1.30(m,1H). 13C NMR(151MHz,Chloroform-d)δ144.16,143.45,138.05,135.46,129.39,126.24,124.13,124. 11,56.11,52.15,51.75,46.15,45.76,44.38,29.98,24.42,23.25.ESI-HRMS:m / zcalcd.for C 18 H 25 ClN5[M+H] + 346.1798; found 346.1800.

[0079] (2) Preparation of 9-chloro-6-(2-(piperidin-1-yl)ethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-2)

[0080] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-2), 0.13 g, yield 46.3%, mp 136.3-138.5 °C. 1 H NMR(600MHz,Chloroform-d)δ7.46(d,J=2.4Hz,1H),7.42(d,J=8.6Hz,1H),7.14(dd,J=8.6 ,2.4Hz,1H),4.85-4.78(m,1H),3.95-3.86(m,1H),3.79-3.71(m,1H),3.54-3.48(m,1H),3. 45-3.40(m,1H),3.35-3.30(m,1H),2.71-2.63(m,3H),2.63-2.47(m,4H),1.92-1.88(m,1H ),1.87-1.83(m,1H),1.82-1.78(m,1H),1.67-1.59(m,4H),1.59-1.43(m,4H),1.38-1.30(m 1H). 13 C NMR(151MHz,Chloroform-d)δ144.14,143.37,138.02,135.48,129.39,126.25,124.14,124.0 9,55.22,54.74,52.25,51.91,45.46,44.43,29.96,25.64,24.39,24.08,23.28.ESI-HRMS:m / z calcd.for C 21 H 29 ClN5[M+H] +386.2111; found 386.2115.

[0081] (3) Preparation of 4-(2-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)ethyl)morpholine (I-3)

[0082] Same preparation method as in “Example 2-(1)”. Light green solid (I-3), 50 mg, yield 17.7%, mp 130.6-132.8℃. 1 H NMR(600MHz,Chloroform-d)δ7.45(d,J=2.4Hz,1H),7.43(d,J=8.6Hz,1H),7.15(dd,J=8.6,2 .4Hz,1H),4.84-4.80(m,1H),3.94-3.88(m,1H),3.75-3.66(m,5H),3.51-3.47(m,4.0Hz,1H) ,3.46-3.42(m,1H),3.36-3.31(m,1H),2.72-2.63(m,3H),2.57(s,4H),1.93-1.89(m,1H),1. 88-1.84(m,1H),1.83-1.78(m,1H),1.61-1.53(m,1H),1.53-1.45(m,1H),1.39-1.32(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.10,143.38,137.98,135.46,129.46,126.28,124.20,12 4.06,66.91,55.31,53.87,52.21,51.88,45.08,44.46,30.00,24.37,23.28.ESI-HRMS:m / z calcd.for C 20 H 27 ClN5O[M+H] + 388.1904; found 388.1908.

[0083] (4) Preparation of 2-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-ethanol (I-4)

[0084] The same preparation method as in “Example 2-(1)” was used. A pale yellow solid (I-4) was obtained, 1.51 g, yield 40.7%, mp 154.4-156.5℃. 1H NMR(600MHz,Chloroform-d)δ7.47(d,J=2.4Hz,1H),7.44(d,J=8.6Hz,1H),7.18(dd,J =8.7,2.4Hz,1H),4.84-4.79(m,1H),3.97-3.90(m,2H),3.84-3.78(m,2H),3.52-3.49 (s,1H),3.49-3.46(m,1H),3.40-3.35(m,1H),2.70(td,J=13.0,3.1Hz,1H),1.94-1.8 6(m,2H),1.84-1.80(m,1H),1.62-1.54(m,1H),1.53-1.46(m,1H),1.39-1.32(m,1H). 13 C NMR(151MHz,DMSO-d6)δ144.43,143.83,138.22,135.50,128.30,126.69, 123.70,123.54,58.39,51.96,51.91,50.70,44.40,29.61,24.36,23.09.

[0085] (5) Preparation of 3-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-propanamine (I-5)

[0086] Same preparation method as in “Example 2-(1)”. Colorless bulk crystals (I-5), 0.11 g, yield 42.0%, mp 130.8-132.1 °C. 1 H NMR(600MHz,Chloroform-d)δ7.47(d,J=2.4Hz,1H),7.42(d,J=8.6Hz,1H),7.14(dd,J=8 .6,2.4Hz,1H),4.84-4.79(m,1H),3.77-3.70(m,1H),3.70-3.62(m,1H),3.48-3.42(m,1H ),3.38-3.30(m,2H),2.68(td,J=13.0,3.1Hz,1H),2.43-2.36(m,2H),2.29(s,6H),1.94- 1.83(m,4H),1.83-1.78(m,1H),1.61-1.53(m,1H),1.53-1.44(m,1H),1.38-1.30(m,1H). 13C NMR(151MHz,Chloroform-d)δ144.13,143.57,138.09,135.41,129.40,126.24,124.11,12 4.09,56.99,52.18,51.41,46.30,45.28,44.40,30.01,24.43,24.41,23.26.ESI-HRMS:m / z calcd.for C 19 H 27 ClN5[M+H] + 360.1955; found 360.1960.

[0087] (6) Preparation of 3-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-diethyl-1-propanamine (I-6)

[0088] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-6), 70 mg, yield 24.8%, mp 97.9-99.0 °C. 1 H NMR(600MHz,Chloroform-d)δ7.47(d,J=2.4Hz,1H),7.42(d,J=8.6Hz,1H),7.14(dd,J =8.6,2.4Hz,1H),4.85-4.79(m,1H),3.74-3.68(m,1H),3.67-3.61(m,1H),3.48-3.42( m,1H),3.38-3.30(m,2H),2.68(td,J=13.0,3.1Hz,1H),2.61-2.49(m,6H),1.92-1.78( m,5H),1.61-1.53(m,1H),1.52-1.45(m,1H),1.38-1.31(m,1H),1.04(t,J=7.1Hz,6H). 13 C NMR(151MHz,Chloroform-d)δ144.14,143.60,138.12,135.40,129.39,126.22,124.10,124.0 6,52.20,51.31,50.33,46.76,46.53,44.39,30.01,24.41,23.90,23.26,11.42.ESI-HRMS:m / z calcd.for C 21 H 31 ClN5[M+H] + 388.2268; found 388.2272.

[0089] (7) Preparation of 9-chloro-6-(3-(piperidin-1-yl)propyl)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-7)

[0090] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-7), 0.10 g, yield 34.4%, mp 125.7-128.5 °C. 1 H NMR(600MHz,Chloroform-d)δ7.46(d,J=2.4Hz,1H),7.41(d,J=8.6Hz,1H),7.13(dd,J =8.6,2.4Hz,1H),4.85-4.79(m,1H),3.75-3.69(m,1H),3.69-3.62(m,1H),3.48-3.44 (m,1H),3.38-3.29(m,2H),2.67(td,J=13.0,3.1Hz,1H),2.52-2.26(m,6H),1.92-1.8 3(m,4H),1.82-1.77(m,1H),1.62-1.57(m,4H),1.57-1.40(m,4H),1.37-1.30(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.14,143.60,138.12,135.38,129.38,126.21,124.10,124.03,5 6.49,54.55,52.18,51.35,46.40,44.40,30.02,25.82,24.41,24.34,23.82,23.27.ESI-HRMS:m / z calcd.for C 22 H 31 ClN5[M+H] + 400.2268; found 400.2271.

[0091] (8) Preparation of 2-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-propanol (I-8)

[0092] The same preparation method as in “Example 2-(1)” was used. A pale yellow solid (I-8) was obtained, 0.52 g, yield 45.2%, mp 120.9-123.2℃. 1H NMR(600MHz,Chloroform-d)δ7.45-7.41(m,2H),7.16(dd,J=8.7,2.3Hz,1H),5.25 (s,1H),4.83-4.75(m,1H),3.89-3.83(m,1H),3.78-3.72(m,1H),3.56-3.51(m,1H ),3.51-3.46(m,1H),3.44-3.38(m,1H),3.38-3.29(m,2H),2.69(td,J=13.1,3.1H z,1H),1.94-1.79(m,5H),1.62-1.54(m,1H),1.53-1.45(m,1H),1.38-1.31(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.06,143.85,136.88,135.31,130.04,126.43, 124.60,123.24,57.62,51.86,51.20,44.62,44.41,29.98,29.94,24.26,23.14.

[0093] (9) Preparation of 6-phenyl-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-9)

[0094] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-9), 0.28 g, yield 42.0%, mp 170.1-171.4 °C. 1 H NMR (600MHz, Chloroform-d) δ7.48 (d, J = 8.9 Hz, 1H), 7.38-7.23 (m, 5H), 6.99 (s, 1H), 6.90 (dd, J = 8. 9,2.8Hz,1H),5.05(d,J=15.0Hz,1H),4.90(d,J=15.0Hz,1H),4.80(d,J=13.4Hz,1H),3.86(s,3H),3 .36-3.17(m,3H),2.67(td,J=13.1,2.9Hz,1H),1.85(ddt,J=15.2,5.3,2.8Hz,2H),1.69(dt,J=12. 7,2.8Hz,1H),1.64-1.50(m,1H),1.43(dt,J=13.1,3.5Hz,1H),1.28(tdd,J=13.2,10.7,3.5Hz,1H). 13C NMR (151MHz, CDCl3) δ157.37,143.68,142.82,138.15,138.13,137.53,128.60,128.23,127.33,126 .20,114.50,105.75,55.53,52.21,50.60,50.35,44.55,30.00,24.49,23.32.HRMS(ESI,m / z):Calcd for C 22 H 25 N4O[M+H] + 361.2028; found 361.2026.

[0095] (10) Preparation of 2-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-ethylamine (I-10)

[0096] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-10), 0.10 g, yield 26.3%, mp 105.9-107.1 °C. 1 H NMR(600MHz,DMSO-d6)δ7.32(d,J=8.8Hz,1H),6.84(d,J=2.8Hz,1H),6.80(dd,J=8.8, 2.8Hz,1H),4.62-4.52(m,1H),3.85(dt,J=13.5,6.6Hz,1H),3.78(s,3H),3.65-3.54(m ,2H),3.40-3.32(m,2H),3.25(tt,J=10.5,2.8Hz,1H),2.66-2.58(m,1H),2.57-2.51( m,1H),2.20(s,6H),1.79(d,3H),1.45(d,J=10.5Hz,2H),1.24(dt,J=11.9,2.5Hz,1H). 13 C NMR (151MHz, DMSO) δ157.12,143.46,142.91,138.41,131.27,126.23,113.71,105.98,56. 31,55.66,51.95,51.25,45.92,45.43,44.50,29.63,24.37,23.22.HRMS(ESI,m / z):Calcd for C 19 H 28 N5O[M+H] + 342.2294; found 342.2292.

[0097] (11) Preparation of 4-(2-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)ethyl)morpholine (I-11)

[0098] Same preparation method as in "Example 2-(1)". Pale yellow solid (I-11), 0.30 g, yield 70.4%. 1 H NMR (600MHz, DMSO-d6) δ7.33(d,J=8.8Hz,1H),6.89-6.78(m,2H),4.59(dt,J=13.2,2.2Hz,1H),3.89(d,J=9.9Hz,1H),3.78(s,3H),3.70-3.46 (m,6H),3.44-3.20(m,2H),2.62(td,J=10.7,9.8,4.9Hz,1H),2.50(p, J=1.9Hz,6H),1.86-1.72(m,3H),1.51-1.38(m,2H),1.31-1.20(m,1H). 13 C NMR (151MHz, CDCl3) δ157.28,143.34,142.94,138.23,131.58,126.23,114.13,105.72,66.97 ,55.51,55.39,53.90,52.24,52.17,45.02,44.54,29.99,24.45,23.36.HRMS(ESI,m / z):Calcd for C 21 H 30 N5O2[M+H] + 384.2400; found 384.2398.

[0099] (12) Preparation of 2-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-ethanol (I-12)

[0100] The preparation method was the same as in "Example 2-(1)". A yellow solid (I-12) was obtained, 1.20 g, yield 34.4%, mp 106.1-107.4 °C. 1H NMR(600MHz,Chloroform-d)δ7.48-7.42(m,1H),6.95-6.87(m,2H),5.51(s,1H),4.79-4.71(m 1H),3.97-3.89(m,2H),3.84(s,3H),3.83-3.74(m,2H),3.49-3.42(m,2H),3.34-3.27(m,1H),2.66(td,J=13. 1,3.0Hz,1H),1.92-1.84(m,2H),1.81-1.77(m,1H),1.61-1.53(m,1H),1.50-1.42(m,1H),1.36-1.28(m,1H). 13 C NMR (151MHz, Chloroform-d) δ157.50,144.54,143.03,136.87,126.37,114.92,104.95,62.77,53.65,52.29,44.52,29.90,24.41,23.22.

[0101] (13) Preparation of 3-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-propylamine (I-13)

[0102] Same preparation method as in “Example 2-(1)”. Yellow solid (I-13), 0.27 g, yield 68.4%, mp 81.7-83.3 °C. 1 H NMR(600MHz,DMSO-d6)δ7.32(d,J=8.8Hz,1H),6.84(d,J=2.8Hz,1H),6.80(dd,J=8.8, 2.8Hz,1H),4.64-4.54(m,1H),3.78(s,3H),3.68(ddd,J=13.3,8.4,6.4Hz,1H),3.60- 3.48(m,2H),3.35-3.22(m,2H),2.65-2.57(m,1H),2.27(t,J=7.0Hz,2H),2.16(s,6H) ,1.77(ddq,J=19.0,13.8,7.0Hz,5H),1.50-1.38(m,2H),1.23(tt,J=11.3,4.1Hz,1H). 13C NMR(151MHz,DMSO)δ157.09,143.53,142.93,138.48,131.29,126.23,113.68,105.99,56.99, 55.63,51.97,51.11,46.12,45.56,44.45,29.65,24.38,24.37,23.23.HRMS(ESI,m / z):Calcd for C 20 H 30 N5O[M+H] + 356.2450; found 356.2451.

[0103] (14) Preparation of N,N-diethyl-3-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-propylamine (I-14)

[0104] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-14), 0.31 g, yield 72.8%, mp 62.2-63.7℃. 1 H NMR (600MHz, DMSO-d6) δ7.32(d,J=8.8Hz,1H),6.84(d,J=2.8Hz,1H),6.80(dd,J=8.8,2.8Hz,1 H),4.59(d,1H),3.78(s,3H),3.67(ddd,J=13.3,8.4,6.3Hz,1H),3.60-3.49(m,2H),3.40-3.2 3(m,3H),2.61(td,J=12.8,3.0Hz,1H),2.54-2.49(m,4H),2.44(dt,J=6.8,4.4Hz,2H),1.85-1 .70(m,5H),1.44(tdd,J=15.1,12.9,5.8,3.4Hz,2H),1.30-1.18(m,2H),0.96(t,J=7.1Hz,6H). 13 C NMR (151MHz, DMSO) δ157.07,143.56,142.93,138.49,131.28,126.22,113.65,105.97,55.60,52. 00,51.05,50.30,46.58,46.32,44.44,29.65,24.39,23.87,23.23,12.02.HRMS(ESI,m / z):Calcd for C 22 H 34 N5O[M+H] +384.2763; found 384.2760.

[0105] (15) Preparation of 9-methoxy-6-(3-(piperidin-1-yl)propyl)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-15)

[0106] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-15), 0.53 g, yield 72.4%, mp 129.4-131.5 °C. 1 H NMR(600MHz,Chloroform-d)δ7.43(d,J=8.9Hz,1H),6.95(d,J=2.8Hz,1H),6.86(dd,J=8.8,2.8Hz,1H) ,4.77(ddt,J=13.3,4.2,2.0Hz,1H),3.86(s,3H),3.78-3.62(m,2H),3.43(dd,J=11.7,3.7Hz,1H),3.3 5(dd,J=11.7,8.7Hz,1H),3.26(ddt,J=11.8,8.7,3.4Hz,1H),2.64(td,J=13.0,3.1Hz,1H),2.47-2.31 (m,6H),1.97-1.73(m,4H),1.64-1.52(m,6H),1.51-1.41(m,3H),1.33(tdd,J=12.9,11.2,3.7Hz,1H). 13 C NMR (151MHz, CDCl3) δ157.24,143.57,142.98,138.37,131.50,126.17,114.02,105.74,56.61,55.50 ,54.61,52.24,51.63,46.29,44.49,30.02,25.95,24.50,24.45,23.97,23.37.HRMS(ESI,m / z):Calcd for C 23 H 34 N5O[M+H] + 396.2763; found 396.2767.

[0107] (16) Preparation of 4-(3-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido-1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)propyl)morpholine (I-16)

[0108] Same preparation method as in "Example 2-(1)". Pale yellow oily substance (I-16), 0.23 g, yield 40.7%. 1 H NMR(600MHz,DMSO-d6)δ7.31(d,J=8.8Hz,1H),6.85(d,J=2.8Hz,1H),6.80(dd,J=8.8,2.8Hz,1H),4 .62-4.55(m,1H),4.10(t,J=5.8Hz,2H),3.85(d,J=6.8Hz,1H),3.66-3.60(m,1H),3.57(dt,J=7.3,4 .1Hz,6H),3.53(t,J=4.7Hz,4H),3.38(dd,J=12.1,8.4Hz,1H),3.31-3.24(m,1H),2.69(t,J=5.8Hz, 2H),2.62-2.53(m,2H),2.49-2.41(m,8H),1.83-1.71(m,3H),1.50-1.39(m,2H),1.30-1.19(m,1H). 13 C NMR (151MHz, DMSO) δ156.25,143.43,142.90,138.36,131.35,126.20,114.10,106.86,66.75,66.67,66. 01,57.60,55.36,54.14,53.95,52.04,51.38,44.65,44.54,29.64,24.33,23.26.HRMS(ESI,m / z):Calcd for C 26 H 39 N6O3[M+H] + 483.3084; found 483.3080.

[0109] (17) Preparation of 9-methoxy-6-(3-(4-methylpiperazin-1-yl)propyl)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-17)

[0110] Same preparation method as in “Example 2-(1)”. Pale yellow solid (I-17), 0.25 g, yield 54.8%, mp 88.7-91.2 °C. 1H NMR (600MHz, DMSO-d6) δ7.31(d,J=8.7Hz,1H),6.83-6.77(m,2H),4.63-4.52(m,1H),3.78(s,3H),3.69(ddd,J=13.4,8.3,6.6Hz,1H),3.59-3.50(m, 2H),3.41-3.23(m,10H),2.61(td,J=12.7,3.2Hz,1H),2.31(t,J=6.9Hz,2 H),2.15(s,3H),1.83-1.72(m,5H),1.50-1.39(m,2H),1.29-1.21(m,1H). 13 C NMR (151MHz, DMSO) δ157.07,143.56,142.95,138.47,131.27,126.23,113.66,105.93,55.61,55.53, 55.26,53.02,51.99,51.15,46.20,46.13,44.45,29.67,24.40,23.64,23.23.HRMS(ESI,m / z):Calcd for C 23 H 35 N6O[M+H] + 411.2872; found 411.2870.

[0111] (18) Preparation of 3-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-propanol (I-18)

[0112] The preparation method was the same as in "Example 2-(1)". A yellow solid (I-18) was obtained, 1.76 g, yield 48.3%, mp 103.0-105.9℃. 1 H NMR(600MHz,Chloroform-d)δ7.47-7.42(m,1H),6.92-6.85(m,2H),5.70(s,1H),4. 77-4.72(m,1H),3.90-3.85(m,1H),3.84(s,3H),3.80-3.75(m,1H),3.57-3.53(m,1 H),3.52-3.48(m,1H),3.40-3.33(m,2H),3.29-3.24(m,1H),2.67(td,J=13.1,3.0H z,1H),1.92-1.79(m,5H),1.63-1.55(m,1H),1.51-1.43(m,1H),1.37-1.30(m,1H).13 C NMR(151MHz,Chloroform-d)δ157.69,143.95,142.60,137.07,131.38,126.44,114 .72,104.60,57.57,55.55,51.90,51.52,44.72,44.34,30.03,29.93,24.33,23.22.

[0113] (19) Preparation of 2-(1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-ethanol (I-19)

[0114] The same preparation method as in "Example 2-(1)" was used. A pale yellow solid (I-19) was obtained, 1.80 g, yield 60.9%, mp 143.3-145.7℃. 1 H NMR(600MHz,Chloroform-d)δ7.56-7.52(m,1H),7.50-7.45m,1H),7.25-7.22(m ,2H),5.42(s,1H),4.87-4.83m,1H),3.96-3.89m,2H),3.83-3.76(m,2H),3.46( d,J=6.3Hz,2H),3.39-3.33(m,1H),2.70(td,J=13.0,3.1Hz,1H),1.93-1.84(m, 2H),1.82-1.77(m,1H),1.62-1.53(m,1H),1.53-1.45(m,1H),1.38-1.30m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.29,144.29,137.15,135.99,125.43,124. 87,124.51,124.34,62.67,53.67,53.36,52.38,44.44,29.93,24.39,23.22.

[0115] (20) Preparation of 3-(1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-propanol (I-20)

[0116] The same preparation method as in “Example 2-(1)” was used. A yellow solid (I-20) was obtained, 3.0 g, yield 53.1%, mp 115.1-116.9℃. 1H NMR(600MHz,Chloroform-d)δ7.56-7.52(m,1H),7.48-7.44(m,1H),7.25-7.21(m,2H ),5.48(s,1H),4.88-4.82(m,1H),3.90-3.85(m,1H),3.80-3.74(m,1H),3.58-3.53( m,1H),3.53-3.48(m,1H),3.43-3.38(m,1H),3.37-3.30(m,2H),2.71(td,J=13.1,3. 1Hz,1H),1.94-1.78(m,5H),1.64-1.56(m,1H),1.54-1.46(m,1H),1.39-1.32(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.88,143.73,136.80,136.26,125.50,125.06, 124.26,124.07,57.66,52.07,51.33,44.66,44.38,30.18,29.99,24.31,23.25.

[0117] (21) Preparation of 6-phenyl-9,10-difluoro-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-21)

[0118] Same preparation method as in “Example 2-(1)”. Yellow solid (I-21), 0.25 g, yield 62.8%, mp 129.9-132.3 °C. 1 H NMR(600MHz,Chloroform-d)δ7.37-7.31(m,4H),7.31-7.27(m,2H),7.27-7.22 (m,1H),4.98(d,J=14.9Hz,1H),4.85(d,J=14.9Hz,1H),4.83-4.79(m,1H),3.35 -3.27(m,2H),3.21(dd,J=11.4,8.3Hz,1H),2.71-2.64(m,1H),1.89-1.82(m,2 H),1.74-1.68(m,1H),1.59-1.51(m,1H),1.49-1.41(m,1H),1.31-1.26(m,1H). 13C NMR(151MHz,Chloroform-d)δ144.04,143.39,137.20,133.67,133.60,133.50,133.43,128.65,128.27,127.65, 127.47,111.62,111.50,111.34,111.22,52.18,50.71,50.04,44.41,29.99,24.40,23.23.HRMS(ESI):m / z[M+H] + Calcd for C 21 H 21 N4F2:367.1734; Found:367.1738.

[0119] (22) Preparation of 2-(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-ethylamine (I-22)

[0120] Same preparation method as in “Example 2-(1)”. Yellow solid (I-22), 0.30 g, yield 79.5%, mp 101.9-108.9 °C. 1 H NMR(600MHz,Chloroform-d)δ7.28-7.24(m,1H),7.24-7.20(m,1H),4.81-4.75(m ,1H),3.85-3.79(m,1H),3.76-3.69(m,1H),3.47(dd,J=11.7,3.8Hz,1H),3.40(d d,J=11.7,8.6Hz,1H),3.35-3.30(m,1H),2.63-2.53(m,2H),2.31(s,6H),2.06(s ,1H),1.92-1.84(m,2H),1.83-1.79(m,1H),1.58-1.44(m,2H),1.38-1.30(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.19,143.12,133.15,111.59,111.48,111.22,111.10 ,56.07,52.12,51.65,46.13,45.79,44.35,29.95,24.40,23.23.HRMS(ESI):m / z[M+H] + Calcd for C 18 H 24 N5F2:348.2000; Found:348.2001.

[0121] (23) Preparation of 4-(2-(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)ethyl)morpholine (I-23)

[0122] Same preparation method as in “Example 2-(1)”. Yellow solid (I-23), 0.28 g, yield 66.2%, mp 126.5-129.4 °C. 1 H NMR(600MHz,Chloroform-d)δ7.28-7.23(m,1H),7.20(dd,J=11.5,8.2Hz,1H),4.8 0-4.76(m,1H),3.90-3.85(m,1H),3.68(q,J=6.6,5.5Hz,5H),3.47(dd,J=11.7,3. 9Hz,1H),3.44-3.39(m,1H),3.35-3.29(m,1H),2.70-2.61(m,3H),2.54(t,J=4.6H z,4H),1.94-1.83(m,2H),1.83-1.77(m,1H),1.61-1.44(m,2H),1.40-1.31(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.12,143.05,133.80,111.63,111.52,111.15,111.04,67 .04,55.39,53.92,52.20,51.77,45.05,44.43,29.98,24.35,23.27.HRMS(ESI):m / z[M+H] + Calcd for C 20 H 26 N5OF2:390.2105; Found:390.2107.

[0123] (24) Preparation of 2-(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-ethanol (I-24)

[0124] The preparation method was the same as in "Example 2-(1)". A yellow solid (I-24) was obtained, 1.50 g, yield 43.1%, mp 161.9-163.2℃. 1H NMR(600MHz,Chloroform-d)δ7.27(dd,J=11.5,8.3Hz,1H),7.20(dd,J=11.4,8.2Hz, 1H),4.80-4.75(m,1H),4.55(s,1H),3.96-3.89(m,2H),3.82-3.76(m,2H),3.51-3.44 (m,2H),3.40-3.34(m,1H),2.68(td,J=13.0,3.1Hz,1H),1.93-1.89(m,1H),1.89-1.8 5(m,1H),1.84-1.80(m,1H),1.61-1.53(m,1H),1.53-1.45(m,1H),1.38-1.31(m,1H). 13 C NMR(151MHz,Chloroform-d)δ149.32,147.70,144.23,144.22,133.46,132. 46,111.86,110.80,62.32,53.08,53.07,52.24,44.40,29.90,24.32,23.14.

[0125] (25) Preparation of 3-(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-propylamine (I-25)

[0126] Same preparation method as in “Example 2-(1)”. Yellow solid (I-25), 0.29 g, yield 73.9%, mp 113.1-118.5 °C. 1 H NMR(600MHz,Chloroform-d)δ7.27-7.24(m,1H),7.24-7.19(m,1H),4.81-4.76(m,1H),3.74-3.69(m,1H),3.66-3.61(m,1H),3.47-3.42 (m,1H),3.37-3.29(m,2H),2.69-2.64(m,1H),2.37-2.32(m,2H),2.26(s,6H),1.93-1.78(m,5H),1.59-1.45(m,2H),1.38-1.31(m,1H). 13C NMR(151MHz,Chloroform-d)δ144.16,133.93,133.86,133.11,111.58,111.47,111.22,111.1 0,57.10,52.20,51.37,46.37,45.48,44.37,30.00,24.60,24.39,23.26.HRMS(ESI):m / z[M+H] + Calcd for C 19 H 26 N5F2:362.2156; Found:362.2160.

[0127] (26) Preparation of 9,10-difluoro-6-(3-(piperidin-1-yl)propyl)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-26)

[0128] Same preparation method as in “Example 2-(1)”. Yellow crystals (I-26), 0.23 g, yield 52.7%, mp 97.0-99.0 °C. 1 H NMR(600MHz,Chloroform-d)δ7.25(d,J=3.3Hz,1H),7.23-7.19(m,1H),4.81-4.76 (m,1H),3.72-3.66(m,6.3Hz,1H),3.65-3.60(m,1H),3.45(h,J=6.6,6.1Hz,1H),3 .36-3.29(m,2H),2.71-2.63(m,1H),2.44-2.29(m,6H),2.09(s,1H),1.93-1.84(m ,4H),1.81-1.77(m,1H),1.62-1.54(m,5H),1.47-1.41(m,2H),1.38-1.30(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.16,143.26,111.57,111.46,111.18,111.07,56.57,54.62 ,52.20,51.29,46.45,44.37,30.00,25.97,24.44,24.39,23.90,23.26.HRMS(ESI):m / z[M+H] + Calcd for C 22 H 30 N5F2:402.2469; Found:402.2473.

[0129] (27) Preparation of 3-(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-propanol (I-27)

[0130] The same preparation method as in “Example 2-(1)” was used. A pale yellow solid (I-27) was obtained, 1.77 g, yield 41.8%, mp 132.6-134.8℃. 1 H NMR(600MHz,Chloroform-d)δ7.30-7.26(m,1H),7.20(dd,J=11.4,8.1Hz,1H),4 .96(s,1H),4.80-4.76(m,1H),3.89-3.82(m,1H),3.78-3.72(m,1H),3.58-3.53 (m,1H),3.53-3.48(m,1H),3.45-3.39(m,1H),3.39-3.29(m,2H),2.73-2.66(m, 1H),1.95-1.80(m,5H),1.63-1.55(m,1H),1.54-1.46(m,1H),1.40-1.32(m,1H). 13 C NMR(151MHz,Chloroform-d)δ149.01,147.49,143.87,143.69,133.16,132.68, 111.96,110.54,57.84,51.95,51.22,44.62,44.45,29.99,29.95,24.23,23.15.

[0131] (28) Preparation of 2-(9,10-dichloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-ethanol (I-28)

[0132] The same preparation method as in “Example 2-(1)” was used. A yellow solid (I-28) was obtained, 1.46 g, yield 51.1%, mp 179.1-181.9℃. 1H NMR(600MHz,Chloroform-d)δ7.57(s,1H),7.51(s,1H),4.82-4.75(m,1H),4.45(s,1H),3.96-3.88(m,2H),3.84-3.74(m,2H) ,3.51-3.43(m,2H),3.40-3.42(m,1H),2.67(td,J=13.0,3.2Hz,1H),1.94-1.79(m,3H),1.60-1.45(m,2H),1.38-1.28(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.56,144.50,136.40,135.44,127.69,127. 34,126.02,124.99,62.13,53.02,52.94,52.17,44.39,29.89,24.27,23.07.

[0133] (29) Preparation of 3-(9,10-dichloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-propanol (I-29)

[0134] The same preparation method as in “Example 2-(1)” was used. A pale yellow solid (I-29) was obtained, 1.0 g, yield 38.3%, mp 134.8-136.3℃. 1 H NMR(600MHz,Chloroform-d)δ7.59(s,1H),7.52(s,1H),5.04(s,1H),4.80-4.7 5(m,1H),3.89-3.82(m,1H),3.77-3.71(m,1H),3.56-3.51(m,1H),3.51-3.46( m,1H),3.45-3.40m,1H),3.37-3.35(m,1H),3.35-3.32(m,1H),2.72-2.66(m,1 H),1.94-1.90(m,1H),1.90-1.79(m,4H),1.61-1.46(m,2H),1.39-1.31(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.21,144.00,136.05,135.44,128.00,127.28, 126.08,124.62,57.71,51.86,51.07,44.62,44.54,29.93,29.92,24.19,23.07.

[0135] Preparation of (30) 6-Phenylacet-9,10-dimethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-30)

[0136] Same preparation method as in “Example 2-(1)”. White solid (I-30), 0.23 g, yield 57.3%, mp 138.6-143.9 °C. 1 H NMR(600MHz,Chloroform-d)δ7.38-7.34(m,2H),7.33-7.28(m,4H),7.27-7.24(m,1H ),5.00(d,J=14.9Hz,1H),4.88(d,J=14.9Hz,1H),4.87-4.81(m,1H),3.32-3.25(m,2 H),3.19(td,J=10.1,1.9Hz,1H),2.71-2.64(m,1H),2.33(d,J=2.2Hz,6H),1.88-1.8 1(m,2H),1.70-1.65(m,1H),1.60-1.52(m,1H),1.48-1.40(m,1H),1.30-1.25(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.78,137.72,135.51,133.78,133.26,128.54,128.32,127.25,12 5.34,125.07,52.38,50.63,50.22,44.48,30.04,24.53,23.36,19.79,19.76.HRMS(ESI):m / z[M+H] + Calcd for C 23 H 27 N4:359.2236; Found:359.2239.

[0137] (31) Preparation of 2-(9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-ethylamine (I-31)

[0138] Same preparation method as in “Example 2-(1)”. Yellow solid (I-31), 0.28 g, yield 73.7%, mp 122.8-127.8 °C. 1H NMR(600MHz,Chloroform-d)δ7.32(s,1H),7.27(s,1H),4.83-4.79(m,1H),3.90-3 .82(m,2H),3.49(dd,J=11.5,3.6Hz,1H),3.42-3.38(m,1H),3.33(tt,J=8.7,3.4H z,1H),2.78(q,J=6.6Hz,2H),2.66(d,J=3.1Hz,1H),2.46(s,6H),2.33(d,J=2.1Hz ,6H),1.90-1.84(m,2H),1.82-1.79(m,1H),1.57-1.45(m,2H),1.36-1.29(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.92,135.44,135.28,133.74,133.29,125.40,124.94,55.71 ,52.38,52.06,45.77,45.29,44.36,29.96,24.51,23.32,19.80,19.77.HRMS(ESI):m / z[M+H] + Calcd for C 20 H 30 N5:340.2501; Found:340.2505.

[0139] (32) Preparation of 4-(2-(9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)ethyl)morpholine (I-32)

[0140] Same preparation method as in “Example 2-(1)”. Yellow solid (I-32), 0.56 g, yield 56.2%, mp 149.7-157.8 °C. 1 H NMR(600MHz,Chloroform-d)δ7.32(s,1H),7.26(s,1H),4.84-4.80(m,1H),3. 95-3.88(m,1H),3.70(q,J=7.1,5.7Hz,5H),3.47-3.40(m,2H),3.33-3.28(m, 1H),2.71-2.63(m,3H),2.57(s,4H),2.32(d,J=1.9Hz,6H),1.92-1.84(m,2H) ,1.81-1.76(m,1H),1.62-1.53(m,1H),1.52-1.44(m,1H),1.39-1.30(m,1H).13 C NMR(151MHz,Chloroform-d)δ143.89,142.76,135.62,133.72,133.04,125.37,124.92,67.03,55 .36,53.91,52.38,52.02,45.02,44.47,30.02,24.48,23.39,19.82,19.77.HRMS(ESI):m / z[M+H] + Calcd for C 22 H 32 N5O:382.2607; Found:382.2610.

[0141] (33) Preparation of 2-(9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-ethanol (I-33)

[0142] The same preparation method as in “Example 2-(1)” was used. A yellow solid (I-33) was obtained, 2.20 g, yield 63.0%, mp 184.2-186.7℃. 1 H NMR(600MHz,Chloroform-d)δ7.32(s,1H),7.26(s,1H),5.72(s,1H),4.83-4.78(m,1H), 3.94-3.91(m,1H),3.91-3.81(m,1H),3.80-3.75(m,1H),3.75-3.71(m,1H),3.48-3.40( m,2H),3.35-3.30(m,1H),2.67(td,J=13.0,3.0Hz,1H),2.32(s,3H),2.31(s,3H),1.92- 1.83(m,2H),1.81-1.76(m,1H),1.61-1.53(m,1H),1.51-1.43(m,1H),1.37-1.29(m,1H). 13 C NMR(151MHz,Chloroform-d)δ144.01,143.97,135.45,134.20,134.13,133.69,125 .43,124.35,62.84,53.92,53.60,52.46,44.43,29.93,24.44,23.26,19.75,19.74.

[0143] (34) Preparation of 9,10-dimethyl-6-(3-(piperidin-1-yl)propyl)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-34)

[0144] Same preparation method as in “Example 2-(1)”. Yellow solid (I-34), 0.27 g, yield 61.3%, mp 112.6-118.6 °C. 1 H NMR(600MHz,Chloroform-d)δ7.31(s,1H),7.27(s,1H),4.84-4.79(m,1H),3.7 3-3.64(m,2H),3.42(dt,J=11.2,3.1Hz,1H),3.35-3.27(m,2H),2.68-2.62(m,1 H),2.41(t,J=6.9Hz,6H),2.32(d,J=2.9Hz,6H),1.99-1.80(m,5H),1.79-1.75( m,1H),1.63(ddt,J=8.6,5.9,2.6Hz,4H),1.49-1.42(m,3H),1.37-1.30(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.90,143.03,135.72,135.11,133.56,125.35,124.98,56.60,54.54,52 .39,51.44,46.16,44.42,30.04,25.77,24.51,24.32,23.84,23.39,19.77,19.70.HRMS(ESI):m / z[M+H] + Calcd for C 24 H 36 N5:394.2971; Found:394.2975.

[0145] (35) Preparation of 3-(9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-N,N-dimethyl-1-propylamine (I-35)

[0146] Same preparation method as in “Example 2-(1)”. Yellow solid (I-35), 0.25 g, yield 63.2%, mp 89.8-93.6 °C. 1H NMR(600MHz,Chloroform-d)δ7.31(s,1H),7.28(s,1H),4.84-4.79(m,1.9Hz,1H),3.77- 3.71(m,1H),3.67-3.62(m,1H),3.41(dd,J=11.2,3.4Hz,1H),3.37-3.29(m,2H),2.69-2 .63(m,1H),2.37(ddd,J=7.9,6.3,4.7Hz,2H),2.32(d,J=2.7Hz,6H),2.27(s,6H),1.91- 1.83(m,4H),1.81-1.76(m,1H),1.60-1.53(m,1H),1.50-1.44(m,1H),1.38-1.31(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.92,143.00,135.07,133.62,132.90,125.33,124.98,57.17,52 .36,51.51,46.15,45.50,44.43,30.04,24.63,24.52,23.38,19.81,19.75.HRMS(ESI):m / z[M+H] + Calcd for C 21 H 32 N5:354.2658; Found:354.2659.

[0147] (36) Preparation of 3-(9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)-1-propanol (I-36)

[0148] The preparation method was the same as in "Example 2-(1)". A yellow solid (I-36) was obtained, 2.94 g, yield 80.6%, mp 162.7-163.3℃. 1H NMR(600MHz,Chloroform-d)δ7.32(s,1H),7.24(s,1H),5.88-5.78(m,1H),4.82-4.76(m,1H),3. 88-3.83(m,1H),3.75-3.70(m,1H),3.56-3.51(m,1H),3.50-3.46(m,1H),3.38(dd,J=11.5,3.9Hz ,1H),3.36-3.32(m,1H),3.32-3.26(m,1H),2.68(td,J=13.1,3.1Hz,1H),2.31(s,3H),2.31(s,3H ),1.92-1.84(m,2H),1.84-1.76(m,3H),1.62-1.54(m,1H),1.52-1.44(m,1H),1.38-1.30(m,1H). 13 C NMR(151MHz,Chloroform-d)δ143.57,143.42,135.01,134.44,134.38,133.44,125.49 ,124.02,57.55,52.06,51.44,44.65,44.33,30.22,29.97,24.36,23.26,19.75,19.71.

[0149] (37) Preparation of 6-phenethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-9-ol (I-37)

[0150] In a clean round-bottom flask, dissolve 4 L (0.50 g, 1.95 mmol, 1 eq) of the key intermediate in 10 mL of DMF. Add 60% sodium hydride (0.47 g, 19.6 mmol, 10 eq) under ice bath conditions and stir for 15 min. Add (2-bromoethyl)benzene (1.45 g, 7.80 mmol, 4 eq), reflux at 60 °C, and react for 4 h. Monitor the reaction by TLC until completion. Quench with 30 mL of water, extract successively with ethyl acetate (3 x 10 mL), then with 30 mL of saturated brine, dry to anhydrous sodium sulfate, concentrate, and purify by column chromatography (V). DCM :V MeOH =50:1), yielding a white solid (I-37), 0.22 g, yield 31.3%. 1H NMR (600MHz, DMSO-d6) δ7.47 (s, 1H), 7.32 (q, J = 8.1Hz, 5H), 7.22 (t, J = 7.1Hz, 1H), 6. 79(d,J=9.3Hz,2H),4.62(d,J=13.1Hz,1H),4.20(t,J=6.7Hz,2H),3.44(d,J=11.5Hz, 1H),3.30-3.13(m,2H),3.04(t,J=6.7Hz,2H),2.63(t,J=12.0Hz,1H),1.78(d,J=13. 3Hz, 3H), 1.45 (d, J=10.4Hz, 2H), 1.24 (q, J=12.2, 11.0Hz, 1H). HRMS (ESI, m / z): Calcd for C 22 H 25 N4O[M+H] + 361.2028; found 361.2028.

[0151] (38) Preparation of 6-phenyl-9-benzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-38)

[0152] Same preparation method as in “Example 2-(37)”. White solid (I-38), 80 mg, yield 31.3%, mp 182.1-183.5 °C. 1 H NMR(600MHz,DMSO-d6)δ7.46(d,2H),7.42-7.30(m,8H),7.24-7.28(m,1H),6.98(d,J=2.8H z,1H),6.91(dd,J=8.9,2.8Hz,1H),5.13(s,2H),4.95(d,J=15.2Hz,1H),4.86(d,J=15.2Hz, 1H),4.64-4.57(m,1H),3.48(dd,J=11.8,3.6Hz,1H),3.33(s,1H),3.26(dd,J=11.9,8.6Hz, 1H),2.65(td,J=12.8,2.5Hz,1H),1.83-1.69(m,3H),1.50-1.38(m,2H),1.28-1.14(m,1H). 13CNMR(151MHz,DMSO)δ156.21,143.62,142.94,138.15,137.87,137.80,131.77,128.97,128.86,128.21,128.18,128 .07,127.54,126.30,114.67,107.35,69.83,51.90,50.49,50.43,44.54,29.66,24.35,23.20.HRMS(ESI,m / z):Calcd for C 28 H 29 N4O[M+H] + 437.2341; found 437.2345.

[0153] (39) Preparation of 4-(2-(9-(2-morpholinethoxy)-1,2,3,4,4a,5-hexahydro-6H-pyridine[1',2':1,6]pyrazine[2,3-b]quinoxaline-6-yl)ethyl)morpholine (I-39)

[0154] Same preparation method as in “Example 2-(37)”. Pale yellow solid (I-39), 0.23 g, yield 40.7%, mp 106.7-107.8 °C. 1 H NMR(600MHz,DMSO-d6)δ7.31(d,J=8.8Hz,1H),6.85(d,J=2.8Hz,1H),6.80(dd,J=8.8,2.8Hz,1H),4 .62-4.55(m,1H),4.10(t,J=5.8Hz,2H),3.85(d,J=6.8Hz,1H),3.66-3.60(m,1H),3.57(dt,J=7.3,4 .1Hz,6H),3.53(t,J=4.7Hz,4H),3.38(dd,J=12.1,8.4Hz,1H),3.31-3.24(m,1H),2.69(t,J=5.8Hz, 2H),2.62-2.53(m,2H),2.49-2.41(m,8H),1.83-1.71(m,3H),1.50-1.39(m,2H),1.30-1.19(m,1H). 13C NMR (151MHz, DMSO) δ156.25,143.43,142.90,138.36,131.35,126.20,114.10,106.86,66.75,66.67,66. 01,57.60,55.36,54.14,53.95,52.04,51.38,44.65,44.54,29.64,24.33,23.26.HRMS(ESI,m / z):Calcd for C 26 H 39 N6O3[M+H] + 483.3084; found 483.3080.

[0155] (40) Preparation of 3-(9-(3-(dimethylamine)propoxy)-1,2,3,4,4a,5-hexahydro-6H-pyridine[1',2':1,6]pyrazine[2,3-b]quinoxalin-6-yl)-N,N-dimethylpropane-1-amine (I-40)

[0156] Same preparation method as in “Example 2-(37)”. Pale red solid (I-40), 0.16 g, yield 32.0%, mp 54.6-56.8 °C. 1 H NMR (600MHz, DMSO-d6) δ7.31(d,J=8.8Hz,1H),6.83(d,J=2.7Hz,1H),6.79(dd,J=8.8,2 .8Hz,1H),4.65-4.52(m,1H),4.01(t,J=6.4Hz,2H),3.68(dt,J=14.1,7.3Hz,1H),3.61 -3.47(m,3H),3.36-3.23(m,2H),2.44(t,J=7.2Hz,2H),2.35(t,J=7.0Hz,2H),2.21(d, J=9.1Hz,13H),1.88(q,J=6.8Hz,2H),1.78(dq,J=14.3,5.2Hz,5H),1.51-1.37(m,2H). 13 C NMR (151MHz, DMSO) δ156.41,143.56,142.94,138.39,131.29,126.20,114.05,106.79,66.30,56.77,56. 06,52.00,51.07,45.99,45.36,45.22,44.46,29.65,27.16,24.38,24.09,23.23.HRMS(ESI,m / z):Calcd for C 24 H 39N6O[M+H] + 427.3285; found 427.3182.

[0157] Preparation of (41) (4-chlorophenyl)(1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalo-6-yl) methyl ketone (I-41)

[0158] Take a clean round-bottom flask and add p-chlorobenzoic acid (0.68 g, 2.8 mmol, 1 eq), HATU (1.08 g, 2.8 mmol, 1 eq), and 15 mL of dry N,N-dimethylformamide sequentially. Stir to dissolve, and slowly add DIEA (0.73 g, 5.6 mmol, 2 eq) dropwise. Activate at room temperature for 1 h, and monitor the activation by TLC until completion. Add intermediate (0.3 g, 1.9 mmol, 0.7 eq) for 4 h, reflux at 60 °C, and react for 3 h, monitoring the reaction by TLC until completion. Cool the reaction solution to room temperature, quench with 50 mL of water, extract with EA (3 x 50 mL), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, concentrate, and purify by column chromatography to give a yellow solid (I-41), 0.32 g, yield 44.3%, mp 233.5–238.3 °C. 1 H NMR(600MHz,Chloroform-d)δ7.58(dd,J=8.3,1.4Hz,1H),7.40(ddd,J=8.4,7.0,1.5Hz,1 H),7.38-7.33(m,2H),7.25-7.21(m,2H),7.18(ddd,J=8.2,6.9,1.4Hz,1H),7.10(dd,J=8 .2,1.5Hz,1H),5.19-5.11(m,1H),4.51-4.42(m,1H),3.65-3.57(m,2H),2.92-2.84(m,1H ),2.01(dq,J=10.7,3.9Hz,1H),1.96-1.87(m,2H),1.65-1.56(m,2H),1.51-1.43(m,1H). 13 C NMR(151MHz,Chloroform-d)δ169.81,143.85,140.23,137.95,136.43,134.70,134.58,129.83,128. 37,128.18,127.00,125.38,124.74,54.32,45.50,43.74,30.10,24.86,23.55.HRMS(ESI):m / z[M+Na] + Calcd for C21 H 19 N4ONaCl:401.1145; Found:401.1150.

[0159] Preparation of (42) (1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)(4-methoxyphenyl) methyl ketone (I-42)

[0160] Same preparation method as in “Example 2-(41)”. Yellow solid (I-42), 0.38 g, yield 53.1%, mp 231.5-233.2 °C. 1 H NMR(600MHz,Chloroform-d)δ7.60-7.56(m,1H),7.45-7.40(m,2H),7.39(td,J= 6.0,3.1Hz,1H),7.19-7.13(m,2H),6.77-6.72(m,2H),5.20-5.12(m,1H),4.44- 4.38(m,1H),3.78(d,J=1.1Hz,3H),3.66-3.58(m,2H),2.89(td,J=12.7,3.1Hz, 1H),2.03-1.96(m,1H),1.94-1.87(m,2H),1.64-1.58(m,2H),1.51-1.44(m,1H). 13 C NMR(151MHz,Chloroform-d)δ170.50,161.56,143.96,140.11,138.85,134.87,130.80,128.05,128.02, 127.13,125.28,124.47,113.18,55.32,54.46,45.78,43.73,30.13,24.93,23.61.HRMS(ESI):m / z[M+Na] + Calcd for C 22 H 22 N4O2Na:397.1640; Found:397.1645.

[0161] Preparation of (43) (4-chlorophenyl)(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalo-6-yl) methyl ketone (I-43)

[0162] Take a clean round-bottom flask and add p-chlorobenzoic acid (0.25 g, 1.6 mmol, 1 eq), HATU (0.61 g, 1.6 mmol, 1 eq), and 15 mL of dry N,N-dimethylformamide in sequence. Stir to dissolve, and slowly add DIEA (0.42 g, 3.2 mmol, 2 eq) dropwise. Activate at room temperature for 1 h, and monitor the activation by TLC until completion. Add intermediate 4i (0.3 g, 1.1 mmol, 0.7 eq), and reflux at 60 °C for 3 h, monitoring the reaction until completion by TLC. Cool the reaction solution to room temperature, quench with 50 mL of water, extract with EA (3 x 50 mL), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, concentrate, and purify by column chromatography to give a yellow solid (I-43), 0.26 g, yield 57.8%, mp 255.1–255.7 °C. 1 H NMR(600MHz,Chloroform-d)δ7.40-7.33(m,2H),7.31(dd,J=11.3,8.1Hz,1H),7.27-7.23(m,2H),6.84(dd,J=10.7,8.3Hz,1H),5.13-5.03(m,1H ),4.47-4.40(m,1H),3.64-3.58(m,2H),2.90-2.84(m,1H),2.01(dt,J=9 .3,3.2Hz,1H),1.98-1.88(m,2H),1.65-1.56(m,2H),1.51-1.42(m,1H). 13 C NMR(151MHz,Chloroform-d)δ169.79,150.42,143.80,138.20,136.72,134.46,129.76,128. 27,112.93,111.59,111.47,54.21,45.46,43.72,30.05,24.78,23.44.HRMS(ESI):m / z[M+Na] + Calcd for C 21 H 17 N4ONaClF2:437.0957; Found:437.0959.

[0163] Preparation of (44) (9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)(4-methoxyphenyl) methyl ketone (I-44)

[0164] Same preparation method as in “Example 2-(43)”. Yellow solid (I-44), 0.18 g, yield 40.3%, mp 266.8-232.4 °C. 1 H NMR(600MHz,Chloroform-d)δ7.43-7.39(m,2H),7.30(dd,J=11.4,8.1Hz,1H),6.89(dd,J=10.9,8.3Hz,1H),6.79-6.74(m,2H),5.09(dp,J=13.3,1.8Hz ,1H),4.42-4.36(m,1H),3.81(s,3H),3.64-3.58(m,2H),2.90-2.83(m,1H), 2.04-1.98(m,1H),1.94-1.88(m,2H),1.66-1.55(m,2H),1.51-1.43(m,1H). 13 C NMR(151MHz,Chloroform-d)δ170.51,161.74,143.89,137.06,130.75,127.80,113.23,113.14, 113.03,111.46,111.35,55.35,54.33,45.73,43.72,30.08,24.84,23.50.HRMS(ESI):m / z[M+Na] + Calcd for C 22 H 20 N4O2F2Na:433.1452; Found:433.1456.

[0165] Preparation of (45) (4-chlorophenyl)(9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalo-6-yl) methyl ketone (I-45)

[0166] Take a clean round-bottom flask and add p-chlorobenzoic acid (0.26 g, 1.6 mmol, 1 eq), HATU (0.64 g, 1.6 mmol, 1 eq), and 15 mL of dry N,N-dimethylformamide in sequence. Stir to dissolve, and slowly add DIEA (0.43 g, 3.3 mmol, 2 eq) dropwise. Activate at room temperature for 1 h, and monitor the activation by TLC until completion. Add intermediate 4K (0.3 g, 1.1 mmol, 0.7 eq), and reflux at 60 °C for 3 h, monitoring the reaction until completion by TLC. Cool the reaction solution to room temperature, quench with 50 mL of water, extract with EA (3 x 50 mL), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, concentrate, and purify by column chromatography to give a yellow solid (I-45), 0.32 g, yield 70.4%, mp 188.6–189.7 °C. 1 H NMR(600MHz,Chloroform-d)δ7.37(s,1H),7.36-7.34(m,2H),7.24-7.21(m,2H),6.86(d,J=1.1Hz,1H),5.13-5.08(m,1H),4.48-4.43(m,1H),3.63 -3.54(m,2H),2.86(td,J=12.6,3.2Hz,1H),2.33(s,3H),2.25(s,3H),2. 02-1.96(m,1H),1.94-1.87(m,2H),1.63-1.57(m,2H),1.49-1.41(m,1H). 13 C NMR(151MHz,Chloroform-d)δ169.56,143.55,138.40,137.23,136.28,134.79,134.41,133.19, 129.86,128.17,126.53,54.44,45.58,30.07,24.91,23.60,20.13,19.70.HRMS(ESI):m / z[M+Na] + Calcd for C 23 H 23 N4ONaCl:429.1458; Found:429.1459.

[0167] Preparation of (46) (9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)(4-methoxyphenyl) methyl ketone (I-46)

[0168] The same preparation method as in "Example 2-(45)" was used. Brown crystals (I-46) were obtained, 0.28 g, yield 62.2%, mp 187.1-190.6℃. 1 H NMR(600MHz,Chloroform-d)δ7.43-7.39(m,2H),7.37(s,1H),6.92(s,1H),6.79-6.71(m,2H),5.17-5.08(m,1H),4.43-4.38(m,1H),3.81-3.76(m ,3H),3.65-3.54(m,2H),2.91-2.83(m,1H),2.33(s,3H),2.23(s,3H),2. 02-1.96(m,1H),1.92-1.85(m,2H),1.64-1.55(m,2H),1.51-1.43(m,1H). 13 C NMR(151MHz,Chloroform-d)δ170.26,161.43,143.65,138.14,137.95,134.05,130.81,128.16,126.69 ,125.05,113.16,55.32,54.57,45.86,43.73,30.10,24.98,23.67,20.10,19.68.HRMS(ESI):m / z[M+Na] + Calcd for C 24 H 26 N4O2Na:425.1953; Found:425.1956.

[0169] Secondly, the following specific experimental examples demonstrate the beneficial effects of the present invention.

[0170] Experimental Example 1: CCK-8 assay for the anti-solid tumor activity of the anticancer drug TNBG-D compound

[0171] Human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MDA-MB-231 were all cultured in DMEM medium (10% FBS fetal bovine serum, 1% penicillin-streptomycin) at 37°C, 5% CO2, and 95% humidity. The cells were then digested with 0.25% trypsin, and digestion was stopped by adding 10% fetal bovine serum to DMEM medium. The cells were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in complete culture medium to a concentration of approximately 4 x 102 cells per 100 μL of cell suspension. 3Accurately weigh the test compound and set the working solution concentrations to 0.5 μM, 1 μM, 2 μM, 4 μM, 8 μM, 16 μM, 32 μM, and 64 μM. Add 200 μL of PBS to the outermost ring of a 96-well cell culture plate, and add 100 μL of cell suspension to each of the remaining wells. Incubate for 24 h to allow cell adhesion, and set up 3 replicates for each concentration. Add 100 μL of the prepared drug working solution to each well and continue incubation for 72 h. Remove the 96-well plate, discard the culture medium, and add 100 μL of fresh culture medium containing 10% (v / v) CCK-8 to each well. Continue incubation at 37°C for 90 min, and then measure the absorbance (A) at 450 nm using a microplate reader. Calculate the cell inhibition rate and perform probit regression analysis to obtain the IC50 of the anticancer drug TNBG-D compound against tumor cell proliferation. 50 value.

[0172] Table 1. Activity of the anticancer drug TNBG-D compound against solid tumor cell lines.

[0173] Note: "a" represents the average of three repeated experiments; "-" indicates no test; "*" indicates the compound concentration is 32 μM.

[0174] Table 1 shows that most of the anticancer drugs TNBG-D can inhibit tumor cells to the μM level, exhibiting varying degrees of inhibitory effects on the three types of solid tumor cells mentioned above. The monosubstituted compound I-13 and the disubstituted compound I-40 have the same side chain, but compound I-40 shows significantly better activity than compound I-13. This indicates that adding the same side chain to a monosubstituted active side chain can enhance the antitumor activity of the compound. Therefore, the anticancer drug TNBG-D compounds have significant value in the development of anti-solid tumor drugs.

[0175] Experimental Example 2: CCK-8 assay for the anticancer drug TNBG-D compound's activity against non-solid tumors

[0176] The anticancer drug TNBG-D was tested for in vitro activity using human leukemia cell lines, including human erythroleukemia cell line HEL, human acute medulloblastic leukemia cell line Kasumi-1, human monocytic cell line THP-1, and human acute myeloid leukemia cell line U937. All cells were incubated in DMEM medium (High Glucose, 10% FBS fetal bovine serum, 1% penicillin-streptomycin) at 37°C, 5% CO2, and 95% humidity. Cells were digested with 0.25% trypsin, and digestion was stopped by adding 10% fetal bovine serum to DMEM medium. The cells were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in complete culture medium. The compound was prepared into a 10 mM solution using DMSO, diluted to 50 μM, and used for initial screening. Compounds showing significant inhibitory activity were screened and subjected to concentration gradient experiments. Drug concentration gradients were set at 0.4 μM, 2 μM, 10 μM, 50 μM, and 250 μM, with a final volume of 100 μL per well (cells + culture medium + drug). Each concentration was tested in triplicate. After culturing for 24 h and 48 h, 10 μL of CCK-8 reagent was added, and absorbance was measured approximately 1-4 h later. The absorbance (A) of each well was measured at 450 nm using a microplate reader. After calculating the cell inhibition rate, probit regression analysis was performed to obtain the IC50 (inhibitory value) of the anticancer drug TNBG-D against non-solid tumor cell lines. 50 value.

[0177] Table 2. Activity of the anticancer drug TNBG-D compound against non-solid tumor cell lines.

[0178] Note: "a" represents the average of three repeated trials.

[0179] Table 2 shows that the anticancer drug TNBG-D compounds have potential anti-leukemia activity, with some compounds exhibiting inhibitory levels reaching μM. They also show slight inhibitory effects on the four types of non-solid tumor cancer cells mentioned above. Compounds I-22 and I-31 show superior inhibitory activity against HEL and U937 cells compared to TNBG, while compound I-31's inhibitory activity against THP-1 cells is comparable to that of TNBG. Therefore, there is broad potential for further research on the anticancer drug TNBG-D compounds in the treatment of non-solid tumors.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in, R1-R5 are selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, amino, carboxyl, formula II or formula III, etc. n1 is an integer selected from 1 to 8, with the sign... Represents a single bond or a double bond; R6 and R7 are selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, or cyclobutyl; and methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, or cyclobutyl with substituents. n2 is an integer selected from 1 to 8, with the sign... Represents a single bond or a double bond; n3 is an integer selected from 1 to 2, with the sign... Represents a single bond or a double bond; X is selected from oxygen, nitrogen, or carbon, etc.; R8 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, amino or carboxyl, etc.

2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, In R5, the substituted amino group is usually dimethylamino, diethylamino, etc.; in R2, the substituted six-membered heterocycle is usually morpholine, piperidine, N-methylpiperazine, and the benzoyl group is usually p-methoxybenzoyl, p-chlorobenzoyl, etc.

3. The synthesis of the anticancer drug TNBG-D compound shown in Formula I has the following characteristics: First, the key intermediate 4 was synthesized through cyclization, chlorination and cyclization reactions. Finally, the target compound of formula I was obtained through substitution reaction (d1) or amide condensation (d2). The cyclization reaction is the reaction of the starting material with diethyl oxalate under acidic conditions (dilute hydrochloric acid); the chlorination reaction is the conversion of hydroxyl groups into chlorine atoms using phosphorus oxychloride; the cyclization reaction is the formation of a four-membered ring key intermediate 4 with 2-aminomethylpiperidine under alkaline conditions (potassium carbonate); the substitution reaction is the substitution of hydrogen on the secondary amine under strongly alkaline conditions (NaH (60%)) to obtain target products I-1 to I-40; the amide condensation reaction is the condensation reaction under alkaline conditions (DIEA) using HATU as a condensing agent to obtain target products I-41 to I-46.

4. The compound of formula I or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that: The compounds mentioned include, for example, the following representative compounds:

5. Use of the compound described in claim 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the treatment and / or prevention of cancer.

6. The use according to claim 5, characterized in that: The prepared anticancer drug is used to treat both solid tumors and non-solid tumors.

7. The use according to claim 6, characterized in that: Preferably, the solid tumor includes liver cancer, lung cancer, breast cancer, etc., and the non-solid tumor includes hematologic malignancies, etc.

8. A medicament comprising a preparation thereof having the active ingredient being the compound of claim 7 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and in combination with suitable excipients or auxiliary ingredients.

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