Preparation and application of novel anticancer drug TNBG-D compound

Abstract

The invention provides preparation and application of a novel anticancer drug TNBG-D compound, and belongs to the field of chemical medicines. The structure of an anti-cancer drug TNBG is simplified, that is, a D ring (benzene ring) is deleted, and a series of compounds shown in the formula I or salts or stereoisomers of the compounds are obtained. The anti-cancer drug TNBG-D compound and a preparation prepared from the anti-cancer drug TNBG-D compound matched with appropriate auxiliary materials or auxiliary components have a good inhibition effect on solid tumor cells such as liver cancer, lung cancer and breast cancer and non-solid tumor cells such as hematoma, have the potential of treating solid tumors and non-solid tumors and have wide research and application prospects.

Description

Technical Field

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

[0002] Studies on tumor metabolomics and anti-tumor drugs have shown that tumor lipid metabolism involves many intracellular processes, including cell growth, proliferation, differentiation, survival, and membrane homeostasis, and plays an important role in tumor metabolism. On the one hand, due to the specific biosynthetic needs of tumor cells, if the lipid raw materials and energy supply required for tumor cell growth are cut off, tumor cells will show a "fat starvation" state, achieving an anti-tumor effect, such as acetyl-CoA carboxylase inhibitors (ND-654), fatty acid synthase inhibitors (orlistat, TVB-2640), carnitine palmitoyltransferase 1 inhibitors (etomoxil), monoacylglycerol lipase (MAGL) inhibitors JZL184, etc. On the other hand, if excessive lipids accumulate in tumor cells, that is, the lipotoxicity of tumor cells, it will not only affect basic cellular processes, but also induce tumor cell apoptosis or death. Therefore, since metabolic changes in tumor cells may lead to dependence on specific metabolic cascade reactions, using tumor metabolic characteristics to interfere with tumor lipid metabolism processes to treat tumors may also become a new strategy for preventing and treating tumors, and this will also be of great significance.

[0003] In our previous Chinese invention patent CN95111450.6, a new azasteroid compound Tetrazanbigen (TNBG) was disclosed, and its structure is shown below:

[0004]

[0005] TNBG is a molecular targeted anti-tumor drug based on lipotoxicity. Its structure is an azasteroid compound containing a novel isoquinoline structure. It has good anti-tumor activity in vitro and in vivo, and has no cross-resistance with other commonly used anti-tumor drugs. The mechanism of action of TNBG is to activate SCAP (SREBP Cleavage Activating Protein), SREBP-1 (Sterol Regulated Element Binding Protein-1) and PPARγ (Peroxisome Proliferators Activated Receptorsγ), inhibit lipid transport MTTP (Microsomal TriglyceridTransfer Protein), cause lipid aggregation in tumor cells, and lead to tumor cell "lipotoxicity" and death. TNBG has a significant inhibitory effect on most tumor cells, especially liver cancer and lung cancer cells, and shows a certain selectivity. However, due to the strong lipid solubility and poor water solubility of TNBG, it affects absorption, blood drug concentration and tissue concentration, and its drugability is limited.

[0006] In summary, based on the characteristics of tumor cell lipid metabolism and the structure of the anticancer drug TNBG, the method of "reducing rigidity and increasing flexibility" is adopted to improve the water solubility of TNBG and enhance its antitumor activity. To this end, the design and development of new anticancer drug TNBG minus D ring (ie, TNBG-D) compounds will have a very important role and significance. Summary of the invention

[0007] The present invention uses the anticancer drug TNBG as the lead compound, and through the strategy of "reducing rigidity and increasing flexibility", i.e. deleting the D ring (benzene ring, i.e. TNBG-D) in the TNBG parent structure, innovatively obtains a series of new TNBG-D compounds with good drugability and can be used for anti-tumor.

[0008] One object of the present invention is to provide a preparation method and use of a novel anticancer drug TNBG-D compound shown in Formula I.

[0009] Another object of the present invention is to provide a method for preparing the novel anticancer drug TNBG-D compound shown in Formula I, or a salt thereof, or a stereoisomer thereof.

[0010] To achieve the above purpose, the present invention provides the following technical solutions:

[0011] In the first aspect, the present invention provides an anticancer drug TNBG-D compound or a pharmaceutically acceptable salt or a stereoisomer thereof as shown in Formula I:

[0012]

[0013] in,

[0014] R1-R5 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, amino, carboxyl, formula II or formula III, etc.;

[0015]

[0016] n1 is an integer selected from 1 to 8, the symbol represents a single bond or a double bond;

[0017] R6 and R7 are selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl or cyclobutyl, etc.; and methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl or cyclobutyl, etc. having a substituent;

[0018] n2 is an integer selected from 1 to 8, the symbol represents a single bond or a double bond;

[0019] n3 is an integer selected from 1 to 2, the symbol represents a single bond or a double bond;

[0020] X is selected from oxygen, nitrogen or carbon;

[0021] R8 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, amino or carboxyl;

[0022] In some preferred embodiments, the compound of formula I or its pharmaceutically acceptable salt or stereoisomer thereof, wherein the substituted amine in R5 is often preferably dimethylamino, diethylamino, etc.; the substituted six-membered heterocyclic ring in R2 is often preferably morpholine, piperidine, N-methylpiperazine, and the benzoyl group is often preferably p-methoxybenzoyl, p-chlorobenzoyl, etc.

[0023] The present invention provides a synthetic route of the anticancer drug TNBG-D compound shown in Formula I, as follows:

[0024]

[0025] The synthesis of the anticancer drug TNBG-D compound shown in Formula I has the following characteristics:

[0026] The synthesis is carried out through cyclization reaction, chlorination reaction, and ring-closure reaction to obtain the key intermediate 4, and finally the target compound of formula I is obtained through substitution reaction (d1) or amide condensation (d2);

[0027] The cyclization reaction is a reaction of the starting material with diethyl oxalate under acidic conditions (dilute hydrochloric acid); the chlorination reaction is the conversion of the hydroxyl group into a chlorine atom 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 the hydrogen on the secondary amine under strong alkaline conditions (NaH (60%)) to obtain the target products I-1 to I-40; the amide condensation reaction is the use of HATU as a condensing agent under alkaline conditions (DIEA) to obtain the target products I-41 to I-46.

[0028] In a second aspect, the present invention provides the following representative compounds or pharmaceutically acceptable salts or stereoisomers thereof:

[0029]

[0030]

[0031]

[0032] In a third aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in preparing a drug for treating and / or preventing cancer;

[0033] The prepared anticancer drug is a drug for treating solid tumors and non-solid tumors, characterized in that: preferably, the solid tumor includes liver cancer, lung cancer, breast cancer, etc., and the non-solid tumor is a blood tumor, etc.;

[0034] A medicine is a preparation prepared by using the compound shown in formula I or its pharmaceutically acceptable salt or stereoisomer as an active ingredient and adding suitable excipients or auxiliary ingredients. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 It is a schematic diagram of the general structure of the patent of this invention. DETAILED DESCRIPTION

[0035] Unless otherwise specified, the reagents and instruments used in the present invention are all commercially available, wherein the chemical reagents are all AR grade and do not require further purification. The present invention is now further described in detail in conjunction with the examples, but is not limited to these examples.

[0036] The structures of the compounds in the following examples are mainly determined by nuclear magnetic resonance (NMR) or high-resolution mass spectrometry (HRMS). NMR determination was performed using a Bruker AV-600 nuclear magnetic spectrometer (USA), with deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as internal standard; high-resolution mass spectrometry was performed using a Waters G2-S QTOF-MS mass spectrometer (USA); melting point data were collected using a WRS-2C melting point instrument (Shanghai, China).

[0037] In the first aspect, the synthesis of compounds of formula I:

[0038] Example 1: Synthesis of key intermediates 4a-4k

[0039] The synthetic routes of key intermediates 4a-4k are as follows:

[0040]

[0041] Reagents and conditions a are: diethyl oxalate, dilute hydrochloric acid, 90°C;

[0042] Reagents and conditions b are: phosphorus oxychloride, N,N-dimethylformamide, 90°C;

[0043] Reagents and conditions c were: 2-aminomethylpiperidine, N,N-dimethylformamide, 90°C;

[0044] The specific preparation method is as follows:

[0045] (1) Preparation of 6-fluoro-(2,3-dihydroxyquinoxaline) (Compound 2a)

[0046] Take a clean eggplant-shaped bottle, add 4-fluoro-1,2-phenylenediamine (2.0g, 15.9mmol, 1eq), diethyl oxalate (3.5g, 23.8mmol, 1.5eq) and 15mL 4mol / L hydrochloric acid in sequence, reflux at 90℃, react for 2h, and monitor by TLC until the reaction is complete. Cool to room temperature, add 50mL water, a large amount of solid precipitates, filter, wash with water, and dry to obtain a brown-yellow solid (compound 2a), 2.3g, yield 80.4%, mp>300℃.

[0047] (2) Preparation of 6-chloro-(2,3-dihydroxyquinoxaline) (Compound 2b)

[0048] Take a clean eggplant-shaped bottle, add 4-chloro-1,2-phenylenediamine (5.0g, 35.1mmol, 1eq), diethyl oxalate (7.7g, 52.6mmol, 1.5eq) and 50mL 4mol / L hydrochloric acid in sequence, reflux at 90℃, react for 2h, and monitor by TLC until the reaction is complete. Cool to room temperature, add 100mL water, a large amount of solid precipitates, filter, wash with water, and dry to obtain a light pink solid (compound 2b), 6.6g, yield 95.8%, mp>300℃. 1 HNMR(600MHz,DMSO-d6)δ11.98(s,1H),11.96(s,1H),7.14-7.09(m,3H). 13 CNMR(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.

[0049] (3) The preparation method of compounds 2c-2k is the same as that of "Example 1-(1)"

[0050] (4) Preparation of 2,3-dichloro-6-fluoro-quinoxaline (Compound 3a)

[0051] Take a clean eggplant-shaped bottle, add compound 2a (2.3g, 12.7mmol, 1eq), 10mL N,N-dimethylformamide and phosphorus oxychloride (3.6mL, 38.3mmol, 1.5eq) in sequence, reflux at 90℃, react for 2h, and monitor by TLC until the reaction is complete. Pour the reaction solution into ice water to quench, precipitate a large amount of solid, filter, wash with water, and dry to obtain a purple solid (compound 3a), 2.2g, yield 79.4%.

[0052] (5) Preparation of 2,3,6-trichloroquinoxaline (Compound 3b)

[0053] Take a clean eggplant-shaped bottle, add compound 2b (6.6g, 33.6mmol, 1eq), 80mL N,N-dimethylformamide and phosphorus oxychloride (9.4mL, 100.4mmol, 1.5eq) in sequence, reflux at 90℃, react for 2h, and monitor by TLC until the reaction is complete. Pour the reaction solution into ice water to quench, precipitate a large amount of solid, filter, wash with water, and dry to obtain a white solid (compound 3b), 7.5g, yield 95.7%, mp 145.4-146.8℃. 1HNMR(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 / zcalcd.for C8H4Cl3N2[M+H] + 232.9440; found 232.9431.

[0054] (6) The preparation method of compounds 3c-3k is the same as that of "Example 1-(4)"

[0055] (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)

[0056] Take a clean eggplant-shaped bottle, add compound 3a (2.2g, 4.6mmol, 1eq), 15ml N,N-dimethylformamide, anhydrous potassium carbonate (1.91g, 13.8mmol, 3eq) and 2-aminomethylpiperidine (0.79g, 6.9mmol, 1.5eq) in sequence, stir well, reflux at 90°C until the reaction is completed by TLC monitoring. Add 100mL of water to the reaction solution, stir, precipitate a large amount of solid, filter, and dry; extract the filtrate with ethyl acetate (2x100mL), combine the organic phases, wash with 100mL of saturated NaCl solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (mobile phase is V PE :V EA =5:1), concentrated to give a yellow solid (Compound 4a), 1.5 g, yield 57.8%, mp 244.4-245.0°C. 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). 13CNMR(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.

[0057] (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)

[0058] Take a clean eggplant-shaped bottle, dissolve compound 3b (7.1 g, 30.3 mmol, 1 eq) in 150 mL N, N-dimethylformamide, add anhydrous potassium carbonate (12.6 g, 91.0 mmol, 3 eq) and 2-aminomethylpiperidine (5.2 g, 45.6 mmol, 1.5 eq) in turn, stir well, reflux at 90 ° C until the reaction is completed by TLC monitoring. After cooling to room temperature, add 300 mL of water, precipitate a large amount of solid, filter, and dry; repeatedly beat with ethyl acetate (5 x 20 mL) at room temperature to remove isomers, and then use dichloromethane and methanol (V DCM / V MeOH =3:2) was recrystallized at 90°C and allowed to stand 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). 13C 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.

[0059] (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)

[0060] Same preparation method as in "Example 1-(7)". Yellow solid (Compound 4c), 1.6 g, yield 50%, mp 229.8-231.0°C. 1 H 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.

[0061] (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)

[0062] 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). 13 C 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.

[0063] (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)

[0064] Same preparation method as in "Example 1-(7)". Yellow solid (Compound 4e), 2.0 g, yield 73.7%, mp 208.8-210.2°C. 1H 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.

[0065] (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)

[0066] 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). 13CNMR(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.

[0067] (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 4g)

[0068] Same preparation method as in "Example 1-(7)". White solid (Compound 4g), 1.5g, yield 47.8%, mp 209.8-211.5℃. 1 H 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.

[0069] (14) Preparation of 2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (Compound 4h)

[0070] Same preparation method as in "Example 1-(7)". White solid (Compound 4h), 1.8 g, yield 74.6%, mp 200.5-202.3°C. 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). 13 C 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.

[0071] (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)

[0072] Same preparation method as in "Example 1-(7)". Yellow solid (Compound 4i), 2.2 g, yield 79.3%, mp 235.9-238.6°C. 1H 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.

[0073] (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)

[0074] The 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.

[0075] (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)

[0076] 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 21 N4:269.1766;Found:269.1771.

[0077] (18) Preparation of 6-phenethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-9-ol (Compound 41)

[0078] Take a clean round-bottom flask, add compound 4e (7.0 g, 0.026 mol, 1 eq) and 80 mL of 40% hydrobromic acid solution in sequence, reflux at 130°C, react for 6 h, and monitor by TLC until the reaction is complete. Concentrate the hydrobromic acid reaction solution, adjust the pH to 7-8 with saturated sodium hydroxide solution, filter and dry the precipitated solid; recrystallize from methanol to obtain a brown solid (compound 4l), 6.0 g, with a yield of 90.4%, mp220.1-221.5°C. 1H 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.

[0079] Example 2: Synthesis of compounds of formula I

[0080] The synthetic route of the compound of formula I is as follows:

[0081]

[0082] Reagents and conditions d1 are (compounds I-1 to I-36): various basic or neutral halogenated side chains, sodium hydride (60%), N,N-dimethylformamide, 45°C;

[0083] Reagents and conditions d2 are (compounds I-37 to I-42): p-chlorobenzoic acid / p-methoxybenzoic acid, HATU, DIEA, N,N-dimethylformamide, 60°C-room temperature.

[0084] The specific preparation method is as follows:

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

[0086] Take a clean eggplant-shaped bottle, add compound 4b (0.20g, 0.73mmol, 1eq), 12mL N,N-dimethylformamide, then add sodium hydride (0.12g, 2.90mmol, 4eq) in an ice bath, activate for 0.5h, add N,N-dimethylaminoethyl bromide hydrobromide (0.20g, 0.87mmol, 1.2eq), reflux at 45°C until the reaction is completed by TLC monitoring. Under ice bath stirring, water was added dropwise to the reaction solution to quench the reaction, the insoluble matter was removed by suction, the filtrate was retained, extracted with dichloromethane (3x 20mL) and water (2x50mL) in turn, washed with 50mL saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified 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 °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,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). 13 C 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.

[0087] (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)

[0088] Same preparation method as "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 CNMR(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.

[0089] (3) Preparation of 4-(2-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)ethyl)morpholine (I-3)

[0090] Same preparation method as "Example 2-(1)". Light green solid (I-3), 50 mg, yield 17.7%, mp 130.6-132.8°C. 1H 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.

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

[0092] The same preparation method as in "Example 2-(1)" was used to obtain a light yellow solid (I-4), 1.51 g, yield 40.7%, mp 154.4-156.5°C. 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.

[0093] (5) Preparation of 3-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-N,N-dimethyl-1-propylamine (I-5)

[0094] The same preparation method as in "Example 2-(1)". Colorless block 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.

[0095] (6) Preparation of 3-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-N,N-diethyl-1-propylamine (I-6)

[0096] 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.

[0097] (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)

[0098] Same preparation method as "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.

[0099] (8) Preparation of 2-(9-chloro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-1-propanol (I-8)

[0100] The same preparation method as in "Example 2-(1)" was used to obtain a light yellow solid (I-8), 0.52 g, yield 45.2%, mp 120.9-123.2°C. 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 CNMR(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.

[0101] (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)

[0102] 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) δ157.37,143.68,142.82,138.15,138.13,137.53,128.60,128.23,127.33,126.2 0,114.50,105.75,55.53,52.21,50.60,50.35,44.55,30.00,24.49,23.32.HRMS(ESI,m / z):Calcdfor C 22 H 25 N4O[M+H] + 361.2028; found 361.2026.

[0103] (10) Preparation of 2-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-N,N-dimethyl-1-ethylamine (I-10)

[0104] 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.

[0105] (11) Preparation of 4-(2-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)ethyl)morpholine (I-11)

[0106] 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.

[0107] (12) Preparation of 2-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-1-ethanol (I-12)

[0108] The same preparation method as in "Example 2-(1)" was used to obtain a yellow solid (I-12), 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.

[0109] (13) Preparation of 3-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-N,N-dimethyl-1-propylamine (I-13)

[0110] 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.

[0111] (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)

[0112] Same preparation method as in "Example 2-(1)". Pale yellow solid (I-14), 0.31 g, yield 72.8%, mp 62.2-63.7°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,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.

[0113] (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)

[0114] 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.

[0115] (16) Preparation of 4-(3-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido1',2':1,6]pyrazino[2,3-b]quinoxalin-6-yl)propyl)morpholine (I-16)

[0116] Same preparation method as in "Example 2-(1)". Pale yellow oil (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 forC 26 H 39 N6O3[M+H] + 483.3084; found 483.3080.

[0117] (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)

[0118] 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.

[0119] (18) Preparation of 3-(9-methoxy-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-1-propanol (I-18)

[0120] The same preparation method as in "Example 2-(1)" was used to obtain a yellow solid (I-18), 1.76 g, yield 48.3%, mp 103.0-105.9°C. 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.

[0121] (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)

[0122] The same preparation method as in "Example 2-(1)" was used to obtain a light yellow solid (I-19), 1.80 g, yield 60.9%, mp 143.3-145.7°C. 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.

[0123] (20) Preparation of 3-(1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-1-propanol (I-20)

[0124] The same preparation method as in "Example 2-(1)" was used to obtain a yellow solid (I-20), 3.0 g, with a yield of 53.1%, and mp 115.1-116.9°C. 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.

[0125] (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)

[0126] 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.

[0127] (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)

[0128] Same preparation method as "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.

[0129] (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]quinoxalin-6-yl)ethyl)morpholine (I-23)

[0130] Same preparation method as "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.

[0131] (24) Preparation of 2-(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-1-ethanol (I-24)

[0132] The same preparation method as in "Example 2-(1)" was used to obtain a yellow solid (I-24), 1.50 g, yield 43.1%, mp 161.9-163.2°C. 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.

[0133] (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)

[0134] 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.

[0135] (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)

[0136] The same preparation method as in "Example 2-(1)". Yellow crystal (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.

[0137] (27) Preparation of 3-(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)-1-propanol (I-27)

[0138] The same preparation method as in "Example 2-(1)" was used to obtain a light yellow solid (I-27), 1.77 g, yield 41.8%, mp 132.6-134.8°C. 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.

[0139] (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)

[0140] The same preparation method as in "Example 2-(1)" was used to obtain a yellow solid (I-28), 1.46 g, yield 51.1%, mp 179.1-181.9°C. 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.

[0141] (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)

[0142] The same preparation method as in "Example 2-(1)" was used to obtain a light yellow solid (I-29), 1.0 g, yield 38.3%, mp 134.8-136.3°C. 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.

[0143] (30) Preparation of 6-phenyl-9,10-dimethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline (I-30)

[0144] 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.

[0145] (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)

[0146] Same preparation method as "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.

[0147] (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]quinoxalin-6-yl)ethyl)morpholine (I-32)

[0148] Same preparation method as "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.

[0149] (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)

[0150] The same preparation method as in "Example 2-(1)" was used to obtain a yellow solid (I-33), 2.20 g, yield 63.0%, mp 184.2-186.7°C. 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.

[0151] (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)

[0152] Same preparation method as "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.

[0153] (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)

[0154] 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.

[0155] (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)

[0156] The same preparation method as in "Example 2-(1)" was used to obtain a yellow solid (I-36), 2.94 g, with a yield of 80.6%, and mp 162.7-163.3°C. 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.

[0157] (37) Preparation of 6-phenylethyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxalin-9-ol (I-37)

[0158] Take a clean round-bottom flask, dissolve the key intermediate 4l (0.50g, 1.95mmol, 1eq) in 10mL DMF, add 60% sodium hydride (0.47g, 19.6mmol, 10eq) under ice bath and stir for 15min, add (2-bromoethyl)benzene (1.45g, 7.80mmol, 4eq), reflux at 60℃, react for 4h, and monitor by TLC until the reaction is complete. Add 30mL water to quench, extract with ethyl acetate (3x 10mL) and 30mL saturated brine in turn, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (V DCM :V MeOH =50:1) to give 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.

[0159] (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)

[0160] Same preparation method as "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 forC 28 H 29 N4O[M+H] + 437.2341; found 437.2345.

[0161] (39) Preparation of 4-(2-(9-(2-morpholinethoxy)-1,2,3,4,4a,5-hexahydro-6H-pyridin[1',2':1,6]pyrazin[2,3-b]quinoxalin-6-yl)ethyl)morpholine (I-39)

[0162] Same preparation method as "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.

[0163] (40) Preparation of 3-(9-(3-(dimethylamino)propoxy)-1,2,3,4,4a,5-hexahydro-6H-pyridin[1',2':1,6]pyrazin[2,3-b]quinoxalin-6-yl)-N,N-dimethylpropane-1-amine (I-40)

[0164] Same preparation method as "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.

[0165] (41) Preparation of (4-chlorophenyl)(1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)methanone (I-41)

[0166] Take a clean round-bottom flask, add p-chlorobenzoic acid (0.68g, 2.8mmol, 1eq), HATU (1.08g, 2.8mmol, 1eq) and 15mL dry N,N-dimethylformamide in sequence, stir to dissolve, slowly add DIEA (0.73g, 5.6mmol, 2eq) to the bottle, activate at room temperature for 1h, monitor by TLC until the activation is complete, add intermediate 4h (0.3g, 1.9mmol, 0.7eq), reflux at 60℃, react for 3h, monitor by TLC until the reaction is complete. The reaction solution was cooled to room temperature, quenched by adding 50mL water, extracted with EA (3x50mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a yellow solid (I-41), 0.32g, yield 44.3%, mp 233.5-238.3℃. 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.

[0167] (42) Preparation of (1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)(4-methoxyphenyl)methanone (I-42)

[0168] Same preparation method as "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.

[0169] (43) Preparation of (4-chlorophenyl)(9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)methanone (I-43)

[0170] Take a clean round-bottom flask, add p-chlorobenzoic acid (0.25g, 1.6mmol, 1eq), HATU (0.61g, 1.6mmol, 1eq) and 15mL dry N,N-dimethylformamide in sequence, stir to dissolve, slowly add DIEA (0.42g, 3.2mmol, 2eq) to the bottle, activate at room temperature for 1h, monitor by TLC until the activation is complete, add intermediate 4i (0.3g, 1.1mmol, 0.7eq), reflux at 60℃ for 3h, monitor by TLC until the reaction is complete. The reaction solution was cooled to room temperature, quenched by adding 50mL water, extracted with EA (3x50mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a yellow solid (I-43), 0.26g, yield 57.8%, mp 255.1-255.7℃. 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 CNMR(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.

[0171] Preparation of (44) (9,10-difluoro-1,2,3,4,4a,5-hexahydro-6H-pyrido[1',2':1,6]pyrazino[2,3-b]quinoxaline-6-yl)(4-methoxyphenyl)methanone (I-44)

[0172] Same preparation method as "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.

[0173] (45) Preparation of (4-chlorophenyl) (9,10-dimethyl-1,2,3,4,4a,5-hexahydro-6H-pyrido [1',2':1,6] pyrazino [2,3-b] quinoxalin-6-yl)methanone (I-45)

[0174] Take a clean round-bottom flask, add p-chlorobenzoic acid (0.26g, 1.6mmol, 1eq), HATU (0.64g, 1.6mmol, 1eq) and 15mL dry N,N-dimethylformamide in sequence, stir to dissolve, slowly add DIEA (0.43g, 3.3mmol, 2eq) to the bottle, activate at room temperature for 1h, monitor by TLC until the activation is complete, add intermediate 4k (0.3g, 1.1mmol, 0.7eq), reflux at 60℃ for 3h, monitor by TLC until the reaction is complete. The reaction solution was cooled to room temperature, quenched by adding 50mL water, extracted with EA (3x50mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a yellow solid (I-45), 0.32g, yield 70.4%, mp 188.6-189.7℃. 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.

[0175] (46) Preparation of (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)methanone (I-46)

[0176] The same preparation method as in "Example 2-(45)" was used to obtain brown crystals (I-46), 0.28 g, yield 62.2%, mp 187.1-190.6°C. 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,1 H),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

[0177] -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.

[0178] In the second aspect, the beneficial effects of the present invention are demonstrated by specific experimental examples as follows.

[0179] Experimental Example 1: CCK-8 method to detect the anti-solid tumor activity of the anticancer drug TNBG-D compound

[0180] 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 in an incubator. The above cells were digested with 0.25% trypsin, and the digestion was stopped by adding DMEM culture medium containing 10% fetal bovine serum. The cells were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in complete culture medium so that the number of cells in each 100 μL cell suspension was about 4x10 3. Accurately weigh the test compound and set the sample working solution concentration to 0.5μM, 1μM, 2μM, 4μM, 8μM, 16μM, 32μM and 64μM. Add 200μL of PBS to the outermost circle of the 96-well cell culture plate, and add 100μL of cell suspension to each of the remaining wells. Culture for 24 hours to allow the cells to adhere to the wall. Set up 3 replicate wells for each concentration, add 100μL of the prepared drug working solution to each well, and continue to culture for 72 hours. Take out the 96-well plate, discard the culture medium, add 100μL of new culture medium containing 10% (v / v) CCK-8 to each well, continue to culture at 37°C for 90 minutes, place it in an enzyme reader to measure the absorbance value (A) at a wavelength of 450nm, calculate the cell inhibition rate, and perform probit regression analysis to obtain the IC value of the anti-tumor cell proliferation of the anticancer drug TNBG-D compound. 50 value.

[0181] Table 1 Activity of anticancer drug TNBG-D compound on solid tumor cell lines

[0182]

[0183] Note: “a” indicates the average value of three repeated experiments; “-” indicates not tested; “*” indicates the compound concentration is 32 μM.

[0184] As can be seen from Table 1, the inhibition level of most anticancer drugs TNBG-D can reach the μM level, and they have different degrees of inhibition on the above three solid tumor cancer cells. The monosubstituted compound I-13 has the same side chain as the disubstituted compound I-40, and the activity of compound I-40 is significantly better than that of compound I-13. This shows that continuing to add the same side chain on the basis of the monosubstituted active side chain can enhance the anti-tumor activity of the compound. Therefore, the anticancer drug TNBG-D compound has great value in being developed into an anti-solid tumor drug.

[0185] Experimental Example 2: CCK-8 method to detect the anti-non-solid tumor activity of the anticancer drug TNBG-D compound

[0186] The anticancer drug TNBG-D compound was tested for in vitro activity using human leukemia cell lines, including human erythroleukemia cell line HEL, human acute myeloid leukemia cell line Kasumi-1, human monocytic cell line THP-1, and human acute myeloid leukemia cell line U937, all of which were cultured in DMEM medium (High Glucose, 10% FBS fetal bovine serum, 1% penicillin-streptomycin) at 37°C, 5% CO2, and 95% humidity in a constant temperature incubator. The above cells were digested with 0.25% trypsin, and the digestion was stopped by adding DMEM culture medium containing 10% fetal bovine serum. The cells were centrifuged at 1000rpm for 5min, the supernatant was discarded, and the cells were resuspended in complete culture medium. The compound was prepared into a solution with a concentration of 10mM using DMSO, diluted to 50μM, and screened. The compounds with obvious inhibitory effects were screened for concentration gradient experiments. The drug gradient concentrations were set at 0.4μM, 2μM, 10μM, 50μM and 250μM. The final volume of each well (cells + culture medium + drug) was 100μL. Three replicate wells were set for each concentration. Then, 10μL of CCK-8 reagent was added after 24h / 48h of culture, and the absorbance was detected after about 1-4h. The absorbance (A) of each well was measured at a wavelength of 450nm using an ELISA reader. After calculating the cell inhibition rate, probit regression analysis was performed to obtain the IC value of the anticancer drug TNBG-D compound on non-solid tumor cell lines. 50 value.

[0187] Table 2 Activity of anticancer drug TNBG-D compound on non-solid tumor cell lines

[0188]

[0189] Note: “a” represents the average value of three repeated experiments.

[0190] As shown in Table 2, the anticancer drug TNBG-D compound has a potential anti-leukemia effect, and the inhibition level of some compounds can reach the μM level, which has a slight inhibitory effect on the above four non-solid tumor cancer cells. The inhibitory activity of compounds I-22 and I-31 on HEL cells and U937 cells is better than that of TNBG, and the inhibitory activity of compound I-31 on THP-1 cells is comparable to that of TNBG. Therefore, the research on the anticancer drug TNBG-D compound on non-solid tumors also has broad space.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or a stereoisomer thereof, in, R1-R5 is 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, the symbol 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, etc.; and methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl or cyclobutyl, etc. having a substituent; n2 is an integer selected from 1 to 8, the symbol represents a single bond or a double bond; n3 is an integer selected from 1 to 2, the symbol represents a single bond or a double bond; X is selected from oxygen, nitrogen or carbon; R8 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, 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: The substituted amino group in R5 is often preferably dimethylamino, diethylamino, etc.; the substituted six-membered heterocyclic ring in R2 is preferably morpholine, piperidine, N-methylpiperazine, and the benzoyl group is often preferably 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 synthesis is carried out through cyclization reaction, chlorination reaction, and ring-closure reaction to obtain the key intermediate 4, and finally the target compound of formula I is obtained through substitution reaction (d1) or amide condensation (d2); The cyclization reaction is a reaction of the starting material with diethyl oxalate under acidic conditions (dilute hydrochloric acid); the chlorination reaction is the conversion of the hydroxyl group into a chlorine atom 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 the hydrogen on the secondary amine under strong alkaline conditions (NaH (60%)) to obtain the target products I-1 to I-40; the amide condensation reaction is the use of HATU as a condensing agent under alkaline conditions (DIEA) to obtain the target products I-41 to I-46.

4. A compound of formula I or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that: The compounds described herein are representative compounds such as the following:

5. Use of the compound according to claim 4 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for treating and / or preventing cancer.

6. The use according to claim 5, characterized in that: The prepared anticancer drug is a drug for treating 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 blood tumor, etc.

8. A medicine, which is a preparation prepared by using the compound according to claim 7 or its pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient and adding suitable excipients or auxiliary ingredients.

Images