A pentacyclic thiazolyl indolinone piperazine amide derivative and uses thereof

Abstract

The present application relates to a kind of five-ring thiazole indole ketone piperazine amide derivatives and purposes thereof.The derivatives take ethyl cyanoacetate as starting material, generate hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid;Obtain 2-amino ethyl cyanoacetate (B) by reduction, in turn with acetic anhydride, lawson reagent is reacted, and 5-amino-4-carboxylate thiazole compound (D) is obtained;After bromination by NBS, under the catalysis of phosphorus oxychloride, react with tetrahydropyridine indole ketone, generate 2-bromo-6,7-dihydrothiazolo [5'',4'':4',5'] pyrimido [1',2':1,2] pyrindo [3,4-b] indole-4 (12H) -ketone (F), again under alkaline condition, first with Boc piperazine, then by Boc treatment and obtain compound (H);Finally, react with acyl chloride, and 28 different substitution structures of five-ring thiazole indole ketone piperazine amide compound (I1-I28) are synthesized.The 28 compounds are tested on three kinds of cancer cells, and the results show that: 28 compounds have significant inhibitory activity on Hela cervical cancer cells, HT-29 human colon cancer cells and HGC-27 human gastric cancer cells.

Description

Technical Field

[0001] This invention relates to a pentacyclic thiazole indole piperazine amide derivative and its uses. Background Technology

[0002] Cancer, a common name for malignant tumors, is a type of disease that seriously endangers human life and health. In recent years, the incidence and mortality rates of cancer have been on the rise. Therefore, finding highly effective new anti-tumor drugs has become a very important and urgent topic in current cancer treatment research.

[0003] Small molecule targeted antitumor agents, characterized by high targeting and significant efficacy, have improved patients' quality of life and have become a highly sought-after category in clinical medication. In the medical field, saturated heterocyclic compounds, represented by piperidine and pyrimidine, are already well-known and are currently the most representative saturated heterocyclic systems among all small molecule therapeutics listed in the US FDA Orange Book. Building upon this foundation, introducing non-purely aromatic or isoaromatic cyclic systems such as benzene, pyrrole, pyrazole, pyrimidine, and pyridine into the molecule often yields unexpected effects, including greater diversity (through stereoisomerization) with a slight increase in molecular weight, and further enriching the structural novelty of these compounds. Therefore, the structure of drug molecules is gradually changing, and saturated ring systems, represented by heterocycles, are attracting increasing attention.

[0004] Thiazole rings are an important class of five-membered aromatic heterocycles containing nitrogen and sulfur heteroatoms. They possess abundant electrons and readily form various non-covalent interactions, including hydrogen bonding, coordination with metal ions, electrostatic interactions, and hydrophobic interactions. This structure endows thiazole compounds with many unique properties, offering broad potential applications in numerous fields and attracting significant attention from researchers. Related research, including the development of synthetic methods, is increasingly prevalent. Especially with the successful clinical and agricultural applications of a series of thiazole compounds, their development has become one of the hottest research areas in recent years. In the pharmaceutical field, thiazole compounds can bind to various enzymes and receptors in vivo, exhibiting diverse biological activities, covering almost the entire pharmaceutical field. Many thiazole compounds are already used clinically, such as the antibiotic cefixime, the anticancer drug dasatinib, the antiparasitic drug nitrozole, and the anti-inflammatory drug meloxicam, all of which are first-line drugs preferred in clinical practice.

[0005] Therefore, the activity of thiazopyrimidine derivatives shows that the study of the synthesis and biological activity of these compounds has significant theoretical and practical value for finding lead compounds for new medicines.

[0006] References: [1] Zhou Yongyi, Guo Qihua, Gu Xuexin. A brief introduction to the research dynamics of anticancer drugs [J]. Chemical Education, 2004, 5: 10-13. [2] Ye Youzhu. A Preliminary Discussion on the Development Trend of Anticancer Drugs in my country [J]. Strait Pharmaceutical Journal, 1995, 3(7): 63-64. [3] Huang, JM; et al. Studies of a-Thiocarbonyl Phosphonic AcidDerivative Quinazolone Analogues Containing Phosphorus. Chem. J, Chin, Univ. 2000, 8(21), 1216-1220. [4] 2Bai, ZS; Wang, DX Heterocyclic Compounds GeneticEngineering and Pesticides in 21 Century. Pesticides 1998, 37(6), 2-6. [5] Feng, KS; Chen, RY; et al. Synthesis and Structure of 3,4-Dipheny-3-diazaphos-pholid- In-2-thione-4-oxides Sulfides. Chem. J. Chin, Univ. 1993, 14(9), 1244-1249. [6] Zhang, C X.; Zhan, ZB; et al Synthesis of CyclicGlycerophospho-lipid Conjugates of Adenosine. Chem. J. Chin. Univ. 199, 19(6), 913-916. [7] Zhou, J; et al. Synthesis and Herbicidal Activity of l-Aryl-2-phenyl-3-methyl-3-isopropyl- 1,4,2-diazaphosp-holidin-5-one-2-oxides. Chem, J. Chin, Univ, 1999, 20(7), 1058-1062. [8] Zhang, H. Z, Zhao, Z. L, Zhou, C. H. Recent advance inoxazolebased medicinal chemistry, [J]. Eur J Med Chem,2018, 144:444-492. [9] Zhang, H. Z,Gan, L. L, Wang, H. et al.New progress in azolecompounds as antimicrobial agents, [J]. Mini - Rev Med Chem, 2017, 17(2):122-166.

[10] Mayer, J. C. P.; Sauer, A. C.; Iglesias, B. A.; et al.Ferrocenylethenyl substituted 1,3,4-oxadiaz-olyl-1,2,4-oxadiazoles:Synthesis,characterization and DNA-binding assays [J]. J Organomet Chem, 2017, 841:1-11.

[11] Revuelta, J, Machetti, F, Cicchi, S. Modern Heterocyclic Chemistry. Berlin: Wiley, 2011.

[12] Hanusek, J. Study of formation and transformation of some five-and six-membered heterocyclic compounds containing nitrogen and sulfur. Chem Listy , 2008, 102(9): 801-810.

[13] Abele, E.; Abele, R.; Lukevics, E. Chemistry of Heterocyclic Compounds . New York: Springer, 2007. Based on a comprehensive analysis of relevant domestic and international patents and literature, this invention involves the total synthesis of pentacyclic thiazole indole piperazine amide compounds, followed by systematic modification and alteration. Isothiocyanates with different substituents were introduced into these compounds to improve their drug-likeness. The inhibitory activity of these compounds against cancer cells (HeLa cervical cancer cells, HT-29 human colon cancer cells, and HGC-27 human gastric cancer cells) was investigated, aiming to discover candidate drugs with significant therapeutic effects and clearly defined antitumor activities. Activity screening results showed that compounds I14, I21, I27, and I28 all exhibited significant inhibitory activity against HeLa cervical cancer cells; compounds I9, I11, I14, and I21 showed significant inhibitory activity against HT-29 human colon cancer cells; and all compounds showed significant inhibitory activity against HGC-27 human gastric cancer cells. Summary of the Invention

[0007] The purpose of this invention is to provide a pentacyclic thiazole indole-piperazinamide derivative and its uses. This derivative uses ethyl cyanoacetate as a starting material, which, under the synergistic effect of sodium nitrite and phosphoric acid, generates a hydroxylamine compound (A); after reduction with sodium hydrosulfite, ethyl 2-aminocyanoacetate (B) is obtained. Subsequently, it reacts sequentially with acetic anhydride and Lawson's reagent to obtain a 5-amino-4-carboxylate thiazole compound (D); after bromination with NBS, it reacts with tetrahydropyridine indole ketone under the catalysis of phosphorus oxychloride to generate 2-bromo-6,7-dihydrothiazo[5'',4'':4',5']pyrimido[1',2':1, 2]Pyrido[3,4-b]indol-4(12H)-one (F); under alkaline conditions, it was first reacted with Boc piperazine, and then subjected to deBoc treatment to obtain compound (H); finally, compound (H) reacted with acyl chlorides with different substituents to synthesize 28 pentacyclic thiazole indolone piperazine amide compounds (I1-I28) with different substitution structures; the inhibitory activity of these 28 compounds against three types of cancer cells (HeLa cervical cancer cells, HT-29 human colon cancer cells, and HGC-27 human gastric cancer cells) was investigated. The results showed that compounds I14, I21, I27, and I28 all showed significant inhibitory activity against HeLa cervical cancer cells; compounds I9, I11, I14, and I21 showed significant inhibitory activity against HT-29 human colon cancer cells; and compounds I1-I28 all showed significant inhibitory activity against HGC-27 human gastric cancer cells.

[0008] The present invention discloses a pentacyclic thiazole indole-piperazinamide derivative, the structural formula of which is as follows:

[0009] in: Compound I1 is 2-(4-benzoylpiperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I2 is 2-(4-(2-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I3 is 2-(4-(3-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I4 is 2-(4-(4-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I5 is 2-(4-(3-chlorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I6 is 2-(4-(4-chlorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I7 is 2-(4-(2-bromobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I8 is 2-(4-(4-bromobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I9 is ​​2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I10 is 2-(4-(3-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I11 is 2-(4-(4-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I12 is 2-(4-(2-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I13 is 2-(4-(3-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I14 is 2-(4-(2-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I15 is 2-(4-(3-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I16 is 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H)-ketone; Compound I17 is 2-(4-(2-(trifluoromethoxy)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I18 is 2-(4-(3-nitrobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I19 is 2-(4-(4-nitrobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I20 is 4-(4-(4-oxo-4,6,7,12-tetrahydrothiazol[5'',4'':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indolyl)piperazine-1-formyl)benzonitrile; Compound I21 is 2-(4-(cyclopentylformyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I22 is 4-oxo-4-(4-(4-oxo-4,6,7,12-tetrahydrothiazolium[5'',4'':4',5']pyrido[1',2':1,2]pyrido[3,4- b Methyl indolyl piperazine-1-yl butyrate; Compound I23 is 2-(4-(thiophene-2-formyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I24 is 2-(4-morpholino-4-formyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I25 is 2-(4-(3,5-difluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I26 is 2-(4-(2-chloro-6-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I27 is 2-(4-(3,4-dimethoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I28 is 2-(4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone.

[0010] Use of compounds I14, I21, I27, and I28 from the pentacyclic thiazole indole piperazine amide derivatives in the preparation of drugs for treating HeLa cervical cancer.

[0011] Use of compounds I9, I11, I14 and I21 in the pentacyclic thiazole indole piperazine amide derivatives in the preparation of a drug for treating HT-29 human colon cancer.

[0012] Use of compounds I1-I28 from the pentacyclic thiazole indole piperazine amide derivatives in the preparation of drugs for treating HGC-27 human gastric cancer.

[0013] The pentacyclic thiazole indole-piperazinamide derivatives of this invention are synthesized starting from ethyl cyanoacetate, which, under the synergistic effect of sodium nitrite and phosphoric acid, generates a hydroxylamine compound (A); after reduction with sodium hydrosulfite, ethyl 2-aminocyanoacetate (B) is obtained. Subsequently, compound (B) reacts sequentially with acetic anhydride and Lawson's reagent to obtain a 5-amino-4-carboxylate thiazole compound (D); after bromination with NBS, this compound reacts with tetrahydropyridine indole ketone under the catalysis of phosphorus oxychloride to generate 2-bromo-6,7-dihydrothiazo[5'',4'':4',5']pyrimido[1',2':1,2]pyrido[3,4-b]indole-4(12H)-one (F). Compound (F) was first reacted with Boc piperazine under alkaline conditions, followed by Boc removal to yield compound (H). Finally, compound (H) was reacted with acyl chlorides with different substituents to successfully synthesize 28 pentacyclic thiazole indole-piperazine amide compounds (I1-I28) with different substitution structures. The synthetic route is as follows: Detailed Implementation

[0014] The present invention will be further described with reference to the embodiments, but the present invention is not limited to these embodiments; Reagents: All reagents were commercially available analytical grade; Example 1

[0015] Preparation of compound A: At -10°C, 57.3 ml (0.83 mol) of sodium nitrite and 100 g (0.83 mol) of ethyl cyanoacetate were dissolved in 700 ml of pure water. Then, 36.6 ml (0.055 mol) of 85% concentrated phosphoric acid was slowly added dropwise for 3 hours. The temperature was then raised to 45°C and stirred for 1 hour. Then, 74 ml (0.88 mol) of concentrated hydrochloric acid was added and the mixture was stirred overnight at 0°C. A large amount of white solid precipitated out. After filtration, the white compound A was obtained as ethyl 2-cyano-2-hydroxyimino. Preparation of compound B: At room temperature, 43 g (0.3 mol) of the obtained white compound A, 2-cyano-2-hydroxyimino ethyl acetate, was dissolved in 500 ml of pure water. 350 ml of saturated sodium bicarbonate solution was slowly added dropwise with stirring, followed by 156 g (0.9 mol) of sodium dithionite. The mixture was heated to 35 °C and reacted for 1 hour, then at room temperature for 3 hours. The mixture was extracted three times with 500 ml of dichloromethane. The organic phases were combined, dried, concentrated, and eluted by gradient column chromatography with a petroleum ether:ethyl acetate eluent in a volume ratio of 2:1. This yielded compound B, 2-amino-2-cyanoethyl acetate. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 4.81 (s, 2H), 4.34 (q, J = 7.0Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); Preparation of compound C: Acetic anhydride (6.48 g, 63.6 mmol) was slowly added dropwise to a solution of formic acid (2.22 g, 53 mmol). The mixture was heated to 50 °C and reacted for 5 h. Compound B (ethyl 2-amino-2-cyanoacetate) (3.9 g, 25 mmol) was slowly added dropwise under ice bath conditions. The reaction was allowed to proceed at room temperature until the starting material was completely eliminated. The mixture was extracted three times with 500 ml of dichloromethane. The organic phases were combined, dried, concentrated, and eluted by gradient column chromatography with a petroleum ether:ethyl acetate eluent (5:1 v / v). This yielded compound C (ethyl 2-formamido-2-cyanoacetate); yield: 76%, pale yellow solid, melting point: 128-130 °C. 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 6.46 (s, 1H), 5.51 (d, J = 5.1Hz, 1H), 4.34 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); Preparation of compound D: The obtained compound C, 1.56 g (10 mmol) of ethyl 2-formamido-2-cyanoacetate, was dissolved in 20 mL of toluene. Then, 4.5 g (11 mmol) of Lawson's reagent was added, and the mixture was heated under reflux for 24 hours until the starting material was completely eliminated. The reaction solution was filtered, concentrated, and eluted by column chromatography with a gradient of petroleum ether:ethyl acetate in a volume ratio of 1:1 to obtain compound D, ethyl 5-amino-thiazolyl-4-carboxylate, with a yield of 73%, as a pale yellow solid with a melting point of 135-136 °C. 1 H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 6.00 (s, 2H), 4.39 (q, J = 7.1Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); Preparation of compound E: The obtained compound D, 1.72 g (10 mmol) of 5-amino-thiazolium-4-carboxylate, was dissolved in 20 mL of anhydrous tetrahydrofuran. 2.2 g (12 mmol) of N-bromosuccinimide (NBS) was added in small, repeated additions. The reaction was carried out at room temperature for 3 h until the starting material was completely eliminated. The reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a petroleum ether:ethyl acetate eluent in a 5:1 volume ratio. This yielded compound E, 2-bromo-5-amino-thiazolium-4-carboxylate, in 73% of a pale yellow solid at 151-152 °C. 1 H NMR (400 MHz, CDCl3) δ 6.03 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.39(t, J = 7.1 Hz, 3H); Preparation of compound F: The obtained compound E (2.5 g, 10 mmol) was dissolved in 50 mL of 1,2-dichloroethane, and 2.2 g (12 mmol) of tetrahydropyridineindolone was added. Then, 2.4 mL (25 mmol) of phosphorus oxychloride was slowly added dropwise. The mixture was refluxed until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using a 1:1 volume ratio of petroleum ether to ethyl acetate to obtain compound 6, which is 2-bromo-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H )-ketone, yield: 75%, pale yellow solid, melting point: 232-233℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.02 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 4.43(t, J = 7.0 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H); Preparation of compound G: The resulting compound F was 2-bromo-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.37 g (1 mmol) of 4-(4-oxo-4,6,7,12-tetrahydrothiazolium[5'',4'':4',5']pyrimidine[1',2':1,2']pyridine[3,4-] b Indole-2-yl)piperazine-1-carboxylic acid tert-butyl ester, yield: 89%, pale yellow solid, melting point: 265-266℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.85 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.39(d, J = 8.2 Hz, 1H), 7.26 – 7.13 (m, 1H), 7.06 (t, J = 7.5 Hz, 1H), 4.40 (t, J =7.1 Hz, 2H), 3.50 (d, J = 5.6 Hz, 4H), 3.47 (d, J = 5.5 Hz, 4H), 3.12 (t, J = 7.1Hz, 2H), 1.42 (s, 9H); Preparation of compound H: The resulting compound G is 4-(4-oxo-4,6,7,12-tetrahydrothiazole[5'',4'':4',5']pyrimidine[1',2':1,2]pyridine[3,4- b 0.48 g (1 mmol) of tert-butyl indole-2-yl)piperazin-1-carboxylate was dissolved in 10 mL of 2 M ethyl acetate hydrochloride solution. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was then concentrated under reduced pressure to obtain compound 8, which is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimido[1',2':1,2]pyrido[3,4- b Indole-4(12)H )-ketone, yield: 94%, pale yellow solid, melting point: 378-379℃; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.86 (s, 1H), 9.13 (s, 2H), 7.61 (d, J = 8.0Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 4.41 (t, J = 7.0 Hz, 2H), 3.94 – 3.57 (m, 4H), 3.32 – 3.20 (m, 4H), 3.13(t, J = 7.0 Hz, 2H). Example 2

[0016] Preparation of compound I1: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of benzoyl ketone was dissolved in 10 mL of anhydrous dichloromethane. 0.05 g (0.36 mmol) of benzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. Extraction was performed with dichloromethane, drying over anhydrous sodium sulfate, and concentration under reduced pressure. Gradient elution was performed by column chromatography with petroleum ether:ethyl acetate in a 1:1 volume ratio to obtain compound I1, 2-(4-benzoylpiperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone, yield: 81%, pale yellow solid, melting point: 345-346℃; 1 H NMR (400 MHz, DMSO) δ: 11.82 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52– 7.41 (m, 5H), 7.39 (d, J= 8.3 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.05 (t, J =7.5 Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.86 – 3.33 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H). Example 3

[0017] Preparation of compound I2: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 2-methylbenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.055 g (0.36 mmol) of 2-methylbenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I2 was 2-(4-(2-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone, yield: 86%, pale yellow solid, melting point: 376-377℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.36 – 7.16 (m, 5H), 7.06 (t, J = 7.5 Hz, 1H), 4.40 (t, J =7.0 Hz, 2H), 3.80 (s, 2H), 3.62 (s, 2H), 3.48 (s, 2H), 3.28 (d, J = 4.4 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H), 2.23 (s, 3H). Example 4

[0018] Preparation of compound I3: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of methylbenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.055 g (0.36 mmol) of 3-methylbenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I3 was 2-(4-(3-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone, yield: 83%, pale yellow solid, melting point: 322-323℃; 1 H NMR (400 MHz, DMSO) δ: 11.82 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39(d, J = 8.3 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.21 (dd, J = 12.3, 5.7 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 4.38 (t, J = 7.0 Hz, 2H), 3.94 –3.37 (m, 6H), 3.10 (t, J = 7.0 Hz, 1H), 2.33 (s, 2H). Example 5

[0019] Preparation of compound I4: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 4-methylbenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.055 g (0.36 mmol) of 4-methylbenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution of petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I4 was 2-(4-(4-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- ... b Indole-4(6) H )-ketone. Yield: 88%, pale yellow solid, melting point: 378-379℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39(d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 7.21 (t, J =7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.86 – 3.35 (m,8H), 3.11 (t, J = 7.1 Hz, 2H), 2.33 (s, 3JJH). Example 6

[0020] Preparation of compound I5: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 3-chlorobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.063 g (0.36 mmol) of 3-chlorobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate to obtain compound I5, 2-(4-(3-chlorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 79%, pale yellow solid, melting point: 320-321℃; 1 H NMR (400 MHz, DMSO) δ: 11.85 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.52(tt, J = 15.7, 7.9 Hz, 3H), 7.40 (dd, J = 7.9, 3.0 Hz, 2H), 7.22 (t, J = 7.7 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 4.40 (t, J = 7.0 Hz, 2H), 3.98 – 3.34 (m, 8H), 3.12 (t, J = 7.0 Hz, 2H). Example 7

[0021] Preparation of compound I6: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 4-chlorobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.063 g (0.36 mmol) of 4-chlorobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution of petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I6 was 2-(4-(4-chlorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- ... b Indole-4(6) H )-ketone. Yield: 75%, pale yellow solid, melting point: 369-370℃. 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.59(d, J = 7.5 Hz, 1H), 7.52 (d, J = 6.3 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.39 (d, J =8.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.0Hz, 2H), 3.93 – 3.37 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H). Example 8

[0022] Preparation of compound I7: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 2-bromobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.078 g (0.36 mmol) of 2-bromobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I7 was 2-(4-(2-bromobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 77%, pale yellow solid, melting point: 311-312℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 7.67 (dt, J = 6.9, 2.0 Hz,1H), 7.64 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 10.3, 4.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39(t, J = 7.1 Hz, 2H), 4.04 – 3.37 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H). Example 9

[0023] Preparation of compound I8: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 4-bromobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.078 g (0.36 mmol) of 4-bromobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I8 was 2-(4-(4-bromobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- ... b Indole-4(6) H )-ketone. Yield: 74%, pale yellow solid, melting point: 373-374℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.35 – 7.15 (m, 5H), 7.06 (t, J = 7.5 Hz, 1H), 4.40 (t, J =7.0 Hz, 2H), 3.80 (s, 2H), 3.62 (s, 2H), 3.48 (s, 2H), 3.28 (dd, J = 4.3, 0.7Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H). Example 10

[0024] Preparation of compound I9: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 2-fluorobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.057 g (0.36 mmol) of 2-fluorobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution of petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I9 was 2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 70%, pale yellow solid, melting point: 349-350℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.51(dd, J = 13.3, 6.5 Hz, 1H), 7.44 (t, J = 6.7 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H),7.35 – 7.26 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.0 Hz, 2H), 3.80 (d, J = 0.4 Hz, 2H), 3.61 (d, J = 4.1 Hz, 2H), 3.51 (d, J =4.1 Hz, 2H), 3.37 (s, 2H), 3.11 (t, J = 7.0 Hz, 2H). Example 11

[0025] Preparation of compound I10: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 3-fluorobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.057 g (0.36 mmol) of 3-fluorobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I10 was 2-(4-(3-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 68%, pale yellow solid, melting point: 340-341℃; 1 H NMR (400 MHz, DMSO) δ: 11.82 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.57– 7.45 (m, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.36 – 7.25 (m, 3H), 7.21 (t, J = 7.7Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.87 – 3.36 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H). Example 12

[0026] Preparation of compound I11: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 4-fluorobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.057 g (0.36 mmol) of 4-fluorobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I11 was 2-(4-(4-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- ... b Indole-4(6) H )-ketone. Yield: 74%, pale yellow solid, melting point: 368-369℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51(dd, J = 8.4, 5.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 8.8 Hz, 2H), 7.21(t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.0 Hz, 2H), 3.77 –3.33 (m, 8H), 3.11 (t, J = 7.0 Hz, 2H). Example 13

[0027] Preparation of compound I12: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 2-trifluoromethylbenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.075 g (0.36 mmol) of 2-trifluoromethylbenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution of petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I12 was 2-(4-(2-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-] b Indole-4(6) H )-ketone. Yield: 63%, pale yellow solid, melting point: 345-346℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.76(t, J = 7.5 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.54 (d, J =7.6 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5Hz, 1H), 4.39 (t, J = 7.0 Hz, 2H), 3.79 (ddd, J = 19.0, 12.9, 5.3 Hz, 2H), 3.66 –3.55 (m, 2H), 3.54 – 3.34 (m, 2H), 3.29 – 3.16 (m, 2H), 3.11 (t, J = 7.0 Hz, 2H). Example 14

[0028] Preparation of compound I13: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 3-trifluoromethylbenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.075 g (0.36 mmol) of 3-trifluoromethylbenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I13 was 2-(4-(3-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[ ... b Indole-4(6) H )-ketone. Yield: 66%, pale yellow solid, melting point: 325-326℃; 1 H NMR (400 MHz, DMSO) δ: 11.82 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.80(s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.20 (dd, J = 11.3, 4.0 Hz, 1H), 7.04 (t, J = 7.6Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.91 – 3.34 (m, 8H), 3.10 (t, J = 7.1 Hz, 2H). Example 15

[0029] Preparation of compound I14: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 2-methoxybenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.061 g (0.36 mmol) of 2-methoxybenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I14 was 2-(4-(2-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 74%, pale yellow solid, melting point: 343-344℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39(t, J = 8.4 Hz, 2H), 7.21 (t, J = 7.1 Hz, 2H), 7.14 – 6.89 (m, 3H), 4.38 (t, J =6.8 Hz, 2H), 3.79 (s, 3H), 3.76 – 3.20 (m, 8H), 3.10 (t, J = 6.9 Hz, 2H). Example 16

[0030] Preparation of compound I15: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 2-(4-(3-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2']pyrido[3,4-] b Indole-4(6)H )-ketone. Yield: 78%, pale yellow solid, melting point: 292-293℃; 1 H NMR (400 MHz, DMSO) δ: 11.82 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.37(dd, J = 14.5, 8.0 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.09 – 6.99 (m, 2H), 6.99 –6.93 (m, 2H), 4.39 (t, J = 7.0 Hz, 2H), 3.77 (s, 3H), 3.67 – 3.37 (m, 8H), 3.10(t, J = 7.0 Hz, 2H). Example 17

[0031] Preparation of compound I16: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 4-methoxybenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.061 g (0.36 mmol) of 4-methoxybenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I16 was 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- ... b Indole-4(6) H )-ketone. Yield: 76%, pale yellow solid, melting point: 330-331℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.40(t, J = 7.8 Hz, 3H), 7.21 (t, J= 7.7 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.98 (d, J =8.7 Hz, 2H), 4.39 (t, J = 7.0 Hz, 2H), 3.78 (s, 3H), 3.72 – 3.46 (m, 8H), 3.11(t, J = 7.0 Hz, 2H). Example 18

[0032] Preparation of compound I17: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 2-trifluoromethoxybenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.081 g (0.36 mmol) of 2-trifluoromethoxybenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I17 was 2-(4-(2-(trifluoromethoxy)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[ ... b Indole-4(6) H )-ketone. Yield: 73%, pale yellow solid, melting point: 348-349℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.63 – 7.56 (m, 2H), 7.56 –7.51 (m, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.38 (d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.7Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.97 – 3.28 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H). Example 19

[0033] Preparation of compound I18: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 3-nitrobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.067 g (0.36 mmol) of 3-nitrobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I18 was 2-(4-(3-nitrobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 62%, pale yellow solid, melting point: 326-327℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 8.33 – 8.28 (m, 1H), 8.26(d, J = 1.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.59 (d, J =8.0 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.86 – 3.35 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H). Example 20

[0034] Preparation of compound I19: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 4-nitrobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.067 g (0.36 mmol) of 4-nitrobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I19 was 2-(4-(4-nitrobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[ ... b Indole-4(6) H )-ketone. Yield: 64%, pale yellow solid, melting point: 337-338℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 8.29 (d, J = 8.5 Hz, 2H), 7.72(d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.21 (t, J =7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 6.6 Hz, 2H), 3.92 – 3.36 (m,8H), 3.11 (t, J = 6.9 Hz, 2H). Example 21

[0035] Preparation of compound I20: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 4-cyanobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.06 g (0.36 mmol) of 4-cyanobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I20 was 4-(4-(4-oxo-4,6,7,12-tetrahydrothiazolyl[5'',4'':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indolyl)piperazine-1-formyl)benzonitrile. Yield: 75%, pale yellow solid, melting point: 406-407℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.63(d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.21 (t, J =7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.0 Hz, 2H), 3.86 – 3.33 (m,8H), 3.11 (t, J = 7.0 Hz, 2H). Example 22

[0036] Preparation of compound I21: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of cyclopentyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.048 g (0.36 mmol) of cyclopentyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I21 was 2-(4-(cyclopentylformyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 79%, pale yellow solid, melting point: 347-348℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39(d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J =7.1 Hz, 2H), 3.79 – 3.37 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H), 3.05 – 2.90 (m,1H), 1.92 – 1.37 (m, 8H). Example 23

[0037] Preparation of compound I22: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of 4-chloro-4-oxybutyrate methyl ester (0.050 g, 0.36 mmol) and triethylamine (0.12 ml, 0.9 mmol) were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution of petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I22 was 4-oxo-4-(4-(4-oxo-4,6,7,12-tetrahydrothiazolyl[5'',4'':4',5']pyrido[1',2':1,2]pyrido[3,4- b Methyl indolyl(piperazin-1-yl)butyrate. Yield: 76%, pale yellow solid, melting point: 374-375℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.38(d, J = 8.2 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J =7.0 Hz, 2H), 3.65 – 3.39 (m, 8H), 3.56 (s, 3H), 3.11 (t, J = 7.0 Hz, 2H), 2.62(t, J = 6.4 Hz, 2H), 2.51 (t, J = 6.6 Hz, 2H). Example 24

[0038] Preparation of compound I23: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of thiophene-2-formyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.054 g (0.36 mmol) of thiophene-2-formyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I23 was 2-(4-(thiophene-2-formyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 84%, pale yellow solid, melting point: 358-359℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.78 (d, J = 4.9 Hz, 1H), 7.60(d, J = 7.9 Hz, 1H), 7.46 (d, J = 3.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.21 (t, J =7.6 Hz, 1H), 7.17 – 7.11 (m, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.40 (t, J = 7.0 Hz, 2H), 3.80 (t, J = 9.4 Hz, 4H), 3.73 – 3.50 (m, 4H), 3.11 (t, J = 7.0 Hz, 2H). Example 25

[0039] Preparation of compound I24: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H0.11 g (0.3 mmol) of morpholino-4-formyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.053 g (0.36 mmol) of morpholino-4-formyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I24 was 2-(4-morpholino-4-formyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-] b Indole-4(6) H )-ketone. Yield: 85%, pale yellow solid, melting point: 313-314℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 4.39 (t, J =6.2 Hz, 2H), 3.67 – 3.40 (m, 8H), 3.32 – 3.14 (m, 8H), 3.10 (t, J = 6.8 Hz, 2H). Example 26

[0040] Preparation of compound I25: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 3,5-difluorobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.064 g (0.36 mmol) of 3,5-difluorobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by gradient column chromatography with a 1:1 volume ratio of petroleum ether to ethyl acetate. The resulting compound I25 was 2-(4-(3,5-difluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4,4-]pyrido[5'',4':4',5']pyrido[1',2':1,2]pyrido[3 ...5'',4':4',5']pyrido[1',2':1,2']pyrido[5'',4':4',5']pyrido[1',2':1,2']pyrido[5'',4':4',5']pyrido[1',2':1,2',3',4',4',4b Indole-4(6) H )-ketone. Yield: 65%, pale yellow solid, melting point: 332-333℃; 1 H NMR (400 MHz, DMSO) δ: 11.83 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.42– 7.33 (m, 2H), 7.25 – 7.16 (m, 3H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.1Hz, 2H), 3.81 – 3.33 (m, 8H), 3.11 (t, J = 7.0 Hz, 2H). Example 27

[0041] Preparation of compound I26: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 2-chloro-6-fluorobenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.069 g (0.36 mmol) of 2-chloro-6-fluorobenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I26 was 2-(4-(2-chloro-6-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 64%, pale yellow solid, melting point: 382-383℃; 1 H NMR (400 MHz, DMSO) δ: 11.84 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.53(dd, J = 14.6, 8.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (dd, J= 14.1, 8.4 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.39 (t, J = 7.0 Hz, 2H),4.08 – 3.73 (m, 2H), 3.73 – 3.56 (m, 2H), 3.57 – 3.44 (m, 2H), 3.38 – 3.33(m, 2H), 3.11 (t, J = 7.0 Hz, 2H). Example 28

[0042] Preparation of compound I27: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 3,4-dimethoxybenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.072 g (0.36 mmol) of 3,4-dimethoxybenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I27 was 2-(4-(3,4-dimethoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[5'',4':4',5']pyrido[1',2':1,2 ...5'',4':4',5']pyrido[1',2':1,2']pyrido[5'',4':4',5']pyrido[1',2':1,2']pyrido[5'',4':4',5']pyrido[1',2':1,2']pyrido[5'',4': b Indole-4(6) H )-ketone. Yield: 72%, pale yellow solid, melting point: 301-302℃; 1 H NMR (400 MHz, DMSO) δ: 11.82 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39(d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.01 (d, J =1.1 Hz, 1H), 7.00 (s, 2H), 4.39 (t, J= 7.0 Hz, 2H), 3.78 (s, 3H), 3.77 (s,3H), 3.71 – 3.42 (m, 8H), 3.11 (t, J = 7.1 Hz, 2H). Example 29

[0043] Preparation of compound I28: The compound H obtained in Example 1 is 2-(piperazin-1-yl)-6,7-dihydrothiazo[5'',4'':4',5']pyrimidino[1',2':1,2]pyridino[3,4- b Indole-4(12) H 0.11 g (0.3 mmol) of 3,4,5-trimethoxybenzoyl chloride was dissolved in 10 mL of anhydrous dichloromethane. 0.083 g (0.36 mmol) of 3,4,5-trimethoxybenzoyl chloride and 0.12 mL (0.9 mmol) of triethylamine were added separately. The reaction was carried out at room temperature until the starting material was completely eliminated. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted by column chromatography with a gradient elution using petroleum ether:ethyl acetate in a 1:1 volume ratio. The resulting compound I28 was 2-(4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4-]pyrido[3,4-]pyrido[4 ... b Indole-4(6) H )-ketone. Yield: 81%, pale yellow solid, melting point: 365-366℃; 1 H NMR (400 MHz, DMSO) δ: 11.79 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.39(d, J = 8.3 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.73 (s,2H), 4.38 (t, J = 7.0 Hz, 2H), 3.79 (s, 6H), 3.69 (s, 3H), 3.66 – 3.44 (m, 8H), 3.10 (t, J = 7.0 Hz, 2H). Example 30

[0044] Screening for antitumor activity of the pentacyclic thiazole indole piperazine amide compounds described in this invention: Thiazol blue assay for cell viability: Experimental procedure: Cells growing in the logarithmic growth phase were aspirated, washed once with phosphate-buffered saline, digested with trypsin, and terminated with liquid RPMI-1640 complete medium. Cells were gently pipetted, counted, and seeded at the appropriate cell density in 96-well plates (100 μl / well). Incubation was performed overnight, followed by the addition of a compound (20 μl / well). A concentration gradient was established for each compound, with three replicates per concentration. Cells were incubated at 37°C with CO2 for 48 hours. The old medium was discarded, and 100 μl of thiazolyl blue was added. Incubation continued for another 2 hours at 37°C. The absorbance (OD) at 570 nm was measured using an MB microplate reader. Calculation formula: Cell viability percentage % = (Compound OD - Blank OD / Control group OD - Blank OD) × 100%; Cell inhibition rate % = 1 - Cell viability percentage % = [1 - (Compound OD - Blank OD / Control group OD - Blank OD)] × 100%, Sample preparation: The sample was dissolved in thionyl chloride and stored at low temperature. The concentration of thionyl chloride in the final system was controlled within a range that would not affect the detection activity.

[0045] The table shows the inhibitory activity of the 28 pentacyclic thiazole indole piperazine amide derivatives described in this invention against cancer cells (HeLa cervical cancer cells, HT-29 human colon cancer cells, and HGC-27 human gastric cancer cells). The results indicate that compounds I14, I21, I27, and I28 all exhibit significant inhibitory activity against HeLa cervical cancer cells; compounds I9, I11, I14, and I21 have significant inhibitory activity against HT-29 human colon cancer cells; and compounds I1-I28 all have significant inhibitory activity against HGC-27 human gastric cancer cells.

Claims

1. A pentacyclic thiazole indole-piperazinamide derivative, characterized in that... The structural formula of this type of derivative is: in: Compound I1 is 2-(4-benzoylpiperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I2 is 2-(4-(2-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I3 is 2-(4-(3-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I4 is 2-(4-(4-methylbenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I5 is 2-(4-(3-chlorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I6 is 2-(4-(4-chlorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I7 is 2-(4-(2-bromobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I8 is 2-(4-(4-bromobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I9 is ​​2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I10 is 2-(4-(3-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I11 is 2-(4-(4-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I12 is 2-(4-(2-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I13 is 2-(4-(3-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I14 is 2-(4-(2-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I15 is 2-(4-(3-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I16 is 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I17 is 2-(4-(2-(trifluoromethoxy)benzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I18 is 2-(4-(3-nitrobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I19 is 2-(4-(4-nitrobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I20 is 4-(4-(4-oxo-4,6,7,12-tetrahydrothiazol[5'',4'':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indolyl)piperazine-1-formyl)benzonitrile; Compound I21 is 2-(4-(cyclopentylformyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I22 is 4-oxo-4-(4-(4-oxo-4,6,7,12-tetrahydrothiazolium[5'',4'':4',5']pyrido[1',2':1,2]pyrido[3,4- b Methyl indolyl piperazine-1-yl butyrate; Compound I23 is 2-(4-(thiophene-2-formyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I24 is 2-(4-morpholino-4-formyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I25 is 2-(4-(3,5-difluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I26 is 2-(4-(2-chloro-6-fluorobenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I27 is 2-(4-(3,4-dimethoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone; Compound I28 is 2-(4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl)-7,12-dihydrothiazo[5'',4':4',5']pyrido[1',2':1,2]pyrido[3,4- b Indole-4(6) H )-ketone.

2. Use of compounds I14, I21, I27 and I28 of the pentacyclic thiazole indole piperazine amide derivatives as described in claim 1 in the preparation of a drug for treating HeLa cervical cancer.

3. Use of compounds I9, I11, I14 and I21 of the pentacyclic thiazole indole piperazine amide derivatives as described in claim 1 in the preparation of a medicament for treating HT-29 human colon cancer.

4. Use of compounds I1-I28 in the pentacyclic thiazole indole piperazine amide derivatives as described in claim 1 in the preparation of medicaments for treating HGC-27 human gastric cancer.

Images