Tricyclic compounds, preparation methods thereof, pharmaceutical compositions and uses

Abstract

The present invention discloses a tricyclic compound, a preparation method thereof, a pharmaceutical composition and an application thereof. The structure of this kind of compound is as shown in Formula 1, and it also includes its isomers, pharmaceutically acceptable salts or mixtures thereof, and further forms a pharmaceutical composition thereof with a pharmaceutically acceptable carrier. This kind of compound and its pharmaceutical composition can effectively inhibit PARP enzyme, PARP-1 enzyme and various tumor cells, can exert drug effects at both the molecular level and the cellular level, and the effects are better than existing drugs, having good application prospects; the preparation method of the compound has good generality and is conducive to the structural expansion of the compound.

Description

Technical Field

[0001] The present invention relates to a tricyclic compound, a preparation method thereof, a pharmaceutical composition and an application, and particularly relates to a tricyclic compound having PARP inhibitory activity, a preparation method thereof, a pharmaceutical composition and an application. Background Art

[0002] During the occurrence and development of cancer, a large number of DNA mutations will accumulate, causing cancer cells to divide faster than normal cells and proliferate and spread in an uncontrolled manner, which is the individuality and commonality of cancer cells. Most of the currently clinically used chemotherapeutic drugs, such as platinum drugs (cisplatin, oxaliplatin, carboplatin, etc.), alkylating agents (cyclophosphamide, nitrogen mustard, carmustine, etc.) and topoisomerase inhibitors (irinotecan, hydroxycamptothecin, etoposide, etc.) kill cancer cells by causing DNA damage. Their common feature is strong anti-cancer activity, but due to the lack of selectivity for cancer cells, they often have relatively large toxic side effects. With the development of cancer molecular biology, people have gradually realized that developing molecular targeted drugs targeting DNA repair pathways is one of the more effective methods for treating cancer.

[0003] PolyADP-ribose polymerase (PARP) is a key regulatory factor in the DNA damage repair pathway and plays an important role in maintaining gene stability, keeping telomere length and the cell's response to external stimuli. The PARP protein family has a total of 17 members, among which PARP-1 undertakes more than 90% of the biological functions of the family and has been proven to participate in the cell's response to DNA damage through ADP ribosylation reactions. Currently, five PARP inhibitors (PARPi) have been approved for clinical use, and multiple compounds have entered clinical research. They have shown good efficacy in dozens of refractory cancers such as BRCA1 / 2 mutant ovarian cancer, pancreatic cancer, triple-negative breast cancer and prostate cancer. However, with the widespread clinical application of PARPi, many problems that need to be solved urgently have emerged in clinical practice for the currently approved PARPi, as follows:

[0004] (1) Poor physicochemical properties, such as low water solubility, low bioavailability, low tissue distribution and safety risks caused by formulation instability;

[0005] (2) Relatively serious toxic side effects, which will cause varying degrees of hematological toxicity (anemia, neutropenia, thrombocytopenia, etc.), non-hematological toxicity (nausea, vomiting, fatigue, etc.), neurological toxicity, off-target toxicity and cardiovascular system adverse reactions and other side effects in clinical applications;

[0006] (3) The application scope is narrow and it is only effective for cancer patients with homologous recombination repair defects, especially those with BRCA1 / 2 mutations. However, the number of such patients is relatively small. For example, the number of patients with BCRA1 / 2 mutations in epithelial ovarian cancer only accounts for 14 - 15% of the total number of patients, about 7.5% in pancreatic cancer, and only 2% - 3% in breast cancer;

[0007] (4) Drug resistance: So far, different degrees of drug resistance have emerged in clinical applications.

[0008] Therefore, based on the problems existing in the clinical application of PARPi, new PARPi need to be developed to overcome the deficiencies of existing drugs. Summary of the Invention

[0009] Object of the Invention: The first object of the present invention is to provide a tricyclic compound, the second object is to provide a preparation method of the compound, the third object is to provide a pharmaceutical composition containing the compound, and the fourth object is to provide an application of the compound and its pharmaceutical composition in the preparation of anti-tumor drugs.

[0010] Technical Solution: The tricyclic compound described in the present invention has the structure of Formula 1, and also includes its isomers, pharmaceutically acceptable salts or mixtures thereof:

[0011]

[0012] Wherein:

[0013] Selected from

[0014] R1 is selected from

[0015] R2 is selected from halogen, C1 - C4 alkyl, C1 - C4 alkoxy, C1 - C4 haloalkyl, C1 - C4 haloalkoxy.

[0016] Preferably, the tricyclic compound has the structure of Formula I,

[0017]

[0018] Wherein:

[0019] R1 is selected from

[0020] Preferably, the tricyclic compound has the structure of Formula II,

[0021]

[0022] Wherein:

[0023] selected from

[0024] R1 is selected from Preferably, the tricyclic compound has the structure of formula III,

[0025]

[0026] Wherein:

[0027] selected from R2 is selected from 4-Cl, 4-Br, 4-CH3, 4-OCH3, 5-F, 5-Cl, 5-Br.

[0028] More preferably, the tricyclic compound is selected from any one of the following compounds:

[0029]

[0030]

[0031]

[0032]

[0033] Preferably, the pharmaceutically acceptable salt of the tricyclic compound is a salt formed with an acid selected from any one of the following:

[0034] hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.

[0035] The present invention uses benzofuran pyrimidinone as the parent body, and uses terephthalaldehyde, 4-acetylbenzaldehyde, isophthalaldehyde, p-hydroxybenzaldehyde, p-hydroxyacetophenone, 2,5-diformylfuran, 4-imidazolecarboxaldehyde, piperidin-4-one, 3-pyrrolidinone, etc. as linkers, and respectively undergoes condensation reactions with the parent compound and thiosemicarbazide and its analogs, semicarbazide or aminoguanidine to obtain novel compounds with structures such as formulas I to III. These compounds have strong inhibitory effects on the activities of PARP and PARP-1 enzymes, and show good anti-proliferation effects on various cancer cells, and can be used for preparing anti-tumor drugs.

[0036] The preparation method of the tricyclic compound described in the present invention is selected from any one of the following methods:

[0037] (1) When the compound has the structure of Formula I, compound 3a cyclizes with terephthalaldehyde, and then compound 4a condenses with R1-NH2 to obtain the compound of Formula I;

[0038]

[0039] The reaction reagents and conditions for cyclization in the synthetic routes of compounds 1-11 are as follows: raw material: terephthalaldehyde, catalyst: I2, solvent: CH3CN; the reaction reagents and conditions for condensation are as follows: raw materials: thiosemicarbazide, semicarbazide and their derivatives, solvent: ethanol, catalyst: glacial acetic acid, reaction temperature: heating under reflux;

[0040] The preparation method of intermediate 3a is as follows:

[0041]

[0042] (2) When the compound has the structure of Formula II, compound 3a cyclizes with p-acetylbenzaldehyde, isophthalaldehyde, 2,4-dialdehyde furan respectively, and then compounds 5a-6a, 10a condense with R1-NH2 respectively to obtain the compound of Formula II; or compound 3a cyclizes with 2-chloro-1,1,1-trimethoxyethane, and then compound 7a couples with 4-hydroxybenzaldehyde, 4-hydroxybenzophenone, 2-aldehyde imidazole, 4-piperidone, 3-pyrrolidone respectively. Finally, compounds 8a-9a, 11a-13a condense with R1-NH2 respectively to obtain the compound of Formula II;

[0043]

[0044] The reaction reagents and conditions for cyclization and condensation in the synthetic routes of compounds 12-17, 23-25 are as shown in the preparation method of the compound of Formula I;

[0045] The reaction reagents and conditions for cyclization in the synthetic routes of compounds 18-22 are as follows: raw material: 2-chloro-1,1,1-trimethoxyethane, catalyst: p-toluenesulfonic acid, solvent: toluene, reaction temperature: 110 °C; the reaction reagents and conditions for coupling are as follows: raw materials: coupling aromatic aldehyde and aromatic ketone derivatives, catalyst: K2CO3, KI, solvent: DMF, reaction temperature: 80 °C; the reaction reagents and conditions for condensation are as shown in the preparation method of the compound of Formula I;

[0046]

[0047] The reaction reagents and conditions for the coupling in the synthetic routes of Compounds 26 - 32 are as follows: Raw materials: Coupled aromatic aldehyde or aromatic ketone derivatives, catalyst K2CO3, KI, solvent: DMF, reaction temperature: 80 °C, or raw materials: 4-piperidone hydrate hydrochloride, 3-pyrrolidone hydrochloride, catalyst: triethylamine or N-ethyldiisopropylamine, potassium iodide, solvent: N,N-dimethylacetamide, reaction temperature: 80 °C; The reaction reagents and conditions for the condensation are as shown in the preparation method of the compound of Formula I;

[0048] (3) When the compound has the structure of Formula III, Compounds 3b - 3h are respectively cyclized with terephthalaldehyde, and then Compounds 4b - 4c, 4f - 4h are respectively condensed with R1-NH2 to obtain the compound of Formula III; or Compounds 3b - 3h are respectively cyclized with 2-chloro-1,1,1-trimethoxyethane, and then Compounds 7b - 7h are respectively coupled with 4-piperidone, and finally Compounds 12b - 12h are respectively condensed with R1-NH2 to obtain the compound of Formula III;

[0049]

[0050] The reaction reagents and conditions for the cyclization, condensation, and coupling in the synthetic routes of Compounds 33 - 44 are as shown in the preparation methods of the compounds of Formulas I - II;

[0051] The preparation methods of Intermediates 3b - 3h are as follows:

[0052]

[0053] Among them, the definitions of R 1 and R 2 are as described above;

[0054] The corresponding acid is salted with the compounds of Formulas I - III prepared by the above methods to obtain the pharmaceutically acceptable salts of the said compounds.

[0055] Furthermore, the tricyclic compounds of the present invention are added with a pharmaceutically acceptable carrier to form the pharmaceutical composition of the present invention; specifically, by adding common pharmaceutical excipients such as flavors, sweeteners, liquid / solid fillers, diluents, etc., common pharmaceutical preparations are made, such as tablets, capsules, syrups, suspensions or injections.

[0056] The tricyclic compounds or their pharmaceutical compositions of the present invention are used in the preparation of PARP inhibitor drugs, specifically prepared as anti-tumor drugs; especially as PARP-1 inhibitor drugs for the treatment of ovarian cancer, colon cancer, breast cancer, triple-negative breast cancer, etc.

[0057] Advantageous effects: Compared with the prior art, the present invention has the following remarkable advantages:

[0058] This class of compounds and their pharmaceutical compositions can effectively inhibit PARP enzyme (the optimal inhibition rate is higher than 90%), PARP-1 enzyme (the optimal inhibition rate is higher than 95%), and a variety of tumor cells (the optimal IC 50 value is lower than 10 μM). They can exert pharmacological effects at both the molecular level and the cellular level, and the effects are better than existing drugs, showing good application prospects; the preparation method of the compounds has good generality, which is conducive to the structural expansion of the compounds. Detailed implementation mode

[0059] The technical solutions of the present invention will be further described below in conjunction with the embodiments.

[0060] All reagents in the examples are of analytical purity. The nuclear magnetic spectra of the compounds were measured by a Bruker ARX-600 nuclear magnetic resonance spectrometer with TMS as the internal standard; the high-resolution mass spectra were measured by an Agilent 6224 TOF LC / MS instrument.

[0061] Example 1: Preparation of intermediate 2a

[0062] Weigh 1.0 g (8.4 mmol) of 1a into a 100 mL flask, add 50 mL of N,N-dimethylacetamide (DMA), and continue to add 6.8 g of CS2CO3 under stirring. Then heat the mixture to 75 °C, and then add 1.4 g (10 mmol) of 2-bromoacetamide. Continue the reaction for 3 h. Monitor the reaction process by thin-layer chromatography (TLC). After the reaction is completed, add a large amount of water to precipitate it. Filter, wash with water (20 mL × 3), and take the filter cake to dry to obtain 1.2 g of white solid with a yield of 79%. 1 1H NMR (600 MHz, DMSO-d6) δ 7.74 (dd, J = 7.6, 1.5 Hz, 1H), 7.66 - 7.63 (m, 1H), 7.45 (d, J = 30.1 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 4.67 (s, 2H) ppm.

[0063] Example 2: Preparation of intermediate 2b

[0064] Referring to the synthesis method of 2a, use 1b as the raw material instead of 1a to participate in the reaction, and obtain 1.2 g of white solid with a yield of 78%. 1 1H NMR (600 MHz, DMSO-d6) δ 7.94 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 9.1, 2.6 Hz, 1H), 7.49 (d, J = 44.4 Hz, 2H), 7.09 (d, J = 9.1 Hz, 1H), 4.70 (s, 2H) ppm.

[0065] Example 3: Preparation of Intermediate 2c

[0066] Referring to the synthesis method of 2a, using 1c as the raw material instead of 1a to participate in the reaction, 1.1 g of white solid was obtained, with a yield of 74%. 1 HNMR(600MHz,DMSO-d6)δ7.72(d,J=8.7Hz,1H),7.50(d,J=35.6Hz,2H),7.34(dd,J=6.8,1.7Hz,2H),4.75(s,2H)ppm.

[0067] Example 4: Preparation of Intermediate 2d

[0068] Referring to the synthesis method of 2a, using 1d as the raw material instead of 1a to participate in the reaction, 1.0 g of white solid was obtained, with a yield of 72%. 1 HNMR(600MHz,DMSO-d6)δ7.61(d,J=7.8Hz,1H),7.45(d,J=8.1Hz,2H),6.94(d,J=7.9Hz,1H),6.91(s,1H),4.65(s,2H),2.35(s,3H)ppm.

[0069] Example 5: Preparation of Intermediate 2e

[0070] Referring to the synthesis method of 2a, using 1e as the raw material instead of 1a to participate in the reaction, 1.1 g of white solid was obtained, with a yield of 76%. 1 HNMR(600MHz,DMSO-d6)δ7.66(d,J=8.6Hz,1H),7.45(s,2H),6.69(dd,J=8.6,2.1Hz,1H),6.60(d,J=2.1Hz,1H),4.67(s,2H),3.82(s,3H)ppm.

[0071] Example 6: Preparation of Intermediate 2f

[0072] Referring to the synthesis method of 2a, using 1f as the raw material instead of 1a to participate in the reaction, 0.9 g of white solid was obtained, with a yield of 71%. 1 HNMR(600MHz,DMSO-d6)δ7.76(dd,J=8.1,3.2Hz,1H),7.55(ddd,J=9.1,8.5,3.2Hz,1H),7.48(d,J=31.0Hz,2H),7.09(dd,J=9.4,4.1Hz,1H),4.67(s,2H)ppm.

[0073] Example 7: Preparation of Intermediate 2g

[0074] Referring to the synthesis method of 2a, using 1g as the raw material instead of 1a to participate in the reaction, 1.2g of white solid was obtained, with a yield of 74%. 1 HNMR(600MHz, DMSO - d6) δ7.94(d, J = 2.6Hz, 1H), 7.72(dd, J = 9.1, 2.6Hz, 1H), 7.49(d, J = 44.4Hz, 2H), 7.09(d, J = 9.1Hz, 1H), 4.70(s, 2H) ppm.

[0075] Example 8: Preparation of Intermediate 2h

[0076] Referring to the synthesis method of 2a, using 1h as the raw material instead of 1a to participate in the reaction, 1.3g of white solid was obtained, with a yield of 76%. 1 HNMR(600MHz, DMSO - d6) δ8.03(d, J = 2.4Hz, 1H), 7.83(dd, J = 9.1, 2.4Hz, 1H), 7.49(d, J = 52.8Hz, 2H), 7.04(d, J = 9.1Hz, 1H), 4.70(s, 2H) ppm.

[0077] Example 9: Preparation of Intermediate 3a

[0078] Take 1.0g of 2a (5.7mmol) in a 250mL flask, add 120mL of ethanol, add 0.95g of KOH (17mmol) under stirring, heat up to 80°C, stir for 10h, and monitor the reaction by TLC. After the reaction is completed, adjust the pH = 7 with HCl (1mol / L), rotary evaporate the solvent, and purify by column chromatography (V PE :V EA = 2:1), 0.93g of white solid was obtained, with a yield of 93%. 1 H NMR(600MHz, DMSO - d6) δ7.85(d, J = 7.8Hz, 1H), 7.44 - 7.40(m, 2H), 7.24(ddd, J = 8.0, 6.3, 1.8Hz, 3H), 6.01(s, 2H) ppm.

[0079] Example 10: Preparation of Intermediate 3b

[0080] Referring to the synthesis method of 3a, using 2b as the raw material instead of 2a to participate in the reaction, 1.0g of white solid was obtained, with a yield of 88%. 1 HNMR(600MHz, DMSO - d6) δ7.88(d, J = 8.4Hz, 1H), 7.54(s, 1H), 7.30(t, J = 14.4Hz, 3H), 6.09(s, 2H) ppm.

[0081] Example 11: Preparation of Intermediate 3c

[0082] Referring to the synthesis method of 3a, using 2c as the raw material instead of 2a to participate in the reaction, 1.4 g of white solid was obtained, with a yield of 91%. 1 HNMR(600MHz,DMSO-d6)δ7.83(d,J=8.4Hz,1H),7.67(s,1H),7.44(dd,J=8.4,1.0Hz,1H),7.30(s,2H),6.10(s,2H)ppm.

[0083] Example 12: Preparation of Intermediate 3d

[0084] Referring to the synthesis method of 3a, using 2d as the raw material instead of 2a to participate in the reaction, 1.2 g of white solid was obtained, with a yield of 91%. 1 HNMR(600MHz,DMSO-d6)δ7.71(d,J=8.0Hz,1H),7.21(s,3H),7.06(d,J=8.0Hz,1H),5.98(s,2H),2.42(s,3H)ppm.

[0085] Example 13: Preparation of Intermediate 3e

[0086] Referring to the synthesis method of 3a, using 2e as the raw material instead of 2a to participate in the reaction, 1.3 g of white solid was obtained, with a yield of 92%. 1 HNMR(600MHz,DMSO-d6)δ7.73(d,J=8.6Hz,1H),7.08(s,2H),6.93(s,1H),6.87(d,J=8.7Hz,1H),6.00(s,2H),3.82(s,3H)ppm.

[0087] Example 14: Preparation of Intermediate 3f

[0088] Referring to the synthesis method of 3a, using 2f as the raw material instead of 2a to participate in the reaction, 0.74 g of white solid was obtained, with a yield of 78%. 1 HNMR(600MHz,DMSO-d6)δ7.71(dd,J=8.7,2.7Hz,1H),7.44(dd,J=9.0,4.0Hz,1H),7.27(td,J=9.1,2.7Hz,1H),6.31(s,4H)ppm.

[0089] Example 15: Preparation of Intermediate 3g

[0090] Referring to the synthesis method of 3a, using 2g as the raw material instead of 2a to participate in the reaction, 1.1 g of white solid was obtained, with a yield of 90%. 1HNMR(600MHz, DMSO-d6) δ 7.97 (s, 1H), 7.45 (d, J = 2.2 Hz, 2H), 7.32 (s, 2H), 6.03 (s, 2H) ppm.

[0091] Example 16: Preparation of Intermediate 3h

[0092] Referring to the synthesis method of 3a, using 2h as the raw material instead of 2a to participate in the reaction, 1.3 g of white solid was obtained, with a yield of 92%. 1 HNMR(600MHz, DMSO-d6) δ 8.11 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.31 (s, 2H), 6.02 (s, 2H) ppm.

[0093] Example 17: Preparation of Intermediate 4a

[0094] Take 0.61 g (4.5 mmol) of terephthalaldehyde in a 100 mL flask, add 30 mL of acetonitrile to dissolve, and successively add 0.69 g (2.7 mmol) of I2 and 0.40 g (2.3 mmol) of 3a under stirring. After stirring at room temperature for 10 h, monitor the reaction by TLC. After the reaction is completed, quench the reaction with sodium thiosulfate solution, filter out the solid, and purify the filter cake by column chromatography (V DCM :V MeOH = 180:1), to obtain 0.39 g of light yellow solid, with a yield of 50%. 1 HNMR(600MHz, DMSO-d6) δ 13.34 (s, 1H), 10.13 (s, 1H), 8.38 (d, J = 8.0 Hz, 2H), 8.15 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H) ppm.

[0095] Example 18: Preparation of Intermediate 4b

[0096] Referring to the synthesis of 4a, using 3b as the raw material instead of 3a to participate in the reaction, 0.42 g of light yellow solid was obtained, with a yield of 55%. 1 HNMR(600MHz, DMSO-d6) δ 13.37 (s, 1H), 10.12 (s, 1H), 8.35 (d, J = 6.4 Hz, 2H), 8.09 (dd, J = 25.0, 7.7 Hz, 4H), 7.56 (d, J = 7.1 Hz, 1H) ppm.

[0097] Example 19: Preparation of Intermediate 4c

[0098] Referring to the synthesis of 4a, using 3c as the raw material instead of 3a to participate in the reaction, 0.36 g of pale yellow solid was obtained, with a yield of 45%. 1 HNMR(600MHz, DMSO-d6) δ 13.36(s, 1H), 10.12(s, 1H), 8.35(d, J = 8.2Hz, 2H), 8.23(d, J = 1.3Hz, 1H), 8.07(t, J = 8.6Hz, 3H), 7.69(dd, J = 8.3, 1.5Hz, 1H) ppm.

[0099] Example 20: Preparation of Intermediate 4f

[0100] Referring to the synthesis of 4a, using 3f as the raw material instead of 3a to participate in the reaction, 0.27 g of pale yellow solid was obtained, with a yield of 37%. 1 HNMR(600MHz, DMSO-d6) δ 13.38(s, 1H), 10.13(s, 1H), 8.36(d, J = 8.2Hz, 2H), 8.09(d, J = 8.3Hz, 2H), 7.96 - 7.93(m, 2H), 7.59(td, J = 9.1, 2.7Hz, 1H) ppm.

[0101] Example 21: Preparation of Intermediate 4g

[0102] Referring to the synthesis of 4a, using 3g as the raw material instead of 3a to participate in the reaction, 0.45 g of pale yellow solid was obtained, with a yield of 55%. 1 HNMR(600MHz, DMSO-d6) δ 13.42(s, 1H), 10.13(s, 1H), 8.37(d, J = 8.1Hz, 2H), 8.17(d, J = 2.0Hz, 1H), 8.09(d, J = 8.3Hz, 2H), 7.94(d, J = 8.9Hz, 1H), 7.75(dd, J = 8.9, 2.2Hz, 1H) ppm.

[0103] Example 22: Preparation of Intermediate 4h

[0104] Referring to the synthesis of 4a, using 3h as the raw material instead of 3a to participate in the reaction, 0.36 g of pale yellow solid was obtained, with a yield of 48%. 1HNMR(600MHz, DMSO-d6) δ 12.90(s, 1H), 10.12(s, 1H), 8.36(d, J = 8.3 Hz, 2H), 8.25(d, J = 2.4 Hz, 1H), 8.07(d, J = 8.4 Hz, 2H), 8.01(dd, J = 8.7, 2.4 Hz, 1H), 7.74(d, J = 8.7 Hz, 1H) ppm.

[0105] Example 23: Preparation of Intermediate 5a

[0106] Take 0.67 g (4.5 mmol) of 4-acetylbenzaldehyde in a 100 mL flask, add 40 mL of acetonitrile to dissolve, and successively add 0.69 g (2.7 mmol) of I2 and 0.40 g (2.3 mmol) of 3a under stirring. After stirring at room temperature for 10 h, monitor the reaction by TLC. After the reaction is completed, quench the reaction with sodium thiosulfate solution, filter the precipitated solid, and purify the filter cake by column chromatography (V DCM :V MeOH = 150:1) to obtain 0.41 mg of a pale yellow solid with a yield of 58%. 1 HNMR(600MHz, DMSO-d6) δ 13.24(s, 1H), 8.33(d, J = 8.4 Hz, 2H), 8.13(dd, J = 11.4, 8.2 Hz, 3H), 7.87(d, J = 8.4 Hz, 1H), 7.73 - 7.69(m, 1H), 7.53(t, J = 7.4 Hz, 1H), 2.66(s, 3H) ppm.

[0107] Example 24: Preparation of Intermediate 6a

[0108] Take 0.61 g (4.5 mmol) of isophthalaldehyde in a 100 mL flask, add 40 mL of acetonitrile to dissolve, and successively add 0.69 g (2.7 mmol) of I2 and 0.40 g (2.3 mmol) of 3a under stirring. After stirring at room temperature for 10 h, monitor the reaction by TLC. After the reaction is completed, quench the reaction with sodium thiosulfate solution, filter the precipitated solid, and purify the filter cake by column chromatography (V DCM :V MeOH = 180:1) to obtain 0.04 g of a pale yellow solid with a yield of 60%. 1HNMR(600MHz, DMSO-d6) δ 13.33 (s, 1H), 10.15 (s, 1H), 8.71 (s, 1H), 8.47 (d, J = 7.5 Hz, 1H), 8.14 (dd, J = 13.4, 7.7 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H) ppm.

[0109] Example 25: Preparation of Intermediate 7a

[0110] Weigh 2.0 g (11 mmol) of 3a into a 100 mL flask, add 50 mL of toluene, and then add 3.5 g (23 mmol) of 2-chloro-1,1,1-trimethoxyethane and 0.20 g (1.1 mmol) of p-toluenesulfonic acid while stirring. Subsequently, heat the mixture to 110 °C and react for 4 h, monitoring the reaction using TLC. After the reaction is completed, remove it from the heat and cool. Filter the resulting precipitate, wash it with toluene (10 mL × 3), and dry the filter cake to obtain 2.4 g of a grayish-white solid with a yield of 90%. 1 H NMR(600MHz, DMSO-d6) δ 13.29 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.72 - 7.68 (m, 1H), 7.52 (t, J = 7.5 Hz, 1H), 4.67 (s, 2H) ppm.

[0111] Example 26: Preparation of Intermediate 7b

[0112] Referring to the synthesis method of 7a, use 3b as the raw material instead of 3a to participate in the reaction to obtain 1.6 g of a white solid with a yield of 68%. 1 HNMR(600MHz, DMSO-d6) δ 13.36 (s, 1H), 8.07 (dd, J = 15.8, 4.9 Hz, 2H), 7.55 (dd, J = 8.4, 1.7 Hz, 1H), 4.67 (s, 2H) ppm.

[0113] Example 27: Preparation of Intermediate 7c

[0114] Referring to the synthesis method of 7a, use 3c as the raw material instead of 3a to participate in the reaction to obtain 1.4 g of a white solid with a yield of 60%. 1 HNMR(600MHz, DMSO-d6) δ 13.35 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 4.65 (s, 2H) ppm.

[0115] Example 28: Preparation of Intermediate 7d

[0116] Referring to the synthesis method of 7a, using 3d as the raw material instead of 3a to participate in the reaction, 2.4 g of white solid was obtained with a yield of 92%. 1 HNMR(600MHz,DMSO-d6)δ13.23(s,1H),7.92(d,J=8.0Hz,1H),7.67(s,1H),7.34(d,J=8.0Hz,1H),4.65(s,2H),2.52(s,3H)ppm.

[0117] Example 29: Preparation of Intermediate 7e

[0118] Referring to the synthesis method of 7a, using 3e as the raw material instead of 3a to participate in the reaction, 2.4 g of white solid was obtained with a yield of 90%. 1 HNMR(600MHz,DMSO-d6)δ13.18(s,1H),7.91(d,J=8.7Hz,1H),7.44(d,J=2.0Hz,1H),7.11(dd,J=8.7,2.2Hz,1H),4.65(s,2H),3.90(s,3H)ppm.

[0119] Example 30: Preparation of Intermediate 7f

[0120] Referring to the synthesis method of 7a, using 3f as the raw material instead of 3a to participate in the reaction, 1.7 g of white solid was obtained with a yield of 67%. 1 HNMR(600MHz,DMSO-d6)δ13.33(s,1H),8.10(s,1H),7.87(d,J=8.2Hz,1H),7.41(s,1H),4.66(s,2H)ppm.

[0121] Example 31: Preparation of Intermediate 7g

[0122] Referring to the synthesis method of 7a, using 3g as the raw material instead of 3a to participate in the reaction, 1.6 g of white solid was obtained with a yield of 63%. 1 HNMR(600MHz,DMSO-d6)δ13.39(s,1H),8.10(s,1H),7.92(d,J=8.9Hz,1H),7.73(dd,J=8.9,1.9Hz,1H),4.66(s,2H)ppm.

[0123] Example 32: Preparation of Intermediate 7h

[0124] Referring to the synthesis method of 7a, using 3h as the raw material instead of 3a to participate in the reaction, 1.3 g of white solid was obtained with a yield of 60%. 1HNMR(600MHz, DMSO-d6) δ 13.39(s, 1H), 8.23(s, 1H), 7.88 - 7.83(m, 2H), 4.66(s, 2H) ppm.

[0125] Example 33: Preparation of Intermediate 8a

[0126] Weigh 0.50 g of p-hydroxybenzaldehyde (4.1 mmol) into a 50 mL flask, add 20 mL of DMA, add 1.7 g of K2CO3 (12 mmol) under stirring, then add 1.0 g of 7a (4.3 mmol) and 0.71 g of KI (4.3 mmol). Heat the mixture to 80 °C and react for 10 h, monitoring the reaction using TLC. After the reaction is completed, remove it from the heat and cool it down. Add 60 mL of water and extract with dichloromethane (80 mL × 3). Collect the organic phase and evaporate it to dryness. Purify it by column chromatography (V DCM :V MeOH = 150:1), obtaining 0.49 g of a yellow solid with a yield of 38%. 1 1H NMR(600MHz, DMSO-d6) δ 13.24(s, 1H), 9.90(s, 1H), 8.04(d, J = 7.7 Hz, 1H), 7.92(d, J = 8.6 Hz, 2H), 7.86(d, J = 8.4 Hz, 1H), 7.70(t, J = 7.7 Hz, 1H), 7.51(t, J = 7.5 Hz, 1H), 7.29(d, J = 8.6 Hz, 2H), 5.24(s, 2H) ppm.

[0127] Example 34: Preparation of Intermediate 9a

[0128] Weigh 0.30 g (2.2 mmol) of p-hydroxyacetophenone into a 50 mL flask, add 20 mL of DMF, add 0.91 g (6.6 mmol) of K2CO3 under stirring, then add 0.54 g (2.3 mmol) of 7a and 0.37 g (2.2 mmol) of KI. Heat the mixture to 80 °C and react for 10 h, monitoring the reaction using TLC. After the reaction is completed, remove it from the heat and cool it down. Add 60 mL of water and extract with dichloromethane (80 mL × 3). Collect the organic phase and evaporate it to dryness. Purify it by column chromatography (V DCM :V MeOH = 190:1), obtaining 0.42 g of a yellow solid with a yield of 57%. 11H NMR (600 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.97 (d, J = 5.9 Hz, 2H), 7.85 (dd, J = 8.4, 2.1 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.51 (t, J = 6.3 Hz, 1H), 7.19 (d, J = 6.0 Hz, 2H), 5.21 (s, 2H), 2.53 (s, 3H) ppm.

[0129] Example 35: Preparation of Intermediate 10a

[0130] Take 0.51 g (4.1 mmol) of furan-2,5-dicarbaldehyde in a 100 mL flask, add 50 mL of acetonitrile to dissolve it, and successively add 0.86 g (3.4 mmol) of I2 and 0.40 g (2.3 mmol) of 3a under stirring. After stirring at room temperature for 10 h, monitor the reaction by TLC. After the reaction is completed, quench the reaction with sodium thiosulfate solution, filter the precipitated solid, and purify the filter cake by column chromatography (V DCM :V MeOH = 190:1) to obtain 0.40 mg of a pale yellow solid with a yield of 63%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.48 (s, 1H), 9.78 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 2.9 Hz, 1H), 7.74 - 7.71 (m, 2H), 7.60 - 7.60 (m, 1H), 7.54 (t, J = 7.5 Hz, 1H) ppm.

[0131] Example 36: Preparation of Intermediate 11a

[0132] Weigh 0.15 g (1.6 mmol) of 4-imidazolecarbaldehyde in a 50 mL flask, add 20 mL of DMF, add 0.75 g (5.4 mmol) of K2CO3 under stirring, then add 0.40 g (1.7 mmol) of 7a and 0.28 g (1.7 mmol) of KI, heat up to 80 °C, react for 10 h, and monitor the reaction by TLC. After the reaction is completed, cool it down, add 60 mL of water, extract with dichloromethane (80 mL × 3), collect the organic phase and evaporate it to dryness, and purify it by column chromatography (V DCM :V MeOH = 30:1) to obtain 0.21 mg of a yellow solid with a yield of 46%. 1HNMR(600MHz, DMSO-d6) δ 13.28 (s, 1H), 9.76 (s, 1H), 8.17 (d, J = 1.0 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.68 - 7.65 (m, 1H), 7.47 (d, J = 7.4 Hz, 1H), 5.41 (s, 2H) ppm.

[0133] Example 37: Preparation of Intermediate 12a

[0134] Weigh 0.20 g (1.3 mmol) of 4-piperidone monohydrate hydrochloride into a 50 mL flask, add 20 mL of DMF, add 0.26 g (2.6 mmol) of Et3N under stirring, stir for 30 min, then add 0.20 g (0.85 mmol) of 7a and 0.14 g (0.85 mmol) of KI, heat up to 80 °C, react for 10 h, and monitor the reaction using TLC. After the reaction is completed, add 60 mL of water, extract with dichloromethane (80 mL × 3), collect the organic phase and spin dry, and purify by column chromatography (V DCM :V MeOH = 110:1), to obtain 0.19 g of a white solid with a yield of 77%. 1 HNMR(600MHz, DMSO-d6) δ 12.71 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 3.71 (s, 2H), 2.87 (t, J = 6.0 Hz, 4H), 2.40 (t, J = 6.0 Hz, 4H) ppm.

[0135] Example 38: Preparation of Intermediate 12b

[0136] Referring to the synthesis method of 12a, using 7b as the raw material instead of 7a to participate in the reaction, 0.17 g of a white solid is obtained with a yield of 73%. 1 H NMR(600MHz, DMSO-d6) δ 12.76 (s, 1H), 8.06 (dd, J = 10.3, 5.0 Hz, 2H), 7.54 (dd, J = 8.4, 1.8 Hz, 1H), 3.72 (s, 2H), 2.87 (t, J = 5.8 Hz, 4H), 2.40 (t, J = 6.0 Hz, 4H) ppm.

[0137] Example 39: Preparation of Intermediate 12c

[0138] Referring to the synthesis method of 12a, using 7c as the raw material instead of 7a to participate in the reaction, 0.15 g of white solid was obtained, with a yield of 68%. 1 H NMR(600MHz,DMSO-d6)δ12.75(s,1H),8.19(d,J=1.4Hz,1H),7.98(d,J=8.3Hz,1H),7.65(dd,J=8.3,1.6Hz,1H),3.69(d,J=22.0Hz,2H),2.87(s,4H),2.39(t,J=5.7Hz,4H)ppm.

[0139] Example 40: Preparation of Intermediate 12d

[0140] Referring to the synthesis method of 12a, using 7d as the raw material instead of 7a to participate in the reaction, 0.17 g of white solid was obtained, with a yield of 69%. 1 H NMR(600MHz,DMSO-d6)δ12.62(s,1H),7.91(d,J=7.9Hz,1H),7.65(s,1H),7.32(d,J=8.0Hz,1H),3.71(s,2H),3.10(s,3H),2.86(s,4H),2.40(s,4H)ppm.

[0141] Example 41: Preparation of Intermediate 12e

[0142] Referring to the synthesis method of 12a, using 7e as the raw material instead of 7a to participate in the reaction, 0.15 mg of white solid was obtained, with a yield of 65%. 1 H NMR(600MHz,DMSO-d6)δ12.58(s,1H),7.90(d,J=8.7Hz,1H),7.42(d,J=2.1Hz,1H),7.08(dd,J=8.7,2.1Hz,1H),3.89(s,3H),3.70(s,2H),2.86(t,J=5.2Hz,4H),2.40(t,J=5.9Hz,4H)ppm.

[0143] Example 42: Preparation of Intermediate 12f

[0144] Referring to the synthesis method of 12a, using 7f as the raw material instead of 7a to participate in the reaction, 0.12 g of white solid was obtained, with a yield of 52%. 11H NMR (600 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.09 (dd, J = 8.6, 5.6 Hz, 1H), 7.85 (dd, J = 9.2, 2.0 Hz, 1H), 7.38 (td, J = 9.4, 2.1 Hz, 1H), 3.72 (s, 2H), 2.87 (s, 4H), 2.40 (s, 4H) ppm.

[0145] Example 43: Preparation of Intermediate 12g

[0146] Referring to the synthesis method of 12a, using 7g as the raw material instead of 7a to participate in the reaction, 0.12 mg of white solid was obtained, with a yield of 55%. 1 1H NMR (600 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.9, 2.1 Hz, 1H), 3.72 (s, 2H), 2.87 (t, J = 6.0 Hz, 4H), 2.40 (t, J = 6.0 Hz, 4H) ppm.

[0147] Example 44: Preparation of Intermediate 12h

[0148] Referring to the synthesis method of 12a, using 7h as the raw material instead of 7a to participate in the reaction, 0.14 g of white solid was obtained, with a yield of 59%. 1 1H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 3.6 Hz, 2H), 3.64 (s, 2H), 2.86 (s, 4H), 2.38 (s, 4H) ppm.

[0149] Example 45: Preparation of Intermediate 13a

[0150] Weigh 0.78 g (6.4 mmol) of 3-pyrrolidone hydrochloride into a 100 mL flask, add 20 mL of CH3CN, add 2.5 g (19 mmol) of DIPEA under stirring, stir for 10 min, then add 1.0 g (4.3 mmol) of 7a and 0.71 g (4.3 mmol) of KI, heat up to 80 °C, react for 10 h, and monitor the reaction using TLC. After the reaction is completed, remove it and cool it down, rotary evaporate the reaction solution, add 60 mL of water, extract with dichloromethane (80 mL × 3), collect the organic phase and rotary evaporate it, and purify it by column chromatography (V DCM :V MeOH = 180:1), obtaining 0.43 g of gray solid, with a yield of 36%. 11H NMR (600 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.69 - 7.66 (m, 1H), 7.49 (t, J = 7.5 Hz, 1H), 3.81 (s, 2H), 3.11 (s, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.38 (t, J = 6.9 Hz, 2H) ppm.

[0151] Example 46: Preparation of Compound 1

[0152] Take 0.20 g (0.69 mmol) of 4a and 0.076 g (0.83 mmol) of thiosemicarbazide in a 100 mL flask, add 50 mL of ethanol, dropwise add 2 drops of acetic acid, heat to reflux, stir for 10 h, and monitor the reaction by TLC. After the reaction is completed, cool and filter. The filter cake is washed successively with ethanol, hot MeOH:DCM (v:v) = 1:1, and cold ethanol (5 mL each) to obtain 0.21 g of a pale yellow solid with a yield of 85%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.16 (s, 1H), 11.60 (s, 1H), 8.33 (s, 1H), 8.23 (d, J = 8.2 Hz, 2H), 8.19 - 8.14 (m, 2H), 8.12 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 178.65, 156.80, 154.22, 153.90, 144.11, 141.45, 138.47, 137.43, 133.42, 130.45, 128.69, 127.86, 124.88, 122.87, 121.96, 113.51 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 13 N5O2S, [M + H] - : 362.0717; found: 362.0714.

[0153] Example 47: Preparation of Compound 2

[0154] Using 4a and 2-methylthiosemicarbazide as raw materials and referring to the synthesis method of Compound 1, 0.13 g of a pale yellow solid was obtained with a yield of 78%. 1HNMR(600MHz, DMSO-d6) δ 13.16 (s, 1H), 8.51 (d, J = 42.2Hz, 2H), 8.24 (d, J = 7.7Hz, 2H), 8.15 (d, J = 7.8Hz, 3H), 7.98 (s, 1H), 7.87 (d, J = 8.2Hz, 1H), 7.71 (t, J = 7.5Hz, 1H), 7.54 (t, J = 7.2Hz, 1H), 3.82 (s, 3H) ppm. 13 C NMR(150MHz, DMSO-d6) δ 181.20, 156.80, 154.24, 153.89, 144.11, 140.39, 138.46, 137.65, 133.36, 130.42, 128.63, 128.35, 124.86, 122.88, 121.94, 113.49, 33.34 ppm. HR-MS(m / z)(ESI): calcd for C 19 H 15 N5O2S, [M + H] - : 376.0873; found: 376.0872.

[0155] Example 48: Preparation of Compound 3

[0156] Using 4a and 4-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.17 g of light yellow solid was obtained with a yield of 72%. 1 H NMR(600MHz, DMSO-d6) δ 13.17 (s, 1H), 11.66 (s, 1H), 8.68 (d, J = 4.4Hz, 1H), 8.24 (d, J = 8.2Hz, 2H), 8.17 - 8.11 (m, 2H), 8.00 (d, J = 8.3Hz, 2H), 7.87 (d, J = 8.4Hz, 1H), 7.71 (t, J = 7.7Hz, 1H), 7.54 (t, J = 7.5Hz, 1H), 3.05 (d, J = 4.5Hz, 3H) ppm. 13 C NMR(150MHz, DMSO-d6) δ 178.30, 156.80, 154.19, 153.90, 144.12, 140.89, 138.45, 137.51, 133.31, 130.44, 128.68, 127.73, 124.87, 122.86, 121.95, 113.50, 31.37 ppm. HR-MS(m / z)(ESI): calcd for C 19 H 15 N5O2S, [M + H] -: 376.0874; found: 376.0870.

[0157] Example 49: Preparation of Compound 4

[0158] Using 4a and N-ethylhydrazinecarbothioamide as starting materials and referring to the synthesis method of Compound 1, 0.11 g of a pale yellow solid was obtained with a yield of 70%. 1 H NMR (600 MHz, DMSO-d6) δ 13.18 (s, 1H), 11.60 (s, 1H), 8.73 (t, J = 5.8 Hz, 1H), 8.24 (d, J = 8.3 Hz, 2H), 8.16 - 8.11 (m, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.54 (t, J = 7.5 Hz, 1H), 3.62 (dd, J = 13.5, 6.8 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H) ppm. 13 C NMR (150 MHz, DMSO-d6) δ 177.23, 156.80, 154.19, 153.92, 144.11, 141.00, 138.46, 137.47, 133.34, 130.45, 128.67, 127.78, 124.88, 122.86, 121.95, 113.52, 38.83, 15.07 ppm. HR-MS (m / z) (ESI): calcd for C 20 H 17 N5O2S, [M + H] - : 390.1030; found: 390.1030.

[0159] Example 50: Preparation of Compound 5

[0160] Using 4a and 4,4-dimethyl-3-thiosemicarbazide as starting materials and referring to the synthesis method of Compound 1, 0.12 g of a pale yellow solid was obtained with a yield of 78%. 1 H NMR (600 MHz, DMSO-d6) δ 13.17 (s, 1H), 11.13 (s, 1H), 8.31 - 8.22 (m, 3H), 8.14 (d, J = 7.5 Hz, 1H), 7.85 (dd, J = 25.1, 8.2 Hz, 3H), 7.71 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 3.34 (s, 3H), 3.33 (s, 3H) ppm. 1313C NMR(150MHz, DMSO-d6) δ 181.02, 156.82, 154.33, 153.89, 144.14, 143.08, 137.78, 130.44, 129.32, 128.92, 127.22, 126.65, 124.89, 122.89, 121.94, 113.50, 42.65 ppm. HR-MS (m / z) (ESI): calcd for C 20 H 17 N5O2S, [M+H] - : 390.1030; found: 390.1030.

[0161] Example 51: Preparation of Compound 6

[0162] Using 4a and semicarbazide hydrochloride as raw materials and referring to the synthesis method of Compound 1, 0.13 g of pale yellow solid was obtained, with a yield of 71%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.12 (s, 1H), 10.44 (s, 1H), 8.21 (d, J = 8.3 Hz, 2H), 8.15 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 7.6 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 3.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 6.57 (d, J = 52.1 Hz, 3H) ppm. 13 13C NMR(150MHz, DMSO-d6) δ 157.14, 157.10, 156.82, 153.90, 139.28, 138.56, 135.76, 130.44, 130.03, 128.67, 127.19, 127.11, 124.88, 122.90, 121.96, 113.51 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 13 N5O3, [M+H] - : 346.0946; found: 346.0941.

[0163] Example 52: Preparation of Compound 7

[0164] Using 4a and aminoguanidine hydrochloride as raw materials and referring to the synthesis method of Compound 1, 0.10 g of pale yellow solid was obtained, with a yield of 72%. 11H NMR (600 MHz, DMSO-d6) δ 13.18 (s, 1H), 12.07 (s, 1H), 8.27 (d, J = 5.4 Hz, 3H), 8.15 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.4 Hz, 3H), 7.72 (t, J = 7.7 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 156.81, 155.96, 154.13, 153.91, 146.21, 144.10, 138.52, 136.54, 134.10, 130.47, 128.71, 128.17, 124.90, 122.85, 121.95, 113.52 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 14 N6O2, [M + H] - : 345.1105; found: 345.1105.

[0165] Example 53: Preparation of Compound 8

[0166] Using 4a and 1-amino-S-methylisothiourea hydroiodide as starting materials and referring to the synthesis method of Compound 1, 0.11 g of a pale yellow solid was obtained with a yield of 71%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.23 (s, 1H), 9.66 (s, 2H), 8.42 (s, 1H), 8.31 (d, J = 8.1 Hz, 2H), 8.19 - 8.11 (m, 3H), 7.88 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 2.76 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 167.12, 156.82, 153.88, 151.21, 144.07, 138.57, 135.60, 135.11, 130.52, 129.04, 128.80, 126.44, 124.94, 122.80, 121.93, 113.54, 14.02 ppm. HR-MS (m / z) (ESI): calcd for C 19 H 15 N5O2S, [M + H] - : 376.0874; found: 376.0867.

[0167] Example 54: Preparation of Compound 9

[0168] Using 4a and 4-phenyl-3-thiosemicarbazide as raw materials and referring to the synthesis method of Compound 1, 0.30 g of pale yellow solid was obtained with a yield of 80%. 1 H NMR(600MHz,DMSO-d6)δ13.19(s,1H),12.00(s,1H),10.28(s,1H),8.28-8.22(m,3H),8.13(dd,J=19.1,8.1Hz,3H),7.87(d,J=8.4Hz,1H),7.71(t,J=7.8Hz,1H),7.56(dd,J=13.7,7.7Hz,3H),7.40(t,J=7.8Hz,2H),7.24(t,J=7.4Hz,1H)ppm. 13 C NMR(150MHz,DMSO-d6)δ176.75,156.81,154.19,153.91,144.13,142.11,139.53,138.48,137.24,133.58,130.45,128.66,128.57,128.19,126.67,125.98,124.89,122.87,121.96,113.51ppm.HR-MS(m / z)(ESI):calcd for C 24 H 17 N5O2S,[M+H] - :438.1030;found:438.1024.

[0169] Example 55: Preparation of Compound 10

[0170] Using 4a and 4-(4-chlorophenyl)-3-thiosemicarbazide as raw materials and referring to the synthesis method of Compound 1, 0.12 g of pale yellow solid was obtained with a yield of 72%. 1 H NMR(600MHz,DMSO-d6)δ13.19(s,1H),12.08(s,1H),10.30(s,1H),8.30-8.22(m,3H),8.13(dd,J=20.6,8.0Hz,3H),7.87(d,J=8.4Hz,1H),7.71(t,J=7.7Hz,1H),7.62(d,J=8.6Hz,2H),7.54(t,J=7.5Hz,1H),7.46(d,J=8.6Hz,2H)ppm. 13CNMR(150MHz, DMSO-d6) δ 176.73, 156.82, 154.17, 153.91, 144.12, 142.46, 138.52, 137.14, 133.66, 130.46, 129.97, 128.66, 128.46, 128.27, 128.23, 128.08, 124.89, 122.87, 121.95, 113.52 ppm. HR-MS(m / z)(ESI): calcd for C 24 H 16 ClN5O2S, [M+H] - : 472.0640; found: 472.0631.

[0171] Example 56: Preparation of Compound 11

[0172] Using 4a and 1'-[2-(4-morpholino)ethyl]-1-thiosemicarbazide as starting materials and referring to the synthesis method of Compound 1, 0.12 g of a pale yellow solid was obtained with a yield of 76%. 1 H NMR(600MHz, DMSO-d6) δ 13.15(s, 1H), 11.70(s, 1H), 8.61(t, J = 5.3Hz, 1H), 8.26(d, J = 8.3Hz, 2H), 8.15(d, J = 8.9Hz, 2H), 7.97(d, J = 8.3Hz, 2H), 7.87(d, J = 8.4Hz, 1H), 7.71(t, J = 7.6Hz, 1H), 7.54(t, J = 7.5Hz, 1H), 3.70(dd, J = 12.5, 6.4Hz, 2H), 3.65 - 3.60(m, 4H), 2.57(t, J = 6.7Hz, 2H), 2.48(s, 4H) ppm. 13 C NMR(150MHz, DMSO-d6) δ 177.51, 156.80, 154.21, 153.98, 144.13, 141.13, 138.48, 137.35, 133.56, 130.44, 128.76, 127.60, 124.88, 122.88, 121.95, 113.51, 66.82, 56.98, 53.70, 40.84 ppm. HR-MS(m / z)(ESI): calcd for C 24 H 24 N6O3S, [M+H] - : 475.1558; found: 475.1552.

[0173] Example 57: Preparation of Compound 12

[0174] 0.10 g (0.33 mmol) of 5a and 0.040 g (0.39 mmol) of 2-methylthiourea were respectively taken in a 100 mL flask, 50 mL of ethanol was added, 2 drops of acetic acid were added dropwise, heated to reflux, stirred for 10 h, and the reaction was monitored by TLC. After the reaction was completed, it was cooled and filtered, and the filter cake was purified by column chromatography (V DCM :V MeOH = 150:1), and 0.13 g of a pale yellow solid was obtained, with a yield of 48%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.33 (d, J = 8.4 Hz, 2H), 8.11 (dd, J = 13.9, 8.2 Hz, 3H), 7.82 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.09 (s, 2H), 3.45 (s, 3H), 2.37 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 157.60, 156.80, 143.36, 141.30, 130.48, 130.42, 128.84, 128.28, 126.56, 124.94, 124.85, 122.91, 121.97, 113.54, 27.47, 13.64 ppm. HR-MS (m / z) (ESI): calcd for C 20 H 17 N5O2S, [M + H] - : 390.1030; found: 390.1026.

[0175] Example 58: Preparation of Compound 13

[0176] Using 5a and 1-amino-S-methylisothiourea hydroiodide as raw materials, referring to the synthesis method of Compound 12, 0.076 g of a pale yellow solid was obtained, with a yield of 59%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.22 (s, 1H), 9.40 (s, 2H), 8.25 (d, J = 9.8 Hz, 4H), 8.15 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.57 - 7.52 (m, 1H), 2.72 (s, 3H), 2.49 (s, 3H) ppm. 1313C NMR (150 MHz, DMSO-d6) δ 156.82, 154.10, 153.93, 148.79, 144.55, 144.11, 138.55, 130.51, 128.84, 128.35, 128.03, 127.25, 124.92, 122.83, 121.93, 113.55, 15.81, 14.02 ppm. HR-MS (m / z) (ESI): calcd for C 20 H 17 N5O2S, [M+H] - : 390.1030; found: 390.1026.

[0177] Example 59: Preparation of Compound 14

[0178] Using 5a and semicarbazide hydrochloride as starting materials and referring to the synthesis method of Compound 12, 0.053 g of a pale yellow solid was obtained, with a yield of 44%. 1 1H NMR (600 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.31 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 6.54 (s, 2H), 3.51 (s, 1H), 2.23 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 157.68, 157.18, 157.05, 144.00, 139.67, 139.36, 139.10, 138.40, 137.07, 135.17, 128.96, 127.07, 126.82, 126.59, 13.67 ppm. HR-MS (m / z) (ESI): calcd for C 19 H 15 N5O3, [M+H] - : 360.1102; found: 360.1097.

[0179] Example 60: Preparation of Compound 15

[0180] Using 6a and 2-methylthiocarbohydrazide as starting materials and referring to the synthesis method of Compound 1, 0.083 g of a pale yellow solid was obtained, with a yield of 80%. 11H NMR (600 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.65 (d, J = 25.8 Hz, 2H), 8.46 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 8.02 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 3.83 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 181.24, 156.87, 156.83, 154.35, 153.89, 140.47, 138.54, 135.53, 133.25, 131.39, 130.48, 129.65, 126.59, 124.92, 122.89, 121.92, 113.54, 33.25 ppm. HR-MS (m / z) (ESI): calcd for C 19 H 15 N5O2S, [M + H] - : 376.0874; found: 376.0870.

[0181] Example 61: Preparation of Compound 16

[0182] Using 6a and 1-amino-S-methylisothiourea hydroiodide as starting materials and referring to the synthesis method of Compound 1, 0.088 g of a pale yellow solid was obtained, with a yield of 84%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.64 (s, 2H), 8.61 (s, 1H), 8.46 (s, 1H), 8.27 (dd, J = 13.5, 7.8 Hz, 2H), 8.15 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.55 (t, J = 7.5 Hz, 1H), 2.77 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 166.99, 156.81, 154.27, 153.82, 151.50, 144.06, 138.54, 133.64, 131.34, 130.85, 130.51, 129.72, 128.85, 124.93, 122.80, 121.96, 113.54, 14.05 ppm. HR-MS (m / z) (ESI): calcd for C 19 H15 N5O2S, [M+H] - : 376.0874; found: 376.0864.

[0183] Example 62: Preparation of Compound 17

[0184] Using 6a and semicarbazide hydrochloride as raw materials and referring to the synthesis method of Compound 1, 0.077 g of a pale yellow solid was obtained with a yield of 78%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.09 (s, 1H), 10.42 (s, 1H), 8.46 (s, 1H), 8.16 (t, J = 7.5 Hz, 2H), 7.98 - 7.93 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 6.62 (s, 2H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 157.18, 156.82, 153.88, 140.23, 138.62, 135.86, 133.32, 130.46, 129.58, 129.52, 128.90, 127.92, 126.22, 124.89, 124.28, 122.89, 122.02, 113.52 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 13 N5O3, [M+H] - : 346.0946; found: 346.0942.

[0185] Example 63: Preparation of Compound 18

[0186] Using 8a and 2-methylthiocarbohydrazide as raw materials and referring to the synthesis method of Compound 1, 0.087 g of a pale yellow solid was obtained with a yield of 84%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.30 (d, J = 32.6 Hz, 2H), 8.05 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 9.7 Hz, 2H), 7.70 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 3.76 (s, 3H) ppm. 1313C NMR(150 MHz, DMSO-d6) δ 180.73, 159.57, 156.63, 154.34, 153.41, 143.54, 141.25, 138.85, 130.43, 129.91, 128.45, 124.95, 122.58, 121.83, 115.44, 113.52, 67.95, 33.18 ppm. HR-MS (m / z) (ESI): calcd for C 20 H 17 N5O3S, [M + H] - : 406.0979; found: 406.0973.

[0187] Example 64: Preparation of Compound 19

[0188] Using 8a and 1-amino-S-methylisothiourea hydroiodide as starting materials and referring to the synthesis method of Compound 1, 0.083 g of a pale yellow solid was obtained, with a yield of 81%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.22 (s, 1H), 9.48 (s, 2H), 8.29 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 5.21 (s, 2H), 2.73 (s, 3H) ppm. 13 13C NMR(150 MHz, DMSO-d6) δ 166.01, 160.93, 156.63, 154.17, 153.42, 151.90, 143.52, 138.84, 130.76, 130.47, 126.49, 124.98, 122.55, 121.79, 115.70, 113.55, 68.00, 13.89 ppm. HR-MS (m / z) (ESI): calcd for C 20 H 17 N5O3S, [M + H] - : 406.0979; found: 406.0973.

[0189] Example 65: Preparation of Compound 20

[0190] Using 8a and semicarbazide hydrochloride as starting materials and referring to the synthesis method of Compound 1, 0.081 g of a pale yellow solid was obtained, with a yield of 74%. 11H NMR (600 MHz, DMSO-d6) δ 13.18 (s, 1H), 10.12 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.72 - 7.67 (m, 3H), 7.51 (t, J = 7.9 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.43 (s, 2H), 5.14 (s, 2H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 158.94, 157.27, 156.63, 154.41, 153.41, 143.54, 139.32, 138.84, 130.43, 128.83, 128.50, 124.95, 122.59, 121.84, 115.44, 113.52, 67.95 ppm. HR-MS (m / z) (ESI): calcd for C 19 H 15 N5O4, [M + H] - : 376.1051; found: 376.1048.

[0191] Example 66: Preparation of Compound 21

[0192] Using 9a and 1-amino-S-methylisothiourea hydroiodide as starting materials and referring to the synthesis method of Compound 1, 0.12 g of a pale yellow solid was obtained, with a yield of 78%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.39 (s, 2H), 8.05 (d, J = 7.4 Hz, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.72–7.69 (m, 1H), 7.51 (dd, J = 11.2, 3.9 Hz, 1H), 7.17 (dd, J = 25.4, 8.9 Hz, 3H), 5.20 (s, 2H), 2.71 (s, 3H), 2.39 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 170.42, 156.63, 154.31, 153.42, 143.53, 138.82, 130.95, 130.47, 129.66, 124.98, 122.55, 121.81, 115.15, 115.08, 113.55, 67.93, 15.68, 13.99 ppm. HR-MS (m / z) (ESI): calcd for C 21 H 19 N5O3S, [M + H] -: 420.1136; found: 420.1126.

[0193] Example 67: Preparation of Compound 22

[0194] Using 9a and semicarbazide hydrochloride as raw materials and referring to the synthesis method of Compound 1, 0.11 g of a pale yellow solid was obtained, with a yield of 83%. 1 H NMR (600 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.23 (s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.71 - 7.68 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.46 (s, 2H), 5.14 (s, 2H), 2.15 (s, 3H) ppm. 13 C NMR (150 MHz, DMSO-d6) δ 158.54, 157.80, 156.63, 154.51, 153.43, 144.12, 143.55, 138.82, 132.19, 130.43, 127.88, 124.94, 122.58, 121.85, 114.92, 113.52, 67.91, 13.66 ppm. HR-MS (m / z) (ESI): calcd for C 20 H 17 N5O4, [M + H] - : 390.1208; found: 390.1204.

[0195] Example 68: Preparation of Compound 23

[0196] Using 10a and 2-methylthiocarbohydrazide as raw materials and referring to the synthesis method of Compound 1, 0.10 g of a pale yellow solid was obtained, with a yield of 77%. 1 H NMR (600 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 3.4 Hz, 2H), 7.73 - 7.69 (m, 1H), 7.63 (s, 1H), 7.54 (td, J = 7.6, 2.6 Hz, 1H), 7.28 (t, J = 3.2 Hz, 1H), 3.78 (d, J = 2.4 Hz, 3H) ppm. 1313C NMR(150 MHz, DMSO-d6) δ 181.13, 156.77, 153.39, 153.08, 146.97, 145.83, 144.05, 138.32, 130.50, 129.74, 124.96, 122.66, 121.88, 116.42, 115.09, 113.52, 32.98 ppm. HR-MS (m / z) (ESI): calcd for C 17 H 13 N5O3S, [M + H] - : 366.0666; found: 366.0661.

[0197] Example 69: Preparation of Compound 24

[0198] Using 10a and 1-amino-S-methylisothiourea hydroiodide as starting materials and referring to the synthesis method of Compound 1, 0.12 g of a pale yellow solid was obtained, with a yield of 71%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.45 (s, 2H), 8.31 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.75 - 7.73 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 2.73 (s, 3H) ppm. 13 13C NMR(150 MHz, DMSO-d6) δ 178.64, 166.83, 156.78, 153.34, 151.17, 148.32, 145.53, 143.91, 140.89, 138.50, 130.58, 125.03, 122.60, 121.94, 116.59, 113.57, 14.01 ppm. HR-MS (m / z) (ESI): calcd for C 17 H 13 N5O3S, [M + H] - : 366.0666; found: 366.0660.

[0199] Example 70: Preparation of Compound 25

[0200] Using 10a and semicarbazide hydrochloride as starting materials and referring to the synthesis method of Compound 1, 0.10 g of a pale yellow solid was obtained, with a yield of 85%. 11H NMR (600 MHz, DMSO-d6) δ 13.02 (s, 1H), 10.56 (s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.85 (t, J = 4.2 Hz, 2H), 7.70 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 7.64 (d, J = 3.6 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.08 (d, J = 3.7 Hz, 1H), 6.59 (s, 2H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 182.62, 156.83, 156.75, 151.01, 146.23, 145.89, 144.01, 138.19, 130.45, 128.95, 124.89, 122.69, 122.01, 116.51, 113.47, 112.53 ppm. HR-MS (m / z) (ESI): calcd for C 16 H 11 N5O4, [M + H] - : 336.0738; found: 336.0732.

[0201] Example 71: Preparation of Compound 26

[0202] Using 11a and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.087 g of a pale yellow solid was obtained, with a yield of 84%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.48 (t, J = 7.6 Hz, 1H), 5.58 (s, 2H), 3.70 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 180.66, 156.56, 154.21, 153.36, 143.34, 142.50, 138.55, 133.88, 132.71, 130.48, 128.01, 124.91, 122.31, 121.92, 113.46, 48.31, 33.20 ppm. HR-MS (m / z) (ESI): calcd for C 17 H 15 N7O2S, [M + H] -: 380.0935; found: 380.0937.

[0203] Example 72: Preparation of Compound 27

[0204] Using 11a and 1 - amino - S - methylisothiourea hydroiodide as raw materials and referring to the synthesis method of Compound 1, 0.13 g of pale yellow solid was obtained with a yield of 72%. 1 H NMR(600 MHz, DMSO - d6) δ 8.13(s, 1H), 7.94(d, J = 7.6 Hz, 1H), 7.91(s, 1H), 7.59(d, J = 8.3 Hz, 1H), 7.49 - 7.45(m, 2H), 7.30(t, J = 7.4 Hz, 1H), 7.24(s, 1H), 5.36(s, 2H), 4.17(s, 2H), 2.31(s, 3H) ppm. 13 C NMR(150 MHz, DMSO - d6) δ 162.63, 162.11, 161.40, 157.68, 155.16, 144.60, 143.35, 141.74, 140.14, 134.20, 124.31, 122.97, 122.94, 121.68, 112.64, 49.03, 12.61 ppm. HR - MS(m / z)(ESI): calcd for C 17 H 15 N7O2S, [M + H] - : 380.0935; found: 380.0942.

[0205] Example 73: Preparation of Compound 28

[0206] Using 11a and semicarbazide hydrochloride as raw materials and referring to the synthesis method of Compound 1, 0.11 g of pale yellow solid was obtained with a yield of 80%. 1 H NMR(600 MHz, DMSO - d6) δ 13.45(s, 1H), 10.67(s, 1H), 9.30(s, 1H), 7.99(s, 1H), 7.92(d, J = 7.8 Hz, 1H), 7.86 - 7.83(m, 2H), 7.68(t, J = 8.4 Hz, 1H), 7.47(t, J = 7.5 Hz, 1H), 6.64(s, 2H), 5.59(s, 2H) ppm. 1313C NMR (150 MHz, DMSO-d6) δ 156.99, 156.54, 153.20, 152.85, 143.30, 138.61, 130.52, 124.97, 122.29, 122.09, 121.08, 113.51, 50.21 ppm. HR-MS (m / z) (ESI): calcd for C 16 H 13 N7O3, [M+H] - : 350.1007; found: 350.1003.

[0207] Example 74: Preparation of Compound 29

[0208] Using 12a and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.096 g of pale yellow solid was obtained, with a yield of 73%. 1 1H NMR (600 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.72 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.69 - 7.66 (m, 1H), 7.49 (t, J = 7.5 Hz, 1H), 5.88 (s, 1H), 3.56 (s, 2H), 3.10 (s, 3H), 2.74 - 2.69 (m, 2H), 2.46 - 2.41 (m, 2H), 1.70 (t, J = 5.1 Hz, 4H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 178.85, 156.57, 156.53, 153.53, 143.62, 138.65, 130.23, 124.76, 122.76, 121.88, 113.42, 74.11, 60.31, 49.73, 35.03, 34.59 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 20 N6O2S, [M+H] - : 383.1296; found: 383.1292.

[0209] Example 75: Preparation of Compound 30

[0210] Using 12a and 1-amino-S-methylisothiourea hydroiodide as raw materials and referring to the synthesis method of Compound 1, 0.12 g of pale yellow solid was obtained, with a yield of 66%. 11H NMR (600 MHz, DMSO-d6) δ 8.00 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 6.44 (s, 2H), 3.55 (s, 2H), 2.72 (t, J = 5.6 Hz, 2H), 2.70 - 2.66 (m, 2H), 2.60 (t, J = 5.7 Hz, 2H), 2.37 (d, J = 5.8 Hz, 2H), 2.30 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 168.26, 156.57, 153.39, 143.36, 138.77, 130.46, 124.98, 122.50 121.92, 113.53, 53.29, 53.24, 52.25, 30.26, 22.18, 13.59 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 20 N6O2S, [M + H] - : 383.1296; found: 383.1299.

[0211] Example 76: Preparation of Compound 31

[0212] Using 12a and semicarbazide hydrochloride as raw materials and referring to the synthesis method of Compound 1, 0.14 g of a pale yellow solid was obtained with a yield of 71%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.30 (s, 1H), 9.39 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 6.28 (s, 2H), 4.46 (s, 2H), 3.44 (dd, J = 13.9, 6.9 Hz, 8H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 179.14, 157.76, 156.56, 153.13, 143.05, 139.15, 130.56, 125.06, 122.38, 121.93, 113.58, 52.70, 51.12, 25.99, 24.07 ppm. HR-MS (m / z) (ESI): calcd for C 17 H 18 N6O3, [M + H] - : 353.1386; found: 353.1375.

[0213] Example 77: Preparation of Compound 32

[0214] Using 13a and semicarbazide hydrochloride as raw materials and referring to the synthesis method of Compound 1, 0.11 g of a pale yellow solid was obtained, with a yield of 69%. 1 H NMR(600MHz,DMSO-d6)δ13.32(s,1H),11.34(s,1H),9.48(s,2H),8.11(t,J=8.6Hz,1H),7.88(d,J=8.4Hz,1H),7.72(t,J=7.3Hz,1H),7.54(t,J=7.6Hz,1H),6.35(s,2H),4.60(s,2H),4.15(s,2H),2.77(s,2H)ppm. 13 C NMR(150MHz,DMSO-d6)δ157.30,157.22,156.59,156.56,153.12,143.82,142.99,138.89,130.58,125.03,121.92,113.59,56.47,56.39,53.69,26.65ppm.HR-MS(m / z)(ESI):calcd for C 16 H 16 N6O3,[M+H] - :339.1211;found:339.1209.

[0215] Example 78: Preparation of Compound 33

[0216] Using 4b and 2-methylthiocarbohydrazide as raw materials and referring to the synthesis method of Compound 1, 0.12 g of a yellow solid was obtained, with a yield of 79%. 1 HNMR(600MHz,DMSO-d6)δ13.18(s,1H),8.50(d,J=47.9Hz,2H),8.22(d,J=8.2Hz,2H),8.13(dd,J=8.2,4.3Hz,3H),8.06(s,1H),7.96(s,1H),7.57-7.54(m,1H),3.82(s,3H)ppm. 13 C NMR(150MHz,DMSO-d6)δ181.22,156.79,154.61,153.72,143.61,140.30,139.05,137.71,134.72,133.20,128.62,128.30,125.46,123.06,121.93,113.94,33.32ppm.HR-MS(m / z)(ESI):calcd for C 19H 14 ClN5O2S, [M+H] - : 410.0484; found: 410.0473.

[0217] Example 79: Preparation of Compound 34

[0218] Using 4c and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.11 g of yellow solid was obtained with a yield of 75%. 1 HNMR(600 MHz, DMSO-d6) δ 13.22(s, 1H), 8.51(d, J = 44.7 Hz, 2H), 8.22(d, J = 6.4 Hz, 3H), 8.14(d, J = 8.3 Hz, 2H), 8.07(d, J = 8.3 Hz, 1H), 7.97(s, 1H), 7.69(d, J = 8.2 Hz, 1H), 3.82(s, 3H) ppm. 13 C NMR(150 MHz, DMSO-d6) δ 181.22, 156.94, 154.64, 153.75, 143.64, 140.34, 137.74, 129.99, 129.27, 128.66, 128.34, 128.17, 123.38, 122.95, 122.26, 116.84, 33.34 ppm. HR-MS(m / z)(ESI): calcd for C 19 H 14 BrN5O2S, [M+H] - : 453.9979; found: 453.9967.

[0219] Example 80: Preparation of Compound 35

[0220] Using 4f and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.11 g of yellow solid was obtained with a yield of 86%. 1 HNMR(600 MHz, DMSO-d6) δ 13.20(s, 1H), 8.51(d, J = 43.6 Hz, 2H), 8.23(d, J = 8.3 Hz, 2H), 8.15(d, J = 8.4 Hz, 2H), 7.97(s, 1H), 7.95 - 7.91(m, 2H), 7.57(td, J = 9.1, 2.6 Hz, 1H), 3.82(s, 3H) ppm. 1313C NMR(150 MHz, DMSO-d6) δ 181.22, 160.32, 158.73, 154.27, 153.87, 153.04, 143.89, 140.35, 137.71, 133.24, 128.64, 128.33, 123.89 (d, J=10.5 Hz), 118.26 (d, J=26.2 Hz), 115.12 (d, J=9.5 Hz), 107.45 (d, J=25.4 Hz), 33.33 ppm. HR-MS (m / z) (ESI): calcd for C 19 H 14 FN5O2S, [M+H] - : 394.0779; found: 394.0770.

[0221] Example 81: Preparation of Compound 36

[0222] Using 4g and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.12 g of yellow solid was obtained, with a yield of 81%. 1 1H NMR (600 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.24 (d, J=8.3 Hz, 2H), 8.19 (d, J=1.9 Hz, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.98 (s, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.74 (dd, J=8.9, 2.0 Hz, 1H), 3.82 (s, 3H) ppm. 13 13C NMR(150 MHz, DMSO-d6) δ 181.21, 155.18, 154.50, 153.83, 143.20, 140.35, 139.62, 137.76, 133.18, 130.32, 129.34, 128.66, 128.34, 124.46, 121.27, 115.34, 33.34 ppm. HR-MS (m / z) (ESI): calcd for C 19 H 14 ClN5O2S, [M+H] - : 410.0484; found: 410.0475.

[0223] Example 82: Preparation of Compound 37

[0224] Using 4h and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.11 g of yellow solid was obtained, with a yield of 75%. 1HNMR(600MHz, DMSO-d6) δ 13.23(s, 1H), 8.52(d, J = 40.3Hz, 2H), 8.30(s, 1H), 8.23(d, J = 8.1Hz, 2H), 8.15(d, J = 8.2Hz, 2H), 7.97(s, 1H), 7.86(d, J = 5.2Hz, 2H), 3.82(s, 3H) ppm. 13 C NMR(150MHz, DMSO-d6) δ 181.17, 155.54, 154.48, 153.80, 143.07, 140.36, 139.39, 137.77, 133.15, 132.99, 128.66, 128.35, 124.99, 124.26, 117.13, 115.73, 33.34 ppm. HR-MS(m / z)(ESI): calcd for C 19 H 14 BrN5O2S, [M + H] - : 453.9979; found: 453.9971.

[0225] Example 83: Preparation of Compound 38

[0226] Using 12b and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.11 g of pale yellow solid was obtained with a yield of 85%. 1 H NMR(600MHz, DMSO-d6) δ 12.66(s, 1H), 8.73(s, 1H), 8.07 - 8.05(m, 2H), 7.53(dd, J = 8.4, 1.7Hz, 1H), 5.87(s, 1H), 3.55(s, 2H), 3.11(s, 3H), 2.74 - 2.69(m, 2H), 2.46 - 2.41(m, 2H), 1.70(t, J = 4.8Hz, 4H) ppm. 13 C NMR(150MHz, DMSO-d6) δ 178.82, 156.97, 156.57, 153.37, 143.09, 139.29, 134.52, 125.38, 123.04, 121.80, 113.91, 74.09, 60.28, 49.73, 35.01, 34.55 ppm. HR-MS(m / z)(ESI): calcd for C 18 H 19 ClN6O2S, [M + H] - : 417.0906; found: 417.0904.

[0227] Example 84: Preparation of Compound 39

[0228] Using 12c and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.10 g of pale yellow solid was obtained with a yield of 78%. 1 H NMR(600MHz,DMSO-d6)δ12.66(s,1H),8.73(s,1H),8.20(s,1H),7.99(d,J=8.1Hz,1H),7.66(d,J=7.9Hz,1H),5.87(s,1H),3.55(s,2H),3.11(s,3H),2.70(s,2H),2.44(s,2H),1.70(s,4H)ppm. 13 C NMR(150MHz,DMSO-d6)δ178.84,157.00,156.74,153.40,143.15,139.11,128.08,123.34,122.74,122.14,116.78,74.09,60.28,49.73,35.02,34.56ppm.HR-MS(m / z)(ESI):calcd for C 18 H 19 BrN6O2S,[M+H] - :461.0401;found:461.0393.

[0229] Example 85: Preparation of Compound 40

[0230] Using 12d and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.12 g of pale yellow solid was obtained with a yield of 80%. 1 H NMR(600MHz,DMSO-d6)δ12.51(s,1H),8.72(s,1H),7.91(d,J=8.0Hz,1H),7.64(s,1H),7.32(d,J=8.1Hz,1H),5.86(s,1H),3.54(s,2H),3.10(s,3H),2.73-2.69(m,2H),2.51(s,3H),2.46-2.41(m,2H),1.70(t,J=4.9Hz,4H)ppm. 13 C NMR(150MHz,DMSO-d6)δ178.85,157.06,156.42,153.43,143.77,140.80,138.22,126.21,121.37,120.25,113.25,74.11,60.31,49.74,35.02,34.59,22.04ppm.HR-MS(m / z)(ESI):calcd for C19 H 22 N6O2S, [M+H] - : 397.1452; found: 397.1444.

[0231] Example 86: Preparation of Compound 41

[0232] Using 12e and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.15 g of pale yellow solid was obtained with a yield of 78%. 1 H NMR (600 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.73 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.7, 2.2 Hz, 1H), 5.86 (s, 1H), 3.89 (s, 3H), 3.53 (s, 2H), 3.10 (s, 3H), 2.73 - 2.69 (m, 2H), 2.45 - 2.40 (m, 2H), 1.70 (t, J = 5.1 Hz, 4H) ppm. 13 C NMR (150 MHz, DMSO-d6) δ 178.83, 161.96, 158.33, 156.51, 153.05, 144.06, 137.89, 122.25, 115.59, 114.30, 97.25, 74.11, 60.29, 56.39, 49.74, 35.01, 34.58 ppm. HR-MS (m / z) (ESI): calcd for C 19 H 22 N6O3S, [M+H] - : 413.1401; found: 413.1393.

[0233] Example 87: Preparation of Compound 42

[0234] Using 12f and 2-methylthiourea as raw materials and referring to the synthesis method of Compound 1, 0.12 g of pale yellow solid was obtained with a yield of 84%. 1 HNMR (600 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.74 (s, 1H), 8.08 (dd, J = 8.3, 5.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 8.3 Hz, 1H), 5.88 (s, 1H), 3.56 (s, 2H), 3.11 (s, 3H), 2.72 (s, 2H), 2.44 (s, 2H), 1.70 (s, 4H) ppm. 1313C NMR(150 MHz, DMSO-d6) δ 178.83, 164.29, 162.66, 156.88 (d, J = 14.4 Hz), 153.19, 143.36, 139.36 (d, J = 2.9 Hz), 123.21 (d, J = 10.6 Hz), 119.47, 113.49, 113.32, 101.37, 101.19, 74.09, 60.26, 49.73, 35.01, 34.56 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 19 FN6O2S, [M+H] - : 401.1201; found: 401.1199.

[0235] Example 88: Preparation of Compound 43

[0236] Using 12 g and 2-methylthiourea as starting materials, referring to the synthesis method of Compound 1, 0.12 g of light yellow solid was obtained, with a yield of 85%. 1 1H NMR (600 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.73 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.9, 2.1 Hz, 1H), 5.87 (s, 1H), 3.55 (s, 2H), 3.11 (s, 3H), 2.74 - 2.69 (m, 2H), 2.47 - 2.41 (m, 2H), 1.70 (t, J = 4.7 Hz, 4H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 178.84, 156.82, 154.94, 153.45, 142.71, 139.84, 130.11, 129.22, 124.28, 121.16, 115.24, 74.09, 60.23, 49.73, 35.02, 34.56 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 19 ClN6O2S, [M+H] - : 417.0906; found: 417.0903.

[0237] Example 89: Preparation of Compound 44

[0238] Using 12 h and 2-methylthiourea as starting materials, referring to the synthesis method of Compound 1, 0.13 g of light yellow solid was obtained, with a yield of 89%. 11H NMR (600 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.75 (s, 1H), 8.21 (s, 1H), 7.84 - 7.81 (m, 2H), 5.88 (s, 1H), 3.55 (s, 2H), 3.11 (s, 3H), 2.70 (s, 2H), 2.44 (s, 2H), 1.70 (s, 4H) ppm. 13 13C NMR (150 MHz, DMSO-d6) δ 178.81, 156.88, 155.32, 153.47, 142.56, 139.64, 132.83, 124.86, 124.19, 117.04, 115.69, 74.09, 60.27, 49.71, 35.00, 34.56 ppm. HR-MS (m / z) (ESI): calcd for C 18 H 19 BrN6O2S, [M + H] - : 461.0401; found: 461.0391.

[0239] Example 90: Evaluation of the Enzyme Inhibitory Activity of the Target Compound

[0240] 1. Experimental Method

[0241] The inhibitory effect of the compound on exogenous enzyme activity was detected by a commercial PARP and PARP-1 enzyme-linked immunosorbent assay kit provided by Shanghai Fusheng Industrial Co., Ltd., and the operation was specifically carried out according to the instruction manual provided in the kit. The experimental steps are briefly described as follows: The experiment was set up with a blank group, a test group, and a positive control group. The target protein dilution was added to each well, and a 1 μmol / L solution of the test compound and the positive control drug Olaparib were added to the test group and the positive control group, respectively. After sealing the plate, it was incubated in an incubator at 37 °C for 2 h. After washing 5 times with the washing solution, except for the blank group, 50 μL of the enzyme-labeled reagent was added to each well, and the plate was sealed and incubated in an incubator at 37 °C for another 30 min. After completion, 50 μL of chromogenic reagent A was added first, and then 50 μL of chromogenic reagent B was added, and it was gently shaken and mixed well, and incubated at 37 °C in the dark for 10 min. Finally, 50.0 μL of the termination solution was added to each well. Using the blank well as zero adjustment, the absorbance (OD value) of each well was measured in sequence at a wavelength of 490 nm with an enzyme-labeled instrument. Each compound was independently experimented in parallel three times, and the results were averaged over the three experiments to calculate the inhibition rate.

[0242] 2. Experimental Results

[0243] Table 1. Inhibition Rates of Compounds 1 - 44 (1 μM) on PARP Enzyme Activity

[0244]

[0245] Table 2. Inhibition rate of compounds (1 μM) on PARP-1 enzyme activity

[0246]

[0247] As can be seen from Table 1:

[0248] (1) At a concentration of 1 μM, the inhibition rate of olaparib on PARP enzyme activity was only 57.65%, and among the compounds tested, 27 compounds had an inhibition rate higher than that of olaparib. Among them, the inhibition rates of compounds 3, 4, 6, 7, 9, 11, 21, 24, and 29 were between 80% and 89%, and the inhibition rates of compounds 2, 8, 12, and 30 exceeded 90%. Compound 8 showed the best performance, with an inhibition rate as high as 98.60%, which was 1.7 times that of olaparib. Analysis of the structure-activity relationship of these compounds showed that using thiosemicarbazide as an active fragment and terephthalaldehyde bound to the benzofuran pyrimidinone parent structure could effectively improve the inhibition of compounds on PARP enzyme activity. For example, the inhibition rate of compound 1 was 60.27%, higher than that of olaparib; when the NH group in the thiosemicarbazide structure was mono-substituted, whether using short-chain alkyl or aryl groups helped to improve the activity of the compound. For example, the inhibition rates of compounds 2, 3, 4, 9, and 11 were significantly higher than that of compound 1; however, when the NH2 group in the thiosemicarbazide structure was di-substituted, the activity of the compound would be significantly reduced. For example, the inhibition rate of compound 5 was only 15%, indicating that the NH group in the thiosemicarbazide terminal structure fragment of the compound plays an important role in maintaining the biological activity of the compound. In addition, when semicarbazide (compound 6) or aminoguanidine (compound 7) was used to replace the thiosemicarbazide fragment, the compound still had good inhibitory activity.

[0249] (2) When using 2-methylthiosemicarbazide, semicarbazide, and 1-amino-S-methylisothiourea as active fragments to explore the influence of different linkers on the activity of compounds, it was found that when terephthalaldehyde was replaced with p-acetylbenzaldehyde and piperidin-4-one, the inhibition of compounds on PARP enzyme activity could be basically maintained. For example, the inhibition rates of compounds 12 and 30 reached 90.13% and 92.98% respectively. However, when the position of the substituent in the linker (isophthalaldehyde) was changed or a five-membered heterocycle (furan-2,5-dialdehyde, 4-imidazolecarboxaldehyde, or 3-pyrrolidinone) was used, the inhibition of compounds on PARP enzyme activity would be reduced. For example, among compounds 13-32, except for compounds 21, 24, 29, and 30, the inhibition rates of the remaining compounds were lower than 80%. In addition, when using piperidin-4-one as the linker, the activity was the best when the terminal of the compound was 2-methylthiosemicarbazide and 1-amino-S-methylisothiourea. For example, the inhibition rates of compounds 29 and 30 were greater than 86%.

[0250] (3) When terephthalaldehyde and piperidin-4-one are selected as the linker and 2-methylaminothiourea as the active fragment, introducing different substituents into the benzene ring of the benzofuran pyrimidinone structure can have a significant impact on the activity of the compound. It is found that whether an electron-withdrawing group (-F, -Cl, and -Br) is introduced, or an electron-donating group (-CH3 and -OCH3) is introduced, or the position of the substituent is changed, the activity of the compound will be greatly reduced.

[0251] As can be seen from Table 2, the measured compounds also showed relatively excellent inhibitory effects on PARP-1 enzyme activity. At a concentration of 1 μM, the inhibition rates of compounds 2, 8, 12, 16, 19, 27, 28, and 31 on PARP-1 enzyme activity were between 50% and 60%; the inhibition rates of compounds 6, 13, 14, 15, 17, 18, 20, 22, 25, 30, 32, and 40 on PARP-1 enzyme activity were between 60% and 80%; the inhibition rates of compounds 3, 4, 9, 11, 21, 26, and 29 on PARP-1 enzyme activity all exceeded 80%. Among the measured compounds, compound 4 had the highest inhibition rate on PARP-1, reaching 97.45%, higher than 86.37% of olaparib.

[0252] Example 91: Evaluation of the in vitro cytotoxic activity of the compound

[0253] 1. Experimental method

[0254] The MTT method was used to test the cytotoxic activity of the compounds of the present invention. Cells in the logarithmic growth phase were counted and inoculated into a 96-well culture plate, with about 8000 - 10000 cells per well. After culturing overnight, the cells were administered drugs after they adhered to the wall, and the drug administration group and the control group were set respectively. The compounds to be tested were prepared into stock solutions with DMSO solution and diluted into a series of concentrations with cell culture medium before use, where the final concentration of DMSO did not exceed 4‰. Three replicates were set for each concentration. After adding the drug, the cells were cultured for 72 h, 20 μL of MTT with a concentration of 5 mg / mL was added, and incubated at 37 °C for 4 h. The supernatant was removed, and 150 μL of DMSO was added to dissolve. The OD value of each well was measured with an enzyme-labeled instrument at a wavelength of 490 nm, the inhibition rate was calculated, and a concentration-inhibition rate curve was made to calculate the IC 50 value.

[0255] 2. Experimental results

[0256] Table 3. Antiproliferative activities of representative compounds against cancer cells

[0257]

[0258] As can be seen from Table 3, most of the representative compounds showed good antiproliferative activities against the five types of cancer cells tested, and also had relatively low toxicity to normal cells. Except for compounds 7 and 11, the IC of the remaining compounds against normal hepatocytes L0250 The values are all greater than 50 μM, and the IC 50 values of some compounds exceed 100 μM, showing low toxicity. The tested compounds are relatively sensitive to ovarian cancer cells. Among them, the IC 50 values of compounds 3, 4, 8, 21, and 29 against SK-OV-3 cells are lower than 10 μM. Compound 4 shows the best performance, and its anti-proliferative activity is twice that of olaparib. In addition, compounds 4, 8, and 29 are relatively sensitive to colorectal cancer cell line HCT-116, compounds 6, 9, and 21 are relatively sensitive to triple-negative breast cancer cell line MDA-MB-231, and compound 8 is relatively sensitive to ovarian cancer cell line A2780. Their cytotoxicity is comparable to or better than that of olaparib.

[0259] In summary, the present invention uses benzofuran pyrimidinone as the parent compound and different aromatic compounds as linkers, which react with the parent compound and thiosemicarbazide and its analogs, semicarbazide or aminoguanidine respectively to obtain a class of novel compounds. This class of compounds has excellent inhibitory effects on PARP enzyme activity and PARP-1 enzyme activity, and shows good anti-proliferative activity against various cancer cells. The inhibitory effects of some compounds are better than those of the positive drug olaparib. For example, compounds 3 and 4 are better than olaparib in both enzyme inhibition activity and anti-proliferative activity against SK-OV-3 cells, and can be used for the preparation of anti-tumor drugs.

Claims

1. A tricyclic compound, characterized in that, Selected from any one of the following compounds:

2. A pharmaceutically acceptable salt of the tricyclic compound according to claim 1, characterized in that, The pharmaceutically acceptable salt is a salt formed by the compound and an acid selected from any one of the following: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.

3. A method for preparing the tricyclic compound according to claim 1, characterized in that (1) Compound 3a is cyclized with terephthalaldehyde, and then compound 4a is condensed with R1-NH2 to obtain compounds 1 to 11; (2) Compound 3a is cyclized with p-acetylbenzaldehyde, isophthalaldehyde, 2,4-dialdehyde furan respectively, and then compounds 5a-6a, 10a are condensed with R1-NH2 to obtain compounds 12 to 17, compounds 23 to 25; or compound 3a is cyclized with 2-chloro-1,1,1-trimethoxyethane, and then compounds 7a are coupled with 4-hydroxybenzaldehyde, 4-hydroxybenzophenone, 2-aldehyde imidazole, 4-piperidone, 3-pyrrolidone respectively, and finally compounds 8a-9a, 11a-13a are condensed with R1-NH2 to obtain compounds 18 to 22, compounds 26 to 32; (3) Compounds 3b-3h are cyclized with terephthalaldehyde respectively, and then compounds 4b-4c, 4f-4h are condensed with R1-NH2 to obtain compounds 33 to 37; or compounds 3b-3h are cyclized with 2-chloro-1,1,1-trimethoxyethane respectively, and then compounds 7b-7h are coupled with 4-piperidone, and finally compounds 12b-12h are condensed with R1-NH2 to obtain compounds 38 to 44; R1 is selected from R2 is selected from fluorine, chlorine, bromine, methyl, and methoxy.

4. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the tricyclic compound according to claim 1 and a pharmaceutically acceptable carrier.

5. Use of the tricyclic compound according to claim 1 or the pharmaceutical composition according to claim 4 in the preparation of a PARP inhibitor drug.

6. The application according to claim 5, characterized in that, The drug is a PARP-1 inhibitor drug.

7. The application according to claim 5, wherein The drug is an anti-tumor drug.

8. The application according to claim 7, wherein The drug is a drug for treating ovarian cancer, colon cancer, breast cancer, triple-negative breast cancer.

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