A pyrazoloazoxadiazepine compound, its preparation method and use

Abstract

The present invention provides a pyrazolo[1,5-a]pyrimidine-7-oxide compound, a preparation method and uses thereof, belonging to the field of chemical drugs. The structure of the pyrazolo[1,5-a]pyrimidine-7-oxide compound is shown in Formula I. Experimental results show that such compounds can effectively inhibit the growth of various tumor cells including lung cancer cells, breast cancer cells, prostate cancer cells, bladder cancer cells, and esophageal cancer cells, and have broad application prospects in the preparation of drugs for preventing and / or treating tumors.

Description

Technical Field

[0001] The present invention belongs to the field of chemical drugs, and particularly relates to a pyrazolo[1,5 - a]pyrrolo[3,4 - c]pyridazine compound, a preparation method thereof and uses thereof. Background Art

[0002] Malignant tumors are a kind of diseases that seriously endanger human health. With the increasing exposure of people to chemical, radioactive, viral and other carcinogens, the incidence rate is increasing day by day. Chemotherapy is an important means for treating malignant tumors.

[0003] Paclitaxel is a drug with good anti - tumor effects after doxorubicin and cisplatin. It has greatly improved the treatment efficiency of various tumors and has extremely high development and utilization value. Currently, paclitaxel is used to treat various types of tumors, including bladder cancer, breast cancer, esophageal cancer, gastric cancer, lung cancer, ovarian cancer and prostate cancer. However, due to the emergence of drug resistance, its clinical efficacy is greatly limited. Therefore, there is an urgent need to develop new anti - tumor drugs. Summary of the Invention

[0004] The purpose of the present invention is to provide a pyrazolo[1,5 - a]pyrrolo[3,4 - c]pyridazine compound, a preparation method thereof and uses thereof.

[0005] The present invention provides a pyrazolo[1,5 - a]pyrrolo[3,4 - c]pyridazine compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and the structure of the compound is shown in Formula I:

[0006]

[0007] Wherein, R1 is selected from hydrogen and the following groups substituted by 0, 1, 2, 3 or 4 R5: phenyl, naphthyl, 5 - to 6 - membered heteroaryl, C 1-8 alkyl; each R5 is independently selected from C 1-8 alkyl, halogen - substituted C 1-8 alkyl, C 1-8 alkoxy, halogen - substituted C 1-8 alkoxy, C 1-8 alkylthio, halogen - substituted C 1-8 alkylthio, halogen, nitro, cyano, hydroxyl, carboxyl;

[0008] R2 is selected from hydrogen, C 1-8 alkyl, halogen - substituted C 1-8 alkyl, C 1-8 alkoxy, halogen - substituted C 1-8 alkoxy, C 1-8 alkylthio, halogen - substituted C 1-8 alkylthio, halogen, nitro, cyano, hydroxyl, carboxyl;

[0009] R3 is X1X2R6, where X1 is selected from nothing, O, S, and X2 is selected from nothing, C 1-8 alkylene, and R6 is selected from hydrogen, phenyl, naphthyl, 5- to 6-membered heteroaryl, C 1-8 alkyl;

[0010] R4 is selected from X3R8 substituted with 0, 1, 2, 3, or 4 R7s, and each R7 is independently selected from C 1-8 alkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkoxy, halogen-substituted C 1-8 alkoxy, C 1-8 alkylthio, halogen-substituted C 1-8 alkylthio, halogen, nitro, cyano, hydroxy, carboxy, and X3 is selected from nothing, C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, and R8 is selected from hydrogen, phenyl, naphthyl, 5- to 6-membered heteroaryl.

[0011] Furthermore, R1 is selected from hydrogen and the following groups substituted with 0, 1, 2, or 3 R5s: phenyl, naphthyl; and each R5 is independently selected from C 1-5 alkyl, halogen-substituted C 1-5 alkyl, C 1-5 alkoxy, halogen-substituted C 1-5 alkoxy, halogen.

[0012] Furthermore, R2 is selected from hydrogen, C 1-5 alkyl, halogen-substituted C 1-5 alkyl, C 1-5 alkoxy, halogen-substituted C 1-5 alkoxy, halogen.

[0013] Furthermore, R3 is X1X2R6, where X1 is selected from nothing, O, S, and X2 is selected from nothing, C 1-5 alkylene, and R6 is selected from hydrogen, phenyl, naphthyl, C 1-5 alkyl.

[0014] Furthermore, R4 is selected from X3R8 substituted with 0, 1, 2, or 3 R7s, and each R7 is independently selected from C 1-5 alkyl, halogen-substituted C 1-5 alkyl, C 1-5 alkoxy, halogen-substituted C 1-5 alkoxy, C 1-5 alkylthio, halogen-substituted C 1-5 alkylthio, halogen, nitro, cyano, and X3 is selected from nothing, C 1-5 alkylene, C 2-5 alkenylene, C 2-5An alkynylene group, and R8 is selected from hydrogen, phenyl, naphthyl, and 5- to 6-membered heteroaryl groups.

[0015] Furthermore, the structure of the compound is shown in Formula II or Formula III:

[0016]

[0017] Wherein, R4 is selected from X3R8 substituted with 0, 1, 2, or 3 R7 groups, and each R7 is independently selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl, C 1-3 alkoxy, halogen-substituted C 1-3 alkoxy, C 1-3 alkylthio, halogen-substituted C 1-3 alkylthio, halogen, nitro, cyano, and X3 is selected from none, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, and R8 is selected from phenyl, naphthyl, and 5- to 6-membered heteroaryl groups.

[0018] Furthermore, the compound is selected from:

[0019]

[0020] The present invention also provides a method for preparing the above-mentioned pyrazolo[1,5-a]pyrrolo[3,4-c]pyridazine-5,7-dione compound, its pharmaceutically acceptable salt, or its stereoisomer, and the method includes the following steps:

[0021] (1) Reacting compound d with compound e to obtain compound f;

[0022] (2) Reacting compound f with R4CHO to obtain compound g;

[0023] (3) Reacting compound g with compound c under the action of a base to obtain the compound shown in Formula I;

[0024]

[0025] Wherein, R1-R4 are as described above.

[0026] The present invention also provides a pharmaceutical composition for preventing and / or treating tumors, and the pharmaceutical composition is a preparation prepared from the above-mentioned pyrazolo[1,5-a]pyrrolo[3,4-c]pyridazine-5,7-dione compound, its pharmaceutically acceptable salt, or its stereoisomer as an active ingredient, plus pharmaceutically acceptable excipients.

[0027] The present invention also provides the use of the above-mentioned pyrazolo[1,5-a]pyrimidine-6,8-dione compounds, their pharmaceutically acceptable salts or their stereoisomers in the preparation of drugs for preventing and / or treating tumors; the tumors are preferably lung cancer, breast cancer, prostate cancer, bladder cancer, and esophageal cancer.

[0028] Definition of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to such groups or terms throughout the specification; for terms not specifically defined herein, meanings that can be given to them by those skilled in the art should be provided based on the disclosure and context.

[0029] The minimum and maximum carbon atom contents in a hydrocarbon group are indicated by a prefix. For example, the prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, "C 1-8 alkyl" refers to a straight-chain or branched-chain alkyl group containing 1-8 carbon atoms, and "C 1-8 alkylene" refers to a straight-chain or branched-chain alkylene group containing 1-8 carbon atoms, and "C 2-8 alkenylene" refers to a straight-chain or branched-chain alkenylene group containing 2-8 carbon atoms, and "C 2-8 alkynylene" refers to a straight-chain or branched-chain alkynylene group containing 2-8 carbon atoms.

[0030] "Halogen" is fluorine, chlorine, bromine or iodine.

[0031] "Heteroaryl" refers to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to here include oxygen, sulfur, and nitrogen. "5-6-membered heteroaryl" refers to a heteroaryl group having 5 or 6 ring atoms. For example,

[0032] "Pharmaceutically acceptable" means that a certain carrier, vehicle, diluent, excipient, and / or the formed salt is generally chemically or physically compatible with other components constituting a pharmaceutical dosage form and is physiologically compatible with the receptor.

[0033] "Salt" refers to acid salts and / or basic salts formed by reacting a compound with inorganic and / or organic acids and / or bases, also including zwitterionic salts (inner salts), and also including quaternary ammonium salts such as alkylammonium salts. These salts can be directly obtained in the final separation and purification of the compound. They can also be obtained by appropriately mixing (for example, in an equivalent amount) the compound with a certain amount of acid or base. These salts may form a precipitate in solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by lyophilization after reaction in an aqueous medium.

[0034] The "pharmaceutically acceptable salts" in the present invention may be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0035] In the present invention, Ph represents phenyl and Bn represents benzyl.

[0036] The pyrazoloazoxabicyclic compounds provided by the present invention have the following novel parent nucleus structure: The experimental results show that such compounds can effectively inhibit the growth of various tumor cells including lung cancer cells, breast cancer cells, prostate cancer cells, bladder cancer cells and esophageal cancer cells, and have broad application prospects in the preparation of drugs for preventing and / or treating tumors.

[0037] The preparation method of the pyrazoloazoxabicyclic compounds of the present invention is simple, the reaction is mild, and the yield is high, which is suitable for industrial production.

[0038] Obviously, based on the above content of the present invention, according to the common general technical knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0039] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. Specific Embodiments

[0040] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0041] The pyrazoloazoxabicyclic compounds 1-24 of the present invention are prepared according to the following route:

[0042]

[0043]

[0044] Example 1: Preparation of Compound 1

[0045] 1. Preparation of Substrate

[0046] 1.1 Preparation of Substrate c

[0047]

[0048] In a 250 mL three-necked flask, successively add O-benzylhydroxylamine a (12.3 g, 0.1 mol, 1 equiv.), triethylamine (10.1 g, 0.1 mol, 1 equiv.) and 100 mL of anhydrous dichloromethane. Cool to 0 °C in an ice bath and slowly add dropwise bromoacetyl bromide b (20.2 g, 0.1 mol, 1 equiv.). After the addition is complete, maintain the reaction at 0 °C for 6 hours. Monitor the reaction by TLC until it is complete. Add a little water (about 10 mL) to quench the reaction, then raise the temperature to room temperature. Add 100 mL of water, separate the phases, take the dichloromethane phase, and then extract the aqueous phase twice with 60 mL of dichloromethane. Combine the dichloromethane phases, wash the organic phase twice with 50 mL of water, and dry the organic phase with anhydrous magnesium sulfate. Concentrate to remove the dichloromethane solvent, and purify the residue by column chromatography to obtain compound c

[0049] 18.2 g, yield 74.6%.

[0050] 1.2 Preparation of substrate g1

[0051]

[0052] In a 500 mL three-necked flask, using acetic acid (150 mL) as the solvent, add phenylhydrazine d1 (10.8 g, 0.1 mol, 1 equiv.) and ethyl trifluoroacetoacetate e (18.4 g, 0.1 mol, 1 equiv.). Heat to 130 °C and reflux for 6 - 7 hours. After the reaction is complete, cool in an ice bath, and a solid will precipitate in the system. Filter, wash the filter cake with petroleum ether 1 - 2 times, and dry to obtain a light white intermediate f1. Then directly react the intermediate f1 (2.3 g, 0.01 mol, 1 equiv.) with benzaldehyde (1.3 g, 0.012 mol, 1.2 equiv.) at 160 - 170 °C without solvent for 4 - 6 h. Then cool to room temperature, add anhydrous ether (6 mL) and grind it fine with a steel knife and filter to obtain a dark brown filter cake. Recrystallize in n-heptane (10 mL), filter and dry to obtain a light brown solid powder g1 (1.6 g), and the reaction yield is 88%.

[0053] 2. Preparation of target compound 1

[0054]

[0055] In a reaction tube, add substrate g1 (0.1 mmol, 1 equiv.), substrate c (0.15 mmol, 1.5 equiv.) and potassium carbonate (0.15 mmol, 1.5 equiv.). React at room temperature for 15 - 30 minutes. Monitor the reaction by TLC until completion. Concentrate under reduced pressure. Then add 2 - 3 mL of water and extract twice with 3 mL of ethyl acetate. Combine the ethyl acetate phases, dry over anhydrous magnesium sulfate and concentrate to dryness. Purify by column chromatography to obtain compound 1 with a yield of 88 - 94%.

[0056] Example 2 - 14: Preparation of Compounds 2 - 24

[0057] Referring to the method for preparing compound 1 in Example 1, replace the raw materials correspondingly to prepare compounds 2 - 24.

[0058] The structures and characterization data of compounds 1 - 24 are as follows:

[0059] 5-(benzyloxy)-1,4-diphenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 1

[0060]

[0061] 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.69 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.44–7.27 (m, 8H), 7.26–7.20 (m, 3H), 5.78 (s, 1H), 5.15 and 5.10 (ABq, J = 11.2 Hz, 2H), 4.52 (d, J = 12.8 Hz, 1H), 4.24 (d, J = 12.8 Hz, 1H).

[0062] 13 C NMR (100 MHz, CDCl3) δ (ppm): 164.3, 151.2, 140.2, 138.7 (q, J = 37.6 Hz, 1C), 137.1, 134.5, 130.2, 129.44, 129.39, 129.1, 128.7, 128.6, 128.2, 126.4, 122.6, 121.0 (q, J = 269.3 Hz, 1C), 96.7, 77.2, 71.5, 61.2.

[0063] 19 F NMR (376 MHz, CDCl3) δ (ppm): -61.749.

[0064] HRMS(ESI): m / z calculated for C 26 H 20 F3N3O3 + H + : 480.1530, found: 480.1516.

[0065] 5-(benzyloxy)-4-(4-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 2

[0066]

[0067] 1 H NMR(400 MHz, CDCl3) δ (ppm): 7.69 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.44–7.33 (m, 3H), 7.25–7.17 (m, 5H), 6.87–6.82 (m, 2H), 5.73 (s, 1H), 5.13 and 5.09 (ABq, J = 11.2 Hz, 2H), 4.52 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 3.77 (s, 3H).

[0068] 13 C NMR(100 MHz, CDCl3) δ (ppm): 164.3, 159.7, 151.2, 138.5 (q, J = 36.8 Hz, 1C), 137.1, 134.5, 132.3, 130.5, 130.2, 129.4, 128.5, 128.2, 127.7, 122.6, 121.0 (q, J = 269.3 Hz, 1C), 114.4, 97.0, 77.4, 71.5, 60.8, 55.4.

[0069] 19 F NMR(376 MHz, CDCl3) δ (ppm): -61.837.

[0070] HRMS(ESI): m / z calculated for C 27 H 22 F3N3O4 + H + : 510.1635, found: 510.1623.

[0071] 5-(benzyloxy)-4-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 3

[0072]

[0073] 1 H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J=7.6Hz,2H),7.51(t,J=7.2Hz,2H),7.45–7.39(m,1H),7.39–7.29(m,4H),7.25–7.18(m,5H),5.71(s,1H),5.14 and 5.10(ABq,J=11.2Hz,2H),4.55(d,J=13.6Hz,1H),4.20(d,J=13.6Hz,1H).

[0074] 13 C NMR(100MHz,CDCl3)δ(ppm):164.2,151.2,138.7,138.5(q,J=36.8Hz,1C),137.0,134.8,134.4,130.2,129.5,129.4,129.3,128.6,128.3,127.8,122.6,120.8(q,J=268.6Hz,1C),96.3,77.3,71.5,60.7.

[0075] 19 F NMR(376MHz,CDCl3)δ(ppm):-61.782.

[0076] HRMS(ESI):m / z calculated for C 26 H 19 ClF3N3O3+H + :514.1140,found:514.1127.

[0077] 5-(benzyloxy)-4-(4-bromophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 4

[0078]

[0079] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.68 (d, J = 8.0 Hz, 2H), 7.57–7.45 (m, 4H), 7.44–7.39 (m, 1H), 7.38–7.31 (m, 2H), 7.25–7.14 (m, 5H), 5.68 (s, 1H), 5.14 and 5.10 (ABq, J = 11.2 Hz, 2H), 4.54 (d, J = 13.2 Hz, 1H), 4.19 (d, J = 13.2 Hz, 1H).

[0080] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 164.2, 151.2, 139.3, 138.5 (q, J = 37.5 Hz, 1C), 137.0, 134.4, 132.30, 130.25, 129.5, 129.4, 128.6, 128.3, 128.2, 123.0, 122.6, 121.4 (q, J = 249.4 Hz, 1C), 96.2, 77.3, 71.5, 60.8.

[0081] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.782.

[0082] HRMS (ESI): m / z calculated for C 26 H 19 BrF3N3O3 + H + : 558.0635, found: 558.0627.

[0083] 5-(Benzyloxy)-1-phenyl-4-(p-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-Compound 5

[0084]

[0085] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.43–7.36 (m, 2H), 7.37–7.28 (m, 3H), 7.24–7.16 (m, 5H), 5.76 (s, 1H), 5.11 and 5.06 (ABq, J = 10.8 Hz, 2H), 4.53 (d, J = 13.6 Hz, 1H), 4.27 (d, J = 13.6 Hz, 1H), 2.32 (s, 3H).

[0086] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 165.2, 151.7, 138.8, 138.3 (q, J = 36.8 Hz, 1C), 137.0, 134.9, 134.1, 130.3, 129.7, 129.4, 129.3, 128.7, 128.3, 127.5, 122.6, 121.0 (q, J = 269.1 Hz, 1C), 96.3, 77.3, 71.5, 60.7, 21.7.

[0087] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.7**62**.

[0088] HRMS (ESI): m / z calculated for C 27 H 22 F3N3O3 + H + : 494.1686, found: 494.1674.

[0089] 5-(benzyloxy)-4-(4-fluorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 6

[0090]

[0091] 1 Note: In the 19F NMR data, the "62" in "-61.762" seems a bit odd. It might be a typo in the original. If it's a significant digit, it should be presented more clearly in the original text for accurate translation. Here, I've just translated it as is.1H NMR (400 MHz, CDCl3) δ (ppm): 7.68 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.45–7.34 (m, 3H), 7.32–7.21 (m, 5H), 7.03 (t, J = 8.4 Hz, 2H), 5.72 (s, 1H), 5.14 and 5.10 (ABq, J = 10.8 Hz, 2H), 4.55 (d, J = 13.2 Hz, 1H), 4.22 (d, J = 13.2 Hz, 1H).

[0092] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 164.3, 162.8 (d, J = 247.0 Hz, 1C), 151.2, 138.5 (q, J = 36.9 Hz, 1C), 137.1, 136.1, 134.4, 130.2, 129.5, 129.4, 128.6, 128.35, 128.27, 122.6, 120.8 (q, J = 268.6 Hz, 1C), 116.1 (d, J = 21.6 Hz, 1C), 96.5, 77.3, 71.5, 60.7.

[0093] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.830, -113.155.

[0094] HRMS (ESI): m / z calculated for C 26 H 19 F4N3O3 + H + : 498.1435, found: 498.1420.

[0095] 5-(Benzyloxy)-4-(2-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 7

[0096]

[0097] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.70 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.45–7.37 (m, 3H), 7.35–7.28 (m, 1H), 7.26–7.22 (m, 3H), 7.00–6.91 (m, 2H), 6.88 (t, J = 7.6 Hz, 1H), 6.12 (s, 1H), 5.16 (d, J = 10.8 Hz, 1H), 5.02 (d, J = 10.8 Hz, 1H), 4.81 (d, J = 13.6 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 3.88 (s, 3H).

[0098] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 163.3, 157.6, 151.3, 138.1 (q, J = 36.8 Hz, 1C), 137.2, 134.9, 130.5, 129.9, 129.3, 129.2, 129.1, 128.5, 128.1, 127.5, 122.6, 120.3, 119.9 (q, J = 95.3 Hz, 1C), 111.6, 97.8, 76.4, 71.8, 57.5, 55.8.

[0099] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -62.257.

[0100] HRMS (ESI): m / z calculated for C 27 H 22 F3N3O4 + H + : 510.1635, found: 510.1623.

[0101] 5-(benzyloxy)-4-(3-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 8

[0102]

[0103] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.69 (d, J = 7.6 Hz, 2H), 7.52–7.35 (m, 6H), 7.23–7.14 (m, 4H), 6.87–6.82 (m, 2H), 5.81 (s, 1H), 5.15 and 5.11 (ABq, J = 10.8 Hz, 2H), 4.49 (d, J = 12.8 Hz, 1H), 4.31 (d, J = 12.8 Hz, 1H), 3.82 (s, 3H).

[0104] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 163.9, 159.7, 151.0, 138.7 (q, J = 36.0 Hz, 1C), 137.3, 134.5, 132.2, 130.3, 130.2, 129.4, 129.2, 128.7, 128.5, 127.9, 127.3, 122.4, 120.9 (q, J = 269.3 Hz, 1C), 114.3, 97.1, 77.3, 71.6, 60.9, 55.3.

[0105] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.931.

[0106] HRMS (ESI): m / z calculated for C 27 H 22 F3N3O4+H + : 510.1635, found: 510.1633.[[ID=********]] [[ID=********]]

[0107] 5-(benzyloxy)-1-phenyl-4-(m-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-Compound 9

[0108]

[0109] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.66 (d, J = 7.6 Hz, 2H), 7.48–7.35 (m, 3H), 7.36–7.27 (m, 4H), 7.26–7.18 (m, 5H), 5.81 (s, 1H), 5.12 and 5.08 (ABq, J = 11.2 Hz, 2H), 4.55 (d, J = 13.6 Hz, 1H), 4.28 (d, J = 13.6 Hz, 1H), 2.34 (s, 3H).

[0110] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 166.0, 151.3, 138.9, 138.5 (q, J = 36.8 Hz, 1C), 137.0, 134.9, 134.3, 130.3, 129.8, 129.4, 129.3, 129.0, 128.7, 128.3, 127.5, 126.3, 122.6, 120.9 (q, J = 269.1 Hz, 1C), 96.7, 77.4, 71.6, 60.9, 21.2.

[0111] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -62.102.

[0112] HRMS (ESI): m / z calculated for C 27 H 22 F3N3O3 + H + : 494.1686, found: 494.1677.

[0113] 5-(benzyloxy)-4-(4-nitrophenyl)-1-phenyl-3-(trifluoromethyl)-[4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-Compound 10

[0114]

[0115] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.69 (d, J = 7.6 Hz, 2H), 7.48–7.36 (m, 4H), 7.38–7.28 (m, 3H), 7.26–7.17 (m, 5H), 5.86 (s, 1H), 5.18 and 5.12 (ABq, J = 11.2 Hz, 2H), 4.57 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.6 Hz, 1H).

[0116] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 164.2, 152.7, 138.9, 138.2 (q, J = 36.8 Hz, 1C), 137.2, 134.8, 134.2, 130.6, 129.9, 129.6, 129.2, 128.8, 128.3, 127.7, 122.8, 121.0 (q, J = 269.1 Hz, 1C), 96.5, 77.4, 71.3, 60.8.

[0117] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.795.

[0118] HRMS (ESI): m / z calculated for C 26 H 19 F3N4O5+H + : 525.1380, found: 525.1367.

[0119] 5-(benzyloxy)-4-(4-(methylthio)phenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 11

[0120]

[0121] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.63 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.41–7.33 (m, 4H), 7.25–7.18 (m, 4H), 6.85–6.82 (m, 2H), 5.77 (s, 1H), 5.14 and 5.10 (ABq, J = 10.8 Hz, 2H), 4.53 (d, J = 13.2 Hz, 1H), 4.27 (d, J = 13.2 Hz, 1H), 2.63 (s, 3H).

[0122] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 165.6, 158.7, 151.2, 138.8 (q, J = 36.0 Hz, 1C), 136.9, 135.0, 133.3, 130.3, 130.2, 129.7, 128.5, 128.3, 127.7, 123.6, 120.8 (q, J = 269.4 Hz, 1C), 115.4, 97.1, 77.3, 71.2, 60.7, 19.2.

[0123] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.833.

[0124] HRMS (ESI): m / z calculated for C 27 H 22 F3N3O3S+H + : 526.1407, found: 526.1413.

[0125] 4-(5-(benzyloxy)-6-oxo-1-phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4-yl)benzonitrile 12

[0126]

[0127] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.66 (d, J = 7.6 Hz, 2H), 7.52–7.35 (m, 6H), 7.26–7.16 (m, 4H), 6.83–6.81 (m, 2H), 5.78 (s, 1H), 5.15 and 5.10 (ABq, J = 11.2 Hz, 2H), 4.58 (d, J = 13.2 Hz, 1H), 4.28 (d, J = 13.2 Hz, 1H).

[0128] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 166.6, 159.1, 151.3, 138.8 (q, J = 36.0 Hz, 1C), 137.1, 136.0, 135.3, 131.3, 130.9, 130.7, 128.5, 128.3, 127.8, 123.6, 120.9 (q, J = 269.14 Hz, 1C), 119.1, 116.4, 97.3, 77.4, 71.1, 60.6.

[0129] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.893.

[0130] HRMS (ESI): m / z calculated for C 27 H 19 F3N4O3+H + : 505.1482, found: 505.1477.

[0131] 5-(benzyloxy)-4-(3,4-difluorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 13

[0132]

[0133] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (d, J = 8.0 Hz, 2H), 7.57–7.49 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.33–7.27 (m, 4H), 7.24–7.16 (m, 3H), 5.78 (s, 1H), 5.13 and 5.08 (ABq, J = 10.8 Hz, 2H), 4.57 (d, J = 13.2 Hz, 1H), 4.28 (d, J = 13.2 Hz, 1H).

[0134] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 165.9, 153.1, 152.7 (d, J = 13.2 Hz, 1C), 151.0, (d, J = 13.3 Hz, 1C), 149.5 (d, J = 13.3 Hz, 1C), 148.6 (d, J = 13.3 Hz, 1C), 139.8 (q, J = 36.8 Hz, 1C), 137.3, 134.5, 132.2, 130.3, 129.4, 128.7, 127.3, 122.4, 121.3 (q, J = 264.4 Hz, 1C), 117.3 (d, J = 15.8 Hz, 1C), 114.3 (d, J = 20.1 Hz, 1C), 96.8, 77.4, 71.3, 61.1.

[0135] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.798, -115.953.

[0136] HRMS (ESI): m / z calculated for C 26 H 18 F5N3O3+H + : 516.1341, found: 516.1358.

[0137] 5-(benzyloxy)-4-(2,4-dichlorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 14

[0138]

[0139] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.64 (d, J = 8.0 Hz, 2H), 7.46–7.36 (m, 3H), 7.34–7.27 (m, 4H), 7.26–7.18 (m, 4H), 5.81 (s, 1H), 5.12 and 5.08 (ABq, J = 10.8 Hz, 2H), 4.56 (d, J = 13.2 Hz, 1H), 4.32 (d, J = 12.8 Hz, 1H).

[0140] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 164.2, 152.7, 138.9, 138.2 (q, J = 36.8 Hz, 1C), 137.2, 134.8, 134.2, 130.6, 129.9, 129.61, 129.58, 129.2, 128.8, 128.5, 128.3, 127.7, 122.8, 121.0 (q, J = 269.1 Hz, 1C), 96.5, 77.4, 71.3, 60.8.

[0141] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.698.

[0142] HRMS (ESI): m / z calculated for C 26 H 18 Cl2F3N3O3 + H + : 548.0750, found: 548.0739.

[0143] (E)-5-(benzyloxy)-1-phenyl-4-styryl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 15

[0144]

[0145] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.68 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.44–7.35 (m, 3H), 7.33–7.26 (m, 8H), 6.34 (s, 2H), 5.28 (s, 1H), 5.09 and 5.08 (ABq, J = 10.8 Hz, 2H), 4.71 (s, 2H).

[0146] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 164.9, 151.3, 138.4 (q, J = 36.8 Hz, 1C), 137.1, 135.2, 134.5, 132.9, 130.2, 129.44, 129.39, 128.9, 128.71, 128.66, 128.3, 127.1, 126.9, 122.7, 121.0 (q, J = 268.6 Hz, 1C), 96.5, 77.3, 71.9, 59.9.

[0147] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -62.047.

[0148] HRMS (ESI): m / z calculated for C 28 H 22 F3N3O3 + H + : 506.1686, found: 506.1675.

[0149] 5-(Benzyloxy)-4-(naphthalen-2-yl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 16

[0150]

[0151] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.88–7.69 (m, 5H), 7.60–7.35 (m, 9H), 7.39–7.21 (m, 3H), 5.92 (s, 1H), 5.20 and 5.14 (ABq, J = 10.8 Hz, 2H), 4.49 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 12.8 Hz, 1H).

[0152] 1313C NMR (100 MHz, CDCl3) δ (ppm): 164.1, 151.3, 138.7 (q, J = 36.8 Hz, 1C), 137.7, 137.1, 134.5, 133.1, 133.0, 130.3, 129.44, 129.37, 128.8, 128.6, 128.3, 128.2, 127.7, 126.89, 126.87, 125.7, 123.8, 122.5, 121.0 (q, J = 268.6 Hz, 1C), 96.6, 77.4, 71.4, 61.4.

[0153] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.690.

[0154] HRMS (ESI): m / z calculated for C 30 H 22 F3N3O3 + H + : 530.1686, found: 530.1677.

[0155] 5-(benzyloxy)-4-(naphthalen-1-yl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 17

[0156]

[0157] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.92–7.72 (m, 6H), 7.68–7.39 (m, 8H), 7.42–7.22 (m, 3H), 5.89 (s, 1H), 5.23 and 5.17 (ABq, J = 11.2 Hz, 2H), 4.59 (d, J = 13.2 Hz, 1H), 4.31 (d, J = 13.2 Hz, 1H).

[0158] 1313C NMR (100 MHz, CDCl3) δ (ppm): 165.1, 151.1, 138.6 (q, J = 36.0 Hz, 1C), 137.3, 137.1, 134.6, 133.8, 133.2, 130.6, 129.5, 129.1, 128.84, 128.81, 128.3, 128.2, 127.5, 126.9, 126.7, 125.3, 123.6, 122.6, 120.9 (q, J = 268.9 Hz, 1C), 96.8, 77.6, 71.8, 61.2.

[0159] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.796.

[0160] HRMS (ESI): m / z calculated for C 30 H 22 F3N3O3 + H + : 530.1686, found: 530.1672.

[0161] 5-(Benzyloxy)-1-phenyl-4-(pyridin-3-yl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 18

[0162]

[0163] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.66 (d, J = 8.0 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.49–7.27 (m, 6H), 7.26–7.21 (m, 4H), 5.73 (s, 1H), 5.11 and 5.07 (ABq, J = 11.2 Hz, 2H), 4.59 (d, J = 13.2 Hz, 1H), 4.28 (d, J = 13.2 Hz, 1H).

[0164] 1313C NMR (100 MHz, CDCl3) δ (ppm): 166.3, 151.4, 140.4, 138.7 (q, J = 37.6 Hz, 1C), 137.8, 134.6, 132.0, 130.2, 129.8, 129.3, 129.1, 128.9, 128.6, 128.4, 126.8, 122.7, 121.1 (q, J = 269.7 Hz, 1C), 96.9, 77.2, 71.2, 61.6.

[0165] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.786.

[0166] HRMS (ESI): m / z calculated for C 25 H 19 F3N4O3 + H + : 481.1482, found: 481.1488.

[0167] 5-(benzyloxy)-1-phenyl-4-(thiophen-2-yl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 19

[0168]

[0169] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.68 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.45–7.27 (m, 6H), 7.25–7.21 (m, 3H), 5.81 (s, 1H), 5.15 and 5.11 (ABq, J = 10.8 Hz, 2H), 4.53 (d, J = 12.8 Hz, 1H), 4.27 (d, J = 12.8 Hz, 1H).

[0170] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 165.3, 151.3, 140.3, 138.8 (q, J = 37.6 Hz, 1C), 137.3, 134.6, 130.2, 129.4, 129.3, 129.0, 128.9, 128.6, 128.3, 126.4, 122.7, 121.0 (q, J = 269.7 Hz, 1C), 96.8, 77.3, 71.2, 61.7.

[0171] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.795.

[0172] HRMS (ESI): m / z calculated for C 24 H 18 F3N3O3S + H + : 486.1094, found: 486.1073.

[0173] 5-(benzyloxy)-1-(naphthalen-2-yl)-4-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 20

[0174]

[0175] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 8.14 (d, J = 2.4 Hz, 1H), 8.00–7.82 (m, 4H), 7.61–7.54 (m, 2H), 7.42–7.30 (m, 7H), 7.28–7.26 (m, 2H), 7.25–7.21 (m, 1H), 5.82 (s, 1H), 5.18 and 5.13 (ABq, J = 11.2 Hz, 2H), 4.57 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H).

[0176] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 164.3, 151.4, 140.2, 138.8 (q, J = 36.8 Hz, 1C), 134.6, 134.5, 133.2, 132.5, 130.3, 129.7, 129.5, 129.2, 128.8, 128.7, 128.6, 128.5, 128.0, 127.3, 127.0, 126.4, 121.0 (q, J = 268.6 Hz, 1C), 120.7, 96.9, 77.4, 71.5, 61.2.

[0177] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.693.

[0178] HRMS(ESI): m / z calculated for C 30 H 22 F3N3O3 + H + : 530.1686, found: 530.1675.

[0179] 5-(benzyloxy)-4-phenyl-1-(p-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 21

[0180]

[0181] 1 H NMR(400 MHz, CDCl3) δ(ppm): 7.66(d, J = 7.6 Hz, 2H), 7.46(t, J = 7.6 Hz, 2H), 7.45–7.36(m, 3H), 7.34–7.28(m, 2H), 7.26–7.16(m, 5H), 5.79(s, 1H), 5.16 and 5.10(ABq, J = 11.2 Hz, 2H), 4.57(d, J = 13.6 Hz, 1H), 4.29(d, J = 13.6 Hz, 1H), 2.30(s, 3H).

[0182] 13 C NMR(100 MHz, CDCl3) δ(ppm): 164.9, 151.7, 138.4, 138.1(q, J = 36.0 Hz, 1C), 137.3, 135.9, 134.6, 131.1, 129.8, 129.1, 129.0, 128.7, 128.5, 127.5, 122.7, 121.1(q, J = 268.7 Hz, 1C), 96.7, 77.4, 71.6, 60.7, 21.9.

[0183] 19 F NMR(376 MHz, CDCl3) δ(ppm): -61.738.

[0184] HRMS(ESI): m / z calculated for C 27 H 22 F3N3O3 + H + : 494.1686, found: 494.1670.

[0185] 5-(benzyloxy)-1-(4-fluorophenyl)-4-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 22

[0186]

[0187] 1 H NMR(400MHz,CDCl3)δ(ppm):7.72–7.63(m,2H),7.41–7.27(m,7H),7.25–7.15(m,5H),5.79(s,1H),5.15 and 5.11(ABq,J=10.8Hz,2H),4.51(d,J=13.6Hz,1H),4.24(d,J=13.2Hz,1H).

[0188] 13 C NMR(100MHz,CDCl3)δ(ppm):164.2,162.0(d,J=246.9Hz,1C),151.0,140.1,138.7(q,J=36.8Hz,1C),134.5,133.2,130.2,129.4,129.2,128.7,128.6,126.3,124.5(d,J=8.7Hz,1C),,120.8(q,J=269.4Hz,1C),116.3(d,J=23.1Hz,1C),96.8,77.2,71.5,61.1.

[0189] 19 F NMR(376MHz,CDCl3)δ(ppm):-61.789,-112.827,.

[0190] HRMS(ESI):m / z calculated for C 26 H 19 F4N3O3+H + :498.1435,found:498.1424.

[0191] 5-(benzyloxy)-1-(4-bromophenyl)-4-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 23

[0192]

[0193] 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (d, J = 8.0 Hz, 2H), 7.56–7.50 (m, 3H), 7.49–7.41 (m, 2H), 7.38–7.33 (m, 2H), 7.26–7.17 (m, 5H), 5.77 (s, 1H), 5.16 and 5.12 (ABq, J = 11.2 Hz, 2H), 4.59 (d, J = 12.8 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H).

[0194] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 165.1, 151.1, 139.0, 138.6 (q, J = 37.5 Hz, 1C), 137.6, 134.4, 133.3, 131.5, 129.5, 129.4, 128.8, 128.3, 128.1, 122.8, 122.6, 121.3 (q, J = 249.7 Hz, 1C), 96.7, 77.4, 71.5, 60.9.

[0195] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.796.

[0196] HRMS (ESI): m / z calculated for C 26 H 19 BrF3N3O3 + H + : 558.0635, found: 558.0621.

[0197] 5-(Benzyloxy)-4-(3-bromophenyl)-1-(3-chlorophenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)- Compound 24

[0198]

[0199] 11H NMR (400 MHz, CDCl3) δ (ppm): 7.66 (d, J = 7.6 Hz, 2H), 7.59–7.50 (m, 3H), 7.45–7.41 (m, 1H), 7.38–7.36 (m, 2H), 7.26–7.18 (m, 5H), 5.81 (s, 1H), 5.12 and 5.08 (ABq, J = 10.8 Hz, 2H), 4.61 (d, J = 12.8 Hz, 1H), 4.31 (d, J = 12.8 Hz, 1H).

[0200] 13 13C NMR (100 MHz, CDCl3) δ (ppm): 165.1, 151.1, 139.0, 138.6 (q, J = 37.5 Hz, 1C), 137.6, 134.4, 133.3, 132.6, 131.5, 129.54, 129.48, 129.1, 129.0, 128.8, 128.6, 128.3, 128.1, 122.8, 122.�, 121.3 (q, J = 249.7 Hz, 1C), 96.7, 77.4, 71.5, 60.9.

[0201] 19 19F NMR (376 MHz, CDCl3) δ (ppm): -61.793.

[0202] HRMS (ESI): m / z calculated for C 26 H 18 BrClF3N3O3 + H + : 592.0245, found: 592.0261.

[0203] The beneficial effects of the compounds of the present invention are demonstrated by the following experimental examples.

[0204] Experimental Example 1: In vitro anti-tumor experiment

[0205] 1. Test cell lines

[0206] Tumor cell lines (lung cancer cell HCC827, human breast cancer cell HCC1954, human breast cancer cell MCF7, prostate cancer cell PC3, bladder cancer cell T24, esophageal cancer cell Eca109) were all provided by the State Key Laboratory of Biotherapy of Sichuan University, and the above tumor cells were all cryopreserved in the State Key Laboratory of Biotherapy of Sichuan University.

[0207] 2. Test method

[0208] 2.1 Preparation and treatment of cells

[0209] All 6 kinds of tumor cells were cultured in RPMI - 1640 culture medium containing 10% inactivated newborn calf serum and grown to 80% cell fusion in an incubator at 37°C and 5% CO2. They were digested with 0.1% trypsin solution to make single - cell suspensions, and the cell concentration was adjusted to 5×10 4 cells / mL. They were evenly inoculated into 96 - well micro - culture plates, with 3 replicate wells in each group and 100 μL per well. After culturing for 24 h in an incubator at 37°C with saturated humidity and 5% CO2, the normal control group was added with the same amount of culture medium; test drugs with concentration gradients (100, 50, 25, 12.5, 6.25 μg / mL) were added, with 3 replicate wells for each concentration, and the experiment was repeated twice in parallel. After the drugs acted on the cells for 24 h, 10 μL of MTT solution (5 mg / mL) was added to each well, and after continuing to culture for 4 h, 100 μL of DMSO was added to each well. The mixture was shaken well to fully dissolve the crystals, and the absorbance value (A value) was measured at a wavelength of 490 nm with an enzyme - linked immunosorbent assay (ELISA) reader. The average value was taken for each concentration group.

[0210] 2.2 Determination of tumor cell proliferation inhibition rate

[0211] The cell proliferation inhibition rate was calculated according to the following formula: Cell proliferation inhibition rate (%)=(1 - A value of the test group / A value of the control group)×100%. All experimental data were statistically analyzed using SPSS13.0. The experimental results were used to obtain the IC 50 value by Probit.

[0212] 3. Test results

[0213] The test results are shown in Table 1.

[0214] Table 1 Inhibitory effects of different compounds on the growth of test cells

[0215]

[0216] The experimental results show that the compounds of the present invention can effectively inhibit the growth of various cancer cells and have excellent anti - tumor effects. Among them, compound 19 has the best anti - tumor effect.

[0217] In summary, the present invention provides a pyrazolo[1,5 - a]pyrimidine - 7 - one compound, its preparation method and use. The pyrazolo[1,5 - a]pyrimidine - 7 - one compound can effectively inhibit the growth of various tumor cells including lung cancer cells, breast cancer cells, prostate cancer cells, bladder cancer cells, and esophageal cancer cells, and has broad application prospects in the preparation of drugs for preventing and / or treating tumors.

Claims

1. A pyrazolo[1,5-a]pyrimidine-7-oxide compound or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from: 。 2. A method for preparing the pyrazolo[1,5-a]pyrimidine-7-oxide compound according to claim 1, characterized in that, The method comprises the following steps: (1) Compound d reacts with compound e to obtain compound f; (2) Compound f reacts with R4CHO to obtain compound g; (3) Compound g reacts with compound c under the action of a base to obtain the compound shown by formula I; Wherein, the compound shown by formula I is the pyrazoloazoxabicyclic compound described in claim 1.

3. A pharmaceutical composition for preventing and / or treating tumors, characterized in that, The pharmaceutical composition is composed of the pyrazoloazoxabicyclic compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. Use of the following pyrazolo[1,5-a]pyrido[3,4-e][1,4]diazepine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating esophageal cancer: 。 5. Use of the following pyrazolo[1,5-a]pyrido[3,4-e][1,4]diazepine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating lung cancer or bladder cancer: 。 6. Use of the following pyrazolo[1,5-a]diazocine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating breast cancer, bladder cancer or esophageal cancer: .

7. Use of the following pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating lung cancer, bladder cancer or esophageal cancer: .

8. Use of the following pyrazolo[1,5-a]diazocine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating breast cancer or esophageal cancer: .

9. Use of the following pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating esophageal cancer: .

10. Use of the following pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating lung cancer, breast cancer, prostate cancer, bladder cancer or esophageal cancer: .

11. Use of the following pyrazolo[1,5-a]pyrrolo[3,4-c]pyridazine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating esophageal cancer: 。 12. Use of the following pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepine compounds or pharmaceutically acceptable salts thereof in the preparation of a drug for preventing and / or treating bladder cancer: .

13. Use of the following pyrazolo[1,5-a]diazepino[5,4-e][1,4]diazepine compounds or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating breast cancer, prostate cancer or esophageal cancer: .

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