Thiazole spiro compound and preparation method and application thereof

Abstract

The application discloses a thiazole spiro compound and a preparation method and application thereof; the thiazole spiro compound has the structure shown in formula I: wherein, n is greater than or equal to 1; 1 is less than or equal to 5, R 1 is selected from H, halogen, C 1～6 alkyl; R 2 is independently selected from H, C 1～12 alkyl, C 1～12 haloalkyl, C 1～12 alkoxy; R 3 is selected from H, C 1～12 alkyl, phenyl. The application provides a series of novel thiazole spiro compounds, and the compounds have inhibitory effect on tumor cells.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and in particular to a thiazole spiro compound and a preparation method and application thereof. BACKGROUND

[0002] Thiazole ring is an important five-membered heteroaromatic ring containing nitrogen and sulfur atoms. Its special structure makes thiazole compounds have broad application prospects in many fields such as pharmacy and material science, showing great development value and attracting widespread attention. For example, (a) Pamicogrel is successfully used in clinical practice and plays an important role in cancer treatment; (b) Iridium benzothiazole complex is a new type of organic light-emitting diode emitter with potential application value, which has high thermal stability and good photoelectric performance; (c) Dithiazanine plays an important role in the treatment of human whipworm disease.

[0003]

[0004] Thiazole compounds containing spiro ring structure are a very unique molecular structure, which has important theoretical and practical application value. First, due to the rigidity of the spiro ring structure, it often shows strong invariability and stereospecificity in molecules. This feature makes the spiro ring structure an important structural basis for many natural products and biologically active molecules.

[0005] Therefore, it has great research value to study and explore the synthesis of spiro ring structure. SUMMARY

[0006] The present application aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present application provides a thiazole spiro compound or a pharmaceutically acceptable salt thereof, which has anti-tumor cell activity.

[0007] The second aspect of the present application also provides a preparation method of the thiazole spiro compound.

[0008] The third aspect of the present application also provides an application of the thiazole spiro compound.

[0009] The thiazole spiro compound or the pharmaceutically acceptable salt thereof provided by the first aspect of the present application has the structure shown in formula I:

[0010]

[0011] wherein n≥1; 1≤m≤5, R 1 is selected from H, halogen, C 1～6 alkyl;

[0012] R 2independently selected from H, C 1～12 alkyl, C 1～12 haloalkyl, C 1～12 alkoxy.

[0013] R 3 independently selected from H, C 1～12 alkyl, phenyl.

[0014] According to the thiazole spiro compound or the pharmaceutically acceptable salt thereof, at least the following beneficial effects are achieved:

[0015] The present application provides a series of novel thiazole spiro compounds or pharmaceutically acceptable salts thereof, which have inhibitory effect on tumor cells.

[0016] According to some embodiments of the present application, R 2 independently selected from H, C 1～6 alkyl, C 1～6 haloalkyl, C 1～6 alkoxy.

[0017] According to some embodiments of the present application, the thiazole spiro compound or the pharmaceutically acceptable salt thereof is selected from one of the following structural formulae:

[0018]

[0019] According to the second aspect of the present application, the preparation method of the thiazole spiro compound or the pharmaceutically acceptable salt thereof comprises the following steps:

[0020] Mixing compound 1, compound 2, metal catalyst and base to react to obtain;

[0021] wherein the structural formulae of compound 1 and compound 2 are as follows:

[0022]

[0023] According to the preparation method of the thiazole spiro compound or the pharmaceutically acceptable salt thereof, at least the following

[0024] beneficial effects are achieved:

[0025] Since the preparation method adopts all the technical solutions of the thiazole spiro compound of the above-mentioned embodiments, at least all the beneficial effects brought by the technical solutions of the above-mentioned embodiments are achieved. Further, the raw material of the preparation method is simple, and the product is obtained by one-step synthesis, which has the advantages of high yield, etc.

[0026] According to some embodiments of the present application, the molar ratio of the compound 1, the compound 2 and the base is 1: (0.5-10): (0.1-4).

[0027] According to some embodiments of the present application, the metal catalyst comprises at least one of copper salt, cobalt salt, iron salt, palladium salt, ruthenium complex or iridium complex.

[0028] According to some embodiments of the present application, the metal catalyst comprises at least one of copper acetate, copper triflate, copper sulfate, copper chloride, cuprous chloride, cuprous iodide, iron chloride, cobalt acetate, cobalt chloride, palladium acetate, triruthenium dodecacarbonyl, dichloro(pentamethylcyclopentadienyl)iridium(III) dimer.

[0029] According to some embodiments of the present application, the base comprises at least one of sodium acetate, sodium methoxide, sodium hydroxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, cesium carbonate, aniline.

[0030] According to some embodiments of the present application, the temperature of the reaction is 60-150℃.

[0031] According to some embodiments of the present application, the time of the reaction is 2-24h.

[0032] According to some embodiments of the present application, the reaction is carried out under air or nitrogen.

[0033] According to some embodiments of the present application, the reaction is carried out in a solvent, which comprises at least one of ethanol, tert-amyl alcohol, isopropyl alcohol, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, p-xylene, water.

[0034] According to some embodiments of the present application, the volume molar ratio of the solvent to the compound 1 is 0.5-3mL:0.15-0.3mmol.

[0035] According to some embodiments of the present application, the method further comprises a step of purification after the reaction, and the eluent of the purification is a mixed solution of petroleum ether, dichloromethane and ethyl acetate.

[0036] According to some embodiments of the present application, the eluent of the column chromatography purification is a mixed solution of petroleum ether:dichloromethane:ethyl acetate in a volume ratio of 10-100:0-20:1.

[0037] The third aspect of the present application provides a use of the thiazole spiro compound or the pharmaceutically acceptable salt thereof in the preparation of an antitumor drug for treating and / or preventing.

[0038] The preparation method of the thiazole spiro compound or the pharmaceutically acceptable salt thereof according to the embodiments of the present application at least has the following

[0039] Advantages:

[0040] Since the preparation method adopts all the technical solutions of the thiazole spiro compound in the above embodiments, at least all the beneficial effects brought by the technical solutions of the above embodiments are possessed.

[0041] According to some embodiments of the present application, the tumor comprises chronic myelogenous leukemia, acute promyelocytic leukemia, cervical cancer and gastric cancer.

[0042] Definitions and general terms

[0043] "C 1-6 alkyl" means an alkyl group having a total number of carbon atoms of 1-6, including C 1-6 linear alkyl, C 1-6 branched alkyl and C 3-6 cycloalkyl, for example, can be a linear alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkyl group having a total number of carbon atoms of 3, 4, 5 or 6, for example, can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, and the like. The "C 1-12 alkyl" has a similar explanation as this, except that the number of carbon atoms is different.

[0044] "C 1～6 haloalkyl" means the definition of "C 1-6 alkyl", except that any 1 H atom in "C 1-6 haloalkyl" is replaced by any halogen. The "C 1～12 haloalkyl" has a similar definition as "C 1～6 haloalkyl", except that the number of carbon atoms is different.

[0045] "C 1-6 alkoxy" means an alkoxy group having a total number of carbon atoms of 1-6, including C 1-6 linear alkoxy, C 1-6 branched alkoxy and C 2-6 cycloalkoxy, for example, can be a linear alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkoxy group having a total number of carbon atoms of 2, 3, 4, 5 or 6, for example, can be methoxy, ethoxy, n-propoxy, isopropoxy, and the like. The "C 1-12 alkoxy" has a similar explanation as this, except that the number of carbon atoms is different.

[0046] Other features and advantages of the present application will be set forth in the following description, and in part will become apparent from the description, or can be learned by practice of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0048] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 1;

[0049] Figure 2 is the carbon NMR spectrum of the compound of Example 1;

[0050] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 2;

[0051] Figure 4 is the carbon NMR spectrum of the compound of Example 2;

[0052] Figure 5 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 3;

[0053] Figure 6 is the carbon NMR spectrum of the compound of Example 3;

[0054] Figure 7 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 4;

[0055] Figure 8 is the carbon NMR spectrum of the compound of Example 4;

[0056] Figure 9 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 5;

[0057] Figure 10 is the carbon NMR spectrum of the compound of Example 5;

[0058] Figure 11 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 6;

[0059] Figure 12 is the carbon NMR spectrum of the compound of Example 6;

[0060] Figure 13 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 7;

[0061] Figure 14 is the carbon NMR spectrum of the compound of Example 7;

[0062] Figure 15 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 8;

[0063] Figure 16 is the carbon NMR spectrum of the compound of Example 8;

[0064] Figure 17 NMR of hydrogen spectrum of the compound of Example 9;

[0065] Figure 18 NMR of carbon spectrum of the compound of Example 9;

[0066] Figure 19 NMR of hydrogen spectrum of the compound of Example 10;

[0067] Figure 20 NMR of carbon spectrum of the compound of Example 10;

[0068] Figure 21 NMR of hydrogen spectrum of the compound of Example 11;

[0069] Figure 22 NMR of carbon spectrum of the compound of Example 11; DETAILED DESCRIPTION

[0070] The following are specific examples of the present application, and the technical solutions of the present application are further described in combination with the examples, but the present application is not limited to these examples.

[0071] The reagents, methods and equipment used in the present application are all conventional reagents, methods and equipment in the technical field unless otherwise specified.

[0072] Example 1

[0073] Example 1 provides a thiazole spiro compound, the structure is as follows: the preparation method is as follows:

[0074]

[0075] 76.6 mg of 3-benzyl-5-bromobenzothiazole salt (0.2 mmol), 39.4 mg of cyclohexanone (0.4 mmol), cuprous iodide (10 mol%), 55.8 mg of aniline (0.6 mmol), 1 mL of acetonitrile were mixed uniformly, stirred under the condition of nitrogen at 100°C for 5 hours to obtain a crude product; the crude product was purified by column chromatography to obtain the compound; the yield of the preparation method is 90%, and the compound is a yellow solid.

[0076] The NMR of hydrogen spectrum of the obtained compound is as shown in Figure 1 , the NMR of carbon spectrum is as shown in Figure 2 , and the structure characterization data are as follows:

[0077] NMR of hydrogen spectrum data: 1H NMR (500 MHz, Chloroform-d) δ 7.38 (d, J = 4.4 Hz, 4H), 7.31 (dd, J = 9.5, 5.2 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.74 (dd, J = 8.0, 1.8 Hz, 1H), 6.22 (d, J = 1.8 Hz, 1H), 4.42 (s, 2H), 2.26 (d, J = 12.7 Hz, 2H), 1.85 - 1.78 (m, 4H), 1.75 - 1.70 (m, 1H), 1.61 (dt, J = 13.3, 3.5 Hz, 2H), 1.17 - 1.09 (m, 1H)

[0078] Carbon NMR data: 13 C NMR (126 MHz, Chloroform-d) δ 148.61, 137.91, 128.80, 127.24, 126.31, 123.50, 122.22, 120.59, 118.52, 109.99, 85.52, 47.05, 37.00, 24.96, 24.02.

[0079] High resolution mass spectrometry (electrospray ionization mass spectrometry): C 19 H 21 BrNS [M+H] + Theoretical calculated value: 374.0572; test data: 374.0563.

[0080] Example 2

[0081] Example 2 provides a thiazole spiro compound, the structural formula of which is as follows: the preparation method is as follows:

[0082]

[0083] 66.6 mg of 3-(3,5-dimethylbenzyl)benzothiazole salt (0.2 mmol), 39.4 mg of cyclohexanone (0.4 mmol), cuprous chloride (10 mol%), 55.8 mg of aniline (0.6 mmol), 1 mL of acetonitrile were uniformly mixed, stirred at 100°C under nitrogen for 5 hours to obtain a crude product; the crude product was purified by column chromatography to obtain the compound; the yield of the preparation method is 77%, and the compound is a yellow solid.

[0084] The proton nuclear magnetic resonance spectrum of the obtained compound is as shown in Figure 3 , the carbon nuclear magnetic resonance spectrum is as shown in Figure 4 , and the structural characterization data are as follows:

[0085] Proton nuclear magnetic resonance spectrum data: 1H NMR (500 MHz, Chloroform-d) δ 7.12 - 7.07 (m, 1H), 7.04 (s, 2H), 6.94 (s, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 6.16 (d, J = 8.0 Hz, 1H), 4.38 (s, 2H), 2.36 (s, 6H), 2.30 (s, 2H), 1.85 (q, J = 12.7, 12.0 Hz, 4H), 1.79 - 1.60 (m, 4H).

[0086] NMR Carbon spectrum data: 13 C NMR (126 MHz, Chloroform-d) δ 147.52, 138.83, 138.20, 128.72, 125.30, 124.12, 124.08, 121.37, 117.98, 107.55, 84.83, 47.43, 36.79, 25.15, 24.14, 21.45.

[0087] High resolution mass spectrum (electrospray ionization mass spectrum): C 21 H 26 NS[M+H] + Theoretical calculation: 324.1780; Test data: 324.1771.

[0088] Example 3

[0089] Example 3 provides a thiazole spiro compound, the structural formula of which is as follows: and the preparation method is as follows:

[0090]

[0091] Mix 67.0 mg of 3-(3-methoxybenzyl)benzothiazole salt (0.2 mmol), 39.4 mg of cyclohexanone (0.4 mmol), ferrous chloride (10 mol%), 55.8 mg of aniline (0.6 mmol), and 1 mL of acetonitrile uniformly, stir the reaction under the condition of nitrogen at 100°C for 5 hours to obtain a crude product; the crude product is purified by column chromatography to obtain the compound; the yield of the preparation method is 92%, and the compound is a yellow solid.

[0092] The nuclear magnetic resonance hydrogen spectrum of the obtained compound is as shown in Figure 5 , the nuclear magnetic resonance carbon spectrum is as shown in Figure 6 , and the structural characterization data are as follows:

[0093] NMR Hydrogen spectrum data: 1H NMR (500 MHz, Chloroform-d) δ 7.29 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.87 - 6.81 (m, 2H), 6.65 (t, J = 7.5 Hz, 1H), 6.14 (d, J = 7.9 Hz, 1H), 4.41 (s, 2H), 3.83 (s, 3H), 2.30 (d, J = 12.7 Hz, 2H), 1.87 - 1.79 (m, 4H), 1.77 - 1.71 (m, 1H), 1.64 (tt, J = 12.9, 3.3 Hz, 2H), 1.15 (tdd, J = 13.1, 9.4, 4.0 Hz, 1H).

[0094] 1.79 (m, 4H), 1.77 - 1.71 (m, 1H), 1.64 (tt, J = 12.9, 3.3 Hz, 2H), 1.15 (tdd, J = 13.1, 9.4, 4.0 Hz, 1H).

[0095] NMR Carbon Spectrum Data: 13 C NMR (126 MHz, Chloroform-d) δ 159.99, 147.25, 140.68, 129.69, 125.23, 124.13, 121.37, 118.74, 118.10, 112.25, 112.08, 107.46, 84.63, 55.22, 47.33, 36.89, 25.11, 24.11.

[0096] High Resolution Mass Spectrum (Electrospray Ionization Mass Spectrum): C 20 H 24 NOS [M+H] + Theoretical calculated value: 326.1573; test data: 326.1559.

[0097] Example 4

[0098] Example 4 provides a thiazole spiro compound, the structural formula of which is as follows: and the preparation method is as follows:

[0099]

[0100] Mix 72.2 mg of 3-(4-(tert-butyl)benzyl)benzothiazole salt (0.2 mmol), 39.4 mg of cyclohexanone (0.4 mmol), palladium acetate (2 mol%), 55.8 mg of aniline (0.6 mmol), 1 mL of acetonitrile uniformly, stir the reaction under the condition of nitrogen at 100°C for 5 hours to obtain a crude product; the crude product is purified by column chromatography to obtain the compound; the yield of the preparation method is 61%, and the compound is a yellow solid.

[0101] The nuclear magnetic resonance hydrogen spectrum of the obtained compound is as follows: Figure 7 , and the nuclear magnetic resonance carbon spectrum is as follows:Figure 8 The structural characterization data are as follows:

[0102] Nuclear magnetic resonance hydrogen spectrum data: 1 H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.87 (t, J = 7.7 Hz, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.16 (d, J = 8.0 Hz, 1H), 4.43 (s, 2H), 2.32 (d, J = 12.6 Hz, 2H), 1.90 - 1.81 (m, 4H), 1.75 (d, J = 13.5 Hz, 1H), 1.66 (t, J = 13.0 Hz, 2H), 1.38 (s, 9H), 1.18 (tt, J = 12.4, 3.6 Hz, 1H).

[0103] Nuclear magnetic resonance carbon spectrum data: 13 C NMR (126 MHz, Chloroform-d) δ 149.84, 147.35, 135.68, 126.11, 125.55, 125.22, 124.14, 121.37, 117.97, 107.46, 84.71, 47.00, 36.92, 34.51, 31.49, 25.15, 24.13.

[0104] High resolution mass spectrum (electrospray ionization mass spectrum): C 23 H 30 NS[M+H] + Theoretical calculation: 352.2093; Test data: 352.2090.

[0105] Example 5

[0106] Example 5 provides a thiazole spiro compound, the structural formula of which is as follows: and the preparation method thereof is as follows:

[0107]

[0108] Mix 61.0 mg of 3-benzylbenzothiazole salt (0.2 mmol), 69.6 mg of 4-phenylcyclohexan-1-one (0.4 mmol), triruthenium dodecacarbonyl (5 mol%), 55.8 mg of aniline (0.6 mmol), and 1 mL of acetonitrile uniformly, stir the reaction under the condition of nitrogen at 100°C for 5 hours to obtain a crude product; the crude product is purified by column chromatography to obtain the compound; the yield of the preparation method is 33%, and the compound is a yellow solid.

[0109] The nuclear magnetic resonance hydrogen spectrum of the obtained compound is as follows:Figure 9 NMR carbon spectrum data as shown in Figure 10 Figure 1, and the structural characterization data are as follows:

[0110] NMR hydrogen spectrum data: 1 H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 7.6 Hz, 2H), 7.41 (s, 2H), 7.38 (d, J = 6.5 Hz, 2H), 7.34 (s, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.14 (dd, J = 7.7, 2.8 Hz, 1H), 6.90 (t, J = 7.7 Hz, 1H), 6.70 (td, J = 7.6, 2.8 Hz, 1H), 6.20 (dd, J = 8.1, 3.0 Hz, 1H), 4.52 (s, 2H), 2.57 (dd, J = 10.0, 5.7 Hz, 1H), 2.47 - 2.41 (m, 2H), 2.12 (dt, J = 13.3, 6.7 Hz, 2H), 2.03 - 1.94 (m, 4H).

[0111] NMR carbon spectrum data: 13 C NMR (101 MHz, Chloroform-d) δ 147.29, 146.05, 138.72, 128.74, 128.56, 127.10, 126.86, 126.45, 126.38, 125.41, 123.96, 121.54, 118.27, 107.63, 84.10, 47.36, 43.27, 36.87, 31.69.

[0112] High resolution mass spectrum (electrospray ionization mass spectrum): C 25 H 26 NS[M+H] + Theoretical calculated value: 372.1780; Test data: 372.1789.

[0113] Example 6

[0114] Example 6 provides a thiazole spiro compound, the structural formula of which is as follows: and the preparation method is as follows:

[0115]

[0116] A mixture of 61.0 mg of 3-benzylbenzothiazole salt (0.2 mmol), 61.6 mg of 4-(tert-butyl)cyclohexan-l-one (0.4 mmol), iridium trichloride (1 mol%), 55.8 mg of aniline (0.6 mmol), 1 mL of acetonitrile was mixed uniformly, stirred at 100°C for 5 hours under nitrogen condition to obtain a crude product; the crude product was purified by column chromatography to obtain the compound; the yield of the preparation method was 62%, and the compound was a yellow solid.

[0117] The nuclear magnetic resonance hydrogen spectrum of the obtained compound is as shown in Figure 11 , and the nuclear magnetic resonance carbon spectrum is as shown in Figure 12 The structural characterization data are as follows:

[0118] Nuclear magnetic resonance hydrogen spectrum data: 1 H NMR (400 MHz, Chloroform-d) δ 7.41 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.33-7.28 (m, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.85 (t, J = 7.9 Hz, 1H), 6.65 (t, J = 7.5 Hz, 1H), 6.13 (d, J = 7.8 Hz, 1H), 4.44 (s, 2H), 2.34 (d, J = 13.1 Hz, 2H), 1.90 (dt, J = 22.1, 7.9 Hz, 4H), 1.44 (dd, J = 11.9, 3.0 Hz, 2H), 1.04 (dt, J = 12.2, 2.9 Hz, 1H), 0.94 (d, J = 2.2 Hz, 9H).

[0119] Nuclear magnetic resonance carbon spectrum data: 13 C NMR (101 MHz, Chloroform-d) δ 147.36, 138.81, 128.65, 126.98, 126.41, 125.24, 124.02, 121.39, 118.04, 107.39, 84.67, 47.21, 47.12, 37.01, 32.38, 27.63, 24.93.

[0120] High resolution mass spectrum (electrospray ionization mass spectrum): C 23 H 30 NS[M+H] + Theoretical calculation value: 352.2093; test data: 352.2090.

[0121] Example 7

[0122] Example 7 provides a thiazole spiro compound, the structural formula of which is as follows: the preparation method is as follows:

[0123]

[0124] To 61.0 mg of 3-benzylbenzothiazole salt (0.2 mmol), 50.4 mg of cyclooctanone (0.4 mmol), palladium chloride (5 mol%), 55.8 mg of aniline (0.6 mmol), 1 mL of acetonitrile were mixed uniformly, and the reaction was stirred at 100°C for 5 hours under nitrogen condition to obtain a crude product; the crude product was purified by column chromatography to obtain the compound; the yield of the preparation method was 53%, and the compound was a yellow solid.

[0125] The nuclear magnetic resonance hydrogen spectrum of the obtained compound is as shown in Figure 13 , and the nuclear magnetic resonance carbon spectrum is as shown in Figure 14 The structural characterization data are as follows:

[0126] Nuclear magnetic resonance hydrogen spectrum data: 1 H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J = 7.7 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.82 (t, J = 7.8 Hz, 1H), 6.63 (t, J = 7.5 Hz, 1H), 6.06 (d, J = 7.9 Hz, 1H), 4.47 (s, 2H), 2.42 (dd, J = 14.5, 9.5 Hz, 2H), 2.22 (dd, J = 14.6, 8.6 Hz, 2H), 1.86 - 1.79 (m, 2H), 1.73 (d, J = 10.5 Hz, 2H), 1.67 - 1.62 (m, 2H), 1.55 (d, J = 10.3 Hz, 2H), 0.97 - 0.85 (m, 2H).

[0127] Nuclear magnetic resonance carbon spectrum data: 13 C NMR (126 MHz, Chloroform-d) δ 147.24, 138.69, 128.65, 126.97, 126.39, 125.15, 124.15, 121.64, 118.23, 107.80, 87.85, 48.31, 36.33, 29.73, 27.87, 23.36.

[0128] High resolution mass spectrum (electrospray ionization mass spectrum): C 21 H 26 NS[M+H] + Theoretical calculated value: 324.1780; test data: 324.1771.

[0129] Example 8

[0130] Example 8 provides a thiazole spiro compound, having the following structural formula:

[0131]

[0132] A mixture of 61.0 mg of 3-benzylbenzothiazole salt (0.2 mmol), 94.4 mg of 4'-butyl-[1,1'-bi(cyclohexane)]-4-one (0.4 mmol), copper acetate (10 mol%), 55.8 mg of aniline (0.6 mmol), 1 mL of acetonitrile was stirred at 100°C for 5 hours under nitrogen to obtain a crude product; the crude product was purified by column chromatography to obtain the compound; the yield of the preparation method was 92%, and the compound was a yellow solid.

[0133] The proton magnetic resonance spectrum of the obtained compound is shown in Figure 15 , and the carbon magnetic resonance spectrum is shown in Figure 16 The structural characterization data are as follows:

[0134] Proton magnetic resonance spectrum data: 1 H NMR (500 MHz, Chloroform-d) δ 7.41 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H), 6.12 (d, J = 7.9 Hz, 1H), 4.43 (s, 2H), 2.32 (d, J = 12.7 Hz, 2H), 1.90 (d, J = 11.3 Hz, 2H), 1.82 (dt, J = 26.0, 13.1 Hz, 7H), 1.51 - 1.42 (m, 3H), 1.34 (d, J = 5.7 Hz, 6H), 1.14 (ddt, J = 17.1, 11.5, 2.7 Hz, 2H), 1.05 (dd, J = 13.5, 10.8 Hz, 3H), 0.98 - 0.90 (m, 3H).

[0135] Carbon magnetic resonance spectrum data: 13 C NMR (126 MHz, Chloroform-d) δ 147.32, 138.80, 128.65, 126.98, 126.42, 125.22, 124.09, 121.39, 118.03, 107.38, 84.83, 47.24, 42.85, 42.25, 37.87, 37.22, 36.86, 33.58, 30.19, 29.32, 27.45, 23.11, 14.25.

[0136] High resolution mass spectrum (electrospray ionization mass spectrum): C 29 H 39 NS[M+H] + Theoretical calculation: 434.2876; test data: 434.2875.

[0137] Example 9

[0138] Example 9 provides a thiazole spiro compound, the structure of which is as follows: and the preparation method thereof is as follows:

[0139]

[0140] Mix 61.0 mg of 3-benzylbenzothiazole salt (0.2 mmol), 33.6 mg of cyclopentanone (0.4 mmol), copper acetate (10 mol%), 55.8 mg of aniline (0.6 mmol), and 1 mL of acetonitrile uniformly, stir the reaction under the condition of nitrogen at 100°C for 5 hours to obtain a crude product; the crude product is purified by column chromatography to obtain the compound; the yield of the preparation method is 95%, and the compound is a yellow solid.

[0141] The nuclear magnetic resonance hydrogen spectrum of the obtained compound is as shown in Figure 17 , the nuclear magnetic resonance carbon spectrum is as shown in Figure 18 , and the structure characterization data are as follows:

[0142] Nuclear magnetic resonance hydrogen spectrum data: 1 H NMR (500 MHz, Chloroform-d) δ 7.38 (dt, J = 15.0, 7.6 Hz, 4H), 7.29 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.85 (t, J = 7.7 Hz, 1H), 6.65 (t, J = 7.5 Hz, 1H), 6.11 (d, J = 7.9 Hz, 1H), 4.42 (s, 2H), 2.28-2.21 (m, 2H), 2.16 (dt, J = 14.0, 7.3 Hz, 2H), 1.87-1.71 (m, 4H).

[0143] Nuclear magnetic resonance carbon spectrum data: 13 C NMR (126 MHz, Chloroform-d) δ 147.0, 138.3, 128.7, 127.0, 126.3, 125.2, 124.5, 121.4, 118.1, 107.4, 88.7, 47.3, 38.3, 22.6.

[0144] High resolution mass spectrum (electrospray ionization mass spectrum): C 18 H 20 NS[M+H] +Theoretical calculated value of C26H26N4O2S2: 518.1411; Test data: 518.1411.

[0145] Example 10

[0146] Example 10 provides a thiazole spiro compound, the structural formula of which is as follows: and the preparation method thereof is as follows:

[0147]

[0148] Mix 61.0 mg of 3-benzylbenzothiazole salt (0.2 mmol), 39.2 mg of cyclohexanone (0.4 mmol), copper acetate (10 mol%), 55.8 mg of aniline (0.6 mmol), and 1 mL of acetonitrile uniformly under the condition of nitrogen, stir the reaction at 100°C for 5 hours to obtain a crude product; the crude product is purified by column chromatography to obtain the compound; the yield of the preparation method is 73%, and the compound is a yellow solid.

[0149] The proton magnetic resonance spectrum of the obtained compound is as shown in Figure 19 , and the carbon magnetic resonance spectrum is as shown in Figure 20 The structural characterization data of the compound are as follows:

[0150] Proton magnetic resonance spectrum data: 1 H NMR (500 MHz, Chloroform-d) δ 7.41 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.84 (t, J = 7.7 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 6.12 (d, J = 7.9 Hz, 1H), 4.45 (s, 2H), 2.30 (d, J = 12.6 Hz, 2H), 1.84 (td, J = 16.4, 14.5, 6.6 Hz, 4H), 1.74 - 1.60 (m, 4H).

[0151] Carbon magnetic resonance spectrum data: 13 C NMR (126 MHz, Chloroform-d) δ 147.2, 138.7, 128.6, 126.9, 126.4, 125.2, 124.1, 121.3, 118.0, 107.4, 84.6, 47.2, 36.8, 25.1, 24.1.

[0152] High resolution mass spectrum (electrospray ionization mass spectrum): C 19 H 22 NS[M+H] + Theoretical calculated value of C26H26N4O2S2: 518.1411; Test data: 518.1411.

[0153] Example 11

[0154] Example 11 provides a thiazole spiro compound, having the following structural formula:

[0155]

[0156] A mixture of 61.0 mg of 3-benzylbenzothiazole salt (0.2 mmol), 44.8 mg of cycloheptanone (0.4 mmol), copper acetate (10 mol%), 55.8 mg of aniline (0.6 mmol), 1 mL of acetonitrile was stirred at 100 °C for 5 hours under nitrogen condition to obtain a crude product; the crude product was purified by column chromatography to obtain the compound; the yield of the preparation method was 50%, and the compound was a yellow solid.

[0157] The proton magnetic resonance spectrum of the obtained compound is shown in Figure 21 , and the carbon magnetic resonance spectrum is shown in Figure 22 The structural characterization data are as follows:

[0158] Proton magnetic resonance spectrum data: 1 H NMR (500 MHz, Chloroform-d) δ 7.41 (d, J = 7.2 Hz, 2H), 7.36 (dd, J = 8.5, 6.7 Hz, 2H), 7.29 (d, J = 7.0 Hz, 1H), 7.08 (dd, J = 7.4, 1.3 Hz, 1H), 6.83 (td, J = 7.7, 1.3 Hz, 1H), 6.64 (td, J = 7.4, 1.1 Hz, 1H), 6.06 (dd, J = 8.0, 1.0 Hz, 1H), 4.45 (s, 2H), 2.42 (ddt, J = 10.4, 4.6, 2.1 Hz, 2H), 2.16 - 2.08 (m, 2H), 1.72 (tt, J = 7.3, 3.9 Hz, 6H), 1.62 - 1.54 (m, 2H).

[0159] Carbon magnetic resonance spectrum data: 13 C NMR (126 MHz, Chloroform-d) δ 147.0, 138.6, 128.6, 127.0, 126.4, 125.2, 124.1, 121.6, 118.1, 107.5, 87.9, 47.7, 39.7, 27.5, 23.1.

[0160] High resolution mass spectrum (electrospray ionization mass spectrum): C 20 H 24 NS[M+H] + Theoretical calculation value: 310.1624; test data: 310.1614.

[0161] Activity test

[0162] The products obtained in Examples 1-8 were subjected to anti-tumor cell activity test.

[0163] (1) Test method: Each compound was prepared into a 100 μg·mL -1 methanol solution, the positive control drugs 5-fluorouracil (5-FU) and docetaxol were prepared into a 100 μg·mL -1 DMSO solution, respectively, and the methanol and DMSO solvents were used as blank controls, respectively, and the MTT method was used to test the inhibitory effect of each compound on K562 cells, HL-60 cells, HeLa cells and BGC-823 cells.

[0164] (2) Preparation of cell culture solution: One bag of RPMI-1640 medium powder (Net wt 10.4 g) was poured into a clean beaker, dissolved with 900 mL of ultrapure water, and 100 mg·mL -1 of streptomycin 1 mL, penicillin 0.5 mL and NaHCO32 g were added. After magnetic stirring, the solution was filtered through a 0.22 μm filter membrane under a high-pressure sterilized Zeiss filter in an ultraclean bench, and the filtrate was directly stored in a glass bottle (450 mL / bottle) after moist heat sterilization. Before use, the frozen serum was inactivated at 56°C for 30 min, then added to the prepared RPMI-1640 culture solution (50 mL of serum was added to 450 mL of culture medium), gently shaken, covered, sealed with tin foil paper, and stored in a 4°C refrigerator. MTT solution was prepared: 50 mg of MTT (3-(4,5-dimethylthiazole-2)-2,5-diphenyl tetrazolium bromide) powder was dissolved in 10 mL of PBS solution, filtered with a 0.22 μm filter membrane, and stored in a 4°C refrigerator.

[0165] (3) Anti-tumor activity test: K562 cells, HL-60 cells, HeLa cells and BGC-823 cells in the logarithmic growth phase were centrifuged at 4°C, 3000 rpm for 3 min, the supernatant was removed, and fresh RPMI-1640 culture medium was added to dilute the cell suspension to 1×10 5 cells / mL. 200 μL of each was inoculated into a 96-well plate, incubated at 37°C, 5% CO2 in a cell incubator for 1 h, then 2 μL of sample solution was added to each well, 3 parallel holes were set for each sample, and two groups of three holes were set as blank controls. After adding the sample, it was incubated under the same conditions for 24 h. After 24 h, the morphological changes of the cells were observed under a light microscope, and the cytotoxic activity of the sample was preliminarily judged, and if necessary, a photograph was taken. 5 mg·mL -1MTT solution 20 μL each, and incubated in the incubator for 4 h. The 96-well plate was taken out and centrifuged (4℃, 2000 rpm, 20 min) to remove the supernatant, 150 μL DMSO was added to each well, and the purple precipitate was fully dissolved by shaking. The optical density OD value was measured on an enzyme marker at 570 nm, and the average value of each sample was calculated according to the formula IR% = (OD 空白 -OD 样品 ) / OD 空白 ×100% to calculate the inhibition rate (IR%).

[0166] The MTT method was used to test the proliferation inhibition activity of the compounds of Examples 1-8 on four tumor cells, and the results are shown in Table 1.

[0167] Table 1 MTT test results of the proliferation inhibition activity of Examples 1-8 on four tumor cells (%)

[0168] Cells 1 2 3 4 5 6 7 8 K562 33.1 31.3 69.5 31.7 35.6 30.5 55.1 62.1 HL-60 30.3 36.2 70.4 43.2 29.7 32.4 55.4 63.4 HeLa 34.2 32.2 62.6 29.6 24.1 35.5 54.6 59.5 BGC-823 36.9 33.5 61.1 25.4 23.7 30.4 54.2 56.7

[0169] As can be seen from Table 1, the thiazole spiro compound prepared in the application has a certain inhibitory effect on K562 cells, HL-60 cells, HeLa cells and BGC-823 cells, indicating that it has a certain anti-tumor cell activity and has potential application value in anti-tumor cell drugs.

[0170] The above is a detailed description in combination with the examples of the application, but the application is not limited to the above examples, and various changes can be made within the knowledge possessed by those skilled in the art without departing from the spirit of the application.

Claims

1. A thiazole spiro compound or a pharmaceutically acceptable salt thereof, characterized in that: It has the structure shown in formula I: ； Among them, n≥1; 1≤m≤5, R 1 Selected from H, halogen, C 1~6 Alkyl; R 2 Independently selected from H, C 1~12 Alkyl, C 1~12 haloalkyl, C 1~12 Alkoxy; R 3 Selected from H, C 1~12 Alkyl, phenyl.

2. The thiazole spiro compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2 Independently selected from H, C 1~6 Alkyl, C 1~6 haloalkyl, C 1~6 of alkoxy.

3. A thiazole spiro compound or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following structural formula: 、 、 、 、 、 、 、 、 、 、 。 4. The method for preparing the thiazole spiro compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The steps include: Compound 1, compound 2, a metal catalyst and a base are mixed and reacted to obtain the product; The structural formulas of compound 1 and compound 2 are as follows: 。 5. The preparation method according to claim 4, characterized in that The molar ratio of the compound 1, the compound 2 and the base is 1: (0.5-10): (0.1-4).

6. The preparation method according to claim 4, characterized in that The metal catalyst includes at least one of copper salt, cobalt salt, iron salt, palladium salt, ruthenium complex or iridium complex.

7. The preparation method according to claim 4, characterized in that The base includes at least one of sodium acetate, sodium methoxide, sodium hydroxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, cesium carbonate, and aniline.

8. The preparation method according to claim 4, characterized in that The reaction temperature is 60-150°C.

9. Use of the thiazole spiro compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a drug for treating and / or preventing antitumor.

10. The use according to claim 9, characterized in that Such tumors include chronic myeloid leukemia, acute promyelocytic leukemia, cervical cancer, and gastric cancer.

Images