Pyrimido triazole derivative as well as preparation method and application thereof

Abstract

The invention discloses a pyrimido triazole derivative, the pyrimido triazole derivative is a pyrimido triazole derivative containing amino dithio ester, and the pyrimido triazole derivative has the following general formula I: # imgabs0 #. The reversion activity of the pyrimido triazole derivative containing amino dithio ester disclosed by the invention is obviously superior to that of an ABCB1 inhibitor Verapamil, and the reversion activity of the pyrimido triazole derivative containing amino dithio ester is obviously superior to that of the ABCB1 inhibitor Verapamil; the compound can be used as a candidate or lead compound for further development and is applied to preparation of a drug resistance reversal agent.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry and relates to a pyrimido[4,5-d][1,2,3]triazole derivative, a preparation method thereof, and a use thereof. Background Art

[0002] Heterocycles are one of the most active fields in medicinal chemistry research. Pyrimido[4,5-d][1,2,3]triazole is a purine analogue with a nitrogen-containing aromatic fused heterocyclic structure, which is composed of a pyrimidine ring fused with a 1,2,3-triazole ring. Due to having a molecular structure highly similar to that of the bioactive molecule purine, pyrimido[4,5-d][1,2,3]triazole structures have received extensive attention in the biomedical field and are used as enzyme inhibitors, tubulin regulators, angiogenesis inhibitors, DNA intercalators, transcriptional regulators, gene regulators, etc. Therefore, the synthesis of novel pyrimido[4,5-d][1,2,3]triazoles is an effective way to discover novel drugs. Summary of the Invention

[0003] In view of the above problems, the present invention provides a pyrimido[4,5-d][1,2,3]triazole derivative, a preparation method thereof, and a use thereof, which well solve the problems in the prior art.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0005] A pyrimido[4,5-d][1,2,3]triazole derivative, wherein the pyrimido[4,5-d][1,2,3]triazole derivative is a pyrimido[4,5-d][1,2,3]triazole derivative containing an aminodithioester, and the pyrimido[4,5-d][1,2,3]triazole derivative has the following general formula I:

[0006]

[0007] Wherein, when R 1 is methyl and the X position is N, R 2 is any one of phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, tert-butyl carboxylate, methyl, and 4-hydroxyphenyl;

[0008] When R 2 is tert-butyl acetate and the X position is N, R 1 is any one of ethyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, and propyl;

[0009] When R 1 is methyl, the X-R 2 position is 0, S, or C;

[0010] When R 1 is methyl and the X position is C, R 2 is phenyl.

[0011] Optionally, when the pyrimido[4,5-d][1,2,3]triazole derivative R 2 is tert-butyl acetate, R1 is benzyl or propyl.

[0012] A preparation method, which is the preparation method of a pyrimido-triazole derivative as described in any one of the above, including:

[0013] Dissolve 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and a substituted indole compound in hexafluoroisopropanol, add a Bronsted acid catalyst, and stir and react at 100 °C. The Bronsted acid catalyst is bis(trifluoromethanesulfonyl)imide. After the reaction is complete, the product of general formula II is obtained through separation and purification as follows:

[0014]

[0015] Dissolve the product in the general formula, carbon disulfide and a substituted piperazine compound in acetone, add a base catalyst and stir and react at room temperature. After the reaction is complete, the pyrimido-triazole derivative containing aminodithioester is obtained through separation and purification. The base catalyst is sodium phosphate.

[0016] Optionally, the substituted indole compound is 1-methyl-1H-indole.

[0017] Optionally, the substituted piperazine compound is any one of phenylpiperazine, 1-(4-methoxyphenyl)piperazine, 1-(2-methoxyphenyl)piperazine, 1-(4-trifluoromethylphenyl)piperazine, 1-(4-fluorophenyl)piperazine, tert-butyl piperazine-1-carboxylate, morpholine, N-methylpiperazine, 4-(piperazin-1-ylmethyl)phenol, thiomorpholine, 4-phenylpiperidine, piperidine.

[0018] Optionally, the substituted piperazine compound is tert-butyl 2-(piperidin-1-yl)acetate.

[0019] Optionally, the substituted indole compound is any one of 1-ethyl-1H-indole, 1-benzyl-1H-indole, 1-(4-chlorobenzyl)-1H-indole, 1-(4-methylbenzyl)-1H-indole, 1-propyl-1H-indole.

[0020] A use, the pyrimido-triazole derivative according to any one of the above can be used to prepare a drug resistance reversal agent.

[0021] Optionally, the structural formula of the pyrimido-triazole derivative used to prepare the drug resistance reversal agent is as follows:

[0022]

[0023] Optionally, the structural formula of the pyrimido-triazole derivative used to prepare the drug resistance reversal agent is as follows:

[0024]

[0025] A use, the pyrimidine-triazole derivatives described in any one of the above can be used to prepare a multidrug resistance reversing agent.

[0026] Compared with the prior art, the present invention has the following beneficial effects: by synthesizing pyrimidine-triazole derivatives containing amino dithiocarbonate, the reversal activities of some of the compounds are significantly better than those of the ABCB1 inhibitor Verapamil (VRP), and they can be used as candidate or lead compounds for further development and applied to the preparation of multidrug resistance reversing agents. Detailed implementation manners

[0027] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0028] The embodiments of the present invention disclose a pyrimidine-triazole derivative, which is a pyrimidine-triazole derivative containing amino dithiocarbonate, and the pyrimidine-triazole derivative has the following general formula I:

[0029]

[0030] Wherein, when R 1 is methyl and the X position is N, R 2 is any one of phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, tert-butyl carboxylate, methyl and 4-hydroxyphenyl;

[0031] When R 2 is tert-butyl acetate and the X position is N, R 1 is any one of ethyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl and propyl;

[0032] When R 1 is methyl, the X-R 2 position is O, S or C;

[0033] When R 1 is methyl and the X position is C, R 2 is phenyl.

[0034] For the convenience of preparing a pyrimidine-triazole derivative in the present invention, the present invention also discloses a preparation method.

[0035] Example 1:

[0036] Dissolve 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and a substituted indole compound in hexafluoroisopropanol, add a Bronsted acid catalyst (bis(trifluoromethanesulfonyl)imide), and stir the reaction at 100 °C. After the reaction is complete, perform separation and purification to obtain the product general formula II as follows:

[0037]

[0038] Dissolve the product in the general formula, carbon disulfide, and a substituted piperazine compound in acetone, add an alkali catalyst (sodium phosphate), and stir the reaction at room temperature. After the reaction is complete, perform separation and purification to obtain a pyrimido-triazole derivative containing aminodithioate.

[0039] Among them, the method for synthesizing the product of general formula II from 1-methyl-1H-indole is as follows: Take 1 g (about 1 eq) of 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and 0.775 g (about 1.2 eq) of 1-methyl-1H-indole, add them to a 50 mL round-bottom flask, then add 10 mL of hexafluoroisopropanol solvent, then add 0.138 g (about 0.1 eq) of bis(trifluoromethanesulfonyl)imide, and reflux in an environment of 100 °C for 6 - 8 h. Monitor the reaction system by TLC until the reaction is complete. After the reaction system cools to room temperature, perform column chromatography separation and purification to obtain the pure compound 5-(chloromethyl)-7-(1-methyl-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.

[0040] The method for preparing a pyrimido-triazole derivative containing aminodithioate based on 5-(chloromethyl)-7-(1-methyl-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine is as follows:

[0041] Take 0.2 g (about 1 eq) of 5-(chloromethyl)-7-(1-methyl-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, 0.076 g (about 1.5 eq) of carbon disulfide, and a substituted piperazine compound, add them to a 50 mL round-bottom flask, then add 0.11 (about 1.0 eq) of sodium phosphate and 10 mL of acetone solvent, and stir the reaction at room temperature. Monitor the reaction system by TLC until the reaction is complete. After the reaction system cools to room temperature, perform column chromatography separation and purification to obtain a pure compound.

[0042] Example 2:

[0043] When the substituted piperazine compound in Example 1 is 0.13 g (about 1.2 eq) of phenylpiperazine, the compound is a white solid, and its yield is calculated to be about 78% by detection. The structural formula of the compound is:

[0044]

[0045] The characterization results are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.44 (s, 1H), 8.10 - 8.04 (m, 1H), 7.88 (s, 1H), 7.39 - 7.35 (m, 1H), 7.30 (dq, J = 5.5, 1.8 Hz, 2H), 7.21 - 7.17 (m, 2H), 6.82 (dd, J = 8.4, 7.7 Hz, 3H), 4.92 (s, 2H), 4.45 (s, 2H), 4.07 (s, 2H), 3.85 (s, 3H), 3.25 - 3.18 (m, 4H).

[0046] 13 NMR (100 MHz, CDCl 3 ) δ 195.86, 163.02, 156.00, 155.34, 150.23, 143.06, 137.54, 136.99, 129.40, 125.90, 123.54, 122.56, 120.68, 120.57, 116.40, 110.65, 106.12, 104.35, 48.85, 42.69, 42.65, 33.86.

[0047] Example 3:

[0048] When the substituted piperazine compound in Example 1 is 0.15 g (about 1.2 eq) of 1-(4-methoxyphenyl)piperazine, the compound is a white solid, and its yield is calculated to be about 68% by detection. The structural formula of the compound is:

[0049]

[0050] The characterization results are as follows: 1 H NMR (400 MHz, CDCl 3) δ 8.96 (s, 1H), 8.52 (s, 1H), 8.16 (dd, J = 5.9, 3.1 Hz, 1H), 7.98 (s, 1H), 7.48 - 7.34 (m, 3H), 6.91 - 6.77 (m, 4H), 5.01 (s, 2H), 4.53 (s, 2H), 4.14 (s, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 3.26 - 3.09 (m, 4H).

[0051] 13 NMR (100 MHz, CDCl 3 ) δ 195.67, 163.18, 156.00, 155.33, 143.06, 137.55, 136.94, 125.93, 123.52, 122.55, 120.62, 110.61, 106.17, 104.40, 54.50, 45.65, 42.77, 42.72, 33.86.

[0052] Example 4:

[0053] When the substituted piperazine compound in Example 1 was 0.15 g (about 1.2 eq) of 1-(2-methoxyphenyl)piperazine, the compound was a white solid, and its yield was calculated to be about 68% by detection. The structural formula of the compound is:

[0054]

[0055] The characterization results were: 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.05 (s, 1H), 8.73 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 7.91 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.42 - 7.28 (m, 2H), 6.98 (dt, J = 14.6, 5.9 Hz, 2H), 6.87 (d, J = 3.7 Hz, 2H), 4.96 (s, 2H), 4.43 (s, 2H), 4.14 (s, 2H), 3.98 (s, 3H), 3.79 (s, 3H), 3.16 - 3.04 (m, 4H).

[0056] 13 NMR (100 MHz, CDCl 3)δ 195.70, 163.23, 156.03, 155.35, 152.35, 143.10, 139.98, 137.57, 136.94, 125.96, 123.94, 123.54, 122.59, 121.17, 120.64, 118.66, 111.50, 110.62, 106.23, 104.43, 55.55, 50.47, 50.35, 42.72, 33.87。

[0057] Example 5:

[0058] When the substituted piperazine compound in Example 1 is 0.15 g (about 1.2 eq) of 1-(4-trifluoromethylphenyl)piperazine, this compound is a white solid, and its yield is about 68% as detected and calculated. The structural formula of this compound is:

[0059]

[0060] The characterization results are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (s, 1H), 8.45 (s, 1H), 8.10 (dd, J = 6.4, 2.4 Hz, 1H), 7.91 (s, 1H), 7.46 - 7.38 (m, 3H), 7.35 - 7.28 (m, 2H), 6.81 (d, J = 8.7 Hz, 2H), 4.95 (s, 2H(, 4.45 (s, 2H), 4.11 (s, 2H), 3.89 (s, 3H), 3.42 - 3.31 (m, 4H).

[0061] 13 NMR (100 MHz, CDCl 3 ) δ 196.19, 162.89, 156.04, 155.39, 152.16, 143.15, 137.59, 137.05, 126.71, 126.67, 125.93, 123.57, 122.60, 122.57, 120.56, 114.56, 110.68, 106.20, 104.37, 47.31, 45.51, 42.71, 33.88.

[0062] Example 6:

[0063] When the substituted piperazine compound in Example 1 is 0.14 g (about 1.2 eq) of 1-(4-fluorophenyl)piperazine, this compound is a white solid, and its yield is about 68% as detected and calculated. The structural formula of this compound is:

[0064]

[0065] The characterization results are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, 1H), 8.45 (s, 1H), 8.08 (dd, J = 6.2, 2.7 Hz, 1H), 7.90 (s, 1H), 7.41 - 7.37 (m, 1H), 7.34 - 7.27 (m, 2H), 6.93 - 6.85 (m, 2H), 6.80 - 6.75 (m, 2H), 4.93 (s, 2H), 4.45 (s, 2H), 4.05 (dd, J = 8.1, 6.1 Hz, 2H), 3.87 (s, 3H), 3.13 (M, 4H).

[0066] 13 NMR (100 MHz, CDCl 3 ) δ 195.99, 163.03, 156.04, 155.38, 146.97, 143.12, 137.58, 137.00, 125.94, 123.55, 122.57, 120.59, 118.57, 118.50, 115.99, 115.77, 110.65, 106.20, 104.40, 50.04, 42.74, 42.69, 33.87.

[0067] Example 7:

[0068] When the substituted piperazine compound in Example 1 is 0.15 g (about 1.2 eq) of tert-butyl piperazine-1-carboxylate, this compound is a white solid, and its yield is calculated to be about 72% by detection. The structural formula of this compound is:

[0069]

[0070] The characterization results are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.73 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.37 (dt, J = 14.8, 7.2 Hz, 2H), 4.95 (s, 2H), 4.15 (d, J = 97.1 Hz, 4H), 3.99 (s, 3H), 3.55 - 3.43 (m, 4H), 1.42 (s, 9H).

[0071] 13 NMR (100 MHz, CDCl 3)δ196.29, 162.92, 156.02, 155.37, 154.47, 143.12, 137.58, 137.00, 125.93, 123.57, 122.55, 120.56, 110.66, 106.17, 104.39, 80.75, 42.70, 42.65, 33.91, 33.87, 28.43.

[0072] Example 8:

[0073] When the substituted piperazine compound in Example 1 is 0.07 g (about 1.2 eq) of morpholine, the compound is a white solid, and its yield is about 49% as detected and calculated. The structural formula of the compound is:

[0074]

[0075] The characterization results are: 1 H NMR (400 MHz, CDCl 3 )δ8.90 (s, 1H), 8.45 (s, 1H), 8.08 (dd, J = 6.1, 2.8 Hz, 1H), 7.89 (s, 1H), 7.35 (dtt, J = 15.6, 7.3, 3.8 Hz, 3H), 4.92 (s, 2H), 4.38 - 3.84 (m, 7H), 3.70 (s, 4H).

[0076] 13 NMR (100 MHz, CDCl 3 ) 6196.32, 162.96, 156.02, 155.37, 143.12, 137.58, 137.00, 125.94, 123.57, 122.55, 120.57, 110.66, 106.19, 104.39, 66.33, 66.26, 42.54, 33.87.

[0077] Example 9:

[0078] When the substituted piperazine compound in Example 1 is 0.08 g (about 1.2 eq) of N-methylpiperazine, the compound is a white solid, and its yield is about 59% as detected and calculated. The structural formula of the compound is:

[0079]

[0080] The characterization results are: 1 H NMR (400 MHz, DMSO-d 6) δ 9.06 (s, 1H), 8.73 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.38 (dt, J = 14.7, 7.1 Hz, 2H), 4.94 (s, 2H), 4.27 (s, 2H), 3.99 (s, 5H), 2.45 - 2.36 (m, 4H), 2.20 (s, 3H).

[0081] 13 C NMR (100 MHz, DMSO-d 6 ) δ 194.57, 163.08, 155.90, 155.86, 142.73, 137.99, 137.79, 125.54, 123.71, 122.71, 120.40, 112.03, 105.77, 103.34, 54.56, 52.08, 50.42, 45.57, 42.42, 33.99.

[0082] Example 10:

[0083] When the substituted piperazine compound in Example 1 was 0.14 g (about 1.2 eq) of 4-(piperazin-1-ylmethyl)phenol, the compound was a white solid, and its yield was calculated to be about 53% by detection. The structural formula of the compound is:

[0084]

[0085] The characterization results were as follows: 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.08 (s, 1H), 8.92 (s, 1H), 8.73 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.43 - 7.30 (m, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.9 Hz, 2H), 4.97 (s, 2H), 4.41 (s, 4H), 4.00 (s, 3H), 3.16 - 3.04 (m, 4H).

[0086] 13 C NMR (100 MHz, DMSO-d 6)δ194.65, 163.12, 155.94, 152.05, 143.66, 142.78, 138.03, 137.82, 125.57, 123.74, 122.75, 120.42, 118.89, 116.09, 112.09, 105.86, 103.36, 50.49, 50.40, 42.41, 34.01。

[0087] Example 11:

[0088] When the substituted piperazine compound in Example 1 is 0.083 g (about 1.2 eq) of thiomorpholine, the compound is a white solid, and its yield is about 52% as detected and calculated. The structural formula of the compound is:

[0089]

[0090] The characterization results are: 1 H NMR (400 MH, DMSO-a 6 )δ9.07 (s, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.90 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.45 - 7.32 (m, 2H), 4.95 (s, 2H), 4.44 (d, j_-97.4 Hz, 4H), 4.00 (s, 3H), 2.88 - 2.64 (m, 4H).

[0091] 13 C NMR (100 MHz, DMSO-d 6 )δ195.63, 162.93, 156.01, 155.35, 143.10, 137.57, 137.00, 125.91, 123.57, 122.53, 120.51, 110.67, 106.05, 104.35, 42.81, 42.77, 33.87, 27.45.

[0092] Example 12:

[0093] When the substituted piperazine compound in Example 1 is 0.13 g (about 1.2 eq) of 4-phenylpiperidine, the compound is a white solid, and its yield is about 47% as detected and calculated. The structural formula of the compound is:

[0094]

[0095] The characterization results are: 11H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.73 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.43 - 7.15 (m, 7H), 5.52 (s, 1H), 4.96 (d, J = 5.2 Hz, 2H), 4.73 (s, 1H), 3.99 (s, 3H), 3.51 (s, 2H), 2.96 (t, J = 12.0 Hz, 1H), 1.94 (d, J = 12.8 Hz, 2H), 1.63 (d, J = 11.4 Hz, 2H).

[0096] 13 13C NMR (100 MHz, DMSO-d 6 ) δ 194.91, 163.43, 156.01, 155.32, 144.24, 143.09, 137.57, 136.93, 128.73, 126.81, 125.97, 123.55, 122.63, 120.66, 110.62, 106.24, 104.45, 53.19, 42.95, 42.64, 33.89, 32.93.

[0097] Example 13:

[0098] When the substituted piperazine compound in Example 1 was 0.068 g (about 1.2 eq) of piperidine, the compound was a white solid, and its yield was calculated to be about 45% by detection. The structural formula of the compound is:

[0099]

[0100] Characterization results were as follows: 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.05 (s, 1H), 8.72 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.37 (dt, J = 25.9, 7.3 Hz, 2H), 4.93 (s, 2H), 4.28 (s, 2H), 3.99 (s, 5H), 1.72 - 1.54 (m, 6H).

[0101] 13 13C NMR (100 MHz, DMSO-d 6)δ 194.28, 163.55, 155.97, 155.26, 143.00, 137.53, 136.89, 125.93, 123.49, 122.47, 120.67, 110.58, 106.16, 104.42, 54.03, 42.78, 33.85, 26.20, 24.30.

[0102] Example 14:

[0103] When the substituted indole compound is 1-ethyl-1H-indole, take 1 g (about 1 eq) of 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and 0.858 g (about 1.2 eq) of 1-ethyl-1H-indole, and add them to a 50 mL round-bottom flask. Then add 10 mL of hexafluoroisopropanol solvent, and then add 0.138 g (about 0.1 eq) of bis(trifluoromethanesulfonyl)imide and reflux in an environment of 100 °C for 6 - 8 h. Monitor the reaction system by TLC until the reaction is complete. After the reaction system cools to room temperature, separate and purify it by column chromatography to obtain the pure compound 5-(chloromethyl)-7-(1-ethyl-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine. Take 0.2 g (about 1 eq) of 5-(chloromethyl)-7-(1-ethyl-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, 0.073 g (about 1.5 eq) of carbon disulfide, and 0.15 g (about 1.2 eq) of tert-butyl 2-(piperidin-1-yl)acetate, and add them to a 50 mL round-bottom flask. Then add 1.0 eq of sodium phosphate and 10 mL of acetone solvent, and stir the reaction at room temperature. Monitor the reaction system by TLC until the reaction is complete. After the reaction system cools to room temperature, separate and purify it by column chromatography to obtain the pure compound. This compound is a white solid, and its yield is about 43% after detection and calculation. The structural formula of this compound is:

[0104]

[0105] The characterization results are as follows: 1 H NMR (400 MHz, DMSO-d 6 )δ 9.12 (s, 1H), 8.74 (s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.93 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.43 - 7.31 (m, 2H), 4.95 (s, 2H), 4.45 (q, J = 7.2 Hz, 2H), 4.28 (s, 2H), 4.00 (s, 2H), 3.19 (s, 2H), 2.72 - 2.62 (m, 4H), 1.46 (t, J = 7.2 Hz, 3H), 1.38 (s, 9H).

[0106] 13 C NMR (100 MHz, DMSO-d 6 ) δ 194.46, 169.56, 163.09, 155.91, 155.83, 142.72, 136.71, 136.44, 125.72, 123.68, 122.69, 120.59, 112.03, 105.89, 103.55, 80.88, 58.66, 52.16, 51.75, 51.65, 50.53, 42.38, 41.89, 28.24, 15.70.

[0107] Example 15:

[0108] When the substituted indole compound is 1-benzyl-1H-indole, take 1 g (about 1 eq) of 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and 0.858 g (about 1.2 eq) of 1-benzyl-1H-indole, and add them to a 50 mL round-bottom flask. Then add 10 mL of hexafluoroisopropanol solvent, and then add 0.138 g (about 0.1 eq) of bis(trifluoromethanesulfonyl)imide and reflux in an environment of 100 °C for 6 - 8 h. Monitor the reaction system by TLC until the reaction is complete. After the reaction system cools to room temperature, purify it by column chromatography to obtain the pure compound 7-(1-benzyl-1H-indol-3-yl)-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine. Take 0.2 g (about 1 eq) of 7-(1-benzyl-1H-indol-3-yl)-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine, 0.061 g (about 1.5 eq) of carbon disulfide and 0.13 g (about 1.2 eq) of tert-butyl 2-(piperidin-1-yl)acetate, and add them to a 50 mL round-bottom flask. Then add 1.0 eq of sodium phosphate and 10 mL of acetone solvent, and stir and react at room temperature. Monitor the reaction system by TLC until the reaction is complete. After the reaction system cools to room temperature, purify it by column chromatography to obtain the pure compound. This compound is a white solid, and its yield is about 49% after detection and calculation. The structural formula of this compound is:

[0109]

[0110] Characterization results are as follows: 1 H NMR (400 MHz, DMSO-d 6)δ9.27(s, 1H), 8.74(s, 1H), 8.20(dd, J = 6.5, 2.7Hz, 1H), 7.97(s, 1H), 7.71(dd, J = 6.5, 2.8Hz, 1H), 7.41 - 7.21(m, 7H), 5.70(s, 2H), 4.97(s, 2H), 4.28(s, 2H), 4.03(dd, J = 14.3, 7.2Hz, 2H), 3.19(s, 2H), 2.76 - 2.59(m, 4H), 1.37(s, 9H).

[0111] 13 C NMR(101MHz, DMSO-d 6 )δ194.44, 169.53, 163.20, 155.97, 155.82, 142.54, 137.31, 136.91, 136.54, 132.85, 129.58, 129.22, 125.80, 123.92, 122.87, 120.68, 112.44, 106.24, 104.16, 80.88, 58.62, 52.10, 51.55, 49.53, 42.37, 28.22.

[0112] Example 16:

[0113] When the substituted indole compound is 1-(4-chlorobenzyl)-1H-indole, take 1 g (about 1 eq) of 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and 0.858 g (about 1.2 eq) of 1-(4-chlorobenzyl)-1H-indole, and add them to a 50 mL round-bottom flask. Then add 10 mL of hexafluoroisopropanol solvent, and further add 0.138 g (about 0.1 eq) of bis(trifluoromethanesulfonyl)imide and reflux in an environment of 100 °C for 6 - 8 h. Monitor this reaction system by TLC until the reaction is complete. After this reaction system cools to room temperature, perform column chromatography separation and purification to obtain the pure compound 7-(1-(4-chlorobenzyl)-1H-indol-3-yl)-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine. Take 0.2 g (about 1 eq) of 7-(1-(4-chlorobenzyl)-1H-indol-3-yl)-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine, 0.055 g (about 1.5 eq) of carbon disulfide, and 0.12 g (about 1.2 eq) of tert-butyl 2-(piperidin-1-yl)acetate, and add them to a 50 mL round-bottom flask. Then add 1.0 eq of sodium phosphate and 10 mL of acetone solvent, and stir and react at room temperature. Monitor this reaction system by TLC until the reaction is complete. After this reaction system cools to room temperature, perform column chromatography separation and purification to obtain the pure compound. This compound is a white solid, and its yield is approximately 46% as detected and calculated. The structural formula of this compound is:

[0114]

[0115] The characterization results are as follows: 1 H NMR(400MHz, DMSO-d 6 )δ9.28(s, 1H), 8.75(s, 1H), 8.20(dd, J = 6.5, 2.7Hz, 1H), 7.97(s, 1H), 7.69(dd, J = 6.5, 2.7Hz, 1H), 7.36(ddd, J = 15.4, 14.5, 8.5Hz, 6H), 5.71(s, 2H), 4.97(s, 2H), 4.28(s, 2H), 4.00(s, 2H), 3.19(s, 2H), 2.73 - 2.58(m, 4H), 1.37(s, 9H).

[0116] 13 C NMR(100MHz, DMSO-d 6)δ 194.44, 169.53, 163.20, 155.97, 155.82, 142.54, 137.31, 136.91, 136.54, 132.85, 129.58, 129.22, 125.80, 123.92, 122.87, 120.68, 112.44, 106.24, 104.16, 80.88, 58.62, 52.10, 51.69, 51.55, 49.53, 42.37, 28.22。

[0117] Example 17:

[0118] When the substituted indole compound is 1-(4-methylbenzyl)-1H-indole, take 1 g (about 1 eq) of 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and 0.858 g (about 1.2 eq) of 1-(4-methylbenzyl)-1H-indole, and add them to a 50 mL round-bottom flask. Then add 10 mL of hexafluoroisopropanol solvent, and then add 0.138 g (about 0.1 eq) of bis(trifluoromethanesulfonyl)imide and reflux in an environment of 100 °C for 6 - 8 h. Monitor this reaction system by TLC until the reaction is complete. After this reaction system cools to room temperature, it is separated and purified by column chromatography to obtain the pure compound 5-(chloromethyl)-7-(1-(4-methylbenzyl)-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine. Take 0.2 g (about 1 eq) of 5-(chloromethyl)-7-(1-(4-methylbenzyl)-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, 0.058 g (about 1.5 eq) of carbon disulfide, and 0.12 g (about 1.2 eq) of tert-butyl 2-(piperidin-1-yl)acetate, and add them to a 50 mL round-bottom flask. Then add 1.0 eq of sodium phosphate and 10 mL of acetone solvent, and stir and react at room temperature. Monitor this reaction system by TLC until the reaction is complete. After this reaction system cools to room temperature, it is separated and purified by column chromatography to obtain the pure compound e16. This compound is a white solid, and its yield is about 53% after detection and calculation. The structural formula of this compound is:

[0119]

[0120] The characterization results are: 1 H NMR(400MHz, DMSO-d 6)δ 9.25 (s, 1H), 8.74 (s, 1H), 8.19 (dd, J = 6.4, 2.7 Hz, 1H), 7.96 (s, 1H), 7.69 (dd, J = 6.4, 2.8 Hz, 1H), 7.35 (dd, J = 6.1, 3.1 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 5.63 (s, 2H), 4.96 (s, 2H), 4.09 (dd, J = 57.8, 50.8 Hz, 4H), 3.19 (s, 2H), 2.73 - 2.57 (m, 4H), 2.24 (s, 3H), 1.37 (s, 9H).

[0121] 13 C NMR (100 MHz, DMSO-d 6 )δ 163.14, 155.95, 155.83, 142.61, 137.48, 137.29, 136.98, 134.41, 129.75, 127.73, 125.81, 123.78, 122.76, 120.60, 112.53, 106.13, 103.93, 58.59, 51.58, 50.11, 42.38, 28.22, 21.13.

[0122] Example 18:

[0123] When the substituted indole compound is 1-propyl-1H-indole, take 1 g (about 1 eq) of 7-chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and 0.858 g (about 1.2 eq) of 1-propyl-1H-indole, and add them to a 50 mL round-bottom flask. Then add 10 mL of hexafluoroisopropanol solvent, and then add 0.138 g (about 0.1 eq) of bis(trifluoromethanesulfonyl)imide and reflux in an environment of 100 °C for 6 - 8 h. Monitor this reaction system by TLC until the reaction is complete. After this reaction system cools to room temperature, it is separated and purified by column chromatography to obtain the pure compound 5-(chloromethyl)-7-(1-propyl-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine. Take 0.2 g (about 1 eq) of 5-(chloromethyl)-7-(1-propyl-1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, 0.070 g (about 1.5 eq) of carbon disulfide, and 0.15 g (about 1.2 eq) of tert-butyl 2-(piperidin-1-yl)acetate, and add them to a 50 mL round-bottom flask. Then add 1.0 eq of sodium phosphate and 10 mL of acetone solvent, and stir and react at room temperature. Monitor this reaction system by TLC until the reaction is complete. After this reaction system cools to room temperature, it is separated and purified by column chromatography to obtain the pure compound e17. This compound is a white solid, and its yield is about 61% after detection and calculation. The structural formula of this compound is:

[0124]

[0125] The characterization results are as follows: 1 H NMR(400MHz, DMSO-d 6 )δ9.11(s, 1H), 8.74(s, 1H), 8.19(d, J = 7.4Hz, 1H), 7.94(s, 1H), 7.76(d, J = 7.4Hz, 1H), 7.47 - 7.28(m, 2H), 4.95(s, 2H), 4.35(dd, J = 26.8, 19.8Hz, 4H), 4.04(dd, J = 14.4, 7.2Hz, 2H), 3.20(s, 2H), 2.65(s, 4H), 1.86(dd, J = 14.2, 7.1Hz, 2H), 1.39(s, 9H), 0.90(t, J = 7.3Hz, 3H).

[0126] 13 C NMR(100MHz, DMSO-d 6) δ 194.48, 169.51, 163.07, 155.91, 155.83, 142.70, 137.08, 125.63, 123.66, 122.64, 120.56, 112.15, 105.91, 103.45, 80.89, 58.64, 51.65, 50.48, 48.40, 42.40, 28.23, 23.40, 11.52.

[0127] Verification example:

[0128] The compounds obtained in the examples were used to determine the reversal activity and reversal fold (mean ± SD, n = 3) of combined use of PTX, DPX, and VCR against MCF-7 / ADR cells by the MTT method. The results are as follows:

[0129]

[0130] The experimental results show that the sensitivity of the drug-resistant cell line MCF 7 / ADR to the drugs PTX, D0X, and VCR was significantly enhanced under the action of the non-toxic concentration of 2 μM of some pyrimido-triazole derivatives of aminodithioesters, indicating that such derivatives have obvious ability to reverse drug resistance. Among them, the reversal activities of MY-1924, MY-2524, MY-2532, MY-2533, MY-2543, and MY-2544 were significantly better than those of the ABCB1 inhibitor Verapamil (VRP), and they can be used as candidates or lead compounds for further development and applied to the preparation of drug resistance reversal agents. Among them, the reversal activity of MY-2532 against the drug PTX and DOX and that of MY-2544 against the drug VCR were significantly better than others.

[0131] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent substitution on some of the technical features. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A pyrimidotriazole derivative, characterized in that: The pyrimidotriazole derivative is a pyrimidotriazole derivative containing an aminodithioester, and the pyrimidotriazole derivative has the following general formula I: Wherein, when R1 is methyl and X is N, R2 is any one of phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, tert-butyl carboxylate, methyl and 4-hydroxyphenyl; When R2 is tert-butyl acetate and the X position is N, R1 is any one of ethyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl and propyl; When R1 is methyl, the X-R2 position is O, S or C; When R1 is methyl and X is C, R2 is phenyl.

2. A pyrimidotriazole derivative according to claim 1, characterized in that: When R2 of the pyrimidotriazole derivative is tert-butyl acetate, R1 is benzyl or propyl.

3. A preparation method, characterized in that: The preparation method is a preparation method of a pyrimidotriazole derivative according to any one of claims 1 to 2, comprising: 7-Chloro-5-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine and substituted indole compounds are dissolved in hexafluoroisopropanol, and a Bronsted acid catalyst is added. The mixture is stirred and reacted at 100° C. The Bronsted acid catalyst is bistrifluoromethanesulfonimide. After the reaction is complete, the product is separated and purified to obtain a product of the general formula II as follows: The product in the general formula, carbon disulfide and substituted piperazine compounds are dissolved in acetone, and a base catalyst is added to react under stirring at room temperature. After the reaction is complete, the aminodithioester-containing pyrimidotriazole derivative is obtained by separation and purification, and the base catalyst is sodium phosphate.

4. A preparation method according to claim 3, characterized in that: The substituted indole compound is 1-methyl-1H-indole.

5. A preparation method according to claim 4, characterized in that: The substituted piperazine compound is any one of phenylpiperazine, 1-(4-methoxyphenyl)piperazine, 1-(2-methoxyphenyl)piperazine, 1-(4-trifluoromethylphenyl)piperazine, 1-(4-fluorophenyl)piperazine, piperazine-1-carboxylic acid tert-butyl ester, morpholine, N-methylpiperazine, 4-(piperazin-1-ylmethyl)phenol, thiomorpholine, 4-phenylpiperidine, and piperidine.

6. A preparation method according to claim 3, characterized in that: The substituted piperazine compound is tert-butyl 2-(piperidin-1-yl)acetate.

7. A preparation method according to claim 6, characterized in that: The substituted indole compound is any one of 1-ethyl-1H-indole, 1-benzyl-1H-indole, 1-(4-chlorobenzyl)-1H-indole, 1-(4-methylbenzyl)-1H-indole and 1-propyl-1H-indole.

8. A use, characterized in that: The pyrimidine triazole derivative according to any one of claims 1 to 3 can be used to prepare a drug resistance reversal agent.

9. A use according to claim 8, characterized in that: The structural formula of the pyrimidine triazole derivatives used to prepare drug resistance reversal agents is as follows:

10. A use according to claim 8, characterized in that: The structural formula of the pyrimidine triazole derivatives used to prepare drug resistance reversal agents is as follows:

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