A 5-benzyl-2-amino-1,3-thiazole derivative and its synthesis method and application

Abstract

The invention relates to a 5-benzyl-2-amino-1,3-thiazole derivative and a synthesis method and application thereof. The thiazole derivative has at least one of the following structural formulas: wherein R is one of a halogen substituent, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxyl group, a C2-C3 straight-chain or branched alkoxy group or a morpholine propoxy group; R2 is one of an aromatic substituent or a heterocyclic substituent; is one of or; compared with the prior art, the invention uses 5-benzyl-2-amino-1,3-thiazole as a skeleton, connects different substituents at the 2-position of thiazole and connects different substituents on the benzyl benzyl ring, thereby providing a new compound structure, and the obtained compound has good inhibitory activity on THP-1 and MV-4-11, and provides new possibilities for anti-leukemia research.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a 5-benzyl-2-amino-1,3-thiazole derivative and a synthesis method thereof and an application thereof in preparing a drug for inhibiting leukemia. Background Art

[0002] Leukemia is a malignant clonal disease of hematopoietic stem cells, which is essentially caused by the malignant proliferation of hematopoietic stem cells or genetic abnormalities of their own characteristics. Leukemia and lymphoma account for about 10% of cancer cases worldwide. Bone marrow transplantation has made important breakthroughs in the treatment of childhood leukemia, but chemotherapy is still the main treatment for adult leukemia patients, especially for elderly patients with low treatment success rates. Acute myeloid leukemia (AML) is a heterogeneous disease characterized by multiple genetic mutations. The cause is the proliferation, cloning, abnormal differentiation and occasional poorly differentiated cells of the hematopoietic system infiltrating the bone marrow, blood and various other organs and tissues. The main symptoms are lymph node and liver and spleen enlargement, bleeding and anemia and secondary infection. It is one of the most difficult malignant tumors to treat. Therefore, there is an urgent need to find new drugs for acute myeloid leukemia that can control tumor growth and minimize side effects.

[0003] 2-aminothiazole is one of the most widely studied thiazole compounds. As an isostere of phenol, catechol and other groups, 2-aminothiazole can effectively improve pharmacokinetics, lipid solubility and the tendency to regulate biological targets. The 2-amino group is an active functional group that can be connected to many active fragments through different reactions. Due to its unique chemical structure, 2-aminothiazole has good pharmacological and biological activities and is used as an important structural component unit in medicine and organic synthesis. It shows great application value in the field of medicine, such as antibacterial, anti-inflammatory, antiviral, anti-tumor, antihypertensive and neuroprotective agents. So far, many 2-aminothiazole compounds have been used in clinical treatment and play an important role in protecting human health. Summary of the invention

[0004] The purpose of the present invention is to provide a 5-benzyl-2-amino-1,3-thiazole derivative and a synthesis method and application thereof.

[0005] The purpose of the present invention can be achieved by the following technical solutions:

[0006] A 5-benzyl-2-amino-1,3-thiazole derivative having at least one of the following structural formulas:

[0007]

[0008] In the formula, R is one of a halogen substituent, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxyl group, a C2-C3 straight-chain or branched-chain alkoxy group, or a morpholine propoxy group;

[0009] R2 is one of an aromatic substituent or a heterocyclic substituent;

[0010] for One of;

[0011] Further, when R2 is an aromatic substituent, the aromatic substituent is one of phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl, alkoxy-substituted phenyl, trifluoromethyl-substituted phenyl, naphthyl, hydroxy-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, trifluoromethyl-substituted benzyl or halogen-substituted phenyl; preferably, one of phenyl, p-fluorophenyl, p-chlorophenyl, p-methylphenyl, p-hydroxyphenyl, 4-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 3,5-dichlorophenyl, p-cyanophenyl or p-nitrophenyl;

[0012] When R2 is a heterocyclic substituent, the heterocyclic substituent is one of thienyl, furanyl, pyridyl, pyrrolyl, indolyl, thiazolyl, benzothienyl, C1-C4 alkyl substituted thienyl, halogen substituted thienyl, C1-C4 alkyl substituted pyridyl, halogen substituted pyridyl or trifluoromethyl substituted pyridyl; preferably, 6-methylpyridyl, 6-bromopyridyl, 6-trifluoromethylpyridyl, 6-fluoropyridyl, 5-chloropyridyl, 6-chloropyridyl or 4-methylpyridyl.

[0013] A method for preparing 5-benzyl-2-amino-1,3-thiazole derivatives, the method comprising the following steps:

[0014]

[0015] S1: subjecting the compound represented by formula A to diazotization reaction with nitrite to obtain a diazonium salt;

[0016] S2: mixing the diazonium salt with magnesium oxide, a solution containing copper chloride and acrolein under ice bath conditions, and then reacting at room temperature to obtain a first intermediate as shown in formula B;

[0017] S3: mixing the first intermediate with thiourea and heating them for reaction to obtain a second intermediate as shown in formula C;

[0018] S4: mixing the second intermediate with pyridine and phenyl chloroformate in an ice bath, and then reacting at room temperature to obtain a third intermediate as shown in formula D;

[0019]

[0020] S5: reacting the third intermediate with cesium carbonate and a secondary amine as shown in formula G to obtain a thiazole derivative as shown in formula I accordingly.

[0021] Furthermore, in step S1, the molar ratio of the compound as shown in formula A to the nitrite is 1:(1-1.2); the reaction conditions of the diazotization reaction include ice-salt bath conditions;

[0022] In step S2, the molar ratio of the diazonium salt, magnesium oxide, copper chloride and acrolein is 1:(0.2-0.3):(0.25-0.35):(0.5-1.5);

[0023] In step S3, the molar ratio of the first intermediate to thiourea is 1:(1-1.2); in the heating reaction, the reaction solvent is ethanol, the reaction temperature is 80-100° C., and the reaction time is 4-5 h;

[0024] In step S4, the molar ratio of the second intermediate to pyridine and phenyl chloroformate is 1:(2-4):(3-5), the reaction time is 4-6 hours, and the reaction is carried out under the protection of an inert gas;

[0025] In step S5, the molar ratio of the third intermediate to cesium carbonate and the secondary amine is 1:(1.5-2.5):(0.8-1.2); during the reaction, the reaction solvent is 1,4-dioxane, the reaction temperature is 90-110° C., the reaction time is 4-5 h, and the reaction is carried out under the protection of an inert gas.

[0026] A method for preparing 5-benzyl-2-amino-1,3-thiazole derivatives, when the thiazole derivatives have a structural formula as shown in Formula I and R is a C2-C3 straight-chain or branched alkoxy group, the method comprises:

[0027]

[0028] The compound of formula H is mixed with boron tribromide in an ice bath, and then reacted at room temperature to obtain a compound of formula J; wherein the molar ratio of the compound of formula H to boron tribromide is 1:(3-5);

[0029] In formula H, R' is a C2-C3 straight chain or branched chain alkoxy group.

[0030] A method for preparing 5-benzyl-2-amino-1,3-thiazole derivatives, when the thiazole derivatives have a structural formula of formula III and R is a C2-C3 straight-chain or branched alkoxy group, the method comprises:

[0031]

[0032] The compound shown in Formula J is heated to react with K2CO3 and compound R"X to obtain a thiazole derivative shown in Formula III; wherein the molar ratio of the compound shown in Formula J to compound R"Cl and K2CO3 is 1:(0.8-1.2):(1.8-2.2); during the heating reaction, the reaction temperature is 45-55°C and the reaction time is 4-5h;

[0033] In the compound RX, X is a halogen substituent.

[0034] A method for preparing a 5-benzyl-2-amino-1,3-thiazole derivative, wherein the thiazole derivative has a structural formula as shown in Formula I and for hour,

[0035] The method comprises the following steps:

[0036]

[0037] N1: N-Boc-piperazine, compound R2X, base, Pd2dpa3, and XantPhos are mixed in an organic solvent and reacted in an inert gas atmosphere to obtain a compound as shown in formula K; or, N-Boc-piperazine, compound R2X, and NEt3 are mixed in an organic solvent and reacted at room temperature to obtain a compound as shown in formula K;

[0038] Wherein, in the compound R2X, X is a halogen substituent; the base is Cs2CO3;

[0039] N2: Mix the compound represented by formula K with trifluoroacetic acid in an ice bath, and then react at room temperature to obtain the compound represented by formula L;

[0040] N3: Mix the compound represented by formula L, the compound represented by formula M and Cs2CO3 in an organic solvent, and heat the mixture in an inert gas atmosphere to react, thereby obtaining a thiazole derivative represented by formula I.

[0041] Furthermore, in step N1, the molar ratio of N-Boc-piperazine, compound R2X, base, Pd2dpa3, and XantPhos is (1.5-1.8):(1.3-1.6):(2-2.2):(0.05-0.08):(0.1-0.15); the reaction temperature is 100-120°C;

[0042] The molar ratio of N-Boc-piperazine, compound R2X, and NEt3 is (1.4-1.8):(2-2.2):(1.4-1.8);

[0043] In step N2, the feed ratio of the compound represented by formula K to trifluoroacetic acid is (1-1.2) mmol: (3-5) mL;

[0044] In step N3, the molar ratio of the compound represented by formula L to the compound represented by formula M and Cs2CO3 is (0.2-0.3):(0.2-0.3):(0.3-0.5), the reaction solvent is 1,4-dioxane, and the reaction temperature of the heating reaction is 100-110°C.

[0045] An application of 5-benzyl-2-amino-1,3-thiazole derivatives, comprising using the thiazole derivatives to prepare a drug having inhibitory activity on human peripheral blood mononuclear cell lines and / or human myelomonocytic leukemia cells.

[0046] Compared with the prior art, the present invention has the following characteristics:

[0047] 1) The compound of the present invention uses 5-benzyl-2-amino-1,3-thiazole as the skeleton, connects different substituents at the 2-position of thiazole, connects different substituents on the benzyl ring and changes the position of the substituents, providing a new compound structure. The synthesized compounds are screened for activity, providing new possibilities for anti-leukemia research.

[0048] 2) The activity test data of the compounds synthesized by the present invention show that 5-benzyl-2-amino-1,3-thiazole derivatives have good inhibitory activity on peripheral blood mononuclear cell lines (THP-1) and human myelomonocytic leukemia cells (MV-4-11), providing a new framework for the treatment of leukemia. DETAILED DESCRIPTION

[0049] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments are implemented based on the above technical solution of the present invention, and provide detailed implementation methods and specific operation processes, but the protection scope of the present invention is not limited to the following embodiments.

[0050] Example 1: The preparation method of compound 5a comprises the following steps:

[0051]

[0052] S1: Dissolve compound a (0.3 g, 2.35 mmol) in 3 ml of 2M hydrochloric acid solution, transfer to an ice-salt bath and cool and stir. Dissolve sodium nitrite (0.178 g, 2.59 mmol) in 2 ml of ice water and slowly add dropwise to the above system to generate a diazonium salt, compound 1a, through diazotization reaction. Adjust the pH to neutral with saturated sodium bicarbonate aqueous solution. Proceed directly to the next step without post-treatment.

[0053] S2: Add magnesium oxide (24 mg, 0.59 mmol) to the crude product of compound 1a, and stir for half an hour under ice bath conditions to obtain system a. Add copper chloride (120 mg, 0.71 mmol) and acrolein (0.16 ml, 2.34 mmol) to 5 ml of acetone solvent, and stir for 5 minutes under ice bath conditions to obtain an acetone system. Slowly drop system a with magnesium oxide added to the above acetone system at 0°C, and stir at room temperature for 12 hours after the addition is complete. After the reaction is completed, extract with ethyl acetate, wash the organic phase with water and saturated brine, dry over anhydrous Na2SO4, and spin dry to obtain a crude product of intermediate compound 2a, which is directly subjected to the next step of reaction.

[0054] S3: The crude product of compound 2a and thiourea (0.12 g, 1.7 mmol) were dissolved in 6 ml of anhydrous ethanol, refluxed with stirring for 4-5 hours, cooled, and the solvent was removed by vortexing. The extraction was carried out with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous Na2SO4, and dried to give a crude product. The crude product was separated and purified to give 232 mg of a yellow solid 3a. The yield was 43.9%.

[0055] S4: Compound 3a (232 mg, 1.032 mmol) and pyridine (0.3 ml, 3.1 mmol) were dissolved in 10 ml of dichloromethane. Phenyl chloroformate (0.51 ml, 4.23 mmol) was slowly added dropwise to the above system in an ice-water bath under nitrogen protection. After the addition was completed, the mixture was stirred at room temperature for 5 hours, the solvent was removed by vortexing, and the mixture was extracted with dichloromethane. The organic phase was washed with water and saturated brine, dried over anhydrous Na2SO4, and dried to obtain a crude product. The crude product was separated and purified to obtain 284 mg of white solid 4a. The yield was 79.9%;

[0056] S5: Compound 4a (150 mg, 0.436 mmol), cesium carbonate (298.3 mg, 0.91 mmol), and 1-(4-chlorophenyl)piperazine (85.7 mg, 0.436 mmol) were added to 10 ml of 1,4-dioxane, and refluxed for 4-5 hours under nitrogen protection. TLC was followed until the reaction was completed. The mixture was cooled, dried by rotation, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous Na2SO4 to obtain a crude product. The crude product was separated and purified to obtain the final compound 5a as a light yellow solid (117.8 mg). The yield was 60.4%.

[0057] The H NMR spectrum is 1H NMR (500MHz, CDCl3) δ (ppm) 7.25 (d, J = 8.9 Hz, 2H), 7.22 (m, 3H), 7.13 (m, 1H), 7.01 (s,1H),6.84(d,J=8.9Hz,2H),4.02(s,2H),3.75–3.67(m,4H),3.19–3.10(m,4H);

[0058] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 154.2, 149.4, 141.2, 134.5, 132.1, 129.9, 129.1 ,128.5,127.0,126.6,125.5,124.5,124.0,119.1,117.9,49.3,44.0,34.8;

[0059] The following compounds can be synthesized in the same manner (unless otherwise specified, the remaining preparation steps and conditions of the following compounds are the same as those of compound 5a):

[0060] Compound 5b (using 3-methoxyaniline to replace compound a)

[0061]

[0062] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.24–7.22 (m, 1H), 7.22 (d, J = 2.2Hz, 1H), 7.21–7.17 (m, 1H), 6.97 (s, 1H), 6.84–6.79 ( m,3H),6.76(d,J=1.0Hz,1H),6.75–6.73(m,1H),3.99(s,2H),3.76(s,3H),3.70–3.65(m,4H),3.16–3.10(m,4H);

[0063] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 160.0, 149.5, 140.8, 129.8, 129.2, 125.6, 120.9, 118.0, 114.5, 112.1, 55.3, 49.4, 44.0, 33.1;

[0064] Compound 5c (using 3-methylaniline to replace compound a)

[0065]

[0066] The H NMR spectrum is 1H NMR (500MHz, CDCl3) δ (ppm) 7.24–7.22 (m, 1H), 7.23–7.20 (m, 1H), 7.15 (t, J = 7.5Hz, 1H), 7.02 (s, 2H), 7.01 (s, 1H), 6.95(s,1H),6.83–6.81(m,1H),6.81–6.79(m,1H),3.98(s,2H),3.70–3.64(m,4H),3.14–3.08(m,4H),2.29(s,3H);

[0067] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 149.5, 139.2, 138.4, 129.3, 128.7, 127.6, 125.6, 117.9, 49.4, 44.0, 33.1, 21.5;

[0068] Compound 5d (using p-methoxyaniline to replace compound a)

[0069]

[0070] The H NMR spectrum is 1 H NMR (500MHz, DMSO) δ (ppm) 11.11 (s, 1H), 7.24 (d, J = 2.2Hz, 1H), 7.22 (d, J = 2.2Hz, 1H), 7.17–7.15 (m, 1H), 7.15–7.14 (m, 1H), 7.05 (s, 1H), 6.98 –6.96(m,1H),6.95(d,J=2.2Hz,1H),6.88–6.86(m,1H),6.86(d,J=2.1H z,1H),3.91(s,2H),3.72(s,3H),3.64–3.59(m,4H),3.13–3.08(m,4H);

[0071] The carbon NMR spectrum is 13 C NMR (126MHz, DMSO) δ (ppm) 158.3, 150.1, 132.5, 129.8, 129.1, 123.2, 117.7, 114.3, 55.4, 48.5, 43.6, 30.2;

[0072] Compound 5e (using 4-chloroaniline to replace compound a)

[0073]

[0074] The H NMR spectrum is 1H NMR (500MHz, DMSO) δ (ppm) 11.01 (s, 1H), 7.28 (d, J = 8.4Hz, 2H), 7.19 (d, J = 8.4Hz, 2H), 7.16 (d, J = 8 .9Hz,2H),7.03(s,1H),6.88(d,J=9.0Hz,2H),3.92(s,2H),3.58–3.55(m,4H),3.07–3.01(m,4H);

[0075] The carbon NMR spectrum is 13 C NMR (126MHz, DMSO) δ (ppm) 150.1, 139.7, 131.5, 130.6, 129.1, 128.9, 123.2, 117.7, 48.5, 43.7, 31.9;

[0076] Compound 5f (using 2-chloroaniline to replace compound a)

[0077]

[0078] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.33 (dd, J=7.4, 1.8Hz, 1H), 7.30–7.23 (m, 3H), 7.22–7.14 (m ,2H),6.99(s,1H),6.87–6.80(m,2H),4.16(s,2H),3.73–3.63(m,4H),3.17–3.06(m,4H);

[0079] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 154.4, 149.5, 137.0, 133.8, 132.4, 130.6, 129.7, 129.1, 128.4, 127.2, 125.5, 117.9, 49.3, 44.0, 30.8;

[0080] Compound 5g (using 3-trifluoromethylaniline to replace compound a)

[0081]

[0082] The H NMR spectrum is 1H NMR(500MHz,CDCl3)δ(ppm)7.50(d,J=9.0Hz,2H),7.46–7.41(m,2H),7.25(d,J=8.8Hz,2H ),7.03(s,1H),6.84(d,J=8.9Hz,2H),4.12(s,2H),3.76–3.69(m,4H),3.21–3.12(m,4H);

[0083] The fluorine NMR spectrum is 19 F NMR (471MHz, CDCl3) δ (ppm)-62.52 (s, 3F);

[0084] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 149.4 140.2, 131.8, 131.2, 129.1, 125.1, 123.7, 122.9, 119.1, 117.8, 49.3, 43.9, 31.4;

[0085] Compound 5h (using 4-trifluoromethylaniline to replace compound a)

[0086]

[0087] The H NMR spectrum is 1 H NMR(500MHz,DMSO)δ(ppm)7.66(d,J=8.1Hz,2H),7.47(d,J=8.5Hz,2H),,7.23(d,J=8 .9Hz,2H),7.18(s,1H),6.95(d,J=9.0Hz,2H),4.11(s,2H),3.64(m,4H),3.12(m,4H);

[0088] The fluorine NMR spectrum is 19 F NMR (471MHz, DMSO) δ (ppm)-60.87 (s, 3F);

[0089] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 154.8, 150.2, 134.3, 133.8, 132.7, 132.5, 132.3, 130.5, 128.4, 128.0, 122.4, 53.3, 48.4, 37.0;

[0090] Compound 5i (using 2-trifluoromethylaniline to replace compound a)

[0091]

[0092] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.64 (d, J = 7.8Hz, 1H), 7.47 (t, J = 7.5Hz, 1H), 7.39 (d, J = 7.6Hz, 1H), 7.33 (t, J = 7.6Hz, 1H),7.26(d,J=9.0Hz,2H),6.97(s,1H),6.84(d,J=9.0Hz,2H),4.24(s,2H),3.73–3.65(m,4H),3.16–3.07(m,4H);

[0093] The fluorine NMR spectrum is 19 F NMR (471MHz, CDCl3) δ (ppm)-59.18 (s, 3F);

[0094] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 154.4, 149.4, 137.6, 132.7, 132.1, 131.4, 129.1, 128.4, 128.1, 127.0, 126.1, 125.5, 117.8, 49.2, 43.9, 29.6.

[0095] Compound 5j (using 2-methoxyaniline to replace compound a)

[0096]

[0097] The H NMR spectrum is 1 H NMR(500MHz, CDCl3)δ(ppm)7.25–7.23(m,1H),7.23–7.21(m,1H),7.15–7.13(m,1H),7.13–7.11(m,1 H),6.92(s,1H),6.83–6.79(m,4H),3.96(s,2H),3.76(s,3H),3.68–3.64(m,4H),3.14–3.09(m,4H);

[0098] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 158.44 (s, 2H), 149.47 (s, 2H), 131.37 (d, J = 6.4Hz, 3H), 129.49 (s, 12H),129.15(s,14H),125.63(d,J=7.0Hz,2H),117.84(s,12H),114.05(s,12H),49.45(s,1H).

[0099] Compound 5k (using 4-bromoaniline to replace compound a, and using 1-phenylpiperazine to replace 1-(4-chlorophenyl)piperazine)

[0100]

[0101] The H NMR spectrum is 1 H-NMR (500MHz, CDCl3) δ (ppm) 10.38 (s, 1H), 7.3 9(d,J=8.3Hz,2H),7.32-7.28(m,2H),7.10(d,J=8.3Hz,2H),6.97(s,1H ),6.94-6.90(m,3H),3.98(s,2H),3.70-3.67(m,4H),3.20-3.16(m,4H);

[0102] The carbon NMR spectrum is 13 C-NMR(125MH z, CDCl3) δ (ppm) 160.82, 150.88, 139.71, 131.34, 130.60, 128.95, 128.48, 12 8.33,126.39,126.31,119.46,119.27,116.25,115.87,48.33,43.36,31.44.

[0103] Compound 51 (using 3-bromoaniline to replace compound a, and using 1-phenylpiperazine to replace 1-(4-chlorophenyl)piperazine)

[0104]

[0105] The H NMR spectrum is 1 H-NMR (500MHz, CDCl3) δ (ppm) 10.84 (s, 1H), 7.36 (s, 1H), 7.34-7.27 (m, 3H), 7.20-7. 07(m,2H),6.99(s,1H),6.91(d,J=7.7Hz,3H),4.00(s,2H),3.69(s,4H),3.17(s,4H);

[0106] The carbon NMR spectrum is 13 C-NMR (125MHz, CDCl3) δ (ppm) 160.85,155.62,155.56,150.93,143.24,131.02,130 .67,129.25,128.96,127.48,121.72,119.26,116.26,115.87,48.38,43.36,31.64.

[0107] Compound 5m (using 2-bromoaniline to replace compound a, and using 1-phenylpiperazine to replace 1-(4-chlorophenyl)piperazine)

[0108]

[0109] The H NMR spectrum is 1 H-NMR (500MHz, CDCl3) δ (ppm) 7.50 (dd, J = 8.0, 1.1Hz, 1H), 7.31-7.26 (m, 3H), 7.24-7.20 (m, 1H), 7.09-7.05 (m, 1H) ),6.97(s,1H),6.94-6.90(m,3H),6.59(s,1H),4.15(s,2H),3.72-3.67(t,J=5Hz,4H),3.19-3.13(m,J=5Hz,4H);

[0110] The carbon NMR spectrum is 13 C-NMR (125MHz, CDCl3) δ (ppm) 162.51, 154.07, 150.92, 138.61, 133.19, 130.70, 129.36, 128.84,128.74,128.58,127.95,126.95,124.36,120.74,116.80,49.40,44.21,33.44.

[0111] Compound 5n (using 4-bromoaniline to replace compound a, and using 1-(4-methylphenyl)piperazine to replace 1-(4-chlorophenyl)piperazine)

[0112]

[0113] The H NMR spectrum is 1 H-NMR (500MHz, CDCl3) δ (ppm) 7.40-7.36 (m, 2H), 7.10 (dd, J = 10.0, 8.6Hz, 4H), 6.96 (s, 1H ),6.83(d,J=8.5Hz,2H),3.97(s,2H),3.69-3.66(m,4H),3.11-3.09(m,4H),2.29(s,3H);

[0114] The carbon NMR spectrum is 13C-NMR (125MHz, CDCl3) δ (ppm) 162.43, 154.33, 148.84, 139.42, 138.47, 132.59, 131.86, 130 .44,130.28,129.92,128.79,128.57,126.83,120.72,117.15,50.02,44.24,32.56,20.58.

[0115] Compound 5o (using 3-bromoaniline to replace compound a, and using 1-(4-methylphenyl)piperazine to replace 1-(4-chlorophenyl)piperazine)

[0116]

[0117] The H NMR spectrum is 1 H-NMR (500MHz, CDCl3) δ (ppm) 7.36-7.31 (m, 1H), 7.25 (d, J = 3.0Hz, 1H), 7.23-7.18 (m, 1H), 7.14 (dd, J = 9.3, 7.5Hz, 1H),7.09(d,J=8.3Hz,2H),6.98(s,1H),6.82(d,J=8.3Hz,2H),3.99(s,2H),3.67(m,4H),3.10(m,4H),2.28(s,3H);

[0118] The carbon NMR spectrum is 13 C-NMR (125MHz, CDCl3) δ (ppm) 162.45,154.34,148.84,141.80,139.45,131.58,130.33,130 .00,129.95,128.79,128.59,127.20,126.83,122.82,117.18,50.01,44.25,32.70,20.59.

[0119] Compound 5p (using 2-bromoaniline to replace compound a, and using 1-(4-methylphenyl)piperazine to replace 1-(4-chlorophenyl)piperazine)

[0120]

[0121] The nuclear magnetic resonance hydrogen spectrum is -NMR (500MHz,CDCl3)δ(ppm)10.76(s,1H),7.51(dd,J=8.0,1.1Hz,1H),7.28-7.25(m,1H),7.22(dt,J=7.5,1.2Hz,1H),7.10(d,J=8.2Hz,2H),7.09-7.05(m,1H),6.98(s,1H),6.85-6.81(m,2H),4.15(s,1H),3.68-3.64(m,4H),3.11-3.08(m,4H);

[0122] Compound 5q (using 4-bromoaniline to replace compound a)

[0123]

[0124] The H NMR spectrum is 1 H-NMR (500MHz, CDCl3) δ (ppm) 7.39 (d, J = 8.3 Hz, 2H), 7.23 ( d, J = 8.9 Hz, 3H), 7.09 ( d,J=8.2Hz,2H),6.82(s,1H),6.80(s,1H),3.97(s,2H),3.68(m,4H),3.12(m,4H);

[0125] The carbon NMR spectrum is 13 C-NMR (125MHz, CDCl3) δ (ppm) 162.09,149.67,143.13,131.34,131.01,130.67,130.60,129.64,129 .28,128.64,128.49,128.33,127.47,126.37,122.73,121.72,119.46,117.27,48.07,43.20,31.56.

[0126] Compound 5i (using 3-bromoaniline to replace compound a)

[0127]

[0128] The H NMR spectrum is 1 H-NMR(500MHz, CDCl3)δ(ppm)7.36-7.32(m,2H),7.24-7.21(m,2H),7.17-7.13(m,2H ),6.98(s,1H),6.83-6.80(m,2H),3.99(s,2H),3.69-3.66(m,4H),3.15-3.11(m,4H);

[0129] Compound 5s (using 2-bromoaniline to replace compound a)

[0130]

[0131] The H NMR spectrum is 1 H-NMR (500MHz, CDCl3) δ (ppm) 7.50 (dd, J=8.0, 1.2Hz, 1H), 7.27 (dd, J=3.5, 1.2Hz, 1H), 7.24-7.21 (m, 3H ),7.08-7.05(m,1H),6.96(s,1H),6.84-6.78(m,2H),4.15(s,2H),3.69-3.62(m,4H),3.13-3.07(m,4H);

[0132] The carbon NMR spectrum is 13 C-NMR (125MHz, CDCl3) δ (ppm) 162.22,154.34,149.58,138.79,133.19,130 .74,129.25,128.72,127.96,125.66,124.39,118.01,49.40,44.07,33.49.

[0133] Compound 5t (using 4-bromoaniline to replace compound a, and using 1-(4-hydroxyphenyl)piperazine to replace 1-(4-chlorophenyl)piperazine)

[0134]

[0135] The H NMR spectrum is 1 H NMR(500MHz,CDCl3)δppm 7.41-7.38(m,1H),7.36-7.33(m,1H),7.16-7.14(m,1H),7.09(d,J=8.3Hz,1H ),7.00(d,J=12.2Hz,1H),6.78(m,4H),3.98(s,2H),3.57(m,4H),2.89(m,4H);

[0136] Example 2: The preparation method of compound 16b comprises the following steps:

[0137]

[0138] M1: Compound 5c (500 mg, 1.13 mmol) was dissolved in 15 ml of ultra-dry dichloromethane, and boron tribromide (1.13 ml, 4.52 mmol) was slowly added dropwise to the reaction system under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 12-13 hours. The reaction was monitored by TLC until the reaction was completed. Methanol was added and then directly spin-dried to obtain a crude product. The crude product was purified to obtain 359.6 mg of white solid 2b, with a yield of 74.2%.

[0139] 2b NMR data H NMR spectrum is 1 H NMR(500MHz,DMSO-d6)δ(ppm)9.37(s,1H),7.27–7.21(m,2H),7.13–7.07(m,2H),6.9 9–6.93(m,2H),6.70–6.61(m,3H),3.91(s,2H),3.68–3.59(m,4H),3.17–3.08(m,4H);

[0140] The carbon NMR spectrum is 13 C NMR (126MHz, DMSO-d6) δ (ppm) 157.9 150.1, 142.0, 129.8, 129.1, 123.2, 119.4, 117.7, 115.6, 113.8, 48.5, 43.6, 32.6;

[0141] M2: Compound 2b (100 mg, 0.233 mmol), ethyl bromide (25.4 mg, 0.233 mmol), and K2CO3 (64.4 mg, 0.466 mmol) were dissolved in 10 ml of DMF and refluxed for 4-5 hours; cooled, the solvent was removed by vortexing, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous Na2SO4 to obtain a crude product. The crude product was separated and purified to obtain 33.7 mg of a yellow solid 16b with a yield of 31.7%.

[0142] The H NMR spectrum is 1 H NMR (500MHz, DMSO) δ (ppm) 9.38 (s, 1H), 7.26–7.22 (m, 2H), 7.13 (s, 1H), 7.13–7.09 (m, 1H), 7.00–6.95 (m, 2H), 6.67 (d, J= 7.7Hz,1H),6.63(d,J=7.2Hz,2H),4.01(q,J=7.2Hz,2H),3.84-3.76(m,4H),3.58(s,2H),3.15–3.07(m,4H),1.26(t,3H);

[0143] The carbon NMR spectrum is 13C NMR (126MHz, DMSO) δ (ppm) 166.2, 161.3, 157.9, 150.4, 140.8, 129.1, 123.1, 122.7, 117.7, 68.2, 48.8, 39.8, 39.6, 39.4;

[0144] The following compounds can be synthesized by the same method: (Except where otherwise specified, the remaining preparation steps and conditions of the following compounds are the same as those of compound 16b)

[0145] Compound 16c (using 2-bromopropane instead of bromoethane)

[0146]

[0147] The H NMR spectrum is 1 H NMR(500MHz,DMSO)δ(ppm)9.39(s,1H),7.28(s,1H),7.26–7.22(m,2H),7.13–7.08(m,1H),6.99–6.95(m,2H),6.67(d,J =7.8Hz,1H),6.65–6.62(m,2H),4.98–4.84(m,1H),3.82(s,4H),3.58(s,2H),3.16–3.03(m,4H),1.37(d,J=6.8Hz,6H);

[0148] 13 C NMR (126 MHz, DMSO) δ (ppm) 166.1, 161.2, 157.9, 150.4, 141.0, 129.9, 129.1, 123.1, 120.0, 119.4, 117.7, 115.6, 114.0, 49.2, 48.8 33.4, 21.5;

[0149] Compound 16d (using N-(3-chloropropyl)morpholine to replace ethyl bromide)

[0150]

[0151] The H NMR spectrum is 1H NMR (600MHz, CDCl3) δ (ppm) 7.20 (d, J = 8.9Hz, 2H), 7.11 (t, J = 7.8Hz, 1H), 6.83 (d, J = 8.9Hz, 2H), 6.78 (s, 1H), 6.74 (d, J = 8.1Hz, 1H), 6.69 (d, J = 7.5Hz,1H),6.47(s,1H),4.02(t,J=6.5Hz,2H),3.88(m,2H),3.72(m,8 H),3.10(m,4H),2.49(m,4H),2.39(t,J=6.4Hz,2H),2.02–1.96(m,2H);

[0152] The carbon NMR spectrum is 13 C NMR(126MHz,DMSO)δ(ppm)166.3,161.1,157.9,150.3,140.8,129.9,129.1,123.7, 123.1,122.6,119.5,117.8,115.7,114.0,66.5,55.3,53.5,48.8,46.0,33.2,24.8;

[0153] Example 3: Preparation of Compound 17d

[0154]

[0155] N1: N-Boc-piperazine (307 mg, 1.65 mmol), 1,3-bis(trifluoromethyl)-5-bromobenzene (439.5 mg, 1.5 mmol), Cs2CO3 (684.2 mg, 2.1 mmol), Pd2dpa3 (54.9 mg, 0.06 mmol), XantPhos (69.4 mg, 0.12 mmol) were dissolved in 12 ml of 1,4-dioxane solvent. The mixture was heated to reflux and stirred at 110°C for 12-13 hours under nitrogen protection. After the reaction was completed, the mixture was cooled and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous Na2SO4, and dried to obtain a crude product. The crude product was separated and purified to obtain 456.5 mg of white solid 17b with a yield of 76.4%.

[0156] N2: 17b (456.5 mg, 1.14 mmol) was dissolved in 15 ml of dichloromethane, and 4 ml of trifluoroacetic acid was slowly added dropwise to the above system at 0°C. After the trifluoroacetic acid was added dropwise, the entire reaction system was transferred to room temperature and stirred for 2-3 hours. The pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was washed with water and saturated brine, dried over anhydrous Na2SO4, and spin-dried to obtain a crude product. The crude product was separated and purified to obtain 284 mg of a yellow oil 17c, with a yield of 83.7%.

[0157] N3: (5-(3-bromobenzyl)-2-thiazole)aminobenzoate (100 mg, 0.257 mmol), 17c (69.6, 0.233 mmol) and Cs2CO3 (159.7 mg, 0.49 mmol) were dissolved in 10 ml of 1,4-dioxane solvent. The mixture was heated to reflux at 100-110°C for 5 hours under nitrogen protection. TLC was followed until the reaction was completed. The mixture was cooled, dried by rotation, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous Na2SO4 to obtain a crude product. The crude product was separated and purified to obtain the final compound 17d, which was a light yellow powder (76 mg) with a yield of 49.8%.

[0158] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.37–7.33 (m, 2H), 7.31 (dt, J = 7.2, 1.8Hz, 1H), 7.24 (s, 2H) ),7.17–7.11(m,2H),6.98(s,1H),4.00(s,2H),3.77–3.70(m,4H),3.37–3.25(m,4H);

[0159] The fluorine NMR spectrum is 19 F NMR (471MHz, CDCl3) δ (ppm)-62.99 (s, 6F);

[0160] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 154.6, 151.2, 141.5, 132.9, 132.7, 132.4, 132.1, 13 1.4,130.2,129.9,127.0,124.5,122.8,122.3,115.2,113.3,48.1,43.7,32.6;

[0161] The following compounds can be synthesized by the same method: (Except where otherwise specified, the remaining preparation steps and conditions of the following compounds are the same as those of compound 17d)

[0162] Compound 17e (using p-trifluoromethylbromobenzene to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0163]

[0164] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.51 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.33 (dt, J = 7.2, 1.8Hz, 1H), 7.18–7 .11(m,2H),6.98(s,1H),6.91(s,1H),6.89(s,1H),4.00(s,2H),3.74–3.68(m,4H),3.30–3.25(m,4H);

[0165] The fluorine NMR spectrum is 19 F NMR (471MHz, CDCl3) δ (ppm)-61.42 (s, 3F);

[0166] The carbon NMR spectrum is 13 C NMR (125MHz, CDCl3) δ (ppm) 154.6, 152.9, 141.7, 131.6, 130.4, 130.1, 127.2, 126.7, 125.8, 123.6, 122.9, 121.7, 121.4, 115.2, 48.1, 43.9, 32.7;

[0167] Compound 17f (using p-fluorobromobenzene to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0168]

[0169] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.35 (s, 1H), 7.32 (dt, J = 7.2, 1.8Hz, 1H), 7.17–7.10 (m, 2H), 7.01–6.95(m,3H),6.89–6.84(m,2H),3.99(s,2H),3.71–3.66(m,4H),3.10–3.05(m,4H);

[0170] The fluorine NMR spectrum is 19 F NMR(471MHz, CDCl3)δ(ppm)-122.90–-123.08(m,1F);

[0171] The carbon NMR spectrum is 13C NMR (125MHz, CDCl3) δ (ppm) 158.5, 156.9, 154.1, 147.5, 141.5, 132.3, 131.5, 130.2, 129.9, 127.1, 122.7, 118.7, 115.8, 115.7,, 50.3, 44.1, 32.6;

[0172] Compound 17g (using p-cyanobromobenzene to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0173]

[0174] The H NMR spectrum is 1 H NMR(500MHz,DMSO)δ(ppm)7.59(d,J=9.0Hz,2H),7.46(d,J=0.8Hz,1H),7.44–7.41(m,1H),7.29–7 .27(m,2H),7.14(s,1H),7.03(d,J=9.1Hz,2H),4.02(s,2H),3.65–3.63(m,4H), 3.38–3.36(m,4H);

[0175] The carbon NMR spectrum is 13 C NMR (126MHz, DMSO) δ (ppm) 153.4, 143.5, 133.7, 131.4, 131.1, 129.7, 127.9, 122.2, 120.4, 114.6, 98.9, 46.5, 43.3, 32.0;

[0176] Compound 17h (using p-nitrobromobenzene to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0177]

[0178] The H NMR spectrum is 1 H NMR (500MHz, DMSO) δ (ppm) 11.15 (s, 1H), 8.06 (d, J = 9.4Hz, 2H), 7.46 (s, 1H), 7.44–7.39 (m, 1H), 7.2 6(s,2H),7.14(s,1H),7.01(d,J=9.5Hz,2H),4.01(s,2H),3.67(d,J=4.2Hz,4H),3.53–3.48(m,4H);

[0179] The carbon NMR spectrum is 13C NMR (126MHz, DMSO) δ (ppm) 154.9, 143.5, 137.4, 131.4, 131.1, 129.7, 127.9, 126.1, 122.2, 113.0, 46.4, 43.2, 32.0;

[0180] Compound 17i (using 2-bromo-6-methylpyridine to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0181]

[0182] The H NMR spectrum is 1 H NMR(500MHz, CDCl3)δ(ppm)7.43(dd,J=8.3,7.4Hz,1H),7.39(s,1H),7.35(dt,J=7.2,1.8Hz,1H),7.20–7.14(m,2H),7.03(s,1H) ,6.57(d,J=7.3Hz,1H),6.45(d,J=8.4Hz,1H),4.02(s,2H),3.68(dd,J=6.4,3.8Hz,4H),3.59(dd,J=6.4,3.8Hz,4H),2.42(s,3H);

[0183] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 158.6, 156.9, 154.2, 141.7, 137.9, 131.5, 130.2, 129.8, 127.1, 122.7, 113.3, 103.9, 45.0, 43.8, 32.6, 24.5.

[0184] Compound 17j (using 2,6-dibromopyridine to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0185]

[0186] The H NMR spectrum is 1 H NMR(500MHz, CDCl3)δ(ppm)7.38(d,J=1.5Hz,1H),7.36-7.32(m,2H),7.21–7.15(m,2H),7.01 (s,1H),6.82(d,J=7.4Hz,1H),6.52(d,J=8.3Hz,1H),4.02(s,2H),3.67(m,4H),3.59(m,4H);

[0187] The carbon NMR spectrum is 13C NMR (126MHz, CDCl3) δ (ppm) 162.4, 158.6, 154.4, 141.6, 140.2, 139.7, 132.5, 131.4, 130.3, 129.9, 127.2, 122.7, 116.8, 105.0, 44.5, 43.6, 32.6;

[0188] Compound 17k (using 2-bromo-6-trifluoromethylpyridine to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0189]

[0190] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.61 (t, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.33 (dt, J = 6.8, 1.9 Hz, 1H), 7.1 8–7.11(m,2H),6.99(d,J=7.3Hz,2H),6.77(d,J=8.7Hz,1H),4.00(s,2H),3.66(d,J=4.6Hz,8H);

[0191] The fluorine NMR spectrum is 19 F NMR (471MHz, CDCl3) δ (ppm)-68.69 (s, 3F);

[0192] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 158.3, 146.5, 146.3, 141.6, 138.6, 131.4, 130.2, 129.9, 127.1, 122.6, 120.4, 109.77, 44.40 (s, 15H), 43.5, 32.6;

[0193] Compound 171 (using 2-bromo-6-fluoropyridine to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0194]

[0195] The H NMR spectrum is 1H NMR (500MHz, CDCl3) δ (ppm) 7.56 (dd, J = 16.4, 8.2Hz, 1H), 7.37 (s, 1H), 7.35–7.32 (m, 1H), 7.16 (m, 2H), 6.9 9(s,1H),6.41(dd,J=8.2,2.3Hz,1H),6.22(dd,J=7.7,2.7Hz,1H),4.00(s,2H),3.65(m,4H),3.58(m,4H);

[0196] The fluorine NMR spectrum is 19 F NMR (471MHz, CDCl3) δ (ppm)-68.24 (d, J = 8.6Hz, 1F);

[0197] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 163.6, 161.8, 157.8, 142.1, 141.6, 131.4, 130.2, 129.9, 127.1, 122.7, 102.8, 97.0, 96.7, 44.5, 43.5, 32.6;

[0198] Compound 17m (using o-chlorobromobenzene to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0199]

[0200] The H NMR spectrum is 1 H NMR(500MHz, CDCl3)δ(ppm)7.38(dd,J=7.9,1.4Hz,1H),7.35(s,1H),7.30–7.27(m,1H),7.23(td,J=7.8,1. 5Hz,1H),7.11(dt,J=15.3,7.7Hz,2H),7.04–6.96(m,3H),3.98(s,2H),3.75–3.68(m,4H),3.06–2.98(m,4H)

[0201] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 154.1, 148.6, 141.6, 132.5, 131.5, 130.7, 130.2, 129.9, 128.9, 127.7, 127.1, 124.3, 122.7, 120.5, 51.0, 44.4, 32.5;

[0202] Compound 17n (using 2-bromo-5-chloropyridine to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0203]

[0204] The H NMR spectrum is 1 H NMR(500MHz, CDCl3)δ(ppm)8.14(d,J=2.5Hz,1H),7.48(dd,J=9.0,2.6Hz,1H),7.39(s,1H),7.38–7.35(m,1H),7.18(t, J=6.3Hz,2H),7.02(s,1H),6.59(d,J=9.0Hz,1H),4.02(s,2H),3.68(dd,J=6.4,3.9Hz,4H),3.58(dd,J=6.4,4.0Hz,4H);

[0205] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 157.2, 146.3, 141.6, 137.3, 131.4, 130.2, 129.9, 127.1, 122.7, 120.9, 107.8, 44.9, 43.6, 32.6;

[0206] Compound 17o (using 2-bromo-4-methylpyridine to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0207]

[0208] The H NMR spectrum is 1 H NMR(500MHz, CDCl3)δ(ppm)8.05(d,J=5.1Hz,1H),7.36(s,1H),7.33(dt,J=6.9,2.0Hz,1H),7.18–7.12(m, 2H),7.00(s,1H),6.52(d,J=5.1Hz,1H),6.46(s,1H),3.99(s,2H),3.66(m,4H),3.57(m,4H),2.27(s,3H);

[0209] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 159.2, 148.7, 147.6, 141.7, 131.5, 130.2, 129.8, 127.1, 122.7, 115.5, 107.7, 45.0, 43.7, 32.6, 21.4;

[0210] Compound 17p (1-Boc-homopiperazine is used to replace N-Boc-piperazine, and 2-bromo-6-chloropyridine is used to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0211]

[0212] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.34 (m, 3H), 7.17–7.12 (m, 2H), 7.04 (s, 1H), 6.53 (d, J = 7.4Hz, 1H), 6.34 (d, J = 8. 4Hz,1H),3.99(s,2H),3.83–3.76(m,2H),3.70–3.64(m,2H),3.62(m,2H),3.42(m,2H),1.97(p,J=6.2Hz,2H);

[0213] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 157.0, 149.8, 141.8, 133.3, 131.4, 130.2, 129.8, 127.1, 122.6, 111.3, 103.4, 48.7, 47.4, 45.8, 32.6, 29.7, 25.2.

[0214] Compound 17q (1-Boc-homopiperazine is used to replace N-Boc-piperazine, and p-chlorobromobenzene is used to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0215]

[0216] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.37–7.33 (m, 2H), 7.15 (m, 4H), 7.01 (s, 1H), 6.60 (d, J = 9.1Hz, 2H), 4.00 (d ,J=14.0Hz,2H),3.68(m,2H),3.62–3.56(m,2H),3.54(t,J=6.2Hz,2H),3.38(m,2H),2.04–1.97(m,2H);

[0217] The carbon NMR spectrum is 13C NMR (126MHz,CDCl3)δ(ppm)145.4),131.4,130.2,129.8,129.4,127.1,122.7,112.8,50.4,46.5,45.7,32.6,25.1; Compound 17r (1,3-dichloro-5-bromobenzene is used to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0218]

[0219] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.35 (s, 1H), 7.34–7.31 (m, 1H), 7.15 (dd, J = 3.8, 2.3Hz, 2H), 6.96 (s, 1H) ),6.85(t,J=1.7Hz,1H),6.72(d,J=1.7Hz,2H),4.00(s,2H),3.70–3.63(m,4H),3.21–3.15(m,4H);

[0220] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 154.4, 152.1, 141.5, 135.6, 131.5, 130.2, 129.9, 127.1, 122.7, 119.7, 114.3, 48.2, 43.7, 32.6;

[0221] Compound 17s (N-Boc-3-methylpiperazine is used to replace N-Boc-piperazine, and p-chlorobromobenzene is used to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0222]

[0223] The H NMR spectrum is 1 H NMR (500MHz, DMSO) δ7.44(s,1H),7.41(d,J=7.0Hz,1H),7.26(d,J=7.3Hz,2H),7.16(d,J=8.9Hz,2H),7.12(s,1H),6.61(d,J=8 .9Hz,2H),4.56(s,1H),4.01(s,2H),3.52(d,J=8.1Hz,1H),3.35(d,J=9.3Hz,4H),3.00(d,J=9.1Hz,1H),1.95(d,J=9.7Hz,3H).

[0224] Compound 17t (using 8-Boc-3,8-diazabicyclo[3.2.1]octane to replace N-Boc-piperazine, and using p-chlorobromobenzene to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0225]

[0226] The H NMR spectrum is 1 H NMR(500MHz, CDCl3)δ(ppm)7.37–7.33(m,2H),7.20–7.17(m,2H),7.17–7.14(m,2H),6.99(s,1H),6.72–6.68(m,2H), 4.47(s,2H),4.00(m,2H),3.36(dd,J=11.3,2.1Hz,2H),3.01(dd,J=11.1,1.5Hz,2H),2.02–1.95(m,2H),1.92(m,2H);

[0227] Compound 17u ((1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane is used to replace N-Boc-piperazine, and p-chlorobromobenzene is used to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0228]

[0229] The H NMR spectrum is 1 H NMR (500MHz, DMSO) δ (ppm) 10.76 (s, 1H), 7.44 (s, 1H), 7.41 (dd, J = 6.4, 4.4Hz, 1H), 7.26 (q, J = 7.7Hz, 2H), 7.16 (d, J = 8.9Hz, 2H), 7.12 (s, 1H), 6.61 (d,J=8.9Hz,2H),4.57(s,1H),4.04(s,2H),3.53(d,J=9.1Hz,1H),3.45( m,2H),3.18(s,1H),3.00(d,J=9.2Hz,1H),1.95(dd,J=19.1,9.0Hz,2H);

[0230] The carbon NMR spectrum is 13 C NMR (126MHz, DMSO) δ (ppm) 146.1, 143.7, 131.4, 131.1, 129.7, 129.1, 127.9, 122.1, 120.1, 114.4, 56.9, 51.9, 49.1, 31.8, 30.3;

[0231] Compound 17v (using 2-bromo-6-chloropyridine to replace 1,3-bis(trifluoromethyl)-5-bromobenzene)

[0232]

[0233] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.46 (dd, J = 8.3, 7.6Hz, 1H), 7.39 (s, 1H), 7.38–7.35 (m, 1H), 7.21–7.16 (m, 2H), 7.02 (s, 1H) ),6.68(d,J=7.5Hz,1H),6.50(d,J=8.3Hz,1H),4.03(s,2H),3.67(dd,J=6.4,3.5Hz,4H),3.62(dd,J=6.4,3.3Hz,4H);

[0234] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 158.5, 149.6, 141.6, 139.9, 131.5, 130.2, 129.9, 127.1, 122.7, 112.9, 104.6, 44.5, 43.5, 32.6;

[0235] Compound 17w (replacing 1,3-bis(trifluoromethyl)-5-bromobenzene with p-chlorobromobenzene, replacing N-Boc-piperazine with 1-Boc-homopiperazine, and replacing (5-(4-methoxybenzyl)-2-thiazole)aminobenzoate with (5-(3-bromobenzyl)-2-thiazole)aminobenzoate)

[0236]

[0237] The nuclear magnetic resonance hydrogen spectrum is 1H NMR (500MHz, CDCl3) δ (ppm) 7.17–7.12 (m, 4H), 6.96 (s, 1H), 6.84–6.80 (m, 2H), 6.61–6.56 (m, 2H), 3.96 (s, 2H), 3.78 (s, 3H), 3.68 (d, J = 11.5Hz, 2H), 3.60–3.55 (m, 2H), 3.53 (t, J = 6.2Hz, 2H), 3.36 (t, J = 5.4Hz, 2H), 2.05–1.96 (m, 2H);

[0238] The carbon NMR spectrum is 13C NMR (126MHz, CDCl3) δ (ppm) 158.4, 145.4, 129.5, 121.4, 114.1, 112.8, 55.3, 50.5, 46.5, 45.7, 32.2, 25.1;

[0239] Compound 17x (replacing 1,3-bis(trifluoromethyl)-5-bromobenzene with p-chlorobromobenzene, replacing N-Boc-piperazine with 8-Boc-3,8-diazabicyclo[3.2.1]octane, and replacing (5-(4-methoxybenzyl)-2-thiazole)aminobenzoate with (5-(3-bromobenzyl)-2-thiazole)aminobenzoate)

[0240]

[0241] The H NMR spectrum is 1 H NMR (500MHz, CDCl3) δ (ppm) 7.20–7.15 (m, 2H), 7.13 (d, J = 8.6Hz, 2H), 6.93 (s, 1H), 6.81 (d, J = 8.6Hz, 2H), 6.68 (d, J = 9.1H z,2H),4.47(s,2H),3.97(s,2H),3.76(s,3H),3.34(d,J=11.2Hz,2H),2.99(d,J=11.0Hz,2H),1.96(m,2H),1.90(m,2H);

[0242] The carbon NMR spectrum is 13 C NMR (126MHz, CDCl3) δ (ppm) 158.4, 149.2, 131.4, 129.5, 128.9, 124.1, 115.7, 114.1, 55.3, 53.8, 53.3, 32.2, 27.8;

[0243] Application Example: Inhibitory Effect of 5-Benzyl-2-amino-1,3-thiazole Derivatives on THP-1 and MV-4-11 Cells

[0244] MTS method was used to detect cell viability: the samples were dissolved in DMSO and stored at low temperature. THP-1 and MV-4-11 cell lines were used as test materials. The cells growing in the logarithmic growth phase were gently blown and counted. 90 μL of cell suspension was inoculated in each well of a 96-well plate, and 10 μL of compound was added. A concentration gradient was set for each compound, and triplicate wells were set for each concentration. The compound was added to the corresponding wells. The final concentration of DMSO was 0.2%. The cells were cultured at 37°C in a 4.5% CO2 incubator for 72 hours, and 20 μL of MTS was added. After incubation at 37°C for 3 hours, the light absorption value at 490nm (L1) was measured using Spectra MAX×340, and the reference wavelength was 690nm (L2). The (L1-L2) value was plotted against different concentrations of the inhibitor. The percentage activity (%) = compound OD value - BLANK OD value / DMSO OD value - BLANK OD * 100%, and the IC was obtained by fitting the formula 50 The reported compound Gilteritinib was used for comparison.

[0245] Test Results

[0246] The compounds of the present invention, 5-benzyl-2-amino-1,3-thiazole derivatives, have good anti-leukemia activity, as shown in Table 1 and Table 2. Some compounds have significant inhibitory activity on human peripheral blood mononuclear cell line (THP-1) and human myelomonocytic leukemia cells (MV-4-11), two leukemia-related cells. Experiments show that the 5-benzyl-2-amino-1,3-thiazole derivatives of the present invention can be used as potential drugs for treating leukemia and have good application prospects in anti-tumor.

[0247] Table 1 Inhibitory effects of some compounds on human peripheral blood mononuclear cell line (THP-1)

[0248]

[0249]

[0250] Table 2 Inhibitory effects of some compounds on human myelomonocytic leukemia cells (MV-4-11)

[0251] Compound <![CDATA[IC 50 (μM) <!-- 21 -->]]> Gilteritinib 0.024±0.003 5e 0.386±0.027 5b 0.129±0.003 5h 0.234±0.006 5n 1.11±0.11 5m 1.46±0.19 5a 0.386±0.027 17f 0.174±0.013 17n 0.616±0.004 17x 0.313±0.012 17w 0.305±0.054

[0252] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A 5-benzyl-2-amino-1,3-thiazole derivative, characterized in that: The structural formula of the thiazole derivative is: ； In the formula, R is one of halogen, trifluoromethyl, methyl, methoxy, hydroxyl, C2~C3 straight chain or branched alkoxy; R2 is one of phenyl, halogen-substituted phenyl, C1-C4 alkyl-substituted phenyl or pyridyl; for .

2. A 5-benzyl-2-amino-1,3-thiazole derivative according to claim 1, characterized in that: The structural formula of the thiazole derivative is: 。 3. The method for preparing a 5-benzyl-2-amino-1,3-thiazole derivative according to claim 1, characterized in that: The method comprises the following steps: ， S1: subjecting the compound represented by formula A to diazotization reaction with nitrite to obtain a diazonium salt; ， S2: mixing the diazonium salt with magnesium oxide, a solution containing copper chloride and acrolein under ice bath conditions, and then reacting at room temperature to obtain a first intermediate as shown in formula B; ， S3: mixing the first intermediate with thiourea and heating them for reaction to obtain a second intermediate as shown in formula C; ， S4: mixing the second intermediate with pyridine and phenyl chloroformate in an ice bath, and then reacting at room temperature to obtain a third intermediate as shown in formula D; ， S5: reacting the third intermediate with cesium carbonate and a secondary amine as shown in formula G to obtain a thiazole derivative as shown in formula I accordingly.

4. The method for preparing a 5-benzyl-2-amino-1,3-thiazole derivative according to claim 3, characterized in that: In step S1, the molar ratio of the compound as shown in formula A to the nitrite is 1:(1-1.2); the reaction conditions of the diazotization reaction include ice-salt bath conditions; In step S2, the molar ratio of the diazonium salt, magnesium oxide, copper chloride and acrolein is 1:(0.2-0.3):(0.25-0.35):(0.5-1.5); In step S3, the molar ratio of the first intermediate to thiourea is 1:(1-1.2); in the heating reaction, the reaction solvent is ethanol, and the reaction temperature is 80-100° C.; In step S4, the molar ratio of the second intermediate to pyridine and phenyl chloroformate is 1:(2-4):(3-5), and the reaction is carried out under the protection of an inert gas; In step S5, the molar ratio of the third intermediate to cesium carbonate and the secondary amine is 1:(1.5-2.5):(0.8-1.2); during the reaction, the reaction solvent is 1,4-dioxane, the reaction temperature is 90-110° C., and the reaction is carried out under the protection of an inert gas.

5. The use of a 5-benzyl-2-amino-1,3-thiazole derivative as claimed in claim 1 or 2, characterized in that: The thiazole derivatives are used for preparing drugs with inhibitory activity on human peripheral blood mononuclear cell lines or human myelomonocytic leukemia cells.

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