Chidaaniline derivative as well as preparation method and application thereof

Abstract

The invention relates to a chidaaniline derivative as well as a preparation method and application thereof. Specifically disclosed is a compound I or a pharmaceutically acceptable salt thereof. The compound provided by the invention has good tumor inhibition activity and excellent medicinal value.

Description

Technical Field

[0001] This invention relates to a compound, and more particularly to a cinda-aniline derivative thereof, its preparation method, and its application. Background Technology

[0002] Chidamide is a selective histone deacetylase (HDAC) inhibitor that inhibits tumor cell proliferation and induces apoptosis through epigenetic mechanisms, and has been widely used in the treatment of malignant tumors such as peripheral T-cell lymphoma. However, existing HDAC inhibitors still suffer from problems such as insufficient metabolic stability, limited targeting, or significant toxic side effects, which restrict further improvement in their clinical efficacy.

[0003] Summary of the Invention

[0004] The technical problem to be solved by this invention is to overcome the deficiency of the limited variety of antitumor drugs in the prior art. Therefore, a chidamide derivative, its preparation method, and its application are provided.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a compound I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Where m and n are each independently 0, 1, 2 or 3;

[0009] R 1 and R 2 It is an -OC1-C3 alkyl group;

[0010] Or, R 1 and R 2 Together with the carbon atom directly attached thereto, they form a 5- to 6-membered heterocyclic alkyl group, wherein the heteroatom is O, and the number of heteroatoms is 1, 2 or 3;

[0011] Linker is a chemical bond, -(CH2) p -or

[0012] p is an integer from 1 to 6;

[0013] q is an integer from 1 to 3;

[0014] Each R 3 and R 4 Each can be independently hydrogen, halogen, hydroxyl, amino, nitro or -OC1-C3 alkyl.

[0015] In some implementation schemes, R 1 and R 4 In the -OC1-C3 alkyl group, the C1-C3 alkyl group is methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0016] In some implementation schemes, R 1 and R 2 In the 5-6 membered heterocyclic alkyl group, the number of heteroatoms is 2; the 5-6 membered heterocyclic alkyl group is preferably...

[0017] In some implementation schemes, R 3 and R 4 In the -OC1-C3 alkyl group, the C1-C3 alkyl group is methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0018] In some implementation schemes, R 3 and R 4 In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine or bromine.

[0019] In some implementation schemes, R 1 and R 2 For -OCH3; or, R 1 and R 2 It forms together with the carbon atoms directly attached to it.

[0020] In some implementations, the linker is a chemical bond or

[0021] In some implementations, p is 1, 2, or 3.

[0022] In some implementations, q is 1, 2 or 3, preferably 1 or 2.

[0023] In some implementation schemes, R 3 It is hydrogen.

[0024] In some implementations, m is 0.

[0025] In some implementation schemes, each R 4 Each is independently halogenated, amino, or -OC1-C3 alkyl; preferably halogenated or amino.

[0026] In some implementations, n is 1, 2, or 3, preferably 2.

[0027] In some implementation schemes, for

[0028] In some implementation schemes, For chemical bonds,

[0029] In some implementation schemes, for

[0030] In some embodiments, compound I is compound I-1:

[0031]

[0032] Among them, R 1 R 2 The definition of Linker is as described above;

[0033] R 4-1 and R 4-2 Each can be independently hydrogen, halogen, hydroxyl, amino, nitro or -OC1-C3 alkyl.

[0034] In some embodiments, in compound I-1, R 4-1 It is an amino group or an -OC1-C3 alkyl group; R 4-2 It is a halogen.

[0035] In some embodiments, compound I is:

[0036]

[0037]

[0038] This invention provides a compound 3:

[0039]

[0040] R 1 R 2 R 3 The definitions of m and Linker are as described above.

[0041] In some embodiments, compound 3 is:

[0042]

[0043] The present invention also provides a method for preparing compound I, comprising the following steps: reacting compound 3 and compound 4 via an amidation reaction to obtain compound I:

[0044]

[0045] Among them, R 1 R 2 R 3 R4 The definitions of m, n and Linker are as described above.

[0046] In some embodiments, the method for preparing compound I further includes the preparation of compound 3, wherein compound 1 and substituted p-aminomethylbenzoic acid are subjected to an amidation reaction to obtain compound 3:

[0047]

[0048] Among them, R 1 R 2 R 3 The definitions of m and Linker are as described above.

[0049] In the preparation steps of compound I and compound 3, the amidation reaction temperature is 0–40 °C.

[0050] In the preparation steps of compound I and compound 3, the solvent for the amidation reaction is dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, acetonitrile, or anhydrous ethanol, preferably acetonitrile and dichloromethane, preferably acetonitrile; the condensing agent for the reaction is 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N,N′,N′-tetramethylurea hexafluorophosphate (HBTU), 1-butylphosphine (T4P), or O-benzotriazole-N,N,N′,N′-tetramethylurea tetrafluoroborate (TBTU). The reaction base is tetramethylchlorourea hexafluorophosphate (TCFH), carbonyl diimidazole (CDI), or (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholine-carbomony hexafluorophosphate (COMU), preferably N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (TCFH); the base for the reaction is potassium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylimidazole (NMI), preferably N,N-diisopropylethylamine (DIPEA) and N-methylimidazole (NMI), preferably N-methylimidazole (NMI).

[0051] This invention provides a pharmaceutical composition comprising:

[0052] (1) Compound I as described above, or a pharmaceutically acceptable salt thereof, and

[0053] (2) Pharmaceutically acceptable excipients.

[0054] The present invention provides the use of compound I as described above or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the preparation of a medicament for treating tumors.

[0055] In some implementations, the tumor is cervical cancer or breast cancer.

[0056] Terminology Explanation

[0057] In this invention, the structural segments This means that the structural segment is connected to the rest of the molecule through this bond.

[0058] In this invention, the "-" at the end of a group indicates that the group is connected to the rest of the molecule through that site. For example, -OC1-C3 alkyl refers to C1-C3 alkoxy.

[0059] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0060] In this invention, the term "alkyl" refers to a saturated monovalent hydrocarbon group that has a specified number of carbon atoms (e.g., C1-C3), is straight-chain or branched. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0061] In this invention, the term "heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 5-6, 5-6, or 6-membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (e.g., O). Heterocyclic alkyl groups are attached to the remainder of the molecule via carbon atoms or heteroatoms. Heterocyclic alkyl groups include, but are not limited to: wait.

[0062] Based on what is contrary to common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0063] The reagents and raw materials used in this invention are all commercially available.

[0064] The positive and progressive effects of the present invention are as follows: Compared with the prior art, the present invention has the following significant advantages: (1) The chadniline derivative developed in the present invention showed a significant inhibitory effect on tumor cells (e.g., cervical cancer and breast cancer cells), and the compound activity was superior to chadniline; (2) The compound showed an inhibitory effect on the IC50 of MDA-MB-231 cells. so It can reach 1.99±0.47μM, and its IC50 value for HeLa cells can reach 1.99±0.47μM. 50 It can reach 1.04±0.38μM. Detailed Implementation

[0065] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0066] Example 1

[0067] The chadniline derivative of this invention has the chemical name (E)-N-(2-amino-4-fluorophenyl)-4-((3-(benzo[d][1,3]dioxane-5-yl)acrylamide)methyl)benzamide, and its structural formula is as follows:

[0068]

[0069] Its preparation method includes the following steps:

[0070] (1) Synthesis of (E)-4-((3-(benzo[d][1,3]dioxane-5-yl)acrylamido)methyl)benzoic acid, with the following structural formula:

[0071]

[0072] 500 mg (2.60 mmol) of (E)-3-(benzo[d][1,3]dioxane-5-yl)acrylic acid, 393 mg (2.60 mmol) of 4-aminomethylbenzoic acid, 1361 mg (7.81 mmol) of DIPEA and 5 mL of dichloromethane were added sequentially to a reaction flask. 1358 mg (3.90 mmol) of T4P was added dropwise in an ice bath. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 85:1) to obtain 200 mg of the target product, with a yield of 23.6%.

[0073] (2) Synthesis of (E)-N-(2-amino-4-fluorophenyl)-4-((3-(benzo[d][1,3]dioxane-5-yl)acrylamide)methyl)benzamide

[0074] (E)-4-((3-(benzo[d][1,3]dioxane-5-yl)acrylamido)methyl)benzoic acid 200 mg (0.62 mmol), HATU 282 mg (0.74 mmol), K2CO3 255 mg (1.84 mmol) and 5 mL of dichloromethane were added sequentially to the reaction flask. After reacting at room temperature for 30 min, 4-fluorobenzene-1,2-diamine 78 mg (0.62 mmol) was added. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain 50 mg of the target product, with a yield of 18.8%.

[0075] The target compound is a pale yellow solid; 1H NMR(400MHz, DMSO-d6)δ 9.58 (s, 1H), 8.62 (t, J=6.1Hz, 1H), 7.95 (d, J=7.9Hz, 2H), 7.46-7.36 (m, 3H), 7.17 (d, J=1.7Hz, 1H), 7.14-7.03 (m, 2H), 6.95 (d, J=8.0Hz, 1H), 6.60-6.48 (m, 2H), 6.36 (td, J=8.5, 2.9Hz, 1H), 6.07 (s, 2H), 5.22 (s, 2H), 4.47 (s, 2H). 13 C NMR(101MHz, DMSO-d6)δ 165.58, 162.34, 159.97, 148.70, 148.16, 145.70, 145.59, 143.37, 138.99, 133.19, 129.51, 128.77 , 128.14, 127.19, 123.52, 120.41, 119.64, 119.62, 108.81, 106.47, 102.33, 102.11, 101.67, 42.21.

[0076] Example 2

[0077] The chadniline derivative of this invention has the chemical name N-(2-amino-4-fluorophenyl)-4-(((2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamide)methyl)benzamide, and its structural formula is as follows:

[0078]

[0079] Its preparation method includes the following steps:

[0080] (1) Synthesize 4-(((2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamido)methyl)benzoic acid, with the following structural formula:

[0081]

[0082] 500 mg (2.29 mmol) of (2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienoic acid, 381 mg (2.52 mmol) of 4-p-aminomethylbenzoic acid, 888 mg (6.87 mmol) of DIPEA and 5 mL of dichloromethane were added sequentially to the reaction flask. 1196 mg (3.44 mmol) of T4P was added dropwise in an ice bath. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane to methanol = 50:1) to obtain 100 mg of the target product, with a yield of 12.4%.

[0083] (2) Synthesis of N-(2-amino-4-fluorophenyl)-4-(((2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamide)methyl)benzamide

[0084] 100 mg (0.28 mmol) of 4-(((2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamido)methyl)benzoic acid, 291 mg (0.34 mmol) of HATU, 118 mg (0.85 mmol) of K2CO3 and 5 mL of N,N-dimethylformamide were added sequentially to the reaction flask. After reacting at room temperature for 30 min, 39 mg (0.31 mmol) of 4-fluorobenzene-1,2-diamine was added. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was extracted three times with water and ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain 59 mg of the target product, with a yield of 45.9%.

[0085] The target compound is a pale yellow solid; 1 H NMR(400MHz, DMSO-d6)δ 9.64 (s, 1H), 8.72 (t, J=6.1Hz, 1H), 7.95 (d, J=7.9Hz, 2H), 7.42-7.09 (m, 5H), 7.02-6.85 (m, 4H), 6.55 (dd, J=11.2 , 2.9Hz, 1H), 6.35 (td, J=8.5, 2.9Hz, 1H), 6.19 (d, J=15.0Hz, 1H), 6.04 (s, 2H), 5.24 (s, 2H), 4.44 (d, J=5.9Hz, 2H). 13 C NMR(101MHz, DMSO-d6)δ 165.84, 162.64, 160.26, 148.41, 148.23, 145.97, 145.85, 140.33, 138.62, 131.30, 127.52, 127.44, 125.68, 124.6 5, 123.79, 123.18, 119.82, 119.80, 108.92, 106.13, 102.60, 102.37, 102.08, 101.83, 101.74, 42.43, 27.02, 25.21.

[0086] Example 3

[0087] The chadniline derivative of this invention, chemically named N-(2-amino-4-fluorophenyl)-4-((3-(benzo[d][1,3]dioxane-5-yl)formamide)methyl)benzamide, has the following structural formula:

[0088]

[0089] Its preparation method includes the following steps:

[0090] (1) Synthesis of 4-((benzo[d][1,3]dioxolane-5-carbamate)methyl)benzoic acid, with the following structural formula:

[0091]

[0092] 500 mg (3.01 mmol) of benzo[1,3]dioxane-5-carboxylic acid, 454 mg (3.01 mmol) of 4-p-aminomethylbenzoic acid, 1569 mg (9.03 mmol) of DIPEA and 5 mL of dichloromethane were added sequentially to the reaction flask. 1610 mg (4.51 mmol) of T4P was added dropwise in an ice bath. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 85:1) to obtain 313 mg of the target product, with a yield of 45.0%.

[0093] (2) Synthesis of N-(2-amino-4-fluorophenyl)-4-((3-(benzo[d][1,3]dioxane-5-yl)formamide)methyl)benzamide

[0094] 200 mg (0.67 mmol) of 4-((benzo[d][1,3]dioxolane-5-carbamate)methyl)benzoic acid, 305 mg (0.80 mmol) of HATU, 279 mg (2.01 mmol) of K2CO3 and 5 mL of N,N-dimethylformamide were added sequentially to the reaction flask. After reacting at room temperature for 30 min, 84 mg (0.67 mmol) of 4-fluorobenzene-1,2-diamine was added. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was extracted three times with water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 70:1) to obtain 20 mg of the target product, with a yield of 7.4%.

[0095] The target compound is a pale yellow solid; 1H NMR (400MHz, DMSO-d6)δ 9.56 (s, 1H), 8.97 (t, J=6.0Hz, 1H), 7.94 (d, J=8.0Hz, 2H), 7.72 (s, 1H), 7.5 1 (dd, J=8.1, 1.8Hz, 1H), 7.41 (s, 1H), 7.16 (s, 1H), 7.10 (ddd, J=11.0, 8.7, 6 .3Hz, 1H), 7.01 (d, J=8.1Hz, 1H), 6.96 (s, 1H), 6.51 (ddd, J=28.1, 11.2, 2.9 Hz, 1H), 6.41-6.27 (m, 1H), 6.10 (s, 2H), 4.52 (d, J=5.9Hz, 2H), 3.66 (s, 2H). 13 CNMR (101MHz, DMSO-d6) δ165.90, 165.88, 150.25, 147.84, 145.96, 145.84, 143.82, 138.11, 133.45, 128 .93, 128.68, 128.30, 127.37, 122.74, 121.24, 119.98, 119.78, 119.75, 108.38, 107.79, 102.15, 42.93.

[0096] Example 4

[0097] The chadniline derivative of this invention has the chemical name N-(2-methoxy-5-bromo)-4-(((2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamide)methyl)benzamide, and its structural formula is as follows:

[0098]

[0099] Its preparation method is as follows:

[0100] 200 mg (0.57 mmol) of 4-(((2E 4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamido)methyl)benzoic acid (prepared according to step 1 of Example 2), 260 mg (0.68 mmol) of HATU, 238 mg (1.71 mmol) of K2CO3, and 5 mL of N,N-dimethylformamide were added sequentially to the reaction flask. After reacting at room temperature for 30 min, 92 mg (0.46 mmol) of 5-bromo-2-methoxyaniline was added. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was extracted three times with water and ethyl acetate. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain 22 mg of the target product, with a yield of 7.2%.

[0101] The target compound is a pale yellow solid;1 H NMR(400MHz, DMSO-d6)δ 9.45 (s, 1H), 8.66 (t, J = 6.1Hz, 1H), 8.05 (d, J = 2.5Hz, 1H), 7.92 (d, J = 8.0Hz, 2H), 7.43-7.19 (m, 4H), 7.11-6.82 (m, 5H), 6.18 (d, J=15.0Hz, 1H), 6.05 (s, 2H), 4.45 (d, J=6.0Hz, 2H), 3.85 (s, 3H). 13 C NMR(101MHz, DMSO-d6)δ 165.83, 165.39, 150.87, 148.40, 148.23, 144.21, 140.41, 138.68, 133.05, 131.29, 130.12, 128.96, 128.22 , 128.13, 127.73, 126.33, 125.66, 124.55, 123.22, 113.78, 111.73, 108.91, 106.11, 101.74, 56.58, 42.41.

[0102] Example 5

[0103] The chadniline derivative of this invention has the chemical name N-(2-amino-4-fluoro)-4-(((2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamide)methyl)benzamide, and its structural formula is as follows:

[0104]

[0105] (1) Synthesis of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-carbamate)methyl)benzoic acid, with the following structural formula:

[0106]

[0107] 500 mg (2.77 mmol) of 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid, 462.68 mg (3.05 mmol) of 4-p-aminomethylbenzoic acid, 1361 mg (7.81 mmol) of DIPEA, and 5 mL of dichloromethane were added sequentially to a reaction flask. 1358 mg (3.90 mmol) of T4P was added dropwise in an ice bath. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain 168 mg of the target product, with a yield of 18.8%.

[0108] (2) Synthesis of N-(4-((2-amino-4-fluorophenyl)carbamoyl)benzyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxamide

[0109] 120 mg (0.38 mmol) of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-carboxamido)methyl)benzoic acid, 305 mg (0.80 mmol) of HATU, 279 mg (2.01 mmol) of K2CO3 and 5 mL of N,N-dimethylformamide were added sequentially to the reaction flask. After reacting at room temperature for 30 min, 53 mg (0.42 mmol) of 4-fluorophenyl-1,2-diamine was added. The mixture was stirred at 25–35 °C for 3 hours. The reaction solution was extracted three times with water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 70:1) to obtain 47 mg of the target product, with a yield of 28.1%.

[0110] The target compound is a pale yellow solid; 1 H NMR(400MHz, DMSO-d6)δ 9.56 (s, 1H), 8.96 (t, J=6.0Hz, 1H), 7.94 (d, J=8.0Hz, 2H), 7.49-7.39 (m, 4H), 7.12 (dd, J=8.7, 6.4Hz, 1H), 6.93 (d, J=8.2Hz, 1 H), 6.55 (dd, J=11.2, 2.9Hz, 1H), 6.35 (td, J=8.5, 2.9Hz, 1H), 5.20 (s, 2H), 4.51 (d, J=6.0Hz, 2H), 4.29 (tq, J=5.1, 2.5Hz, 4H). 13 C NMR (101MHz, DMSO-d6) δ165.91, 162.65, 160.28, 146.57, 145.97, 145.85, 143.89, 143.42, 133.41, 128.95 , 128.30, 127.69, 127.33, 121.19, 119.78, 119.75, 117.28, 116.77, 102.61, 102.38, 64.80, 64.47, 42.85.

[0111] Example 6

[0112] The chadniline derivative of this invention has the chemical name (E)-N-(4-((2-amino-5-fluorophenyl)carbamoyl)benzyl)-3-(3,4-dimethoxyphenyl)acrylamide, and its structural formula is as follows:

[0113]

[0114] (1) Synthesis of (E)-4-((3-(3-)dimethoxyphenyl)acrylamido)methyl)benzoic acid, with the following structural formula:

[0115]

[0116] 600 mg (2.88 mmol) of (E)-3-(3,4-dimethoxyphenyl)acrylic acid, 462.68 mg (3.05 mmol) of 4-p-aminomethylbenzoic acid, 1361 mg (7.81 mmol) of DIPEA, and 5 mL of dichloromethane were added sequentially to a reaction flask. 1358 mg (3.90 mmol) of T4P was added dropwise in an ice bath. The mixture was stirred at 25–35 °C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane to methanol = 50:1) to obtain 358 mg of the target product, with a yield of 35.6%.

[0117] (2) Synthesis of (E)-N-(4-((2-amino-5-fluorophenyl)carbamoyl)benzyl)-3-(3,4-dimethoxyphenyl)acrylamide

[0118] 120 mg (0.38 mmol) of (E)-4-((3-(3-)dimethoxyphenyl)acrylamido)methyl)benzoic acid, 305 mg (0.80 mmol) of HATU, 279 mg (2.01 mmol) of K2CO3 and 5 mL of N,N-dimethylformamide were added sequentially to the reaction flask. After reacting at room temperature for 30 min, 53 mg (0.42 mmol) of 4-fluorobenzene-1,2-diamine was added. The mixture was stirred at 25–35 °C for 4 hours. The reaction solution was extracted three times with water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 70:1) to obtain 107 mg of the target product, with a yield of 62.9%.

[0119] The target compound is a pale yellow solid; 1 H NMR(400MHz, DMSO-d6)δ 9.63 (s, 1H), 8.68 (t, J=6.1Hz, 1H), 7.96 (d, J=7.9Hz, 2H), 7.46-7.37 (m, 3H), 7.19 (d, J=2.0Hz, 1H), 7.13 (td, J=8.8, 4.1Hz, 2H), 6.99 (d, J=8.3Hz, 1H), 6.67-6.51 (m, 2H), 6.36 (td, J=8.5, 2.9Hz, 1H), 5.25 (s, 2H), 4.47 (d, J=6.0Hz, 2H), 3.80 (d, J=6.1Hz, 6H). 13C NMR (101MHz, DMSO-d6) δ165.90, 162.65, 160.28, 150.62, 149.36, 145.98, 145.86, 143.64, 139.62, 133.47, 128.96 , 128.35, 128.12, 127.42, 121.90, 120.15, 112.20, 110.51, 102.61, 102.39, 102.08, 101.83, 56.01, 55.89, 42.48.

[0120] Comparative Example 1

[0121] The chadniline derivative of this invention has the chemical name (E)-N-(2-amino-4-fluorophenyl)-4-((3-(benzo[d][1,3]dioxane-6-bromo-5-yl)acrylamide)methyl)benzamide, and its structural formula is as follows:

[0122]

[0123] (1) Synthesis of (E)-4-((3-(6-bromo-benzo[d][1,3]dioxacyclopenten-5-yl)acrylamido)methyl)benzoic acid

[0124]

[0125] 500 mg (1.84 mmol) of (E)-3-(6-bromobenzo[d][1,3]dioxacyclopenten-5-yl)acrylic acid, 278 mg (1.84 mmol) of 4-(aminomethyl)benzoic acid, 800 mg (4.60 mmol) of DIPEA and 5 mL of dichloromethane were added sequentially to a reaction flask. 1000 mg (2.87 mmol) of T4P was added dropwise in an ice bath. The mixture was stirred at 25–35 °C for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1). The solution was then concentrated under reduced pressure to obtain 358 mg of the target product, with a yield of 35.6%.

[0126] (2) Synthesis of (E)-N-(2-amino-4-fluorophenyl)-4-((3-(benzo[d][1,3]dioxane-6-bromo-5-yl)acrylamide)methyl)benzamide

[0127] (E)-4-((3-(6-bromo-benzo[d][1,3]dioxane-5-yl)acrylamido)methyl)benzoic acid 200 mg (0.49 mmol), HATU 305 mg (0.80 mmol), K2CO3 279 mg (2.01 mmol) and 5 mL N,N·dimethylformamide were added sequentially. After reacting at room temperature for 30 min, 4-fluorobenzene-1,2-diamine 80 mg (0.63 mmol) was added. The mixture was stirred at 25–35 °C for 4 hours. The reaction solution was extracted three times with water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1). The solution was concentrated under reduced pressure to obtain 107 mg of the target product, with a yield of 62.9%.

[0128] The target compound is a white solid; 1 H NMR (400MHz, DMSO-d6) δ8.80 (t, J=6.0Hz, 1H), 7.91 (d, J=8.0Hz, 2H), 7.67 (d, J=15. 5Hz, 1H), 7.40 (d, J = 7.9Hz, 2H), 7.31 (s, 1H), 7.25 (d, J = 13.8Hz, 1H), 6.63 (d, J = 15.6 Hz, 1H), 6.13 (s, 2H), 4.62 (s, 1H), 4.46 (d, J=6.0Hz, 2H), 3.61-3.35 (m, 10H), 3.05 (q , J=7.3Hz, 3H), 1.46 (p, J=6.9Hz, 1H), 1.25 (t, J=6.4Hz, 22H), 0.87 (t, J=7.4Hz, 1H). 13 C NMR (101MHz, DMSO-d6) δ167.95, 165.30, 149.92, 148.34, 144.69, 137.38, 129.87, 129.81, 128.04, 127.75, 123.66, 116. 77, 113.16, 106.64, 102.96, 72.79, 70.46, 70.23, 69.98, 60.66, 53.24, 42.60, 41.72, 31.76, 19.29, 18.09, 14.25, 13.10.

[0129] Comparative Example 2

[0130] The chadniline derivative of this invention has the chemical name N-(3-trifluoromethyl-4-methyl)-4-(((2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)penta-2,4-dienamide)methyl)benzamide, and its structural formula is as follows:

[0131]

[0132] Its preparation method is as follows:

[0133] 200 mg (0.56 mmol) of 4-(((2E,4E)-5-(benzo[d][1,3]dioxo-5-yl)penta-2,4-dienamido)methyl)benzoic acid (prepared using step 1 of Example 2), 305 mg (0.80 mmol) of HATU, 279 mg (2.01 mmol) of K2CO3, and 5 mL of N,N-dimethylformamide were added sequentially to the reaction flask. After reacting at room temperature for 30 min, 100 mg (0.56 mmol) of 4-methyl-3-(trifluoromethyl)aniline was added. The mixture was stirred at 25–35 °C for 4 hours. The reaction solution was extracted three times with water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 90:1) to obtain 40 mg of the target product, with a yield of 14.1%.

[0134] The target compound is a pale yellow solid; 1 H NMR (400MHz, DMSO-d6) δ10.40 (s, 1H), 8.66 (t, J = 6.0Hz, 1H), 8.18 (d, J = 2.3Hz, 1H), 7.95 (dq, J = 8.4, 2.1Hz, 3H), 7.42 (dd, J = 8.2, 6 .3Hz, 3H), 7.29-7.24 (m, 1H), 7.04-6.84 (m, 4H), 6.18 (d, J=15.0Hz, 1H), 6.05 (s, 2H), 4.46 (d, J=5.9Hz, 2H), 2.41 (d, J=2.0Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ165.93, 165.84, 148.41, 148.24, 144.13, 140.39, 138.66, 137.91, 133.44, 133.00, 131.30, 131.06, 131 .04, 128.25, 127.65, 126.30, 125.67, 124.58, 124.03, 123.58, 123.18, 117.74, 117.68, 108.91, 106.12, 101.73, 42.45, 18.67.

[0135] Effect Test Case

[0136] MTT assay for antitumor activity

[0137] Cell culture: Human cancer cell lines HeLa and MDA-MB-231 were purchased from the National Biomedical Laboratory in Beijing and cultured in DMEM (KGM12800-500) or MEM (KGM41500-500) medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin, in a Thermo Fisher Scientific, BB150 incubator at 37°C with 5% CO2. When the cell confluence reached 70%–80%, 0.25% trypsin was added for digestion, resuspending, and culturing. Cells in the logarithmic growth phase and in good growth condition were selected for further study.

[0138] Methyl thiazolyl tetrazolium (MTT) was used to determine cell viability. Hemocytometer counting was used for cell counting, and cell viability was greater than 95% in all experiments. MDA-MB-231 and HeLa cells were counted at 1 × 10⁻⁶ cells / mL. 4 Cells were seeded in 96-well plates. 100 μL of medium (containing 1% FBS) was added to each well to dissolve different concentrations of the drug (0–50 μM), and the cells were incubated for 24 h. After centrifugation (5 min, 2000 rpm), the supernatant was discarded, and 10 μL of MTT (5 mg / mL) solution was added to each well. The cells were incubated at 37°C for 4 h, centrifuged again, and the supernatant was discarded. 100 μL of DMSO was added to each well, and the cells were shaken for 10 min to fully dissolve the formazan crystals. The absorbance was measured at 570 nm using a microplate reader (BioTek, USA). Cytotoxicity was assessed compared to the control group (DMSO). The concentration at which the drug induced 50% cell growth inhibition (IC50) was determined using a curve fitting algorithm in GraphPad Prism9 (GraphPad software, La Jolla, CA, USA) via nonlinear regression. 50 Table 1 shows the effects of the compounds on the activity of different tumor cells, and the half-maximal inhibitory concentration (IC50) of the drugs on each cell line was calculated. 50 (48h).

[0139] Table 1. Inhibitory activity of compounds against different tumor cells (IC50) 50 )

[0140] Example Hela (μM) MDA-MB-231(μM) Example 1 / 9.23±2.25 Example 2 1.04±0.38 1.99±0.47 Example 3 2.67±0.53 5.10±0.91 Example 4 / 3.83±0.12 Example 5 4.29±1.57 6.07±0.44 Example 6 7.44±0.13 2.39±0.22 Cidaraniline 16.1±0.31 18.94±0.43 Comparative Example 1 123.97±1.00 106.11±5.37 Comparative Example 2 448.17±29.514 158.57±33.71

[0141] " / " indicates that it was not measured.

[0142] Table 1 shows that the compound has a significant inhibitory effect on HeLa and MDA-MB-231 tumor cells, with some reaching about 1 μM, which is significantly better than that of chidamide. This indicates that the compound has good activity against tumor cells and has good research value.

Claims

1. A compound I or a pharmaceutically acceptable salt thereof: in, m and n are each independently 0, 1, 2 or 3; R 1 and R 2 It is an -OC1-C3 alkyl group; Or, R 1 and R 2 Together with the carbon atom directly attached thereto, they form a 5-6 membered heterocyclic alkyl group, wherein the heteroatom is O, and the number of heteroatoms is 1, 2 or 3; Linker is a chemical bond, -(CH2) p -or p is an integer from 1 to 6; q is an integer from 1 to 3; Each R 3 and R 4 Each can be independently hydrogen, halogen, hydroxyl, amino, nitro or -OC1-C3 alkyl.

2. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1)R 1 and R 2 In the -OC1-C3 alkyl group, the C1-C3 alkyl group is methyl, ethyl, n-propyl or isopropyl, preferably methyl; (2)R 1 and R 2 In the 5-6 membered heterocyclic alkyl group, the number of heteroatoms is 2; the 5-6 membered heterocyclic alkyl group is preferably... (3)R 3 and R 4 In the -OC1-C3 alkyl group, C 1- The C3 alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl; and (4)R 3 and R 4 In this context, the halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine or bromine.

3. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1)R 1 and R 2 For -OCH3; or, R 1 and R 2 It forms together with the carbon atoms directly attached to it. (2) Linker is a chemical bond or (3) p is 1, 2 or 3; (4) q is 1, 2 or 3, preferably 1 or 2; (5)R 3 It is hydrogen; (6) m is 0; (7) Each R4 is independently halogenated, amino, or -OC1-C3 alkyl; preferably halogenated or amino; and (8) n is 1, 2 or 3, preferably 2.

4. The compound I as described in claim 3, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1) for (2) For chemical bonds, and (3) for 5. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound I is compound I-1: Among them, R 1 R 2 The definition of Linker is as described in claim 1; R 4-1 and R 4-2 Each can be independently hydrogen, halogen, hydroxyl, amino, nitro or -OC1-C3 alkyl; Preferred, R 4-1 It is an amino group or an -OC1-C3 alkyl group; R 4-2 It is a halogen.

6. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound I is:

7. A method for preparing compound I according to any one of claims 1-6, characterized in that, The following steps are included: Compound 3 and Compound 4 are amidated to obtain Compound I: R 1 R 2 R 3 R 4 The definitions of m, n and Linker are as described in claim 1.

8. A compound 3: R 1 R 2 R 3 The definitions of m and Linker are as described in claim 1. Preferably, compound 3 is:

9. A pharmaceutical composition comprising: (1) Compound I or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6; (2) Pharmaceutically acceptable excipients.

10. The use of compound I or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-6, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating tumors; wherein the tumor is preferably cervical cancer or breast cancer.

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