Benzylurea compounds, methods of making and using the same

Abstract

The present application relates to the technical field of drug synthesis, in particular to a benzylurea compound, a preparation method and application thereof. The structural formula of the benzylurea compound is shown in the following: wherein R1 represents any one of a connecting bond, a substituted or unsubstituted amide bond and a C1-C10 unsubstituted alkyl bond, and R2 is selected from any one of a substituted or unsubstituted single aromatic heterocyclic group, or a substituted or unsubstituted single aromatic ring group, or a substituted or unsubstituted benzo-fused ring group. The benzylurea compound can effectively inhibit the activity of tumor cells, and has a good therapeutic effect on esophageal cancer, lung cancer, gastric cancer, breast cancer, colorectal cancer, laryngeal cancer, nasopharyngeal cancer, oral cancer, pancreatic cancer, renal cancer, prostate cancer, bladder cancer, cervical cancer, lymphoma, acute leukemia, osteosarcoma, Ewing's sarcoma and thyroid cancer.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a benzene cyclopropyl urea compound, a preparation method thereof and application thereof. BACKGROUND

[0002] Compounds or groups containing heteroatoms, such as thiazole, oxazole, pyridine and furan, often have different physiological or biochemical, and thus can be used for the synthesis of small molecule compounds, but different small molecule compounds have different effects, and some small molecule compounds containing heteroatoms have low drug efficacy or cannot produce therapeutic effects.

[0003] In view of this, the present application is proposed. SUMMARY

[0004] The present application aims to provide a benzene cyclopropyl urea compound, a preparation method thereof and application thereof. The benzene cyclopropyl urea compound can effectively inhibit the activity of tumor cells and has good therapeutic effect on tumors.

[0005] The present application is achieved in the following manner:

[0006] In a first aspect, the present application provides a benzene cyclopropyl urea compound, the structural formula of which is as follows:

[0007] wherein R1 represents any one of a bond, a substituted or unsubstituted amide bond and a C1-C10 unsubstituted alkyl group, and R2 is selected from any one of a substituted or unsubstituted single aromatic heterocyclic group, or a substituted or unsubstituted single aromatic ring group, or a substituted or unsubstituted benzo-fused ring group.

[0008] In a second aspect, the present application provides a preparation method of the benzene cyclopropyl urea compound according to the foregoing embodiments, which synthesizes the benzene cyclopropyl urea compound according to the following synthesis path:

[0009]

[0010] In a third aspect, the present application provides use of the benzene cyclopropyl urea compound according to the foregoing embodiments in the preparation of a drug for treating cancer.

[0011] The present application has the following beneficial effects: the present application provides a new benzene cyclopropyl urea compound, which can effectively inhibit the activity of tumor cells and has good therapeutic effect on tumors. DETAILED DESCRIPTION

[0012] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. The specific conditions not mentioned in the embodiments are implemented according to the conventional conditions or the conditions suggested by the manufacturers. The reagents or instruments not mentioned by the manufacturers are all conventional products that can be purchased in the market.

[0013] The present embodiment provides a phenylpropionamide compound, the structural formula of which is as follows:

[0014] In the formula, R1 represents any one of a connecting bond, a substituted or unsubstituted amide bond and a C1-C10 unsubstituted alkyl group, and R2 is selected from any one of a group of functional groups formed by a substituted or unsubstituted single aromatic heterocyclic group, or a substituted or unsubstituted single aromatic ring group, a substituted or unsubstituted benzo-fused ring group.

[0015] Specifically, R1 represents any one of a connecting bond, a C1-C5 alkyl-substituted or unsubstituted amide bond and a C1-C5 unsubstituted straight-chain alkyl group; preferably, R1 represents a connecting bond.

[0016] That is, when R1 represents a connecting bond, the structural formula of the phenylpropionamide compound is as follows:

[0017]

[0018] Further, R2 is selected from any one of a group of functional groups formed by a substituted or unsubstituted benzene ring, a substituted or unsubstituted isoxazole group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted pyrimidine group, a substituted or unsubstituted pyridine ring group, a substituted or unsubstituted naphthalene group, a substituted or unsubstituted pyrazole ring group, a substituted or unsubstituted benzothiazole ring group, a substituted or unsubstituted benzoxazole ring group and a substituted or unsubstituted benzopyrazole group.

[0019] Specifically, the substituted benzene ring can be mono-substituted, for example, meta-substituted, ortho-substituted or para-substituted, preferably meta-substituted. It can also be di-substituted, for example, meta, para-substituted, meta, ortho-substituted or ortho, para-substituted.

[0020] Further, the substituents of the benzene ring are selected from any one of halogen (e.g. fluorine, bromine and chlorine), tertiary amine group, nitro group, substituted secondary amine group, phenoxy group, C1-C3alkoxy group (e.g. methoxy, ethoxy), phenyl group and aromatic heterocycle; further, the substituents of the benzene ring are selected from any one of halogen, tertiary amine group, nitro group, benzene ring substituted secondary amine group, benzene ring carbamide substituted secondary amine group, phenoxy group, C1-C3alkoxy group, phenyl group and C3-C6oxygen and nitrogen containing aromatic heterocycle. That is, the above-mentioned groups can substitute one H on the benzene ring as substituents (i.e. mono-substitution), or substitute 2 H on the benzene ring (i.e. di-substitution), and when di-substitution, the two groups can be the same or different.

[0021] Further, the substituents of the substituted pyrimidine group include halogen and carbonyl; the substituents of the substituted pyrimidine group are located at the 6 position on the pyrimidine ring.

[0022] The substituents of the substituted pyridine ring group include halogen; the substituents of the substituted pyridine ring group are located at the 6 position on the pyridine ring.

[0023] It should be noted that the dotted line in the structural formula provided by the embodiment of the present application represents the connection position of the substituent, and the black thick solid line represents the connection position of the thiazole ring and the urea group.

[0024] Further, the substituents of the substituted benzothiazole ring group are selected from any one of halogen, nitro group and alkyl group (e.g. C1-C10alkyl group, C1-C5alkyl group) to form a functional group group; the substituents of the substituted benzothiazole ring group are selected from any one of fluorine, chlorine and bromine to form a functional group group; the substituted benzothiazole ring group is a mono-substituted group (e.g. meta-substitution) or a di-substituted group; the substituents of the substituted benzothiazole ring group are located at at least one of the 4 position 5 position 6 position and 7 position , such as 4 position substitution, 5 position substitution, 6 position substitution, 7 position substitution alone, 4, 7 position double substitution, 4, 5 position double substitution, 4, 6 position double substitution, 5, 6 position double substitution, etc. Double substitution, 4, 5, 6 triple substitution, 5, 6, 7 triple substitution, 4, 5, 7 triple substitution, 4, 6, 7 triple substitution, etc. Triple substitution, and 4, 5, 6, 7, four substitution.

[0025] Further, the substituents of the substituted benzothiazole ring group are selected from any one of halogen, nitro group and alkyl group (e.g. C1-C10alkyl group, C1-C5alkyl group) to form a functional group group; the substituents of the substituted benzothiazole ring group are selected from any one of fluorine, chlorine and bromine to form a functional group group; the substituted benzothiazole ring group is a mono-substituted group (e.g. meta-substitution) or a di-substituted group; the substituents of the substituted benzothiazole ring group are located at at least one of the 4 position 5 position 6 position and 7 position Any one of the above, for example, 4-position substitution, 5-position substitution, 6-position substitution, 7-position substitution, 4, 7-position double substitution, 4, 5-position double substitution, 4, 6-position double substitution, 5, 6-position double substitution, 4, 5, 6-triple substitution, 5, 6, 7-triple substitution, 4, 5, 7-triple substitution, 4, 6, 7-triple substitution, 4, 5, 6, 7-quadruple substitution, etc.

[0026] The substituent of the substituted benzopyrazole group is selected from any one of the functional group group consisting of halogen, nitro, cyano and C1-C5 alkyl.

[0027] It should be noted that the halogen described in the embodiments of the present application includes any one of fluorine, chlorine, bromine and iodine.

[0028] The alkyl group is not only C1-C5 alkyl such as methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl and n-pentyl, but also further substituted alkyl, and the further substituted substituent can be halogen, nitro, cyano, amine and carboxyl.

[0029] The substitution described in the embodiments of the present application can be single substitution of hydrogen on one carbon, or double substitution or multiple substitution of hydrogen on two or more carbons.

[0030] The phenylurea compound is selected from any one of the compounds shown in the following structural formula:

[0031]

[0032]

[0033] and

[0034]

[0035] The embodiments of the present application also provide a preparation method of the phenylurea compound, and the phenylurea compound is synthesized by referring to the following synthesis path:

[0036]

[0037] Specifically, the above amine substance and alkaline substance (such as potassium carbonate and sodium carbonate) are dissolved in a solvent (such as DMSO), then an isocyanate compound is added and the reaction is carried out by heating, water and ethyl acetate (volume ratio of 3:1) are added after the reaction is completed, then extraction is carried out, and finally silica gel column chromatography is carried out to obtain the corresponding phenylurea compound.

[0038] The above extraction and silica gel column chromatography are processes known in the art, and the embodiments of the present application will not be described in detail.

[0039] Further, the molar ratio of the amine compound to the isocyanate compound is 1:1.5; the reaction temperature is 50-100 DEG C, and the reaction time is 10-120 minutes.

[0040] The application provides application of the above-mentioned phenylurea compound in preparation of a medicine for treating cancer.

[0041] The features and performances of the application are further described in detail in combination with the following examples.

[0042] Example 1

[0043] The example provides a phenylurea compound (denoted as compound 1), and a structural formula of the compound is as shown in the following:

[0044]

[0045] The example provides a preparation method of the above-mentioned phenylurea compound, and the preparation method comprises the following steps:

[0046] 1 mol of 3-aminoisoxazole and 1 mol of alkali are dissolved in 30 ml of DMSO, then 1.5 mol of trans-2-phenylcyclopropyl isocyanate is added, the temperature is increased to 80 DEG C, and the temperature is kept for 30 minutes; TCL is used to monitor the reaction; after the reaction is completed, water and EA (a volume ratio of 3:1) are used for extraction, and then column chromatography is performed.

[0047] The prepared compound is characterized, and detection data are as follows:

[0048] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 1.0 Hz, 1H), 7.73 (s, 1H), 7.27-7.22 (m, 2H), 7.13-7.10 (m, 3H), 7.07-7.04 (m, 2H), 6.27 (d, J = 3.3 Hz, 1H), 2.62 (tt, J = 6.6, 3.2 Hz, 1H), 2.01 (ddd, J = 9.4, 6.6, 3.3 Hz, 1H), 1.23-1.14 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 13 H 13 N3O2: 243.1008; found: 243.2859.

[0049] Example 2

[0050] The example provides a phenylurea compound (denoted as compound 2), and a structural formula of the compound is as shown in the following:

[0051]

[0052] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is cyclopentylamine, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 60 DEG C, and the reaction time is 60 minutes.

[0053] The prepared compound is characterized, and the detection data are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 7.22-7.20 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.08 (m, 1H), 7.06-7.02 (m, 2H), 6.10 (d, J=3.2 Hz, 1H), 5.68 (d, J=7.4 Hz, 1H), 2.57 (ddt, J=7.7, 4.5, 3.2 Hz, 1H), 1.87-1.80 (m, 1H), 1.75-1.68 (m, 2H), 1.58-1.50 (m, 2H), 1.48-1.39 (m, 2H), 1.24 (ddq, J=13.0, 7.8, 6.4 Hz, 2H), 1.06-0.98 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 15 H 20 N2O:244.1576;found:244.5644.

[0054] Embodiment 3

[0055] The embodiment provides a phenylurea compound (denoted as compound 3), and a structural formula of the phenylurea compound is as shown in the following:

[0056]

[0057] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is 4-amino-6-chloropyrimidine, the molar ratio of the amine compound to the isocyanate compound is 1.2:1; the reaction temperature is 75 DEG C, and the reaction time is 45 minutes.

[0058] The prepared compound is characterized, and the detection data are as follows:

[0059] 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 1.0 Hz, 1H), 7.76 (s, 1H), 7.30 - 7.25 (m, 2H), 7.17 - 7.13 (m, 2H), 7.11 - 7.07 (m, 2H), 6.30 (d, J = 3.3 Hz, 1H), 2.65 (tt, J = 6.6, 3.2 Hz, 1H), 2.04 (ddd, J = 9.4, 6.6, 3.3 Hz, 1H), 1.26 - 1.17 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 14 H 13 ClN4O:288.0778;found:288.0784.

[0060] Example 4

[0061] This example provides a phenyl cyprocarbazole compound (denoted as compound 4), the structural formula of which is as shown below:

[0062]

[0063] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has basically the same operation as the preparation method provided in Example 1, and the difference lies in that the amine substance is 4-fluorobenzhydrazide, the molar ratio of the amine compound to the isocyanate compound is 1.4:1; the reaction temperature is 70°C, and the reaction time is 40 minutes.

[0064] The prepared compound is characterized, and the detection data are as follows:

[0065] 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.96 (ddd, J = 10.9, 6.5, 3.7 Hz, 2H), 7.33 (t, J = 8.8 Hz, 2H), 7.25 (td, J = 7.8, 2.3 Hz, 2H), 7.18 - 7.06 (m, 3H), 6.98 - 6.89 (m, 1H), 2.70 (dq, J = 7.4, 3.4 Hz, 1H), 1.91 (dddd, J = 16.5, 9.1, 6.5, 3.2 Hz, 1H), 1.21 - 1.03 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 16 FN3O2; 317.1227; found: 318.1261.

[0066] Example 5

[0067] The present embodiment provides a phenylurea compound (denoted as compound 5), the structural formula of which is shown as follows:

[0068]

[0069] The present embodiment provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Embodiment 1 in operation, and the difference lies in that the amine substance is cytosine, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0070] The prepared compound is characterized, and the detection data are as follows:

[0071] 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.34 (s, 1H), 7.67 (d, J = 7.0 Hz, 1H), 7.26 (d, J = 7.5 Hz, 2H), 7.20 - 7.14 (m, 2H), 7.14 - 7.06 (m, 1H), 6.19 (s, 1H), 4.03 (q, J = 7.1 Hz, 1H), 2.83 (dq, J = 7.3, 3.6 Hz, 1H), 2.04 (ddd, J = 9.6, 6.5, 3.3 Hz, 1H), 1.25 - 1.18 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 14 H 14 N4O2: 270.1117; found: 271.1284.

[0072] Embodiment 6

[0073] The present embodiment provides a phenylurea compound (denoted as compound 6), the structural formula of which is shown as follows:

[0074]

[0075] The present embodiment provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Embodiment 1 in operation, and the difference lies in that the amine substance is 5-aminomethyl-2-chloropyridine, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0076] The prepared compound is characterized, and the detection data are as follows:

[0077] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.2, 2.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 7.5 Hz, 2H), 7.17 - 7.11 (m, 1H), 7.11 - 7.06 (m, 2H), 6.59 - 6.46 (m, 2H), 2.66 (td, J = 6.8, 5.9, 3.0 Hz, 1H), 1.94 - 1.87 (m, 1H), 1.09 (dd, J = 8.8, 5.4 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 16 H 16 ClN3O:301.0982;found:301.1625.

[0078] Example 7

[0079] This example provides a phenyl cyprocarbazole compound (denoted as compound 7), the structural formula of which is as follows:

[0080]

[0081] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has substantially the same operation as the preparation method provided in Example 1, except that the amine substance is 4-nitrophenethylamine hydrochloride, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0082] The prepared compound is characterized, and the detection data are as follows:

[0083] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.2, 2.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 7.5 Hz, 2H), 7.17 - 7.11 (m, 1H), 7.11 - 7.06 (m, 2H), 6.59 - 6.46 (m, 2H), 2.66 (td, J = 6.8, 5.9, 3.0 Hz, 1H), 1.94 - 1.87 (m, 1H), 1.09 (dd, J = 8.8, 5.4 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 18 H 19N3O3: 325.1426; found: 326.1578.

[0084] Example 8

[0085] This example provides a phenylurea compound (denoted as compound 8), the structural formula of which is as shown below:

[0086]

[0087] This example provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Example 1 in operation, and the difference lies in that the amine substance is p-dimethylaminobenzhydrazide, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0088] The prepared compound is characterized, and the detection data are as follows:

[0089] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 3.8 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.17 - 7.08 (m, 3H), 6.83 (d, J = 3.4 Hz, 1H), 6.75 - 6.68 (m, 2H), 2.98 (s, 6H), 2.73 - 2.66 (m, 1H), 1.92 (ddd, J = 9.5, 6.2, 3.3 Hz, 1H), 1.22 - 1.02 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 19 H 22 N4O2; 338.1743; found: 338.2241.

[0090] Example 9

[0091] This example provides a phenylurea compound (denoted as compound 9), the structural formula of which is as shown below:

[0092]

[0093] This example provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Example 1 in operation, and the difference lies in that the amine substance is p-dimethylaminobenzhydrazide, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0094] The prepared compound was characterized, and the detection data were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.47-8.38 (m, 1H), 7.96 (s, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 7.4 Hz, 3H), 7.27-7.23 (m, 2H), 7.21 (dd, J = 8.0, 1.5 Hz, 3H), 7.08-7.04 (m, 2H), 7.04-7.00 (m, 2H), 6.79 (td, J = 7.3, 1.2 Hz, 1H), 2.83-2.77 (m, 1H), 2.04 (ddd, J = 9.3, 7.6, 4.5 Hz, 1H), 1.23 (ddd, J = 12.9, 8.0, 5.2 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 22 H 21 N3O:343.1685:found:343.4217.

[0095] Example 10

[0096] This example provides a phenyl cyprocarbazole compound (denoted as compound 10), the structural formula of which is as follows:

[0097]

[0098] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has basically the same operation as the preparation method provided in Example 1, and the difference lies in that the amine substance is 4-aminodiphenyl ether, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0099] The prepared compound was characterized, and the detection data were as follows:

[0100] 1 H NMR (400 MHz, DMSO-d6) δ 8.47-8.38 (m, 1H), 7.96 (s, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 7.4 Hz, 3H), 7.27-7.23 (m, 2H), 7.21 (dd, J = 8.0, 1.5 Hz, 3H), 7.08-7.04 (m, 2H), 7.04-7.00 (m, 2H), 6.79 (td, J = 7.3, 1.2 Hz, 1H), 2.83-2.77 (m, 1H), 2.04 (ddd, J = 9.3, 7.6, 4.5 Hz, 1H), 1.23 (ddd, J = 12.9, 8.0, 5.2 Hz, 2H). HRMS (ESI) m / z: (M+H) +C 22 H 20 N2O2:331.1025;found:331.1274.

[0101] Example 11

[0102] This example provides a phenylurea compound (denoted as compound 11), the structural formula of which is as shown below:

[0103]

[0104] This example provides a preparation method of the above-mentioned phenylurea compound, which has substantially the same operation as the preparation method provided in Example 1, except that the amine substance is 4-(4-morpholinyl) aniline, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0105] The prepared compound is characterized, and the detection data are as follows:

[0106] 1 H NMR (600 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.24-7.20 (m, 3H), 7.20 (d, J = 2.2 Hz, 1H), 7.13-7.10 (m, 1H), 7.09-7.07 (m, 2H), 6.81-6.75 (m, 2H), 6.43 (d, J = 3.2 Hz, 1H), 3.69-3.66 (m, 4H), 2.96-2.93 (m, 4H), 2.67 (ddt, J = 7.8, 4.7, 3.2 Hz, 1H), 1.90 (ddd, J = 9.4, 6.3, 3.2 Hz, 1H), 1.12-1.06 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 20 H 23 N3O2:337.1790:found:337.4127.

[0107] Example 12

[0108] This example provides a phenylurea compound (denoted as compound 12), the structural formula of which is as shown below:

[0109]

[0110] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is 2-methoxy-4 morpholinyl aniline, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80 DEG C, and the reaction time is 30 minutes.

[0111] The prepared compound is characterized, and detection data are as follows:

[0112] 1 H NMR (600 MHz, DMSO-d6) δ 7.79 (d, J = 8.9 Hz, 1H), 7.21 (dt, J = 14.3, 7.6 Hz, 3H), 7.12 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 7.7 Hz, 2H), 7.04 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 3.1 Hz, 1H), 6.36 (dd, J = 8.9, 2.7 Hz, 1H), 3.72 (s, 3H), 3.69 - 3.66 (m, 4H), 3.03 - 2.92 (m, 4H), 2.66 (dd, J = 7.6, 4.1 Hz, 1H), 1.88 (ddd, J = 9.6, 6.2, 3.4 Hz, 1H), 1.09 - 1.01 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 21 H 25 N3O3: 366.1896; found: 366.2628.

[0113] Embodiment 13

[0114] The embodiment provides a phenylurea compound (denoted as compound 13), and a structural formula of the phenylurea compound is as shown in the following:

[0115]

[0116] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is 2-methoxy-4 morpholinyl aniline, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80 DEG C, and the reaction time is 30 minutes.

[0117] The prepared compound is characterized, and detection data are as follows:

[0118] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.71 (t, J = 1.8 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.31 (dd, J = 7.8, 2.6 Hz, 2H), 7.24 (dt, J = 20.2, 7.6 Hz, 3H), 7.13 (dd, J = 7.6, 4.4 Hz, 2H), 7.09 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 3.1 Hz, 1H), 2.70 (dq, J = 7.3, 3.5 Hz, 1H), 1.92 (ddt, J = 9.4, 6.3, 3.2 Hz, 1H), 1.14 - 1.08 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 22 H 20 N2O:328.1576;found:328.4509.

[0119] Example 14

[0120] This example provides a phenylcyclopropylurea compound (denoted as compound 14), the structural formula of which is as follows:

[0121]

[0122] This example provides a preparation method of the above-mentioned phenylcyclopropylurea compound, which has substantially the same operation as the preparation method provided in Example 1, except that the amine substance is 1-naphthalene acetic hydrazide, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0123] The prepared compound is characterized, and the detection data are as follows:

[0124] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.71 (t, J = 1.8 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.31 (dd, J = 7.8, 2.6 Hz, 2H), 7.24 (dt, J = 20.2, 7.6 Hz, 3H), 7.13 (dd, J = 7.6, 4.4 Hz, 2H), 7.09 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 3.1 Hz, 1H), 2.70 (dq, J = 7.3, 3.5 Hz, 1H), 1.92 (ddt, J = 9.4, 6.3, 3.2 Hz, 1H), 1.14 - 1.08 (m, 2H). HRMS (ESI) m / z: (M+H) +C 22 H 21 N3O2: 359.1634; found: 359.4723.

[0125] Example 15

[0126] This example provides a phenyl cyprocarbazole compound (denoted as compound 15), the structural formula of which is as shown below:

[0127]

[0128] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has basically the same operation as the preparation method provided in Example 1, except that the amine substance is 4,6-difluoro-1,3-benzothiazol-2-amine, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0129] The prepared compound is characterized, and the detection data are as follows:

[0130] 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.71 (dd, J = 8.5, 2.5 Hz, 1H), 7.29 (pd, J = 7.0, 5.3, 3.5 Hz, 3H), 7.24 - 7.15 (m, 4H), 7.10 (dd, J = 9.7, 7.6 Hz, 1H), 2.82 (s, 1H), 2.08 (ddd, J = 10.4, 7.0, 3.3 Hz, 1H), 1.23 (dh, J = 10.5, 5.1, 4.7 Hz, 2H). HRMS (ESI) m / z: (M+H)+calcd for C17H13F2N3OS: 345.0747; found: 345.1237.

[0131] Example 16

[0132] This example provides a phenyl cyprocarbazole compound (denoted as compound 16), the structural formula of which is as shown below

[0133]

[0134] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has basically the same operation as the preparation method provided in Example 1, except that the amine substance is 4,6-difluoro-1,3-benzothiazol-2-amine, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0135] The prepared compound was characterized, and the detection data were as follows:

[0136] 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 - 7.15 (m, 2H), 7.11 - 7.07 (m, 2H), 6.29 (d, J = 3.1 Hz, 1H), 2.67 - 2.58 (m, 1H), 2.07 (ddd, J = 9.6, 6.6, 3.3 Hz, 1H), 1.31 - 1.18 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 14 BrN3OS:387.0041;found:388.2332.

[0137] Example 17

[0138] This example provides a phenyl cyprocarbazole compound (denoted as compound 17), the structural formula of which is as shown below

[0139]

[0140] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has basically the same operation as the preparation method provided in Example 1, except that the amine substance is 2-amino-5,7-difluorobenzothiazole, the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0141] The prepared compound was characterized, and the detection data were as follows:

[0142] 1H NMR (600 MHz, DMSO-d6) δ 7.35 (d, J = 9.8 Hz, 1H), 7.24 (t, J = 7.6 Hz, 2H), 7.22 - 7.13 (m, 2H), 7.12 (d, J = 8.2 Hz, 2H), 2.78 (s, 1H), 2.06 - 2.02 (m, 1H), 1.23 - 1.16 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C17H13F2N3OS: 345.0747; found: 345.2321.

[0143] Example 18

[0144] The embodiment provides a phenylurea compound (denoted as compound 18), and a structural formula is as shown in the following

[0145]

[0146] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is a benzoxazole amine, a molar ratio of the amine compound and the isocyanate compound is 1.5:1; a reaction temperature is 80 DEG C, and a reaction time is 30 minutes.

[0147] The prepared compound is characterized, and detection data are as follows:

[0148] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.68-7.59 (m, 2H), 7.37-7.24 (m, 3H), 7.25-7.14 (m, 3H), 7.11 (d, J=7.6 Hz, 1H), 2.90 (dq, J=7.6, 3.7 Hz, 1H), 2.18-2.10 (m, 1H), 1.30 (tt, J=13.2, 5.8 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 14 ClN3O2: 327.0775; found: 327.2345.

[0149] Embodiment 19

[0150] The embodiment provides a phenylurea compound (denoted as compound 19), and a structural formula is as shown in the following

[0151]

[0152] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is a benzoxazole amine, a molar ratio of the amine compound and the isocyanate compound is 1.5:1; a reaction temperature is 80 DEG C, and a reaction time is 30 minutes.

[0153] The prepared compound is characterized, and detection data are as follows:

[0154] 1H NMR (400 MHz, DMSO-d6) δ 8.13 (t, J = 1.0 Hz, 1H), 8.04 (dd, J = 8.1, 0.8 Hz, 1H), 7.69 (dd, J = 8.1, 1.2 Hz, 1H), 7.24 (dd, J = 8.2, 6.9 Hz, 2H), 7.17 - 7.09 (m, 2H), 6.71 (s, 2H), 6.31 (d, J = 3.2 Hz, 1H), 2.63 (ddt, J = 7.0, 4.9, 3.2 Hz, 1H), 1.89 (ddd, J = 9.2, 6.6, 3.2 Hz, 1H), 1.11 - 1.04 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 18 H 14 N4O2: 318.1117; found: 318.1261.

[0155] Example 20

[0156] This example provides a phenyl cyprocarbazole compound (denoted as compound 20), the structural formula of which is as shown below

[0157]

[0158] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has substantially the same operation as the preparation method provided in Example 1, except that the amine substance is 3,4-methylenedioxyaniline, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0159] The prepared compound is characterized, and the detection data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (t, J = 1.0 Hz, 1H), 8.04 (dd, J = 8.1, 0.8 Hz, 1H), 7.69 (dd, J = 8.1, 1.2 Hz, 1H), 7.24 (dd, J = 8.2, 6.9 Hz, 2H), 7.17 - 7.09 (m, 2H), 6.71 (s, 2H), 6.31 (d, J = 3.2 Hz, 1H), 2.63 (ddt, J = 7.0, 4.9, 3.2 Hz, 1H), 1.89 (ddd, J = 9.2, 6.6, 3.2 Hz, 1H), 1.11 - 1.04 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 16 N2O3; 296.1161; found: 297.1207.

[0160] Example 21

[0161] The present embodiment provides a phenylurea compound (denoted as compound 21), the structural formula of which is shown below

[0162]

[0163] The present embodiment provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Embodiment 1, except that the amine substance is 2-amino-5-bromobenzoxazole, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0164] The prepared compound is characterized, and the detection data are as follows:

[0165] 1 H NMR (600 MHz, DMSO-d6) δ 7.22 (dt, J = 24.3, 7.5 Hz, 3H), 7.12 (dq, J = 20.9, 7.4 Hz, 2H), 7.04 (d, J = 7.6 Hz, 2H), 6.32 - 6.21 (m, 1H), 2.58 (dq, J = 7.5, 3.7 Hz, 1H), 1.85 (t, J = 9.6 Hz, 1H), 1.03 (h, J = 5.4, 5.0 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 14 BrN3O2; 372.2220: 372.2148.

[0166] Embodiment 22

[0167] The present embodiment provides a phenylurea compound (denoted as compound 22), the structural formula of which is shown below

[0168]

[0169] The present embodiment provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Embodiment 1, except that the amine substance is 2-amino-5-bromobenzoxazole, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0170] The prepared compound is characterized, and the detection data are as follows:

[0171] 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 3.0 Hz, 1H), 7.57 (dt, J = 7.5, 3.8 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.29 (d, J = 7.3 Hz, 2H), 7.20 (d, J = 7.1 Hz, 3H), 7.14 - 7.06 (m, 1H), 2.82 (d, J = 7.6 Hz, 1H), 2.15 - 2.07 (m, 1H), 1.28 (dq, J = 10.3, 5.4, 4.6 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 16 N4O:292.1324;found:292.1315.

[0172] Example 23

[0173] This example provides a phenyl cyprocarbazole compound (denoted as compound 23), the structural formula of which is as shown below

[0174]

[0175] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has substantially the same operation as the preparation method provided in Example 1, except that the amine substance is 2-aminobenzoxazole, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0176] The prepared compound is characterized, and the detection data are as follows:

[0177] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 3.0 Hz, 1H), 7.57 (dt, J = 7.5, 3.8 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.29 (d, J = 7.3 Hz, 2H), 7.20 (d, J = 7.1 Hz, 3H), 7.14 - 7.06 (m, 1H), 2.82 (d, J = 7.6 Hz, 1H), 2.15 - 2.07 (m, 1H), 1.28 (dq, J = 10.3, 5.4, 4.6 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 15 N3O2:294.1198;found:294.1464.

[0178] Example 24

[0179] The embodiment provides a phenylurea compound (denoted as compound 24), and a structural formula is as shown in the following

[0180]

[0181] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is 2-amino-6-nitrobenzimidazole, and a molar ratio of the amine compound to the isocyanate compound is 1.5:1; a reaction temperature is 80 DEG C, and a reaction time is 30 minutes.

[0182] The prepared compound is characterized, and detection data are as follows:

[0183] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 2.3 Hz, 1H), 8.03 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.29 (dd, J = 8.1, 6.9 Hz, 2H), 7.21 - 7.15 (m, 3H), 2.81 (s, 1H), 2.09 (td, J = 8.0, 3.3 Hz, 1H), 1.18 (t, J = 7.1 Hz, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 15 N5O3: 337.1175; found: 337.4127.

[0184] Embodiment 25

[0185] The embodiment provides a phenylurea compound (denoted as compound 25), and a structural formula is as shown in the following

[0186]

[0187] The embodiment provides a preparation method of the above-mentioned phenylurea compound, and the preparation method is basically same as the preparation method provided in the embodiment 1, and the difference is that the amine substance is 5-aminoindazole, and a molar ratio of the amine compound to the isocyanate compound is 1.5:1; a reaction temperature is 80 DEG C, and a reaction time is 30 minutes.

[0188] The prepared compound is characterized, and detection data are as follows:

[0189] 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.71 (q, J = 2.8 Hz, 2H), 7.48 (dd, J = 8.6, 2.6 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.24 (d, J = 7.6 Hz, 2H), 7.17 - 7.13 (m, 2H), 7.08 (d, J = 2.0 Hz, 1H), 6.33 - 6.25 (m, 1H), 2.69 - 2.60 (m, 1H), 1.90 (ddd, J = 10.2, 5.7, 2.3 Hz, 1H), 1.27 - 1.14 (m, 2H). HRMS (ESI) m / z: (M+H) + calcd for C 17 H 16 N4O: 292.1324; found: 292.1336.

[0190] Example 26

[0191] This example provides a phenylcyclopropylurea compound (denoted as compound 26), the structural formula of which is as shown below

[0192]

[0193] This example provides a preparation method of the above-mentioned phenylcyclopropylurea compound, which has basically the same operation as the preparation method provided in Example 1, except that the amine substance is o-phenylenediamine, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0194] The prepared compound is characterized, and the detection data are as follows:

[0195] 1 1H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 2H), 7.27 - 7.24 (m, 4H), 7.12 (dd, J = 7.0, 1.5 Hz, 4H), 6.79 (td, J = 7.5, 1.5 Hz, 2H), 6.72 - 6.64 (m, 4H), 6.53 (td, J = 7.6, 1.6 Hz, 2H), 2.74 (tt, J = 6.7, 3.3 Hz, 2H), 1.97 (ddd, J = 9.8, 5.5, 2.6 Hz, 2H), 1.18 - 1.07 (m, 4H). HRMS (ESI) m / z: (M+H) + calcd for C 26 H 26 N4O2: 426.5200; found: 427.0258.

[0196] Example 27

[0197] This embodiment provides a phenylurea compound (denoted as compound 27), the structural formula of which is as shown below

[0198]

[0199] This embodiment provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Example 1 in operation, except that the amine substance is m-phenylenediamine, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0200] The prepared compound is characterized, and the detection data are as follows:

[0201] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 2H), 7.46 (d, J = 2.1 Hz, 1H), 7.27 (t, J = 7.5 Hz, 4H), 7.19 - 7.12 (m, 6H), 7.08 - 7.01 (m, 1H), 7.01 - 6.95 (m, 2H), 6.53 (d, J = 3.1 Hz, 2H), 2.70 (dh, J = 6.6, 3.1 Hz, 2H), 1.96 (ddd, J = 9.5, 6.3, 3.3 Hz, 2H), 1.20 - 1.09 (m, 4H). HRMS (ESI) m / z: (M+H) + calcd for C 26 H 26 N4O2: 426.2056; found: 426.5123.

[0202] Example 27

[0203] This embodiment provides a phenylurea compound (denoted as compound 27), the structural formula of which is as shown below

[0204]

[0205] This embodiment provides a preparation method of the above-mentioned phenylurea compound, which is basically the same as the preparation method provided in Example 1 in operation, except that the amine substance is m-phenylenediamine, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0206] The prepared compound is characterized, and the detection data are as follows:

[0207] 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.36 (d, J = 7.3 Hz, 4H), 7.33 (d, J = 5.1 Hz, 5H), 7.28 - 7.24 (m, 2H), 7.24 - 7.19 (m, 4H), 6.64 - 6.53 (m, 2H), 2.80 (tt, J = 7.5, 3.3 Hz, 2H), 2.04 (ddd, J = 9.2, 6.3, 3.2 Hz, 2H), 1.21 (tdd, J = 12.8, 7.3, 5.7 Hz, 4H). HRMS (ESI) m / z: (M+H) + calcd for C 26 H 26 N4O2: 426.2056; found: 426.2749.

[0208] Example 29

[0209] This example provides a phenyl cyprocarbazole compound (denoted as compound 29), the structural formula of which is as shown below

[0210]

[0211] This example provides a preparation method of the above-mentioned phenyl cyprocarbazole compound, which has substantially the same operation as the preparation method provided in Example 1, except that the amine substance is 4-chloro-1,2-phenylenediamine, and the molar ratio of the amine compound to the isocyanate compound is 1.5:1; the reaction temperature is 80°C, and the reaction time is 30 minutes.

[0212] The prepared compound is characterized, and the detection data are as follows:

[0213] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.36 (d, J = 7.3 Hz, 4H), 7.33 (d, J = 5.1 Hz, 5H), 7.28 - 7.24 (m, 2H), 7.24 - 7.19 (m, 4H), 6.64 - 6.53 (m, 2H), 2.80 (tt, J = 7.5, 3.3 Hz, 2H), 2.04 (ddd, J = 9.2, 6.3, 3.2 Hz, 2H), 1.21 (tdd, J = 12.8, 7.3, 5.7 Hz, 4H). HRMS (ESI) m / z: (M+H) + calcd for C 26 H 25 ClN4O2: 460.1666; found: 460.1168.

[0214] Experimental Example 1: Cell proliferation inhibition activity

[0215] (1) Preparation of experimental reagents: 10% fetal bovine serum and 1% double-antigen reagent were added to DMEM medium, and the fetal bovine serum solution, double-antigen reagent and medium were shaken well and mixed uniformly to prepare complete medium and were divided and stored in a 4°C refrigerator for standby. A cell freezing solution was prepared by mixing dimethyl sulfoxide (DMSO) 1 part and fetal bovine serum 9 parts uniformly, and a CCK-8 reagent was prepared by mixing 1 part of complete medium and 10 parts of CCK-8 reagent.

[0216] (2) Preparation of mother liquor: 2 mg of the sample to be tested was dissolved in DMSO to prepare a 10 mM mother liquor, which was divided and stored in a -20°C refrigerator in the dark to avoid repeated freezing and thawing. An appropriate amount of mother liquor was taken and diluted with complete medium to 10 mM, and then diluted by 3 times from 10 mM, to obtain 6 different concentrations of drug working solution, and the final concentration of each well was 10 mM, 3.333 mM, 1.111 mM, 0.370 mM, 0.123 mM and 0.041 mM, respectively.

[0217] (3) Cell culture: when the cells grew to 70%-80% of the area of the culture dish, the cells were collected by trypsin digestion, centrifuged, resuspended with medium and inoculated into a 100 mm diameter disposable cell culture dish, and placed in a 37°C, 5% carbon dioxide incubator for incubation. The medium was changed according to the growth of the cells.

[0218] (4) Cell passage: after a period of culture, when the cells grew to 70%-80% of the area of the culture dish, the cell passage work was started, the original culture medium was discarded, the cell culture dish was washed 3 times with PBS solution, trypsin was added for 1-2 min, and then complete medium was added to terminate digestion. The cells were collected and centrifuged, resuspended with medium, inoculated into a 100 mm diameter disposable cell culture dish at a ratio of 1:3, and placed in a 37°C, 5% carbon dioxide incubator for incubation. The medium was changed according to the growth of the cells.

[0219] 4 x 10 3 Each well was inoculated into a 96-well cell plate, and the test cell strain was allowed to adhere and grow for 24 h, and then the old culture medium was discarded. The control group, blank group and drug treatment group were set up. The control group was 100 μL of culture medium containing DMSO, the blank group was 100 μL of complete culture medium containing DMSO and cells, and the experimental group was 100 μL of culture medium containing different concentrations of drugs and cells. Each concentration had 3 replicate wells, and after incubation for 24 h, the old culture medium was removed, 110 μL of diluted CCK-8 reagent was added, and incubation was continued for 2 h. The OD value was detected at 450 nm by an enzyme-labeled instrument.

[0220] The experiment was repeated 3 times, and the average of the experimental results was taken as the final experimental result. The growth inhibition rate (%) Inh was calculated according to the formula: [(OD of experimental group-OD of blank group) / (OD of control group-OD of blank group)]*100%. The IC 50 value was obtained by nonlinear fitting of sample activity to sample concentration.

[0221] The detection results are shown in the following table:

[0222]

[0223]

[0224] Experimental Example 2 HTRF experiment of programmed cell death ligand 1 (PD-L1)

[0225] (1) Preparation of reaction system: sample solution: transfer the test compound into the detection plate in 100% DMSO with Echo, and the final fraction of DMSO is 1%; Tag1-PD-L1 and Tag-PD-1 solution; anti-Tag1-Eu and anti-Tag2-XL665 solution;

[0226] (2) Operate with Echo acoustic controlled pipetting system, transfer 5 μL Tag1-PD-L1 and Tag1-PD-1 solution to the detection plate and low control transfer 5 μL detection buffer, incubate at room temperature for 60 minutes.

[0227] (3) Wash the enzyme-labeled plate: remove the liquid in the hole, wash the enzyme-labeled plate with buffer to remove unbound substances.

[0228] (4) Transfer 5 μL anti-Tag1-Eu and anti-Tag2-XL665 solution to the detection plate, incubate at room temperature for 60 minutes to allow the secondary antibody to bind to PD-1 or PD-L1.

[0229] (5) Read data

[0230] (6) Data processing: inhibition rate (Inh%) = (Max-Signal) / (Max-Min)*100; %Inh and compound concentration are substituted into the following formula in GraphPad Prism 9 software to obtain IC50 value: Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)*HillSlope), X is the complex concentration.

[0231] (7) The experimental results are as follows (BMS202 is a positive compound):

[0232] ​

[0233]

[0234] According to the above results, the phenylurea compound provided by the embodiment of the present application can inhibit the proliferation of various tumor cells, thereby indicating that the phenylurea compound can be used for treating tumors.

[0235] The above only describes the preferred embodiments of the present application and is not intended to limit the present application, and various modifications and changes can be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A phenylcyclopropionamide compound, characterized in that, It is selected from any one of the compounds shown in the following structural formulas: , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

2. A method for preparing the phenylcyclopropionamide compound according to claim 1, characterized in that, The phenylcyclopropionamide compounds were synthesized according to the following synthetic route: In this context, R1 and R2 are selected with reference to the groups of the benzocyclopropionamide compounds described in claim 1.

3. The preparation method according to claim 2, characterized in that, The molar ratio of amine compounds to isocyanate compounds is 1:1.5; the reaction temperature is 50-100℃; and the reaction time is 10-120 minutes.

4. The use of the phenylcyclopropionamide compound of claim 1 in the preparation of a medicament for treating cancer, wherein the cancer is colon cancer or lung cancer.

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