A quinazoline derivative, its preparation method and application

Abstract

The application provides a quinazoline derivative and a preparation method and application thereof, and relates to the technical field of chemical medicines.The quinazoline derivative provided by the application has the action of extremely strong targeted inhibition of the activity of DDR1 / 2, reaches low nanomolar concentration in terms of the kinase inhibition activity of DDR1 / 2, can inhibit the activity of DDR1 / 2 in a dose-dependent manner, the inhibition activity of part of the compounds to DDR1 reaches the pM level, and the quinazoline derivative can be used for preparing a medicine for treating and / or preventing an abnormal disease of a DDR1 and / or DDR2 related signal path, is in a leading position among the currently reported target DDR compounds, and has good selectivity.The application provides the preparation method of the quinazoline derivative, the synthesis path is short, the operation process is safe, and the preparation method has the feasibility of scale-up production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical medicines, in particular to a quinazoline derivative and a preparation method and application thereof. BACKGROUND

[0002] Discoidin Domain Receptors (DDRs) are named for their unique extracellular N-terminal discoidin receptor binding domain, are transmembrane receptor tyrosine kinases with collagen as a signaling molecule, belong to the receptor tyrosine kinase (RTK) family, and mainly include two receptors DDR1 and DDR2. DDR1 is mainly expressed in epithelial cells, while DDR2 is usually expressed in connective tissue cells.

[0003] DDRs were considered as an orphan receptor class in the early 20th century. In 1997, Shrivastava et al. named DDR as a non-integrin collagen-binding receptor, which needs to bind with collagen to initiate cellular responses in the human body. In the same year, Vogel et al. proved that these receptors are a subfamily of RTKs with catalytic kinase domains (KD) and need different types of collagens to be activated. The N-terminal discoidin protein (DS) domain of DDR has similar homology with DS-I protein obtained from molds, which can mediate cell aggregation. In addition to another extracellular DS homodomain for collagen binding, DDR has KD in the intracellular part. When collagen binds with the DS domain, both of the two receptors DDR1 and DDR2 are activated, and then initiate downstream signaling pathways. Unlike other RTKs, DDR shows an unusually slow and delayed autophosphorylation when the ligand (collagen) binds with DDR, and the phosphorylation level can last for up to 18 hours. DDR and its downstream signaling pathways play an important role in regulating cell proliferation, migration, adhesion, aggregation and ECM remodeling.

[0004] It has been found that the dysfunction of both DDR1 / 2 is related to the progression of many cancers, metastatic tumor development, such as pancreatic cancer, breast cancer, primary invasive breast cancer, triple-negative breast cancer, non-small cell lung cancer, squamous cell carcinoma, prostate cancer, esophageal cancer and nasopharyngeal carcinoma, etc. Therefore, inhibiting the expression of DDR1 or DDR2 can become a successful strategy to control the progression of these cancers, and these receptors are proved to be a promising therapeutic target for various small molecule TKIs. However, there is no selective DDR drug on the market at present, so it is promising to develop small molecule inhibitors targeting DDR. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a quinazoline derivative and a preparation method and application thereof. The quinazoline derivative provided by the present application has a strong activity of targeting and inhibiting DDR1 and DDR2.

[0006] To achieve the above object, the present application provides the following technical solutions.

[0007] The present application provides a quinazoline derivative having a structure shown in Formula I or a pharmaceutically acceptable salt thereof.

[0008]

[0009] In Formula I, X is hydrogen, fluorine or chlorine, Y is hydrogen, fluorine or chlorine, and R is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0010] Preferably, the heteroaryl is thienyl, pyridyl, pyrazolyl or indolyl.

[0011] Preferably, the substituents in the substituted aryl and substituted heteroaryl are one or more of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, alkylsulfonyl, alkylamino and alkylamide.

[0012] Preferably, the quinazoline derivative is at least one of the following compounds:

[0013]

[0014]

[0015] The present application provides a preparation method of the quinazoline derivative described in the above technical solution, comprising the following steps:

[0016] Compound 1, compound 2, K2CO3 and an organic solvent are mixed to perform a substitution reaction to obtain compound 3;

[0017] The compound 3, a carboxylic acid, HATU, DIPEA and an organic solvent are mixed to perform a condensation reaction to obtain the quinazoline derivative.

[0018] The structural formulae of the compound 1, compound 2, compound 3 and carboxylic acid are shown in the following order:

[0019]

[0020] Preferably, the molar ratio of the compound 1, compound 2 and K2CO3 is 1:(1-5):(1-10); the temperature of the substitution reaction is 0-90℃, and the time is 1-18h.

[0021] Preferably, the molar ratio of the compound 3, carboxylic acid, HATU and DIPEA is (0.8-3):1:(1-5):(1-5); the temperature of the condensation reaction is 0-50℃, and the time is 4-24h.

[0022] The application provides application of the quinazoline derivative or the pharmaceutically acceptable salt thereof in preparation of a medicine for treating and / or preventing a disease related to abnormal DDR1 and / or DDR2 signal pathways.

[0023] Preferably, the disease related to abnormal DDR1 and / or DDR2 signal pathways comprises organ fibrosis, atherosclerosis, nervous system degenerative disease, inflammatory disease or cancer.

[0024] Preferably, the cancer comprises pancreatic cancer, breast cancer, non-small cell lung cancer, squamous cell carcinoma, prostate cancer, esophageal cancer or nasopharyngeal cancer.

[0025] The application provides a quinazoline derivative or a pharmaceutically acceptable salt thereof with a structure shown in formula I.

[0026] The application provides a preparation method of the quinazoline derivative. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 A graph of the kinase selectivity effect of compound 4e in the examples. DETAILED DESCRIPTION

[0028] The application provides a quinazoline derivative or a pharmaceutically acceptable salt thereof with a structure shown in formula I.

[0029]

[0030] In formula I, X is hydrogen, fluorine or chlorine, Y is hydrogen, fluorine or chlorine, and R is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0031] In the application, the aryl is preferably phenyl, and the heteroaryl is preferably thienyl, pyridyl, pyrazolyl or indolyl.

[0032] In the present application, the substituents in the substituted aryl and the substituted heteroaryl are preferably one or more of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, alkylsulfonyl, alkylamino and alkylamide, and the substituents in the substituted heteroaryl are more preferably one or several of alkyl, halogen, haloalkyl and alkoxy. In the present application, the alkyl is preferably C1-5 alkyl, more preferably methyl, ethyl, propyl or butyl, the halogen is preferably fluorine or chlorine, the haloalkyl is preferably fluoroalkyl or chloroalkyl, more preferably trifluoromethyl or trichloromethyl, the alkoxy is preferably methoxy or ethoxy, the haloalkoxy is preferably fluoromethoxy or chloromethoxy, more preferably trifluoromethoxy or trichloromethoxy, the alkylsulfonyl is preferably methylsulfonyl or ethylsulfonyl, the alkylamino is preferably dimethylamino or diethylamino, and the alkylamide is preferably acetamido.

[0033] In the present application, the quinazoline derivative is at least one of the following compounds:

[0034]

[0035]

[0036] The corresponding relationship of X, Y and R in the compounds represented by formulae 4a-4z is shown in Table 1.

[0037] Table 1 Compounds represented by formulae 4a-4z

[0038]

[0039]

[0040] In Table 1, represents a connection site.

[0041] The quinazoline derivative provided by the present application has very strong activity in targeting and inhibiting DDR1 / 2, and has good selectivity; the activity of the compounds represented by formulae 4e, 4g, 4h, 4l, 4n, 4o, 4q, 4u and 4z among the quinazoline derivatives represented by formulae 4a-4z is the best.

[0042] The present application provides a preparation method of the quinazoline derivative described in the above technical solution, which comprises the following steps:

[0043] Compound 1, compound 2, K2CO3 and an organic solvent are mixed to perform a substitution reaction to obtain compound 3;

[0044] Compound 3, a carboxylic acid, HATU, DIPEA and an organic solvent are mixed to perform a condensation reaction to obtain the quinazoline derivative;

[0045] The structural formula of the compound 1, the compound 2, the compound 3 and the carboxylic acid are shown as follows respectively:

[0046]

[0047] The reaction route for preparing the quinazoline derivative is as follows:

[0048]

[0049] The preparation method of the quinazoline derivative is described in detail below in combination with the above reaction route.

[0050] In the present application, if not specially stated, the raw materials involved are all commercially available or prepared according to the methods well known to those skilled in the art.

[0051] The compound 1, the compound 2, K2CO3 and an organic solvent are mixed to carry out a substitution reaction to obtain the compound 3 in the present application. In the present application, X and Y in the structural formula of the compound 2 and the compound 3 are consistent with X and Y in the structure shown in formula I. In the present application, the K2CO3 is used as an acid-binding agent. In the present application, the molar ratio of the compound 1, the compound 2 and the K2CO3 is preferably 1:(1-5):(1-10), and more preferably 1:1.2:2. In the present application, the organic solvent is preferably DMF, and the present application does not have special requirements for the amount of the organic solvent, which can only ensure that the raw materials are dissolved and the reaction is carried out smoothly.

[0052] The compound 1 is dissolved in an organic solvent, and then the compound 2 and the K2CO3 are sequentially added thereto in the present application.

[0053] In the present application, the temperature of the substitution reaction is preferably 0-90℃, and more preferably 30-40℃, and the time is preferably 1-18h, and more preferably 6-10h.

[0054] After the completion of the substitution reaction, the obtained substitution reaction solution is preferably subjected to post-treatment in the present application, and the method of the post-treatment is preferably as follows: the substitution reaction solution is cooled to room temperature, water is added to precipitate a solid, stirring is carried out for 1h, and the solid crude product is obtained by filtration; the mixed solvent of petroleum ether (PE) and ethyl acetate (EA) is added to the solid crude product, stirring is carried out at room temperature for 3h, and the compound 3 is obtained by filtration. In the present application, the volume ratio of PE to EA in the mixed solvent of PE and EA is preferably 7:1.

[0055] After obtaining compound 3, the present application mixes compound 3, a carboxylic acid, HATU (2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate), DIPEA (N,N-diisopropyl ethylamine) and an organic solvent to perform a condensation reaction to obtain the quinazoline derivative. In the present application, R in the structural formula of the carboxylic acid is consistent with R in the structure shown in formula I. In the present application, the HATU is a condensation agent to activate the carboxyl group, and the DIPEA is a base catalyst. In the present application, the molar ratio of compound 3, the carboxylic acid, HATU and DIPEA is preferably (0.8-3):1:(1-5):(1-5), and more preferably (1-1.2):1:(1-1.2):(1.2-3.2). In the present application, the organic solvent is preferably DMAC, and the present application does not have a special requirement for the amount of the organic solvent, which can only ensure that the raw materials are dissolved and the reaction is smoothly performed.

[0056] Preferably, in the present application, the carboxylic acid and HATU are added to a reaction container and dissolved in an organic solvent, then DIPEA is added thereto, the reaction container is replaced with argon for three times, and the reaction is performed at room temperature for 30 min, and then compound 3 is added. The carboxyl group is activated by the reaction at room temperature for 30 min in the present application.

[0057] In the present application, the temperature of the condensation reaction is preferably 0-50℃, and more preferably 20-30℃, and in the examples of the present application, the condensation reaction is performed at room temperature; and the time of the condensation reaction is preferably 4-24 h, and more preferably 10-16 h.

[0058] After the condensation reaction is completed, the present application preferably performs post-treatment on the obtained condensation reaction liquid, and the method of the post-treatment is preferably as follows: water is added to the condensation reaction liquid to quench, then the condensation reaction liquid is washed with a saturated sodium chloride solution, and then extracted with ethyl acetate, the obtained organic phase is concentrated and purified by a silica gel column chromatography method to obtain the quinazoline derivative. In the present application, the eluent used in the silica gel column chromatography method is preferably dichloromethane and methanol, and the dichloromethane and methanol are eluted in turn according to the volume ratio of 60:1 and 40:1.

[0059] The preparation method provided by the present application has a short synthesis path, a safe operation process and the feasibility of scale-up production.

[0060] The present application provides the use of the quinazoline derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing an abnormal disease of a DDR1 and / or DDR2 related signal pathway.

[0061] In the present application, the DDR1 and / or DDR2 related signal pathway abnormal disease preferably includes organ fibrosis, atherosclerosis, nervous system degenerative disease, inflammatory disease or cancer; the inflammatory disease preferably includes arthritis; the cancer preferably includes pancreatic cancer, breast cancer, non-small cell lung cancer, squamous cell carcinoma, prostate cancer, esophageal cancer or nasopharyngeal cancer, and the breast cancer is preferably primary breast cancer, invasive breast cancer or triple-negative breast cancer.

[0062] The quinazoline derivative provided by the present application is a novel structure targeted DDR compound, which has a low nanomolar concentration of DDR1 / 2 kinase inhibition activity, can inhibit the activity of DDR 1 / 2 in a dose-dependent manner, and can be used to prepare a drug for treating and / or preventing DDR1 and / or DDR2 related signal pathway abnormal disease.

[0063] In order to further illustrate the present application, the quinazoline derivative provided by the present application and the preparation method and application thereof are described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0064] Example 1

[0065] Synthetic route and specific preparation process of compound 4a:

[0066] (1) Preparation process of intermediate 3a:

[0067]

[0068] Compound 1 (10.0 g, 44.5 mmol) was dissolved in DMF (120 mL), then compound 2a (7.67 g, 53.4 mmol) and K2CO3 (12.2 g, 88.3 mmol) were added in sequence, and the reaction was carried out at 40°C for 6 h. After the reaction was completed, it was cooled to room temperature, 150 mL of pure water was added to precipitate the solid, stirred for 1 h, and the crude product was obtained as a gray solid after filtration. Then 56.0 mL of a mixed solvent of PE:EA=7:1 was added, stirred at room temperature for 3 h, filtered, and compound 3a (white solid, 10.1 g, 68%) was obtained.

[0069] Compound 3a was detected, and the detection results were as follows: M.p. 238.7-239.6°C. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.22 (d, J = 2.6 Hz, 1H), 7.00 (dd, J = 8.7, 2.7 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.35 (s, 2H), 3.98 (d, J = 7.6 Hz, 6H). 13C NMR (100 MHz, DMSO-d6) δ 165.6, 156.1, 152.8, 150.5, 149.2, 143.1, 142.6, 123.1, 122.2, 117.1, 115.8, 110.1, 107.2, 101.2, 56.6, 56.4. HRMS (ESI) calculated for C 16 H 15 ClN3O3 + [M+H] + : 332.0796, found: 332.0800.

[0070] (2) Preparation of compound 4a:

[0071]

[0072] Into a three-necked flask was added phenylacetic acid (41.1 mg, 0.302 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114 mg, 0.300 mmol) and dissolved in N,N-dimethylacetamide (2 mL), then added N,N-diisopropylethylamine (96.8 mg, 0.749 mmol), the reaction device was replaced with argon three times, reacted at room temperature for 30 min, then added compound 3a (100 mg, 0.300 mmol), reacted at room temperature for 16 h. After the reaction was completed, quenched with aqueous solution (2.00 mL), washed with saturated sodium chloride solution (2.00 mL), extracted with ethyl acetate (8.00 mL), the organic phase was concentrated, then purified by silica gel column chromatography (dichloromethane and methanol were eluted in turn according to the volume ratio of 60:1, 40:1), to obtain compound 4a (white solid, 61.9 mg, 55%).

[0073] Compound 4a was detected, and the detection results were as follows: M.p. 274.3-275.2 °C. IR (KBr): 3262, 1656, 1617, 1581, 1511, 1420, 1377, 1236, 1212, 1194, 1031, 996, 918, 765, 702 cm -1 . 1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.52 (d, J = 9.0 Hz, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.47-7.42 (m, 2H), 7.38 (d, J = 7.0 Hz, 3H), 7.32 (s, 1H), 7.17 (dd, J = 9.0, 2.7 Hz, 1H), 4.06 (d, J = 1.4 Hz, 6H), 3.82 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 169.1, 165.1, 156.0, 152.7, 150.4, 149.5, 148.2, 133.9, 132.4, 129.7, 129.4, 128.0, 123.1, 122.8, 121.8, 121.4, 110.5, 106.9, 100.8, 56.4, 56.4, 45.1. HRMS (ESI) calculated for C 24 H 21 ClN3O4 + [M+H] + : 450.1215, found 450.1213.

[0074] Example 2

[0075] Synthetic route and specific preparation procedure of compound 4b:

[0076] The synthetic route was the same as 4a, using p-tolylacetic acid (37.5 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4b (white solid, 63.6 mg, 55%).

[0077] Compound 4b was tested and the results of the test are as follows: M.p. 280.6-281.7 °C. IR (KBr): 3262, 2926, 1656, 1617, 1581, 1511, 1420, 1377, 1230, 1218, 1195, 1045, 996, 917, 819 cm -1 . 1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.50 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 7.31 (s, 1H), 7.25 (dd, J = 9.4, 2.8 Hz, 5H), 7.17 (dd, J = 9.0, 2.7 Hz, 1H), 4.05 (s, 6H), 3.77 (s, 2H), 2.38 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 169.4, 165.1, 156.0, 152.7, 150.3, 149.4, 148.2, 137.6, 132.4, 130.8, 130.0, 129.6, 123.2, 122.8, 121.9, 121.4, 110.5, 106.8, 100.8, 56.4, 56.4, 44.7, 21.1. HRMS (ESI) calculated for C 25 H 23 ClN3O4 + [M+H] + : 464.1372, found 464.1375.

[0078] Example 3

[0079] Synthetic route and specific preparation procedure of compound 4c:

[0080] The synthetic route was the same as 4a, using p-fluorophenylacetic acid (38.5 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) to give compound 4c (white solid, 66.7 mg, 57%).

[0081] Compound 4c was tested and the results of the test are as follows: M.p. 273.0-273.8 °C. IR (KBr): 3270, 1651, 1627, 1587, 1545, 1517, 1422, 1378, 1329, 1231, 1193, 1125, 1070, 990, 914, 823 cm -1 . 1HNMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.51 (d, J = 9.0 Hz, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.38 - 7.31 (m, 3H), 7.29 (d, J = 2.7 Hz, 1H), 7.18 (dd, J = 9.0, 2.7 Hz, 1H), 7.16 - 7.10 (m, 2H), 4.06 (d, J = 1.4 Hz, 6H), 3.79 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 168.8, 165.1, 163.7, 156.0, 152.7, 150.4, 149.5, 148.3, 132.2, 131.4, 131.3, 129.7, 123.1, 122.8, 121.9, 121.5, 116.4, 116.2, 110.5, 106.9, 100.8, 56.4, 56.4, 44.2. 19 F NMR (376 MHz, Chloroform-d) δ -114.10. HRMS (ESI) calculated for C 24 H 20 ClFN3O4 + [M+H] + : 468.1121, found 468.1116.

[0082] Example 4

[0083] Synthetic route and specific preparation process of compound 4d:

[0084] The synthetic route was the same as 4a, using p-chlorobenzoic acid (42.6 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were used as eluents in a volume ratio of 60:1, 40:1, and 20:1, respectively) to give compound 4d (white solid, 70.2 mg, 58%).

[0085] Compound 4d was detected, and the detection results are as follows: M.p. 283.1-283.9 °C. IR (KBr): 3430, 2959, 2924, 2854, 1750, 1659, 1520, 1460, 1402, 1374, 1283, 1261, 1216, 1194, 1054, 1033, 1016, 800, 772 cm -1 . 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.57 (t, J = 1.3 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 3.2 Hz, 5H), 7.32 (dd, J = 8.9, 2.7 Hz, 1H), 3.98 (dd, J = 7.8, 1.9 Hz, 6H), 3.77 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 169.8, 165.1, 156.3, 152.6, 150.6, 149.4, 135.3, 132.9, 131.8, 131.6, 128.7, 127.7, 123.8, 121.9, 110.1, 107.2, 101.1, 56.7, 56.5, 42.1. HRMS (ESI) calculated for C 24 H 20 Cl2N3O4 + [M+H] + : 484.0825, found 484.0828.

[0086] Example 5

[0087] Synthetic route and specific preparation process of compound 4e:

[0088] The synthetic route was the same as 4a, using p-trifluoromethyl phenylacetic acid (51.0 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) to give compound 4e (white solid, 87.9 mg, 68%).

[0089] Compound 4e was detected, and the detection results are as follows: M.p. 276.5-277.8 °C. IR (KBr): 3272, 1659, 1620, 1585, 1539, 1510, 1420, 1377, 1328, 1239, 1193, 1115, 1070, 997, 915, 819 cm -1 . 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.57 (s, 1H), 7.73 (dd, J = 8.5, 5.4 Hz, 3H), 7.64-7.57 (m, 3H), 7.55 (s, 1H), 7.40 (s, 1H), 7.32 (dd, J = 8.8, 2.7 Hz, 1H), 3.98 (d, J = 7.9 Hz, 6H), 3.89 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 169.4, 165.1, 156.3, 152.6, 150.6, 150.1, 149.5, 141.2, 132.8, 130.6, 128.0, 127.9, 127.7, 125.7, 125.6, 123.9, 121.9, 110.1, 107.2, 101.1, 56.7, 56.5, 42.6. 19 F NMR (376 MHz, DMSO-d6) δ -60.82. HRMS (ESI) calculated for C 25 H 20 ClF3N3O4 + [M+H] + : 518.1089, found 518.1093.

[0090] Example 6

[0091] Synthetic route and specific preparation process of compound 4f:

[0092] The synthetic route was the same as 4a, using p-methoxyphenylacetic acid (41.5 mg, 0.250 mmol) to replace phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were eluted in sequence with a volume ratio of 60:1, 40:1, respectively), to obtain compound 4f (white solid, 65.9 mg, 55%).

[0093] Compound 4f was detected, and the detection results were as follows: M.p. 285.2-286.2 °C. IR (KBr): 3262, 2926, 1656, 1617, 1581, 1511, 1420, 1377, 1236, 1212, 1194, 1031, 996, 918, 819 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 1.2 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 7.70 (s, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.33 - 7.27 (m, 4H), 7.17 (dd, J = 9.2, 2.6 Hz, 1H), 7.01 - 6.91 (m, 2H), 4.06 (d, J = 1.5 Hz, 6H), 3.84 (d, J = 1.3 Hz, 3H), 3.76 (s, 2H). 13C NMR (100 MHz, Chloroform-d) δ 169.6, 165.1, 159.3, 156.0, 152.7, 150.4, 149.5, 148.2, 132.4, 130.8, 125.8, 123.1, 122.8, 121.8, 121.4, 114.8, 110.5, 106.9, 100.8, 56.4, 56.4, 55.4, 44.2. HRMS (ESI) calculated for C 25 H 23 ClN3O5 + [M+H] + : 480.1321, found 480.1323.

[0094] Example 7

[0095] Synthetic route and detailed preparation procedure of compound 4g:

[0096] The synthetic route was the same as 4a, using p-trifluoromethoxyphenylacetic acid (55.0 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4g (white solid, 69.3 mg, 52%).

[0097] Compound 4g was tested and the results of the test are as follows: M.p. 281.4-282.2 °C. IR (KBr): 3260, 1658, 1617, 1580, 1518, 1420, 1377, 1286, 1236, 1212, 1194, 1031, 998, 918, 822 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.49 (d, J = 9.0 Hz, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.45-7.39 (m, 2H), 7.30 (dd, J = 10.2, 7.9 Hz, 4H), 7.19 (dd, J = 9.0, 2.7 Hz, 1H), 4.06 (d, J = 1.1 Hz, 6H), 3.82 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 168.4, 165.1, 156.0, 152.7, 150.4, 149.5, 148.9, 148.4, 132.7, 132.1, 131.1, 123.2, 122.9, 121.9, 121.8, 121.5, 110.5, 106.9, 100.8, 56.4, 56.4, 44.2.19 F NMR (376 MHz, Chloroform-d) δ -57.91. HRMS (ESI) calculated for C 25 H 20 ClF3N3O5 + [M+H] + : 534.1038, found 534.1035.

[0098] Example 8

[0099] Synthetic route and specific preparation process of compound 4h:

[0100] The synthetic route was the same as 4a, using m-trifluoromethyl phenylacetic acid (51.0 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were used as eluents in a volume ratio of 60:1, 40:1, 20:1, 10:1, 5:1, 2:1, 1:1, 1:2, 1:5, 1:10, 1:20, 1:40, 1:60, respectively) to give compound 4h (white solid, 77.6 mg, 60%).

[0101] Compound 4h was detected, and the detection results are as follows: M.p. 276.5-277.8 °C. IR (KBr): 3272, 1659, 1620, 1585, 1539, 1510, 1420, 1377, 1328, 1239, 1193, 1115, 1070, 997, 915, 788, 697 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.48 (d, J = 9.0 Hz, 1H), 7.70-7.61 (m, 3H), 7.61-7.54 (m, 2H), 7.49 (s, 1H), 7.35-7.29 (m, 2H), 7.19 (dd, J = 9.0, 2.7 Hz, 1H), 4.06 (s, 6H), 3.88 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 168.0, 165.1, 156.1, 152.7, 150.4, 149.5, 148.4, 134.9, 133.0, 132.1, 129.7, 126.4, 126.3, 124.7, 124.7, 123.3, 122.9, 122.1, 121.5, 110.5, 106.9, 100.8, 56.4, 56.4, 44.6. 19 F NMR (376 MHz, Chloroform-d) δ -62.70. HRMS (ESI) calculated for C 25 H 20ClF3N3O4 + [M+H] + : 518.1089, found 518.1087.

[0102] Example 9

[0103] Synthetic route and specific preparation process of compound 4i:

[0104] Synthetic route same as 4a, replace phenylacetic acid with o-trifluoromethyl phenylacetic acid (51.0 mg, 0.250 mmol). Purification by column chromatography on silica gel (dichloromethane and methanol eluted in turn according to the volume ratio of 60:1, 40:1), to obtain compound 4i (white solid, 78.7 mg, 61%).

[0105] Compound 4i was detected, and the detection results are as follows: M.p. 276.4-277.7 °C. IR (KBr): 3268, 1620, 1577, 1534, 1512, 1420, 1377, 1327, 1236, 1193, 1115, 1075, 992, 915, 756 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.48 (t, J = 8.2 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.60 (dp, J = 15.0, 7.5 Hz, 3H), 7.49 (q, J = 7.3, 5.6 Hz, 2H), 7.33-7.28 (m, 2H), 7.17 (dt, J = 8.3, 4.2 Hz, 1H), 4.05 (d, J = 7.6 Hz, 6H), 3.99 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 167.8, 165.1, 156.0, 152.7, 150.4, 149.5, 148.3, 132.6, 132.6, 132.3, 132.3, 129.0, 128.1, 126.6, 126.6, 123.2, 122.8, 122.0, 121.4, 110.5, 106.9, 100.8, 56.4, 56.4, 41.7. 19 F NMR (376 MHz, Chloroform-d) δ -59.49. HRMS (ESI) calculated for C 25 H 20 ClF3N3O4 + [M+H] + : 518.1089, found 518.1087.

[0106] Example 10

[0107] Synthetic route and specific preparation process of compound 4j:

[0108] The synthetic route was the same as 4a, using p-cyanobenzoic acid (40.3 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by column chromatography on silica gel (eluted with dichloromethane and methanol in the ratio of 60:1, 40:1 by volume, respectively) to give compound 4j (white solid, 73.5 mg, 62%).

[0109] Compound 4j was detected, and the detection results are as follows: M.p. 297.0-297.8 °C. IR (KBr): 3412, 3248, 2230, 1651, 1580, 1503, 1464, 1422, 1376, 1302, 1234, 1210, 1028, 998, 921, 888, 854, 828 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 1.3 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 7.72-7.62 (m, 4H), 7.57-7.48 (m, 2H), 7.33 (t, J = 1.8 Hz, 2H), 7.24-7.18 (m, 1H), 4.07 (s, 6H), 3.85 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 167.5, 165.1, 156.1, 152.7, 150.4, 149.5, 148.5, 135.5, 134.0, 133.0, 132.0, 131.5, 129.9, 123.3, 122.9, 122.2, 121.6, 118.3, 113.3, 110.5, 106.9, 100.8, 56.4, 56.4, 44.1. HRMS (ESI) calculated for C 25 H 20 ClN4O4 + [M+H] + : 475.1168, found 475.1163.

[0110] Example 11

[0111] Synthetic route and specific preparation process of compound 4k:

[0112] The synthetic route was the same as 4a, using p-toluenesulfonyl phenylacetic acid (53.5 mg, 0.234 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (eluted with dichloromethane and methanol in the ratio of 60:1, 40:1 by volume) gave compound 4k (white solid, 79.1 mg, 60%).

[0113] Compound 4k was detected and the detection results are as follows: M.p. 319.0-319.8 °C. IR (KBr): 3293, 1656, 1580, 1501, 1420, 1376, 1300, 1229, 1208, 1155, 996, 915, 856, 771, 548 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.64-8.57 (m, 1H), 8.43 (dt, J = 9.3, 2.6 Hz, 1H), 7.98 (dt, J = 8.5, 2.4 Hz, 2H), 7.74 (d, J = 3.1 Hz, 1H), 7.67-7.56 (m, 2H), 7.51-7.47 (m, 1H), 7.32 (dq, J = 5.2, 2.5 Hz, 2H), 7.19 (dq, J = 8.0, 2.6 Hz, 1H), 4.13-4.02 (m, 6H), 3.96-3.86 (m, 2H), 3.15-3.04 (m, 3H). 13 CNMR (100 MHz, Chloroform-d) δ 167.6, 165.0, 156.1, 152.6, 150.4, 149.5, 148.6, 140.4, 139.9, 132.0, 130.5, 128.1, 123.5, 122.9, 122.4, 121.6, 110.4, 106.8, 100.8, 56.4, 56.4, 44.6, 44.5. HRMS (ESI) calculated for C 25 H 23 ClN3O6S + [M+H] + : 528.0991, found 528.0986.

[0114] Example 12

[0115] Synthetic route and specific preparation process of compound 4l:

[0116] The synthetic route was the same as 4a, using 4- dimethylamino phenylacetic acid (44.8 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (eluted with dichloromethane and methanol in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4l (white solid, 64.0 mg, 52%).

[0117] Compound 4l was tested and the results of the test are as follows: M.p. 291.3-292.2 °C. IR (KBr): 3283, 1659, 1619, 1577, 1508, 1445, 1420, 1376, 1236, 1210, 996, 916, 845 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.52 (d, J = 9.0 Hz, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.32 (s, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 7.17 (dd, J = 9.0, 2.7 Hz, 1H), 6.80-6.75 (m, 2H), 4.08-4.05 (m, 6H), 3.71 (s, 2H), 2.97 (s, 6H). 13 C NMR (100 MHz, Chloroform-d) δ 170.3, 165.2, 156.0, 152.7, 150.3, 150.3, 149.5, 148.0, 132.6, 130.5, 123.1, 122.7, 121.8, 121.3, 121.1, 113.3, 110.5, 106.9, 100.8, 56.4, 56.4, 44.2, 40.6. HRMS (ESI) calculated for C 26 H 26 ClN4O4 + [M+H] + : 493.1637, found 493.1633.

[0118] Example 13

[0119] Synthetic route and detailed preparation procedure of compound 4m:

[0120] The synthetic route was the same as 4a, using 4- dimethylamino phenylacetic acid (44.8 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (eluted with dichloromethane and methanol in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4l (white solid, 64.0 mg, 52%).

[0121] Compound 4m was detected and the detection results are as follows: M.p. 330.2-331.2 °C. IR (KBr): 3280, 2926, 1656, 1507, 1419, 1375, 1311, 1235, 1211, 1194, 997, 920, 844, 812, 647, 547. 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.50 (dd, J = 9.1, 2.7 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.33 (d, J = 7.0 Hz, 3H), 7.26 (s, 1H), 7.17 (dd, J = 9.0, 2.6 Hz, 1H), 4.06 (s, 6H), 3.78 (s, 2H), 2.20 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 165.7, 164.7, 156.2, 154.1, 152.5, 150.5, 149.7, 137.4, 134.5, 132.4, 131.7, 131.5, 129.5, 127.8, 124.0, 121.1, 110.5, 106.9, 100.7, 56.5, 56.4, 44.1, 21.1. HRMS (ESI) calculated for C 26 H 24 ClN4O5 + [M+H] + : 507.1430, found 507.1429.

[0122] Example 14

[0123] Synthetic route and specific preparation process of compound 4n:

[0124] The synthetic route was the same as 4a, and 2-fluoro-3-trifluoromethyl phenylacetic acid (55.5 mg, 0.250 mmol) was used to replace phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were eluted in sequence with a volume ratio of 60:1, 40:1) to obtain compound 4n (white solid, 80.1 mg, 60%).

[0125] Compound 4n was detected and the detection results are as follows: M.p. 275.0-275.9 °C. IR (KBr): 3272, 1659, 1620, 1585, 1539, 1510, 1420, 1377, 1328, 1239, 1193, 1115, 1070, 997, 915, 788, 697 cm -1 .1 H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 1.2 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 7.80 (s, 1H), 7.63 (q, J = 6.9 Hz, 2H), 7.50 (d, J = 1.2 Hz, 1H), 7.36 - 7.28 (m, 3H), 7.19 (dt, J = 9.2, 1.8 Hz, 1H), 4.06 (d, J = 1.2 Hz, 6H), 3.89 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 166.9, 165.1, 159.2, 156.0, 152.7, 150.4, 149.5, 148.5, 135.6, 135.6, 132.1, 126.9, 124.6, 123.4, 123.3, 123.1, 122.9, 122.2, 121.5, 110.5, 106.9, 100.8, 56.4, 56.4, 37.6. 19 F NMR (376 MHz, Chloroform-d) δ -61.36 (d, J = 13.0 Hz), -118.45 - -118.60 (m). HRMS (ESI) calculated for C 25 H 19 ClF4N3O4 + [M+H] + : 536.0995, found 536.1000.

[0126] Example 15

[0127] Synthetic route and detailed preparation procedure of compound 4o:

[0128] The synthetic route was the same as 4a, using 2-fluoro-4-trifluoromethyl phenylacetic acid (55.5 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4o (white solid, 83.0 mg, 62%).

[0129] Compound 4o was tested and the results of the tests are as follows: M.p. 275.1 - 275.9 °C. IR (KBr): 3272, 1659, 1620, 1585, 1539, 1510, 1420, 1377, 1328, 1239, 1193, 1115, 1070, 997, 915, 870, 850, 697 cm -1 . 1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.82 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.51 - 7.39 (m, 3H), 7.36 - 7.30 (m, 2H), 7.19 (dd, J = 9.0, 2.6 Hz, 1H), 4.06 (s, 6H), 3.89 (d, J = 1.4 Hz, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 166.8, 165.1, 161.8, 159.4, 156.0, 152.7, 150.4, 149.5, 148.5, 132.4, 132.1, 125.7, 123.3, 122.9, 122.2, 121.6, 121.5, 113.4, 113.1, 110.5, 106.9, 100.8, 56.4, 56.4, 37.9. 19 F NMR (376 MHz, Chloroform-d) δ -62.80, -114.38 (t, J = 8.4 Hz). HRMS (ESI) calculated for C 25 H 19 ClF4N3O4 + [M+H] + : 536.0995, found 536.0998.

[0130] Example 16

[0131] Synthetic route and detailed preparation procedure of compound 4p:

[0132] Synthetic route as 4a, using 2-chloro-4-trifluoromethylphenylacetic acid (59.6 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio 60:1, 40:1 by volume, respectively) to give compound 4p (white solid, 83.0 mg, 60%).

[0133] Compound 4p was tested and the results of the tests are as follows: M.p. 285.1 - 285.8 °C. IR (KBr): 3271, 1654, 1620, 1586, 1532, 1512, 1421, 1370, 1328, 1237, 1193, 1115, 1070, 997, 915, 872, 857, 694 cm -1 . 1H NMR (400 MHz, Chloroform-d) δ 8.61 (q, J = 2.2 Hz, 1H), 8.53-8.45 (m, 1H), 7.75 (d, J = 4.6 Hz, 2H), 7.59 (d, J = 3.9 Hz, 2H), 7.54-7.48 (m, 1H), 7.33 (q, J = 2.3 Hz, 2H), 7.23-7.14 (m, 1H), 4.07 (t, J = 3.1 Hz, 6H), 3.99 (d, J = 3.8 Hz, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 166.7, 165.1, 156.1, 152.7, 150.4, 149.5, 148.5, 136.4, 135.1, 132.3, 132.1, 127.0, 126.9, 124.5, 124.4, 124.3, 123.2, 122.9, 122.1, 121.6, 110.5, 106.9, 100.8, 56.4, 56.4, 42.5. 19 F NMR (376 MHz, Chloroform-d) δ -62.84. HRMS (ESI) calculated for C 25 H 19 Cl2F3N3O4 + [M+H] + : 552.0699, found 552.0697.

[0134] Example 17

[0135] Synthetic route and detailed preparation procedure of compound 4q:

[0136] The synthetic route was the same as 4a, using 3-methoxy-4-trifluoromethylbenzoic acid (58.5 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4q (white solid, 83.4 mg, 61%).

[0137] Compound 4q was tested and the results of the tests are as follows: M.p. 287.8-288.9 °C. IR (KBr): 3256, 1644, 1620, 1586, 1539, 1515, 1420, 1378, 1328, 1231, 1193, 1115, 1070, 997, 915, 872, 841, 696 cm -1 . 1H NMR (400 MHz, Chloroform-d) δ 8.60 (q, J = 2.3 Hz, 1H), 8.53-8.43 (m, 1H), 7.70 (s, 1H), 7.61 (t, J = 5.2 Hz, 1H), 7.53-7.47 (m, 1H), 7.35-7.29 (m, 2H), 7.20 (dq, J = 8.3, 2.6 Hz, 1H), 7.07-6.97 (m, 2H), 4.09-4.03 (m, 6H), 3.95 (q, J = 2.3 Hz, 3H), 3.87-3.81 (m, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 167.9, 165.1, 158.1, 156.0, 152.6, 150.4, 149.5, 148.5, 139.7, 132.1, 128.0, 128.0, 124.8, 123.3, 122.9, 122.1, 121.5, 121.0, 113.1, 110.4, 106.9, 100.8, 56.4, 56.4, 56.0, 45.0. 19 F NMR (376 MHz, Chloroform-d) δ -62.45. HRMS (ESI) calculated for C 26 H 22 ClF3N3O5 + [M+H] + : 548.1195, found 548.1190.

[0138] Example 18

[0139] Synthetic route and detailed preparation procedure of compound 4r:

[0140] The synthetic route of compound 4r was the same as 4a, using 2,4-ditrifluoromethyl phenylacetic acid (68.0 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in a sequence of 60:1, 40:1 by volume) gave compound 4r (white solid, 93.6 mg, 64%).

[0141] Compound 4r was tested and the test results are as follows: M.p. 277.8-278.6 °C. IR (KBr): 3281, 1659, 1613, 1585, 1539, 1510, 1421, 1380, 1328, 1239, 1193, 1112, 1070, 997, 915, 877, 852, 701 cm -1 . 1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 3.7 Hz, 1H), 8.51 - 8.40 (m, 1H), 7.99 (d, J = 4.2 Hz, 1H), 7.87 (t, J = 5.9 Hz, 1H), 7.76 (t, J = 5.9 Hz, 1H), 7.69 (s, 1H), 7.50 (t, J = 3.4 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.24 - 7.14 (m, 1H), 4.06 (t, J = 3.0 Hz, 8H). 13 C NMR (100 MHz, Chloroform-d) δ 166.7, 165.0, 156.1, 152.7, 150.4, 149.5, 148.6, 136.6, 133.4, 132.0, 130.7, 129.1, 123.6, 123.4, 122.9, 122.3, 121.5, 110.5, 106.9, 100.8, 56.4, 56.4, 41.2. 19 F NMR (376 MHz, Chloroform-d) δ -59.75, -62.95. HRMS (ESI) calculated for C 26 H 19 ClF6N3O4 + [M+H] + : 586.0963, found 586.0960.

[0142] Example 19

[0143] Synthetic route and specific preparation process of compound 4s:

[0144] The synthetic route was the same as 4a, using 5-chloro-2-thiopheneacetic acid (44.2 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were used as eluents in a volume ratio of 60:1, 40:1, and 20:1, respectively) to give compound 4s (white solid, 63.6 mg, 52%).

[0145] Compound 4s was detected, and the detection results are as follows: M.p. 285.8-286.6 °C. IR (KBr): 3430, 1750, 1659, 1520, 1460, 1402, 1374, 1283, 1261, 1216, 1194, 1054, 1033, 1016, 800, 772 cm - 1 . 1H NMR (400 MHz, Chloroform-d) δ 8.64-8.58 (m, 1H), 8.49 (dt, J = 6.0, 3.1 Hz, 1H), 7.91 (s, 1H), 7.54-7.49 (m, 1H), 7.39-7.29 (m, 2H), 7.20 (dq, J = 8.6, 2.7 Hz, 1H), 6.93-6.82 (m, 2H), 4.14-4.00 (m, 6H), 3.97-3.87 (m, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 167.1, 165.1, 156.0, 152.7, 150.4, 149.5, 148.5, 133.9, 132.0, 130.4, 127.4, 126.5, 123.4, 122.9, 122.0, 121.5, 110.5, 106.9, 100.8, 56.4, 56.4, 39.0. HRMS (ESI) calculated for C 22 H 18 Cl2N3O4S + [M+H] + : 490.0390, found 490.0391.

[0146] Example 20

[0147] Synthetic route and specific preparation process of compound 4t:

[0148] The synthetic route was the same as 4a, using 2-chloro-5-pyridineacetic acid (42.9 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were used as eluents in a volume ratio of 60:1, 40:1, and 20:1, respectively) to give compound 4t (white solid, 70.1 mg, 58%).

[0149] Compound 4t was detected, and the detection results are as follows: M.p. 296.7-297.6 °C. IR (KBr): 3434, 2959, 1741, 1654, 1521, 1460, 1400, 1374, 1283, 1261, 1216, 1182, 1087, 1022, 832 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.50-8.35 (m, 2H), 7.77-7.69 (m, 2H), 7.50 (s, 1H), 7.41-7.30 (m, 3H), 7.21 (dd, J = 9.0, 2.6 Hz, 1H), 4.07 (s, 6H), 3.80 (s, 2H). 13C NMR(100MHz,Chloroform-d)δ167.3,165.0,156.1,152.6,151.0,150.4,150.2,149.5,148.6,139.8,131. 9,128.7,124.5,123.5,122.9,122.4,121.6,110.5,106.9,100.8,56.4,56.4,40.8.HRMS(ESI)calculated for C 23 H 19 Cl2N4O4 + [M+H] + :485.0778,found 485.0780.

[0150] Example 21

[0151] Synthetic route and specific preparation process of compound 4u:

[0152] The synthetic route was the same as 4a, except that phenylacetic acid was replaced with 2-trifluoromethyl-5-pyridineacetic acid (51.3 mg, 0.250 mmol). Purification was performed by silica gel column chromatography (eluting with dichloromethane and methanol at volume ratios of 60:1 and 40:1, respectively) to give compound 4u (white solid, 71.2 mg, 55%).

[0153] The detection results for compound 4u are as follows: Mp 279.0–279.8℃. IR (KBr): 3271, 1657, 1622, 1581, 1532, 1517, 1421, 1377, 1327, 1232, 1193, 1125, 1072, 996, 915, 818 cm⁻¹ -1 . 1 HNMR(400MHz,Chloroform-d)δ8.76-8.70(m,1H),8.61(s,1H),8.43(d,J=9.1Hz,1H),7.96(dd,J=8.2,2.1Hz,1H),7.8 1-7.70(m,2H),7.50(s,1H),7.36(d,J=2.6Hz,1H),7.33(s,1H),7.21(dd,J=9.0,2.7Hz,1H),4.06(s,6H),3.90(s,1H). 13C NMR (100 MHz, Chloroform-d) δ 166.9, 165.0, 156.1, 152.6, 150.6, 150.4, 149.5, 148.7, 140.9, 138.4, 137.6, 133.1, 131.8, 123.5, 123.0, 122.5, 121.6, 120.5, 120.5, 120.5, 120.5, 110.5, 106.9, 100.8, 56.4, 56.4, 41.2. 19 F NMR (376 MHz, Chloroform-d) δ -67.8. HRMS (ESI) calculated for C 24 H 19 ClF3N4O4 + [M+H] + : 519.1041, found 519.1040.

[0154] Example 22

[0155] Synthetic route and specific preparation process of compound 4v:

[0156] The synthetic route was the same as 4a, using 2-(4-methyl-lH-pyrazol-l- yl)acetic acid (35.0 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4v (white solid, 57.8 mg, 51%).

[0157] Compound 4v was tested and the results of the test are as follows: M.p. 277.9-278.8 °C. IR (KBr): 3246, 3213, 2929, 1671, 1584, 1541, 1506, 1419, 1376, 1212, 996, 918, 846, 651 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.60 (s, 1H), 8.49 (d, J = 9.0 Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.32 (d, J = 9.4 Hz, 3H), 7.18 (dd, J = 9.0, 2.7 Hz, 1H), 4.94 (s, 2H), 4.06 (s, 6H), 2.13 (s, 3H). 13C NMR (100 MHz, Chloroform-d) δ 165.7, 165.1, 156.0, 152.7, 150.3, 149.5, 148.5, 142.4, 132.1, 130.0, 123.6, 123.0, 122.0, 121.3, 117.9, 110.5, 106.9, 100.8, 56.4, 56.4, 55.6, 8.8. HRMS (ESI) calculated for C 22 H 21 ClN5O4 + [M+H] + : 454.1277, found 454.1272.

[0158] Example 23

[0159] Synthetic route and specific preparation process of compound 4w:

[0160] The synthetic route was the same as 4a, using 5-methoxyindole-3-acetic acid (51.3 mg, 0.250 mmol) instead of phenylacetic acid. Purification was performed by column chromatography on silica gel (dichloromethane and methanol were used as eluents in a ratio of 60:1, 40:1 by volume, respectively) to give compound 4w (white solid, 67.3 mg, 52%).

[0161] Compound 4w was tested and the results of the test are as follows: M.p. 324.0-324.9 °C. IR (KBr): 3305, 3262, 2911, 1658, 1617, 1577, 1503, 1427, 1378, 1237, 1213, 1195, 1031, 992, 917, 801 cm -1 . 1 HNMR (400 MHz, Chloroform-d) δ 8.60-8.51 (m, 2H), 8.27 (s, 1H), 8.08 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 10.9, 2.4 Hz, 2H), 7.22-7.13 (m, 2H), 7.04 (d, J = 2.6 Hz, 1H), 6.93 (dd, J = 8.9, 2.5 Hz, 1H), 4.06 (d, J = 2.4 Hz, 6H), 3.95 (d, J = 2.4 Hz, 2H), 3.86 (d, J = 2.4 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) d 169.7, 165.1, 156.0, 154.8, 152.7, 150.3, 149.5, 148.1, 132.5, 131.6, 127.3, 124.5, 123.2, 122.7, 121.8, 121.3, 113.6, 112.3, 110.5, 108.2, 106.9, 100.8, 100.1, 56.4, 56.4, 55.9, 34.7. HRMS (ESI) calculated for C 27 H 24 ClN4O5 + [M+H] + : 519.1430, found 519.1393.

[0162] Example 24

[0163] Synthetic route and specific preparation process of compound 4x:

[0164] (1) Preparation process of intermediate 3b:

[0165] The synthetic route is the same as intermediate 3a. Compound 1 (100 mg, 0.445 mmol), K2CO3(122 mg, 0.883 mmol), DMF (2 mL), and 2-chloro-4-aminophenol (76.7 mg, 0.534 mmol) were used to replace 4-amino-3-chlorophenol, and then the mixture was slurried with PE:EA = 7:1 (6 mL), and then filtered to obtain compound 3b (white solid, 68%).

[0166] Intermediate 3b was detected, and the detection results are as follows: M.p. 238.7-239.6 °C. 1 H NMR (400 MHz, Chloroform-d) d 8.63 (s, 1H), 7.59 (s, 1H), 7.33 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.66 (dd, J = 8.6, 2.7 Hz, 1H), 4.07 (d, J = 4.7 Hz, 6H). 13 C NMR (100 MHz, Chloroform-d) d 165.2, 155.9, 153.0, 150.2, 149.3, 145.4, 140.3, 127.5, 124.4, 116.4, 114.4, 110.4, 106.8, 101.1, 56.4, 56.4. HRMS (ESI) calculated for C 16 H 15ClN3O3 + [M+H] + : 332.0796, found: 332.0800.

[0167] (2) The process of preparing compound 4x from intermediate 3b:

[0168] The synthetic route was the same as 4a, using intermediate 3b (99.5 mg, 0.300 mmol) and p-trifluoromethylphenylacetic acid (51.0 mg, 0.250 mmol) instead of phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4x (white solid, 85.3 mg, 66%).

[0169] Compound 4x was tested and the results of the test are as follows: M.p. 276.5-277.8 °C. IR (KBr): 3272, 1665, 1622, 1585, 1539, 1510, 1420, 1377, 1328, 1239, 1193, 1117, 1074, 998, 915, 811 cm -1 . 1 HNMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 8.6 Hz, 3H), 7.58 (s, 1H), 7.49-7.40 (m, 3H), 7.34 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), 4.07 (d, J = 5.7 Hz, 6H), 3.78 (s, 2H). 13 CNMR (100 MHz, Chloroform-d) δ 168.1, 164.7, 156.2, 152.5, 150.5, 149.5, 145.0, 138.1, 136.3, 129.9, 129.7, 127.6, 126.0, 126.0, 124.2, 121.9, 119.3, 110.3, 106.8, 101.0, 56.4, 56.4, 44.2. 19 F NMR (376 MHz, Chloroform-d) δ -62.61. HRMS (ESI) calculated for C 25 H 20 ClF3N3O4 + [M+H] + : 518.1089, found 518.1087.

[0170] Example 25

[0171] Synthetic route and specific preparation process of compound 4y:

[0172] (1) Preparation process of intermediate 3c:

[0173] Synthetic route was the same as intermediate 3a. Compound 1 (100 mg, 0.445 mmol), K2CO3(122 mg, 0.883 mmol), DMF (2 mL) were used, and 4-aminophenol (58.3 mg, 0.534 mmol) was used to replace 4-amino-3-chlorophenol, and then the mixture was slurried with PE:EA = 7:1 (6 mL), and then filtered to obtain compound 3c (white solid, 65%).

[0174] Intermediate 3c was detected, and the detection results were as follows: M.p. 190.2-191.3 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.56 (s, 1H), 7.32 (s, 1H), 7.07-7.01 (m, 2H), 6.80-6.75 (m, 2H), 4.06 (s, 6H). 13 C NMR (100 MHz, Chloroform-d) δ 166.0, 155.8, 153.2, 150.1, 149.1, 144.5, 144.3, 122.6, 116.6, 116.2, 116.1, 110.8, 106.8, 101.2, 56.4, 56.3. HRMS (ESI) calculated for C 16 H 16 N3O3 + [M+H] + : 298.1186, found: 298.1190.

[0175] (2) Preparation process of compound 4y:

[0176] Synthetic route was the same as 4a, and intermediate 3c (89.2 mg, 0.300 mmol) was used, and p-trifluoromethylphenylacetic acid (51.0 mg, 0.250 mmol) was used to replace phenylacetic acid. Purified by silica gel column chromatography (dichloromethane and methanol were eluted in turn according to the volume ratio of 60:1, 40:1), to obtain compound 4y (white solid, 78.5 mg, 65%).

[0177] Compound 4y was detected, and the detection results are as follows: M.p. 267.0-268.1 °C. IR (KBr): 3270, 1664, 1620, 1585, 1539, 1510, 1420, 1377, 1328, 1239, 1193, 1115, 997, 915, 819 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.70-7.39 (m, 9H), 7.19 (d, J = 8.6 Hz, 2H), 4.07 (s, 6H), 3.82 (s, 2H). 13 C NMR (100 MHz, Chloroform-d) δ 168.2, 165.8, 156.5, 152.1, 150.7, 148.7, 147.8, 138.5, 135.5, 129.8, 125.9, 122.4, 121.3, 110.6, 105.8, 101.1, 56.6, 56.5, 44.3. HRMS (ESI) calculated for C 25 H 21 F3N3O4 + [M+H] + : 484.1479, found 484.1474.

[0178] Example 26

[0179] Synthetic route and specific preparation process of compound 4z:

[0180] (1) Preparation process of intermediate 3d:

[0181] The synthetic route is the same as intermediate 3a. Compound 1 (100 mg, 0.445 mmol), K2CO3 (122 mg, 0.883 mmol), DMF (2 mL), and 4-amino-3-fluorophenol (67.9 mg, 0.534 mmol) were used instead of 4-amino-3-chlorophenol, and then the mixture was slurried with a mixed solvent of PE:EA = 7:1 (6 mL), and then filtered to obtain compound 3d (white solid, 67%).

[0182] Intermediate 3d was detected, and the detection results are as follows: M.p. 189.1-190.3 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.65 (d, J = 10.4 Hz, 1H), 7.54 (d, J = 10.3 Hz, 1H), 7.33 (d, J = 10.3 Hz, 1H), 7.07 - 6.95 (m, 1H), 6.95 - 6.82 (m, 2H), 4.08 (d, J = 10.3 Hz, 6H), 3.77 (d, J = 9.5 Hz, 2H). 13 CNMR (100 MHz, Chloroform-d) δ 165.6, 155.9, 153.0, 150.2, 150.0, 149.3, 132.6, 117.9, 116.9, 110.7, 110.2, 110.0, 106.8, 101.0, 56.4, 56.3. HRMS (ESI) calculated for C 16 H 15 FN3O3 + [M+H] + : 316.1092, found: 316.1096.

[0183] (2) Preparation of compound 4z:

[0184] Synthesis route was the same as 4a, using intermediate 3d (94.6 mg, 0.300 mmol), and p-trifluoromethylphenylacetic acid (51.0 mg, 0.250 mmol) instead of phenylacetic acid. Purification by silica gel column chromatography (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4z (white solid, 83.9 mg, 67%).

[0185] Compound 4z was detected, and the detection results were as follows: M.p. 266.8-267.8 °C. IR (KBr): 3272, 1659, 1620, 1585, 1539, 1510, 1420, 1377, 1328, 1250, 1239, 1193, 1115, 997, 915, 819 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.39 (t, J = 9.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.54 - 7.47 (m, 3H), 7.43 (d, J = 3.1 Hz, 1H), 7.32 (s, 1H), 7.10 - 7.03 (m, 2H), 4.06 (s, 6H), 3.85 (s, 1H). 13C NMR (100 MHz, Chloroform-d) δ 168.0, 165.1, 156.1, 152.7, 150.4, 149.5, 148.6, 138.0, 129.8, 126.1, 126.0, 125.9, 122.3, 118.1, 118.1, 110.5, 109.9, 109.7, 106.9, 100.8, 56.4, 56.4, 44.3. 19 F NMR (376 MHz, Chloroform-d) δ -62.63, -127.78 (td, J = 10.2, 9.2, 2.9 Hz). HRMS (ESI) calculated for C 25 H 20 F4N3O4 + [M+H] + : 502.1384, found 502.1380.

[0186] Enzymatic test experiment:

[0187] HTRF KinEASE-TK kit method was used for DDR kinase activity determination. (1) First, prepare 1 volume of 5X kinase reaction buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT; (2) 1 mM MnCl2, 3-fold gradient dilution of compounds in DMSO in dilution plate, the final starting concentration of the compound is 1 mM. (3) Dilute the compound 40-fold into 1X kinase reaction buffer, shake on a shaker for 20 minutes. (4) Prepare 2X kinase with 1X enzyme reaction buffer, add 2 pL of kinase to each well of the reaction plate. (5) Add 1 pL of diluted compound in buffer to each well, seal the plate with sealing film 1000g centrifugation for 30 seconds, and incubate at room temperature for 10 minutes. (6) Prepare 2.5x TK-substrate-biotin and ATP mixture with 1X enzyme reaction buffer, add 2 pL of TK-substrate-biotin / ATP mixture to the reaction plate. (7) Seal the plate with sealing film 1000g centrifugation for 30 seconds, and incubate at room temperature for 50 minutes. (8) Prepare 4X Sa-XL 665 with HTRF detection buffer. (9) Add 5 pL of Sa-XL 665 and 5 pL of TK-antibody-Cryptate to each well, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 1 hour. (10) Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) with a BMG microplate reader. Calculate the IC 50 (half maximal inhibitory concentration) of the compound and draw the inhibition curve of the compound, and analyze the data with Graphpad 7.0 software. The results are shown in Table 2.

[0188] Table 2. Results of kinase activity test (IC 50 , nM)

[0189]

[0190]

[0191] As can be seen from Table 2, the synthesized compounds show strong inhibitory effect on DDR1 and DDR2; the inhibitory activity of most compounds on DDR1 and DDR2 is higher than that of the positive drug, while the activity on VEGFR2 is eliminated.

[0192] Evaluation of cell killing ability:

[0193] PANC-1, PAN-02, 4T1, EC-9706, SK-MES-1 cells were cultured to the logarithmic growth phase, and then trypsinized, and then the cell suspension was quantitatively inoculated into a 96-well plate, 100 μL of cell suspension was added to each well, the 96-well plate was gently shaken to evenly distribute the cells, the drug was added to the 96-well plate according to different concentrations, and the 96-well plate was placed in a constant temperature cell incubator for further culture for 72 h. After the cell culture was completed, the culture medium in the 96-well plate was aspirated, and the plate was washed with PBS three times to remove unattached cells and residual culture medium. An appropriate amount of MTT reagent was added to allow MTT to contact and stain the cells. After staining was completed, DMSO was used to dissolve the cells to terminate the reaction, and the absorbance value of each well was determined by an enzyme-labeled instrument, the data was recorded and analyzed, the survival rate and inhibition rate of the cells were calculated according to the absorbance value, and a cell survival curve was drawn, and the half maximal inhibitory concentration (IC 50 ) was calculated. The specific test results are shown in Table 3; IC 50 less than 100 nM is marked as A, IC 50 100 nM to 500 nM is marked as B, IC 50 500 nM to 1000 nM is marked as C, IC 50 greater than 1000 nM is marked as D.

[0194] Table 3. Results of cell activity test

[0195] Compound No. PANC-1 PAN-02 4T1 EC-9706 SK-MES-1 4a C D C C C 4b B A B C B 4c C B D B C 4d B B C A B 4e A A A A A 4f B A B B B 4g A A B A A 4h A B B A A 4i C D D D C 4j B A C C B 4k C D D C C 4l A A B B B 4m D D D C C 4n A B B A B 4o A A A B C 4p B C C A D 4q B D A B B 4r B C B C D 4s B D C D D 4t D C C C C 4u A B B A C 4v D D D C D 4w D C C D D 4x B B B C B 4y C C D D D 4z B D C D C

[0196] Evaluation of kinase profile selectivity:

[0197] The ADP-Glo TM method was used to detect the effect of compound 4e on 207 kinds of kinases.

[0198] (1) Sample preparation. a) Prepare test compounds by serial dilution from 10 mM DMSO. b) Dilute test compounds to 0.1 mM (200x the designated test concentration).

[0199] (2) ADP-Glo kinase assay. a) Prepare 2x ATP & substrate solution and 2x kinase & metal solution with assay buffer. b) Transfer 20 nL of compound to a 384 assay plate with Echo 655. Add 2 μL of 2x kinase & metal solution mix and incubate at 25 °C for 10 min in a 384 detection plate. c) Add 2 μL of 2x ATP & substrate solution to the well and incubate at 25 °C for 60 min. d) Add 4 μL of ADP-Glo reagent and incubate at 25 °C for 40 min. e) Add 8 μ of kinase detection reagent and incubate at 25 °C for 40 min. f) Record the fluorescence signal on a microplate reader.

[0200] (3) Data analysis

[0201] The readout value of the reaction control (0.5% DMSO) was set as 0% inhibition, and the readout value of the background (10 μM positive control) was set as 100% inhibition, then the inhibition rate of each test solution was calculated. The % inhibition rate was calculated as follows:

[0202] % inhibition rate = 100% - (compound positive control) / (negative control - positive control) * 100%,

[0203] Positive control: average ratio of positive control (10 μM),

[0204] Negative control: average ratio of negative control (0.5% DMSO).

[0205] The experiment was repeated twice, and the results were averaged. The experimental results are shown in Table 3 and Table 4. Figure 1 and Table 4.

[0206] Table 4 Kinase selectivity of compound 4e (inhibition rate, %)

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] The kinase test concentration was 500 nM. The experimental results showed that compound 4e had strong inhibitory effect on DDR 1 / 2, and also showed good selectivity.

[0213] Animal experiments:

[0214] 1. PANC-1 model

[0215] Collect tumor cells in good growth state, wash twice with 1 * PBS, calculate the total number of cells with a cell counter, and dilute the cell solution with 1 * PBS to 1 * 10 7 cells / mL. Each mouse is inoculated with 1 * 10 6 cells, and 100 μL of cell suspension is inoculated into the axillary region of the mouse forelimb. When the average tumor volume exceeds 50 mm 3 (10% difference in tumor volume between individuals), the mice are randomly divided into 3 groups, namely the blank control group, the experimental group (low dose), and the experimental group (high dose). Each group has 6 mice. The experimental group is orally administered daily, with doses of 7.5 mg / kg and 15 mg / kg, respectively. After the administration is completed, the mice are euthanized, and the tumor weight and volume are measured.

[0216] 2. PAN-02 model

[0217] Collect tumor cells in good growth state, wash twice with 1 * PBS, calculate the total number of cells with a cell counter, and dilute the cell solution with 1 * PBS to 1 * 10 7 cells / mL. Each mouse is inoculated with 1 * 10 6 cells, and 100 μL of cell suspension is inoculated into the axillary region of the mouse forelimb. When the average tumor volume exceeds 50 mm 3 (10% difference in tumor volume between individuals), the mice are randomly divided into 4 groups, namely the blank control group, the positive control group, the experimental group (low dose), and the experimental group (high dose). Each group has 6 mice. The positive control group is intraperitoneally injected with gemcitabine twice a week, with a dose of 50 mg / kg. The experimental group is orally administered daily, with doses of 10 mg / kg and 25 mg / kg, respectively. After the administration is completed, the mice are euthanized, and the tumor weight and volume are measured.

[0218] 3. 4T1 model

[0219] Collect tumor cells in good growth state, wash twice with 1 * PBS, calculate the total number of cells with a cell counter, and dilute the cell solution with 1 * PBS to 1 * 10 7 cells / mL. Each mouse is inoculated with 1 * 10 6 cells, and 100 μL of cell suspension is inoculated into the axillary region of the mouse forelimb. When the average tumor volume exceeds 50 mm 3When the average tumor volume is more than 50mm (the difference of tumor volume among individuals is not more than 10%), the mice are randomly divided into 4 groups, which are blank control group, positive control group, experimental group and combination administration group, respectively. Each group has 6 mice. The experimental group is administered orally by gavage every day, and the dose is 15mg / kg. The combination administration group is administered orally by gavage every day, and the dose is 15mg / kg, and is injected intraperitoneally with PD-1 drug every 3 days, and the dose is 1mg / kg. The positive control group is injected intraperitoneally with PD-1 drug every 3 days, and the dose is 1mg / kg. After the administration is completed, the mice are euthanized, and the tumor weight and volume are measured.

[0220] 4. EC-9706 model

[0221] The tumor cells in good growth state are collected, washed with 1xPBS for 2 times, the total number of cells is calculated by a cell counter, and the cell solution is diluted with 1xPBS to 1*10 7 cells / mL. Each mouse is inoculated with 1*10 6 cells, and 100μL of cell suspension is inoculated into the axillary fossa of the forelimb of the mouse. When the average tumor volume is more than 50mm 3 ( the difference of tumor volume among individuals is not more than 10%), the mice are randomly divided into 4 groups, which are blank control group, positive control group, experimental group (low dose) and experimental group (high dose), respectively. Each group has 6 mice. The positive control group is injected intraperitoneally with cisplatin once a week, and the dose is 5mg / kg. The experimental group is administered orally by gavage every day, and the doses are 10mg / kg and 25mg / kg, respectively. After the administration is completed, the mice are euthanized, and the tumor weight and volume are measured.

[0222] 5. SK-MES-1 model

[0223] The tumor cells in good growth state are collected, washed with 1xPBS for 2 times, the total number of cells is calculated by a cell counter, and the cell solution is diluted with 1xPBS to 1*10 7 cells / mL. Each mouse is inoculated with 1*10 6 cells, and 100μL of cell suspension is inoculated into the axillary fossa of the forelimb of the mouse. When the average tumor volume is more than 50mm 3 ( the difference of tumor volume among individuals is not more than 10%), the mice are randomly divided into 4 groups, which are blank control group, positive control group, experimental group (low dose) and experimental group (high dose), respectively. Each group has 6 mice. The positive control group is injected intraperitoneally with gemcitabine twice a week, and the dose is 50mg / kg. The experimental group is administered orally by gavage every day, and the doses are 10mg / kg and 25mg / kg, respectively. After the administration is completed, the mice are euthanized, and the tumor weight and volume are measured.

[0224] The inhibitory effect of compound 4e on different tumor cells is shown in Table 5.

[0225] Table 5 Inhibition rate (%) of different substances on different tumor cells

[0226]

[0227] From Table 4, it can be seen that, compared with the positive control drug, the compound 4e all shows strong inhibition activity on the proliferation of various tumor cells. The inhibition effect of most compounds on tumor proliferation is stronger than or not weaker than the positive control drug.

[0228] The above only describes the preferred embodiments of the present application, and does not limit the present application in any form. It should be noted that, for those skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A quinazoline derivative having the structure shown in Formula I, or a pharmaceutically acceptable salt thereof; In Formula I, X is hydrogen, fluorine, or chlorine, and Y is hydrogen, fluorine, or chlorine, wherein X and Y are not both H; R is selected from 2. A quinazoline derivative or a pharmaceutically acceptable salt thereof, characterized in that, The quinazoline derivative is at least one of the following compounds:

3. The method for preparing the quinazoline derivative according to claim 1 or 2, characterized in that, Includes the following steps: Compound 1, compound 2, K2CO3 and an organic solvent were mixed and a substitution reaction was carried out to obtain compound 3; The compound 3, carboxylic acid, HATU, DIPEA and organic solvent were mixed and subjected to a condensation reaction to obtain the quinazoline derivative. The structural formulas of compound 1, compound 2, compound 3, and carboxylic acid are shown below in sequence:

4. The preparation method according to claim 3, characterized in that, The molar ratio of compound 1, compound 2 and K2CO3 is 1:(1-5):(1-10); the temperature of the substitution reaction is 0-90℃ and the time is 1-18h.

5. The preparation method according to claim 3, characterized in that, The molar ratio of compound 3, carboxylic acid, HATU and DIPEA is (0.8-3):1:(1-5):(1-5); the condensation reaction is carried out at a temperature of 0-50°C for a time of 4-24 hours.

6. The use of the quinazoline derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diseases of abnormal DDR1 and / or DDR2-related signaling pathways.

7. The application according to claim 6, characterized in that, The diseases associated with abnormal DDR1 and / or DDR2 signaling pathways include organ fibrosis, atherosclerosis, neurodegenerative diseases, inflammatory diseases, or cancer.

8. The application according to claim 7, characterized in that, The cancers mentioned include pancreatic cancer, breast cancer, non-small cell lung cancer, squamous cell carcinoma, prostate cancer, esophageal cancer, or nasopharyngeal cancer.

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