Quinazoline derivative, preparation method therefor, and use thereof

Abstract

The present application relates to the technical field of chemical pharmaceuticals, and provides a quinazoline derivative, a preparation method therefor, and a use thereof. The quinazoline derivative provided in the present application has a strong effect of targeted inhibition of DDR1 / 2 activity, with kinase inhibition activity against DDR1 / 2 reaching low nanomolar concentrations, and can inhibit the activity of DDR1 / 2 in a dose-dependent manner, some compounds achieving pM-level inhibitory activity against DDR1, and being usable in the preparation of a medicament for treating and / or preventing diseases caused by abnormal DDR1 / 2-related signaling pathways. Among the currently reported DDR-targeting compounds in the literature, the derivative is in a leading position and also has relatively good selectivity. The present application provides a preparation method for the quinazoline derivative having a short synthesis route, safe operation process, and feasibility for scaled-up production.

Description

A quinazoline derivative and preparation method and application thereof

[0001] The present application claims priority to the Chinese patent application No. CN202410750771.6, filed on June 12, 2024, and entitled "A quinazoline derivative and preparation method and application thereof", the whole content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the technical field of chemical drugs, in particular to a quinazoline derivative and preparation method and application thereof. BACKGROUND

[0003] 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 signal 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.

[0004] DDRs were considered as an orphan receptor class in the early 20th century. In 1997, Shrivastava et al. named DDRs as non-integrin collagen-binding receptors, which need 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 DDRs has similar homology with DS-I protein obtained from molds, which can mediate cell aggregation. In addition to another extracellular DS homology domain for collagen binding, DDRs have 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, when the ligand (collagen) binds with DDRs, DDRs show abnormally very slow and delayed autophosphorylation, and the phosphorylation level can last for up to 18 hours. DDRs and their downstream signaling pathways play an important role in regulating cell proliferation, migration, adhesion, aggregation and ECM remodeling.

[0005] It has been found that the dysfunction of both DDR1 and DDR2 is associated with the progression of many cancers, 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 cancer. Therefore, inhibiting the expression of DDR1 or DDR2 can be a successful strategy to control the progression of these cancers, and these receptors have been proven to be promising therapeutic targets for various small molecule TKIs. However, there is no selective DDRs drug on the market yet, so it is promising to develop small molecule inhibitors targeting DDRs. SUMMARY

[0006] Therefore, the purpose of the present application is to provide a quinazoline derivative, a preparation method and application thereof. The quinazoline derivative provided by the present application has a strong activity of targeting and inhibiting DDR1 and / or DDR2, and is good in selectivity.

[0007] To achieve the above-mentioned purpose of the application, the present application provides the following technical solutions.

[0008] The present application provides a quinazoline derivative having a structure shown in Formula I or a pharmaceutically acceptable salt thereof.

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

[0014] Compound 1, compound 2, K2CO3 and an organic solvent are mixed to perform a substitution reaction to obtain compound 3;

[0015] The compound 3, a carboxylic acid, HATU, DIPEA and an organic solvent are mixed to perform a condensation reaction to obtain the quinazoline derivative.

[0016] The structural formulas of the compound 1, compound 2, compound 3 and carboxylic acid are shown in the following order:

[0017] Preferably, the molar ratio of the compound 1, the 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.

[0018] Preferably, the molar ratio of the compound 3, the 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.

[0019] The application provides application of the quinazoline derivative or the pharmaceutically acceptable salt thereof in preparation of a medicament for treating and / or preventing a disease caused by abnormality of a DDR1 and / or DDR2 related signal path.

[0020] Preferably, the disease caused by abnormality of the DDR1 and / or DDR2 related signal path comprises organ fibrosis, atherosclerosis, a nervous system degenerative disease, an inflammatory disease or a cancer.

[0021] Preferably, the cancer comprises pancreatic cancer, breast cancer, non-small cell lung cancer, squamous cell carcinoma, prostate cancer, esophageal cancer or nasopharyngeal cancer.

[0022] The application provides a quinazoline derivative or a pharmaceutically acceptable salt thereof with a structure shown in formula I.

[0023] The application provides a preparation method of the quinazoline derivative. DETAILED DESCRIPTION

[0024] The application provides a quinazoline derivative or a pharmaceutically acceptable salt thereof with a structure shown in formula I.

[0025] 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.

[0026] In the present application, the aryl group is preferably a phenyl group; and the heteroaryl group is preferably a thienyl group, a pyridyl group, a pyrazolyl group or an indolyl group.

[0027] In the present application, the substituent group in the substituted aryl group and the substituted heteroaryl group is one or more of an alkyl group, a halogen, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an alkylsulfonyl group, an alkylamino group and an alkylamide group, as an example, the substituent group in the substituted heteroaryl group can be one or more of an alkyl group, a halogen, a haloalkyl group and an alkoxy group. In the present application, the alkyl group is preferably a C1-5 alkyl group, more preferably a methyl group, an ethyl group, a propyl group or a butyl group; the halogen is preferably fluorine or chlorine; the haloalkyl group is preferably a fluoroalkyl group or a chloroalkyl group, more preferably a trifluoromethyl group or a trichloromethyl group; the alkoxy group is preferably a methoxy group or an ethoxy group; the haloalkoxy group is preferably a fluoroalkoxy group or a chloroalkoxy group, more preferably a trifluoromethoxy group or a trichloromethoxy group; the alkylsulfonyl group is preferably a methylsulfonyl group or an ethylsulfonyl group; the alkylamino group is preferably a dimethylamino group or a diethylamino group; and the alkylamide group is preferably an acetamide group.

[0028] In the present application, the quinazoline derivative is at least one of the following compounds:

[0029] The corresponding relationship between X, Y and R in the compounds represented by formulae 4a-4z is shown in Table 1.

[0030] Table 1: Corresponding relationship between X, Y and R in the compounds represented by formulae 4a-4z and formula I

[0031] In Table 1, represents a connection site.

[0032] The quinazoline derivative provided in 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.

[0033] The present application provides a preparation method of the quinazoline derivative described in the above technical solution, which comprises the following steps:

[0034] Mixing compound 1, compound 2, K2CO3 and an organic solvent to perform a substitution reaction to obtain compound 3;

[0035] Mixing the compound 3, a carboxylic acid, HATU, DIPEA and an organic solvent to perform a condensation reaction to obtain the quinazoline derivative;

[0036] The structural formula of the compound 1, the compound 2, the compound 3 and the carboxylic acid are shown as follows respectively:

[0037] As an embodiment, the reaction route for preparing the quinazoline derivative in the present application is as follows:

[0038] The preparation method of the quinazoline derivative is described in detail below in combination with the above reaction route.

[0039] In the present application, if no special description is given, the raw materials involved are all commercially available or prepared according to the methods well known to those skilled in the art.

[0040] In the present application, the compound 1, the compound 2, K2CO3 and the organic solvent are mixed to carry out a substitution reaction to obtain the compound 3. 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. As an embodiment, X is Cl and Y is H in the structural formula of the compound 2, or X is H and Y is Cl, or X is H and Y is H, or X is F and Y is H.

[0041] 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 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 amount of the organic solvent is not particularly required in the present application, as long as the raw materials can be dissolved and the reaction can be carried out smoothly.

[0042] In the present application, the compound 1 is preferably dissolved in the organic solvent, and then the compound 2 and K2CO3 are sequentially added thereto.

[0043] In the present application, the temperature of the substitution reaction is preferably 0-90°C, and more preferably 30-40°C, and the time is preferably 1-18h, and more preferably 6-10h.

[0044] After the completion of the substitution reaction, the obtained substitution reaction solution is preferably subjected to post-treatment, 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.

[0045] After obtaining compound 3, the compound 3, a carboxylic acid, HATU (2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate), DIPEA (N,N-diisopropyl ethylamine) and an organic solvent are mixed 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 the compound 3, the carboxylic acid, the HATU and the 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.

[0046] In the present application, the carboxylic acid and the HATU are preferably added to a reaction vessel and dissolved in an organic solvent, then the DIPEA is added thereto, the reaction vessel is replaced with argon for three times, and the reaction is performed at room temperature for 30 min, and then the compound 3 is added. In the present application, the carboxyl group is activated by the reaction at room temperature for 30 min.

[0047] In the present application, the condensation reaction is preferably performed at a temperature of 0-50°C, and more preferably at a temperature of 20-30°C, and in the examples of the present application, the condensation reaction is performed at room temperature; and the condensation reaction is preferably performed for 4-24 h, and more preferably for 10-16 h.

[0048] After the condensation reaction is completed, the obtained condensation reaction solution is preferably subjected to post-treatment, and the method of the post-treatment is preferably as follows: water is added to the condensation reaction solution to quench, then the solution is washed with a saturated sodium chloride solution, and then extracted with ethyl acetate, and the obtained organic phase is concentrated and purified by a silica gel column chromatography to obtain the quinazoline derivative. In the present application, the eluent used in the silica gel column chromatography is preferably dichloromethane and methanol, and the dichloromethane and the methanol are eluted in turn according to the volume ratio of 60:1 and 40:1.

[0049] The preparation method provided in the present application has a short synthesis path, a safe operation process and the feasibility of scale-up production.

[0050] The present application provides the use of the quinazoline derivative or the pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing a disease caused by an abnormality of a DDR1 and / or DDR2 related signal pathway.

[0051] In the present application, the diseases caused by abnormality of the DDR1 and / or DDR2 related signal pathway preferably include 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.

[0052] 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 diseases caused by abnormality of the DDR1 and / or DDR2 related signal pathway.

[0053] In order to further illustrate the present application, the quinazoline derivative provided by the present application, the preparation method and the 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.

[0054] Example 1

[0055] Synthetic route and specific preparation process of compound 4a:

[0056] (1) Preparation process of intermediate 3a:

[0057] Compound 1 (10.0 g, 44.5 mmol) was dissolved in DMF (120 mL), and 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, and it was stirred for 1 h, and then filtered to obtain the crude product as a gray solid. A mixed solvent of PE:EA = 7:1 (56.0 mL) was added thereto, and it was stirred at room temperature for 3 h, and then filtered to obtain compound 3a (white solid, 10.1 g, 68%).

[0058] 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.

[0059] (2) Preparation of compound 4a:

[0060] 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%).

[0061] 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 . 1 H 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). 13C 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.

[0062] Example 2

[0063] Synthetic route and specific preparation process of compound 4b:

[0064] The synthetic route was the same as 4a, using p-methyl phenylacetic acid (37.5 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 4b (white solid, 63.6 mg, 55%).

[0065] Compound 4b was detected, and the detection results 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 . 1 H 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). 13C 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.

[0066] Example 3

[0067] Synthetic route and specific preparation process of compound 4c:

[0068] 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 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 4c (white solid, 66.7 mg, 57%).

[0069] Compound 4c was detected, and the detection results 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 . 1 H NMR (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). 13C 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 -114.1 HRMS (ESI) calculated for C 24 H 20 ClFN3O4 + [M+H] + : 468.1121, found 468.1116.

[0070] Example 4

[0071] Synthetic route and specific preparation procedure of compound 4d:

[0072] The synthetic route was the same as 4a, using p-chlorobenzoic acid (42.6 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) gave compound 4d (white solid, 70.2 mg, 58%).

[0073] Compound 4d was tested and the results of the tests 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 . 1 H 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). 13C 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.

[0074] Example 5

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

[0076] The synthetic route was the same as 4a, using p-trifluoromethyl phenylacetic 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 4e (white solid, 87.9 mg, 68%).

[0077] Compound 4e was tested and the results of the test 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). 13 C 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. 19F NMR (376 MHz, DMSO-d6) δ -60.82. HRMS (ESI) calculated for C 25 H 20 ClF3N3O4 + [M+H] + : 518.1089, found 518.1093.

[0078] Example 6

[0079] Synthetic route and specific preparation process of compound 4f:

[0080] 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 turn according to the volume ratio of 60:1, 40:1), to obtain compound 4f (white solid, 65.9 mg, 55%).

[0081] 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). 13 C 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.

[0082] Example 7

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

[0084] 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%).

[0085] Compound 4g was detected, and the detection results 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.

[0086] Example 8

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

[0088] The synthetic route was the same as 4a, using m-trifluoromethylphenylacetic acid (51.0 mg, 0.250 mmol) to replace phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in a ratio of 60:1, 40:1 by volume, respectively) gave compound 4h (white solid, 77.6 mg, 60%).

[0089] 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 20 ClF3N3O4 + [M+H] + : 518.1089, found 518.1087.

[0090] Example 9

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

[0092] The synthetic route was the same as 4a, using 3-(trifluoromethyl)benzoic acid (51.0 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) gave compound 4i (white solid, 78.7 mg, 61%).

[0093] Compound 4i was tested and the 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.

[0094] Example 10

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

[0096] The synthetic route was the same as 4a, using 4- methoxybenzoic acid (40.3 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) gave compound 4i (white solid, 73.5 mg, 62%).

[0097] Compound 4j was tested and the 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.

[0098] Example 11

[0099] Synthetic route and detailed preparation procedure of compound 4k:

[0100] The synthetic route was the same as 4a, using 4- methoxybenzoic acid (40.3 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) gave compound 4i (white solid, 73.5 mg, 62%).

[0101] Compound 4k was tested and the test 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 C NMR (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.

[0102] Example 12

[0103] Synthetic route and detailed preparation procedure of compound 4l:

[0104] 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 (dichloromethane and methanol were used as eluents in the ratio of 60:1, 40:1 by volume, respectively) gave compound 4l (white solid, 64.0 mg, 52%).

[0105] Compound 4l was detected and the detection results 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.

[0106] Example 13

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

[0108] The synthetic route was the same as 4a, and 4-acetamidobenzoic acid (48.3 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 4m (white solid, 63.3 mg, 50%).

[0109] 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.

[0110] Example 14

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

[0112] The synthetic route was the same as 4a, using 2-fluoro-3-trifluoromethyl phenylacetic acid (55.5 mg, 0.250 mmol) to replace phenylacetic acid. Purification was performed by silica gel column chromatography (dichloromethane and methanol were eluted in sequence with the volume ratio of 60:1, 40:1) to obtain compound 4n (white solid, 80.1 mg, 60%).

[0113] Compound 4n was detected, and the detection results were 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 . 1H 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.

[0114] Example 15

[0115] Synthetic route and detailed preparation procedure of compound 4o:

[0116] 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%).

[0117] 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.

[0118] Example 16

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

[0120] The synthetic route was the same as 4a, using 2-chloro-4-trifluoromethyl phenylacetic 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 of 60:1, 40:1 by volume, respectively) gave compound 4p (white solid, 83.0 mg, 60%).

[0121] Compound 4p was tested and the results of the test 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.

[0122] Example 17

[0123] Synthetic route and detailed preparation procedure of compound 4q:

[0124] 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%).

[0125] 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.

[0126] Example 18

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

[0128] The synthetic route 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 ratio of 60:1, 40:1 by volume, respectively) gave compound 4r (white solid, 93.6 mg, 64%).

[0129] Compound 4r was tested and the results of the tests 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.

[0130] Example 19

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

[0132] 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 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 4s (white solid, 63.6 mg, 52%).

[0133] Compound 4s was tested and the results of the tests 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.

[0134] Example 20

[0135] Synthetic route and specific preparation process of compound 4t:

[0136] 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%).

[0137] 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).13 C NMR (100 MHz, Chloroform-d) δ 167.3, 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.

[0138] Example 21

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

[0140] The synthetic route was the same as 4a, using 2-trifluoromethyl-5-pyridineacetic acid (51.3 mg, 0.250 mmol) to replace phenylacetic acid. Purification by column chromatography on silica gel (dichloromethane and methanol were used as eluents in a volume ratio of 60:1, 40:1, and 20:1, respectively) to give compound 4u (white solid, 71.2 mg, 55%).

[0141] Compound 4u was detected, and the detection results are as follows: M.p. 279.0-279.8 °C. IR (KBr): 3271, 1657, 1622, 1581, 1532, 1517, 1421, 1377, 1327, 1232, 1193, 1125, 1072, 996, 915, 818 cm -1 . 1 H NMR (400 MHz, Chloroform-d) δ 8.76-8.70 (m, 1H), 8.61 (s, 1H), 8.43 (d, J = 9.1 Hz, 1H), 7.96 (dd, J = 8.2, 2.1 Hz, 1H), 7.81-7.70 (m, 2H), 7.50 (s, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.33 (s, 1H), 7.21 (dd, J = 9.0, 2.7 Hz, 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.

[0142] Example 22

[0143] Synthetic route and specific preparation procedure of compound 4v:

[0144] 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 a sequence of 60:1, 40:1 by volume) gave compound 4v (white solid, 57.8 mg, 51%).

[0145] Compound 4v was tested and the results of the tests 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.

[0146] Example 23

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

[0148] 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 the ratio of 60:1, 40:1 by volume, respectively) to give compound 4w (white solid, 67.3 mg, 52%).

[0149] 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 H NMR (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.

[0150] Example 24

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

[0152] Preparation process of intermediate 3b:

[0153] 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 2-chloro-4-aminophenol (76.7 mg, 0.534 mmol) was used instead of 4-amino-3-chlorophenol, and then the mixture was slurried with PE:EA = 7:1 (6 mL) and filtered to obtain compound 3b (white solid, 68%).

[0154] Intermediate 3b was detected, and the detection results were 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.

[0155] (2) The process of preparing compound 4x from intermediate 3b:

[0156] 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%).

[0157] 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 H NMR (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 C NMR (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.

[0158] Example 25

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

[0160] (1) Preparation process of intermediate 3c:

[0161] 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 instead of 4-amino-3-chlorophenol, and then the compound 3c (white solid, 65%) was obtained by slurry with mixed solvent of PE:EA=7:1 (6 mL) and then filtration.

[0162] 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.

[0163] (2) Preparation process of compound 4y:

[0164] Synthetic route was the same as 4a, intermediate 3c (89.2 mg, 0.300 mmol) was used, and p-trifluoromethylphenylacetic acid (51.0 mg, 0.250 mmol) was used instead of phenylacetic acid. Compound 4y (white solid, 78.5 mg, 65%) was obtained by silica gel column chromatography purification (dichloromethane and methanol were eluted in turn according to the volume ratio of 60:1, 40:1).

[0165] 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.

[0166] Example 26

[0167] Synthetic route and specific preparation process of compound 4z:

[0168] (1) Preparation process of intermediate 3d:

[0169] 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%).

[0170] 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 C NMR (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.

[0171] (2) Preparation of compound 4z:

[0172] Synthesis route was the same as 4a, using intermediate 3d (94.6 mg, 0.300 mmol), and p-trifluoromethyl phenylacetic 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 a volume ratio of 60:1, 40:1, 20:1, 10:1, 5:1, 2:1, 1:1, 0:1, respectively) to give compound 4z (white solid, 83.9 mg, 67%).

[0173] 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.

[0174] Enzymatic test experiment:

[0175] 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 times in 1X kinase reaction buffer, shake on the 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 compound diluted 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.

[0176] Table 2. Results of kinase activity test (IC 50 , nM)

[0177] As can be seen from Table 2, the synthesized compounds show strong inhibitory effect on DDR1 and DDR2; the inhibitory activities of most compounds on DDR1 and DDR2 are higher than that of the positive drug, while the activity on VEGFR2 is eliminated.

[0178] Evaluation of cell killing ability:

[0179] 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 measured 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-500 nM is marked as B, IC 50 500 nM-1000 nM is marked as C, IC 50 greater than 1000 nM is marked as D.

[0180] Table 3. Results of cell activity test

[0181] Evaluation of kinase profile selectivity:

[0182] The experiment used ADP-Glo TM method to detect the effect of compound 4e on 207 kinds of kinases.

[0183] (1) Sample preparation. a) Prepare the test compound by serial dilution from 10 mM DMSO. b) Dilute the test compound to 0.1 mM (200 times the specified test concentration).

[0184] (2) ADP-Glo kinase assay. a) Prepare 2x ATP & substrate solution and 2x kinase & metal solution with experimental buffer. b) Transfer 20 nL of compound onto 384 assay plates with Echo 655. Add 2 pL of 2x kinase & metal solution mix and incubate at 25 °C for 10 min in 384 detection plate. c) Add 2 pL of 2x ATP & substrate solution in the well and incubate at 25 °C for 60 min. d) Add 4 pL of ADP-Glo reagent and incubate at 25 °C for 40 min. e) Add 8 pL of kinase detection reagent and incubate at 25 °C for 40 min. f) Record the fluorescence signal on a microplate reader.

[0185] (3) Data analysis

[0186] The readout value of the reaction control (0.5% DMSO) was set as 0% inhibition, and the readout value of the background (10 mM positive control) was set as 100% inhibition, and then the inhibition rate of each test solution was calculated. The inhibition rate was calculated as follows:

[0187] Inhibition rate % = 100% - (compound positive control) / (negative control - positive control) * 100%,

[0188] Positive control: average ratio of positive control (10 mM),

[0189] Negative control: average ratio of negative control (0.5% DMSO).

[0190] The experiment was repeated twice, and the results were averaged. The experimental results are shown in Table 4.

[0191] Table 4 Kinase selectivity of compound 4e (inhibition rate, %)

[0192] The concentration of the kinase test was 500 nM. The experimental results showed that compound 4e had strong inhibition effect on DDR 1 / 2, and also showed good selectivity.

[0193] Animal experiment:

[0194] 1. PANC-1 model

[0195] Collect tumor cells in good growth state, wash twice with 1x PBS, count the total number of cells with a cell counter, and dilute the cell solution to 1*10 7 cells / mL with 1x PBS. Each mouse was inoculated with 1*10 6 cells, and 100 pL of cell suspension was inoculated into the axillary of the mouse forelimb. When the average volume of the tumor exceeded 50 mm 3When the average tumor volume exceeds 50mm3(the difference in tumor volume between individuals is not more than 10%), the mice are randomly divided into 3 groups, namely a blank control group, an experimental group (low dose), and an experimental group (high dose). Each group has 6 mice. The experimental groups are 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.

[0196] 2. PAN-02 model

[0197] The well-grown tumor cells are washed twice with 1xPBS, the total number of cells is calculated using 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 100 μL of the cell suspension is inoculated into the axillary region of the mouse forelimb. When the average tumor volume exceeds 50mm 3 (the difference in tumor volume between individuals is not more than 10%), the mice are randomly divided into 4 groups, namely a blank control group, a positive control group, an experimental group (low dose), and an 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 groups are 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.

[0198] 3. 4T1 model

[0199] The well-grown tumor cells are washed twice with 1xPBS, the total number of cells is calculated using 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 100 μL of the cell suspension is inoculated into the axillary region of the mouse forelimb. When the average tumor volume exceeds 50mm 3 (the difference in tumor volume between individuals is not more than 10%), the mice are randomly divided into 4 groups, namely a blank control group, a positive control group, an experimental group, and a combination administration group. Each group has 6 mice. The experimental group is orally administered daily, with a dose of 15 mg / kg. The combination administration group is orally administered daily, with a dose of 15 mg / kg, and is intraperitoneally injected with PD-1 drugs once every 3 days, with a dose of 1 mg / kg. The positive control group is intraperitoneally injected with PD-1 drugs once every 3 days, with a dose of 1 mg / kg. After the administration is completed, the mice are euthanized, and the tumor weight and volume are measured.

[0200] 4. EC-9706 model

[0201] The tumor cells in good growth state were collected, washed twice with 1xPBS, and the total number of cells was counted by a cell counter. The cell solution was diluted with 1xPBS to 1*10 7 cells / mL. Each mouse was inoculated with 1*10 6 cells, and 100 μL of the cell suspension was inoculated into the armpit of the mouse forelimb. When the average tumor volume exceeded 50 mm 3 , the mice were randomly divided into 4 groups, namely, a blank control group, a positive control group, an experimental group (low dose), and an experimental group (high dose). Each group had 6 mice. The positive control group was intraperitoneally injected with cisplatin once a week at a dose of 5 mg / kg. The experimental groups were orally administered once a day at doses of 10 mg / kg and 25 mg / kg, respectively. After the administration was completed, the mice were euthanized, and the tumor weight and volume were measured.

[0202] 5. SK-MES-1 model

[0203] The tumor cells in good growth state were collected, washed twice with 1xPBS, and the total number of cells was counted by a cell counter. The cell solution was diluted with 1xPBS to 1*10 7 cells / mL. Each mouse was inoculated with 1*10 6 cells, and 100 μL of the cell suspension was inoculated into the armpit of the mouse forelimb. When the average tumor volume exceeded 50 mm 3 , the mice were randomly divided into 4 groups, namely, a blank control group, a positive control group, an experimental group (low dose), and an experimental group (high dose). Each group had 6 mice. The positive control group was intraperitoneally injected with cisplatin once a week at a dose of 5 mg / kg. The experimental groups were orally administered once a day at doses of 10 mg / kg and 25 mg / kg, respectively. After the administration was completed, the mice were euthanized, and the tumor weight and volume were measured.

[0204] The inhibitory effects of compound 4e on different tumor cells are shown in Table 5.

[0205] Table 5 Inhibition rate (%) of different substances on different tumor cells

[0206] As can be seen from Table 5, compared with the positive control drug, compound 4e showed strong inhibitory activity on the proliferation of multiple tumor cells. Most of the compounds had an inhibitory effect on tumor proliferation that was stronger than or not weaker than the positive control drug.

[0207] The above merely describes the preferred embodiments of the present application, and does not constitute any form of limitation on the present application. It should be noted that, for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as falling within the scope of protection of the present application.

Claims

1. A quinazoline derivative of the formula I ###0001### or a pharmaceutically acceptable salt thereof; ​ 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.

2. The quinazoline derivative according to claim 1, wherein The aryl is phenyl.

3. The quinazoline derivative according to claim 1, wherein The heteroaryl is thienyl, pyridyl, pyrazolyl or indolyl.

4. The quinazoline derivative according to claim 1, wherein The substituent in the substituted aryl and substituted heteroaryl is one or more of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, cyano, alkylsulfonyl, alkylamino and alkylamide.

5. The quinazoline derivative according to claim 4, wherein The alkyl is C1-5 alkyl.

6. The quinazoline derivative according to claim 4, wherein The halogen is fluorine or chlorine.

7. The quinazoline derivative according to claim 4, wherein The haloalkyl is fluoroalkyl or chloroalkyl.

8. The quinazoline derivative according to claim 4, wherein The alkoxy is methoxy or ethoxy.

9. The quinazoline derivative according to claim 4, wherein The haloalkoxy is fluoromethoxy or chloromethoxy.

10. The quinazoline derivative according to claim 4, wherein The alkylsulfonyl is methylsulfonyl or ethylsulfonyl.

11. The quinazoline derivative according to claim 4, wherein The alkylamino is dimethylamino or diethylamino.

12. The quinazoline derivative according to claim 4, wherein The alkylamide is acetylamide.

13. The quinazoline derivative according to any one of claims 1 to 12, wherein The quinazoline derivative is at least one of the following compounds:

14. A process for the preparation of a quinazoline derivative according to any one of claims 1 to 13, characterised in that, The method comprises the following steps: mixing compound 1, compound 2, acid-binding agent and organic solvent to perform substitution reaction to obtain compound 3; mixing the compound 3, carboxylic acid, HATU, DIPEA and organic solvent to perform condensation reaction to obtain the quinazoline derivative; The structural formulas of the compound 1, the compound 2, the compound 3 and the carboxylic acid are shown in the following, respectively:

15. The preparation method according to claim 14, characterized in that, The acid-binding agent is K2CO3, and the molar ratio of the compound 1, compound 2 and acid-binding agent is 1:(1-5):(1-10); the temperature of the substitution reaction is 0-90℃, and the time is 1-18h.

16. The method of claim 14, wherein, 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.

17. Use of the quinazoline derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-13 in the preparation of a DDR1 and / or DDR2 kinase inhibitor.

18. Use of the quinazoline derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-13 in the preparation of a DDR1 and / or DDR2 inhibitor.

19. Use of the quinazoline derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-13 in the preparation of a medicament for treating and / or preventing a disease caused by abnormality of DDR1 and / or DDR2 related signal pathway.

20. The use according to claim 19, characterized in that, The disease caused by abnormality of DDR1 and / or DDR2 related signal pathway includes organ fibrosis, atherosclerosis, nervous system degenerative disease, inflammatory disease or cancer.

21. The use according to claim 20, characterized in that, The inflammatory disease includes arthritis.

22. The use according to claim 20, characterized in that, The cancer includes pancreatic cancer, breast cancer, non-small cell lung cancer, squamous cell carcinoma, prostate cancer, esophageal cancer or nasopharyngeal cancer.

23. A method for treating and / or preventing a disease caused by abnormality of a DDR1 and / or DDR2 related signal pathway, characterized by, The treatment is performed by taking the quinazoline derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-13.

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