A quinazoline derivative, a preparation method thereof, a pharmaceutical composition and an application

Abstract

The present invention belongs to the field of chemical drugs, and discloses a quinazoline derivative, a preparation method thereof, a pharmaceutical composition and an application. The present invention obtains a novel quinazoline derivative as shown in Formula I. The preparation process is simple and feasible, and a variety of quinazoline derivatives are obtained by a sub-pathway method. It can be applied to the preparation of DNA methyltransferase 1 inhibitors, and can form a pharmaceutical composition, which has a certain inhibitory effect on the proliferation of a variety of tumor cells and is suitable for the development of drugs for treating leukemia and myelodysplastic syndrome. Formula I.

Description

Technical Field

[0001] The present invention belongs to the field of chemical drugs, and particularly relates to a quinazoline derivative, a preparation method thereof, a pharmaceutical composition and an application. Background Art

[0002] Tumor is one of the most major diseases threatening human health. Research shows that the occurrence and development of tumors are not only related to gene mutations and deletions, but also related to the imbalance of epigenetic regulation. Epigenetic modification refers to the heritable changes in gene expression without changing the DNA sequence, mainly including DNA methylation, histone modification, chromatin remodeling and the regulatory role of non-coding RNA, etc.

[0003] DNA methylation is one of the earliest discovered and most important epigenetic modifications, which participates in the regulation of gene expression and plays an important role in various biological processes, such as genomic stability, X chromosome inactivation, gene imprinting, etc. DNA methylation is catalyzed by DNA methyltransferases (DNMTs), with S-adenosylmethionine (SAM) as the methyl donor, and transfers a methyl group to the 5th carbon atom of cytosine in cytosine-guanine dinucleotide (CpG). DNMTs mainly include five members: DNMT1, DNMT2, DNMT3A, DNMT3B and DNMT3L. Among them, DNMT1 has the richest content. Since it is located at the DNA replication fork during DNA replication and has a high affinity for hemimethylated DNA double strands, DNMT1 has long been considered a maintenance DNA methyltransferase. In addition, a large amount of evidence shows that DNMT1 also plays a very important role in DNA de novo methylation. DNMT1 also has the ability to regulate the cell cycle and the expression of tumor suppressor genes, and there is a certain correlation between the expression level of DNMT1 and the formation, progression, metastasis and poor prognosis of tumors.

[0004] More and more solid tumor studies have identified DNMT1 as a target, and abnormal DNA hypermethylation is also related to the occurrence of leukemia. Overexpression of DNMT1 has been found in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Therefore, targeting DNMT1 is a promising treatment method for AML and MDS.

[0005] The US Food and Drug Administration (FDA) has currently approved the nucleoside inhibitors azacitidine and decitabine for the treatment of MDS and AML. However, the high toxicity, instability and other disadvantages of nucleoside inhibitors limit their clinical applications; most non-nucleoside inhibitors have problems such as weak activity and poor selectivity, and currently no non-nucleoside small molecule has entered the clinical research stage. Therefore, the discovery of DNMT1 inhibitors with high activity, low toxicity and definite selectivity not only helps the functional research of DNMT1, but also has important significance for the research and development of anti-tumor drugs. Summary of the Invention

[0006] The object of the present invention is to solve the deficiencies of the prior art and provide a quinazoline derivative, its preparation method, pharmaceutical composition and application, and specifically adopt the following technical solutions:

[0007] According to the first aspect of the present invention, a quinazoline derivative is provided, and its structure is shown in Formula I:

[0008] Formula I; or a pharmaceutically acceptable salt thereof, wherein

[0009] R 1 and R 2 are each independently selected from any one of H, alkane, cycloalkane, substituted cycloalkane, aryl, substituted aryl, alkylamide, arylamide, cyclic, substituted cyclic structure;

[0010] R 3 is selected from any one of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyclic non-aryl, substituted cyclic non-aryl, aromatic ethynyl, substituted aromatic ethynyl, heteroaromatic ethynyl, substituted heteroaryl ethynyl.

[0011] Preferably, its structure is shown in Formula II, Formula III or Formula IV:

[0012] Formula II, Formula III, Formula IV;

[0013] wherein, R 4 is selected from any one of the following 1-12:

[0014] 1 7

[0015] 2 8

[0016] 3 9

[0017] 4 10

[0018] 5 11

[0019] 6 12

[0020] ; wherein, R 5 is selected from any one of the following structures 13 - 23:

[0021] 13 19

[0022] 14 20

[0023] 15 21

[0024] 16 22

[0025] 17 23

[0026] 18

[0027] ; wherein, R 6 , R 7 are each independently selected from any one of the following structures 24 - 40:

[0028] 24 33

[0029] 25 34

[0030] 26 35

[0031] 27 36

[0032] 28 37

[0033] 29 38

[0034] 30 39

[0035] 31 40 ;

[0036] 32 。

[0037] More preferably, a quinazoline derivative has a structure as shown in Formula V:

[0038] Formula V.

[0039] The quinazoline derivative as shown in Formula V has the effect of highly selectively inhibiting the protease activity of DNMT1, and has an inhibitory effect on the proliferation of two leukemia cells (Kasumi-1 and SKNO-1), and can inhibit the proliferation of MV-4-11 cells in vivo and thus inhibit tumor growth, and can effectively relieve splenomegaly and has a certain therapeutic effect on leukemia. Therefore, it can be used to prepare drugs for treating leukemia and myelodysplastic syndrome.

[0040] According to the second aspect of the present invention, a method for synthesizing the quinazoline derivative according to claim 1 includes the following steps:

[0041] ;

[0042] First, react raw material A with an amine compound to generate product B; then react product B with a boric acid compound or a borate compound under palladium catalysis to generate product C; or react product B with an alkynyl compound under palladium catalysis to generate product D.

[0043] In the synthesis route of the present invention, first, raw material A and different raw material amines are reacted at room temperature in an alkaline solution and a solvent to generate product B. The alkaline solution is any one of TEA, DIPEA, DABCO, DBU, and tetramethylethylenediamine, and the solvent is any one of DCM, DMF, DMSO, THF, dioxane, and toluene.

[0044] Then it is divided into two paths. Path 1 is that product B and different raw material boric acids or borates are reacted in an alkaline solution and in the presence of a palladium catalyst at high temperature in a solvent to generate product C. The alkaline solution is any one of K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、KO t Bu、Na 2 CO 3 ; The palladium catalyst is Pd 2 (dba) 3 、Pd(OAc)2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppf)Cl 2 ; The solvent is at least one selected from dioxane, H 2 O, THF, DMF, and Toluene.

[0045] Route 2 is that product B and different starting material alkynes react in the presence of a base solution and a palladium catalyst in a solvent under high temperature conditions to form product D. The base solution is any one of TEA, DIPEA, DABCO, DBU, and tetramethylethylenediamine; the palladium catalyst is Pd 2 (dba) 3 , Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppf)Cl 2 ; The solvent is at least one selected from dioxane, H 2 O, THF, DMF, and Toluene.

[0046] According to the third aspect of the present invention, there is also provided the use of the above-mentioned quinazoline derivative or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 1 inhibitor.

[0047] Preferably, the DNA methyltransferase 1 inhibitor can be used in the preparation of a drug for treating diseases associated with abnormal DNA methyltransferase 1. More preferably, the related diseases include leukemia and myelodysplastic syndrome.

[0048] According to the fourth aspect of the present invention, there is also provided a pharmaceutical composition containing the above-mentioned quinazoline derivative or a pharmaceutically acceptable salt thereof as the main active ingredient.

[0049] Preferably, the pharmaceutical composition contains at least one of excipients. The dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form. More preferably, the excipient is at least one of gum arabic, syrup, lanolin, and starch. The excipient has stable properties, no incompatibility with the main drug, no side effects, does not affect the efficacy, is not easily deformed, cracked, mildewed, or infested by insects at room temperature, is harmless to the human body, has no physiological effects, does not produce chemical or physical interactions with the main drug, and does not affect the determination of the content of the main drug.

[0050] According to the fifth aspect of the present invention, there is also provided an application of a pharmaceutical composition in the preparation of a drug for treating leukemia and / or myelodysplastic syndrome.

[0051] The beneficial effects of the present invention are as follows: A novel quinazoline derivative is obtained in the present invention. The preparation process is simple and easy. A variety of quinazoline derivatives are obtained by a sub-pathway method, which can be applied to the preparation of DNA methyltransferase 1 inhibitors and can form a pharmaceutical composition, and has a certain inhibitory effect on the proliferation of various tumor cells, and is suitable for the development of drugs for treating leukemia and myelodysplastic syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The figure shows the tumor treatment effect diagram of quinazoline derivative 17 (Formula V). Among them, (A) shows the change in the body weight of mice after continuous administration for 17 days; (B) shows the change in tumor volume; (C) shows the anatomical diagram of the tumor of mice after continuous administration for 17 days; (D) shows the tumor weight distribution diagram; (E) shows the anatomical diagram of the spleen; (F) shows the spleen weight change distribution diagram. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0053] The following will clearly and completely describe the concept and technical effects generated by the present invention in combination with the embodiments and the drawings, so as to fully understand the purpose, solution and effects of the present invention. It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other.

[0054] Example 1

[0055] A quinazoline derivative (denoted as Compound 1), Compound (1-1), has the following structure:

[0056] Compound 1, Compound (1-1).

[0057] The specific preparation method is as follows:

[0058] 1) Preparation of Compound (1-1): Dissolve 4-methylbenzylamine (280 mg, 2.32 mmol, 1.5 eq) in 3 mL of tetrahydrofuran (THF), add 6 drops of triethylamine (TEA), stir at room temperature for 10 minutes, then dissolve the raw material 2,4-dichloro-6,7-dimethoxyquinazoline (400 mg, 1.54 mmol, 1.0 eq) in 5 mL of THF, and add dropwise to the above system, stir at room temperature for 4 h. Monitor the reaction by TLC (PE:EA = 1:1). After the reaction is completed, concentrate the reaction solution and purify it by silica gel column chromatography (PE:EA = 3:1 to 2:1) to obtain Compound 1-1 (white solid, 440 mg, 83%).

[0059] The NMR test results of compound (1-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (d, J = 7.2Hz, 2H), 7.11 (d, J = 6.0 Hz, 2H), 7.03 (s,2H), 6.43 (s, 1H), 4.78 (s, 2H),3.89 (s, 3H), 3.86 (s, 3H), 2.32 (s, 3H). 13 CNMR (100 MHz, CDCl 3 ) δ 159.8,156.2, 155.0, 149.1, 148.0, 137.7,134.7, 129.4, 128.5, 107., 106.9, 100.2,56.3, 56.2, 45.6, 21.2. HRMS (ESI)calculated for C 18 H 19 ClN 3 O 2 + [M+H] + :344.1460,found: 344.1462。

[0060] 2) Preparation of compound 1: Sequentially add compound (1-1) (200 mg, 0.58 mmol, 1.0 eq), compound 5-methylfuran borate (182 mg, 0.87 mmol, 1.5 eq), and anhydrous potassium carbonate (K 2 CO 3 ) (241 mg, 1.75 mmol, 3.0 eq) into a round-bottom flask. Replace the reaction device with argon three times, then add PdCl 2 (dppf) (43 mg, 0.058 mmol, 0.1 eq), continue to replace the reaction device with argon three times, and finally inject 5 mL of a degassed 1,4-dioxane:water = 4:1 mixed solvent that has been degassed for one hour. Finally, place the reaction system in an 80 °C oil bath and react for 4 h. Monitor the reaction by TLC (PE:EA = 1:1). After the reaction is completed, add diatomaceous earth to the suction funnel to filter off the insoluble substances in the reaction solution. Wash the reaction solution with saturated sodium chloride solution (10 mL), extract with ethyl acetate (10 mL × 3), concentrate the organic phase, and purify it by silica gel column chromatography (PE:EA = 2:1 to 1:1) to obtain compound 1 (pale yellow solid, 140 mg, 62%).

[0061] The NMR test results of Compound 1 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (s, 1H), 7.33(s, 1H), 7.31 (s, 1H), 7.21 (d, J = 3.2 Hz, 1H),7.17 (s, 1H), 7.15 (s, 1H),6.90 (s, 1H), 6.14 (dd, J = 3.2, 1.2 Hz,1H), 5.82 (s, 1H), 4.87 (d, J = 5.3 Hz,2H), 3.94 (s, 3H), 3.90 (s, 3H),2.42 (s, 3H), 2.35 (s, 3H). 13 C NMR (100 MHz,CDCl 3 ) δ158.3, 154.9, 154.4, 153.1, 152.1, 148.6, 147.4, 137.5, 136.0, 129.5,128.6,113.8, 108.4, 108.4, 107.3, 100.0, 56.3, 45.3, 21.3, 14.3. HRMS (ESI)calculated for C 23 H 24 N 3 O 3 + [M+H] + :390.1812, found:390.1813。

[0062] Example 2

[0063] A quinazoline derivative (denoted as Compound 2), Compound (2-1), has the following structure:

[0064] Compound 2, Compound (2-1).

[0065] The specific preparation method is as follows:

[0066] 1) Preparation of Compound (2-1): Similar to the preparation method of Compound (1-1), except that one of the raw materials used is 4-methoxybenzylamine, which is used in equimolar amount to replace 4-methylbenzylamine in the preparation method of Compound (1-1).

[0067] The NMR test results of Compound (2-1) are as follows:1 1H NMR (400 MHz, CDCl 3 ) δ 7.32 (d, J J = 8.7Hz, 2H), 7.09 (s, 1H), 6.86 (d, J J = 6.5 Hz,3H), 5.95 (s, 1H), 4.75 (d, J J = 4.7Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H),3.78 (s, 1H). 13 13C NMR (100 MHz, CDCl 3 ) δ159.7, 159.5,156.3, 155.1, 149.2, 148.2, 130.0, 129.8, 114.3, 107.3, 106.8,99.9, 56.4,56.4, 55.4, 45.4. HRMS (ESI) calculated for C 18 15 19 H 3 14 3 ClN + 3 O + [M+H] + 1 3 :360.1109, found: 360.1112。

[0068] 2) Preparation of Compound 2: Similar to the preparation method of Compound 1, except that one of the raw materials used is Compound (2-1), which is used in equimolar amount to replace (1-1) in the preparation method of Compound 1.

[0069] The NMR test results of Compound 2 are as follows: 1 1H NMR (400 MHz, CDCl 3 )δ 7.40 – 7.35 (m, 2H),7.31 (s, 1H), 7.21 (d, J J = 3.2 Hz, 1H), 6.89 (s,2H), 6.87 (t, J J = 2.2 Hz, 1H),4.84 (d, J J = 5.2 Hz, 2H), 3.95 (s,3H), 3.90 (s, 3H), 3.80 (s, 3H), 2.43 (s,3H). 13 13C NMR (100 MHz,CDCl 3) δ 159.3, 158.3, 154.9, 154.4, 153.1, 152.1, 148.6,147.4,131.1, 129.9, 114.2, 113.8, 108.5, 108.4, 107.3, 100.1, 56.3, 55.4,45.0, 14.3.HRMS (ESI) calculated for C 23 H 24 N 3 O 3 + [M+H] + : 406.1761, found:406.1763。

[0070] Example 3

[0071] A quinazoline derivative (denoted as Compound 3), Compound (3-1), and their structures are as follows:

[0072] Compound 3, Compound (3-1).

[0073] The specific preparation method is as follows:

[0074] 1) Preparation of Compound (3-1): Similar to the preparation method of Compound (1-1), except that one of the raw materials used is 4-(trifluoromethyl)benzylamine, which is used in an equimolar amount to replace 4-methylbenzylamine in the preparation method of Compound (1-2).

[0075] The NMR test results of Compound (3-1) are as follows: 1 H NMR (400 MHz, CDCl 3 )δ 7.55 (d, J = 8.0Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.07 (s,1H), 6.96 (s, 1H), 6.30 (d, J = 5.6Hz, 1H), 4.90 (t, J = 5.5 Hz,2H), 3.92 (s, 3H), 3.90 (s, 3H). 13 C NMR (100 MHz,CDCl 3 )δ 159.8, 156.1, 155.3, 149.4, 148.3, 142.0, 130.3, 120.0, 128.7, 125.7(q, JF-C = 3.5 Hz), 56.4, 45.1. 19 F NMR (376 MHz, CDCl 3 ) δ -62.53.HRMS (ESI) calculated for C 18 H 16 ClF 3 N 3 O 3 + [M+H] + : 398.0878, found: 398.0879。

[0076] 2) Preparation of Compound 3: Similar to the preparation method of Compound 1, except that one of the raw materials used is Compound (3-1), which is used in equimolar amount to replace (1-1) in the preparation method of Compound 1.

[0077] The NMR test results of Compound 3 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (m, 4H), 7.28(s, 1H), 7.12 (s, 1H), 6.27 (t, J = 6.0 Hz, 1H),6.12 (s, 1H), 4.95 (d, J = 5.5Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 2.37(s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ158.4, 155.0, 154.6,153.0, 151.9, 148.8, 147.4, 143.3, 128.5, 125.6, 113.9,108.4, 108.2, 107.3,100.2, 56.3, 44.8, 14.2. 19 F NMR (376 MHz, CDCl 3 ) δ-62.48.HRMS (ESI) calculated for C 23 H 21 F 3 N 3 O 3 + [M+H] + : 444.1530, found: 444.1532。

[0078] Example 4

[0079] A quinazoline derivative (denoted as Compound 4), Compound (4-1), has the following structure:

[0080] Compound 4, Compound (4-1)

[0081] The specific preparation method is as follows:

[0082] 1) Preparation of Compound (4-1): Similar to the preparation method of Compound (1-1), except that one of the raw materials used is 2-aminomethylpyridine, which replaces 4-methylbenzylamine in the preparation method of Compound (1-2) in equimolar amounts.

[0083] The NMR test results of Compound (4-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 4.4Hz, 1H), 8.00 (t, J = 4.8 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (d, J = 7.9Hz, 1H), 7.28 (d, J = 7.2Hz, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 4.90 (d, J = 4.7Hz, 2H), 3.94 (s,3H), 3.78 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.7,156.4,156.1, 155.0, 149.1, 148.9, 147.9, 137.3, 123.1, 122.8, 107.3, 107.2,100.3,56.3, 56.1, 45.8. HRMS (ESI) calculated for C 16 H 16 ClN 4 O 2 + [M+H] + : 331.0956,found: 331.0959。

[0084] 2) Preparation of Compound 4: Similar to the preparation method of Compound 1, except that one of the raw materials used is Compound (4-1), which is used in equimolar amount to replace (1-1) in the preparation method of Compound 1.

[0085] The NMR test results of Compound 4 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, J J = 5.6 Hz, 1H), 7.71 (tt, J J = 7.6, 2.1 Hz, 1H), 7.49 (d, J J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 7.23 (t, J J = 6.8 Hz, 1H), 7.18 (s, 1H), 7.04 (s, 1H), 6.14 (s, 1H), 4.98 (d, J J = 2.9 Hz, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 2.43 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.3, 157.5, 154.9, 154.4, 152.8, 151.9, 149.0, 148.6, 146.8, 137.1, 123.0, 122.6, 113.7, 108.3, 108.0, 107.6, 100.5, 56.3, 56.1, 46.0, 14.3. HRMS (ESI) calculated for C 21 H 21 N 4 O 3 + [M + H] + : 377.1608, found: 377.1609.

[0086] Example 5

[0087] A quinazoline derivative (denoted as Compound 5) and Compound (5-1) have the following structures:

[0088] Compound 5, Compound (5-1).

[0089] The specific preparation method is as follows:

[0090] 1) Preparation of compound (5-1): Similar to the preparation method of compound (1-1), except that one of the raw materials used is 4-methylaminopyridine, which replaces 4-methylbenzylamine in the preparation method of compound (1-1) in equimolar amount.

[0091] The NMR test results of compound (5-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (d, J = 5.0Hz, 2H), 7.27 (s, 1H), 7.11 (d, J = 8.2 Hz,2H), 6.69 (t, J = 5.9 Hz, 1H), 4.87(d, J = 5.7 Hz, 2H), 3.95 (s,3H), 3.90 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 160.0,156.1, 155.4, 150.0, 149.5, 148.4, 147.7, 123.1, 107.3, 106.9, 100.1, 56.5,56.4, 44.3. HRMS (ESI) calculated for C 16 H 16 ClN 4 O 2 + [M+H] + : 331.0956, found:331.0959.

[0092] 2) Preparation of compound 5: Similar to the preparation method of compound 1, except that one of the raw materials used is compound (5-1), which replaces (1-1) in the preparation method of compound 1 in equimolar amount.

[0093] The NMR test results of compound 5 are as follows: 1 H NMR (400 MHz, DMSO- d 6 )δ 8.56 (t, J = 6.1 Hz,1H), 8.50 (d, J = 4.9 Hz, 2H), 7.65 (s,1H), 7.42 (d, J = 4.9 Hz, 2H), 7.19 (s,1H), 6.93 (s, 1H), 3.90 (d, J= 4.1 Hz, 6H), 2.35 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 158.2, 154.1, 153.4, 151.8, 149.5, 149.2, 148.1, 146.6, 122.5, 112.7, 108.1, 107.3, 107.1, 102.2, 56.0, 55.7, 42.9, 13.6. (ESI) calculated for C 21 H 21 N 4 O 3 + [M + H] + : 377.1608, found: 377.1610。

[0094] Example 6

[0095] A quinazoline derivative (denoted as Compound 6), Compound (6-1), and its structure is shown as follows:

[0096] Compound 6, Compound (6-1).

[0097] The specific preparation method is as follows:

[0098] 1) Preparation of Compound (6-1): Similar to the preparation method of Compound 1-1, except that one of the raw materials used is p-methylphenethylamine, which is used in equimolar amount to replace 4-methylbenzylamine in the preparation method of Compound (1-2).

[0099] The NMR test results of Compound 6-1 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.07 (s, 4H), 7.00 (s, 1H), 6.87 (s, 1H), 6.26 (t, J = 5.6 Hz, 1H), 3.85 (s, 3H), 3.85 (d, J = 13.4 Hz, 2H), 3.81 (s, 3H), 2.94 (t, J = 7.1 Hz, 2H), 2.28 (s, 3H). 13 C NMR (100 MHz, CDCl 3) δ 159.9, 156.3, 154.9, 149.0, 147.8, 136.2, 135.6, 129.4, 128.7, 107.0, 106.9, 100.1, 56.2, 56.1, 42.7, 34.7, 21.0. HRMS (ESI) calculated for C 19 H 21 ClN 3 O 2 + [M+H] + : 358.1317, found: 358.13199。

[0100] 2) Preparation of Compound 6: Similar to the preparation method of Compound 1, except that one of the raw materials used is Compound (6-1), which is used in equimolar amount to replace (1-1) in the preparation method of Compound 1.

[0101] The NMR test results of Compound 6 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (s, 1H), 7.22 (d, J = 4.9 Hz, 1H), 7.14 (q, J = 7.8 Hz, 4H), 6.86 (s, 1H), 6.15 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 3.95 (s, 1H), 3.92 (s, 3H), 3.89 (s, 1H), 3.86 (s, 3H), 3.00 (t, J = 7.4 Hz, 2H), 2.41 (s, 3H), 2.32 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.5, 154.8, 154.3, 153.2, 152.2, 148.5, 147.2, 136.3, 136.2, 129.4, 128.9, 113.7, 108.3, 108.3, 107.5, 100.1, 56.3, 56.1, 42.7, 35.2, 21.1, 14.3. (ESI) calculated for C 24 H 25 N 3 O 3 + [M+H] +: 404.1969, found: 404.1967。

[0102] Example 7

[0103] A quinazoline derivative (denoted as Compound 7), Compound (7-1), whose structure is shown below:

[0104] Compound 7, Compound (7-1).

[0105] The specific preparation method is as follows:

[0106] 1) Preparation of Compound (7-1): Similar to the preparation method of Compound (1-1), the difference is that one of the raw materials used is 4-chlorophenethylamine, which replaces 4-methylbenzylamine in the preparation method of Compound (1-2) in equimolar amounts.

[0107] The NMR test results of Compound (7-1) are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43 (t, J J = 5.3Hz, 1H), 7.58 (s, 1H), 7.35 (d, J J = 8.2 Hz,2H), 7.29 (d, J J = 8.2 Hz, 2H), 7.07(s, 1H), 3.88 (s, 3H), 3.87 (s, 3H),3.69 (q, J J = 6.5 Hz, 2H), 2.95 (t, J J = 7.4Hz, 2H). 13 CNMR (100 MHz, DMSO- d 6 ) δ 159.9, 155.1, 154.4, 148.5, 147.2,138.4,130.8, 130.6, 128.3, 106.9, 106.6, 102.2, 56.1, 55.8, 42.2, 33.7. HRMS(ESI)calculated for C 18 H 18 Cl 2 N 3 O 2 + [M+H] + : 378.0771, found: 378.0773。

[0108] 2) Preparation of Compound 7: Similar to the preparation method of Compound 1, except that one of the raw materials used is Compound (7-1), which is used in an equimolar amount to replace (1-1) in the preparation method of Compound 1.

[0109] The NMR test results of Compound 7 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (s, 1H), 7.28(s, 1H), 7.26 (s, 1H), 7.21 – 7.18 (m, 2H), 7.17 (s, 1H),5.64 (t, J = 5.6 Hz,1H), 3.94 (s, 3H), 3.92(d, J = 6.9 Hz, 2H), 3.89 (s, 3H), 3.04 (t, J = 7.3 Hz,2H), 2.43(s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.4, 154.9, 154.5,153.1, 152.1,148.6, 147.3, 138.0, 132.5, 130.4, 128.9, 113.7, 108.4, 108.4,107.4, 99.9,56.3, 56.3, 42.6, 35.0, 14.3. (ESI) calculated for C 23 H 23 ClN 3 O 3 + [M+H] + :424.1422, found: 424.1423.

[0110] Example 8

[0111] A quinazoline derivative (denoted as Compound 8), Compound (8-1), and their structures are as follows:

[0112] Compound 8, Compound (8-1).

[0113] The specific preparation method is as follows:

[0114] 1) Preparation of compound (8-1): Similar to the preparation method of compound (1-1), except that one of the raw materials used is 4-amino-1-methylpiperidine, which replaces 4-methylbenzylamine in the preparation method of compound (1-1) in equimolar amounts.

[0115] The NMR test results of compound (8-1) are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.00 (d, J = 7.6Hz, 1H), 7.65 (s, 1H), 7.05 (s, 1H), 4.20 – 3.99 (m, 1H), 3.89 (s, 3H),3.88(s, 3H), 2.85 (d, J = 11.2 Hz, 2H), 2.20 (s, 3H), δ 2.00 (t, J = 12.1 Hz,2H),1.89 (d, J = 12.1 Hz, 2H).1.66 (qd, J = 12.1, 3.7Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 159.3,155.1, 154.4, 148.5, 147.3, 106.8, 106.5, 102.5, 56.3, 55.8,54.6, 47.9, 45.9,31.2. HRMS(ESI) calculated for C 17 H 24 ClN 4 O 2 + [M+H] + : 351.1582,found: 351.1583。

[0116] 2) Preparation of compound 8: Similar to the preparation method of compound 1, except that one of the raw materials used is compound (8-1), which replaces (1-1) in the preparation method of compound 1 in equimolar amounts.

[0117] The NMR test results of compound 8 are as follows: 1 H NMR (400 MHz, CD3OD)δ 7.55 (s, 1H), 7.18(s, 1H), 7.17 (d, J = 3.3 Hz, 1H), 6.22 (d,J = 3.3 Hz, 1H), 4.51 (tt, J = 11.0, 4.0 Hz, 1H), 3.95 (s, 6H), 3.45 (d, J = 9.6 Hz, 2H), 3.04 (t, J = 13.8 Hz, 2H), 2.78 (s, 3H), 2.43 (s, 3H), 2.33 (d, J = 13.6 Hz, 2H), 2.07 – 1.93 (m, 2H). 13 CNMR (100MHz, CD3OD) δ 159.7, 156.2, 156.0, 153.5, 152.5, 150.2, 147.1, 115.1, 109.4, 108.7, 106.9, 103.1, 56.9, 56.4, 55.1, 47.3, 44.4, 30.6, 13.9. (ESI) calculated for C 21 H 27 N 4 O 3 + [M + H] + : 383.2078, found: 383.3079。

[0118] Example 9

[0119] A quinazoline derivative (denoted as Compound 9), Compound (9-1), whose structure is shown as follows:

[0120] Compound 9, Compound (9-1).

[0121] The specific preparation method is as follows:

[0122] 1) Preparation of Compound (9-1): Similar to the preparation method of Compound (1-1), except that one of the raw materials used is (1-methyl-4-piperidyl)methylamine, which replaces 4-methylbenzylamine in the preparation method of Compound (1-1) in equimolar amounts.

[0123] The NMR test results of Compound (9-1) are as follows: 1 H NMR (400 MHz, DMSO- d 6)δ 8.33 – 8.24 (m,1H), 7.61 (s, 1H), 7.03 (s, 1H), 3.87 (s, 6H), 3.37 (t, J = 6.0 Hz, 2H), 2.72(d, J = 11.0 Hz, 2H), 2.10 (s, 3H), 1.79 (t, J = 11.3 Hz, 2H), 1.66 (d, J = 11.7Hz, 2H), 1.61 (m, 1H), 1.21 (q, J = 6.1 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) δ160.2,155.2, 154.4, 148.5, 147.2, 106.9, 106.5, 102.3, 56.1, 55.8, 55.1,46.3, 46.1,34.6, 29.9. HRMS (ESI) calculated for C 16 H 22 ClN 4 O 2 + [M+H] + : 337.1426,found: 337.1423。

[0124] 2) Preparation of Compound 9: Similar to the preparation method of Compound 1, one of the raw materials used is Compound (9-1), which is used in equimolar amount to replace 1-1 in the preparation method of Compound 1.

[0125] The NMR test results of Compound 9 are as follows: 1 H NMR (400 MHz,CD3OD)δ 7.48 (s, 1H), 7.22(s, 1H), 7.18 (d, J = 3.3 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 3.98 (s, 3H), 3.97(s, 3H), 3.69 (d, J = 6.6 Hz, 2H),3.57 – 3.43 (m, 2H), 2.97 (t, J= 8.2 Hz, 2H), 2.82 (s, 3H), 2.44 (s, 3H), 2.26 – 2.15 (m, 1H), 2.12 – 2.06 (m, 2H), 1.64 (d, J = 11.8 Hz, 2H). 13 C NMR (100 MHz, CD3OD) δ 160.6, 156.2, 155.9, 153.7, 152.6, 150.2, 147.1, 114.9, 109.3, 108.6, 107.1, 102.9, 56.8, 56.5, 55.5, 46.3, 44.1, 34.9, 29.0, 13.8. (ESI) calculated for C 22 H 29 N 4 O 3 + [M + H] + : 397.2234, found: 397.2235。

[0126] Example 10

[0127] A quinazoline derivative (denoted as Compound 10), Compound (10 - 1), and their structures are as follows:

[0128] Compound 10, Compound (10 - 1).

[0129] The specific preparation method is as follows:

[0130] 1) Preparation of Compound (10 - 1): Similar to the preparation method of Compound 1 - 1, except that one of the raw materials used is tert - butyl (1 - methyl - piperidin - 4 - ylmethyl) - carbamate, which is used in an equimolar amount to replace 4 - methylbenzylamine in the preparation method of Compound (1 - 1).

[0131] The NMR test results of Compound (10 - 1) are as follows: 1 H NMR (400 MHz, DMSO - d 6 )δ 8.36 (t, J = 6.1Hz, 1H), 7.62 (s, 1H), 7.06 (s, 1H), 3.98 – 3.92 (m, 2H), 3.88 (s, 6H), 3.40(t, J= 6.4 Hz, 2H), 2.90 – 2.59 (m, 3H), 1.95 –1.79 (m, 2H), 1.70 (d, J = 12.6Hz, 2H), 1.38 (s, 9H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 160.2, 155.2, 154.4, 153.9,148.5,147.2, 106.9, 106.5, 102.3, 78.5, 56.1, 55.8, 45.9, 35.3, 29.7, 28.1. HRMS(ESI) calculated for C 16 H 22 ClN 4 O 2 + [M+H] + : 437.1950, found: 437.1953。

[0132] 2) Preparation of Compound 10: Similar to the preparation method of Compound 1, one of the raw materials used is Compound (10-1), which is used in an equimolar amount to replace (1-1) in the preparation method of Compound 1.

[0133] The NMR test results of Compound 10 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (s, 1H), 7.14(s, 1H), 6.95(s, 1H), 5.78 (t, J = 6.2 Hz, 1H), 4.20 – 4.06 (m, 2H), 3.96 (s,6H),3.62 (s, 2H), 2.72 (t, J = 12.6 Hz, 2H), 2.43 (s, 3H), 1.95 (m, 1H),1.78(d, J = 12.3 Hz, 2H), 1.45 (s, 9H), 1.30 – 1.25 (m, 2H). 13 C NMR (100 MHz, CDCl 3) δ 158.7, 155.0, 154.9, 154.4, 153.1, 152.2, 148.6, 147.3, 113.6, 108.5, 108.3, 107.3, 100.0, 79.6, 56.4, 56.3, 46.8, 36.5, 30.3, 28.6, 25.0, 14.3. (ESI) calculated for C 26 H 35 N 4 O 5 + [M+H] + : 483.2602, found: 483.2601。

[0134] Example 11

[0135] Thirty quinazoline derivatives (denoted as Compound 11 - Compound 40 respectively), and their structures are shown below (where, labeled compounds such as Compound (24 - 1) are intermediate products for preparing the final quinazoline derivatives):

[0136] Compound 11 Compound 12 Compound 13 Compound 14

[0137] Compound 15 Compound 16 Compound 17 Compound 18

[0138] Compound 19 Compound 20 Compound 21 Compound 22

[0139] Compound 23 Compound 24 Compound (24 - 1) Compound 25

[0140] Compound (25 - 1) Compound 26 Compound (26 - 1) Compound 27

[0141] Compound 28 Compound (28 - 1) Compound 29 Compound 30

[0142] Compound (30 - 1) Compound 31 Compound (31 - 1) Compound 32

[0143] Compound (32 - 1) Compound 33 Compound (33 - 1) Compound 34

[0144] Compound (34 - 1) Compound 35 Compound (35 - 1) Compound 36

[0145] Compound (36 - 1) Compound 37 Compound (37 - 1) Compound 38

[0146] Compound (38 - 1) Compound 39 Compound (39 - 1) Compound 40

[0147] Compound (40 - 1).

[0148] (1) The specific preparation method of Compound 11 is as follows: Add Compound 10 (100 mg, 0.207 mmol) to a round-bottom flask equipped with a magnetic stirrer, and then add 2 mL of 4N HCl 1,4-dioxane solution. React at room temperature for 1 h. Monitor the reaction by thin-layer chromatography (TLC) (DCM:MeOH = 6:1). After the reaction is completed, concentrate the reaction solution, adjust the pH to alkaline with 2 mL of sodium carbonate solution, extract with EA, and finally dry and concentrate the organic phase and perform column chromatography to obtain Compound 11 (pale yellow solid, 75 mg, 98%).

[0149] The NMR test results of Compound 11 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (s, 1H), 7.16(d, J = 3.3 Hz, 1H), 6.93 (s, 1H), 6.13 (d, J= 3.2 Hz, 1H), 5.67 (t, J = 5.9 Hz,1H), 3.95 (d, J = 2.3 Hz,6H), 3.60 (t, J = 6.2 Hz, 2H), 3.09 (d, J = 12.3 Hz, 2H),2.59(t, J = 10.7 Hz, 2H), 2.42 (s, 3H), 1.97 – 1.84 (m, 3H), 1.79 (d, J = 13.0Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.7, 154.8,154.3, 153.1, 152.2, 148.5,147.5, 113.7, 108.5, 108.3, 107.3, 100.0, 56.4,56.3, 47.3, 45.9, 36.7, 31.5,14.3. (ESI) calculated for C 21 H 27 N 4 O 3 + [M+H] + : 383.2078, found:383.2079。

[0150] (2) The specific preparation method of compound 12 is as follows: Add compound 10 (300 mg, 0.89 mmol) to a round-bottomed flask equipped with a magnetic stirrer, then add N-Boc-6-bromohexylamine (250 mg, 0.89 mmol), potassium iodide (29 mg, 0.05 mmol), DIPEA (1.0 mL, 2.67 mmol), add 4 mL of DMF, and react at 110 °C for 12 h. Monitor the reaction by thin-layer chromatography (TLC) (DCM:MeOH = 18:1). After the reaction is completed, wash with water, extract three times with ethyl acetate, back-extract three times with saturated brine, dry and concentrate the organic phase, and obtain compound 12 (pale yellow solid, 375 mg, 81.3%) by column chromatography.

[0151] The NMR test results of compound 12 are as follows: 1 H NMR (400 MHz, CDCl 3 )δ 7.64 (s, 1H), 7.50(s, 1H), 7.28 (s, 1H), 7.09 (d,J = 3.2 Hz, 1H), 6.10 (d, J = 3.3 Hz, 1H), 4.58 (t, J = 12.7 Hz, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 3.48 (d, J = 9.6 Hz, 2H), 3.04 (q, J = 6.6 Hz, 2H), 2.87 – 2.78 (m, 2H), 2.71 – 2.58 (m, 2H), 2.40 (s, 3H), 2.30 – 2.18 (m, 2H), 2.06 (t, J = 9.8 Hz, 4H), 1.81 (q, J = 9.5, 8.3 Hz, 3H), 1.41 (s, 9H), 1.29 (dd, J = 6.8, 3.8 Hz, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.9, 156.1, 154.7, 154.2, 152.6, 152.0, 148.5, 146.6, 113.2, 108.1, 107.8, 107.6, 102.2, 79.2, 57.4, 57.0, 56.2, 52.9, 45.7, 40.2, 33.3, 29.8, 28.4, 27.2, 26.4, 26.1, 23.9, 14.2. (ESI) calculated for C 32 H 48 N 5 O 5 + [M + H] + : 582.3650, found: 582.3652。

[0152] (3) The specific preparation method of Compound 13 is as follows: Similar to the preparation method of Compound 1, one of the raw materials used is Compound (9-1), which is used in equimolar amount to replace (1-1) in the preparation method of Compound 1. The other reaction raw material is 5-methylthiophene-2-boronic acid, which is used in equimolar amount to replace 5-methylfuranboronic acid pinacol ester in the preparation method of Compound 1.

[0153] The NMR test results of Compound 13 are as follows: 11H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J J = 3.6 Hz, 1H), 7.19 (s, 1H), 6.92 (s, 1H), 6.77 (d, J J = 3.6 Hz, 1H), 5.70 (t, J J = 5.6 Hz, 1H), 3.97 (s, 6H), 3.64 (t, J J = 6.1 Hz, 2H), 2.91 (d, J J = 11.0 Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.97 (t, J J = 11.5 Hz, 2H), 1.83 (d, J J = 11.9 Hz, 3H), 1.47 (q, J J = 13.4 Hz, 2H). 13 13C NMR (100 MHz, CDCl 3 ) δ 158.6, 156.5, 154.4, 148.4, 147.6, 143.4, 143.0, 127.7, 126.4, 108.0, 107.1, 100.0, 56.4, 56.3, 55.7, 46.8, 46.4, 35.5, 30.3, 15.9. (ESI) calculated for C 22 H 29 N 4 O 2 S + [M + H] + : 413.2006, found: 413.2002。

[0154] (4) The specific preparation method of compound 14 is as follows: Similar to the preparation method of compound 1, one of the raw materials used is compound (9-1), which is used in an equimolar amount to replace (1-1) in the preparation method of compound 1. The other reaction raw material is 2-fluoro-4-formylphenyl-3-methylboronic acid pinacol ester, which is used in an equimolar amount to replace 5-methylfuranboronic acid pinacol ester in the preparation method of compound 1.

[0155] The NMR test results of compound 14 are as follows: 1 1H NMR (400 MHz, DMSO- d 6 ) δ 8.38 (s, 1H), 7.81 (t, J= 6.6 Hz, 1H), 7.77 (s, 1H), 7.35 (t, J = 6.7 Hz, 1H), 7.18 – 7.12 (m, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.51 (d, J = 6.3 Hz, 2H), 3.38 (d, J = 12.1 Hz, 2H), 2.88 (m, 2H), 2.68 (s, 3H), 2.31 (d, J = 2.2 Hz, 3H), 2.07 – 1.96 (m, 1H), 1.90 (d, J = 17.3 Hz, 2H), 1.58 (q, J = 13.4 Hz, 2H). 13 C NMR (100 MHz, DMSO d 6 ) δ 158.7, 157.1, 154.0, 148.6, 132.0, 130.1, 129.1, 125.1, 124.6, 123.4, 120.5, 115.2, 106.9, 102.3, 56.2, 55.7, 53.2, 45.2, 42.5, 32.9, 27.2, 14.5. 19 F NMR (376 MHz, DMSO d 6 ) δ -118.4. (ESI) calculated for C 24 H 30 FN 4 O 2 + [M+H] + : 425.2347, found: 425.2349。

[0156] (5) The specific preparation method of compound 15 is as follows: Similar to the preparation method of compound 1, one of the raw materials used is compound (9-1), which is used in equimolar amount to replace (1-1) in the preparation method of compound 1. The other reaction raw material is 1-methyl-1H-pyrazole-5-boronic acid pinacol ester, which is used in equimolar amount to replace 5-methylfuranboronic acid pinacol ester in the preparation method of compound 1.

[0157] The NMR test results of compound 15 are as follows: 1 H NMR (400 MHz, DMSO- d 6)δ 8.45 – 8.39 (m,1H).δ 7.75 (s, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.13 (s,1H), 6.93 (d, J = 1.9 Hz,1H), 4.34 (s, 3H), 3.91 (s, 6H), 3.51 (d, J = 6.4 Hz, 2H), 3.16 (d, J = 4.1 Hz,2H), 2.87 (t, J = 16.2 Hz,2H), 2.66 (s, 3H), 2.03 (m, 1H), 1.94 – 1.85 (m, 2H),1.59 (q, J = 12.4Hz, 2H). 13 C NMR (100 MHz, DMSO d 6 ) δ 158.5,154.0, 152.6, 148.5,146.2, 141.5, 137.2, 108.3, 107.2, 107.0, 102.4, 56.2,55.7, 53.0, 48.6, 45.2,42.5, 32.4, 27.1. (ESI) calculated for C 21 H 29 N 6 O 2 + [M+H] + : 397.2347, found:397.2349。

[0158] (6) The specific preparation method of compound 16 is as follows: Similar to the preparation method of compound 1, one of the raw materials used is compound (9-1), which is used in equimolar amount to replace (1-1) in the preparation method of compound 1. The other reaction raw material is biphenyl-2-boronic acid pinacol ester, which is used in equimolar amount to replace 5-methylfuranboronic acid pinacol ester in the preparation method of compound 1.

[0159] The NMR test results of compound 16 are as follows: 1 H NMR (400 MHz, CDCl 3 )δ 7.94 – 7.87 (m, 1H),7.52 (s, 1H), 7.48 – 7.38 (m, 3H), 7.28 (s, 1H), 7.22(t, J = 8.2 Hz, 3H), 7.17(t,J = 7.3 Hz, 3H), 4.03 (s, 3H), 3.98(s, 3H), 3.26 (d, J = 11.1 Hz, 2H), 2.87(t, J = 6.2 Hz, 2H),2.63 (s, 3H), 2.55 – 2.41 (m,2H), 1.79 (d, J = 13.3 Hz, 2H),1.65 (q, J = 12.6 Hz, 2H), 1.48 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ162.4, 158.3,154.3, 149.0, 146.8, 143.2, 141.1, 139.5, 130.8, 130.8, 129.6,129.3, 128.9,127.9, 127.5, 126.0, 115.8, 107.4, 107.2, 101.8, 57.2, 56.3,54.5, 45.2, 43.9,32.0, 27.3. (ESI) calculated for C 29 H 33 N 4 O 2 + [M+H] + : 469.2598, found: 469.2599。

[0160] (7) The specific preparation method of compound 17 is as follows: Similar to the preparation method of compound 1, one of the raw materials used is compound (9-1), which is used in equimolar amount to replace (1-1) in the preparation method of compound 1. The other reaction raw material is 1-cyclopentene boronic acid pinacol ester, which is used in equimolar amount to replace 5-methylfuran boronic acid pinacol ester in the preparation method of compound 1.

[0161] The NMR test results of compound 17 are as follows: 1 H NMR (400 MHz, CD 3 OD)δ 7.43 (s, 1H), 7.17(s, 1H), 6.86 (t, J = 2.3 Hz, 1H), 3.95 (s, 6H),3.56 (d, J = 6.6 Hz, 2H), 3.11 –2.74 (m, 4H), 2.58 (td, J= 7.3, 2.4 Hz, 2H), 2.16 – 1.97 (m, 4H), 1.90 – 1.85 (m, 1H), 1.82 (d, J = 12.8 Hz, 2H), 1.47 – 1.32 (m, 2H). 13 C NMR (100 MHz, CD 3 OD) δ 160.2, 160.0, 155.7, 150.0, 147.7, 145.8, 136.0, 108.6, 107.3, 102.6, 56.7, 56.5, 56.4, 47.3, 46.3, 36.4, 34.3, 33.4, 30.9, 24.6. (ESI) calculated for C 22 H 31 N 4 O 2 + [M + H] + : 383.2442, found: 383.2440。

[0162] (8) The specific preparation method of compound 18 is as follows: Similar to the preparation method of compound 1, one of the raw materials used is compound (9-1), which replaces (1-1) in the preparation method of compound 1 in equimolar amounts. The other reaction raw material is 1-cyclohexeneboronic acid pinacol ester, which replaces 5-methylfuranboronic acid pinacol ester in the preparation method of compound 1 in equimolar amounts.

[0163] The NMR test results of compound 18 are as follows: 1 H NMR (400 MHz, CD 3 OD) δ 7.56 (s, 1H), 7.22 (s, 1H), 7.18 – 7.13 (m, 1H), 3.98 (s, 6H), 3.69 (d, J = 6.7 Hz, 2H), 3.45 (dd, J = 13.0, 3.6 Hz, 2H), 2.91 (t, J = 11.0 Hz, 1H), 2.78 (s, 3H), 2.61 (q, J = 5.1, 4.2 Hz, 1H), 2.34 (dq, J = 6.4, 3.6 Hz, 2H), 2.15 (m, 1H), 2.05 (d, J= 19.0 Hz, 2H), 1.88 – 1.77 (m, 2H), 1.76 – 1.70 (m, 2H), 1.68 – 1.55 (m, 2H). 13 C NMR(100MHz, CD 3 OD) δ 161.2, 160.3, 156.6, 150.6, 136.4, 135.2, 108.0, 105.2, 103.0, 102.8, 56.9, 56.6, 55.5, 46.6, 44.1, 34.9, 29.0, 27.1, 26.4, 23.8, 23.0. (ESI) calculated for C 23 H 33 N 4 O 2 + [M + H] + : 397.2598, found: 397.2600。

[0164] (9) The specific preparation method of compound 19 is as follows: Similar to the preparation method of compound 1, one of the raw materials used is compound (9-1), which is used in an equimolar amount to replace (1-1) in the preparation method of compound 1. The other reaction raw material is 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester, which is used in an equimolar amount to replace 5-methylfuranboronic acid pinacol ester in the preparation method of compound 1.

[0165] The NMR test results of compound 19 are as follows: 1 H NMR (400 MHz, CD 3 OD) δ 7.48 (s, 1H), 7.16 (s, 1H), 7.04 – 6.97 (m, 1H), 4.01 (s, 4H), 3.96 (d, J = 2.1 Hz, 6H), 3.65 (d, J = 6.7 Hz, 2H), 3.43 (dt, J = 12.7, 3.3 Hz, 2H), 2.90 (dd, J = 12.5, 2.8 Hz, 2H), 2.84 (td, J = 7.4, 6.3, 1.7 Hz, 2H), 2.77 (s, 3H), 2.52 (dd, J = 4.2, 2.2 Hz, 2H), 2.15 – 2.09 (m, 1H), 2.03 (d, J= 16.9 Hz, 2H), 1.90 (t, J = 6.5 Hz, 2H),1.68 –1.56 (m, 2H). 13 C NMR (100 MHz, CD 3 OD) δ 161.0,160.2, 156.2, 150.4, 145.9,136.8, 130.8, 109.0, 108.3, 106.4, 102.8, 65.4,56.9, 56.5, 55.5, 46.4, 44.1,37.4, 34.9, 32.2, 29.0, 25.8. (ESI) calculatedfor C 25 H 35 N 4 O 4 + [M+H] + :455.2653,found: 455.2654.

[0166] (10) The specific preparation method of compound 20 is as follows: Compound 9-1 (200 mg, 0.516 mmol), 2 mL of triethylamine and 0.5 mL of DMF were added to a round-bottom flask in sequence, and argon was bubbled for 15 minutes. Then, cuprous iodide (CuI) (10 mg, 0.052 mmol) and tetrakistriphenylphosphine palladium (Pd(PPh)) were quickly added. 3 ) 4 ) (60 mg, 0.052 mmol), phenylacetylene (211 mg, 2.06 mmol) was added dropwise at 60 °C and reacted for 24 h. The reaction was monitored by TLC (DCM: MeOH = 8: 1). After the reaction was completed, the reaction solution was washed with saturated sodium chloride solution (10 mL), extracted with ethyl acetate (50 mL) three times, and the organic phase was concentrated and purified by neutral alumina column chromatography (DCM: MeOH = 100: 1) to obtain compound 20 (white solid, 100 mg, 47%).

[0167] The NMR test results of compound 20 are: 1 H NMR (400 MHz, DMSO- d 6 )δ 8.31 (s, 1H), 7.76 (s, 1H), 7.62 (dd, J = 6.7, 3.0 Hz, 2H), 7.46 (dd, J= 5.2, 2.0 Hz, 3H), 7.14 (s,1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.47 (t, J = 6.2 Hz, 2H), 3.23 (d, J = 11.6 Hz,2H), 2.69 (t, J = 10.0 Hz,2H), 2.57 (s, 3H), 2.03 – 1.92 (m, 1H), 1.88 (d, J =12.9 Hz, 2H), 1.54(q, J = 12.3 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 )δ 158.6, 154.0,148.9, 146.7, 146.1, 131.9, 121.5, 107.7, 106.9, 102.4, 90.5,82.6, 56.3,55.8, 53.3, 451, 43.1, 32.9, 27.5. (ESI) calculated for C 25 H 29 N 4 O 2 + [M+H] + :417.2285, found: 417.2284。

[0168] (11) The specific preparation method of Compound 21 is as follows: Similar to the preparation method of Compound 20, one of the raw materials used is p-methoxyphenylacetylene, which is used in an equimolar amount to replace phenylacetylene in the preparation method of Compound 20.

[0169] The NMR test results of Compound 21 are as follows: 1 H NMR (400 MHz, CD 3 OD)δ 7.57 (d, J = 8.8 Hz,2H), 7.51 (s, 1H), 7.03 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.98 (s, 3H), 3.96(s, 3H), 3.84 (s,3H), 3.63 (d, J= 6.9Hz, 2H), 3.53 – 3.45 (m, 2H), 3.04 – 2.91(m, 2H), 2.82 (s, 3H), 2.23 – 2.14(m, 1H), 2.09 (d, J = 15.4 Hz, 2H), 1.63 (q, J = 14.4, 12.7 Hz,2H). 13 C NMR (100 MHz, CD 3 OD) δ 162.2, 160.5, 156.4,151.1,148.8, 147.0, 134.8, 115.4, 115.0, 109.0, 106.7, 102.7, 89.0, 86.3,57.0,56.6, 55.9, 55.3, 46.2, 43.9, 34.3, 28.7. (ESI) calculated for C 24 H 31 N 4 O 3 + [M+H] + :447.2391, found: 447.2394。

[0170] (12) The specific preparation method of Compound 22 is as follows: Similar to the preparation method of Compound 20, one of the raw materials used is 3,5-dimethoxyphenylacetylene, which is used in an equimolar amount to replace phenylacetylene in the preparation method of Compound 20.

[0171] The NMR test results of Compound 22 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (s, 2H), 7.17(s, 1H), 6.78 (s, 2H), 6.47 (s, 1H), 4.05 (s, 3H), 3.95(s, 3H), 3.75 (s, 6H),3.63 (d, J = 7.1 Hz, 2H), 3.39 (d, J =11.1 Hz, 2H), 2.73 (m, 2H), 2.68 (s, 3H),2.21 (m, 1H), 2.11 (d, J =13.4 Hz, 2H), 1.91 (q, J = 12.4 Hz, 2H). 13 C NMR (100MHz,CDCl3 ) δ 160.6, 159.0, 154.6, 149.6, 147.6, 146.7, 123.6, 110.2, 108.5, 107.2, 102.8, 102.2, 89.5, 84.3, 57.3, 56.3, 55.6, 54.8, 45.6, 44.1, 32.7, 27.7. (ESI) calculated for C 27 H 33 N 4 O 4 + [M+H] + : 477.2496, found: 477.2494。

[0172] (13) The specific preparation method of compound 23 is as follows: Similar to the preparation method of compound 20, one of the raw materials used is 2-thiopheneacetylene, which is used to replace phenylacetylene in the preparation method of compound 20 in an equimolar amount.

[0173] The NMR test results of compound 23 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (s, 1H), 7.46 – 7.39 (m, 2H), 7.32 (d, J = 5.2 Hz, 1H), 7.18 (s, 1H), 7.01 (t, J = 4.5 Hz, 1H), 4.07 (s, 3H), 3.96 (s, 3H), 3.63 (t, J = 6.2 Hz, 2H), 3.39 (d, J = 10.2 Hz, 2H), 2.71 (m, 2H), 2.67 (s, 3H), 2.23 (m, 1H), 2.12 (d, J = 13.2 Hz, 2H), 1.92 (q, J = 11.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3) δ 159.0, 154.7, 149.7, 147.6, 146.7, 134.0, 128.6, 127.3, 122.5, 108.4, 107.4, 101.9, 93.8, 90.9, 57.3, 56.3, 54.9, 44.3, 32.8, 29.8, 27.8. (ESI) calculated for C 23 H 27 N 4 O 2 S + [M+H] + : 423.1849, found: 423.1848。

[0174] (14) The specific preparation method of compound 24 is as follows:

[0175] 1) Preparation of compound (24-1): Dissolve 2-chloro-4-amino-6,7-dimethoxyquinazoline (300 mg, 1.25 mmol, 1.5 eq), 1-methylpiperidine-4-carboxylic acid (267 mg, 1.88 mmol, 1.5 eq), DMAP (305 mg, 2.5 mmol, 2.0 eq), and EDCI (479 mg, 2.5 mmol, 2.0 eq) in DMF (4 mL), and react at room temperature for 12 h. Monitor with DCM:MeOH = 8:1. After the reaction is completed, extract with EA three times (10 mL × 3), back-extract with saturated brine three times (10 mL × 3), and separate by column chromatography on neutral alumina with DCM:MeOH = 100:1 to obtain compound 24-1 (white solid, 180 mg, 55%).

[0176] The NMR test results of compound (24-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (s, 1H), 7.15 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.18 (t, J = 9.4 Hz, 1H), 3.07 (d, J = 12.6 Hz, 2H), 2.41 (s, 3H), 2.29 (t, J = 11.8 Hz, 2H), 2.10 (d, J = 14.3 Hz, 2H), 1.99 (q, J = 11.2, 9.3 Hz, 2H). 1313C NMR (100 MHz, CDCl 3 ) δ 176.4, 157.0, 156.2, 153.9, 151.4, 150.1, 110.6, 106.4, 102.4, 56.5, 56.4, 55.0, 46.4, 42.8, 28.7. HRMS (ESI) calculated for C 17 H 22 ClN 4 O 3 + [M+H] + : 365.1375, found: 365.1373。

[0177] 2) Preparation of Compound 24: To a round-bottom flask were successively added Compound (24-1) (92 mg, 0.25 mmol, 1.0 eq), 1-cyclopentene-1-boronic acid pinacol ester (194 mg, 1.0 mmol, 4.0 eq), anhydrous potassium carbonate (K 2 2CO 3 3) (138 mg, 1.0 mmol, 4.0 eq). The reaction apparatus was purged with argon three times, and then PdCl 2 (dppf) (19 mg, 0.025 mmol, 0.1 eq) was added. The reaction apparatus was purged with argon three times again. Finally, 5 mL of a degassed 1,4-dioxane:water = 4:1 mixed solvent was injected. The reaction system was then placed in an 80 °C oil bath and reacted for 4 h. The reaction was monitored by TLC (DCM:MeOH = 6:1). After the reaction was completed, diatomaceous earth was added to a suction funnel to filter off the insoluble substances in the reaction solution. The reaction solution was washed with saturated sodium chloride solution (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was concentrated, and purified by silica gel column chromatography (DCM:MeOH = 25:1 to 10:1) to obtain Compound 24 (white solid, 86 mg, 53.3%).

[0178] The NMR test results of Compound 24 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 7.26 (s, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.47 (d, J J = 11.3 Hz, 2H), 3.22 (s, 1H), 2.97 (s, 2H), 2.87 (d, J= 6.1 Hz, 2H), 2.79 (s, 3H), 2.61 (t, J = 9.3 Hz, 2H), 2.25 (d, J = 14.1 Hz, 2H), 2.09 (q, J = 9.1, 7.5 Hz, 4H). 13 C NMR(100MHz, CD3OD) δ 176.1, 159.1, 157.7, 155.9, 151.3, 150.9, 145.0, 137.6, 112.6, 107.3, 105.7, 103.5, 56.7, 54.7, 44.1, 40.5, 34.5, 33.4, 27.6, 24.4. HRMS (ESI) calculated for C 22 H 29 N 4 O 3 + [M + H] + : 397.2234, found: 397.2230。

[0179] (15) The specific preparation method of compound 25 is as follows:

[0180] 1) Preparation of compound (25-1): Dissolve 4-aminomethyltetrahydropyran (167 mg, 1.45 mmol, 1.5 eq) in 3 mL of tetrahydrofuran (THF), add 6 drops of triethylamine (TEA), stir at room temperature for 10 minutes, then dissolve 2,4-dichloro-6,7-dimethoxyquinazoline (250 mg, 0.97 mmol, 1.0 eq) in 5 mL of THF, add dropwise to the above system, and stir at room temperature for 4 h. Monitor the reaction by TLC (PE:EA = 1:1). After the reaction is completed, concentrate the reaction solution and purify it by silica gel column chromatography (PE:EA = 3:1 to 2:1) to obtain compound (25-1) (pale yellow solid, 180 mg, 55%).

[0181] The NMR test results of compound (25-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.07 (s, 1H), 6.98 (s, 1H), 6.53 (t, J = 5.9 Hz, 1H), 3.91 (dd, J= 11.3, 4.1 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.50 (t, J = 6.2 Hz, 2H), 3.31 (t, J = 11.5 Hz, 2H), 2.03 – 1.88 (m, 1H), 1.65 (d, J = 13.2 Hz, 2H), 1.32 (qd, J = 12.2, 4.3 Hz, 2H). 13 C NMR(100MHz, CDCl 3 ) δ 160.3, 156.2 155.0, 149.1, 147.8, 106.9, 106.8, 100.3, 67.6, 56.2, 56.2, 47.1, 34.8, 30.8. HRMS (ESI) calculated for C 16 H 21 ClN 3 O 3 + [M + H] + : 338.1266, found: 338.1263。

[0182] 2) Preparation of Compound 25: Similar to the preparation method of Compound 24, one of the raw materials used is Compound ((25-1)), which is used in equimolar amount to replace (24-1) in the preparation method of Compound 24.

[0183] The NMR test results of Compound 25 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.20 (s, 1H), 7.02 (s, 1H), 6.91 (p, J = 2.3 Hz, 1H), 4.07 (dd, J = 13.5, 3.7 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.68 (s, 3H), 3.16 – 3.02 (m, 2H), 2.91 – 2.82 (m, 2H), 2.57 (tdd, J = 11.3, 9.5, 8.1, 3.6 Hz, 3H), 2.11 – 2.00 (m, 4H), 1.98 – 1.85 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) δ 175.2, 164.0, 158.0, 154.2, 149.5, 148.0, 144.8, 135.5, 110.1, 107.8, 103.1, 56.2, 56.0, 51.8, 49.4, 41.4, 33.5, 32.4, 28.1, 23.7. HRMS (ESI) calculated for C 22 H 28 N 3 O 4 + [M + H] + : 398.2074, found: 398.2072。

[0184] (16) The specific preparation method of compound 26 is as follows:

[0185] 1) Preparation of compound (26 - 1): Similar to the preparation method of compound (25 - 1), one of the raw materials used is 4 - piperidinecarboxylic acid, which replaces 4 - aminomethyltetrahydropyran in the preparation method of compound (25 - 1) in equimolar amounts.

[0186] The NMR test results of compound (26 - 1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.13 (s, 1H), 7.01 (s, 1H), 4.16 (d, J = 13.2 Hz, 2H), 3.96 (s, 4H), 3.95 (s, 3H), 3.71 (s, 3H), 3.27 – 3.12 (m, 3H), 2.64 (ddt, J = 14.5, 6.6, 3.3 Hz, 2H), 2.10 (d, J = 13.3 Hz, 2H), 2.04 – 1.88 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 174.9, 165.4, 155.2, 155.1, 150.8, 148.5, 109.5, 107.1, 103.3, 56.4, 56.2, 52.1, 49.4, 41.1, 28.1. HRMS (ESI) calculated for C 17 H 21 ClN 3 O 4 + [M + H]+ : 366.1215, found: 366.1213。

[0187] 2) Preparation of Compound 26: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (26-1), which is used in an equimolar amount to replace (24-1) in the preparation method of Compound 24.

[0188] The NMR test results of Compound 26 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.20 (s, 1H), 7.02 (s, 1H), 6.91 (p, J = 2.3 Hz, 1H), 4.07 (dd, J = 13.5, 3.7 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.68 (s, 3H), 3.16 – 3.02 (m, 2H), 2.91 – 2.82 (m, 2H), 2.57 (tdd, J = 11.3, 9.5, 8.1, 3.6 Hz, 3H), 2.11 – 2.00 (m, 4H), 1.98 – 1.85 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 175.2, 164.0, 158.0, 154.2, 149.5, 148.0, 144.8, 135.5, 110.1, 107.8, 103.1, 56.2, 56.0, 51.8, 49.4, 41.4, 33.5, 32.4, 28.1, 23.7. HRMS (ESI) calculated for C 22 H 28 N 3 O 4 + [M + H] + : 398.2074, found: 398.2072。

[0189] (17) The specific preparation method of Compound 27 is as follows: Compound 26 (100 mg, 0.25 mmol, 1.0 eq) is dissolved in THF:MeOH:H 2In O = 3 : 1 : 1, lithium hydroxide monohydrate (30 mg, 1.26 mmol, 5.0 eq) was added, and the reaction was carried out at room temperature for 4 h. Monitored by DCM:MeOH = 8 : 1, after the reaction was completed, the reaction solution was concentrated, acidified with 1N HCl / dioxane, concentrated under reduced pressure again, and triturated with diethyl ether to obtain compound 27 (white solid, 88 mg, 91.1%).

[0190] The NMR test results of compound 27 are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.16 (s, 1H), 7.08(s, 1H), 6.84 (t, J J = 2.3 Hz, 1H), 4.05 (dd, J J = 13.4, 3.7 Hz, 2H), 3.92 (s, 3H),3.90 (s, 3H), 3.18 – 3.08 (m, 2H), 2.79 – 2.73(m, 2H), 2.62 – 2.51 (m, 3H),1.98 (p, J J = 7.3 Hz, 4H), 1.80 (tt, J J = 11.2, 6.1 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) δ176.1, 163.3, 156.7, 154.2, 148.9, 148.0, 144.7, 134.6, 109.3, 107.6,103.5,56.0, 55.7, 49.0, 40.6, 33.1, 32.2, 27.9, 23.3. HRMS (ESI) calculatedfor C 21 H 24 N 3 O 4 + [M-H] + :382.1772, found: 382.1770。

[0191] (18)The specific preparation method of compound 28 is as follows:

[0192] 1) Preparation of compound (28-1): Similar to the preparation method of compound (25-1), one of the raw materials used was 4-(tert-butoxycarbonylamino)piperidine, which was used in an equimolar amount to replace 4-(aminomethyl)tetrahydropyran in the preparation method of compound (25-1).

[0193] The NMR test results of compound (28-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.01 (s, 1H), 6.90 (s, 1H), 4.65 (d, J = 7.8 Hz, 1H), 4.10 (d, J = 13.6 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.78 – 3.59 (m, 1H), 3.22 – 3.04 (m, 2H), 2.04 (d, J = 8.9 Hz, 2H), 1.63 – 1.48 (m, 2H), 1.36 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 155.1, 155.0, 154.8, 150.5, 148.2, 109.1, 106.8, 103.2, 79.4, 56.2, 55.9, 48.6, 32.3, 28.3. HRMS (ESI) calculated for C 20 H 28 ClN 4 O 4 + [M+H] + : 423.1794, found: 423.1793。

[0194] 2) Preparation of compound 28: The specific preparation method is as follows: Similar to the preparation method of compound 24, one of the raw materials used is compound (28-1), which is used in an equimolar amount to replace (24-1) in the preparation method of compound 24.

[0195] The NMR test results of compound 28 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.25 (d, J = 6.5 Hz, 1H), 7.02 (s, 1H), 6.95 (s, 1H), 4.56 (s, 1H), 4.08 (d, J = 13.2 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.72 (m, J = 9.4 Hz, 1H), 3.17 (t, J= 12.2 Hz, 2H), 2.86 (t, J = 7.9 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.03 (dt, J = 15.3, 10.0 Hz, 4H), 1.60 (q, J = 12.0 Hz, 2H), 1.42 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 163.7, 157.8, 155.2, 154.4, 149.4, 148.1, 144.6, 136.0, 109.8, 107.7, 103.4, 79.6, 56.3, 56.0, 48.8, 48.2, 33.6, 32.5, 32.5, 28.5, 23.8. HRMS (ESI) calculated for C 25 H 35 N 4 O 4 + [M + H] + : 455.2653, found: 455.2650。

[0196] (19) The specific preparation method of compound 29 is as follows: Compound 28 (100 mg, 0.22 mmol, 1.0 eq) was added to 2.2 mL of 4 N HCl / dioxane and hydrolyzed for 2 h to obtain the hydrochloride salt of compound 29 (white solid, 80 mg, 46.6%).

[0197] The NMR test results of compound 29 are as follows: 1 H NMR (400 MHz, D 2 O) δ 7.25 (q, J = 1.7 Hz, 1H), 7.08 (s, 1H), 7.01 (s, 1H), 4.81 (s, 1H), 3.97 (s, 4H), 3.95 (s, 4H), 3.67 (dd, J = 9.3, 5.0 Hz, 1H), 3.62 – 3.50 (m, 2H), 2.83 – 2.74 (m, 1H), 2.73 – 2.66 (m, 2H), 2.27 – 2.20 (m, 4H), 2.11 (p, J = 7.7 Hz, 3H), 1.74 (qd, J= 12.3, 3.9 Hz, 3H). 13 C NMR (100 MHz, D 2 O) δ 164.6, 155.8, 151.4, 147.9, 146.0, 137.5, 136.2, 105.4, 105.1, 98.9, 56.5, 56.2, 47.6, 47.4, 34.0, 31.17, 29.6, 22.7. HRMS (ESI) calculated for C 21 H 28 N 3 O 2 + [M + H] + : 354.2176, found: 354.2175。

[0198] (20) The specific preparation method of compound 30 is as follows:

[0199] 1) Preparation of compound (30 - 1): Similar to the preparation method of compound (25 - 1), one of the raw materials used is 4 - N - tert - butoxycarbonyl - 4 - N - methylaminopiperidine, which is used in an equimolar amount to replace 4 - aminomethyltetrahydropyran in the preparation method of compound (25 - 1).

[0200] The NMR test results of compound (30 - 1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.07 (d, J = 4.0 Hz, 1H), 6.97 (d, J = 4.0 Hz, 1H), 4.31 (d, J = 13.4 Hz, 2H), 3.92 (d, J = 4.2 Hz, 6H), 3.12 (t, J = 12.0 Hz, 2H), 2.73 (s, 3H), 1.94 – 1.68 (m, 5H), 1.42 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 164.8, 155.5, 155.1, 155.0, 150.7, 148.3, 109.2, 107.0, 103.4, 79.8, 56.3, 56.1, 52.6, 49.4, 29.3, 28.7, 28.5. HRMS (ESI) calculated for C 21H 30 ClN 4 O 4 + [M+H] + : 437.1950, found: 437.1953。

[0201] 2) Preparation of Compound 30: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (28-1), which is used in equimolar amount to replace (24-1) in the preparation method of Compound 24. After hydrolysis under the same conditions as Compound 29, Compound 30 is obtained.

[0202] The NMR test results of Compound 30 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 (s, 1H), 7.06(s, 1H), 6.93 (q, J = 22.2 Hz, 2H), 4.87 (s, 1H),4.17 (d, J = 12.9 Hz, 2H), 4.00(s, 3H), 3.96 (s, 3H), 3.09 (t, J = 12.5 Hz, 2H), 2.99 (q, J = 5.5, 4.6 Hz, 1H),2.88 (d, J = 7.8Hz, 2H), 2.63 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 2.23 (d, J =12.4Hz, 2H), 2.05 (p, J = 7.3 Hz, 2H), 1.92 (q, J = 11.8, 11.1Hz, 2H). 13 C NMR (100MHz, CDCl 3 ) δ 163.8, 158.1, 154.5,149.8, 148.3, 144.8, 135.7, 110.2, 108.0,103.2, 57.1, 56.4, 56.2, 48.6, 33.6,32.5, 31.5, 30.1, 23.8. HRMS (ESI) calculated for C 21 H 29 N 4 O 2 + [M+H]+ : 369.2285, found: 369.2281.

[0203] (21) The specific preparation method of compound 31 is as follows:

[0204] 1) Preparation of compound (31-1): Similar to the preparation method of compound (25-1), one of the raw materials used is N-cyclopropylpiperidin-4-amine hydrochloride, which is used in equimolar amounts to replace 4-aminomethyltetrahydropyran in the preparation method of compound (25-1).

[0205] The NMR test results of compound (31-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 (s, 1H), 7.04 (s, 1H), 4.23 (dd, J = 13.4, 3.9 Hz, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 3.20 (t, J = 12.6 Hz, 2H), 3.02 (tt, J = 9.8, 3.8 Hz, 1H), 2.25 (dq, J = 6.0, 3.2, 2.8 Hz, 1H), 2.18 (d, J = 16.6 Hz, 2H), 1.68 (q, J = 10.1, 9.4 Hz, 2H), 0.56 (q, J = 5.9, 4.9 Hz, 2H), 0.53 – 0.47 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 174.0, 165.2, 155.2, 150.8, 148.5, 109.6, 107.2, 103.6, 56.4, 56.2, 55.8, 48.8, 32.4, 28.2, 6.3. HRMS (ESI) calculated for C 18 H 24 ClN 4 O 2 + [M + H] + : 363.1582, found: 363.1583.

[0206] 2) The NMR test results of compound 31 are as follows: 11H NMR (400 MHz, CD 3 OD) δ 7.24 (s, 1H), 7.14(s, 1H), 6.93 (t, J J = 2.3 Hz, 1H), 4.30 (d, J J = 13.0 Hz, 2H), 3.97 (s, 3H), 3.95(s, 3H), 3.21 (d, J J = 12.0 Hz, 2H),3.15 (t, J J = 5.6 Hz, 1H), 2.86 (td, J J = 7.6, 2.5Hz, 2H), 2.63 –2.55 (m, 2H), 2.45 (tt, J J = 7.2, 3.8 Hz, 1H), 2.18 (d, J J = 8.9Hz,2H), 2.06 (p, J J = 7.6 Hz, 2H), 1.71 (qd, J J = 12.2, 3.9 Hz,2H), 0.73 – 0.65 (m,2H), 0.61 – 0.55 (m, 2H). 13 13C NMR (100 MHz, CD 3 OD) δ 164.8, 158.9, 156.3, 150.1,149.8, 145.3, 137.0, 110.8, 107.3, 104.8, 57.4,56.5, 49.6, 34.3, 33.3, 32.0,30.8, 28.8, 24.6, 5.5. HRMS (ESI) calculated forC 23 H 31 N 4 O 2 + [M+H] + : 395.2442,found: 395.2443。

[0207] (22) The specific preparation method of compound 32 is as follows:

[0208] 1) Preparation of compound (32-1): Compound 29 (114 mg, 0.25 mmol, 1.0 eq) was dissolved in 2 mL of MeOH and reacted at 64 °C for 3 h. Then, sodium triacetoxyborohydride was dissolved in 1 mL of MeOH, and the resulting solution was added dropwise to the above reaction system, and the reaction was continued for 6 h. The reaction was monitored by DCM:MeOH = 9:1. After the reaction was completed, it was extracted with DCM (10 mL × 3) and water. The organic phase was dried and concentrated, and silica gel column chromatography (DCM:MeOH = 20:1) was used to obtain compound 32-1 (white solid, 65 mg, 59.6%).

[0209] 2) Preparation of compound 32: Similar to the preparation method of compound 24, one of the starting materials used was compound (32-1), which was used in an equimolar amount to replace (24-1) in the preparation method of compound 24.

[0210] The NMR test results of compound 32 are as follows: 1 H NMR (400 MHz, CD 3 OD)δ 7.48 – 7.33 (m, 5H),7.24 (s, 1H), 7.15 (s, 1H), 6.93 (p, J = 2.3 Hz, 1H),4.32 (d, J = 12.2 Hz, 2H),4.08 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H),3.26 – 3.12 (m, 3H), 2.86 (td, J =7.7, 2.2 Hz, 2H), 2.64 – 2.54 (m,2H), 2.19 (d, J = 8.9 Hz, 2H), 2.06 (p, J = 7.6Hz, 2H), 1.80(qd, J = 12.2, 3.9 Hz, 2H). 13 C NMR (100 MHz, CD 3 OD)δ 164.7, 158.9,156.3, 150.3, 149.8, 145.3, 136.9, 136.5, 130.3, 130.0, 129.5,110.8, 107.5,104.8, 56.5, 56.4, 50.3, 49.2, 34.3, 33.3, 31.1, 24.6. HRMS (ESI)calculatedfor C 27 H33 N 4 O 2 + [M+H] + : 445.2598, found: 445.2599。

[0211] (23) The specific preparation method of compound 33 is as follows:

[0212] 1) Preparation of compound (33-1): Similar to the preparation method of compound (25-1), one of the raw materials used is 4-dimethylaminopiperidine, which is used in an equimolar amount to replace 4-aminomethyltetrahydropyran in the preparation method of compound (25-1).

[0213] The NMR test results of compound (33-1) are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.15 (s, 1H), 7.11 (s, 1H), 4.25 (d, J = 12.9 Hz, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.20 – 3.09 (m, 2H), 2.27 (s, 6H), 2.16 (s, 1H), 1.92 (d, J = 9.1 Hz, 2H), 1.66 – 1.53 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 163.9, 154.8, 153.8, 150.0, 147.9, 108.4, 106.6, 104.0, 61.4, 56.0, 55.7, 48.3, 41.3, 27.8. HRMS (ESI) calculated for C 17 H 24 ClN 4 O 2 + [M+H] + : 351.1582, found: 351.1583。

[0214] 2) Preparation of compound 33: Similar to the preparation method of compound 24, one of the raw materials used is compound (33-1), which is used in an equimolar amount to replace (24-1) in the preparation method of compound 24.

[0215] The NMR test results of compound 33 are as follows: 11H NMR (400 MHz, CDCl 3 ) δ 7.25 (s, 1H), 7.06(s, 1H), 6.94 (t, J J = 2.2 Hz, 1H), 4.29 – 4.21 (m,2H), 4.00 (s, 3H), 3.97 (s,3H), 3.12 – 3.02 (m, 2H), 2.89 (tq, J J = 6.8,2.1 Hz, 2H), 2.80 – 2.70 (m, 1H),2.59 (tt, J J = 7.5, 2.5 Hz, 2H), 2.51(s, 6H), 2.12 (d, J J = 10.2 Hz, 2H), 2.06 (q, J J = 8.6, 8.1 Hz,2H), 1.84 (qd, J J = 12.1, 3.8 Hz, 2H). 13 13C NMR (100 MHz, CDCl 3 ) δ163.6, 158.0, 154.5, 149.7, 148.3, 144.8, 135.8, 110.0, 107.9, 103.2, 63.2,56.4, 56.2, 49.1, 41.0, 33.6, 32.5, 27.7, 23.8. HRMS (ESI) calculated forC 22 H 31 N 4 O 2 + [M+H] + :383.2442, found: 383.2444。

[0216] (24) The specific preparation method of Compound 34 is as follows:

[0217] 1) Preparation of Compound (34-1): Similar to the preparation method of Compound (25-1), one of the raw materials used is 4-diethylaminopiperidine, which is used in equimolar amount to replace 4-aminomethyltetrahydropyran in the preparation method of Compound (25-1).

[0218] The NMR test results of Compound (34-1) are as follows: 1 1H NMR (400 MHz, CDCl 3 ) δ 7.13 (s, 1H),7.03 (s, 1H), 4.32 (d,J = 10.9 Hz, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.08 (t, J = 11.6 Hz, 2H), 2.82 (tt, J = 11.3, 3.7Hz, 1H), 2.62 (q, J = 7.1 Hz, 4H), 1.95 (d, J = 12.0 Hz, 2H), 1.71 (qd, J = 12.4, 3.8 Hz, 2H), 1.06 (t, J = 7.1 Hz, 6H). 13 C NMR(100 MHz, CDCl 3 ) δ 165.0, 155.2, 155.1, 150.7, 148.3, 109.4, 107.1, 103.7, 58.1, 56.4, 56.2, 49.7, 43.5, 28.9, 13.5. HRMS (ESI) calculated for C 19 H 28 ClN 4 O 2 + [M + H] + : 379.1895, found: 379.1893。

[0219] 2) Preparation of Compound 34: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (34-1), which is used in equimolar amount to replace (24-1) in the preparation method of Compound 24.

[0220] The NMR test results of Compound 34 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 (s, 1H), 7.05 (s, 1H), 6.94 (s, 1H), 4.27 (d, J = 12.9 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.27 – 3.15 (m, 1H), 3.07 (t, J = 12.6 Hz, 2H), 2.99 – 2.86 (m, 6H), 2.58 (t, J = 8.7 Hz, 2H), 2.16 (d, J= 8.8 Hz, 2H), 2.05 (p, J = 7.4 Hz, 2H), 1.97 (d, J = 11.9 Hz, 2H), 1.33 (t, J = 7.1 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 163.4, 157.9, 154.4, 149.6, 148.3, 144.7, 135.6, 109.9, 107.8, 103.0, 59.3, 56.3, 56.1, 49.2, 44.0, 33.5, 32.4, 27.2, 23.7, 11.4. HRMS (ESI) calculated for C 24 H 35 N 4 O 2 + [M + H] + : 411.2755, found: 411.2752。

[0221] (25) The specific preparation method of Compound 35 is as follows:

[0222] 1) Preparation of Compound (35 - 1): Similar to the preparation method of Compound (25 - 1), one of the raw materials used is 4-(1 - pyrrolidinyl)piperidine, which is used in an equimolar amount to replace 4 - aminomethyltetrahydropyran in the preparation method of Compound (25 - 1).

[0223] The NMR test results of Compound (35 - 1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.14 (s, 1H), 7.03 (s, 1H), 4.21 (d, J = 13.3 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.18 – 3.10 (m, 2H), 2.63 (d, J = 5.9 Hz, 4H), 2.31 (tt, J = 9.6, 3.8 Hz, 1H), 2.09 (d, J = 12.9 Hz, 2H), 1.81 (d, J = 3.6 Hz, 4H), 1.79 – 1.69 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) δ165.3, 155.2, 155.2, 150.7, 148.5, 109.6, 107.1, 103.5, 61.8, 56.4, 56.1, 51.7, 48.8, 31.7, 23.3. HRMS (ESI) calculated for C 19 H 26 ClN 4 O 2 + [M+H] + : 377.1739, found: 377.1741。

[0224] 2) Preparation of Compound 35: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (35-1), which is used in equimolar amount to replace (24-1) in the preparation method of Compound 24.

[0225] The NMR test results of Compound 35 are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.16 (s, 1H), 7.09(s, 1H), 6.84 (t, J J = 2.3 Hz, 1H), 4.08 (d, J J = 12.9 Hz, 2H), 3.92 (s, 3H), 3.89(s, 3H), 3.39 - 3.28 (m, 2H), 3.09 (t, J J = 22.6 Hz, 2H), 2.78 (t, J J = 6.9 Hz, 2H),2.72 - 2.57 (m, 2H), 2.58 – 2.51(m, 3H), 1.99 (q, J J = 8.4, 7.7 Hz, 4H), 1.78 –1.70 (m, 4H), 1.69 - 1.61(m, 2H). 13 C NMR (100 MHz, DMSO- d 6) δ 163.3, 157.1, 154.5, 149.2, 148.2, 145.0, 134.9, 109.6, 107.9, 103.9, 61.6, 56.3, 56.0, 51.2, 48.4, 39.9, 33.4, 32.5, 30.6, 23.6, 23.3. HRMS (ESI) calculated for C 24 H 33 N 4 O 2 + [M + H] + : 409.2598, found: 409.2596。

[0226] (26) The specific preparation method of compound 36 is as follows:

[0227] 1) Preparation of compound (36 - 1): Similar to the preparation method of compound (25 - 1), one of the raw materials used is 4 - piperidinylpiperidine, which replaces 4 - aminomethyltetrahydropyran in the preparation method of compound (25 - 1) in equimolar amounts.

[0228] The NMR test results of compound (36 - 1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.11 (s, 1H), 7.00 (s, 1H), 4.28 (d, J = 12.9 Hz, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.06 (t, J = 11.7 Hz, 2H), 2.54 (t, J = 5.4 Hz, 4H), 2.49 (d, J = 3.7 Hz, 1H), 1.99 (d, J = 12.9 Hz, 2H), 1.72 (qd, J = 12.2, 3.7 Hz, 2H), 1.59 (t, J = 5.8 Hz, 4H), 1.43 (q, J = 6.1 Hz, 2H). 13 C NMR (100 MHz, CDCl 3) δ 165.0, 155.1, 155.1, 150.7, 148.3, 109.4, 107.0, 103.6, 62.6, 56.3, 56.1, 50.5, 49.5, 28.3, 26.3, 24.7. HRMS (ESI) calculated for C 20 H 27 ClN 4 O 2 + [M + H] + : 390.1823, found: 390.1821。

[0229] 2) Preparation of Compound 36: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (36 - 1), which is used in equimolar amount to replace (24 - 1) in the preparation method of Compound 24.

[0230] The NMR test results of Compound 36 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (s, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 4.23 (d, J = 13.0 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.02 (t, J = 12.7 Hz, 2H), 2.89 (d, J = 7.7 Hz, 2H), 2.65 (m, 4H), 2.58 (d, J = 6.2 Hz, 3H), 2.06 (q, J = 6.6, 6.0 Hz, 4H), 1.82 (q, J = 12.1, 10.3 Hz, 2H), 1.69 (t, J = 5.8 Hz, 4H), 1.49 (q, J = 7.5, 6.5 Hz, 2H). 13 C NMR (100 MHz, CDCl 3) δ 163.8, 158.2, 154.3, 149.7, 148.1, 144.9, 135.5, 110.1, 107.9, 103.4, 63.3, 56.3, 56.1, 50.5, 49.6, 33.6, 32.5, 28.1, 26.0, 24.6, 23.8. HRMS (ESI) calculated for C 24 H 35 N 4 O 2 + [M + H] + : 423.2755, found: 423.2757。

[0231] (27) The specific preparation method of compound 37 is as follows:

[0232] 1) Preparation of compound (37 - 1): Similar to the preparation method of compound (25 - 1), one of the raw materials used is 4-(4 - piperidinyl)morpholine, which replaces 4 - aminomethyltetrahydropyran in the preparation method of compound (25 - 1) in equimolar amounts.

[0233] The NMR test results of compound (37 - 1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.14 (s, 1H), 7.02 (s, 1H), 4.29 (d, J = 13.0 Hz, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.73 (t, J = 4.6 Hz, 4H), 3.12 (t, J = 12.7 Hz, 2H), 2.59 (t, J = 4.6 Hz, 4H), 2.53 – 2.41 (m, 1H), 2.04 (d, J = 12.9 Hz, 2H), 1.77 – 1.63 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 165.1, 155.2, 150.8, 148.5, 109.5, 107.2, 103.5, 67.4, 62.0, 56.4, 56.2, 50.1, 49.2, 28.6. HRMS (ESI) calculated for C 19 H 25 ClN 4O 2 + [M+H] + : 392.1615, found: 392.1611。

[0234] 2) Preparation of Compound 37: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (37-1), which is used in an equimolar amount to replace (24-1) in the preparation method of Compound 24.

[0235] The NMR test results of Compound 37 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (s, 1H), 7.08 (s, 1H), 6.94 (p, J = 2.3 Hz, 1H), 4.21 (d, J = 13.1 Hz, 2H), 4.00 (s, 3H), 3.96 (s, 3H), 3.75 (t, J = 4.6 Hz, 4H), 3.04 (t, J = 11.6 Hz, 2H), 2.90 (td, J = 7.5, 2.2 Hz, 2H), 2.64 – 2.60 (m, 4H), 2.60 – 2.56 (m, 2H), 2.44 (tt, J = 11.1, 3.8 Hz, 1H), 2.04 (td, J = 13.2, 11.3, 5.5 Hz, 4H), 1.74 (qd, J = 12.1, 3.8 Hz, 2H). 13 C NMR(100 MHz, CDCl 3 ) δ 163.9, 158.2, 154.3, 149.7, 148.1, 145.0, 135.5, 110.2, 108.0, 103.4, 69.4, 62.4, 56.3, 56.1, 50.1, 49.3, 33.6, 32.5, 28.7, 23.8. HRMS(ESI) calculated for C 24 H 33 N 4 O 3 + [M+H] + : 425.2547, found: 425.2546。

[0236] (28) The specific preparation method of Compound 38 is as follows:

[0237] 1) Preparation of Compound (38-1): Similar to the preparation method of Compound (25-1), one of the raw materials used is 1-(1-methyl-4-piperidyl)piperazine, which is used in an equimolar amount to replace 4-aminomethyltetrahydropyran in the preparation method of Compound (25-1).

[0238] The NMR test results of Compound (38-1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (s, 1H), 6.98 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.72 (t, J = 4.8 Hz, 4H), 2.87 (d, J = 11.5 Hz, 2H), 2.68 (t, J = 4.8 Hz, 4H), 2.28 (dd, J = 11.4, 3.8 Hz, 1H), 2.22 (s, 3H), 1.91 (t, J = 22.4Hz, 2H), 1.77 (d, J = 12.5 Hz, 2H), 1.67 – 1.50 (m, 2H). 13 CNMR (100 MHz, CDCl 3 ) δ 164.5, 155.0, 155.0, 150.8, 148.2, 109.0, 107.0, 103.6, 61.5, 56.3, 56.1, 55.3, 49.9, 49.0, 46.1, 28.1. HRMS (ESI) calculated for C 20 H 29 ClN 5 O 2 + [M + H] + : 406.2004, found: 406.2001.

[0239] 2) Preparation of Compound 38: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (38-1), which is used in an equimolar amount to replace (24-1) in the preparation method of Compound 24.

[0240] The NMR test results of Compound 38 are as follows: 1 H NMR (400 MHz, CD3 OD) δ 7.21 (s, 1H), 7.10(s, 1H), 6.91 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.67(t, J = 4.8 Hz, 4H),2.95 (d, J = 11.5 Hz, 2H), 2.85 (t, J = 8.4 Hz, 1H), 2.81 – 2.75 (m, 4H), 2.74(m, 1H), 2.58 (t, J = 8.1 Hz,2H), 2.27 (s, 3H), 2.05 (t, J = 11.4 Hz, 4H), 1.94(t, J = 12.3Hz, 2H), 1.62 (td, J = 12.1, 3.7 Hz, 2H). 13 C NMR (100 MHz,CD 3 OD) δ164.7, 159.0, 156.2, 150.3, 149.7, 145.4, 136.8, 110.8,107.6, 104.7, 62.6,56.5, 56.5, 56.0, 50.6, 50.3, 46.0, 34.3, 33.3, 28.9, 24.6.HRMS (ESI)calculated for C 25 H 36 N 5 O 2 + [M+H] + :425.2547, found: 425.2546。

[0241] (29) The specific preparation method of compound 39 is as follows:

[0242] 1) Preparation of compound (39-1): Similar to the preparation method of compound (25-1), one of the raw materials used is N,N,N'-trimethylethylenediamine, which is used in equimolar amount to replace 4-aminomethyltetrahydropyran in the preparation method of compound (25-1).

[0243] The NMR test results of compound (39-1) are as follows: 1 H NMR (400 MHz, CDCl 3) δ 7.45 (s, 1H), 7.13 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.79 (t, J = 6.8 Hz, 2H), 3.34 (s, 3H), 2.72 (t, J = 6.8 Hz, 2H), 2.30 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 163.7, 155.1, 154.7, 151.0, 147.8, 108.7, 107.2, 104.8, 57.0, 56.4, 56.3, 52.2, 46.2, 39.9. HRMS (ESI) calculated for C 15 H 22 ClN 4 O 2 + [M + H] + : 325.1426, found: 325.1423。

[0244] 2) Preparation of Compound 39: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (39 - 1), which is used in equimolar amount to replace (24 - 1) in the preparation method of Compound 24.

[0245] The NMR test results of Compound 39 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (s, 1H), 7.30 (s, 1H), 6.95 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.86 (t, J = 7.0 Hz, 2H), 3.34 (s, 3H), 2.90 (q, J = 6.8, 6.4 Hz, 8H), 2.59 (ddt, J = 7.7, 5.2, 2.3 Hz, 2H), 2.44 (s, 6H), 2.05 (p, J = 7.5 Hz, 2H). 13 C NMR (100 MHz, CDCl 3) δ 162.6, 157.3, 154.2, 149.6, 147.6, 144.5, 135.7, 109.2, 107.6, 104.5, 56.4, 56.3, 50.7, 45.6, 40.6, 33.7, 32.6, 29.8, 23.8. HRMS (ESI) calculated for C 20 H 29 N 4 O 2 + [M + H] + : 357.3775, found: 357.4776。

[0246] (30) The specific preparation method of compound 40 is as follows:

[0247] 1) Preparation of compound (40 - 1): Similar to the preparation method of compound (25 - 1), one of the raw materials used is N,N - dimethyl - 1,3 - diaminopropane, which replaces 4 - aminomethyltetrahydropyran in the preparation method of compound (25 - 1) in an equimolar amount.

[0248] The NMR test results of compound (40 - 1) are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (s, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.75–3.70 (m, 2H), 2.62 (t, J = 10.8 Hz, 2H), 2.38 (s, 6H), 1.84 (p, J = 5.6 Hz, 2H). 13 C NMR (100MHz, CDCl 3 ) δ 160.2, 156.8, 154.6, 148.8, 147.6, 107.4, 107.3, 100.3, 60.3, 56.3, 56.0, 45.8, 43.3, 24.1. HRMS (ESI) calculated for C 15 H 22 ClN 4 O 2 + [M + H] + : 325.1426, found: 325.1424。

[0249] 2) Preparation of Compound 40: Similar to the preparation method of Compound 24, one of the raw materials used is Compound (40-1), which is used in equimolar amount to replace (24-1) in the preparation method of Compound 24.

[0250] The NMR test results of Compound 40 are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.17(s, 1H), 6.91 (s, 1H), 6.88 (s, 1H), 3.95 (s, 5H), 3.93(s, 6H), 3.75 (q, J =5.5 Hz, 2H), 2.89 (t, J = 6.2 Hz, 2H), 2.56(t, J = 5.9 Hz, 4H), 2.34 (s, 6H),2.03 (p, J = 7.5 Hz, 2H), 1.85(p, J = 5.6 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ159.2,158.4, 153.8, 148.2, 147.0, 145.3, 134.9, 108.0, 107.6, 100.3, 59.9,56.2,55.9, 45.7, 42.1, 33.5, 32.6, 25.0, 23.8. HRMS (ESI) calculated for C 20 H 29 N 4 O 2 + [M+H] + :357.3775, found: 357.4777。

[0251] Example 12

[0252] In this example, the CCK-8 method was used to detect the in vitro cell anti-proliferation activity of the quinazoline derivatives in Examples 1-40 above, with azacitidine (5-Aza) as the positive control.

[0253] To visually compare the differences in cell proliferation inhibition of quinazoline derivatives, the IC 50 was divided into four categories: 2 μM < IC 50 < 10 μM (+), 500 nM < IC 50 < 2 μM (++), 100 nM < IC50 <500 nM(+++), IC 50 <100nM (++++). The detection results are shown in Table 1 below:

[0254] Table 1 Results of cell anti-proliferation test

[0255] Quinazoline derivative Kasumi-1 IC50 (μM) SKNO-1 IC50 (μM) Quinazoline derivative Kasumi-1 IC50 (μM) SKNO-1 IC50 (μM) 5-Aza +++ ++ 21 +++ ++ 1 ++ ++ 22 +++ + 2 ++ ++ 23 +++ ++ 3 ++ ++ 24 + ++ 4 + + 25 + ++ 5 + + 26 ++ ++ 6 ++ ++ 27 + + 7 + + 28 ++ ++ 8 + + 29 ++++ +++ 9 ++++ +++ 30 + ++ 10 + + 31 +++ +++ 11 + + 32 +++ ++ 12 +++ ++ 33 ++++ +++ 13 +++ +++ 34 +++ ++ 14 + + 35 ++ + 15 + + 36 ++ + 16 + + 37 +++ + 17 ++++ ++++ 38 +++ +++ 18 ++++ +++ 39 + + 19 +++ +++ 40 + ++ 20 +++ ++

[0256] The enzyme activity of the quinazoline derivatives in Examples 1 - 40 above was detected using a bioluminescence-based MTase-Glo™ Assay detection system.

[0257] By monitoring the formation of the reaction product S-adenosylhomocysteine (SAH), the activities of various methyltransferases (DNMT1, DNMT3A, DNMT3B) were monitored. The fluorescence value was measured using a plate reader luminometer, and the inhibition curve of the quinazoline derivative was plotted and the IC of the quinazoline derivative was obtained using a non-linear fitting formula 50 (half inhibitory concentration). To more intuitively compare the differences in the enzyme activities of the quinazoline derivatives, the IC 50 was divided into four categories: 1 μM < IC 50 < 10 μM (+), 500 nM < IC 50 < 1μM (++), 100 nM < IC 50 < 500 nM (+++), IC 50 < 100 nM (++++). The detection results are shown in Table 2 below:

[0258] Table 2 Results of enzyme activity test

[0259] Quinazoline derivative DNMT1 IC50 DNMT3A IC50 DNMT3B IC50 1 + + + 2 + + ++ 3 + ++ + 4 ++ + + 5 ++ + ++ 6 + ++ + 7 ++ ++ ++ 8 ++ ++ ++ 9 +++ + ++ 10 + ++ + 11 ++ + + 12 +++ + + 13 +++ +++ +++ 14 ++ +++ ++ 15 +++ ++ +++ 16 + + + 17 ++++ + + 18 ++++ ++ +++ 19 +++ + + 20 +++ + + 21 ++ + +++ 22 ++ +++ +++ 23 ++ ++ ++ 24 ++ + + 25 +++ + + 26 +++ ++ ++ 27 +++ +++ + 28 + + + 29 ++++ ++ + 30 ++++ ++ ++ 31 ++++ + + 32 +++ ++ ++ 33 ++++ + ++ 34 ++++ ++ ++ 35 ++++ + ++ 36 ++++ ++ +++ 37 +++ +++ ++ 38 ++ + + 39 ++ + + 40 +++ + +++

[0260] As shown in Table 1 and Table 2 above, the results indicate that the quinazoline derivatives 1 - 40 of the present invention have the effect of highly selectively inhibiting the protease activity of DNMT1, and have a certain inhibitory effect on the proliferation of two leukemia cells (Kasumi-1 and SKNO-1). Among them, the quinazoline derivative 17 has the best activity and subsequent test evaluations were carried out.

[0261] Example 13

[0262] The in vivo anti-tumor activity of the quinazoline derivative 17 was detected in this example.

[0263] By constructing a mouse MV-4-11 cell xenograft tumor model, 1×10 6 cells were subcutaneously injected into each mouse, and when the tumor volume grew to 50 - 100 mm 3At about 14:00 p.m., the mice were randomly divided into three groups: control group, 5-Aza group, and 17 group, with 5 mice in each group. The 5-Aza group was intraperitoneally injected with 3 mg / kg daily, the 17 group was intraperitoneally injected with 40 mg / kg daily, and the blank control group was intraperitoneally injected with the same dose of saline daily. The drug was administered for 17 consecutive days, and the tumor volume and mouse body weight were measured every day. After the drug administration, the mice were euthanized and the weight and volume of the tumor and spleen were measured.

[0264] The results showed that Figure 1 (A) It can be seen that the body weights of mice in group 17 and the control group were not much different and fluctuated within the normal range, indicating that quinazoline derivatives have low toxicity. Figure 1 (B) and anatomy Figure 1 (C) and (D) show that the tumor growth of mice was significantly inhibited after administration, and the tumor inhibition effect of group 17 was better than that of the 5-Aza group. In addition, the spleen is a hematopoietic organ. When the white blood cell count of leukemia patients increases abnormally, the liver, spleen, and lymph nodes will swell. Figure 1 (E) and (F) show that after treatment with quinazoline derivative 17, the size and weight of the mouse spleen decreased, and the effect was better than that of the 5-Aza group. These results indicate that quinazoline derivative 17 can inhibit the proliferation of MV-4-11 cells in vivo and thus inhibit the growth of mouse tumors, and can effectively alleviate splenomegaly, and has a certain therapeutic effect on AML.

[0265] The above is only a preferred embodiment of the present invention. The present invention is not limited to the above implementation. As long as the technical effect of the present invention is achieved by the same means, it should belong to the protection scope of the present invention. Within the protection scope of the present invention, its technical scheme and / or implementation method can have various modifications and changes.

Claims

1. A quinazoline derivative, characterized in that, its structure is any one of the following compounds: 。 2. The quinazoline derivative according to claim 1, characterized in that, its structure is as shown in Compound 17: Compound 17.

3. Use of the quinazoline derivative according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 1 inhibitor.

4. The use according to claim 3, characterized in that, the DNA methyltransferase 1 inhibitor can be used in the preparation of a drug for treating diseases related to abnormal DNA methyltransferase 1.

5. The use according to claim 4, characterized in that, the related diseases are leukemia and myelodysplastic syndrome.

6. A pharmaceutical composition, characterized in that, it comprises the quinazoline derivative according to claim 1 or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, characterized in that, the pharmaceutical composition contains at least one of excipients.

8. The pharmaceutical composition according to claim 7, characterized in that, the excipient is at least one of gum arabic, syrup, lanolin, and starch.

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