Selective PCMT1 small-molecule inhibitor as well as preparation method and application thereof

Abstract

The invention relates to the technical field of biological medicine, in particular to a selective PCMT1 small-molecule inhibitor as well as a preparation method and application thereof. The invention provides a compound with a chemical structural formula as shown in a formula (I) or an optical isomer, a racemate, a single enantiomer and a possible diastereoisomer of the compound. The preparation method comprises the following steps: carrying out a Betti reaction on a raw material a containing a quinoline ring, an aldehyde compound b and an amine compound c in the absence of a solvent at 80-100 DEG C to obtain the compound as shown in the formula (I). The compound with the chemical structural formula as shown in the formula (I) provided by the invention has an A ring and R1-R4 substituent groups, and the compound with a brand new structure can fill the blank of systematic selective PCMT1 inhibitor development.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a selective PCMT1 small molecule inhibitor and a preparation method and application thereof. BACKGROUND

[0002] Protein-L-isoaspartate (D-aspartate)-methyltransferase (PCMT1 or PIMT) is an important protein repair enzyme, which mainly catalyzes the conversion of abnormal L-isoaspartate (L-isoAsp) and D-aspartate (D-Asp) in proteins into normal L-aspartate (L-Asp), thereby repairing damaged proteins, maintaining the structural integrity of proteins and regulating their functions. PCMT1 is believed to play a key role in maintaining protein homeostasis and regulating various biological processes in cells, especially in tumor cells, and its repair function may have an important impact on the occurrence and development of cancer. Therefore, PCMT1 is considered as a potential target for tumor treatment. However, so far, no selective PCMT1 inhibitor has been found, which limits our in-depth study of its biological functions and clinical applications.

[0003] Therefore, designing and synthesizing molecules with cell membrane permeability and specific inhibition of PCMT1 activity is not only the key to studying the mechanism of PCMT1 in cells, but also provides an important research basis and value for its potential application in disease treatment. SUMMARY

[0004] The technical problem to be solved by the present application is the lack of research on selective PCMT1 inhibitors in the prior art. To this end, the present application provides a selective PCMT1 small molecule inhibitor and a preparation method and application thereof.

[0005] To achieve the above purpose, the present application provides a compound or its optical isomer, racemate, single enantiomer, possible diastereoisomer, whose chemical structural formula is shown in formula (I) as follows: Wherein: represents the chiral position of the compound; A ring is selected from any one of 3-10 membered carbocyclic group, 4-10 membered heterocycloalkyl group, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; The selection of R1 and R2 has the following two schemes: Scheme one: R1 and R2 are the same or different and each is selected from any one of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, and optionally substituted heteroaryl; ​Option 2: R1 and R2 together with the nitrogen atoms bonded to them form 5- to 8-membered rings that can optionally contain other heteroatoms, either saturated or unsaturated, and optionally substituted. R3 and R4 may be the same or different and are each selected from: hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, sulfonic acid (-SO3H), optionally substituted amino carbonyl, optionally substituted amino sulfonyl, optionally substituted amino, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxy carbonyl, optionally substituted acyloxy, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl.

[0006] Preferably, in compounds with the chemical structural formula shown in formula (I), the carbocyclic group, heterocyclic hydrocarbon group, aromatic ring, or aromatic heterocyclic group of ring A is optionally surrounded by one, two, three, or four R groups. A1 replace; Each R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, and -C. 1~6 Alkyl, -C 2~6 alkenyl, -C 2~6 Alkyne- or halogen-substituted -C 1~6 Alkyl, halogen-substituted -C 2~6 Alkenyl, halogen-substituted -C 2~6 alkynyl group, -C 0~4 Alkylene-OR A2 -C 0-4 Alkylene-OC(O)R A2 -C 0-4 Alkylene-SR A2 -C 0-4 Alkylene-S(O)2R A2 -C 0-4 Alkylene-S(O)R A2 -C 0-4 Alkylene-S(O)2NR A2 R A3 -C 0-4 Alkylene-S(O)NR A2 R A3 -C 0~4 Alkylene-C(O)R A2 -C 0~4 Alkylene-C(O)OR A2 -C 0~4 Alkylene-C(O)NR A2 R A3 -C 0~4 Alkylene-NR A2 R A3 -C 0~4 Alkylene-NR A2C(O)R A3 , -C 0~4 alkylene-NR A2 S(O)2R A3 or -C 0-4 alkylene-NR A2 S(O)R A3 alkyl, halogen-substituted -C A2 alkyl, halogen-substituted -C A3 alkyl, halogen-substituted -C 2-6 alkyl, halogen-substituted -C 2-6 alkyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2-6 alkyl, halogen-substituted -C 2-6 alkyl, halogen-substituted -C R A2 , R A3 are each independently selected from any one of hydrogen, -C 2-6 alkyl, -C 2-6 alkyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2-6 alkyl, halogen-substituted -C 2-6 alkyl, halogen-substituted -C

[0007] Preferably, the chemical structure of the compound is any one of the following formulae 1-28: .

[0008] Under the same technical concept, the present application also provides a preparation method of the compound with the chemical structure shown in formula (I), which is shown as follows: ; wherein, represents a chiral position of the compound; The raw material a containing a quinoline ring, an aldehyde compound b, and an amine compound c are subjected to Betti reaction at 80-100°C without solvent for 3-12 hours to obtain the compound shown in formula (I).

[0009] Preferably, the molar ratio of the raw material a containing a quinoline ring, the aldehyde compound b, and the amine compound c is 1.0:1.0-1.5:1.0-1.5.

[0010] Preferably, the Betti reaction specifically includes: (1) mixing the raw material a containing a quinoline ring, the aldehyde compound b, and the amine compound c, sealing, stirring at 80-100°C for 3-12 hours, cooling, and obtaining a reaction product; (2) dissolving the reaction product, concentrating, adding methanol or acetone to crystallize, filtering, washing, and drying to obtain the compound shown in formula (I).

[0011] More preferably, in the step (2), a solvent capable of dissolving the reaction product is added when the reaction product is dissolved; More preferably, the solvent capable of dissolving the reaction product includes dichloromethane.

[0012] Under the same technical concept, the application further provides a selective PCMT1 small molecule inhibitor, wherein the selective PCMT1 small molecule inhibitor comprises a compound with a chemical structural formula as shown in formula (I) or one or more of optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts, prodrugs, deuterium derivatives, hydrates, solvates of the compound.

[0013] Preferably, the selective PCMT1 small molecule inhibitor further comprises a pharmacologically acceptable excipient or carrier of the compound with a chemical structural formula as shown in formula (I).

[0014] Under the same technical concept, the application further provides a use of the selective PCMT1 small molecule inhibitor for preparing an antitumor drug.

[0015] Preferably, the tumor comprises a solid tumor and / or a hematological tumor.

[0016] The above scheme of the application has the following beneficial effects: (1) The compound with a chemical structural formula as shown in formula (I) provided by the application has an A ring and R1-R4 substituents, and the compound with the novel structure can fill the gap in the development of systematic selective PCMT1 inhibitors; (2) The selective PCMT1 inhibitor in the application is expected to become an antitumor candidate drug for treating various cancers such as solid tumors and hematological tumors, and the in vitro test results of the compound involved in the application show that the compound after specific modification can specifically target PCMT1 and has significant selectivity for PCMT1, indicating that the core skeleton of the compound involved in the application can be used for developing a high-selectivity PCMT1 inhibitor and can be used as a first tool compound to study the role of PCMT1 in tumor cells, thereby providing an important material basis for the biological function research of PCMT1; (3) The synthetic method of the application: the target compound can be synthesized by Betti reaction in one step, and the condition is simple without adding other solvents. BRIEF DESCRIPTION OF DRAWINGS

[0017] In order to more clearly illustrate the technical solutions of the embodiments of the application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or the prior art. Obviously, the following drawings are some embodiments of the application, and for those skilled in the art, other related drawings can also be obtained without creative labor.

[0018] Figure 1 The structural schematic diagram of the compound with a chemical structural formula as shown in formula (I) provided by the application is shown in the following figure: Figure 2 The preparation method flow chart of the compound provided by the present application is shown in formula (I); Figure 3 The nuclear magnetic resonance spectrum of compound 1 of the present application embodiment 1; Figure 4 The nuclear magnetic resonance spectrum of compound 2 of the present application embodiment 2; Figure 5 The nuclear magnetic resonance spectrum of compound 24 of the present application embodiment 24; Figure 6 The nuclear magnetic resonance spectrum of compound 25 of the present application embodiment 25; Figure 7 The nuclear magnetic resonance spectrum of compound 27 of the present application embodiment 27. DETAILED DESCRIPTION

[0019] In order to make the technical problems, technical solutions and advantages of the present application clearer, specific embodiments will be described in detail below with reference to the drawings. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0020] In the description of the present application, it should be noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer" and the like indicate the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the device or element referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as a limitation on the present application. In addition, the terms "first", "second", "third" are only for descriptive purposes and cannot be understood as indicating or implying relative importance.

[0021] In the description of the present application, it should be noted that unless otherwise explicitly specified and limited, the terms "mounting", "connecting", "connecting" should be understood broadly, for example, it can be a locking connection, or a detachable connection, or an integral connection; it can be a mechanical connection, or an electrical connection; it can be directly connected, or indirectly connected through an intermediate medium, or the internal communication of two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0022] In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0023] In the embodiments of the present application, the total chemical structure of the synthesized compound is as followsFigure 1 Formula (I) as shown in the following flow chart of a chemical preparation method as shown in Figure 2 ; Example 1: This example provides a compound as shown in compound 1 in the following chart of chemical structure and a preparation method thereof; wherein the nuclear magnetic resonance spectrum of compound 1 is shown in the following chart: Figure 3 ;

[0024] ; Step: The starting material 1a containing quinoline ring (288.0 mg, 2.0 mmol, 1.00 equivalent), aldehyde compound 1b (224.3 mg, 2 mmol, 1.00 equivalent) and amine compound 1c (188.2 mg, 2 mmol, 1.00 equivalent) were added to a sealed pressure bottle, stirred at 100°C for 12 hours. After the reaction was completed by TLC monitoring, the reaction was dissolved by adding 5 mL of dichloromethane after cooling. The obtained solution was concentrated. 5 mL of methanol was added to crystallize the product. The product was filtered and washed with methanol for 3 times; after drying, white solid was obtained, a total of 1 (220.0 mg, yield 33%) of the target compound was obtained as white solid.

[0025] The nuclear magnetic resonance spectrum of compound 1 is shown in the following chart: Figure 3 1 H NMR (500 MHz, DMSO-d6) δ 10.04 (s,1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.29 (dd, J = 8.4, 1.6 Hz, 1H), 7.95(ddd, J = 5.1, 2.0, 0.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.59 – 7.52 (m,2H), 7.45 – 7.33 (m, 3H), 7.11 (dd, J = 8.9, 1.1 Hz, 1H), 6.90 (dd, J = 5.0,3.5 Hz, 1H), 6.77 (dt, J = 3.5, 1.2 Hz, 1H), 6.69 (dt, J = 8.5, 1.0 Hz, 1H). Example 2: This example provides a compound as shown in compound 2 in the following chart of chemical structure and a preparation method thereof; wherein the nuclear magnetic resonance spectrum of compound 2 is shown in the following chart: Figure 4 ;

[0026] ;

[0027] ​Procedure: 1a (288.0 mg, 2.0 mmol, 1.00 equiv), 2b (408.5 mg, 3 mmol, 1.50 equiv) and 2c (261.4 mg, 2 mmol, 1.50 equiv) were added to a sealed pressure bottle and stirred at 100 °C for 12 hours. After the reaction was monitored to be complete by TLC, the reaction was dissolved by adding 5 mL of dichloromethane after cooling. The resulting solution was concentrated. 3 mL of acetone was added to crystallize the product. The product was filtered and washed with acetone for 3 times. After being dried sufficiently, a white solid was obtained, and the target compound 2 (150.0 mg, yield 21%) was obtained as a white solid.

[0028] According to the attached Figure 4 NMR spectrum of compound 2: 1 H NMR (500 MHz, Chloroform-d) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.03 (dd, J = 8.2, 1.7 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.36 (dd, J = 8.3, 4.2 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.83 - 6.78 (m, 2H), 4.67 (s, 1H), 3.84 - 3.72 (m, 7H), 2.89 - 2.33 (m, 4H). Example 3: The present example provides a compound as shown in the following chart of compound 3 and a preparation method thereof; ; Procedure: 1a (288.0 mg, 2.0 mmol, 1.00 equiv), 3b (312.2 mg, 2 mmol, 1.00 equiv) and 1c (188.2 mg, 2 mmol, 1.00 equiv) were added to a sealed pressure bottle and stirred at 100 °C for 12 hours. After the reaction was monitored to be complete by TLC, the reaction was dissolved by adding 5 mL of dichloromethane after cooling. The resulting solution was concentrated. 5 mL of methanol was added to crystallize the product. The product was filtered and washed with methanol for 3 times. After being dried sufficiently, a white solid was obtained, and the target compound 3 (320.0 mg, yield 49%) was obtained as a white solid.

[0029] NMR spectrum of compound 3: 1H NMR (500 MHz, Chloroform-d) δ 8.73 (dd, J = 4.2, 1.6 Hz, 1H), 8.12– 8.07 (m, 2H), 7.57 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 8.0, 1.3 Hz, 2H),7.41 – 7.29 (m, 5H), 7.26 – 7.22 (m, 1H), 6.57 (ddd, J = 7.2, 5.0, 0.9 Hz,1H), 6.48 – 6.37 (m, 2H), 5.68 (d, J = 6.5 Hz, 1H). Example 4: This example provides a compound having the chemical structure shown in compound 4 below and a method of making the same; ; Procedure: 1a (288.0 mg, 2.0 mmol, 1.00 equiv), 4b (192.1 mg, 2 mmol, 1.00 equiv) and 1c (188.2 mg, 2 mmol, 1.00 equiv) were added to a sealed pressure bottle and stirred at 100 °C for 12 hours. After the reaction was monitored to be complete by TLC, the reaction was dissolved by adding 5 mL of dichloromethane after cooling. The resulting solution was concentrated. The product was crystallized by adding 5 mL of methanol. The product was filtered and washed with methanol for 3 times. After being dried sufficiently, a white solid was obtained, and the target compound 4 (150.0 mg, yield 24%) was obtained as a white solid. The nuclear magnetic resonance spectrum of compound 4 is shown: 1 H NMR (500 MHz, Chloroform-d) δ 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.10(dt, J = 6.5, 1.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.43 – 7.35 (m, 3H),7.31 (d, J = 8.6 Hz, 1H), 6.61 – 6.54 (m, 2H), 6.49 (dd, J = 8.4, 1.0 Hz,1H), 6.32 (dd, J = 3.2, 1.8 Hz, 1H), 6.22 (dt, J = 3.2, 0.9 Hz, 1H), 5.75 (d,J = 7.4 Hz, 1H). Example 5: This example provides a compound having the chemical structure shown in compound 5 below and a method of making the same; ; Procedure: 1a (288.0 mg, 2.0 mmol, 1.00 equiv), 5b (393.4 mg, 3 mmol, 1.50 equiv) and 2c (261.3 mg, 3 mmol, 1.50 equiv) were added to a sealed pressure bottle and stirred at 100 °C for 12 h. After the reaction was monitored to be complete by TLC, the reaction was dissolved by adding 5 mL of dichloromethane after cooling. The resulting solution was concentrated. 5 mL of methanol was added to crystallize the product. The product was filtered and washed with methanol for 3 times. After being dried thoroughly, a white solid was obtained, and the target compound 5 (270.0 mg, yield 38%) was obtained as a white solid. The nuclear magnetic resonance spectrum of compound 5 showed: 1 H NMR (400 MHz, Chloroform-d) δ 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.07(dd, J = 8.3, 1.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.60 – 7.50 (m, 3H),7.40 (dd, J = 8.3, 4.2 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 5.00 (s, 1H), 3.77(q, J = 4.7 Hz, 4H), 2.51 (ddt, J = 17.2, 11.0, 6.1 Hz, 4H). Example 6: This example provides a compound as shown in the following chart of compound 6 and a preparation method thereof; ; Referring to the synthesis method of compound 4, compound 6 (320.0 mg, yield 46%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 6 showed: 1H NMR (500 MHz, Chloroform-d) δ 8.77 (dd, J = 4.3, 1.6 Hz, 1H), 8.17– 8.08 (m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H),7.40 (ddd, J = 8.7, 7.2, 1.9 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.10 (d, J =1.4 Hz, 1H), 6.80 (t, J = 1.4 Hz, 1H), 6.73 (dd, J = 7.9, 1.2 Hz, 1H), 6.61(ddd, J = 7.3, 5.0, 0.9 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.84 (d, J = 7.9Hz, 1H). Example 7: This example provides a compound having the chemical structure shown in compound 7 in the diagram below and a method of making the same; ; Following the procedure for synthesis of Reference Compound 4, compound 7 (260.0 mg, yield 32%) was obtained as a white solid. The nuclear magnetic resonance spectrum of compound 7 showed: 1 H NMR (500 MHz, Chloroform-d) δ 8.77 (dd, J = 4.3, 1.6 Hz, 1H), 8.17– 8.08 (m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H),7.40 (ddd, J = 8.7, 7.2, 1.9 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.10 (d, J =1.4 Hz, 1H), 6.80 (t, J = 1.4 Hz, 1H), 6.73 (dd, J = 7.9, 1.2 Hz, 1H), 6.61(ddd, J = 7.3, 5.0, 0.9 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.84 (d, J = 7.9Hz, 1H). Example 8: This example provides a compound having the chemical structure shown in compound 8 in the diagram below and a method of making the same; ; Procedure: 1a (288.0 mg, 2.0 mmol, 1.00 equiv), 8b (444.6 mg, 3 mmol, 1.50 equiv) and 2c (261.3 mg, 3.0 mmol, 1.50 equiv) were added into a sealed pressure bottle and stirred at 100 °C for 12 h. After the reaction was monitored to be complete by TLC, the reaction was dissolved by adding 5 mL of dichloromethane after cooling. The resulting solution was concentrated. The product was crystallized by adding 5 mL of methanol. The product was filtered and washed with methanol for 3 times. After being dried sufficiently, a white solid was obtained, and the target compound 8 (450.0 mg, yield 62%) was obtained as a white solid.

[0030] The nuclear magnetic resonance spectrum of compound 8 shows: 1 H NMR (400 MHz, Chloroform-d) δ 11.42 (s, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.03 (dd, J = 8.3, 1.7 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.35 (dd, J = 8.3, 4.2 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 4.69 (s, 1H), 3.78 (qdd, J = 11.6, 5.9, 3.4 Hz, 4H), 2.83 (hept, J = 6.9 Hz, 1H), 2.72 - 2.43 (m, 4H), 1.18 (d, J = 6.9 Hz, 6H). Example 9: This example provides a compound as shown in the following chemical structural formula of compound 9 and a preparation method thereof; ; Referring to the synthesis method of compound 8, compound 9 (290.0 mg, yield 44%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 9 shows: 1H NMR (500 MHz, Chloroform-d) δ 8.83 (dd, J = 4.2, 1.7 Hz, 1H), 8.07(dd, J = 8.3, 1.7 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 8.3, 4.2Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 5.1, 1.1 Hz, 1H), 7.11 (d, J= 3.5 Hz, 1H), 6.91 (dd, J = 5.1, 3.5 Hz, 1H), 5.16 (s, 1H), 3.77 (qt, J =11.6, 4.5 Hz, 4H), 2.59 (s, 4H). Example 10: This example provides a compound represented by the following chemical structure of compound 10 and a method for preparing the same; ; Referring to the synthesis method of compound 4, compound 10 (210.0 mg, yield 30%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 10 showed: 1 H NMR (500 MHz, Chloroform-d) δ 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.12– 8.08 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.32 (d, J=8.6 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H), 6.66 (d, J =5.7 Hz, 1H), 6.59 (ddd, J = 7.2, 5.0, 0.9 Hz, 1H), 6.42 (dd, J = 8.4, 1.0 Hz,1H), 5.49 (d, J = 5.7 Hz, 1H), 2.28 (s, 3H). Example 11: This example provides a compound represented by the following chemical structure of compound 11 and a method for preparing the same; ; Referring to the synthesis method of compound 4, compound 11 (310.0 mg, yield 45%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 11 showed: 1 H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.86 (dd, J = 4.1, 1.7 Hz,1H), 8.29 (dd, J = 8.2, 1.7 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (d, J =8.5 Hz, 1H), 7.54 (dd, J = 8.3, 4.2 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.37 –7.30 (m, 2H), 7.23 (dd, J = 8.5, 2.4 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.89(dd, J = 5.0, 3.5 Hz, 1H), 6.77 – 6.72 (m, 1H), 6.62 (d, J = 8.4 Hz, 1H),2.06 (s, 3H). Example 12: The present example provides a compound as shown in the following chart of compound 12 and a preparation method thereof; ; Referring to the synthesis method of compound 4, compound 12 (350.0 mg, yield 50%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 12 showed: 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.86 (dd, J = 4.2, 1.6 Hz,1H), 8.29 (dd, J = 8.3, 1.7 Hz, 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.67 (d, J =8.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 8.3, 4.2 Hz, 1H), 7.44 –7.34 (m, 3H), 7.01 (dd, J = 8.7, 1.1 Hz, 1H), 6.91 (dd, J = 5.1, 3.5 Hz, 1H),6.77 (dt, J = 3.5, 1.2 Hz, 1H), 6.72 (dd, J = 9.2, 3.7 Hz, 1H). This embodiment provides a compound represented by the following structural formula 13 and a preparation method thereof. ; Referring to the synthesis method of compound 4, compound 13 (380.0 mg, yield 52%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 13 showed: 1 H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.86 (dd, J = 4.2, 1.6 Hz,1H), 8.30 (dd, J = 8.4, 1.7 Hz, 1H), 7.95 (d, J = 2.6 Hz, 1H), 7.81 (d, J =8.7 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.3, 4.2 Hz, 1H), 7.47(dd, J = 9.0, 2.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 5.1, 1.2Hz, 1H), 7.07 – 7.02 (m, 1H), 6.91 (dd, J = 5.1, 3.5 Hz, 1H), 6.78 (dt, J =3.6, 1.2 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H). Example 14: This example provides a compound having the chemical structure shown in compound 14 in the diagram below and a method of making the same; ; Following the synthesis procedure for compound 4, the target compound compound 14 (400.0 mg, 55% yield) was obtained as a light pink solid. The nuclear magnetic resonance spectrum of compound 14 showed: 1 H NMR (500 MHz, Chloroform-d) δ 8.76 (dd, J = 4.3, 1.6 Hz, 1H), 8.10(dd, J = 8.3, 1.6 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.6 Hz,1H), 7.40 (dd, J = 8.2, 4.3 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 6.69 (dd, J = 3.5, 1.1 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H),6.55 (dd, J = 3.5, 1.3 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 5.60 (d, J = 7.4Hz, 1H), 2.40 (d, J = 1.0 Hz, 3H), 2.13 (s, 3H). Example 15: This example provides a compound having the chemical structure shown in compound 15 in the diagram below and a method of making the same; ; Following the synthesis procedure for compound 4, the target compound compound 15 (210.0 mg, 27% yield) was obtained as a white solid. The nuclear magnetic resonance spectrum of compound 15 showed: 1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.87 (dd, J = 4.2, 1.7 Hz,1H), 8.56 (dd, J = 2.3, 0.6 Hz, 1H), 8.42 (d, J = 8.6 Hz, 1H), 8.31 (dd, J =8.4, 1.7 Hz, 1H), 7.87 (dd, J = 8.9, 2.4 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H),7.56 (dd, J = 8.3, 4.2 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.38 (dd, J = 5.1,1.3 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.93 (dd, J = 5.1, 3.6 Hz, 1H), 6.80(dt, J = 3.7, 1.2 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H). Example 16: This example provides a compound having the chemical structure shown in compound 16 in the diagram below and a method of making the same; ; Following the procedure for synthesizing reference compound 4, compound 16 (210.0 mg, yield 21%) was obtained as a white solid. The nuclear magnetic resonance spectrum of compound 16 showed: 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.88 (dd, J = 4.2, 1.6 Hz,1H), 8.32 (dd, J = 8.4, 1.7 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.87 - 7.81 (m,1H), 7.73 (d, J = 8.6 Hz, 1H), 7.69 (dt, J = 8.5, 2.4 Hz, 2H), 7.56 (dd, J= 8.3, 4.2 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.30 - 7.23 (m, 2H), 7.21 (dd, J =8.8, 1.3 Hz, 1H), 7.05 (t, J = 0.9 Hz, 1H), 6.78 - 6.71 (m, 1H), 6.53 (ddd, J= 7.0, 5.0, 1.0 Hz, 1H). This embodiment provides a compound represented by the following structural formula and a preparation method thereof. ; Referring to the synthesis method of Compound 4, Compound 17 (380.0 mg, yield 52%) was obtained as a yellow solid target compound. The nuclear magnetic resonance spectrum of Compound 17 showed: 1 H NMR (400 MHz, Chloroform-d) δ 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.16– 8.11 (m, 2H), 8.07 (dd, J = 8.3, 1.6 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.58 (d,J = 8.7 Hz, 1H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H),5.08 (s, 1H), 3.83 - 3.71 (m, 4H), 2.61 - 2.44 (m, 4H). This embodiment provides a compound represented by the following structural formula and a preparation method thereof. ; Referring to the synthesis method of compound 4, compound 18 (180.0 mg, yield 25%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 18 showed: 1 H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.86 (dd, J = 4.1, 1.7 Hz,1H), 8.33 (dd, J = 8.4, 1.7 Hz, 1H), 7.76 (dd, J = 5.2, 1.5 Hz, 1H), 7.57(dd, J = 8.3, 4.2 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.44 – 7.39 (m, 2H),7.25 (tt, J = 2.8, 1.4 Hz, 2H), 6.97 (dd, J = 5.1, 3.5 Hz, 1H), 6.78 (dt, J =3.6, 1.3 Hz, 1H), 6.45 (dd, J = 7.0, 5.3 Hz, 1H), 3.51 (td, J = 9.6, 7.8 Hz,1H), 3.38 (dd, J = 9.8, 6.4 Hz, 1H), 3.05 – 2.88 (m, 2H). Example 19: This example provides a compound represented by the following structural formula and a preparation method thereof: ; Referring to the synthesis method of compound 4, compound 19 (290.0 mg, yield 40%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 19 showed: 1H NMR (500 MHz, Chloroform-d) δ 8.74 (dd, J = 4.2, 1.6 Hz, 1H), 8.10(dd, J = 8.3, 1.6 Hz, 1H), 7.91 (dt, J = 2.5, 0.8 Hz, 1H), 7.66 (d, J = 8.6Hz, 1H), 7.39 (dd, J = 8.2, 4.2 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.20 (dd,J = 8.5, 2.4 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H),6.62 (d, J = 5.6 Hz, 1H), 6.36 (d, J = 8.3 Hz, 1H), 5.37 (d, J = 5.6 Hz, 1H),2.27 (s, 3H), 2.14 (s, 3H). Example 20: This example provides a compound having the chemical structure shown in compound 20 in the following chart and a method of making the same; ; Referring to the synthesis method of compound 4, compound 20 (530.0 mg, yield 72%) was obtained as the target compound in off-white solid. The nuclear magnetic resonance spectrum of compound 20 showed: 1 H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.96 (dd, J = 4.2, 1.6 Hz,1H), 8.46 (dd, J = 8.5, 1.6 Hz, 1H), 7.95 (dd, J = 5.1, 1.8 Hz, 1H), 7.86 (s,1H), 7.70 (dd, J = 8.5, 4.1 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.45 – 7.35(m, 2H), 7.11 (d, J = 8.9 Hz, 1H), 6.92 (dd, J = 5.0, 3.5 Hz, 1H), 6.82 –6.77 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.56 – 6.48 (m, 1H). Example 21: This example provides a compound having the chemical structure shown in compound 21 in the following chart and a method of making the same; ; Referring to the synthesis method of compound 4, compound 21 (400.0 mg, yield 60%) was obtained as the target compound in off-white solid. The nuclear magnetic resonance spectrum of compound 21 showed: 1 H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.85 (dd, J = 4.2, 1.6 Hz,1H), 8.27 (dd, J = 8.3, 1.7 Hz, 1H), 7.92 (ddd, J = 5.1, 2.0, 0.8 Hz, 1H),7.65 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.45 – 7.34 (m,4H), 7.18 (dt, J = 2.7, 1.2 Hz, 1H), 7.07 (dd, J = 5.0, 1.3 Hz, 1H), 6.89 (d,J = 8.8 Hz, 1H), 6.66 (dt, J = 8.5, 1.0 Hz, 1H), 6.46 (ddd, J = 7.0, 5.0, 1.0Hz, 1H). Example 22: This example provides a compound as shown in the following chart of compound 22 and a preparation method thereof; ; Referring to the synthesis method of compound 4, compound 22 (150.0 mg, yield 24%) was obtained as the target compound in yellow solid. The nuclear magnetic resonance spectrum of compound 22 showed: 1 H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.84 (dd, J = 4.1, 1.7 Hz,1H), 8.27 (dd, J = 8.3, 1.7 Hz, 1H), 7.95 – 7.88 (m, 1H), 7.66 (d, J = 8.5Hz, 1H), 7.56 (t, J = 1.7 Hz, 1H), 7.52 (dd, J = 8.2, 4.2 Hz, 1H), 7.41 –7.34 (m, 3H), 7.31 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.66 – 6.61(m, 1H), 6.48 – 6.42 (m, 2H). Example 23: This example provides a compound having the chemical structure shown in compound 23 in the diagram below and a process for making the same; ; Following the procedure for the synthesis of compound 4, compound 23 (280.0 mg, 35% yield) was obtained as a white solid. The nuclear magnetic resonance spectrum of compound 23 is shown in 1 H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.96 (dd, J = 4.2, 1.6 Hz,1H), 8.47 (dd, J = 8.5, 1.6 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.87 (d, J =8.8 Hz, 1H), 7.81 (s, 1H), 7.72 (dd, J = 8.5, 4.2 Hz, 1H), 7.49 (dd, J = 8.9,2.7 Hz, 1H), 7.39 (dd, J = 5.1, 1.3 Hz, 1H), 7.05 (dd, J = 8.7, 1.1 Hz, 1H),6.92 (dd, J = 5.0, 3.5 Hz, 1H), 6.80 (dt, J = 3.6, 1.2 Hz, 1H), 6.73 (d, J =8.9 Hz, 1H). Example 24: This example provides a compound having the chemical structure shown in compound 24 in the diagram below and a process for making the same; ; Following the procedure for the synthesis of compound 4, compound 24 (210.0 mg, 31% yield) was obtained as a white solid. The nuclear magnetic resonance spectrum of compound 24 is shown in Figure 5 1 ​H NMR (500 MHz, Chloroform-d) δ 11.34 (s, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.03 (dd, J = 8.2, 1.7 Hz, 1H), 7.40 (d, J = 7.7 Hz, 2H), 7.35 (dd, J = 8.2, 4.2 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 4.70 (s, 1H), 3.84 - 3.71 (m, 4H), 2.69 - 2.46 (m, 4H), 2.27 (s, 3H). Example 25: This example provides a compound having the chemical structure shown in compound 25 in the diagram below and a method of making the same; ; Following the procedure for synthesis of reference compound 4, compound 25 (240.0 mg, yield 38%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 25 is shown in Figure 6 1 H NMR (500 MHz, Chloroform-d) δ 11.08 (s, 1H), 8.84 (dd, J = 4.3, 1.6 Hz, 1H), 8.03 (dd, J = 8.3, 1.7 Hz, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.36 (dd, J = 8.2, 4.2 Hz, 1H), 7.28 (dd, J = 8.3, 6.8 Hz, 2H), 7.24 - 7.19 (m, 2H), 4.76 (s, 1H), 3.85 - 3.73 (m, 4H), 2.67 - 2.47 (m, 4H). Example 26: This example provides a compound having the chemical structure shown in compound 26 in the diagram below and a method of making the same; ; Following the procedure for synthesis of reference compound 4, compound 26 (270.0 mg, yield 35%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of compound 26 is shown in 1 ​H NMR (500 MHz, Chloroform-d) δ 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.06(dd, J = 8.3, 1.6 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 8.0 Hz,3H), 7.39 (dd, J = 8.3, 4.2 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 4.96 (s, 1H),3.78 (ddt, J = 12.4, 9.9, 5.0 Hz, 4H), 2.68 – 2.45 (m, 4H). In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as represented by the following structural formula: ; According to the synthesis method of Compound 4, Compound 27 (180.0 mg, yield 27%) was obtained as a white solid target compound.

[0031] According to the synthesis method of Compound 4, Compound 27 (180.0 mg, yield 27%) was obtained as a white solid target compound. Figure 7 The nuclear magnetic resonance spectrum of Compound 27 is shown in the following figure: 1 H NMR (500 MHz, Chloroform-d) δ 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.06(dd, J = 8.3, 1.6 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 8.0 Hz,3H), 7.39 (dd, J = 8.3, 4.2 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 4.96 (s, 1H),3.78 (ddt, J = 12.4, 9.9, 5.0 Hz, 4H), 2.68 – 2.45 (m, 4H). In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as represented by the following structural formula: ; According to the synthesis method of Compound 4, Compound 28 (290.0 mg, yield 41%) was obtained as a white solid target compound. The nuclear magnetic resonance spectrum of Compound 28 is shown in the following figure: 1H NMR (400 MHz, Chloroform-d) δ 8.82 (dd, J = 4.2, 1.6 Hz, 1H), 8.05(dd, J = 8.3, 1.7 Hz, 1H), 7.47 (dd, J = 16.1, 8.4 Hz, 3H), 7.38 (dd, J =8.3, 4.2 Hz, 1H), 7.25 (d, J = 8.6 Hz, 3H), 4.80 (s, 1H), 3.77 (qdd, J =11.5, 7.3, 3.7 Hz, 4H), 2.65 – 2.44 (m, 4H). Example 29: The compounds 1-28 prepared in the above Examples 1-28 were tested for PCMT1 enzyme activity using a fluorescence coupling assay.

[0032] 1. Experimental method This method transfers the methyl group on S-adenosyl methionine (SAM) to the polypeptide substrate by PCMT1 to generate S-adenosyl homocysteine (SAH), which is hydrolyzed to homocysteine under the catalysis of S-adenosyl homocysteine hydrolase (SAHH), and undergoes a quantitative Michael addition reaction with a fluorescent dye. The activity of PCMT1 is quantitatively determined by monitoring the change in the fluorescence signal of the product.

[0033] 2. The method specifically comprises the following steps: (1) Buffer solution preparation: Prepare the buffer solution to ensure that the concentrations of the components are: 0.6 μM PCMT1, 7.5 μM SAHH, 10 μM SAM, and 15 μM ThioGlo4.

[0034] The formula of the buffer solution is: 20 mM Tris-HCl, pH 7.5, with the addition of 0.01% Triton X-100.

[0035] The prepared buffer solution needs to be thoroughly mixed before use, and the concentrations of the components need to be accurate.

[0036] Dilute the mother liquor of the test compound (10 mM) according to a certain proportion.

[0037] (2) Incubation step: Take 89 μL of the prepared buffer solution and 1 μL of the gradient diluted solution of the test compound, and distribute them into a 384-well plate, adding each well uniformly.

[0038] Place the 384-well plate in a 37 ℃ incubator for 15 minutes in the dark.

[0039] Ensure that the plate is placed horizontally during incubation to ensure that the solution in each well is mixed thoroughly.

[0040] (3) Substrate addition: Take 10 μL of the polypeptide substrate (e.g. VYP-isoD-HA) at a concentration of 10 μM and carefully add it to each well using a pipette.

[0041] Use a pipette to mix the solution up and down 10 times to ensure that the substrate is evenly distributed in each well.

[0042] (4) Fluorescence monitoring: Place the 384-well plate in the fluorescence module of a multifunctional enzyme label meter, set the excitation wavelength to 400 nm and the emission wavelength to 465 nm.

[0043] Use the fluorescence intensity mode to start the kinetic monitoring program, record the change in fluorescence intensity of each well once per minute.

[0044] Monitor for 20 minutes, during which time fluorescence data is collected every minute to ensure real-time reflection of the change in fluorescence during the reaction.

[0045] (5) Data analysis: Calculate the rate of change in fluorescence intensity to obtain the rate of increase in fluorescence intensity of each well.

[0046] Correspond the rate of increase in fluorescence intensity with the enzyme activity of PCMT1, and further analyze the activity level of PCMT1 under different conditions.

[0047] Fluorescence data can be processed using software (such as Excel or specialized analysis software) to draw reaction rate curves and quantitatively analyze PCMT1 activity.

[0048] 3. Experimental results Table 1 IC values of target compounds on PCMT1 50 Note: + indicates that the IC 50 of the compound is > 100 μM ++ indicates that the IC 50 of the compound is > 10 μM +++ indicates that the IC 50 of the compound is > 1 μM Conclusion: Some representative compounds of the present application can effectively inhibit PCMT1 and have good selectivity.

[0049] Example 30:​ The present embodiment provides a selective PCMT1 small molecule inhibitor, which comprises any one of the compounds 1-28 prepared in the above embodiments 1-28.

[0050] The present embodiment relates to the use of a safe and effective amount of a selective PCMT1 inhibitor in the preparation of an antitumor drug, or an optical isomer, racemate, single enantiomer, possible diastereomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof in the preparation of an antitumor drug, wherein the tumor includes solid tumors and blood tumors, and also includes a pharmacologically acceptable salt and a pharmacologically acceptable excipient or carrier.

[0051] Since the compound of the present application has the activity of inhibiting the proliferation of various tumor cell lines, the compound of the present application and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present application as the main active ingredient can be used for the treatment, prevention and relief of various diseases, including various cancers.

[0052] The "safe and effective amount" of the present application refers to the amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably 5-1000 mg of the compound of the present application per dose. Preferably, the "dose" is a capsule or tablet.

[0053] The "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel materials suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the components in the composition can be mixed with the compound of the present application and between each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0054] The administration of the compound or pharmaceutical composition of the present application is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

[0055] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or solubilizers, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) humectants, such as hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) moisturizing agents, such as glycerol; (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, such as paraffin; (f) absoφtion accelerators, such as quaternary ammonium compounds; (g) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof; and (h) absorbents, such as kaolin and bentonite clay. In some cases, the dosage form can also contain a buffer. In some cases, the dosage form can also contain a preservative.

[0056] Solid dosage forms, such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art. They can contain opacifying agents, and can be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0057] Liquid dosage forms for oral administration include pharmaceutically- acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0058] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0059] Suspensions, in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and colloidal silica among others.

[0060] The compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles that can be employed include water, ethanol, polyols and the like, and suitable mixtures thereof.

[0061] Dosage forms of the compounds of the application for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0062] The compounds of the application can be administered alone, or in combination with other pharmaceutically acceptable compounds.

[0063] When using the pharmaceutical compositions, a safe and effective amount of the compounds of the application is administered to a mammal (e.g., human) in need of treatment, wherein the dosage is administered in an amount pharmaceutically effective to administer, and for a 60 kg body weight human, the daily dosage is usually 1-5000 mg, preferably 5-2000 mg. Of course, the specific dose will also take into account the route of administration, the health condition of the patient, and the like, which are within the skill of the skilled physician.

[0064] The above describes the present application and its embodiments, which is not limited, and the actual structure is not limited. In general, if a person skilled in the art is inspired, without departing from the spirit of the present application, without creative design, similar structure and embodiments of the technical solution should belong to the protection scope of the present application.

Claims

1. A compound of formula (I) or an optical isomer, racemate, single enantiomer, possible diastereomer thereof, characterized in that, The chemical structural formula is as follows: ； wherein: represents a chiral position of the compound; The A ring is selected from any one of 3-10 membered carbocyclic group, 4-10 membered heterocycloalkyl group, 6-10 membered aromatic ring, and 5-10 membered aromatic heterocycle; The selection of R1 and R2 has the following two schemes: Scheme one: R1 and R2 are the same or different and each is selected from any one of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, and optionally substituted heteroaryl; Scheme two: R1 and R2 together with the nitrogen atom to which they are bonded form a saturated or unsaturated, optionally substituted 5-8 membered ring which can optionally contain additional heteroatoms; R3 and R4 are the same or different and each is selected from any one of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, sulfonic acid group, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amino, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted acyloxy, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

2. The compound of claim 1, wherein In compounds of the chemical structure shown as Formula (I), wherein the carbocyclic group, heterocycloalkyl group, aromatic ring, aromatic heterocyclic ring of ring A is optionally substituted by one, two, three or four R A1 substituents; each R A1 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, -C 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen-substituted -C 1~6 alkyl, halogen-substituted -C 2~6 alkenyl, halogen-substituted -C 2~6 alkynyl, -C 0~4 alkylene-OR A2 , -C 0-4 alkylene-OC(O)R A2 , -C 0-4 alkylene-SR A2 , -C 0-4 alkylene-S(O)2R A2 , -C 0-4 alkylene-S(O)R A2 , -C 0-4 alkylene-S(O)2NR A2 R A3 , -C 0-4 alkylene-S(O)NR A2 R A3 , -C 0~4 alkylene-C(O)R A2 , -C 0~4 alkylene-C(O)OR A2 , -C 0~4 alkylene-C(O)NR A2 R A3 , -C 0~4 alkylene-NR A2 R A3 , -C 0~4 alkylene-NR A2 C(O)R A3 , -C 0~4 alkylene-NR A2 S(O)2R A3 or -C 0-4 alkylene-NR A2 S(O)R A3 ; R A2 , R A3 are each independently selected from any one of hydrogen, -C 2-6 alkyl, -C 2-6 alkynyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2-6 alkyl, or halogen-substituted -C 2-6 alkynyl.

3. The compound of claim 1 or 2, wherein The chemical structural formula of the compound is any one of the following formulas 1-28: 。 4. A process for the preparation of a compound of the formula (I) as claimed in any one of claims 1 to 3, characterized in that The preparation method is shown in the following figure: ； wherein: represents a chiral position of the compound; The quinoline ring raw material a, aldehyde compound b and amine compound c are mixed and sealed, stirred at 80-100°C for 3-12 hours, cooled, and the reaction product is obtained.

5. The production method according to claim 4, wherein The molar ratio of the quinoline ring raw material a, aldehyde compound b and amine compound c is 1.0:1.0-1.5:1.0-1.

5.

6. The production method according to claim 5, wherein The Betti reaction specifically includes: (1) mixing the quinoline ring raw material a, aldehyde compound b and amine compound c and sealing, stirring at 80-100°C for 3-12 hours, cooling, and obtaining the reaction product; (2) dissolving the reaction product, concentrating, adding methanol or acetone to crystallize, filtering, washing, and drying to obtain the compound shown in formula (I).

7. A selective PCMTl small molecule inhibitor, characterized in that, The selective PCMT1 small molecule inhibitor comprises the compound shown in formula (I) or one or more of its optical isomers, racemate, single enantiomer, possible diastereoisomer, or pharmaceutically acceptable salt, prodrug, deuterium derivative, hydrate, solvate.

8. The selective PCMTl small molecule inhibitor of claim 7, wherein, The selective PCMT1 small molecule inhibitor also includes a pharmacologically acceptable excipient or carrier of the compound shown in formula (I).

9. Use of a selective PCMTl small molecule inhibitor, characterized in that, The selective PCMT1 small molecule inhibitor is used for preparing an antitumor drug.

10. Use according to claim 9, wherein The tumor includes solid tumor and / or hematological tumor.

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