Benzothiazole pyrimidine amine DYRK2 inhibitors, their preparation method and application

Abstract

The present invention relates to a benzothiazole pyrimidine amine DYRK2 inhibitor, its preparation method and application. The compound of the present invention can inhibit the proliferation of cancer cells and can be used to prepare a therapeutic agent for cancer or tumor-related diseases. TIFF2025540577000125.tif31170

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and in particular to benzothiazole pyrimidine amine DYRK2 inhibitors, methods for their preparation, and their use in the manufacture of drugs for treating related diseases. [Background technology]

[0002] Human dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) are an evolutionarily conserved kinase family characterized by kinase activity directed against their own tyrosine residues and against serine / threonine sites in other proteins. DYRKs belong to the five-member serine / threonine CMGC kinase family. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2), a member of the DYRK family, possesses both tyrosine kinase and serine / threonine kinase activities and has diverse functions in regulating cell proliferation, apoptosis, and differentiation.

[0003] Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) belong to the CMGC kinase group, along with CDK and MAPK family kinases. Five subtypes of DYRK family kinases exist in the human body. DYRK2, a key regulator of 26S protein kinases, enhances proteasome activity by phosphorylating the Thr25 site of the Rpt3 subunit within the 26S proteasome regulatory particle. DYRK2 is highly expressed in tumors and has been shown to play an important role in tumor proliferation and growth. Currently, DYRK2 small molecule inhibitors have demonstrated remarkable anticancer effects against cancers such as prostate cancer, triple-negative breast cancer, and multiple myeloma. Recently, a DYRK2-specific small molecule inhibitor, LDN192960, was reported (Banerjee et al., 2019). Crystal structure analysis and biochemical studies revealed the molecular mechanism by which LDN192960 selectively inhibits DYRK2. By inhibiting DYRK2 activity, LDN192960 can reduce proteasome activity and attenuate the progression of triple-negative breast cancer and multiple myeloma, suggesting that targeting DYRK2 may be an effective treatment for these two tumors. However, the activity of DYRK2 inhibitors in the prior art is still not ideal, and there is an urgent need to provide DYRK2 inhibitors with better activity. Summary of the Invention

[0004] The object of the present invention is to provide a DYRK2 small molecule inhibitor, or a stereoisomer thereof, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing a DYRK2 small molecule inhibitor and a method for producing the same, and its use in the manufacture of a medicament for treating related cancer or tumor diseases. The present invention provides a compound of formula P, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: TIFF2025540577000002.tif31170 [Wherein X is O, NH, S(O)2, C(O) and -(CH2) n - n is 0 or 1 or 2, A, B, and C are each independently selected from the group consisting of C and N; R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkyl, haloC1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C6-C 10 Aryl, C5-C 10 heteroaryl, C4-C8 heterocyclyl, and -NR4R5, wherein R4 and R5 are each independently selected from H, C1-C8 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C5-C 10 selected from the group consisting of heteroaryl and C4-C8 heterocyclyl; R2 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, mercapto, cyano, halogen, nitro, C3-C8 cycloalkyl, C1-C8 alkyl, and C1-C8 alkoxy; R3 is independently hydrogen, deuterium, C1-C8 alkyl, haloC1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, -C(O)OC1-C8 alkyl, -C(O)C3-C8 cycloalkyl, C6-C 10 Aryl, C3-C 10 selected from the group consisting of heteroaryl, C4-C8 heterocyclyl, and -C(O)R6; R6 is independently C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, and C6-C 10 aryl.]

[0005] Preferably, the compound represented by formula P, its stereoisomer, or its pharmaceutically acceptable salt is a compound represented by the following formula PI or formula P-II, its stereoisomer, or its pharmaceutically acceptable salt. TIFF2025540577000003.tif33170 [wherein X is each independently O, NH, S(O)2, C(O) and -(CH2) n- n is 0 or 1 or 2, A, B, and C are each independently selected from the group consisting of C and N; R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkyl, haloC1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C6-C 10 Aryl, C3-C 10 heteroaryl, C4-C8 heterocyclyl, and -NR4R5, wherein R4 and R5 are each independently selected from H, C1-C8 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C3-C 10 selected from the group consisting of heteroaryl and C4-C8 heterocyclyl; R2 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, mercapto, cyano, halogen, nitro, C3-C8 cycloalkyl, C1-C8 alkyl, and C1-C8 alkoxy; R3 is independently hydrogen, deuterium, C1-C8 alkyl, haloC1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, -C(O)OC1-C8 alkyl, -C(O)C3-C8 cycloalkyl, C6-C 10 Aryl, C3-C 10 selected from the group consisting of heteroaryl, C4-C8 heterocyclyl, and -C(O)R6; R6 is independently C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, and C6-C 10 aryl.]

[0006] Preferably, the compound is represented by formula PI or formula P-II, a stereoisomer thereof, or a pharmacologically acceptable salt thereof, X is independently C(O) or —(CH) n -, n is 1; A, B, and C are each independently selected from the group consisting of C and N; R1 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, hydroxy, and -NR4R5, wherein R4 and R5 are selected from the group consisting of H, C1-C6 alkyl, and C4-C8 heterocyclyl; R2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; R3 are each independently hydrogen, C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)C3-C6 cycloalkyl, C6-C 10 selected from the group consisting of aryl and —C(O)R6; R6 is independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C6-C 10 It is preferably selected from the group consisting of aryl.

[0007] More preferably, the compound is represented by formula PI or formula P-II, a stereoisomer thereof, or a pharmacologically acceptable salt thereof, X is independently selected from the group consisting of C(O) and -CH-; A, B, and C are each independently selected from the group consisting of C and N; R1 is selected from the group consisting of hydrogen, methyl, and -NR4R5, wherein R4 and R5 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopentyl, and cyclohexyl; R2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, fluoro, and isopropyl; R3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, -C(O)OC1-C6 alkyl, phenyl, and -C(O)R6; Preferably, each R6 is independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, and cyclopropyl.

[0008] Most preferably, the compound represented by formula PI or formula P-II, its stereoisomer, or its pharmacologically acceptable salt is selected from the group consisting of compounds having the following structure, their stereoisomers, and their pharmacologically acceptable salts: [Table 1] TIFF2025540577000005.tif246170TIFF2025540577000006.tif250170TIFF2025540577000007.tif240170 TIFF2025540577000008.tif255170TIFF2025540577000009.tif242170TIFF2025540577000010.tif218170

[0009] The present invention further provides a compound of formula P, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Among them, the pharmacologically acceptable salt is a salt of a compound represented by formula P with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, trichloroacetic acid, propionic acid, butanoic acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, and tartaric acid. Preferably, the pharmacologically acceptable salt is the hydrochloride salt of the compound represented by formula P.

[0010] The present invention further provides a method for producing a compound represented by formula P, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the method comprising a step of coupling intermediate compound (A) with intermediate compound (B) in the presence of a catalyst. TIFF2025540577000011.tif33170 wherein the substituents X, A, B, C, R1, R2 and R3 are defined as above. Preferably, the catalyst is a palladium catalyst, the reaction is carried out under an argon protective atmosphere, the reaction temperature is 55-125°C, and the reaction time is 5-24 hours.

[0011] The present invention further provides a pharmaceutical composition comprising a compound of formula P, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0012] The present invention further provides use of a compound of formula P, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula P, its stereoisomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament as a DYRK2 target inhibitor. Among them, the DYRK2 target inhibitor is a drug for treating cancer or tumor-related diseases, preferably a drug for treating or preventing lung cancer, leukemia, breast cancer, prostate cancer, multiple myeloma, liver cancer, gastric cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer or endometrial cancer.

[0013] The beneficial technical effect of the present invention is that the present invention has a strong inhibitory activity against DYRK2 kinase activity and IC 50 (nM) value reaches 0.1 nM to 1000 nM, preferably IC 50 The IC (nM) values ​​range from 1 nM to 100 nM, and some compounds have IC 50 The present invention aims to provide a benzothiazole pyrimidine amine DYRK2 inhibitor having a (nM) value of less than 10 nM.

[0014] The following are the interpretations and explanations of the terms used in the present invention. "Cancer" or "malignancy" refers to any of a variety of diseases characterized by the uncontrolled, abnormal growth of cells, the ability of affected cells to spread locally or via the bloodstream or lymphatic system to other parts of the body (metastasis), and any of several characteristic structural and / or molecular features. A "cancer cell" refers to a cell at an early, intermediate, or advanced stage of multistage tumor progression. Cancers include lung cancer, leukemia, breast cancer, prostate cancer, multiple myeloma, liver cancer, stomach cancer, bone cancer, brain cancer, head and neck cancer, colorectal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, and endometrial cancer. The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Information Service, Columbus, Ohio) nomenclature systems.

[0015] Regarding the definitions of terms used in the present invention, unless otherwise specified, the initial definition provided for a group or term in this specification applies to the group or term throughout the specification. Terms not specifically defined in this specification are given the meaning that a person skilled in the art can give them based on the disclosure and context. "Substitution" means that a hydrogen atom in a molecule is replaced with another, different atom or molecule. The minimum and maximum carbon atom content in the hydrocarbon group is indicated by a prefix, e.g., the prefix C a~b Alkyl means an alkyl containing any "a" to "b" carbon atoms. Thus, for example, "C 1~6 "Alkyl" means an alkyl containing 1 to 6 carbon atoms, and "C 1~8 "Alkyl" is an alkyl containing 1 to 8 carbon atoms.

[0016] An "alkyl" is a saturated hydrocarbon chain having a specified number of member atoms. For example, a C1-8 alkyl has 1 to 8 member atoms, a C1-6 alkyl has 1 to 6 member atoms, e.g., an alkyl group having 1 to 4 member atoms, and an alkyl group having 1 to 3 member atoms. An alkyl group can be straight or branched. Representative branched alkyl groups have one, two, or three branches. An alkyl group can be substituted with one or more substituents as defined herein. Examples of alkyl include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. An alkyl group can be part of another group, such as a C1-C8 alkoxy or a C1-C6 alkoxy. "Cycloalkyl" and "cycloalkane" refer to saturated or partially saturated cyclic groups containing carbon atoms, no ring-forming heteroatoms, and a single ring or multiple rings (including fused and linked rings). For multiple ring systems consisting of aromatic and non-aromatic rings without ring-forming heteroatoms, the term "cycloalkyl" applies when the linker is a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthylene-5-yl). The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentylalkenyl, and cyclohexenyl. Examples of cycloalkyl groups containing multiple bicycloalkyl ring systems include bicyclohexyl, bicyclopentyl, and bicyclooctyl.

[0017] "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least one site of ethylenic unsaturation (>C=C<). For example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms, and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like. "Alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" includes those hydrocarbon radicals containing one triple bond and one double bond. For example, C2-C6 alkynyl includes ethynyl, propynyl, etc.

[0018] "Halogen" is fluorine, chlorine, bromine or iodine. "Halogen alkyl" or "halo alkyl" refers to an alkyl in which one or more hydrogen atoms may be replaced with halogen atoms. For example, C 1~8 Halogenalkyl means an alkyl containing 1 to 8 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms; C 1~4Halogenalkyl means an alkyl containing 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms.

[0019] The terms "heterocycle," "heterocycloalkyl," and "heterocycloalkane" refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; where heteroatom is a nitrogen atom, an oxygen atom, or a sulfur atom; the term "heterocyclyl" refers to a heterocycloalkyl, a single ring, or fused rings containing one or more N, O, or S heteroatoms. The term "C4-C8 heterocyclyl" refers to a heterocyclyl containing from 4 to 8 carbon atoms in the ring. C4-C8 heterocyclyl includes, but is not limited to, piperazino, morpholino, piperidino, pyrrolidino, and the like. A "heteroaryl ring" is an aromatic unsaturated ring containing at least one heteroatom; where the heteroatom is a nitrogen atom, an oxygen atom, or a sulfur atom; the term "heteroaryl" refers to a single ring or fused ring group containing one, two, three, or four ring-forming heteroatoms selected from the group consisting of N, O, or S, the remaining ring-forming atoms being C, and having a completely conjugated π-electron system. The term "C-C 10 "Heteroaryl" is a heteroaryl containing from 3 to 10 carbon atoms in its ring. C3-C 10 Heteroaryl includes, but is not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, and pyridine.

[0020] The term “C6-C 10 "Aryl" refers to an all-carbon monocyclic or fused polycyclic group having from 6 to 10 carbon atoms and having a completely conjugated pi-electron system. Typical examples include, but are not limited to, phenyl and naphthyl. The term "pharmacologically acceptable" means that the carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up the pharmaceutical dosage form and physiologically compatible with the recipient.

[0021] The pharmaceutical composition of the present invention may be in the form of any reusable pharmaceutical preparation for oral administration, injection, topical administration, etc. Oral administration forms include tablets, capsules, oral liquids, granules, pills, suspensions, etc. Injectables include aqueous injections and powder injections, etc., and topical administration forms include patches, ointments, etc. All preparations can be prepared according to conventional pharmaceutical techniques, using the compound of the present invention, or any of its stereoisomers, or a pharmaceutically acceptable salt thereof as the pharmaceutically active ingredient, and adding a pharmaceutically acceptable carrier as necessary to prepare the above-mentioned pharmaceutical dosage form suitable for oral administration. In this case, the unit dose of the pharmaceutically active ingredient is 0.1 mg to 1000 mg. For example, each tablet can contain 0.1 mg to 1000 mg, preferably 5 to 500 mg, of the pharmaceutically active ingredient.

[0022] The terms "salt," "pharmaceutically acceptable salt," and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed with the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds or their stereoisomers with a certain amount (e.g., equivalents) of acid or base, as appropriate. These salts precipitate from solution and are collected by filtration, recovered by evaporation of the solvent, or prepared by reaction in an aqueous medium followed by lyophilization. The salts of the present invention may be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate salts of the compounds. [Brief explanation of the drawings]

[0023] [Figure 1] 1 is a graph showing that the compound of Example 20 of the present invention significantly inhibits the proliferation of prostate cancer DU145 cells and 22Rv1 cells. [Figure 2] 1 is a graph showing changes in animal body weight and organ weight in an acute toxicity experiment for Example 20 of the present invention. [Figure 3] 1 is a graph showing that the compound of Example 40 of the present invention significantly inhibits the proliferation of prostate cancer DU145 cells and 22Rv1 cells. [Figure 4] 1 is a graph showing changes in animal body weight and organ weight in an acute toxicity experiment for Example 40 of the present invention. [Figure 5] 1 is a test of the in vivo anti-prostate cancer activity of the compound of Example 20 of the present invention. [Figure 6] 1 is a test of the in vivo anti-prostate cancer activity of the compound of Example 40 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0024] The following examples are provided for a better understanding of the present invention and are not intended to limit the present invention. Unless otherwise specified, all experimental methods in the following examples are conventional methods. Unless otherwise specified, the test materials used in the following examples were purchased from general biochemical reagent stores. The present invention will now be described in detail in conjunction with specific embodiments.

[0025] <Intermediate Production Example 1> Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (A-1) 5-Bromobenzothiazole (0.43 g, 2.0 mmol) was dissolved in 1,4-dioxane (10 mL). Pinacol boronate (0.53 g, 2.1 mmol), Pd(dppf)Cl (22 mg, 0.06 mmol), and potassium acetate (0.59 g, 6.0 mmol) were then added. The mixture was purged with argon three times and heated to 100 °C for 8 hours. The mixture was cooled, filtered, concentrated, and purified using a flash silica gel column to give the following compound: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (0.44 g, 86% yield). 1 HNMR(400 MHz,CDCl3)δ 9.00(s,1H),8.60 - 8.59(m,1H),7.97(dd,J = 8.0,0.7 Hz,1H),7.86(dd,J = 8.0,1.0 Hz,1H),1.39(s,12H).

[0026] <Intermediate Production Example 2> Synthesis of 5-(2-chloro-5-methylpyrimidin-4-yl)benzothiazole (A-2) TIFF2025540577000013.tif30170 Compound 2, 4-dichloro-5-methylpyrimidine (0.28 g, 1.4 mmol) was weighed and placed in a 250 mL three-neck flask. Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), sodium carbonate (0.27 g, 2.5 mmol), ethylene glycol dimethyl ether (10 mL), and water (0.25 mL) were then added. The mixture was purged with argon three times and heated to 80 °C. Compound 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole A-1 (0.26 g, 1.0 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL) and added dropwise to the three-neck flask. The mixture was then reacted for 16 hours. Cooling, filtering, concentrating and purifying by flash silica gel column gave compound 5-(2-chloro-5-methylpyrimidin-4-yl)benzothiazole A-2 (0.21 g, 80% yield). 1HNMR(300 MHz,CDCl3)δ 9.10(s,1H),8.56(s,1H),8.39(dd,J = 1.7,0.6 Hz,1H),8.11(dd,J = 8.4,0.6 Hz,1H),7.78(dd,J = 8.4,1.7 Hz,1H),2.47(s,3H).

[0027] <Intermediate Production Example 3> Synthesis of 5-(2-chloro-5-methoxypyrimidin-4-yl)benzothiazole (A-3) The synthesis method of compound A-2 was referred to in TIFF2025540577000014.tif33170, and the yield was 78%. 1 HNMR(300 MHz,CDCl3)δ 9.07(s,1H),8.98(dd,J = 1.7,0.6 Hz,1H),8.37(s,1H),8.26(dd,J = 8.6,1.7 Hz,1H),8.07(dd,J = 8.6,0.6 Hz,1H),4.05(s,3H).

[0028] <Intermediate Production Example 4> Synthesis of 5-(2-chloropyrimidin-4-yl)benzothiazole (A-4) The synthesis method for compound A-2 was referred to in TIFF2025540577000015.tif33170, and the yield was 73%. 1 HNMR(300 MHz,CDCl3)δ 9.11(s,1H),8.83(d,J = 1.7 Hz,1H),8.71(d,J = 5.3 Hz,1H),8.29(dd,J = 8.5,1.7 Hz,1H),8.12(d,J = 8.5 Hz,1H),7.79(d,J = 5.3 Hz,1H).

[0029] <Intermediate Production Example 5> Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)benzothiazole (A-5) The synthesis method for compound A-2 was referred to in TIFF2025540577000016.tif33170, and the yield was 78%. 1HNMR(400 MHz,CDCl3)δ 9.11(s,1H),8.94(s,1H),8.58(d,J = 3.1 Hz,1H),8.29(dd,J = 8.5,1.7 Hz,1H),8.13(d,J = 8.5 Hz,1H).

[0030] <Intermediate Production Example 6> Synthesis of 6-bromo-N,N-dimethylbenzothiazol-2-amine (A-6) TIFF2025540577000017.tif22170 5-Bromo-2-chlorobenzothiazole (1 g, 4 mmol) and dimethylamine (0.72 g, 16 mmol) were dissolved in THF (15 mL), heated to 75 °C under reflux, reacted for 6 hours, and purified by flash silica gel column to obtain the following: compound 5-bromo-N,N-dimethylbenzothiazol-2-amine A-6 (0.84 g, 82% yield). 1 HNMR(400 MHz,CDCl3)δ 7.69(d,J = 1.9 Hz,1H),7.42(d,J = 8.3 Hz,1H),7.14(dd,J = 8.3,1.9 Hz,1H),3.19(s,6H).

[0031] <Intermediate Production Example 7> Synthesis of N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (A-7) The synthesis method of compound A-1 was referred to in TIFF2025540577000018.tif30170, and the yield was 75%. 1 H NMR(400 MHz,CDCl3)δ 8.03 - 8.02(m,1H),7.60(dd,J = 7.9,0.6 Hz,1H),7.48(dd,J = 7.9,1.1 Hz,1H),3.20(s,6H),1.34(s,12H).

[0032] <Intermediate Production Example 8> Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (A-8) The synthesis method of compound A-2 was referred to in TIFF2025540577000019.tif33170, and the yield was 74%. 1 H NMR(400 MHz,CDCl3)δ 8.49(d,J = 3.3 Hz,1H),8.36 - 8.34(m,1H),7.90 - 7.87(m,1H),7.72(d,J = 8.4 Hz,1H),3.24(s,6H).

[0033] <Intermediate Production Example 9> Synthesis of 5-bromo-N,N-diethylbenzothiazol-2-amine (A-9) TIFF2025540577000020.tif261705-Bromo-2-chlorobenzothiazole (2.49 g, 10 mmol) and diethylamine (2.93 g, 40 mmol) were dissolved in THF (100 mL), heated to 75 °C under reflux, reacted for 12 hours, and purified by flash silica gel column to obtain the following: compound 5-bromo-N,N-diethylbenzothiazol-2-amine A-9 (2.37 g, 83% yield). 1 H NMR(400 MHz,CDCl3)δ 7.66(d,J = 1.9 Hz,1H),7.39(d,J = 8.3 Hz,1H),7.12(dd,J = 8.3,1.9 Hz,1H),3.55(q,J = 7.1 Hz,4H),1.27(t,J = 7.1 Hz,6H).

[0034] <Intermediate Production Example 10> Synthesis of N,N-diethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (A-10) The synthesis method of compound A-1 was referred to in TIFF2025540577000021.tif33170, and the yield was 72%. 1 H NMR(400 MHz,CDCl3)δ 8.01 - 8.00(m,1H),7.58(d,J = 7.8 Hz,1H),7.45(dd,J = 7.8,1.1 Hz,1H),3.56(q,J = 7.0 Hz,4H),1.34(s,12H),1.28(t,J = 7.0 Hz,6H).

[0035] <Intermediate Production Example 11> Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-diethylbenzothiazol-2-amine (A-11) The synthesis method of compound A-2 was referred to in TIFF2025540577000022.tif37170, and the yield was 72%. 1 H NMR(400 MHz,CDCl3)δ 8.47(d,J = 3.3 Hz,1H),8.32(s,1H),7.87 - 7.84(m,1H),7.69(d,J = 8.4 Hz,1H),3.60(q,J = 7.2 Hz,4H),1.31(t,J = 7.2 Hz,6H).

[0036] <Intermediate Production Example 12> Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (A-12) Step 1: Synthesis of 6-bromo-N,N-dimethylbenzothiazol-2-amine (A-12-1) TIFF2025540577000023.tif281704-Bromo-2-iodoaniline (0.60 g, 2.0 mmol), sodium dimethyldithiocarbamate dihydrate (0.72 g, 4.0 mmol), copper acetate (0.36 g, 2.0 mmol), and potassium carbonate (0.55 g, 4.0 mmol) were weighed and dissolved in DMF (10 mL). The mixture was heated to 120 °C and reacted for 6 hours. The mixture was cooled, filtered, concentrated, and purified by flash silica gel column chromatography to obtain the following compound: 6-bromo-N,N-dimethylbenzothiazol-2-amine (A-12-1) (0.44 g, 85% yield). 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 1.9 Hz, 1H), 7.41 - 7.35 (m, 2H), 3.20 (s, 6H). Step 2: Synthesis of N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazol-2-amine (A-12-2) TIFF2025540577000024.tif33170 Intermediate A-12-1 (0.51 g, 2.0 mmol) was dissolved in DMF (10 mL), followed by the addition of pinacol boronate (0.53 g, 2.1 mmol), Pd(dppf)Cl2 (22 mg, 0.06 mmol), and potassium acetate (0.59 g, 6.0 mmol). The mixture was purged with argon three times, heated to 80 °C, and reacted for 24 hours. The mixture was cooled, filtered, concentrated, and purified by flash silica gel column chromatography to give compound N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazol-2-amine A-12-2 (0.54 g, 88% yield). MS (M + H) + : found,305.3. Step 3: Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (A-12) Compound 2, 4-dichloro-5-fluoropyrimidine (0.23 g, 1.4 mmol) was weighed and placed in a 250 mL three-neck flask. Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), sodium carbonate (0.27 g, 2.5 mmol), ethylene glycol dimethyl ether (10 mL), and H2O (0.25 mL) were then added. The mixture was purged with argon three times and heated to 80 °C. N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazol-2-amine A-12-2 (0.3 g, 1.0 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL) and added dropwise to the three-neck flask. The mixture was then allowed to react for 16 hours. Cooling, filtering, concentrating and purifying by flash silica gel column gave compound 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine A-12 (0.25 g, 80% yield). 1 H NMR(400 MHz,CDCl3)δ 8.49(d,J = 1.9 Hz,1H),8.45(d,J = 3.6 Hz,1H),8.17 - 8.14(m,1H),7.62(d,J = 8.7 Hz,1H),3.27(s,6H).

[0037] <Intermediate Production Example 13> Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-diethylbenzothiazol-2-amine (A-13) Step 1: Synthesis of 6-bromo-N,N-diethylbenzothiazol-2-amine (A-13-1) TIFF2025540577000026.tif31170 4-Bromo-2-iodoaniline (0.60 g, 2.0 mmol), sodium diethyldithiocarbamate trihydrate (0.90 g, 4.0 mmol), copper acetate (0.36 g, 2.0 mmol), and potassium carbonate (0.55 g, 4.0 mmol) were weighed and dissolved in DMF (10 mL). The mixture was heated to 120 °C and reacted for 6 hours. The mixture was cooled, filtered, concentrated, and purified by flash silica gel column chromatography to obtain the following compound: 6-bromo-N,N-dimethylbenzothiazol-2-amine (A-13-1) (0.46 g, 80% yield). MS (M + H) + : found,285.1. Step 2: Synthesis of N,N-diethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazol-2-amine (A-13-2) Refer to the synthesis method of compound (A-12-2) in TIFF2025540577000027.tif35170, and the yield was 90%. MS (M + H) + : found,333.3. Step 3: Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-diethylbenzothiazol-2-amine (A-13) The synthesis method for compound (A-12) was referred to in TIFF2025540577000028.tif33170, and the yield was 82%. 1 H NMR(300 MHz,CDCl3)δ 8.44(dd,J = 8.8,2.7 Hz,2H),8.13(d,J = 8.6 Hz,1H),7.58(d,J = 8.7 Hz,1H),3.61(q,J = 7.2 Hz,4H),1.32(t,J = 7.2 Hz,6H).

[0038] <Intermediate Production Example 14> Synthesis of (6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (B-1) TIFF2025540577000029.tif281706-Aminonicotinic acid (0.69 g, 5 mmol) and N,N'-carbonyldiimidazole (1.62 g, 10 mmol) were weighed and dissolved in DMF (30 mL). The mixture was reacted at 70°C for 10 minutes and stirred at room temperature for another hour. N-ethylpiperazine (0.69 g, 6 mmol) was added and the mixture was reacted at room temperature overnight. The mixture was concentrated and purified by flash silica gel column chromatography to obtain the following: Compound B-1 (0.97 g, 83% yield). 1 H NMR(400 MHz,CDCl3)δ 8.18(dd,J = 2.4,0.8 Hz,1H),7.54(dd,J = 8.5,2.4 Hz,1H),6.49(dd,J = 8.5,0.9 Hz,1H),4.95(s,2H),3.67(brs,4H),2.48 - 2.43(m,6H),1.10(t,J = 7.2 Hz,3H).

[0039] <Intermediate Production Example 15> Synthesis of tert-butyl 4-(6-aminonicotinoyl)piperazine-1-carboxylate (B-2) The synthesis method for compound (B-1) was referred to in TIFF2025540577000030.tif28170, and the yield was 85%. 1 H NMR(400 MHz,CDCl3)δ 8.19(dd,J = 2.3,0.8 Hz,1H),7.57(dd,J = 8.5,2.3 Hz,1H),6.51(dd,J = 8.5,0.8 Hz,1H),4.70(s,2H),3.62 - 3.58(m,4H),3.48 - 3.45(m,4H),1.48(s,9H).

[0040] <Intermediate Production Example 16> Synthesis of 1-(4-(6-aminonicotinoyl)piperazin-1-yl)ethyl-1-one (B-3) The synthesis method for compound (B-1) was referred to in TIFF2025540577000031.tif30170, and the yield was 79%. 1 H NMR(400 MHz,CDCl3)δ 8.20(dd,J = 2.3,0.8 Hz,1H),7.56(dd,J = 8.5,2.3 Hz,1H),6.52(dd,J = 8.5,0.8 Hz,1H),4.88(s,2H),3.70 - 3.58(m,8H),2.14(s,3H).

[0041] <Intermediate Production Example 17> Synthesis of 4-(6-aminonicotinoyl)piperazin-1-yl)(cyclopropyl)ketone (B-4) The synthesis method for compound (B-1) was referred to in TIFF2025540577000032.tif35170, and the yield was 79%. 1 H NMR(400 MHz,CDCl3)δ 8.19(dd,J = 2.4,0.8 Hz,1H),7.55(dd,J = 8.6,2.4 Hz,1H),6.52(dd,J = 8.6,0.8 Hz,1H),5.12(s,2H),3.74 - 3.62(m,8H),1.77 - 1.73(m,1H),1.02 - 0.99(m,2H),0.83 - 0.75(m,2H).

[0042] <Intermediate Production Example 18> Synthesis of (6-aminopyridin-3-yl)(4-arylpiperazin-1-yl)ketone (B-5) The synthesis method for compound (B-1) was referred to in TIFF2025540577000033.tif29170, and the yield was 73%. 1 H NMR(400 MHz,CDCl3)δ 8.22(dd,J = 2.3,0.8 Hz,1H),7.58(dd,J = 8.5,2.3 Hz,1H),7.30 - 7.27(m,2H),6.95 - 6.92(m,2H),6.90 - 6.85(m,1H),6.52(dd,J = 8.5,0.8 Hz,1H),4.86(s,2H),3.81 - 3.79(m,4H),3.22 - 3.19(m,4H).

[0043] <Intermediate Production Example 19> Synthesis of ethyl 4-(6-aminonicotinoyl)piperazine-1-carboxylate (B-6) The synthesis method for compound (B-1) was referred to in TIFF2025540577000034.tif37170, and the yield was 73%. 1 H NMR(400 MHz,CDCl3)δ 8.18(s,1H),7.53(d,J = 8.6 Hz,1H),6.52(d,J = 8.6 Hz,1H),5.13(s,2H),4.18 - 4.13(m,2H),3.63 - 3.44(m,8H),1.30 - 1.25(m,3H).

[0044] <Intermediate Production Example 20> Synthesis of (5-aminopyridin-2-yl)(4-ethylpiperazin-1-yl)ketone (B-7) TIFF2025540577000035.tif26170 5-Amino-2-pyridinecarboxylic acid (0.69 g, 5 mmol), N-ethylpiperazine (0.69 g, 6 mmol), HATU (2.85 g, 7.5 mmol), and N-methylmorpholine (1.26 g, 12.5 mmol) were weighed and dissolved in dichloromethane (30 mL). The mixture was stirred at room temperature for 8 hours, concentrated, and purified by flash silica gel column chromatography to obtain Compound B-7 (0.89 g, 76% yield). The yield was 82%. MS (M + H) + : found,235.4

[0045] <Intermediate Production Example 21> Synthesis of (5-aminopyridin-2-yl)(4-isopropylpiperazin-1-yl)ketone (B-8) Refer to the synthesis method of compound (B-7) in TIFF2025540577000036.tif30170, and the yield was 73%. MS (M + H) + : found,249.4

[0046] <Intermediate Production Example 22> Synthesis of tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (B-9) Refer to the synthesis method of compound (B-7) in TIFF2025540577000037.tif28170, and the yield was 75%. MS (M + H) + : found,307.4

[0047] <Intermediate Production Example 23> Synthesis of (2-aminopyrimidin-5-yl)(4-ethylpiperazin-1-yl)ketone (B-10) TIFF2025540577000038.tif28170 2-Aminopyrimidine-5-carboxylic acid (0.60 g, 5 mmol), EDCI (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), and triethylamine (2.53 g, 25 mmol) were weighed and dissolved in DMF (30 mL). The mixture was stirred at room temperature for half an hour, and N-ethylpiperazine (0.69 g, 6 mmol) was added. The mixture was stirred for another 8 hours, concentrated, and purified by flash silica gel column chromatography to obtain the following: Compound B-10 (0.84 g, 71% yield). 1 H NMR(300 MHz,CDCl3)δ 8.41(s,2H),5.55(s,2H),3.70 - 3.58(m,4H),2.48 - 2.41(m,6H),1.09(t,J = 7.2 Hz,3H).

[0048] <Intermediate Production Example 24> Synthesis of tert-butyl 4-(2-aminopyrimidine-5-carbonyl)piperazine-1-carboxylate (B-11) Refer to the synthesis method of compound (B-10) in TIFF2025540577000039.tif28170, and the yield was 73%. MS (M + Na) + : found,330.4

[0049] <Intermediate Production Example 25> Synthesis of 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (B-12) TIFF2025540577000040.tif24170 2-Amino-5-formylpyridine (2.34 g, 10 mmol) and N-ethylpiperazine (1.37 g, 12 mmol) were dissolved in 1,2-dichloroethane (50 mL) and stirred at room temperature for 2 hours. Sodium triacetylborohydride (3.18 g, 15 mmol) was then added and stirred at room temperature for 8 hours. Water was added to quench the mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to give compound B-12 (1.81 g, 82% yield). 1 H NMR(400 MHz,Chloroform-d)δ 7.91(d,J = 2.3 Hz,1H),7.43(dd,J = 8.4,2.3 Hz,1H),6.48(d,J = 8.4 Hz,1H),4.71(s,2H),3.38(s,2H),3.06(brs,4H),2.52 - 2.44(m,6H),1.10(t,J = 7.2 Hz,3H).

[0050] <Intermediate Production Example 26> Synthesis of 5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-amine (B-13) Refer to the synthesis method of compound (B-12) in TIFF2025540577000041.tif26170, and the yield was 79%. MS (M + H) + : found,235.2.

[0051] <Intermediate Production Example 27> Synthesis of tert-butyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1-carboxylate (B-14) Refer to the synthesis method of compound (B-12) in TIFF2025540577000042.tif24170, and the yield was 86%. MS (M + H) + : found,293.3.

[0052] <Intermediate Production Example 28> Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (C-1) The synthesis method for compound (A-1) was referred to in TIFF2025540577000043.tif32170, and the yield was 90%. 1 H NMR(400 MHz,CDCl3)δ 9.05(s,1H),8.45(d,J = 1.1 Hz,1H),8.13(d,J = 8.2 Hz,1H),7.94(dd,J = 8.2,1.1 Hz,1H),1.38(s,12H).

[0053] <Intermediate Production Example 29> Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)benzothiazole (C-2) The synthesis method for compound (A-2) was referred to in TIFF2025540577000044.tif35170, and the yield was 82%. 1 H NMR(400 MHz, CDCl3)δ 9.17(s,1H),8.85(d,J = 1.7 Hz,1H),8.58(d,J = 3.1 Hz,1H),8.35 - 8.26(m,2H).

[0054] <Intermediate Production Example 30> Synthesis of 6-(2-chloro-5-methylpyrimidin-4-yl)benzothiazole (C-3) The synthesis method for compound (A-2) was referred to in TIFF2025540577000045.tif35170, and the yield was 77%. 1 H NMR(400 MHz,DMSO)δ 9.55(s,1H),8.76(s,1H),8.57(d,J = 1.7 Hz,1H),8.23(d,J = 8.5 Hz,1H),7.87(dd,J = 8.5,1.7 Hz,1H),2.41(s,3H).

[0055] <Intermediate Production Example 31> Synthesis of 6-(2-chloro-5-methoxypyrimidin-4-yl)benzothiazole (C-4) The synthesis method for compound (A-2) was referred to in TIFF2025540577000046.tif35170, and the yield was 81%. 1 H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.91 - 8.90 (m, 1H), 8.73 (s, 1H), 8.25 - 8.20 (m, 2H), 4.06 (s, 3H).

[0056] <Intermediate Production Example 32> Synthesis of 6-(2-chloropyrimidin-4-yl)benzothiazole (C-5) The synthesis method for compound (A-2) was referred to in TIFF2025540577000047.tif35170, and the yield was 81%. 1 H NMR(400 MHz,CDCl3)δ 9.14(s,1H),8.85(d,J = 1.7 Hz,1H),8.69(d,J = 5.3 Hz,1H),8.27 - 8.17(m,2H),7.75(d,J = 5.3 Hz,1H).

[0057] <Intermediate Production Example 33> Synthesis of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (C-6) The synthesis method for compound (A-1) was referred to in TIFF2025540577000048.tif32170, and the yield was 90%. 1 H NMR (400 MHz, CDCl3) δ 8.31 - 8.30 (m, 1H), 7.94 - 7.85 (m, 2H), 2.84 (s, 3H), 1.36 (s, 12H).

[0058] <Intermediate Production Example 34> Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylbenzothiazole (C-7) The synthesis method for compound (A-2) was referred to in TIFF2025540577000049.tif35170, and the yield was 84%. 1H NMR(300 MHz,DMSO)δ 9.00(d,J = 3.4 Hz,1H),8.80 - 8.79(m,1H),8.17 - 8.08(m,2H),2.87(s,3H).

[0059] <Intermediate Production Example 35> Synthesis of 6-bromo-N-cyclopentylbenzothiazol-2-amine (C-8) TIFF2025540577000050.tif291706-Bromo-2-chlorobenzothiazole (0.5 g, 2 mmol), cyclopentylamine (0.19 g, 2.2 mmol), and DIPEA (0.39 g, 3 mmol) were dissolved in DMSO (10 mL), purged with argon three times, heated to 80°C, reacted for 12 hours, and purified by flash silica gel column to obtain the following: compound 6-bromo-N-cyclopentylbenzothiazol-2-amine C-8 (0.53 g, 90% yield). 1 H NMR(400 MHz,CDCl3)δ 7.68(d,J = 1.7 Hz,1H),7.38 - 7.33(m,2H),6.28(s,1H),3.98 - 3.93(m,1H),2.14 - 2.04(m,2H),1.72 - 1.54(m,6H).

[0060] <Intermediate Production Example 36> Synthesis of N-cyclopentyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazol-2-amine (C-9) The synthesis method for compound (A-1) was referred to in TIFF2025540577000051.tif32170, and the yield was 88%. 1 H NMR(400 MHz,CDCl3)δ 8.05(d,J = 1.2 Hz,1H),7.73(dd,J = 8.0,1.2 Hz,1H),7.49(d,J = 8.0 Hz,1H),5.74(s,1H),4.03 - 4.00(m,1H),2.13 - 2.07(m,2H),1.76 - 1.56(m,6H),1.35(s,12H).

[0061] <Intermediate Production Example 37> Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylbenzothiazole (C-10) The synthesis method for compound (A-2) was referred to in TIFF2025540577000052.tif35170, and the yield was 83%. 1 H NMR(400 MHz,CDCl3)δ 8.49(d,J = 1.9 Hz,1H),8.46(d,J = 3.5 Hz,1H),8.17 - 8.14(m,1H),7.58(d,J = 8.6 Hz,1H),5.88(s,1H),4.13 - 4.07(m,1H),2.19 - 2.11(m,2H),1.77 - 1.61(m,6H).

[0062] Example 1 Synthesis of 4-(benzothiazol-5-yl)-N-(5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)-5-methylpyrimidin-2-amine (P-1) Compound A-2 (261.7 mg, 1.0 mmol) and B-13 (281.2 mg, 1.2 mmol) were dissolved in dioxane (10 mL). Pd(dba) (45.8 mg, 0.05 mmol), BINAP (62.3 mg, 0.1 mmol), and cesium carbonate (651.6 mg, 2.0 mmol) were then added. The mixture was purged with argon three times, heated to 100 °C, and reacted for 12 hours. After cooling, filtration, and concentration, the following was obtained by column chromatography: compound P-1 (193.0 mg, 42% yield), a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.10(s,1H),8.45 - 8.43(m,3H),8.21(d,J = 2.3 Hz,1H),8.12(d,J = 8.4 Hz,1H),8.04(s,1H),7.78(dd,J = 8.4,1.6 Hz,1H),7.61 - 7.58(m,1H),3.55(s,2H),3.38 - 2.89(m,9H),2.37(s,3H),1.44 - 1.40(m,6H).

[0063] <Example 2> Synthesis of 4-(benzothiazol-5-yl)-5-methyl-N-(5-(piperazine-1-methylene)piperidin-2-yl)pyrimidin-2-amine hydrochloride (P-2) Step 1: Synthesis of intermediate P-2-1 TIFF2025540577000054.tif26170 Intermediate P-2-1 was synthesized in accordance with the synthesis method of Example 1, with a yield of 45% and a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.10(s,1H),8.43 - 8.42(m,3H),8.19(d,J = 2.3 Hz,1H),8.11(dd,J = 8.3,0.6 Hz,1H),7.98(s,1H),7.79(dd,J = 8.3,1.7 Hz,1H),7.66 - 7.64(m,1H),3.46(s,2H),3.43 - 3.40(m,4H),2.39 - 2.37(m,7H),1.45(s,9H). HRMS(ESI)calcd 518.2333; found,518.2326. Step 2: Synthesis of final product P-2 TIFF2025540577000055.tif28170 Intermediate P-2-1 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to obtain the following: compound P-2, 100% yield, pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 11.85(s,1H),9.86(s,2H),9.54(s,1H),8.73(d,J = 0.8 Hz,1H),8.64(d,J = 2.2 Hz,1H),8.47(d,J = 1.6 Hz,1H),8.40(dd,J HRMS(ESI)calcd 418.1808; found,418.1807.

[0064] Example 3 Synthesis of (6-((4-(benzothiazol-5-yl)-5-methylpyrimidin-2-yl)amine)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (P-3) TIFF2025540577000056.tif28170 The synthesis method was described in Example 1, and the yield was 37%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.19(s,1H),9.10(s,1H),8.56 - 8.53(m,3H),8.43(d,J = 1.6 Hz,1H),8.12(d,J = 8.3 Hz,1H),7.80 - 7.75(m,2H),3.77 - 3.60(m,4H),2.48 - 2.42(m,6H),2.36(s,3H),1.10(t,J = 7.2 Hz,3H). HRMS(ESI): calcd 460.1914; found,460.1904.

[0065] Example 4 Synthesis of tert-butyl 4-(6-((4-(benzothiazol-5-yl)-5-methylpyrimidin-2-yl)amine)nicotinoyl)piperazine-1-carboxylate (P-4) TIFF2025540577000057.tif28170 The synthesis method was described in Example 1, and the yield was 38%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.10(s,1H),8.85(s,1H),8.56(dd,J = 8.8,0.8 Hz,1H),8.51 - 8.50(m,1H),8.48(dd,J = 2.4,0.8 Hz,1H),8.43(d,J = 1.6 Hz,1H),8.12(d,J = 8.4 Hz,1H),7.80 - 7.74(m,2H),3.66 - 3.44(m,8H),2.38(s,3H),1.48(s,9H). HRMS(ESI)calcd 532.2125; found,532.2124.

[0066] <Example 5> Synthesis of (6-((4-(benzothiazol-5-yl)-5-methylpyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-5) TIFF2025540577000058.tif33170P-4 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to obtain compound P-5, 100% yield, pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 12.03(s,1H),9.80(s,2H),9.55(s,1H),8.75(s,1H),8.59(d,J = 2.0 Hz,1H),8.47(d,J = 1.5 Hz,1H),8.39(d,J = 8.3 Hz,1H),8.24(dd,J = 8.9,2.0 Hz,1H),7.93(d,J = 8.9 Hz,1H),7.88(dd,J = 8.3,1.6 Hz,1H),3.83 - 3.74(m,4H),3.18 - 3.16(m,4H),2.43(s,3H). HRMS(ESI)calcd 432.1601; found,432.1595.

[0067] Example 6 Synthesis of (6-((4-(benzothiazol-5-yl)-5-methoxypyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-6) Step 1: Synthesis of intermediate P-6-1 TIFF2025540577000059.tif28170 Intermediate P-6-1 was synthesized in accordance with the synthesis method of Example 1, with a yield of 41% and a white solid. 1H NMR(400 MHz,CDCl3)δ 9.08(s,1H),8.96(dd,J = 1.7,0.6 Hz,1H),8.52 - 8.50(m,1H),8.40(dd,J = 2.3,0.8 Hz,1H),8.37(s,1H),8.25(dd,J = 8.5,1.7 Hz,1H),8.17(s,1H),8.09(dd,J = 8.5,0.6 Hz,1H),7.80(dd,J = 8.7,2.4 Hz,1H),3.98(s,3H),3.66 - 3.47(m,8H),1.48(s,9H). HRMS(ESI)calcd 548.2074; found,548.2072. Step 2: Synthesis of final product P-6 TIFF2025540577000060.tif33170 Intermediate P-6-1 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to obtain the following: compound P-6, 100% yield, pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 11.93(s,1H),9.75(s,2H),9.53(s,1H),8.83(d,J = 1.5 Hz,1H),8.66(s,1H),8.56 - 8.55(m,1H),8.37(d,J = 8.5 Hz,1H),8.23(dd,J = 8.3,1.7 Hz,2H),7.94(d,J = 8.9 Hz,1H),4.07(s,3H),3.82 - 3.76(m,4H),3.20 - 3.16(m,4H). HRMS(ESI)calcd 448.1550; found,448.1554.

[0068] Example 7 Synthesis of 4-(benzothiazol-5-yl)-5-methoxy-N-(5-(piperazin-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine hydrochloride (P-7) TIFF2025540577000061.tif24170 Step 1: Intermediate P-7-1 was synthesized according to the synthesis method of Example 1, with a yield of 45% and a white solid. 1H NMR(400 MHz,CDCl3)δ 9.07(s,1H),8.97(dd,J = 1.6,0.6 Hz,1H),8.41(d,J = 8.5 Hz,1H),8.34(s,1H),8.26(dd,J = 8.5,1.6 Hz,1H),8.20 - 8.19(m,1H),8.08(dd,J = 8.5,0.6 Hz,1H),7.93(s,1H),7.68(d,J = 8.6 Hz,1H),3.96(s,3H),3.48(s,2H),3.45 - 3.41(m,4H),2.42 - 2.38(m,4H),1.45(s,9H).HRMS(ESI)calcd 534.2282; found,534.2277. Step 2: Intermediate P-7-1 (100 mg) was dissolved in dichloromethane (15 mL), and 3 mL of 2 M EA-HCl solution was added dropwise. The mixture was stirred for 8 hours and concentrated to obtain compound P-7, 100% yield, a pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 12.26(s,1H),10.13(s,2H),9.53(s,1H),8.83(d,J = 1.6 Hz,1H),8.70(d,J = 2.1 Hz,1H),8.66(s,1H),8.54(dd,J = 9.1,2.1 Hz,1H),8.37(d,J = 8.5 Hz,1H),8.23(dd,J = 8.5,1.7 Hz,1H),7.85(d,J = 9.1 Hz,1H),4.57(s,2H),4.08(s,3H),3.55 - 3.44(m,8H). HRMS(ESI)for C 24 H 24 FN7O2S(M + H) + : calcd 434.1758; found,434.1750.

[0069] Example 8 Synthesis of 4-(benzothiazol-5-yl)-N-(5-(piperazine-1-methylene)pyridin-2-yl)pyrimidin-2-amine hydrochloride (P-8) TIFF2025540577000062.tif24170 Step 1: Intermediate P-8-1 was synthesized according to the synthesis method of Example 1, with a yield of 47% and a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.10(s,1H),8.85(d,J = 1.7 Hz,1H),8.60(d,J = 5.2 Hz,1H),8.53(d,J = 8.5 Hz,1H),8.25 - 8.21(m,2H),8.15(s,1H),8.11(d,J = 8.4 Hz,1H),7.75(dd,J = 9.0,2.2 Hz,1H),7.35(d,J = 5.2 Hz,1H),3.50(s,2H),3.46 - 3.42(m,4H),2.43 - 2.39(m,4H),1.46(s,9H). HRMS(ESI)calcd 504.2176; found,504.2159. Step 2: Intermediate P-8-1 (100 mg) was dissolved in dichloromethane (15 mL), and 3 mL of 2 M EA-HCl solution was added dropwise. The mixture was stirred for 8 hours and concentrated to obtain compound P-8, 100% yield, a pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 11.79(s,1H),9.88(s,2H),9.55(s,1H),8.99(d,J = 1.6 Hz,1H),8.82(d,J = 5.5 Hz,1H),8.67(d,J = 2.2 Hz,1H),8.44 - 8.36(m,3H),8.04 - 8.01(m,2H),4.50(s,2H),3.51 - 3.43(m,8H). HRMS(ESI)calcd 404.1652; found,404.1650.

[0070] Example 9 Synthesis of (6-((4-(benzothiazol-5-yl)pyrimidin-2-yl)amine)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (P-9) TIFF2025540577000063.tif26170 The synthesis method was described in Example 1, and the yield was 36%, resulting in a white solid. 1H NMR(400 MHz,CDCl3)δ 9.10(s,1H),8.84(d,J = 1.7 Hz,1H),8.63(s,1H),8.61(d,J = 2.7 Hz,1H),8.45 - 8.44(m,1H),8.22(dd,J = 8.5,1.7 Hz,2H),8.12(d,J = 8.5 Hz,1H),7.86(dd,J = 8.8,2.4 Hz,1H),7.41(d,J = 5.3 Hz,1H),3.86 - 3.62(m,4H),2.56 - 2.45(m,6H),1.16 - 1.11(m,3H).HRMS(ESI)calcd 446.1758; found,446.1751.

[0071] Example 10 Synthesis of tert-butyl 4-(6-((4-(benzothiazol-5-yl)pyrimidin-2-yl)amine)nicotinoyl)piperazine-1-carboxylate (P-10) TIFF2025540577000064.tif28170 The synthesis method was described in Example 1, and the yield was 39%, resulting in a white solid. 1 H NMR(300 MHz,CDCl3)δ 9.11(s,1H),8.84(d,J = 1.6 Hz,1H),8.66 - 8.63(m,2H),8.45(dd,J = 2.4,0.8 Hz,1H),8.34(s,1H),8.23(dd,J = 8.4,1.7 Hz,1H),8.12(d,J = 8.4 Hz,1H),7.86(dd,J = 8.7,2.3 Hz,1H),7.42(d,J = 5.2 Hz,1H),3.71 - 3.48(m,8H),1.48(s,9H). HRMS(ESI)calcd 518.1969; found,518.1970.

[0072] Example 11 Synthesis of (6-((4-(benzothiazol-5-yl)pyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-11) TIFF2025540577000065.tif30170 Intermediate P-10 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to give compound P-11, 100% yield, pale yellow solid. 100% yield, white solid. 1 H NMR(400 MHz,DMSO)δ 11.59(s,1H),9.69(s,2H),9.55(s,1H),8.99(d,J = 1.5 Hz,1H),8.81(d,J = 5.4 Hz,1H),8.56(d,J = 2.0 Hz,1H),8.43 - 8.37(m,2H),8.20 - 8.11(m,2H),7.99(d,J = 5.3 Hz,1H),3.82 - 3.77(m,4H),3.21 - 3.16(m,4H). HRMS(ESI)calcd 418.1445; found,418.1440.

[0073] Example 12 Synthesis of 4-(benzothiazol-5-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyridin-2-amine (P-12) TIFF2025540577000066.tif24170 The synthesis method was described in Example 1, and the yield was 41%, resulting in a white solid. 1 H NMR(300 MHz,CDCl3)δ 9.10(s,1H),8.93(s,1H),8.54(s,1H),8.51(d,J = 3.4 Hz,1H),8.41(d,J = 8.6 Hz,1H),8.29 - 8.24(m,2H),8.12(d,J = HRMS(ESI)calcd 450.1871; found,450.1869.

[0074] Example 13 Synthesis of 4-(benzothiazol-5-yl)-5-fluoro-N-(5-(piperazine-1-methylene)pyridin-2-yl)pyrimidin-2-amine hydrochloride (P-13) TIFF2025540577000067.tif24170 Step 1: Intermediate P-13-1 was synthesized according to the synthesis method of Example 1, with a yield of 41% and a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.11(s,1H),8.93(dd,J = 1.7,0.8 Hz,1H),8.63(s,1H),8.51(d,J = 3.4 Hz,1H),8.43(dd,J = 8.6,0.8 Hz,1H),8.29(dd,J = 2.3,0.8 Hz,1H),8.26 - 8.23(m,1H),8.12(dd,J = 8.5,0.6 Hz,1H),7.74(dd,J = 8.6,2.3 Hz,1H),3.49(s,2H),3.45 - 3.43(m,4H),2.42 - 2.40(m,4H),1.46(s,9H). HRMS(ESI)calcd 522.2082; found,522.2088. Step 2: Intermediate P-13-1 (100 mg) was dissolved in dichloromethane (15 mL), and 3 mL of 2 M EA-HCl solution was added dropwise. The mixture was stirred for 8 hours and concentrated to give compound P-13, 100% yield, as a pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 11.72(s,1H),9.94(s,2H),9.57 - 9.56(m,1H),8.92 - 8.90(m,1H),8.79(s,1H),8.66(s,1H),8.44 - 8.40(m,2H),8.22 - 8.19(m,1H),8.07(dd,J = 8.9,2.7 Hz,1H),4.51(s,2H),3.53 - 3.44(m,8H). HRMS(ESI)calcd 422.1558; found,422.1558.

[0075] Example 14 Synthesis of (6-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (P-14) TIFF2025540577000068.tif28170 The synthesis method was described in Example 1, and the yield was 33%, resulting in a white solid. 1 H NMR(300 MHz,CDCl3)δ 9.12(s,1H),8.93 - 8.92(m,1H),8.67(s,1H),8.54 - 8.48(m,3H),8.26 - 8.22(m,1H),8.14(d,J = 8.5 Hz,1H),7.84(dd,J = 8.7,2.4 Hz,1H),3.79 - 3.63(m,4H),2.51 - 2.44(m,6H),1.12(t,J = 7.2 Hz,3H). HRMS(ESI)calcd 464.1663; found,464.1662.

[0076] Example 15 Synthesis of 1-(4-(6-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)ethyl-1-one (P-15) TIFF2025540577000069.tif28170 The synthesis method was described in Example 1, and the yield was 38%, resulting in a white solid. 1 H NMR(300 MHz,CDCl3)δ 9.12(s,1H),9.07(s,1H),8.92(s,1H),8.57 - 8.54(m,3H),8.26 - 8.13(m,2H),7.86(dd,J = 8.6,2.4 Hz,1H),3.72 - 3.50(m,8H),2.15(s,3H). HRMS(ESI)calcd 478.1456; found,478.1452.

[0077] Example 16 Synthesis of (4-(6-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)(cyclopropyl)ketone (P-16) TIFF2025540577000070.tif30170 The synthesis method was described in Example 1, and the yield was 41%, giving a white solid. 1 H NMR(300 MHz,CDCl3)δ 9.12(s,1H),8.93 - 8.92(m,1H),8.64(s,1H),8.56 - 8.53(m,2H),8.50(dd,J = 2.4,0.8 Hz,1H),8.26 - 8.22(m,1H),8.16 - 8.13(m,1H),7.86(dd,J = 8.7,2.3 Hz,1H),3.79 - 3.65(m,8H),1.78 - 1.72(m,1H),1.06 - 1.01(m,2H),0.85 - 0.79(m,2H). HRMS(ESI)calcd 504.1612; found,504.1603.

[0078] Example 17 Synthesis of (6-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(4-phenylpiperazin-1-yl)ketone (P-17) TIFF2025540577000071.tif28170 The synthesis method was described in Example 1, and the yield was 39%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.11(s,1H),8.93(d,J = 1.5 Hz,1H),8.54 - 8.51(m,2H),8.48(dd,J = 2.4,0.8 Hz,1H),8.35(s,1H),8.26 - 8.23(m,1H),8.14(d,J = 8.5 Hz,1H),7.87(dd,J = 8.6,2.4 Hz,1H),7.32 - 7.26(m,2H),6.96 - 6.91(m,3H),3.88 - 3.79(m,4H),3.23(brs,4H). HRMS(ESI)calcd 512.1663; found,512.1663.

[0079] Example 18 Synthesis of ethyl 4-(6-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazine-1-carboxylate (P-18) TIFF2025540577000072.tif26170 The synthesis method was described in Example 1, and the yield was 37%, resulting in a white solid. 1 H NMR(300 MHz,CDCl3)δ 9.12(s,1H),8.93 - 8.92(m,1H),8.67(s,1H),8.55 - 8.52(m,2H),8.49(dd,J = 2.4,0.8 Hz,1H),8.26 - 8.22(m,1H),8.14(dd,J = 8.7,0.8 Hz,1H),7.85(dd,J = 8.7,2.4 Hz,1H),4.18(q,J = 7.1 Hz,2H),3.70 - 3.51(m,8H),1.29(t,J = 7.1 Hz,3H). HRMS(ESI)calcd 508.1562; found,508.1556.

[0080] Example 19 Synthesis of tert-butyl 4-(6-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazine-1-carboxylate (P-19) TIFF2025540577000073.tif28170 The synthesis method was described in Example 1, and the yield was 41%, giving a white solid. 1 H NMR(300 MHz,CDCl3)δ 9.33(s,1H),9.11(d,J = 2.0 Hz,1H),8.92(s,1H),8.58 - 8.53(m,3H),8.24(d,J = 8.6 Hz,1H),8.13(dd,J = 8.6,2.0 Hz,1H),7.86(d,J = 8.7 Hz,1H),3.67 - 3.60(m,4H),3.51 - 3.47(m,4H),1.48(s,9H). HRMS(ESI)calcd 536.1875; found,536.1871.

[0081] Example 20 Synthesis of (6-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-20) TIFF2025540577000074.tif28170P-19 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to give compound P-20, 100% yield, a white solid. 1 H NMR(400 MHz,DMSO)δ 11.24(s,1H),9.58 - 9.53(m,3H),8.88(d,J = 3.3 Hz,1H),8.78(s,1H),8.51(d,J = 2.2 Hz,1H),8.43(d,J = 8.5 Hz,1H),8.21 - 8.17(m,2H),8.11 - 8.08(m,1H),3.79 - 3.76(m,3H),3.19 - 3.15(m,3H). HRMS(ESI)calcd 436.1350; found,436.1352.

[0082] <Example 21> Synthesis of (2-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyrimidin-5-yl)(4-ethylpiperazin-1-yl)ketone (P-21) TIFF2025540577000075.tif28170 The synthesis method was described in Example 1, and the yield was 37%, giving a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.11(s,1H),8.97 - 8.96(m,2H),8.78(s,2H),8.67(d,J = 3.3 Hz,1H),8.32 - 8.29(m,1H),8.13(d,J = 8.5 Hz,1H),3.88 - 3.55(m,4H),2.51 - 2.45(m,6H),1.12(t,J = 7.2 Hz,3H). HRMS(ESI)calcd 465.1616; found,465.1614.

[0083] Example 22 Synthesis of tert-butyl 4-(2-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyrimidine-5-carbonyl)piperazine-1-carboxylate (P-22) TIFF2025540577000076.tif28170 The synthesis method was described in Example 1, and the yield was 45%. 1 H NMR(300 MHz,CDCl3)δ 9.11(s,1H),8.98 - 8.97(m,1H),8.76(s,2H),8.67(d,J = 3.4 Hz,1H),8.57(s,1H),8.31(d,J = 8.7 Hz,1H),8.13(dd,J = 8.5,0.6 Hz,1H),3.72 - 3.47(m,8H),1.49(s,9H). HRMS(ESI)calcd 537.1827; found,537.1820.

[0084] Example 23 Synthesis of (2-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyrimidin-5-yl)(piperazin-1-yl)ketone hydrochloride (P-23) TIFF2025540577000077.tif28170P-22 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to give compound P-23, 100% yield, a white solid. 1 H NMR(400 MHz,DMSO)δ 10.98(s,1H),9.56(d,J = 16.5 Hz,3H),8.85(d,J = 3.3 Hz,1H),8.80(d,J = 1.5 Hz,1H),8.75(s,2H),8.39(d,J = 8.5 HRMS(ESI)calcd 437.1303; found,437.1302.

[0085] Example 24 Synthesis of (5-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-2-yl)(4-ethylpiperazin-1-yl)ketone (P-24) TIFF2025540577000078.tif28170 The synthesis method was described in Example 1, and the yield was 37%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.10(s,1H),8.90 - 8.89(m,1H),8.78(dd,J = 2.7,0.7 Hz,1H),8.45(d,J = 3.3 Hz,1H),8.34(dd,J = 8.6,2.7 Hz,1H),8.24 - 8.21(m,1H),8.12(dd,J = 8.5,0.6 Hz,1H),7.74(d,J = 8.5 Hz,1H),7.55(s,1H),3.87 - 3.76(m,4H),2.58 - 2.46(m,6H),1.11(t,J = 7.2 Hz,3H).HRMS(ESI)calcd 464.1663; found,464.1654.

[0086] Example 25 Synthesis of tert-butyl 4-(5-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-2-yl)piperazine-1-carboxylate (P-25) TIFF2025540577000079.tif28170 The synthesis method was described in Example 1, and the yield was 39%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.11(s,1H),8.91(d,J = 1.5 Hz,1H),8.78(d,J = 2.6 Hz,1H),8.46(d,J = 3.3 Hz,1H),8.35(dd,J = 8.6,2.6 Hz,1H),8.24 - 8.22(m,1H),8.13(d,J = 8.5 Hz,1H),7.79(d,J = 8.6 Hz,1H),7.44(s,1H),3.79 - 3.75(m,4H),3.58 - 3.48(m,4H),1.48(s,9H).

[0087] Example 26 Synthesis of (5-((4-(benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-2-yl)(piperazin-1-yl)ketone hydrochloride (P-26): TIFF2025540577000080.tif33170P-25 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to give compound P-26, 100% yield, a white solid. 1 H NMR(400 MHz,DMSO)δ 10.44(s,1H),9.55(s,1H),9.48(d,J = 6.5 Hz,2H),9.02(d,J = 2.5 Hz,1H),8.80(d,J = 3.5 Hz,1H),8.74(t,J = 1.3 HRMS(ESI)calcd 436.1350; found,436.1350.

[0088] Example 27 Synthesis of (6-((4-(2-(dimethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-27) TIFF2025540577000081.tif25170 Step 1: Intermediate P-27-1 was synthesized according to the synthesis method of Example 1, with a yield of 36% and a white solid. 1 H NMR(300 MHz,CDCl3)δ 8.55 - 8.52(m,2H),8.47 - 8.45(m,2H),8.33 - 8.32(m,1H),7.87 - 7.81(m,2H),7.76 - 7.73(m,1H),3.66 - 3.47(m,8H),3.26(s,6H),1.48(s,9H). HRMS(ESI)calcd 579.2297; found,579.2291. Step 2: Intermediate P-27-1 (100 mg) was dissolved in dichloromethane (15 mL), and 3 mL of 2 M EA-HCl solution was added dropwise. The mixture was stirred for 8 hours and concentrated to give compound P-27, 100% yield, as a pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 11.22(s,1H),9.54(s,2H),8.84(d,J = 3.5 Hz,1H),8.51 - 8.50(m,1H),8.25(s,1H),8.20 - 8.12(m,2H),8.06(d,J = 8.3 Hz,1H),7.88 - 7.85(m,1H),3.80 - 3.76(m,4H),3.27(s,6H),3.19 - 3.16(m,4H). HRMS(ESI)calcd 479.1772; found,479.1774.

[0089] Example 28 Synthesis of (6-((4-(2-(diethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-28) TIFF2025540577000082.tif25170 Step 1: Intermediate P-28-1 was synthesized according to the synthesis method of Example 1, with a yield of 39% and a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.39(s,1H),8.59 - 8.56(m,2H),8.52(d,J = 3.5 Hz,1H),8.29(t,J = 1.4 Hz,1H),7.86 - 7.80(m,2H),7.72(d,J = 8.2 Hz,1H),3.67 - 3.58(m,8H),3.50 - 3.47(m,4H),1.48(s,9H),1.32(t,J = 7.1 Hz,6H). HRMS(ESI)calcd 607.2610; found,607.2600. Step 2: Intermediate P-28-1 (100 mg) was dissolved in dichloromethane (15 mL), and 3 mL of 2 M EA-HCl solution was added dropwise. The mixture was stirred for 8 hours and concentrated to give compound P-28, 100% yield, a pale yellow solid. 1H NMR(400 MHz,DMSO)δ 11.35(s,1H),9.64(s,2H),8.85(d,J = 3.3 Hz,1H),8.53(s,1H),8.28(s,1H),8.18 - 8.04(m,3H),7.87(d,J = 8.3 Hz,1H),3.82 - 3.70(m,4H),3.68 - 3.64(m,4H),3.19 - 3.15(m,4H),1.27(t,J = 7.1 Hz,6H). HRMS(ESI)calcd 507.2085; found,507.2089.

[0090] Example 29 Synthesis of (5-((4-(2-(dimethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-2-yl)(4-ethylpiperazin-1-yl)ketone (P-29) TIFF2025540577000083.tif28170 The synthesis method was described in Example 1, and the yield was 33%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 8.75(d,J = 2.6 Hz,1H),8.39 - 8.34(m,2H),8.31(t,J = 1.4 Hz,1H),7.86 - 7.83(m,1H),7.76 - 7.73(m,2H),7.29(s,1H),3.88 - 3.76(m,4H),3.25(s,6H),2.61 - 2.45(m,6H),1.14 - 1.11(m,3H). HRMS(ESI)calcd 507.2085; found,507.2077.

[0091] Example 30 Synthesis of (5-((4-(2-(dimethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-2-yl)(4-isopropylpiperazin-1-yl)ketone (P-30) TIFF2025540577000084.tif28170 The synthesis method was described in Example 1, and the yield was 37%. 1H NMR(400 MHz,CDCl3)δ 8.75(d,J = 2.6 Hz,1H),8.39 - 8.34(m,2H),8.31(s,1H),7.84(d,J = 8.3 Hz,1H),7.73(d,J = 8.4 Hz,2H),7.41(s,1H),3.85 - 3.76(m,4H),3.25(s,6H),2.78 - 2.72(m,1H),2.65 - 2.54(m,4H),1.07(d,J = 6.5 Hz,6H). HRMS(ESI)calcd 521.2242; found,521.2240.

[0092] Example 31 Synthesis of tert-butyl 4-(5-((4-(2-(dimethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-1-yl)piperazine-1-carboxylate (P-31) TIFF2025540577000085.tif26170 The synthesis method was described in Example 1, and the yield was 38%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 8.75(d,J = 2.6 Hz,1H),8.40 - 8.35(m,2H),8.32(d,J = 1.7 Hz,1H),7.85 - 7.83(m,1H),7.79 - 7.73(m,2H),7.33(s,1H),3.79 - 3.75(m,4H),3.57 - 3.48(m,4H),3.26(s,6H),1.48(s,9H). HRMS(ESI)calcd 579.2297; found,579.2290.

[0093] Example 32 Synthesis of (5-((4-(2-(dimethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)ketone hydrochloride (P-32) TIFF2025540577000086.tif28170P-31 (100 mg) was dissolved in dichloromethane (15 mL), 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to obtain the following: Compound P-32, 100% yield, pale yellow solid. 1 H NMR(400 MHz,DMSO)δ 10.42(s,1H),9.63(s,2H),8.98(d,J = 2.5 Hz,1H),8.76(d,J = 3.5 Hz,1H),8.45(dd,J = 8.7,2.5 Hz,1H),8.25(s,1H),8.07(d,J = 8.4 Hz,1H),7.86 - 7.78(m,2H),3.92 - 3.88(m,4H),3.29(s,6H),3.18 - 3.13(m,4H). HRMS(ESI)calcd 479.1772; found,479.1771.

[0094] Example 33 Synthesis of (5-((4-(2-(diethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-2-yl)(4-ethylpiperazin-1-yl)ketone (P-33) TIFF2025540577000087.tif30170 The synthesis method was described in Example 1, and the yield was 38%. 1 H NMR(400 MHz,CDCl3)δ 8.74(d,J = 2.6 Hz,1H),8.39 - 8.35(m,2H),8.29(s,1H),7.82(d,J = 8.3 Hz,1H),7.75 - 7.71(m,2H),7.32(s,1H),3.87 - 3.77(m,4H),3.62(q,J = 7.1 Hz,4H),2.60 - 2.47(m,6H),1.32(t,J = 7.1 Hz,6H),1.12(t,J = 7.2 Hz,3H). HRMS(ESI)calcd 535.2398; found,535.2398.

[0095] Example 34 Synthesis of (5-((4-(2-(diethylamino)benzothiazol-5-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-2-yl)(4-isopropylpiperazin-1-yl)ketone (P-34) TIFF2025540577000088.tif31170 The synthesis method was described in Example 1, and the yield was 35%, resulting in a white solid. 1 H NMR(400 MHz,CDCl3)δ 8.75(d,J = 2.6 Hz,1H),8.38 - 8.35(m,2H),8.28(s,1H),7.81(d,J = 8.3 Hz,1H),7.75 - 7.70(m,2H),7.43(s,1H),3.85 - 3.75(m,4H),3.61(q,J = 7.1 Hz,4H),2.79 - 2.73(m,1H),2.66 - 2.55(m,4H),1.32(t,J = 7.1 Hz,6H),1.07(d,J = 6.5 Hz,6H). HRMS(ESI)calcd 549.2555; found,549.2547.

[0096] Example 35 Synthesis of 1-(4-(6-((4-(2-(dimethylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)ethyl-1-one (P-35) Compound A-12 (309 mg, 1.0 mmol) and B-15 (298 mg, 1.2 mmol) were dissolved in dioxane (10 mL). Pd(dba) (45.8 mg, 0.05 mmol), BINAP (62.3 mg, 0.1 mmol), and cesium carbonate (651.6 mg, 2.0 mmol) were then added. The mixture was purged with argon three times, heated to 100 °C, and reacted for 12 hours. After cooling, filtration, and concentration, the following was obtained by column chromatography: compound P35 (193 mg, 37% yield), a white solid. 1H NMR(300 MHz,DMSO)δ 10.36(s,1H),8.70(d,J = 3.8 Hz,1H),8.53(d,J = 1.8 Hz,1H),8.40(dd,J = 2.4,0.8 Hz,1H),8.31(d,J = 8.7 Hz,1H),8.06(dt,J = 8.8,1.2 Hz,1H),7.90(dd,J = 8.7,2.4 Hz,1H),7.59(d,J = 8.6 Hz,1H),3.55 - 3.47(m,8H),3.21(s,6H),2.03(s,3H). HRMS(ESI)calcd 521.1878; found,521.1880.

[0097] Example 36 Synthesis of (4-(cyclopropylcarbonyl)piperazin-1-yl)(6-((4-(2-(dimethylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)ketone (P-36) TIFF2025540577000090.tif28170 See synthesis in Example 35, yield 35%. 1 H NMR(300 MHz,DMSO)δ 10.33(s,1H),8.70(d,J = 3.8 Hz,1H),8.53(d,J = 1.8 Hz,1H),8.41(dd,J = 2.4,0.8 Hz,1H),8.34 - 8.31(m,1H),8.08 - 8.05(m,1H),7.91(dd,J = 8.7,2.4 Hz,1H),7.59(d,J = 8.6 Hz,1H),3.76 - 3.49(m,8H),3.21(s,6H),2.03 - 1.96(m,1H),0.77 - 0.71(m,4H). HRMS(ESI)calcd 547.2034; found,547.2032.

[0098] Example 37 Synthesis of (6-((4-(2-(dimethylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(4-arylpiperazin-1-yl)ketone (P-37) TIFF2025540577000091.tif26170 Refer to the synthesis in Example 35, the yield was 32%. 1 H NMR(400 MHz,CDCl3)δ 8.52(dd,J = 8.7,0.8 Hz,1H),8.48(dd,J = 2.4,0.8 Hz,1H),8.45 - 8.44(m,2H),8.42(d,J = 3.8 Hz,1H),8.16 - 8.13(m,1H),7.87(dd,J = 8.7,2.3 Hz,1H),7.65(d,J = 8.6 Hz,1H),7.32 - 7.28(m,2H),6.96 - 6.90(m,3H),3.89 - 3.77(m,4H),3.27(s,6H),3.25 - 3.20(m,4H). HRMS(ESI)calcd 555.2085; found,555.2084.

[0099] Example 38 Synthesis of ethyl 4-(6-((4-(2-(dimethylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazine-1-carboxylate (P-38) TIFF2025540577000092.tif30170 Refer to the synthesis in Example 35, the yield was 34%. 1 H NMR(300 MHz,CDCl3)δ 8.52(dd,J = 8.7,0.8 Hz,1H),8.47 - 8.42(m,4H),8.17 - 8.13(m,1H),7.84(dd,J = 8.7,2.3 Hz,1H),7.65(d,J = 8.6 Hz,1H),4.18(q,J = 7.1 Hz,2H),3.70 - 3.52(m,8H),3.28(s,6H),1.31 - 1.26(m,3H). HRMS(ESI)calcd 551.1984; found,551.1984.

[0100] Example 39 Synthesis of 1-(4-(6-((4-(2-(diethylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)ethyl-1-one (P-39) TIFF2025540577000093.tif28170 See synthesis in Example 35, yield 30%. 1 H NMR(300 MHz,CDCl3)δ 8.68(s,1H),8.54(dd,J = 8.8,0.8 Hz,1H),8.45 - 8.41(m,3H),8.15 - 8.12(m,1H),7.86(dd,J = 8.7,2.3 Hz,1H),7.63(d,J = 8.6 Hz,1H),3.72 - 3.54(m,12H),2.15(s,3H),1.33(t,J = 7.1 Hz,6H). HRMS(ESI)calcd 549.2191; found,549.2188.

[0101] <Example 40> Synthesis of (4-(cyclopropylcarbonyl)piperazin-1-yl)(6-((4-(2-(diethylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)ketone (P-40) TIFF2025540577000094.tif28170 Refer to the synthesis in Example 35, the yield was 31%. 1 H NMR(300 MHz,CDCl3)δ 8.89(s,1H),8.56 - 8.52(m,2H),8.45(d,J = 3.8 Hz,1H),8.43(d,J = 1.8 Hz,1H),8.13(ddd,J = 8.6,1.9,1.0 Hz,1H),7.86(dd,J = 8.7,2.4 Hz,1H),7.63(d,J = 8.6 Hz,1H),3.74 - 3.60(m,12H),1.79 - 1.73(m,1H),1.33(t,J = 7.1 Hz,6H),1.04 - 1.01(m,2H),0.85 - 0.80(m,2H). HRMS(ESI)calcd 575.2347; found,575.2344.

[0102] <Example 41> Synthesis of 1-(4-(6-((4-(2-(cyclopentylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)ethyl-1-one (P-41) TIFF2025540577000095.tif31170 Refer to the synthesis in Example 35, yield was 41%. 1 H NMR(400 MHz,CDCl3)δ 8.53 - 8.50(m,2H),8.45(dd,J = 2.4,0.8 Hz,1H),8.43 - 8.42(m,2H),8.13 - 8.10(m,1H),7.84(dd,J = 8.7,2.4 Hz,1H),7.63(d,J = 8.6 Hz,1H),5.82(s,1H),4.11 - 4.05(m,1H),3.73 - 3.53(m,8H),2.24 - 2.17(m,2H),2.15(s,3H),1.83 - 1.68(m,6H). 13 C NMR(126 MHz,CDCl3)δ 168.36,167.73,167.27,155.27,154.98,153.90,151.55,151.05,150.98,149.52,147.08,146.93,137.42,137.31,130.89 ,126.74,126.69,124.93,124.89,124.31,121.53,117.65,110.89,55.71,39.76,39.60,39.43,39.26,39.10,23.25,21.16.

[0103] <Example 42> Synthesis of (4-(6-((4-(2-(cyclopentylamine)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)(cyclopropyl)ketone (P-42) TIFF2025540577000096.tif33170 Refer to the synthesis in Example 35, the yield was 43%. 1H NMR(400 MHz,CDCl3)δ 8.65(s,1H),8.53 - 8.51(m,1H),8.47 - 8.41(m,3H),8.11 - 8.09(m,1H),7.85(dd,J = 8.7,2.4 Hz,1H),7.63(d,J = 8.6 Hz,1H),5.89(s,1H),4.12 - 4.06(m,1H),3.78 - 3.64(m,8H),2.18 - 2.14(m,2H),1.80 - 1.66(m,7H),1.05 - 1.01(m,2H),0.84 - 0.80(m,2H). 13 C NMR(126 MHz,CDCl3)δ 171.18,167.71,167.26,155.26,154.99,153.90,151.54,151.03,150.96,149.52,147.13,146.96,137.40, 137.28,130.88,126.68,124.93,124.89,124.31,121.50,117.65,110.78,55.71,32.22,23.24,10.27,7.05.

[0104] <Example 43> Synthesis of (6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (P-43) TIFF2025540577000097.tif29170 The synthesis method was described in Example 35, and the yield was 41%, giving a white solid. 1 H NMR(400 MHz,CDCl3)δ 9.62(s,1H),9.15(s,1H),8.76(s,1H),8.62 - 8.59(m,2H),8.54 - 8.51(m,1H),8.33 - 8.28(m,2H),7.89 - 7.85(m,1H),3.80 - 3.52(m,4H),2.77 - 2.72(m,1H),2.59 - 2.49(m,4H),1.06(d,J = 6.7 Hz,6H). 13C NMR(126 MHz,DMSO)δ 166.77,159.14,155.19,155.17,154.37,153.61,151.74,150.69,150.62,149.71,147.76,147.55,14 6.85,137.20,134.14,129.91,126.58,126.54,124.83,123.54,123.48,123.16,110.93,53.61,17.97.

[0105] <Example 44> Synthesis of 1-(4-(6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)ethyl-1-one (P-44) TIFF2025540577000098.tif30170 Refer to the synthesis in Example 35, the yield was 44%. 1 H NMR(400 MHz,CDCl3)δ 9.16(s,1H),8.78(s,1H),8.53 - 8.50(m,2H),8.47 - 8.44(m,2H),8.34 - 8.28(m,2H),7.86(dd,J = 8.7,2.3 Hz,1H),3.73 - 3.53(m,9H),2.15(s,3H). 13C NMR(101 MHz,DMSO)δ 168.92, 167.80, 159.73, 155.74, 155.71, 154.95, 154.35, 152.58, 151.28, 151.19, 150.04, 148.37, 148.11, 147.60, 137.93, 134.72, 130.46, 130.41, 127.16, 127.10, 125.07, 124.12, 124.05, 123.73, 111.50, 46.01, 21.73.

[0106] Example 45 Synthesis of (4-(6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)(cyclopropyl)ketone (P-45) TIFF2025540577000099.tif31170 Refer to the synthesis in Example 35, the yield was 42%.1 H NMR(400 MHz,CDCl3)δ 9.16(s,1H),8.78(s,1H),8.52(dd,J = 6.0,2.7 Hz,2H),8.46(d,J = 2.3 Hz,1H),8.35 - 8.28(m,3H),7.87(dd,J = 8.7,2.4 Hz,1H),3.81 - 3.62(m,8H),1.77 - 1.71(m,1H),1.04 - 1.02(m,2H),0.84 - 0.81(m,2H). 13 C NMR(126 MHz,DMSO)δ 171.21,167.22,159.11,155.12,155.10,154.38,153.77,151.75,150.70,150.62,149.72,147.73,147.52,14 7.06,137.44,134.15,129.87,129.83,126.57,126.52,124.48,123.51,123.45,123.14,110.93,10.30,7.06.

[0107] <Example 46> Synthesis of 4-(benzothiazol-6-yl)-N-(5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)-5-methylpyrimidin-2-amine (P-46) TIFF2025540577000100.tif25170 Refer to the synthesis in Example 35, the yield was 42%. 1 H NMR(400 MHz,CDCl3)δ 9.12(s,1H),8.45(s,1H),8.42(d,J = 8.6 Hz,1H),8.30 - 8.24(m,4H),7.82(dd,J = 8.5,1.7 Hz,1H),7.61(d,J = 8.6 Hz,1H),3.55(s,2H),3.33 - 2.86(m,9H),2.34(s,3H),1.38(d,J = 6.8 Hz,6H).

[0108] Example 47 Synthesis of tert-butyl 4-(6-((4-(benzothiazol-6-yl)-5-methylpyrimidin-2-yl)amine)nicotinoyl)piperazine-1-carboxylate (P-47) TIFF2025540577000101.tif30170 Refer to the synthesis in Example 35, the yield was 34%. 1 H NMR(400 MHz,CDCl3)δ 9.12(s,1H),8.53(dd,J = 8.7,0.8 Hz,1H),8.48 - 8.46(m,2H),8.44(dd,J = 2.4,0.8 Hz,1H),8.28 - 8.26(m,2H),7.82(dd,J = 8.6,1.7 Hz,1H),7.76(dd,J = 8.7,2.3 Hz,1H),3.66 - 3.45(m,8H),2.36(s,3H),1.48(s,9H).

[0109] <Example 48> Synthesis of (6-((4-(benzothiazol-6-yl)-5-methylpyrimidin-2-yl)amine)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (P-48) TIFF2025540577000102.tif29170 Refer to the synthesis of Example 35, the yield was 39%. 1 H NMR(400 MHz,CDCl3)δ 9.12(s,1H),8.51 - 8.49(m,1H),8.46(s,1H),8.42(d,J = 2.2 Hz,1H),8.28 - 8.26(m,3H),7.82(dd,J = 8.6,1.6 Hz,1H),7.77(dd,J = 8.7,2.3 Hz,1H),3.75 - 3.55(m,4H),2.77 - 2.71(m,1H),2.59 - 2.36(m,4H),2.36(s,3H),1.06(d,J = 6.5 Hz,6H).

[0110] <Example 49> Synthesis of (6-((4-(benzothiazol-6-yl)-5-methylpyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-49) TIFF2025540577000103.tif31170P47 (100 mg) was dissolved in dichloromethane (15 mL), and 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to give compound P49, 100% yield, as a white solid. 1 H NMR(400 MHz,DMSO)δ 11.83(s,1H),9.68(s,2H),9.56(s,1H),8.73(s,1H),8.62(d,J = 1.7 Hz,1H),8.56(d,J = 2.2 Hz,1H),8.27(d,J = 8.5 Hz,1H),8.20(dd,J = 8.9,2.1 Hz,1H),7.96 - 7.91(m,2H),3.80 - 3.76(m,4H),3.18 - 3.16(m,4H),2.42(s,3H).

[0111] Example 50 Synthesis of 4-(benzothiazol-6-yl)-N-(5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)-5-methoxypyrimidin-2-amine (P-50) TIFF2025540577000104.tif26170 Refer to the synthesis in Example 35, the yield was 52%. H NMR(400 MHz,CDCl3)δ 9.10(s,1H),8.80(dd,J = 1.7,0.7 Hz,1H),8.37(dd,J = 8.6,0.9 Hz,1H),8.35 - 8.32(m,2H),8.24(dd,J = 8.6,0.6 Hz,1H),8.21 - 8.20(m,1H),8.03(s,1H),7.68(dd,J = 8.6,2.3 Hz,1H),3.95(s,3H),3.48(s,2H),2.68 - 2.49(m,9H),1.05(d,J = 6.5 Hz,6H).

[0112] <Example 51> Synthesis of tert-butyl 4-(6-((4-(benzothiazol-6-yl)-5-methoxypyrimidin-2-yl)amine)nicotinoyl)piperazine-1-carboxylate (P-51) TIFF2025540577000105.tif30170 Refer to the synthesis in Example 35, the yield was 43%. 1 H NMR(400 MHz,CDCl3)δ 9.12(s,1H),8.79(d,J = 1.7 Hz,1H),8.53 - 8.49(m,2H),8.45(dd,J = 2.4,0.9 Hz,1H),8.39(s,1H),8.32(dd,J = 8.7,1.7 Hz,1H),8.25(d,J = 8.7 Hz,1H),7.80(dd,J = 8.7,2.4 Hz,1H),3.97(s,3H),3.65 - 3.46(m,8H),1.48(s,9H).

[0113] <Example 52> Synthesis of (6-((4-(benzothiazol-6-yl)-5-methoxypyrimidin-2-yl)amine)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (P-52) TIFF2025540577000106.tif30170 Refer to the synthesis in Example 35, the yield was 45%. 1 H NMR(400 MHz,CDCl3)δ 9.11(s,1H),8.80 - 8.79(m,1H),8.48(dd,J = 8.7,0.9 Hz,1H),8.44(dd,J = 2.4,0.8 Hz,1H),8.40(s,1H),8.38(s,1H),8.32(dd,J = 8.6,1.7 Hz,1H),8.25(dd,J = 8.7,0.6 Hz,1H),7.81(dd,J = 8.7,2.3 Hz,1H),3.96(s,3H),3.81 - 3.56(m,4H),2.79 - 2.71(m,1H),2.61 - 2.52(m,4H),1.07(d,J = 6.5 Hz, 6H).

[0114] <Example 53> Synthesis of (6-((4-(benzothiazol-6-yl)-5-methoxypyrimidin-2-yl)amine)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (P-53) TIFF2025540577000107.tif32170P51 (100 mg) was dissolved in dichloromethane (15 mL), and 3 mL of 2 M EA-HCl solution was added dropwise, stirred for 8 hours, and concentrated to give compound P53, 100% yield, as a white solid. 1 H NMR(400 MHz,DMSO)δ 12.05(s,1H),9.76(s,2H),9.58(s,1H),8.95(d,J = 1.5 Hz,1H),8.66(s,1H),8.58(d,J = 2.2 Hz,1H),8.30 - 8.24(m,3H),7.91(d,J = 9.0 Hz,1H),4.06(s,3H),3.82 - 3.76(m,4H),3.19 - 3.16(m,4H).

[0115] <Example 54> Synthesis of (6-((4-(benzothiazol-6-yl)pyrimidin-2-yl)amine)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (P-54) TIFF2025540577000108.tif30170 Refer to the synthesis in Example 35, and the yield was 42%. 1 H NMR(400 MHz,CDCl3)δ 9.13(s,1H),8.76(d,J = 1.6 Hz,1H),8.62(d,J = 5.3 Hz,1H),8.59(d,J = 8.6 Hz,1H),8.44(d,J = 2.3 Hz,1H),8.27(d,J = 8.6 Hz,1H),8.22(dd,J = 8.6,1.6 Hz,1H),7.86(dd,J = 8.6,2.3 Hz,1H),7.37(d,J = 5.2 Hz,1H),3.80 - 3.55(m,4H),2.79 - 2.72(m,1H),2.60 - 2.52(m,4H),1.07(d,J = 6.5 Hz, 6H). 13C NMR(126 MHz,DMSO)δ 167.38,163.81,159.73,159.60,159.16,155.23,154.24,147.44,137.84,13 4.95,134.07,125.64,125.34,123.79,122.10,112.14,110.35,54.29,18.50.

[0116] Example 55 Synthesis of 5-fluoro-N-(5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-amine (P-55) TIFF2025540577000109.tif25170 Refer to the synthesis in Example 35, with a yield of 51%. 1 H NMR(400 MHz,CDCl3)δ 8.64(s,1H),8.46(d,J = 3.5 Hz,1H),8.38(d,J = 8.5 Hz,1H),8.33 - 8.21(m,3H),8.08(d,J = 8.6 Hz,1H),7.70(d,J = 8.6 Hz,1H),3.54(s,2H),2.91(s,3H),2.88 - 2.50(m,9H),1.24(d,J = 17.2 Hz,6H).

[0117] Example 56 Synthesis of (6-((5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-yl)amine)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (P-56) TIFF2025540577000110.tif29170 Refer to the synthesis in Example 35, the yield was 42%. 1H NMR(400 MHz,CDCl3)δ 8.64(d,J = 1.7 Hz,1H),8.48 - 8.46(m,2H),8.44(dd,J = 2.3,0.8 Hz,1H),8.30(s,1H),8.26 - 8.24(m,1H),8.09(d,J = 8.6 Hz,1H),7.84(dd,J = 8.6,2.3 Hz,1H),3.80 - 3.55(m,4H),2.91(s,3H),2.78 - 2.72(m,1H),2.61 - 2.50(m,4H),1.07(d,J = 6.4 Hz,6H). 13 C NMR(126 MHz,CDCl3)δ 170.03,167.97,155.12,155.10,153.82,152.28,151.79,151.72,150.24,147.54,147.35,147.14,137.9 2,136.27,129.74,129.69,126.80,126.75,125.03,122.65,122.59,122.57,111.03,54.58,20.43,18.37.

[0118] Example 57 Synthesis of 1-(4-(6-((5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-yl)amine)nicotinoyl)piperazin-1-yl)ethyl-1-one (P-57) TIFF2025540577000111.tif29170 Refer to the synthesis in Example 35, the yield was 38%. 1 H NMR(400 MHz,CDCl3)δ 8.64(d,J = 1.7 Hz,1H),8.53 - 8.46(m,4H),8.26 - 8.24(m,1H),8.09(d,J = 8.6 Hz,1H),7.86(dd,J = 8.7,2.4 Hz,1H),3.76 - 3.54(m,8H),2.91(s,3H),2.15(s,3H). 13C NMR(126 MHz,CDCl3)δ 170.13,169.22,168.49,155.06,154.33,152.28,151.81,151.74,150.23,147.68,147.38,147.17,137.98,1 36.25,129.67,129.62,126.77,126.72,124.07,122.65,122.59,122.56,111.16,46.16,41.49,21.39,20.42.

[0119] <Example 58> Synthesis of (4-(cyclopropylcarbonyl)piperazin-1-yl)(6-((5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-yl)amine)pyridin-3-yl)ketone (P-58) TIFF2025540577000112.tif30170 See synthesis in Example 35, yield 30%. 1 H NMR(400 MHz,CDCl3)δ 8.70(s,1H),8.64(d,J = 1.7 Hz,1H),8.54 - 8.50(m,3H),8.26 - 8.23(m,1H),8.09(d,J = 8.6 Hz,1H),7.87(dd,J = 8.7,2.4 Hz,1H),3.79 - 3.63(m,8H),2.91(s,3H),1.78 - 1.72(m,1H),1.05 - 1.01(m,2H),0.85 - 0.80(m,2H). 13 C NMR(101 MHz,DMSO)δ 170.86,167.79,155.71,155.68,155.00,154.37,154.37,152.54,151.31,151.22,150.01,148.26,147.62,1 37.92,136.29,129.71,129.66,127.07,127.01,125.04,123.49,123.41,122.60,111.47,21.23,10.83,7.62.

[0120] <Biological evaluation experiments> <1. DYRK2 kinase activity assay> To investigate the inhibitory effect of example compounds P-1 to P-40 on DYRK2 kinase, a reaction buffer containing 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO was first prepared. DYRK2 kinase and DYRKtide substrate were then added to the reaction buffer and gently mixed. A test compound was added to the reaction mixture. 33 The reaction was initiated by adding P-ATP. The reaction was then visualized on P81 ion-exchange paper and incubated for an additional 2 hours at room temperature. Finally, the residual DYRK2 activity of the test compound group relative to the DMSO control group was calculated by measuring the amount of radioactive phosphorylated substrate remaining on the filter paper. Measured IC 50 The values ​​are shown in the following Table 2. The experimental results show that the example compounds of the present invention have strong inhibitory activity against DYRK2 kinase activity. [Table 2]

[0121] Most of the compounds prepared by the present invention have strong inhibitory activity against DYRK2 kinase, and the IC 50 The measured values ​​were less than 1000 nM, and the IC 50 The measured value was less than 20 nM. Table 2 shows that the compounds of the present invention have excellent inhibitory activity against DYRK2 kinase.

[0122] <2. Cell proliferation inhibitory activity test> The inhibitory effect of compounds on the proliferation of prostate cancer DU145 and 22Rv1 cells was measured according to the CCK-8 method. The preferred compound Example 20, Example 40, or Example 39 was co-incubated with DU145 or 22Rv1 cells in a 96-well plate for 72 hours, after which the CCK-8 reagent was added. The cells were incubated at 37°C and 5% CO2 for 2 hours. After incubation, the absorbance at 450 nm was measured using a plate reader, and the half-maximal inhibitory concentration (IC) of the inhibitory activity of the compounds on cell proliferation was calculated by fitting using GraphPad Prism 6. 50 obtained. [Table 3]

[0123] As can be seen from Table 3, the compounds of Example 20 and Example 40 significantly inhibited the proliferation of prostate cancer DU145 and 22Rv1 cells (see Figures 1 and 2).

[0124] <3. Acute Toxicity Test> 1. Acute toxicity test of compound of Example 20 ICR mice were divided into five groups: one control group and four drug-treated groups. Six mice in each group were orally administered Example 20. The control group received an equal volume of saline orally, while the four drug-treated groups received a single oral dose of the compound of Example 20 at doses of 1000 mg / kg, 2500 mg / kg, 5000 mg / kg, and 10000 mg / kg, respectively. Symptoms of toxicity and death were recorded, and dead animals were necropsied. The observation period was 14 days. The results showed that no abnormalities were observed in the mice of each group within 12 hours after administration. No animal deaths were observed within 24 hours after administration, and no animal deaths were observed after 14 days after administration. The mice were dissected and the weights of major organs such as the heart, liver, spleen, lungs, and kidneys were measured, and it was found that there was no difference in the weights of major organs between the drug-treated group and the control group. Therefore, Example 20 has no obvious toxic side effects and is safe (see Figure 3).

[0125] 2. Acute toxicity test of Example 40 compound ICR mice were divided into five groups: one control group and four drug-treated groups. Six mice in each group were orally administered Example 20. The control group received an equal volume of saline orally, while the four drug-treated groups received a single oral dose of Example 40 at doses of 1000 mg / kg, 2500 mg / kg, 5000 mg / kg, and 10000 mg / kg, respectively. Symptoms of toxicity and mortality were recorded, and dead animals were necropsied. The observation period was 14 days. The results showed that no abnormalities were observed in the mice in each group within 12 hours after administration. No animal deaths were observed within 24 hours after administration, and no animal deaths were observed after 14 days after administration. The mice were dissected and the weights of major organs such as the heart, liver, spleen, lungs, and kidneys were measured, and it was found that there was no difference in the weights of major organs between the drug-treated group and the control group. Therefore, Example 40 has no obvious toxic side effects and is safe (see Figure 4).

[0126] <IV. In vivo efficacy test for frontal adenocarcinoma> 1. In vivo efficacy test for frontal adenocarcinoma of Example 20 DU145 cells were subcutaneously inoculated into the right axilla of BALB / c nude mice, and tumors were approximately 85 mm 3 At the time when the tumors had grown to 100 mg / kg, 24 nude mice bearing tumors with good tumor growth and uniform size were selected and divided into four groups of six mice each: the model group, the low-dose group (100 mg / kg) of Example 20, the high-dose group (200 mg / kg) of Example 20, and the positive drug enzalutamide group (100 mg / kg). Tumor diameters were measured every other day, and the nude mice were weighed at the same time. After 21 days of administration, the nude mice were euthanized, and the tumors were surgically excised and weighed. According to the experimental results, the T / C (%) of the low-dose group of Example 20 against tumors transplanted into nude mice with human prostate cancer cells DU145 was 50.9%, and the tumor inhibition rate was 48.7%. The T / C (%) of the high-dose group of Example 20 against tumors transplanted into nude mice with human prostate cancer cells DU145 was 34.4%, and the tumor inhibition rate was 65.3%. The T / C (%) of the enzalutamide-positive drug group against tumors transplanted into nude mice with human prostate cancer cells DU145 was 42.0%, and the tumor inhibition rate was 57.8%, and no significant decrease in the body weight of nude mice in each group was observed during the drug administration period (see Figure 5).

[0127] 2. In vivo efficacy test for frontal adenocarcinoma of Example 40 DU145 cells were subcutaneously inoculated into the right axilla of BALB / c nude mice, and tumors were approximately 85 mm 3 At the time when the tumors had grown to 100 mg / kg, 28 nude mice bearing tumors with good growth and uniform size were selected and divided into four groups of 7 mice each: the model group, the low-dose group (80 mg / kg) of Example 20, the high-dose group (200 mg / kg) of Example 20, and the positive drug enzalutamide group (80 mg / kg). Tumor diameters were measured every other day, and the nude mice were weighed at the same time. After 21 days of administration, the nude mice were euthanized, and the tumors were surgically excised and weighed. According to the experimental results, the T / C (%) of the low-dose group of Example 40 against tumors transplanted into nude mice with human prostate cancer cells DU145 was 55.3%, and the tumor inhibition rate was 43.6%. The T / C (%) of the high-dose group of Example 20 against tumors transplanted into nude mice with human prostate cancer cells DU145 was 34.8%, and the tumor inhibition rate was 65.0%. The T / C (%) of the enzalutamide-positive drug group against tumors transplanted into nude mice with human prostate cancer cells DU145 was 38.8%, and the tumor inhibition rate was 60.9% (see Figure 6).

Claims

1. A compound of formula P, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Wherein X is O, NH, S(O) ２ , C(O) and -(CH ２ ) ｎ -, n is 0 or 1 or 2; A, B, and C are each independently selected from the group consisting of C and N; R １ are each independently hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C １ -C ８ Alkyl, haloC １ -C ８ Alkyl, C １ -C ８ Alkoxy, C ３ -C ８ Cycloalkyl, C ６ -C １０ Aryl, C ５ -C １０ Heteroaryl, C ４ -C ８ Heterocyclyl and -NR ４ R ５ wherein R ４ , R ５ are independently H, C １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, C ６ -C １０ Aryl, C ５ -C １０ Heteroaryl and C ４ -C ８ heterocyclyl; R ２ are each independently hydrogen, deuterium, hydroxy, mercapto, cyano, halogen, nitro, C ３ -C ８ Cycloalkyl, C １ -C ８ Alkyl and C １ -C ８ alkoxy; R ３ are independently hydrogen, deuterium, C １ -C ８ Alkyl, haloC １ -C ８ Alkyl, C １ -C ８ Alkoxy, C ３ -C ８ Cycloalkyl, —C(O)OC １ -C ８ Alkyl, —C(O)C ３ -C ８ Cycloalkyl, C ６ -C １０ Aryl, C ３ -C １０ Heteroaryl, C ４ -C ８ Heterocyclyl and —C(O)R ６ selected from the group consisting of R ６ However, each independently, C １ -C ８ Alkyl, C １ -C ８ Alkoxy, C ３ -C ８ Cycloalkyl and C ６ -C １０ aryl.

2. The compound according to claim 1, characterized in that it is a compound represented by formula PI or formula P-II, its stereoisomer, or a pharmaceutically acceptable salt thereof. wherein X is independently O, NH, S(O) ２ , C(O) and -(CH ２ ) ｎ -, n is 0 or 1 or 2; A, B, and C are each independently selected from the group consisting of C and N; R １ are each independently hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, nitro, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C １ -C ８ Alkyl, haloC １ -C ８ Alkyl, C １ -C ８ Alkoxy, C ３ -C ８ Cycloalkyl, C ６ -C １０ Aryl, C ３ -C １０ Heteroaryl, C ４ -C ８ Heterocyclyl and -NR ４ R ５ wherein R ４ , R ５ are independently H, C １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, C ６ -C １０ Aryl, C ３ -C １０ Heteroaryl and C ４ -C ８ heterocyclyl; R ２ are each independently hydrogen, deuterium, hydroxy, mercapto, cyano, halogen, nitro, C ３ -C ８ Cycloalkyl, C １ -C ８ Alkyl and C １ -C ８ alkoxy; R ３ are independently hydrogen, deuterium, C １ -C ８ Alkyl, haloC １ -C ８ Alkyl, C １ -C ８ Alkoxy, C ３ -C ８ Cycloalkyl, —C(O)OC １ -C ８ Alkyl, —C(O)C ３ -C ８ Cycloalkyl, C ６ -C １０ Aryl, C ３ -C １０ Heteroaryl, C ４ -C ８ Heterocyclyl and —C(O)R ６ selected from the group consisting of R ６ However, each independently, C １ -C ８ Alkyl, C １ -C ８ Alkoxy, C ３ -C ８ Cycloalkyl and C ６ -C １０ aryl.

3. X is independently C(O) or —(CH ２ ) ｎ -, n is 1; A, B, and C are each independently selected from the group consisting of C and N; R １ are each independently hydrogen, halogen, C １ -C ８ Alkyl, hydroxy, -NR ４ R ５ wherein R ４ , R ５ But H, C １ -C ６ Alkyl and C ４ -C ８ heterocyclyl; R ２ are each independently hydrogen, halogen, hydroxy, C １ -C ６ Alkyl and C １ -C ６ selected from the group consisting of alkoxy; R ３ are each independently hydrogen, C １ -C ６ Alkyl, —C(O)OC １ -C ６ Alkyl, —C(O)C ３ -C ６ Cycloalkyl, C ６ -C １０ Aryl and —C(O)R ６ selected from the group consisting of R ６ However, each independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Cycloalkyl and C ６ -C １０ 3. The compound according to claim 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of aryl.

4. X is independently C(O) or —CH ２ - selected from the group consisting of A, B, and C are each independently selected from the group consisting of C and N; R １ is hydrogen, methyl and -NR ４ R ５ wherein R ４ , R ５ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopentyl, and cyclohexyl; R ２ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, fluoro, and isopropyl; R ３ are each independently hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, —C(O)OC １ -C ６ Alkyl, phenyl and —C(O)R ６ selected from the group consisting of R ６ The compound according to claim 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein each of is independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, and cyclopropyl.

5. The compound according to any one of claims 1 to 4, its stereoisomer, or its pharmaceutically acceptable salt, characterized in that it is selected from the group consisting of compounds having the following structure, its stereoisomer, and its pharmaceutically acceptable salt: Table 1

6. The compound, its stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that the pharmacologically acceptable salt is a salt of a compound represented by formula P with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, trichloroacetic acid, propionic acid, butanoic acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, and tartaric acid.

7. A method for producing the compound according to any one of claims 1 to 6, its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising a step of subjecting intermediate compound (A) and intermediate compound (B) to a coupling reaction in the presence of a catalyst. [Among them, X, A, B, C, R １ , R ２ and R ３ The definition of the substituents is the same as that of any one of claims 1 to 6, the catalyst is a palladium catalyst; The reaction is carried out in an argon protective atmosphere, the reaction temperature is 55-125°C, and the reaction time is 5-24 hours.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmacologically acceptable salt thereof.

9. Use of the compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharmacologically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the manufacture of a medicament as a DYRK2 target inhibitor.

10. Use of the compound according to any one of claims 1 to 6, a stereoisomer thereof, a pharmacologically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the manufacture of a medicament for treating cancer or a tumor-related disease, The cancer is lung cancer, leukemia, breast cancer, prostate cancer, multiple myeloma, liver cancer, stomach cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer or endometrial cancer.

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