CDK6 / DYRK2 dual-target inhibitors and their preparation and application

Abstract

The present invention discloses a compound represented by the following general formula (I) or a pharma- ceutically acceptable salt thereof. The present invention further discloses a method for producing the above compound, and its use in the prophylaxis and / or treatment of cancer or tumor-related diseases, particularly breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, and human glioma. The compound of the present invention is expected to be developed into a new anti-cancer drug.

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, specifically to CDK6 / DYRK2 dual-target inhibitors and their preparation methods and applications. [Background technology]

[0002] Cyclin-dependent kinase 6 (CDK6) is a serine / tyrosine kinase that regulates the transition from G1 to S phase in cell cycle. In the early G1 phase, cyclin D binds to and activates CDK6, and the resulting cyclin D-CDK6 complex promotes the phosphorylation of retinoblastoma protein (Rb). Rb phosphorylation triggers the release of the transcription factor E2F, accelerating the progression from G1 to S phase in cell cycle. Increased expression of the proto-oncogene CDK6 accelerates the progression from G1 to S phase, thereby accelerating cell cycle and cell proliferation. Because uncontrolled cell proliferation is a key feature of cancer, inhibition of CDK6 can delay the progression from G1 to S phase in cell cycle, resulting in antiproliferative and anticancer effects. However, the currently approved CDK6 inhibitors, Palbociclib, Ribociclib, and Abemaciclib, are highly toxic and drug resistance has already emerged.

[0003] Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and CDKs, both members of the CMGC family, exert important regulatory roles on cell cycle and proliferation. DYRK2 regulates cell cycle-dependent Rpt3-T25 phosphorylation, promoting the degradation of CDK inhibitors such as p21 and p27, thereby promoting the progression of cells from G1 to S phase. Inhibition of DYRK2 can also delay the progression of cells from G1 to S phase, resulting in anti-proliferative and anti-cancer effects. Currently, several DYRK2 inhibitors have been reported, including the acridine compound LDN192960, which was first discovered as a Haspin kinase inhibitor and has demonstrated therapeutic activity against triple-negative breast cancer and multiple myeloma. Another drug, curcumin, has also been shown to act on DYRK2 and DYRK3, and when combined with carfilzomib, it has demonstrated some anti-multiple myeloma efficacy. However, the anticancer activity and target selectivity of existing DYRK2 inhibitors still need to be optimized, and improved drug efficacy is particularly desirable. Although targeted drugs exhibit strong efficacy and favorable safety characteristics, due to the complexity and systemic nature of cancer, when a single-target drug inhibits one pathway in cancer, related pathways are activated to compensate for the inhibited pathway, resulting in drug resistance. Summary of the Invention [Problem to be solved by the invention]

[0004] In order to solve the problem of drug resistance to conventional drugs that arise from treatments directed at a single target, the present invention provides a CDK6 / DYRK2 dual-target inhibitor that utilizes the synergistic effect of CDK6 and DYRK2 to simultaneously target CDK6 and DYRK2, and which inhibits DYRK2 while blocking the compensatory pathway between CDK6 and DYRK2, thereby improving the anti-cancer activity of the compound and reducing the drug resistance that is likely to occur with drugs that target CDK6 as a single target. The present invention provides a compound or a pharmaceutically acceptable salt thereof. The present invention also provides specific methods for producing the compounds and drugs applicable to the prevention and / or treatment of cancer or tumor-related diseases, particularly including breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, and human glioma, etc. The present invention is expected to lead to the development of next-generation anticancer drugs. [Means for solving the problem]

[0005] The present invention relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: TIFF0007728287000001.tif48167In which, X is O, (CH2) n , C(O), NH, and S(O)2, n is 0 or 1, and R1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy group, thiol group, cyano group, nitro group, C1-C8 alkyl group, haloC1-C8 alkyl group, C1-C8 alkoxy group, C3-C8 cycloalkyl group, C6-C 10 Aryl groups, C3-C 10 Heteroaryl groups, C4-C8 heterocyclic groups, and -C 0-8 -NR4R5, wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl group, thiol group, cyano group, nitro group, C1-C8 alkyl group, and C3-C8 cycloalkyl groups, and R3 is selected from the group consisting of hydrogen, deuterium, C1-C8 alkyl groups, haloC1-C8 alkyl groups, C1-C8 alkoxy groups, C3-C8 cycloalkyl groups, -C 0-8 -S(O)2R6, and -C 0-8 -C(O)OR7, wherein R4 and R5 are each independently selected from the group consisting of hydrogen, deuterium, a C1-C8 alkyl group, a haloC1-C8 alkyl group, a C1-C8 alkoxy group, and C3-C8 cycloalkyl groups, R6 and R7 are each independently selected from the group consisting of hydrogen, C1-C8 alkyl groups, haloC1-C8 alkyl groups, and It is selected from the group consisting of C3-C8 cycloalkyl groups.

[0006] Preferably, X is C(O) or (CH2) n wherein n is 0 or 1, and R1 is hydrogen, a C1-C8 alkyl group, or -C 0-8 -NR4R5, wherein R4 and R5 are hydrogen, C1-C8 alkyl group and wherein R2 is hydrogen or halogen, and R3 is selected from the group consisting of hydrogen, C1-C8 alkyl group, -C 0-8 -S(O)2R6 or -C 0-8-C(O)OR7, wherein R6 and R7 are selected from the group consisting of C1-C8 alkyl groups.

[0007] Preferably, X is C(O) or (CH2) n wherein n is 0 or 1, R1 is hydrogen, a C1-C3 alkyl group, or -NR4R5, and R4 and R5 are hydrogen, a C1-C3 alkyl group, cyclopentane, and cyclohexane, wherein R2 is hydrogen or F, R3 is hydrogen, a C1-C4 alkyl group, -S(O)2R6 or -C(O)OR7, and R6 and R7 are selected from the group consisting of C1-C4 alkyl groups.

[0008] Preferably, X is (CH2) n , and C(O), n is 0 or 1, and R1 is hydrogen, a methyl group, and -NR4R5, wherein R4 and R5 are selected from the group consisting of hydrogen, a methyl group, an ethyl group, and cyclopentane, wherein R2 is F and R3 is hydrogen, an ethyl group, an isopropyl group, -S(O)2R6, and -C(O)OR7, wherein R6 is a methyl group and R7 is a tert-butyl group; and ethyl groups.

[0009] Preferably, X is (CH2) n , and C(O), n is 0 or 1, and R1 is hydrogen, a methyl group, and -NR4R5, wherein R4 and R5 are selected from the group consisting of hydrogen, a methyl group, an ethyl group, and cyclopentane, wherein R2 is F, and R3 is hydrogen, an ethyl group, an isopropyl group, and -C(O)OR7, wherein R7 is a tert-butyl group. and ethyl groups is selected from the group consisting of:

[0010] Preferably, X is (CH2) n , and C(O), n is 0 or 1, and R1 is hydrogen, a methyl group, and -NR4R5, wherein R4 is hydrogen, a methyl group, and R5 is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopentane, wherein R2 is F, and R3 is hydrogen, an ethyl group, an isopropyl group, and -C(O)OR7, wherein R7 is a tert-butyl group. and ethyl groups is selected from the group consisting of:

[0011] Preferably, the compound according to the present invention is selected from the group consisting of general formula (I-1) to general formula (I-53). [Table 1] JPEG0007728287000003.jpg231161JPEG0007728287000004.jpg234158JPEG0007728287000005.jpg234161JPEG00077282870 00006.jpg235161JPEG0007728287000007.jpg228158JPEG0007728287000008.jpg236161JPEG0007728287000009.jpg119161

[0012] Preferably, X is (CH2) n , and C(O), n is 0 or 1, and R1 is hydrogen, a methyl group, and -NR4R5, wherein R4 and R5 are each selected from the group consisting of hydrogen, methyl, and or wherein R4 is H, R5 is cyclopentane, R2 is F, and R3 is hydrogen, ethyl, and isopropyl groups. The pharmaceutically acceptable salt is an acid addition salt of the compound of general formula (I), wherein the acid for salt formation includes inorganic acids and organic acids, the inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and the organic acids include 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.

[0013] Preferably, the pharmaceutically acceptable salt in the present invention is a hydrochloride salt.

[0014] According to the method for producing the compound of general formula (I) of the present invention, compound (I) is produced by coupling compound (A) with compound (B) in the presence of a palladium catalyst.

[0015] TIFF0007728287000010.tif21164In which, X is O, (CH2) n , C(O), and NH, S(O)2, n is 0 or 1, and R1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy group, thiol group, cyano group, nitro group, C1-C8 alkyl group, haloC1-C8 alkyl group, C1-C8 alkoxy group, C3-C8 cycloalkyl group, C6-C 10 Aryl groups, C3-C 10 Heteroaryl groups, C4-C8 heterocyclic groups, and -C 0-8 -NR4R5, wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl group, thiol group, cyano group, nitro group, C1-C8 alkyl group, and C3-C8 cycloalkyl groups, and R3 is selected from the group consisting of hydrogen, deuterium, C1-C8 alkyl groups, haloC1-C8 alkyl groups, C1-C8 alkoxy groups, C3-C8 cycloalkyl groups, -C 0-8 -S(O)2R6, and -C 0-8 -C(O)OR7, wherein R4 and R5 are each independently selected from the group consisting of hydrogen, deuterium, a C1-C8 alkyl group, a haloC1-C8 alkyl group, a C1-C8 alkoxy group, andC3-C8 cycloalkyl groups, R6 and R7 are each independently selected from the group consisting of hydrogen, C1-C8 alkyl groups, haloC1-C8 alkyl groups, and It is selected from the group consisting of C3-C8 cycloalkyl groups.

[0016] Preferably, the reaction is carried out in an argon protective atmosphere, and the reaction temperature is 95-105°C, preferably the reaction temperature is 100°C.

[0017] The present invention further relates to a compound of the above general formula (I) or a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier. Dual-targeted inhibitors of cyclin-dependent kinase 6 (CDK6) and dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) Disclose. A pharmaceutically acceptable carrier means an excipient or diluent that is not appreciably irritating to an organism and that does not interfere with the biological activity and properties of the compound being administered.

[0018] The present invention relates to the use of the above compound or a pharmaceutically acceptable salt thereof in the manufacture of a CDK6 / DYRK2 dual-target inhibitor medicament. The CDK6 / DYRK2 dual target inhibitor drug is used for the treatment of cancer or tumor-related diseases. The present invention relates to the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating cancer or tumor-related diseases, including breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer and human glioma. The drug is a dual-targeted inhibitor of cyclin-dependent kinase 6 (CDK6) and dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2).

[0019] The compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof has CDK6 / DYRK2 dual target inhibitory activity and is effective in treating malignant proliferative tumors. Terms in the present invention generally have the following meanings unless otherwise specified.

[0020] The term "alkyl group" means a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms. The term "C1-C8 alkyl group" refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl groups. The term "C1-C3 alkyl group" means a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms. The term "alkoxy" refers to an O-alkyl group. The term "C1-C8 alkoxy group" means an O-C1-C8 alkyl group. The term "C(O)" means "-C(O)-" and specifically refers to a carbonyl group. The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. The term "haloalkyl group" means an alkyl group having one or more (including one) halogen substituents. The term "cycloalkyl" means a saturated monocyclic or polycyclic ring structure of all carbon atoms. The term "C3-C8 cycloalkyl group" means a saturated monocyclic or polycyclic ring structure having a total of 3 to 8 carbon atoms. C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0021] The term "cycloalkenyl group" refers to a monocyclic or polycyclic alkyl group substituent having at least one ring-forming carbon-carbon double bond. The term "C3-C8 cycloalkenyl group" refers to a cycloalkenyl group having from 3 to 8 carbon atoms, including, but not limited to, cyclopentenyl and cyclobutenyl groups. The term "C2-C8 alkenyl group" means a straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds and having from 2 to 8 carbon atoms. The term "C2-C8 alkynyl group" means a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and having from 2 to 8 carbon atoms. The term “C6-C 10 "Aryl group" refers to an all-carbon monocyclic or fused polycyclic group having from 6 to 10 carbon atoms and having a completely conjugated π-electron system. Typical examples include, but are not limited to, phenyl and naphthyl groups. The term "heteroaryl group" refers to a monocyclic or fused ring group containing one, two, three, or four ring-forming heteroatoms selected from the group consisting of N, O, and S, the remaining ring-forming cycloatoms being C, and having a completely conjugated π-electron system. The term “C3-C 10 "Heteroaryl group" means a heteroaryl group containing from 3 to 10 carbon atoms in its ring. 10 Heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, and pyridine. The term "heterocyclic group" refers to a heterocycloalkyl group, a monocyclic or fused ring containing one or more N, O, or S heteroatoms. The term "C4-C8 heterocyclic group" means a heterocyclic group containing from 4 to 8 carbon atoms in the ring, including, but not limited to, piperazino, morpholino, piperidino, pyrrolidino, and the like. [Effects of the Invention]

[0022] Compared with the prior art, the present invention has the following notable features. The present invention discloses a novel compound represented by general formula (I), which can simultaneously inhibit multiple pathways of cancer development, has good therapeutic effect, low toxicity, favorable pharmacokinetic properties, and is less susceptible to drug resistance problems, and can be used for the preparation of medicaments for treating cancer or tumor-related diseases. The present invention further discloses a method for preparing the compounds of general formula (I). [Brief explanation of the drawings]

[0023] [Figure 1] 1 shows changes in mouse body weight in acute toxicity measurements of the present invention. [Figure 2] FIG. 1 shows the results of HE staining in acute toxicity measurement according to the present invention. [Figure 3] FIG. 1 shows the results of the present invention on tumor volume in prostate cancer. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention will be described in detail below with reference to specific examples.

[0025] <1. Synthesis of intermediate reactants> Reactant (A) and reactant (B) can be directly purchased or independently developed, and the independently developed reactant (A) and reactant (B) can be significantly reduced in cost. The specific manufacturing method of independently developed reactant (A) and reactant (B) is as follows:

[0026] (1) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)benzothiazole (A-1)

[0027] TIFF0007728287000011.tif35167 Step 1. Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzothiazole: 6-Bromobenzothiazole (0.43 g, 2.0 mmol) was dissolved in DMF (10 mL). Pinacol borate (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, heated to 80 °C, and reacted for 24 hours. After cooling, filtration, concentration, and purification by flash silica gel chromatography, 6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzothiazole (0.47 g, 90% yield) was obtained. 1 HNMR(300MHz, CDCl3)δ 9.07(s,1H),8.46(s,1H),8.14(d,J=8.2Hz,1H),7.94(dd,J=8.2,1.1Hz,1H),1.38(s,12H). formula 3

[0028] TIFF0007728287000012.tif25164 Step 2. Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)benzothiazole (A-1): Compound 2, 4-dichloro-5-fluoropyrimidine (0.23 g, 1.4 mmol) was weighed and added to a 250 mL three-neck flask. Pd(PPh)Cl (21 mg, 0.03 mmol), sodium carbonate (0.27 g, 2.5 mmol), glyme (10 mL), and HO (0.25 mL) were then added. The mixture was purged with argon three times and heated to 80 °C. Compound 6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzothiazole (0.26 g, 1.0 mmol) was dissolved in glyme (5 mL) and added dropwise to the three-neck flask. The mixture was allowed to react for 16 hours. Cooling, filtration, concentration and purification by flash silica gel chromatography gave the compound 6-(2-chloro-5-fluoropyrimidin-4-yl)benzothiazole (0.22 g, 82% yield). 1HNMR (300MHz, CDCl3) δ 9.17 (s, 1H), 8.84 (d, J = 1.7Hz, 1H), 8.58 (d, J = 3.1Hz, 1H), 8.37-8.24 (m, 2H).

[0029] (2) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylbenzothiazole (A-2) Formula 4

[0030] TIFF0007728287000013.tif22164 With reference to the synthesis method of compound (A-1), the yields were 90% and 84%, respectively. 1 H NMR(400MHz, CDCl3)δ 8.70(d,J=1.9Hz,1H),8.55(d,J=3.1Hz,1H),8.28-8.25(m,1H),8.07(d,J=8.6Hz,1H),2.90(s,3H).

[0031] (3) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N-cyclopentylbenzothiazol-2-amine (A-3)

[0032] TIFF0007728287000014.tif20164 Step 1. Synthesis of 6-bromo-N-cyclopentylbenzothiazol-2-amine: 6-Bromo-2-chlorobenzothiazole (0.50 g, 2.0 mmol) was dissolved in DMSO (10 mL), cyclopentylamine (0.19 g, 2.2 mmol) and N-ethyldiisopropylamine (0.39 g, 3.0 mmol) were added, and the mixture was purged with argon three times, heated to 80 °C, and reacted for 12 hours. After cooling, filtration, concentration, and purification by flash silica gel chromatography, the compound 6-bromo-N-cyclopentylbenzothiazol-2-amine (0.53 g, 90% yield) was obtained. 1 H NMR (400MHz, CDCl3) δ 7.68(d,J=1.7Hz,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). formula 6

[0033] TIFF0007728287000015.tif20164 Step 2: Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N-cyclopentylbenzothiazol-2-amine (A-3): The synthesis method of compound (A-1) was used as reference, and the yields were 88% and 83%, respectively. 1 H NMR(400MHz,CDCl3)δ 8.49(d,J=1.9Hz,1H),8.46(d,J=3.5Hz,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).

[0034] (4) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (A-4) Formula 7

[0035] TIFF0007728287000016.tif21164 Step 1. Synthesis of 6-bromo-N,N-dimethylbenzothiazol-2-amine: 4-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. After cooling, filtration, and concentration, the mixture was purified by flash silica gel chromatography to give the compound 6-bromo-N,N-dimethylbenzothiazol-2-amine (0.44 g, 85% yield). 1 H NMR (400MHz, CDCl3) δ 7.69 (d, J=1.9Hz, 1H), 7.41-7.35 (m, 2H), 3.20 (s, 6H). formula 8

[0036] TIFF0007728287000017.tif21164 Step 2: Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (A-4): The synthesis method for compound (A-1) was repeated, and the yields were 88% and 80%. 1 H NMR(400MHz, CDCl3)δ 8.49(d,J=1.9Hz,1H),8.45(d,J=3.6Hz,1H),8.17-8.14(m,1H),7.62(d,J=8.7Hz,1H),3.27(s,6H).

[0037] (5) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-diethylbenzothiazol-2-amine (A-5)

[0038] TIFF0007728287000018.tif22164 Step 1: Synthesis of 6-bromo-N,N-diethylbenzothiazol-2-amine: 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. After cooling, filtration, and concentration, the mixture was purified by flash silica gel chromatography to obtain the compound 6-bromo-N,N-dimethylbenzothiazol-2-amine (0.46 g, 80% yield). Scheme 10

[0039] TIFF0007728287000019.tif24164 Step 2: Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-diethylbenzothiazol-2-amine (A-5): The synthesis method of compound (A-1) was followed, and the yields were 90% and 82%. 1 H NMR(300MHz, CDCl3)δ 8.44(dd,J=8.8,2.7Hz,2H),8.13(d,J=8.6Hz,1H),7.58(d,J=8.7Hz,1H),3.61(q,J=7.2Hz,4H),1.32(t,J=7.2Hz,6H).

[0040] (6) Synthesis of (6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (B-1)

[0041] TIFF0007728287000020.tif24164 6-Aminonicotinic acid (0.28 g, 2.0 mmol) and N,N'-carbonyldiimidazole (0.39 g, 2.4 mmol) were weighed and dissolved in DMF (5 mL), reacted at 70°C for 10 minutes, stirred at room temperature for another 1 hour, N-ethylpiperazine (0.46 g, 4.0 mmol) was added, reacted at room temperature overnight, concentrated, and purified by flash silica gel chromatography to obtain the compound 6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (0.40 g, 85% yield). 1 H NMR(300MHz,CDCl3)δ 8.19-8.17(m,1H),7.57-7.54(m,1H),6.51-6.48(m,0.9Hz,1H),4.79(s,2H),3.73-3.60(m,4H),2.49-2.42(m,6H),1.13-1.08(m,3H).

[0042] (7) Synthesis of 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (B-2) Formula 12

[0043] TIFF0007728287000021.tif18164 2-Amino-5-formylpyridine (0.32 g, 2.6 mmol) and N-ethylpiperazine (0.45 g, 3.9 mmol) were dissolved in 1,2-dichloroethane (20 mL) and stirred at room temperature for 2 h. Sodium triacetylborohydride (0.87 g, 4.1 mmol) was added and stirred at room temperature for 8 h. The mixture was quenched with 1 M NaOH (30 mL), extracted with DCM (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to give 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (0.52 g, 91%). 1HNMR(300MHz,CDCl3)δ 7.94(d,J=2.3Hz,1H),7.40(dd,J=8.3,2.4Hz,1H),6.46(d,J=8.3Hz,1H),4.57(s,2H),3.36(s,2H),2.47-2.37(m,10H),1.07(t,J=7.2Hz,3H).

[0044] (8) Synthesis of tert-butyl 4-((6-aminepyridin-3-yl)methyl)piperazine-1-carboxylate (B-3) Formula 13

[0045] TIFF0007728287000022.tif18164 Referring to the synthesis method of compound (B-2), the yield was 89%. 1 HNMR(300MHz,CDCl3): δ 7.94(d,J=2.3Hz,1H),7.40(dd,J=8.4,2.3Hz,1H),6.48(d,J=8.4Hz,1H),4.54 (s,2H),3.40(t,J=5.1Hz,4H),3.36(s,2H),2.35(t,J=5.1Hz,4H),1.45(s,9H).

[0046] (9) Synthesis of tert-butyl 4-(6-aminenicotinoyl)piperazine-1-carboxylate (B-4) (Equation 14)

[0047] TIFF0007728287000023.tif23164 The yield was 87% by referring to the synthesis method of compound (B-1). 1 H NMR(300MHz,CDCl3)δ 8.18(d,J=2.2Hz,1H),7.56(dd,J=8.5,2.2Hz,1H),6.51(d,J=8.5Hz,1H),4.76(s,2H),3.65-3.56(m,4H),3.48-3.42(m,4H),1.48(s,9H).

[0048] (10) Synthesis of tert-butyl 4-(6-aminepyridin-3-yl)piperazine-1-carboxylate (B-5) (Formula 15)

[0049] TIFF0007728287000024.tif28164 Step 1: Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate: 5-Bromo-2-nitropyridine (0.41 g, 2.0 mmol), tert-butyl piperazine-1-carboxylate (0.48 g, 2.6 mmol), and triethylamine (0.41 g, 4.0 mmol) were weighed and dissolved in DMSO (5 mL). The mixture was heated to 60 °C and reacted for 18 hours. After cooling, filtration, and concentration, the mixture was purified by flash silica gel chromatography to obtain the compound tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (0.49 g, 80% yield). 1 H NMR(400MHz, CDCl3)δ 8.17-8.13(m,2H),7.22(dd,J=9.2,3.1Hz,1H),3.66-3.64(m,4H),3.49-3.46(m,4H),1.49(s,9H). formula 16

[0050] TIFF0007728287000025.tif30157 Step 2: Synthesis of tert-butyl 4-(6-aminepyridin-3-yl)piperazine-1-carboxylate: tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (0.31 g, 1.0 mmol), reduced iron powder (0.17 g, 3.0 mmol), and ammonium chloride (0.49 g, 9.0 mmol) were weighed and dissolved in 70% ethanol (10 mL). The mixture was heated to 70 °C and reacted for 6 hours. The mixture was cooled, filtered, concentrated, and purified by flash silica gel chromatography to obtain the compound tert-butyl 4-(6-aminepyridin-3-yl)piperazine-1-carboxylate (0.24 g, 85% yield). 1 H NMR(300MHz,CDCl3)δ 7.78(d,J=2.9Hz,1H),7.17(dd,J=8.8,2.9Hz,1H),6.49(d,J=8.8Hz,1H),4.19(s,2H),3.59-3.55(m,4H),2.98-2.94(m,4H),1.48(s,9H).

[0051] (11) Synthesis of 5-((4-(methanesulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (B-6) Formula 17

[0052] TIFF0007728287000026.tif18164 Referring to the synthesis method of compound (B-2), the yield was 90%. 1 H NMR(400MHz,CDCl3)δ 8.10-7.79(m,1H),7.40(d,J=8.3Hz,1H),6.57(s,1H),4.55(s,2H),3.41(s,2H),3.22(t,J=4.9Hz,4H),2.77(s,3H),2.53(t,J=5.0Hz,4H).

[0053] (12) Synthesis of ethyl 4-((6-aminepyridin-3-yl)methyl)piperazine-1-carboxylate (B-7) (Formula 18)

[0054] TIFF0007728287000027.tif19164 Referring to the synthesis method of compound (B-2), the yield was 86%. 1 H NMR(400MHz,CDCl3)δ 7.87(d,J=2.2Hz,1H),7.43(dd,J=8.5,2.3Hz,1H),6.51(d,J=8.5Hz,1H),5.71(s,2H),4.12(q, J=7.1Hz,2H), 3.46(t,J=5.1Hz,4H),3.36(s,2H),2.37(t,J=5.1Hz,4H),1.25(t,J=7.1Hz,3H).

[0055] (13) Synthesis of 5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-amine (B-8) Formula 19

[0056] TIFF0007728287000028.tif21164 Referring to the synthesis method of compound (B-2), the yield was 81%. 1H NMR(400MHz,CDCl3)δ 7.88(d,J=2.2Hz,1H),7.43(dd,J=8.4,2.2Hz,1H),6.48(d,J=8.4Hz,1H),4.95( s,2H),3.39(s,2H),2.88-2.80(m,1H),2.72-2.51(m,8H),1.10(d,J=6.6Hz,6H).

[0057] (14) Synthesis of (6-aminopyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (B-9)

[0058] TIFF0007728287000029.tif27164 Referring to the synthesis method of compound (B-1), the yield was 85%. 1 H NMR(300MHz,CDCl3)δ 8.18(s,1H),7.55(d,J=8.4Hz,1H),6.49(dd,J=8.6,2.1Hz,1H),4.86(s,2H),3 .67-3.61(m,4H),2.77-2.71(m,1H),2.55-2.51(m,4H),1.05(d,J=6.0Hz,6H).

[0059] <2. Synthesis of Compounds I-1 to I-53> Example 1: Synthesis of (6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (I-1): Formula 21

[0060] TIFF0007728287000030.tif21164 The compound 6-(2-chloro-5-fluoropyrimidin-4-yl)benzothiazole (133 mg, 0.5 mmol) and 6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (141 mg, 0.6 mmol) were dissolved in dioxane (5 mL), followed by the addition of Pd2(dba)3 (23 mg, 0.025 mmol), Xantphos (58 mg, 0.1 mmol), and cesium carbonate (326 mg, 1.0 mmol). The mixture was purged with argon three times, heated to 100°C, and reacted for 12 hours. The mixture was cooled, filtered, concentrated, and purified by column chromatography (DCM to DCM / MeOH=10:1) to give the compound (6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (88 mg, 38% yield). 1 H NMR(300MHz,CDCl3)δ 9.68(s,1H),9.15(s,1H),8.76-8.75(m,1H),8.61-8.58(m,2H),8.52(dd,J=8.7,0.9Hz,1H),8.33-8 .26(m,2H),7.86(dd,J=8.7,2.3Hz,1H),3.80-3.61(m,4H),2.51-2.44(m,6H),1.12(t,J=7.2Hz,3H).

[0061] Example 2: Synthesis of 4-(benzothiazol-6-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine (I-2): Formula 22

[0062] TIFF0007728287000031.tif19164 The yield was 43% by referring to the synthesis method of compound (I-1). 1H NMR(300MHz,CDCl3)δ 9.15(s,1H),9.11(s,1H),8.78-8.76(m,1H),8.54(d,J=3.5Hz,1H),8.41(d,J=8.6Hz,1H),8.35- 8.26(m,3H),7.73(dd,J=8.6,2.3Hz,1H),3.52(s,2H),2.58-2.47(m,10H),1.14(t,J=7.2Hz,3H).

[0063] Example 3: Synthesis of tert-butyl 4-((6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-3): Formula 23

[0064] TIFF0007728287000032.tif19164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 52%. 1 H NMR(400MHz,CDCl3)δ 9.14(s,1H),8.83(s,1H),8.77(d,J=1.5Hz,1H),8.52(d,J=3.5Hz,1H),8.41(d,J=8.6Hz,1H),8.34-8. 27(m,3H),7.75-7.73(m,1H),3.50(s,2H),3.45-3.43(m,J=5.2Hz,4H),2.43-2.40(m,4H),1.46(s,9H).

[0065] Example 4: Synthesis of 4-(benzothiazol-6-yl)-5-fluoro-N-(5-(piperazin-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine hydrochloride (I-4): Formula 24

[0066] TIFF0007728287000033.tif18164 tert-Butyl 4-((6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate was dissolved in dichloromethane, and HCl gas was introduced at 0°C and reacted for 2 hours. After completion of the reaction, the mixture was concentrated to obtain the compound 4-(benzothiazol-6-yl)-5-fluoro-N-(5-(piperazin-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine hydrochloride, with a yield of 100%. 1 H NMR(300MHz,DMSO-d6)δ 12.17(s,1H),10.08(s,1H),9.62(s,1H),8.95(t,J=2.7Hz,2H),8.71(s,1H),8.53(d,J=8 .8Hz,1H),8.30(q,J=8.7Hz,2H),7.99(d,J=9.0Hz,1H),4.57(s,2H),3.54-3.42(m,10H).

[0067] Example 5: Synthesis of tert-butyl 4-(6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)nicotinoyl)piperazine-1-carboxylate (I-5): Formula 25

[0068] TIFF0007728287000034.tif21164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 52%. 1 H NMR(400MHz,CDCl3)δ 9.16(s,1H),8.78-8.78(m,1H),8.52-8.49(m,2H),8.44(dd,J=2.4,0.8Hz,1H), 8.34-8.28(m,3H),7.84(dd,J=8.7,2.3Hz,1H),3.70-3.44(m,8H),1.48(s,9H).

[0069] Example 6: Synthesis of 6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (I-6): Formula 26

[0070] TIFF0007728287000035.tif21164 The production method for 6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride was carried out with reference to the synthesis method for compound (I-4), and the yield was 100%. 1 H NMR(400MHz,DMSO-d6)δ 11.25(s,1H),9.60-9.58(m,3H),8.93(d,J=1.6Hz,1H),8.88(d,J=3.3Hz,1H),8.51(d,J =2.2Hz,1H),8.32-8.25(m,2H),8.19-8.09(m,2H),3.79-3.76(m,4H),3.18-3.16(m,4H).

[0071] Example 7: Synthesis of tert-butyl 4-(6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (I-7): Formula 27

[0072] TIFF0007728287000036.tif23164 The yield was 47% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 9.15(s,1H),8.77-8.76(m,1H),8.45(d,J=3.4Hz,1H),8.33-8.26(m,3H),8.04-8.02( m,2H),7.38(dd,J=9.1,3.0Hz,1H),3.63-3.60(m,4H),3.11-3.09(m,4H),1.49(s,9H).

[0073] Example 8: Synthesis of 4-(benzothiazol-6-yl)-5-fluoro-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride (I-8): Formula 28

[0074] TIFF0007728287000037.tif24164 The yield was 100% according to the synthesis method of compound (I-4). 1 H NMR(400MHz,DMSO-d6)δ 11.43(s,1H),9.60(s,1H),9.33(s,2H),8.91(s,1H),8.87(d,J=3.3Hz,1H),8.33-8.23(m,2H),8.07(d ,J=9.4Hz,1H),8.01(d,J=2.9Hz,1H),7.85(d,J=9.4Hz,1H),3.44(t,J=5.1Hz,4H),3.27-3.25(m,4H).

[0075] Example 9: Synthesis of 4-(benzothiazol-6-yl)-5-fluoro-N-(5-((4-(methanesulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine (I-9): Formula 29

[0076] TIFF0007728287000038.tif19164 The yield was 45% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 9.15(s,1H),8.78-8.77(m,1H),8.48(d,J=3.4Hz,1H),8.40(dd,J=8.5,0.8Hz,1H),8.34-8.29(m,2H),8.25-8.25(m, 1H),8.18(s,1H),7.70(dd,J=8.6,2.4Hz,1H),3.53(s,2H),3.25(t,J=4.9Hz,4H),2.78(s,3H),2.58(t,J=5.0Hz,4H).

[0077] Example 10: Synthesis of ethyl 4-((6-((4-(benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-10): Formula 30

[0078] The yield was 55% by referring to the synthesis method of compound (I-1) in TIFF0007728287000039.tif18164. 1 H NMR(400MHz,CDCl3)δ 9.15(s,1H),8.78-8.77(m,1H),8.48(d,J=3.4Hz,1H),8.39(dd,J=8.6,0.8Hz,1H),8.34-8.27(m,2H),8.25-8.24(m,2 H),7.72(dd,J=8.6,2.3Hz,1H),4.13(q,J=7.1Hz,2H),3.50-3.47(m,6H),2.42(t,J=5.0Hz,4H),1.26(t,J=7.1Hz,3H).

[0079] Example 11: Synthesis of 4-(benzothiazol-6-yl)-5-fluoro-N-(5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine (I-11): Formula 31

[0080] TIFF0007728287000040.tif17164 The yield was 48% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 9.15(s,1H),8.78(d,J=1.6Hz,1H),8.48(d,J=3.5Hz,1H),8.38(dd,J=8.5,0.8Hz,1H),8.35-8.32(m,1H),8.30-8 .27(m,1H),8.25-8.23(m,2H),7.73(dd,J=8.6,2.3Hz,1H),3.50(s,2H),2.68-2.44(m,9H),1.06(d,J=6.5Hz,6H).

[0081] Example 12: Synthesis of (4-ethylpiperazin-1-yl)(6-((5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)ketone (I-12): Formula 32

[0082] TIFF0007728287000041.tif20164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 40%. 1 H NMR(400MHz,CDCl3)δ 9.25(s,1H),8.63(d,J=1.8Hz,1H),8.56-8.54(m,2H),8.51(d,J=8.7Hz,1H),8.24(dt,J=8.7,1.3Hz,1H),8.09(d,J =8.6Hz,1H),7.86(dd,J=8.7,2.4Hz,1H),3.78-3.64(m,4H),2.90(s,3H),2.51-2.46(m,6H),1.13(t,J=7.1Hz,3H).

[0083] Example 13: Synthesis of N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-amine (I-13): Formula 33

[0084] TIFF0007728287000042.tif18164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 52%. 1 H NMR(300MHz,CDCl3)δ 8.63(d,J=1.8Hz,1H),8.49-8.47(m,2H),8.38(d,J=8.6Hz,1H),8.28-8.24(m,2H),8.08(d,J=8.7Hz, 1H),7.72(dd,J=8.6,2.3Hz,1H),3.51(s,2H),2.90(s,3H),2.55-2.45(m,10H),1.11(t,J=7.2Hz,3H).

[0085] Example 14: Synthesis of tert-butyl 4-((6-((5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-14): Formula 34

[0086] TIFF0007728287000043.tif17164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 55%. 1 H NMR(300MHz,CDCl3)δ 8.63(s,1H),8.46(d,J=3.5Hz,1H),8.39(d,J=8.6Hz,1H),8.32(s,1H),8.27-8.24(m,2H),8.08(d,J=8.7Hz, 1H),7.72(d,J=8.4Hz,1H),3.49(s,2H),3.43(t,J=4.8Hz,4H),2.91(s,3H),2.42-2.39(m,4H),1.46(s,9H).

[0087] Example 15: Synthesis of 5-fluoro-4-(2-methylbenzothiazol-6-yl)-N-(5-(piperazin-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine hydrochloride (I-15): Formula 35

[0088] TIFF0007728287000044.tif16164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),9.90(s,2H),8.89(d,J=3.3Hz,1H),8.80(d,J=1.7Hz,1H),8.64(d,J=2.2Hz,1H),8.40(dd,J=9.0,2.2Hz,1H ),8.21(dt,J=8.6,1.3Hz,1H),8.13(d,J=8.6Hz,1H),8.04(d,J=8.9Hz,1H),4.50(s,2H),3.50-3.45(m,8H),2.88(s,3H).

[0089] Example 16: Synthesis of tert-butyl 4-(6-((5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-yl)amino)nicotinoyl)piperazine-1-carboxylate (I-16): Formula 36

[0090] TIFF0007728287000045.tif20164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 40%. 1 H NMR(400MHz,CDCl3)δ 9.11(s,1H),8.63(s,1H),8.55-8.51(m,3H),8.24(d,J=8.6Hz,1H),8.09(dd,J=8.7, 3.3Hz, 1H), 7.86 (dt, J=8.9, 2.6Hz, 1H), 3.67-3.46 (m, 8H), 2.91 (s, 3H), 1.48 (s, 9H).

[0091] Example 17: Synthesis of (6-((5-fluoro-4-(2-methylbenzothiazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (I-17): Formula 37

[0092] TIFF0007728287000046.tif20164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(300MHz,DMSO-d6)δ 12.04(s,1H),9.85(s,2H),8.92(d,J=2.9Hz,1H),8.81(s,1H),8.60(s,1H),8.28(d,J=9.1Hz,1H),8.21(d,J =8.7Hz,1H),8.13(d,J=8.6Hz,1H),8.06(d,J=9.0Hz,1H),3.83-3.77(m,4H),3.20-3.14(m,4H),2.88(s,3H).

[0093] Example 18: Synthesis of (6-((4-(2-(cyclopentylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (I-18): Formula 38

[0094] TIFF0007728287000047.tif19164 The yield was 45% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.90(s,1H),8.50(d,J=8.7Hz,1H),8.46(d,J=2.2Hz,1H),8.43(d,J=3.6H z,1H),8.40(d,J=1.8Hz,1H),8.07(dd,J=8.7,1.8Hz,1H),7.84(dd,J=8.7 ,2.3Hz,1H),7.64(d,J=8.5Hz,1H),6.08(s,1H),3.80-3.65(m,4H),2.52- 2.47(m,6H),2.18-2.12(m,2H),1.81-1.64(m,6H),1.13(t,J=7.2Hz,3H).

[0095] Example 19: Synthesis of N-cyclopentyl-6-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)benzothiazol-2-amine (I-19): Formula 39

[0096] TIFF0007728287000048.tif17164 The yield was 51% by referring to the synthesis method of compound (I-1). 1H NMR(400MHz,CDCl3)δ 8.59(s,1H),8.43-8.35(m,3H),8.23(d,J=2.2Hz,1H),8.08-8.05(m,1H),7.71(dd,J=8.6,2.3Hz,1H),7.64(d,J=8.6Hz,1H),6.12 (d,J=6.7Hz,1H),4.08-4.04(m,1H),3.50(s,2H),2.54-2.42(m,10H),2.19-2.11(m,2H),1.79-1.64(m,6H),1.10(t,J=7.2Hz,3H).

[0097] Example 20: Synthesis of tert-butyl 4-((6-((4-(2-(cyclopentylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-20): Formula 40

[0098] TIFF0007728287000049.tif17164 The yield was 57% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.43-8.40(m,2H),8.38(d,J=3.7Hz,1H),8.22(s,2H),8.11(d,J=7.8Hz,1H),7.79(s,1H),7.63(d,J=8.4Hz,1H),5.7 1(s,1H),4.13-4.05(m,1H),3.60-3.45(m,6H),2.57-2.43(m,4H),2.20-2.12(m,2H),1.80-1.61(m,6H),1.46(s,9H).

[0099] Example 21: Synthesis of N-cyclopentyl-6-(5-fluoro-2-((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine hydrochloride (I-21): Formula 41

[0100] TIFF0007728287000050.tif15164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(400MHz,DMSO-d6)δ 11.31(s,1H),9.80(s,2H),9.40(s,1H),8.79(d,J=3.6Hz,1H),8.60(d,J=2.2Hz,1H),8.53(d,J=1.8Hz,1H),8.32(dd,J=9.1,2.2Hz,1H),8.1 0-8.06(m,2H),7.65(d,J=8.6Hz,1H),4.44(s,2H),4.29-4.24(m,1H), 3.46-3.38(m,8H),3.17(s,1H),2.06-1.99(m,2H),1.73-1.59(m,6H).

[0101] Example 22: Synthesis of tert-butyl 4-(6-((4-(2-(cyclopentylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)nicotinoyl)piperazine-1-carboxylate (I-22): Formula 42

[0102] TIFF0007728287000051.tif19164 The yield was 53% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.82(s,1H),8.51(d,J=8.4Hz,1H),8.46-8.41(m,3H),8.09(d,J=8.3Hz,1H),7.85-7.82(m,1H),7.63(d,J=8.3 Hz,1H),6.20(s,1H),4.09-4.03(m,1H),3.68-3.45(m,8H),2.18-2.12(m,2H),1.80-1.62(m,6H),1.48(s,9H).

[0103] Example 23: Synthesis of (6-((4-(2-(cyclopentylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (I-23): Formula 43

[0104] TIFF0007728287000052.tif19164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(400MHz,DMSO-d6)δ 11.15(s,1H),9.70(s,1H),9.52(s,2H),8.80(s,1H),8.56-8.50(m,2H),8.15-8.09(m,3H),7.69(d,J=8.6Hz,1 H),4.32-4.25(m,1H),3.80-3.74(m,4H),3.33(s,1H),3.20-3.14(m,4H),2.05-1.99(m,2H),1.76-1.59(m,6H).

[0105] Example 24: Synthesis of ethyl 4-((6-((4-(2-(cyclopentylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-24): Formula 44

[0106] TIFF0007728287000053.tif15164 The yield was 56% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.82(s,1H),8.42-8.38(m,3H),8.25-8.24(m,1H),8.05(d,J=8.3Hz,1H),7.73(d,J=8.4Hz,1H),7.64(d,J=8.3Hz,1H),6.25(s,1H),4.1 4(q,J=7.0Hz,2H),4.08-4.02(m,1H),3.54-3.47(m,6H),2.46-2.42(m,4H),2.19-2.11(m,2H),1.79-1.61(m,6H),1.26(t,J=7.0Hz,3H).

[0107] Example 25: Synthesis of N-cyclopentyl-6-(5-fluoro-2-((5-((4-(methanesulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine (I-25): Formula 45

[0108] TIFF0007728287000054.tif15164 The yield was 53% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.54(s,1H),8.42-8.39(m,3H),8.24(d,J=2.3Hz,1H),8.10-8.07(m,1H),7.69(dd,J=8.6,2.3Hz,1H),7.64(d,J=8.6Hz,1H),5.96(d,J=6. 8Hz,1H),4.09-4.04(m,1H),3.52(s,2H),3.25(t,J=4.9Hz,4H),2.79(s,3H),2.58(t,J=4.9Hz,4H),2.19-2.11(m,2H),1.80-1.70(m,6H).

[0109] Example 26: Synthesis of tert-butyl 4-(6-((4-(2-(cyclopentylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (I-26): Formula 46

[0110] TIFF0007728287000055.tif20164 The yield was 44% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ8.48(s,1H),8.39(d,J=1.8Hz,1H),8.36(d,J=3.7Hz,1H),8.3 1(d,J=9.1Hz,1H),8.08-8.05(m,1H),8.03(d,J=2.9Hz,1H),7.63(d,J=8.5Hz,1H), 7.37(dd,J=9.1,3.0Hz,1H),6.10(d,J=6.6Hz,1H),4.08-4.03(m,1H),3.61(t,J=5. 1Hz, 4H), 3.09 (t, J=5.0Hz, 4H), 2.17-2.11 (m, 2H), 1.77-1.64 (m, 6H), 1.49 (s, 9H).

[0111] Example 27: Synthesis of N-cyclopentyl-6-(5-fluoro-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine hydrochloride (I-27): Formula 47

[0112] TIFF0007728287000056.tif21164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(400MHz,DMSO-d6)δ 11.97(s,1H),10.53(s,1H),9.86(s,2H),8.83(d,J=3.3Hz,1H),8.57(d,J =1.7Hz,1H),8.27(dd,J=9.6,2.6Hz,1H),8.11-8.09(m,1H),8.05(d,J=2.6 Hz,1H),7.86(d,J=9.5Hz,1H),7.77(d,J=8.6Hz,1H),4.41-4.35(m,1H),3 .52-3.50(m,4H),3.26-3.23(m,4H),2.08-2.02(m,2H),1.76-1.60(m,6H).

[0113] Example 28: Synthesis of N-cyclopentyl-6-(5-fluoro-2-((5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine (I-28): Formula 48

[0114] TIFF0007728287000057.tif17164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 50%. 1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.40-8.38(m,3H),8.23(d,J=2.2Hz,1H),8.05(dd,J=8.5,1.8Hz,1H),7.71(dd,J=8.6,2.3Hz,1H),7.65(d,J=8 .6Hz,1H),6.32(d,J=6.2Hz,1H),4.07-4.02(m,1H),3.49(s,2H),2.70-2 .55(m,9H),2.18-2.11(m,2H),1.80-1.64(m,6H),1.06(d,J=6.5Hz,6H).

[0115] Example 29: Synthesis of (6-((4-(2-(cyclopentylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (I-29): Formula 49

[0116] TIFF0007728287000058.tif19164 The yield was 48% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 9.04(s,1H),8.52-8.39(m,4H),8.05(dd,J=8.4,1.9Hz,1H),7.85(dt,J=8.6,2.2Hz,1H),7.64(dd,J=8.6,1.8Hz,1H),6.19(s,1H),4. 09-4.04(m,1H),3.73-3.62(m,4H),2.79-2.75(m,1H),2.60-2.55(m,4H),2.18-2.13(m,2H),1.78-1.64(m,6H),1.08(d,J=6.6Hz,6H).

[0117] Example 30: Synthesis of 6-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (I-30): Formula 50

[0118] TIFF0007728287000059.tif17164 The yield was 42% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.45(d,J=1.8Hz,1H),8.38-8.36(m,2H),8.21(d,J=2.3Hz,1H),8.15(dt,J=8.7,1.2Hz,1H),7.94(s,1H),7.71(d d,J=8.6,2.3Hz,1H),7.65(d,J=8.6Hz,1H),3.49(s,2H),3.27(s,6H),2.60-2.36(m,10H),1.09(t,J=7.2Hz,3H).

[0119] Example 31: Synthesis of (6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (I-31): Formula 51

[0120] TIFF0007728287000060.tif24164 6-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (154 mg, 0.5 mmol) and 6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (141 mg, 0.6 mmol) were dissolved in dioxane (5 mL), followed by the addition of Pd(dba) (23 mg, 0.025 mmol), BINAP (31 mg, 0.05 mmol), and sodium tert-butoxide (96 mg, 1.0 mmol). The mixture was purged with argon three times, heated to 100°C, and reacted for 12 hours. The mixture was cooled, filtered, concentrated, and purified by column chromatography (DCM to DCM / MeOH=10:1) to give the compound (6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (139 mg, 55% yield). 1H NMR(400MHz,DMSO-d6)δ 10.27(s,1H),8.69(d,J=3.8Hz,1H),8.52(d,J=2.0Hz,1H),8.35(d,J=2.4Hz,1H),8.31(d,J=8.7Hz,1H),8.06(d,J=8.6Hz,1H) ,7.86(dd,J=8.6,2.4Hz,1H),7.59(d,J=8.6Hz,1H),3.59-3.47(m,4H),3.21(s,6H),2.44-2.34(m,6H),1.01(t,J=7.1Hz,3H).

[0121] Example 32: Synthesis of tert-butyl 4-((6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-32): Formula 52

[0122] TIFF0007728287000061.tif17164 The yield was 48% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.45(d,J=1.8Hz,1H),8.40-8.36(m,2H),8.20(d,J=2.2Hz,1H),8.15(dt,J=8.8,1.2Hz,1H),7.94(s,1H),7.71(dd,J =8.6,2.3Hz,1H),7.65(d,J=8.6Hz,1H),3.48(s,2H),3.45-3.42(m,4H),3.27(s,6H),2.41-2.39(m,4H),1.46(s,9H).

[0123] Example 33: Synthesis of 6-(5-fluoro-2-((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine hydrochloride (I-33): Formula 53

[0124] TIFF0007728287000062.tif15164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(300MHz,DMSO-d6)δ 11.44(s,1H),9.83(s,2H),8.79(d,J=2.9Hz,1H),8.59(d,J=11.9Hz,2H),8.35(d,J=8.9Hz,1H), 8.07(dd,J=14.1,8.8Hz,2H),7.65(d,J=8.6Hz,1H),4.46(s,2H),3.49-3.41(m,8H),3.24(s,6H).

[0125] Example 34: Synthesis of tert-butyl 4-(6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)nicotinoyl)piperazine-1-carboxylate (I-34): Formula 54

[0126] TIFF0007728287000063.tif19164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 50%. 1 H NMR(400MHz,CDCl3)δ 8.91(s,1H),8.53(dd,J=8.6,0.8Hz,1H),8.50(dd,J=2.4,0.8Hz,1H),8.45(d,J=3.8Hz,1H),8.44(d,J=1.8Hz,1H),8.16-8.1 3(m,1H),7.84(dd,J=8.7,2.4Hz,1H),7.66(d,J=8.6Hz,1H),3.70-3.59(m,4H),3.51-3.46(m,4H),3.27(s,6H),1.48(s,9H).

[0127] Example 35: Synthesis of (6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(piperazin-1-yl)ketone hydrochloride (I-35): Formula 55

[0128] TIFF0007728287000064.tif19164 The synthesis method for compound (I-1) was repeated, and the yield was 100%. 1 H NMR(300MHz,CDCl3)δ 11.70(s,1H),9.84(s,1H),9.71(s,1H),8.83(s,1H),8.58(d,J=17.9Hz,2H),8.21(d,J=8.9Hz,1 H),8.14-8.05(m,2H),7.70(d,J=8.6Hz,1H),3.35-3.32(m,4H),3.28(s,6H),3.20-3.15(m,4H).

[0129] Example 36: Synthesis of 6-(5-fluoro-2-((5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (I-36): Formula 56

[0130] TIFF0007728287000065.tif18164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 52%. 1 H NMR(400MHz,CDCl3)δ 8.45(d,J=1.8Hz,1H),8.38(dd,J=6.3,2.4Hz,2H),8.23(d,J=2.3Hz,1H),8.16-8.14(m,2H),7.71(dd,J=8 .6,2.3Hz,1H),7.65(d,J=8.6Hz,1H),3.49(s,2H),3.27(s,6H),2.68-2.54(m,9H),1.05(d,J=6.5Hz,6H).

[0131] Example 37: Synthesis of 6-(5-fluoro-2-((5-((4-(methanesulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine (I-37): Formula 57

[0132] TIFF0007728287000066.tif15164 The yield was 43% by referring to the synthesis method of compound (I-1). 1H NMR(400MHz,CDCl3)δ 8.44-8.35(m,3H),8.21(d,J=7.7Hz,1H),8.16-8.07(m,2H),7.71(s,1H),7.66 -7.61(m,1H),3.55(s,2H),3.29-3.25(m,10H),2.79(s,3H),2.63-2.57(m,4H).

[0133] Example 38: Synthesis of ethyl 4-((6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-38): Formula 58

[0134] TIFF0007728287000067.tif15164 The yield was 53% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.44-8.36(m,3H),8.31-8.23(m,2H),8.15(d,J=8.3Hz,1H),7.73(s,1H),7.65(d,J=8.3Hz,1H), 4.13(q,J=7.1Hz,2H),3.52-3.49(m,6H),3.27(s,6H),2.46-2.41(m,4H),1.26(t,J=7.3Hz,3H).

[0135] Example 39: Synthesis of (6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (I-39): Formula 59

[0136] TIFF0007728287000068.tif19164 The yield was 44% by referring to the synthesis method of compound (I-1). 1H NMR(400MHz,CDCl3)δ 8.73(s,1H),8.52-8.48(m,2H),8.45-8.44(m,2H),8.16-8.13(m,1H),7.85(dd,J=8.7,2.4Hz,1H),7.65(d, J=8.6Hz,1H),3.75-3.63(m,4H),3.27(s,6H),2.79-2.75(m,1H),2.62-2.55(m,4H),1.08(d,J=6.5Hz,6H).

[0137] Example 40: Synthesis of tert-butyl 4-(6-((4-(2-(dimethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (I-40): Formula 60

[0138] TIFF0007728287000069.tif21164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 40%. 1 H NMR(400MHz,CDCl3)δ 8.44(s,1H),8.36-8.33(m,2H),8.25(s,1H),8.14(dd,J=8.7,1.6Hz,1H),8.00(d,J=2.8Hz,1H),7.64(dd, J=8.6,1.2Hz,1H),7.40(dd,J=9.3,2.9Hz,1H),3.61(t,J=5.0Hz,4H),3.27(s,3H),3.09(t,J=5.0Hz,4H).

[0139] Example 41: Synthesis of 6-(5-fluoro-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N-dimethylbenzothiazol-2-amine hydrochloride (I-41): Formula 61

[0140] JPEG0007728287000070.jpg22163 The synthesis method for compound (I-4) was referenced, and the yield was 100%. 1H NMR(400MHz,DMSO-d6)δ 11.99(s,1H),9.77(s,2H),8.81(d,J=3.5Hz,1H),8.57(d,J=1.8Hz,1H),8.28(dd,J=9.7,2.8Hz,1H),8.12-8.05(m,1H),8 .02(d,J=2.9Hz,1H),7.82(d,J=9.6Hz,1H),7.69(d,J=8.6Hz,1H),3.49(t,J=5.1Hz,4H),3.27(s,6H),3.25-3.23(m,4H).

[0141] Example 42: Synthesis of (6-((4-(2-(diethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-ethylpiperazin-1-yl)ketone (I-42): Formula 62

[0142] TIFF0007728287000071.tif21164 The yield was 44% by referring to the synthesis method of compound (I-1). 1 H NMR(300MHz,CDCl3)δ 8.56(s,1H),8.50(d,J=8.7Hz,1H),8.47(d,J=2.3Hz,1H),8.43-8.41(m,2H),8.13(dd,J=8.7,1.7Hz,1H),7.84(dd,J=8. 7,2.4Hz,1H),7.62(d,J=8.6Hz,1H),3.80-3.60(m,8H),2.54-2.47(m,6H),1.33(t,J=7.1Hz,6H),1.13(t,J=7.1Hz,3H).

[0143] Example 43: Synthesis of N,N-diethyl-6-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-ylbenzothiazol-2-amine (I-43): Formula 63

[0144] TIFF0007728287000072.tif20164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 38%.1 H NMR(400MHz,CDCl3)δ 8.69(s,1H),8.43-8.39(m,3H),8.29(d,J=2.3Hz,1H),8.15-8.12(m,1H),7.71(dd,J=8.6,2.3Hz,1H),7.62(d,J= 8.6Hz,1H),3.63(q,J=7.2Hz,4H),3.50(s,2H),2.53-2.42(m,10H),1.33(t,J=7.1Hz,6H),1.10(t,J=7.2Hz,3H).

[0145] Example 44: Synthesis of tert-butyl 4-((6-((4-(2-(diethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-44): Formula 64

[0146] TIFF0007728287000073.tif20164 The yield was 48% by referring to the synthesis method of compound (I-1). 1 H NMR(400MHz,CDCl3)δ 8.45(s,1H),8.43-8.39(m,3H),8.26(d,J=2.2Hz,1H),8.15-8.12(m,1H),7.73(d,J=8.2Hz,1H),7.62(d,J=8.6Hz, 1H),3.63(q,J=7.1Hz,4H),3.51(s,2H),3.46-3.44(m,4H),2.44-2.41(m,4H),1.46(s,9H),1.33(t,J=7.1Hz,6H).

[0147] Example 45: Synthesis of N,N-diethyl-6-(5-fluoro-2-((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine hydrochloride (I-45): Formula 65

[0148] TIFF0007728287000074.tif18164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1H NMR(400MHz,DMSO-d6)δ 11.71(s,1H),9.94(s,2H),8.80(d,J=3.6Hz,1H),8.65(d,J=2.2Hz,1H),8.56(d,J=1.8Hz,1H),8.42(dd,J=8.9,2.2Hz,1H),8.11-8. 08(m,1H),8.01(d,J=8.9Hz,1H),7.65(d,J=8.6Hz,1H),4.51(s,2H),3.63(q,J=7.1Hz,4H),3.50-3.44(m,8H),1.26(t,J=7.1Hz,6H).

[0149] Example 46: Synthesis of tert-butyl 4-(6-((4-(2-(diethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)nicotinoyl)piperazine-1-carboxylate (I-46): Formula 66

[0150] TIFF0007728287000075.tif21164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 40%. 1 H NMR(400MHz,CDCl3)δ 8.99(s,1H),8.53(dd,J=8.7,0.8Hz,1H),8.51(dd,J=2.4,0.9Hz,1H),8.45(d,J=3.8Hz,1H),8.42(d,J=1.9Hz,1H),8.15-8.12(m, 1H),7.84(dd,J=8.8,2.4Hz,1H),7.64(d,J=8.6Hz,1H),3.67-3.61(m,8H),3.50-3.47(m,4H),1.48(s,9H),1.34(t,J=7.1Hz,6H).

[0151] Example 47: Synthesis of (6-((4-(2-(diethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(piperazin-1-yl)ketone (I-47): Formula 67

[0152] TIFF0007728287000076.tif21164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(400MHz,DMSO-d6)δ 11.78(s,1H),10.03(s,1H),9.88(s,2H),8.83(d,J=3.6Hz,1H),8.60(d,J=1.8Hz,1H),8.58(d,J=2.1Hz,1H),8.23(dd,J=8.9,2.2H z,1H),8.13-8.07(m,2H),7.71(d,J=8.6Hz,1H),3.86-3.78(m,3H),3.67(q,J=7.1Hz,4H),3.19-3.15(m,3H),1.27(t,J=7.1Hz,6H).

[0153] Example 48: Synthesis of N,N-diethyl-6-(5-fluoro-2-((5-((4-(methanesulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine (I-48): Formula 68

[0154] TIFF0007728287000077.tif18164 The yield was 44% by referring to the synthesis method of compound (I-1). 1 H NMR(300MHz,CDCl3)δ 8.92(s,1H),8.44-8.42(m,3H),8.32-8.21(m,1H),8.13(d,J=8.6Hz,1H),7.70(dd,J=8.6,2.3Hz,1H),7.62(d,J=8.7Hz, 1H),3.63(q,J=7.2Hz,4H),3.52(s,2H),3.25(t,J=4.8Hz,3H),2.78(s,3H),2.58(t,J=4.7Hz,4H),1.33(t,J=7.1Hz,6H).

[0155] Example 49: Synthesis of ethyl 4-((6-((4-(2-(diethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazine-1-carboxylate (I-49): Formula 69

[0156] TIFF0007728287000078.tif17164 The synthesis of compound (I-1) was carried out in reference to the synthesis method, and the yield was 50%. 1 H NMR(300MHz,CDCl3)δ 8.82(s,1H),8.45-8.42(m,3H),8.30(d,J=2.2Hz,1H),8.13(d,J=8.6Hz,1H),7.74(d,J=8.6Hz,1H),7.62(d,J=8.6Hz,1H),4. 13(q,J=7.2Hz,2H),3.63(q,J=7.2Hz,4H),3.53-3.49(m,6H),2.46-2.42(m,4H),1.33(t,J=7.1Hz,6H),1.26(t,J=7.1Hz,3H).

[0157] Example 50: Synthesis of N,N-diethyl-6-5-fluoro-2-((5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine (I-50): Formula 70

[0158] TIFF0007728287000079.tif20164 The yield was 48% by referring to the synthesis method of compound (I-1). 1 H NMR(300MHz,CDCl3)δ 9.05(s,1H),8.45-8.40(m,3H),8.32(d,J=2.3Hz,1H),8.14(d,J=8.6Hz,1H),7.71(dd,J=8.7,2.3Hz,1H),7.61(d, J=8.7Hz,1H), 3.62(q,J=7.2Hz,4H),3.49(s,2H),2.68-2.55(m,9H),1.32(t,J=7.1Hz,6H),1.05(d,J=6.4Hz,6H).

[0159] Example 51: Synthesis of (6-((4-(2-(diethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)(4-isopropylpiperazin-1-yl)ketone (I-51): Formula 71

[0160] TIFF0007728287000080.tif21164 The yield was 47% by referring to the synthesis method of compound (I-1). 1 H NMR(300MHz,CDCl3)δ 9.69(s,1H),8.60(d,J=2.3Hz,1H),8.54(d,J=8.7Hz,1H),8.50(d,J=3.7Hz,1H),8.41(s,1H),8.12(d,J=8.6Hz,1H),7.86(dd,J=8.7,2 .3Hz,1H),7.62(d,J=8.6Hz,1H),3.77-3.59(m,8H),2.78-2.72(m,1H),2.59-2.54(m,4H),1.32(t,J=7.1Hz,6H),1.07(d,J=6.4Hz,6H).

[0161] Example 52: Synthesis of tert-butyl 4-(6-((4-(2-(diethylamino)benzothiazol-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (I-52): Formula 72

[0162] TIFF0007728287000081.tif23164 The yield was 49% by referring to the synthesis method of compound (I-1). 1 H NMR(300MHz,CDCl3)δ 8.58(s,1H),8.41(d,J=1.8Hz,1H),8.37(d,J=4.0Hz,1H),8.34(d,J=9.1Hz,1H),8.14-8.10(m,1H),8.06(d,J=2.9Hz,1H),7. 61(d,J=8.6Hz,1H),7.38(dd,J=9.1,3.0Hz,1H),3.66-3.58(m,8H),3.09(t,J=5.1Hz,4H),1.49(s,9H),1.32(t,J=7.1Hz,6H).

[0163] Example 53: Synthesis of N,N-diethyl-6-(5-fluoro-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)benzothiazol-2-amine hydrochloride (I-53): Formula 73

[0164] TIFF0007728287000082.tif24164 The synthesis of compound (I-4) was carried out in reference to the synthesis method, and the yield was 100%. 1 H NMR(300MHz,DMSO-d6)δ 12.15(s,1H),10.04(s,2H),8.79(s,1H),8.57(s,1H),8.34(d,J=9.3Hz,1H),8.08-8.05(m,2H),7.87(d,J=8 .9Hz,1H),7.71(d,J=8.4Hz,1H),3.69-3.67(m,4H),3.56-3.53(m,4H),3.27-3.23(m,4H),1.30-1.25(m,6H). In the above examples, the corresponding pharmaceutically acceptable salts were obtained by dissolving the main product in dichloromethane, introducing HCl gas at 0°C, reacting for 2 hours, and concentrating the mixture after completion of the reaction to obtain the corresponding hydrochloride salt.

[0165] <3. Biological Evaluation Experiments> (1) CDK6 kinase activity analysis test method This experiment was performed using the PerkinElmer Lance Ultra assay. Protein kinase, ULight-labeled polypeptide substrate, ATP, and compounds were mixed in a test plate and incubated. The reaction was then stopped by adding EDTA, and a europium (Eu) chelate-labeled antibody was added for testing. This experiment was performed using a PerkinElmer Envision instrument in TR-FRET mode. After excitation at wavelengths of 320 / 340 nm, fluorescence signals were emitted at wavelengths of 665 nm and 615 nm. Eu transferred energy to the adjacent fluorescent ULight acceptor, which could then be further detected.

[0166] Measured IC 50The values ​​are shown in Table 2 below, and the experimental results show that the example compounds of the present invention have strong inhibitory activity against CDK6 kinase activity. [Table 2]

[0167] (2) DYRK2 kinase activity analysis test method The inhibitory activity of the compounds of the present invention against DYRK2 kinase was measured. The method was briefly described below. (For the specific method, see Banerjee S, Wei T, Wang J, et al. Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression [J]. Proceedings of the National Academy of Sciences, 2019, 116(49): 24881-24891.) 1) Compounds were added at various concentrations to a 384-well experimental plate, the wells were sealed, and then DYRK2 protein and the substrate Woodtide (KKISGRLSPIMTEQ) were added. 33 P-γATP was added and mixed evenly. 2) Incubated at room temperature for 30 minutes. 3) The reaction was stopped with 0.5 M (3%) orthophosphoric acid solution, then transferred to a P81 plate, and washed with 50 mM orthophosphoric acid solution. 4) IC 50 The results were calculated using GraphPad Prism software. Measured IC 50 The values ​​are shown in Table 3 below, and the experimental results demonstrate that the example compounds of the present invention have strong inhibitory activity against DYRK2 kinase activity. [Table 3]

[0168] (3) Measurement of inhibitory effects on the proliferation of multiple types of cancer cells The inhibitory activity of the compounds against 14 types of cell proliferation was measured using the following methods: human breast cancer (MCF-7, triple-negative breast cancer MDA-MB-231) cell lines, multiple myeloma (RPMI8226) cell lines, leukemia (K562) cell lines, gastric cancer (MGC-803) cell lines, ovarian cancer (SK-OV-3) cell lines, colon cancer (HT-29) cell lines, liver cancer (HepG2) cell lines, pancreatic cancer (Panc-1) cell lines, human glioma (U251) cell lines, lung cancer (A-549, non-small cell lung cancer NCI-H1299) cell lines, and prostate cancer (PC-3, Du-145) cell lines. Experimental procedure: The inhibitory effect of compounds on the proliferation of multiple types of cancer cells was measured using the MTT method, and the half-maximal inhibitory concentration (IC) of the compound was measured. 50 was obtained. 1) 1 x 10 cells in logarithmic growth phase 5 Cells were seeded into a 96-well plate at 1000 cells / well and cultured at 37°C in 5% CO2 until the cells reached 90% confluence. After that, the cells were synchronized by incubating them for 2 hours in serum-free DMEM medium, RPMI-1640 medium, L-15 medium, F12K medium, MEM medium, F-12 medium, or IMDM medium (the medium corresponding to each cell type was used). 2) 100 μL of gradient diluted test compound solutions at each concentration was added to the culture plate, and the culture plate was incubated at 37° C. in a 5% CO 2 incubator for 72 hours. 3) Four hours before the completion of incubation, 20 μL of MTT solution (5 mg / mL) was added per well. After the incubation was completed, the supernatant was discarded from each well, 150 μL of DMSO was added per well, and the wells were shaken for 10 minutes using a cell shaker to thoroughly dissolve the crystals. After that, the OD was measured using a multiplate reader. 570 The inhibition rate was calculated as follows: Inhibition rate = (OD value of control group - OD value of experimental group) / OD value of control group x 100%. 4) After obtaining the data, perform fitting using GraphPad Prism 6 to obtain IC 50 was obtained.

[0169] The compound (I-31) of Example 31 and the approved drug, CDK4 / 6 inhibitor, Palbociclib, were tested for their anti-cancer cell proliferation activity, and the measured IC 50 The values ​​are shown in Table 4. Compound I-31 exhibited cell proliferation inhibitory effects against 14 cell lines, including human breast cancer (MCF-7, triple-negative breast cancer MDA-MB-231), multiple myeloma (RPMI8226), leukemia (K562), gastric cancer (MGC-803), ovarian cancer (SK-OV-3), colon cancer (HT-29), liver cancer (HepG2), pancreatic cancer (Panc-1), human glioma (U251), lung cancer (A-549, non-small cell lung cancer NCI-H1299), and prostate cancer (PC-3, Du-145). The inhibitory effects against all 14 cell lines were stronger than those of the approved drug, the CDK4 / 6 inhibitor Palbociclib.

[0170] [Table 4]

[0171] (4) Compound acute toxicity measurement Subjects: ICR mice; 18-22 g; half male and half female; 40 mice in total. Grouping and dose setting: (1) control group: 10 mice, half of which were given the same amount of saline intragastrically; (2) 2500 mg / kg group: 10 mice, half of which were given the drug intragastrically; (3) 5000 mg / kg group: 10 mice, half of which were given the drug intragastrically; (4) 10000 mg / kg group: 10 mice, half of which were given the drug intragastrically;

[0172] [Table 5]

[0173] Laboratory environment: room temperature 24 (2°C), relative humidity 60 (70%). Observation parameters: the test drug (compound prepared in Example 31) was administered once at the doses shown in Table 5, and the symptoms of toxicity and death of the mice were recorded. The dead animals were examined post-mortem. The observation period was 14 days. The results showed that no abnormalities were observed in the animals within 12 hours after administration of each group of mice. No animal deaths were observed within 24 hours after administration, and no animal deaths were observed after administration on the 14th day. No other obvious abnormalities were observed. The changes in body weight are shown in FIG. 1, and no obvious toxic reaction was observed in the cases of intragastric administration of 2500 mg / kg, 5000 mg / kg, and 10000 mg / kg compared to the control group. The HE staining results are shown in Figure 2, and no obvious toxic reaction was observed in the major organs such as the heart, liver, spleen, lungs, and kidneys with the compound (I-31) prepared in Example 31.

[0174] (5) Measurement of compound pharmacokinetics The test product was weighed and placed in a sterile vial, and 250 μL of DMSO was added, followed by 10 μL of methanesulfonic acid. After dissolution, 4.78 mL of 5% glucose injection was added, ultrasonically cleaned, and the mixture was shaken to homogenize, resulting in a 2 mg / mL test product solution, which was used as an intragastric formulation. Also, 0.5 mL of the 2 mg / mL test product solution was taken, and 4.5 mL of 5% glucose injection was added, followed by shaking to homogenize, resulting in a 0.2 mg / mL test product solution, which was used as an intravenous injection formulation. Six SD rats were divided into two groups and administered Example 31 via tail vein injection (1 mg / kg) or intragastric administration (10 mg / kg). For the intravenous group, approximately 0.25 mL of blood samples were collected from the retroorbital venous plexus at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h after administration; for the intragastric group, approximately 0.25 mL of blood samples were collected from the retroorbital venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. The concentrations of Example 31 in the SD rat plasma samples were measured using LC-MS / MS, and pharmacokinetic parameters were calculated using WinNolin software. The results are shown in Table 6.

[0175] The results showed that the compound (I-31) of Example 31 of the present invention was well metabolized in the body of rats, had excellent absorption and exposure, and had high bioavailability. [Table 6]

[0176] (6) Anti-lung cancer activity of compounds The drugs used were compound (I-31) prepared in Example 31 and the approved CDK4 / 6 inhibitor Palbociclib. The cell line used was the human non-small cell lung cancer cell line A-549 cultured in RPMI-1640 medium containing 10% fetal bovine serum. The test animals were SPF BALB / c nude mice; male; five per group. The drug dosages are shown in Table 7.

[0177] [Table 7]

[0178] Pharmaceutical preparation methods: Example 31 (150 mg / kg): 30 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug concentration of 15 mg / mL, and orally administered intragastrically in a dosage volume of 0.2 mL / 20 g. Example 31 (300 mg / kg): 60 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug concentration of 30 mg / mL, and orally administered intragastrically in a dosage volume of 0.2 mL / 20 g. Palbociclib (150 mg / kg): 30 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug concentration of 15 mg / mL, and orally administered intragastrically in a dosage volume of 0.2 mL / 20 g.

[0179] Experimental method: A mouse tumor transplant model of human lung cancer in nude mice was established by subcutaneously inoculating the human lung cancer cell line A549 into the axilla of nude mice. A549 cells in the logarithmic growth phase were inoculated subcutaneously into the right axilla of 30 nude mice under aseptic conditions, with a cell inoculation volume of 5 × 106 The diameter of the tumor was measured with a caliper. 3 When tumors reached a certain size, 20 tumor-bearing nude mice with good growth and uniform tumor size were selected and randomly divided into four groups (five mice per group): a model group, a low-dose group treated with Example 31 (150 mg / kg), a high-dose group treated with Example 31 (300 mg / kg), and a group treated with the active agent Palbociclib (150 mg / kg). The low-dose and high-dose groups of the test drug Example 31, as well as the positive drug group, Palbociclib, were all administered intragastrically once every two days. The model group received the same volume of vehicle control intragastrically. The antitumor effects of the test drug were dynamically monitored by measuring tumor diameter. Tumor diameter measurements were taken once every other day, and nude mice were weighed simultaneously. On day 22, the mice were sacrificed, and tumor masses were surgically excised, fixed in 10% formaldehyde, and stored in liquid nitrogen.

[0180] As can be seen from the experimental results, the relative tumor growth rates T / C (%) in the low-dose group of test drug Example 31 (150 mg / kg) and the high-dose group of test drug Example 31 (300 mg / kg) compared to the model group were 44.8% and 35.9%, respectively, and the tumor growth inhibition rates were 55.2% and 64.1%, respectively. For the active drug Palbociclib, when administered intragastrically at a dose of 150 mg / kg, the relative tumor growth rate T / C (%) was 39.6%, and the tumor growth inhibition rate was 60.4%. Therefore, the test drug prepared in Example 31 exhibited a clear inhibitory effect on the growth of mouse xenograft tumors in nude mice with human lung cancer A549, and its effect was superior to that of the positive control drug Palbociclib.

[0181] (7) Measurement of anti-prostate cancer (PC3) activity of compounds The drugs used were compound (I-31) prepared in Example 31 and the approved CDK4 / 6 inhibitor Palbociclib. The cell line used was human prostate cancer PC-3 cells. The test animals were SPF BALB / c nude mice; male; 8 mice per group. The drug dosages are shown in Table 8.

[0182] [Table 8]

[0183] Pharmaceutical preparation methods: Example 31 (100 mg / kg): 20 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug with a concentration of 10 mg / mL, which was orally administered intragastrically at a dosage volume of 0.2 mL / 20 g. Example 31 (200 mg / kg): 40 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug with a concentration of 20 mg / mL, which was orally administered intragastrically at a dosage volume of 0.2 mL / 20 g. Palbociclib (100 mg / kg): 20 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug with a concentration of 10 mg / mL, which was orally administered intragastrically at a dosage volume of 0.2 mL / 20 g.

[0184] Experimental method: A mouse tumor transplant model of human prostate cancer in nude mice was established by inoculating human prostate cancer PC-3 cells subcutaneously into the axilla of nude mice. Logarithmic growth phase PC-3 cells were inoculated subcutaneously into the right axilla of 40 nude mice under aseptic conditions, with a cell inoculation volume of 5 × 10 6 The diameter of the tumor was measured with a caliper, and the tumor was 90 mm 3 When tumors reached a certain size, 32 tumor-bearing nude mice with good growth and uniform tumor size were selected and randomly divided into four groups (8 mice per group): a model group, a low-dose group (100 mg / kg) of Example 31, a high-dose group (200 mg / kg) of Example 31, and a group treated with the active agent Palbociclib (100 mg / kg). The low-dose and high-dose groups of the test drug Example 31, as well as the positive drug group, Palbociclib, were all administered intragastrically once every two days. The model group received the same volume of vehicle control intragastrically. The antitumor effects of the test drug were dynamically monitored by measuring tumor diameter. Tumor diameter measurements were taken once every other day, and nude mice were weighed simultaneously. On day 29, the mice were sacrificed, and tumor masses were surgically excised, fixed in 10% formaldehyde, and stored in liquid nitrogen.

[0185] As can be seen from the experimental results, in the low-dose group of test drug Example 31 (100 mg / kg) and the high-dose group of Example 31 (200 mg / kg), the relative tumor growth rates T / C (%) were 35.7% and 23.4%, respectively, and the tumor growth inhibition rates were 64.3% and 76.6%, respectively, compared to the model group. For the active drug Palbociclib, when administered intragastrically at a dose of 100 mg / kg, the relative tumor growth rate T / C (%) was 35.5%, and the tumor growth inhibition rate was 64.5%. Therefore, the test drug prepared in Example 31 exhibited a clear inhibitory effect on the growth of mouse xenograft tumors in nude mice with human prostate cancer PC3, and its effect was superior to that of the positive control drug Palbociclib.

[0186] (8) Measurement of the anti-prostate cancer activity of the compound (Du-145) The drugs used were compound (I-31) prepared in Example 31, the approved CDK4 / 6 inhibitor Palbociclib, and the first-line prostate cancer treatment Enzalutamide. The cell line used was human prostate cancer Du-145 cells. The test animals were SPF BALB / c nude mice; male; 10 per group. The drug dosages are shown in Table 9.

[0187] [Table 9]

[0188] Pharmaceutical preparation methods: Example 31 (100 mg / kg): 20 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug with a concentration of 10 mg / mL, which was orally administered intragastrically in a dosage volume of 0.2 mL / 20 g. Example 31 (200 mg / kg): 40 mg of the test compound powder was dissolved in 2 mL of physiological saline to prepare a drug with a concentration of 20 mg / mL, and the drug was orally administered intragastrically in a volume of 0.2 mL / 20 g. Palbociclib (100 mg / kg): 20 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug with a concentration of 10 mg / mL, which was orally administered intragastrically in a volume of 0.2 mL / 20 g. Enzalutamide (100 mg / kg): 20 mg of test compound powder was weighed and dissolved in 2 mL of physiological saline to prepare a drug with a concentration of 10 mg / mL, which was orally administered intragastrically in a volume of 0.2 mL / 20 g.

[0189] Experimental method: A mouse tumor transplant model of human prostate cancer in nude mice was established by inoculating human prostate cancer Du-145 cells subcutaneously into the axilla of nude mice. Logarithmically growing Du-145 cells were inoculated subcutaneously into the right axilla of 60 nude mice under aseptic conditions, with a cell inoculation volume of 5 × 10 6 The diameter of the tumor was measured with a caliper, and the tumor was 90 mm 3 When tumors reached a growth stage of approximately 100 mg / kg, 50 tumor-bearing nude mice with good growth and uniform tumor size were selected and randomly divided into 5 groups (10 mice per group): model group, low-dose Example 31 (100 mg / kg) group, high-dose Example 31 (200 mg / kg) group, active agent Palbociclib (100 mg / kg) group, and active agent Enzalutamide (100 mg / kg) group. The low-dose and high-dose groups of the test drug Example 31, the positive drug group Palbociclib, and the positive drug group Enzalutamide were all administered intragastrically once every two days. The model group received the same volume of vehicle control intragastrically. The antitumor effects of the test drug were dynamically monitored using tumor diameter measurement. Tumor diameter measurements were taken once every other day, and nude mice were weighed at the same time. On day 35, the control group mice were sacrificed, and tumor masses were surgically excised, fixed in 10% formaldehyde, stored in liquid nitrogen, and prepared. On day 49, the remaining mice were sacrificed, and tumor masses were surgically excised, fixed in 10% formaldehyde, stored in liquid nitrogen, and prepared.

[0190] The experimental results are shown in Figure 3. The low-dose group of the test drug Example 31 (100 mg / kg) showed superior tumor growth inhibition to the positive drug Palbociclib (100 mg / kg) group. The low-dose group of the test drug Example 31 (100 mg / kg) and the positive drug Enzalutamide (100 mg / kg) groups had similar tumor growth inhibitory effects. The high-dose group of Example 31 (200 mg / kg) showed clear tumor growth inhibition, superior to the positive drug Palbociclib (100 mg / kg) and the positive drug Enzalutamide (100 mg / kg) groups, and began to reduce tumor volume on day 31. Therefore, the test drug prepared in Example 31 had a clear inhibitory effect on the growth of mouse xenograft tumors in human prostate cancer Du-145 nude mice, and its effect was superior to that of the positive control drug, the CDK4 / 6 inhibitor Palbociclib, and the first-line prostate cancer treatment drug, Enzalutamide.

Claims

1. Any compound selected from the group consisting of the following general formulae (I-1), (I-8), (I-11), (I-17), (I-29), (I-31), (I-39), (I-42), (I-43), (I-45), (I-47) and (I-51), or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, A dual-targeting inhibitor of CDK6 and DYRK2 that simultaneously inhibits two distinct kinases, cyclin-dependent kinase 6 (CDK6) and dual specificity tyrosine phosphorylation-regulated kinase (DYRK2), thereby simultaneously inhibiting multiple pathways of cancer development.

3. A dual-targeted inhibitor of CDK6 and DYRK2 described in claim 2, which reduces drug resistance that occurs in CDK6-only inhibitors that target CDK6 as a single target.

4. A dual-targeted inhibitor of CDK6 and DYRK2 described in claim 3, which has an inhibitory effect on cell proliferation of human breast cancer cell lines, multiple myeloma cell lines, leukemia cell lines, gastric cancer cell lines, ovarian cancer cell lines, colon cancer cell lines, liver cancer cell lines, pancreatic cancer cell lines, human glioma cell lines, lung cancer cell lines, and prostate cancer cell lines.

5. The pharmaceutically acceptable salt is an acid addition salt of any of the compounds described above, Among them, the acid for salt formation is any one selected from the group consisting of inorganic acids and organic acids, the inorganic acid is any one selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and methanesulfonic acid; 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the organic acid is any one selected from the group consisting of 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.

6. 10. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating cancer or a tumor-related disease, comprising: the cancer or tumor-related disease is any one selected from the group consisting of breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, and human glioma; The medicament simultaneously inhibits two different kinases, cyclin-dependent kinase 6 (CDK6) and dual specificity tyrosine phosphorylation-regulated kinase (DYRK2), thereby simultaneously inhibiting multiple pathways of cancer development.

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