Patent Description:
Cyclin-dependent kinase <NUM> (CDK6) is a serine/tyrosine kinase that regulates the transition of the cell cycle from G1 to S. In the early G1 phase of the cell cycle, cyclin D binds to and activates CDK6, and the formed cyclin D-CDK6 complex promotes the phosphorylation of retinoblastoma protein (Rb). The phosphorylation of Rb leads to the release of transcription factor E2F, which accelerates the progression of the cell cycle from G1 to S. Up-regulation of the proto-oncogene CDK6 leads to an accelerated progression of the cell cycle from G1 to S, leading to an accelerated cell cycle and cell proliferation. Uncontrolled proliferation of cells is the main feature of cancer. Therefore, inhibition of CDK6 can slow the process of cell cycle transition from G1 phase to S phase, producing anti-proliferation and anti-cancer effects. However, the currently marketed CDK6 inhibitors, Palbociclib, Ribociclib and Abemaciclib, are highly toxic and have developed resistance.

Dual specificity tyrosine phosphorylation-regulated kinases (DYRK) and CDK belong to the CMGC family and play important regulatory roles in cell cycle and cell proliferation. DYRK2 regulates the phosphorylation of cell cycle-dependent Rpt3-T25, and promotes the degradation of CDK inhibitors such as p21 and p27, as well as the progression of cell cycle from G1 to S. The inhibition of DYRK2 can also slow the process of cell cycle transition from G1 phase to S phase, resulting in anti-proliferation and anti-cancer effects. Only a few DYRK2 inhibitors have been reported so far: the acridine compound LDN192960 was originally found to be a Haspin kinase inhibitor with some therapeutic effects on triple-negative breast cancer and multiple myeloma. Another drug curcumin, also confirmed to act on DYRK2 and DYRK3, can produce certain anti-multiple myeloma effect when combined with carfilzomib. However, the anticancer activity and target selectivity of the existing DYRK2 inhibitors still need to be optimized, and especially the drug-forming property needs to be further improved.

Targeted drugs exhibit the characteristics of strong drug efficacy and good safety. However, due to the complexity and integrity of cancer, when a single target drug inhibits one pathway of cancer, the related pathways will be activated to make up for the inhibited pathways, resulting in drug resistance.

Purpose of the invention: in order to solve the problem of drug resistance generated by the existing drugs in the single target treatment, the invention utilize the synergistic effect of CDK6 and DYRK2 and provides a compound or a pharmaceutically acceptable salt thereof which can be simultaneously targeted to CDK6 and DYRK2, wherein the compound is a CDK6/DYRK2 dual-target inhibitor; and by inhibiting DYRK2 and blocking a compensatory pathway of CDK6 at the same time, the anticancer activity of the compound is improved, and the drug resistance easily generated by a CDK6 single target drug is reduced. The invention also provides a specific preparation method of the compound and a medicament for preventing and/or treating cancer or tumor-related diseases, in particular diseases including breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, human glioma and the like, and is expected to be developed into a new generation anticancer medicament.

Technical solution: the invention is related to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
<CHM>
wherein,.

Preferably, the compound of the present application is selected from I-<NUM> to I-<NUM>:.

The above pharmaceutically acceptable salt is the acidic addition salt of the compound of the general formula (I), wherein the salt-forming acid include inorganic acid and organic acid, wherein said inorganic acid includes: hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and said organic acid includes acetic acid, trichloroacetic acid, propionic acid, butyric 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 pharmaceutically acceptable salt of the invention is hydrochloride.

The invention is related to a preparation method of the compound of the general formula (I) : preparing the compound (I) from a compound (A) and a Compound (B) through coupling reaction under the action of a palladium catalyst:
<CHM>
wherein,.

Preferably, said reaction is conducted under an argon protection atmosphere; and the reaction temperature is <NUM>-<NUM>, and preferably the reaction temperature is <NUM>.

The invention further discloses a pharmaceutical composition, comprising the abovementioned compound of general formula (I) or a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier is referred to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound administered.

The invention is related to the use of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament of CDK6/DYRK2 dual-target inhibitor.

The medicament of CDK6/DYRK2 dual-target inhibitor can be used to treat cancer or tumor related disease.

The invention is related to the use of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and/or treating cancer or tumor related disease. The cancer or tumor related disease includes breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer and human glioma.

The invention is related to the compound of general formula (I) or a pharmaceutically acceptable salt thereof, having CDK6/DYRK2 dual-target inhibitory activity, and showing therapeutic effects on cell malignant proliferation tumor.

The terms in the invention have the following meanings unless otherwise specified.

The term "alkyl group" means a linear or branched saturated hydrocarbon group having the number of carbon atoms.

The term "C<NUM>-C<NUM> alkyl group" is referred to a linear or branched saturated hydrocarbon group having <NUM> to <NUM> carbon atoms. C<NUM>-C<NUM> alkyl group includes but is not limited to methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, isohexyl group, <NUM>,<NUM>-dimethylbutyl group and <NUM>,<NUM>-dimethylbutyl group and the like. The term "C<NUM>-C<NUM> alkyl group" is referred to a linear or branched saturated hydrocarbon group having <NUM> to <NUM> carbon atoms.

The term "alkoxy group" means O- alkyl group. The term "C<NUM>-C<NUM> alkoxy group" is referred to a group having O-C<NUM>-C<NUM> alkyl group.

"C(O)" means "-C (O)-", specifically carbonyl group. The term "halogen" is fluorine, chlorine, bromine or iodine. Preferably, it is fluorine, chlorine, bromine.

The term "halo-alkyl group" means an alkyl group having at least one (including one) halogen substituents.

The term "cycloalkyl group" means a saturated monocyclic or polycyclic ring structure consisting of carbon atoms.

The term "C<NUM>-C<NUM> cycloalkyl group" is referred to a saturated monocyclic or polycyclic ring structure having in total <NUM> to <NUM> atoms. C<NUM> -C<NUM> cycloalkyl group includes but is not limited to cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group.

The term "cycloalkenyl" is referred to a monocyclic or polycyclic alkyl substituent having at least one cyclic carbon-carbon double bonds.

The term "C<NUM>-C<NUM> cycloalkenyl" is referred to a cycloalkenyl having <NUM> to <NUM> carbon atoms. C<NUM>-C<NUM> cycloalkenyl includes but is not limited to cyclopentenyl group, cyclobutenyl group.

The term "C<NUM>-C<NUM> alkenyl" is referred to a linear or branched hydrocarbon group having one or more carbon-carbon double bonds and having <NUM> to <NUM> carbon atoms.

The term "C<NUM>-C<NUM> alkynyl" is referred to a linear or branched hydrocarbon group having one or more carbon-carbon triple bonds and having <NUM> to <NUM> carbon atoms.

The term "C<NUM>-C<NUM> aryl group" means a monocyclic or fused polycyclic group consisting of <NUM> to <NUM> carbon atoms, having a completely conjugated π electron system. Typically, it includes but is not limited to phenyl group, naphthyl group.

The term "heteroaryl group" means a monocyclic or fused cyclic group, having one, two, three or four cyclic heteroatoms selected from a group consisting of N, O or S, with the remainder of cyclic atoms being C, further having a completely conjugated π electron system. The term "C<NUM>-C<NUM> heteroaryl group" is referred to a heteroaryl group having <NUM> to <NUM> carbon atoms in its ring. C<NUM>-C<NUM> heteroaryl group includes but is not limited to pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, pyridine.

The term "heterocyclic group" is heterocycloalkyl group, and means a monocyclic or fused cyclic group having one or more heteroatoms of N, O or S. The term "C<NUM>-C<NUM> heterocyclic group" is referred to a heterocyclic group having <NUM> to <NUM> carbon atoms in its ring. C<NUM>-C<NUM> heterocyclic group includes but is not limited to piperazino group, morpholino group, piperidino group, pyrrolidino group and the like.

Beneficial Effects: Compared with the prior art, the invention has the follow significant characteristics that, the invention discloses a novel compound represented by the general formula (i), which can simultaneously inhibit multiple pathways of cancer, has good treatment effect, low toxicity, good drug metabolism characteristic and is difficult to generate drug resistance, and can be used for manufacturing a medicament for treating cancer or tumor related diseases. The invention also discloses a preparation method of the compound of the general formula (I).

The present application is described in detail below with reference to specific embodiments.

Reactant (A) and reactant (B) can be purchased directly or developed independently, and the cost can be significantly reduced by independent development. The independently developed specific preparation methods of the reactant (A) and the reactant (B) are as follow:.

Step <NUM>. The synthesis of <NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolane-<NUM>-yl)benzothiazole: <NUM>-bromobenzothiazole (<NUM>, <NUM> mmol) was dissolved in DMF (<NUM>). Then pinacol borate (<NUM>, <NUM> mmol), Pd(dppf)Cl<NUM> (<NUM>, <NUM> mmol), potassium acetate (<NUM>, <NUM> mmol) were added. The reaction was replaced with argon three times, heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and purified by flash silica gel column chromatography to obtain Compound <NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolane-<NUM>-yl)benzothiazole (<NUM>, <NUM>% yield).

<NUM>HNMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

Step <NUM>. The synthesis of <NUM>-(<NUM>-chloro-<NUM>-fluoropyrimidine-<NUM>-yl)benzothiazole (A-<NUM>): Compound <NUM>, <NUM>-dichloro-<NUM>-fluoropyrimidine (<NUM>, <NUM> mmol) were weighed and added into <NUM> a three-necked flask. Then Pd(PPh<NUM>)<NUM>Cl<NUM>(<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol), glyme (<NUM>) and H<NUM>O (<NUM>) were added. The reaction was replaced with argon three times, heated to <NUM>. Compound <NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolane-<NUM>-yl)benzothiazole (<NUM>, <NUM> mmol) was dissolved in glyme (<NUM>), added dropwise into a three-necked flask, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and purified by flash silica gel column chromatography to obtain Compound <NUM>-(<NUM>-chloro-<NUM>-fluoropyrimidine-<NUM>-yl)benzothiazole (<NUM>, <NUM>% yield). <NUM>HNMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (A-<NUM>), the yields were respectively <NUM>% and <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

Step <NUM>. The synthesis of <NUM>-bromo-N-cyclopentylbenzothiazole-<NUM>-amine: <NUM>-bromo-<NUM>-chlorobenzothiazole (<NUM>, <NUM> mmol) was dissolved in DMSO (<NUM>), and cyclopentylamine (<NUM>, <NUM> mmol) and N-ethyldiisopropylamine (<NUM>, <NUM> mmol) were added. The reaction was replaced with argon three times, heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and purified by flash silica gel column chromatography to obtain Compound <NUM>-bromo-N-cyclopentylbenzothiazole-<NUM>-amine (<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Step <NUM>. The synthesis of <NUM>-(<NUM>-chloro-<NUM>-fluoropyrimidine-<NUM>-yl)-N-cyclopentylbenzothiazole-<NUM>-amine (A-<NUM>): Referring to the synthesis of Compound (A-<NUM>), the yields were respectively <NUM>% and <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Step <NUM>. The synthesis of <NUM>-bromo-N,N-dimethylbenzothiazole-<NUM>-amine: <NUM>-bromo-<NUM>-iodoaniline (<NUM>, <NUM> mmol), sodium dimethyldithiocarbamate dihydrate (<NUM>, <NUM> mmol), copper acetate (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol) were weighed and dissolved in DMF (<NUM>), heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and purified by flash silica gel column chromatography to obtain Compound <NUM>-bromo-N,N-dimethylbenzothiazole-<NUM>-amine (<NUM>, <NUM>% yield). <NUM>HNMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Step <NUM>. The synthesis of <NUM>-(<NUM>-chloro-<NUM>-fluoropyrimidine-<NUM>-yl)-N,N-dimethylbenzothiazole-<NUM>-amine (A-<NUM>): Referring to the synthesis of Compound (A-<NUM>), the yields were <NUM>% and <NUM> %. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

Step <NUM>. The synthesis of <NUM>-bromo-N,N-diethylbenzothiazole-<NUM>-amine: <NUM>-bromo-<NUM>-iodoaniline (<NUM>, <NUM> mmol), sodium diethyldithiocarbamate trihydrate (<NUM>, <NUM> mmol), copper acetate (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol) were weighed and dissolved in DMF (<NUM>), heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and purified by flash silica gel column chromatography to obtain Compound <NUM>-bromo-N,N-dimethylbenzothiazole-<NUM>-amine (<NUM>, <NUM>% yield).

Step <NUM>. The synthesis of <NUM>-(<NUM>-chloro-<NUM>-fluoropyrimidine-<NUM>-yl)-N,N-diethylbenzothiazole-<NUM>-amine (A-<NUM>): Referring to the synthesis of Compound (A-<NUM>), the yields were <NUM>% and <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

<NUM>-aminonicotinic acid (<NUM>, <NUM> mmol), N,N'-carbonyldiimidazole (<NUM>, <NUM> mmol) were weighed and dissolved in DMF(<NUM>), and reacted at <NUM> for <NUM>. The reaction was stirred at room temperature for <NUM>, and N-ethylpiperazine (<NUM>, <NUM> mmol) was added. The reaction was conducted overnight at room temperature, concentrated, and purified by flash silica gel column chromatography to obtain Compound (<NUM>-aminopyridine-<NUM>-yl)(<NUM>-ethylpiperazine-<NUM>-yl)ketone (<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>-amino-<NUM>-formylpyridine (<NUM>, <NUM> mmol) and N-ethylpiperazine (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dichloroethane (<NUM>), stirred at room temperature for <NUM>. Then sodium triacetylborohydride (<NUM>, <NUM> mmol) was added. The reaction was stirred at room temperature for <NUM>. <NUM> NaOH (<NUM>) was added to quench. The mixture was extracted with DCM (<NUM> ×<NUM>), dried with anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (DCM/MeOH = <NUM>:<NUM>) to obtain Compound <NUM>-((<NUM>-ethylpiperazine-<NUM>-yl)methyl)pyridine-<NUM>-amine (<NUM>, <NUM>%). <NUM>HNMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (B-<NUM>), the yield was <NUM>%. <NUM>HNMR (<NUM>, CDCl<NUM> ): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (B-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Step <NUM>. The synthesis of tert-butyl <NUM>-(<NUM>-nitropyridine-<NUM>-yl)piperazine-<NUM>-carboxylate: <NUM>-bromo-<NUM>-nitropyridine (<NUM>, <NUM> mmol), tert-butylpiperazine-<NUM>-carboxylate (<NUM>, <NUM> mmol) and triethylamine (<NUM>, <NUM> mmol) were weighed and dissolved in DMSO(<NUM>), heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and purified by flash silica gel column chromatography to obtain compound tert-butyl <NUM>-(<NUM>-nitropyridine-<NUM>-yl)piperazine-<NUM>-carboxylate (<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Step <NUM>. The synthesis of tert-butyl <NUM>-(<NUM>-aminopyridine-<NUM>-yl)piperazine-<NUM>-carboxylate: Tert-butyl <NUM>-(<NUM>-nitropyridine-<NUM>-yl)piperazine-<NUM>-carboxylate (<NUM>, <NUM> mmol), reduced iron powder (<NUM>, <NUM> mmol) and ammonium chloride (<NUM>, <NUM> mmol) were weighed and dissolved in <NUM>% ethanol (<NUM>), heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and purified by flash silica gel column chromatography to obtain compound tert-butyl <NUM>-(<NUM>-aminopyridine-<NUM>-yl)piperazine-<NUM>-carboxylate (<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (B-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J= <NUM>, <NUM>).

Referring to the synthesis of Compound (B-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (B-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (B-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Compound <NUM>-(<NUM>-chloro-<NUM>-fluoropyrimidine-<NUM>-yl)benzothiazole(<NUM>, <NUM> mmol) and <NUM>-aminopyridine-<NUM>-yl)(<NUM>-ethylpiperazine-<NUM>-yl)ketone(<NUM>, <NUM> mmol) were dissolved in dioxane (<NUM>). Then Pd<NUM>(dba)<NUM> (<NUM>, <NUM> mmol), Xantphos (<NUM>, <NUM> mmol), cesium carbonate (<NUM>, <NUM> mmol) were added. The reaction was replaced with argon three times, heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and subjected to column chromatography (DCM~DCM/MeOH = <NUM>:<NUM>) to obtain compound (<NUM>-((<NUM>-(benzothiazole-<NUM>-yl)-<NUM>-fluoropyrimidine-<NUM>-yl)amino)pyridine-<NUM>-yl)(<NUM>-ethylpiperazin e-<NUM>-yl)ketone(<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Tert-butyl <NUM>-((<NUM>-((<NUM>-(benzothiazole-<NUM>-yl)-<NUM>-fluoropyrimidine-<NUM>-yl)amino)pyridine-<NUM>-yl)methyl)pipera zine-<NUM>-carboxylate was dissolved in dichloromethane, and introduced with HCl gas under <NUM> condition and reacted for <NUM>. After the reaction was completed, the mixture was concentrated to obtain Compound <NUM>-(benzothiazole-<NUM>-yl)-<NUM>-fluoro-N-(<NUM>-(piperazine-<NUM>-ylmethyl)pyridine-<NUM>-yl)pyrimidine-<NUM>-a mine hydrochloride, the yield was <NUM>%.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

The preparation method of <NUM>-((<NUM>-(benzothiazole-<NUM>-yl)-<NUM>-fluoropyrimidine-<NUM>-yl)amino)pyridine-<NUM>-yl)(piperazine-<NUM>-yl)k etone hydrochloride referred to the synthesis of Compound (I-<NUM>), and the yield was <NUM>%.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m,<NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m,<NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ8. <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ8. <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

<NUM>-(<NUM>-chloro-<NUM>-fluoropyrimidine-<NUM>-yl)-N,N-dimethylbenzothiazole-<NUM>-amine(<NUM>, <NUM> mmol) and <NUM>-aminopyridine-<NUM>-yl)(<NUM>-ethylpiperazine-<NUM>-yl)ketone(<NUM>, <NUM> mmol) was dissolved in dioxane (<NUM>). Then Pd<NUM>(dba)<NUM> (<NUM>, <NUM> mmol), BINAP (<NUM>, <NUM> mmol), sodium tert-butoxide (<NUM>, <NUM> mmol) were added. The reaction was replaced with argon three times, heated to <NUM>, and reacted for <NUM>. The mixture was cooled, filtered and concentrated, and subjected to column chromatography (DCM~DCM/MeOH = <NUM>:<NUM>) to obtain compound (<NUM>-((<NUM>-(<NUM>-(dimethylamino)benzothiazole-<NUM>-yl)-<NUM>-fluoropyrimidine-<NUM>-yl)amino)pyridine-<NUM>-y l)(<NUM>-ethylpiperazine-<NUM>-yl)ketone (<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J= <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J= <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Referring to the synthesis of Compound (I-<NUM>), the yield was <NUM>%. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

The corresponding pharmaceutically acceptable salts in the above examples were reacted by dissolving the main product in dichloromethane and introducing HCl gas at <NUM> for <NUM>. After the reaction is completed, the hydrochloride salt is obtain through concentration.

In this experiment, the Lance Ultra method from PerkinElmer Co. was used for detection. In the test plate, protein kinase, Ulight-labeled polypeptide substrate, ATP, and the compounds were mixed and the reaction was incubated. EDTA was then added to stop the reaction and europium (Eu) chelate-labeled antibody was added for detection. Analysis in this experiment was performed using Envision instrument from PerkinElmer Co. in TR-FRET mode. After excitation at a wavelength of <NUM>/<NUM>, a fluorescence signal at a wavelength of <NUM> and <NUM> could be emitted. Eu could be transferred to the adjacent fluorescent substance ULight receptor by energy transfer, and then the emitted light was detected.

The measured IC<NUM> values are shown in Table <NUM> below. From the experimental results, it can be seen that the compounds of the examples of the present invention have strong inhibitory activity on CDK6 kinase activity.

The DYRK2 kinase inhibitory activity of the compounds of the invention were measured. The method was briefly described as follows (for specific methods, see: <NPL>):.

The measured IC<NUM> values are shown in Table <NUM> below. From the experimental results, it can be seen that the compounds of the examples of the present invention have strong inhibitory activity on DYRK2 kinase activity.

The inhibitory activity of the compounds on the proliferation of <NUM> cells including human breast cancer (MCF-<NUM>), triple negative breast cancer(MDA-MB-<NUM>) cell line, multiple myeloma (RPMI8226) cell line, leukemia (K562) cell line, gastric cancer (MGC-<NUM>) cell line, ovarian cancer (SK-OV-<NUM>) cell line, colon cancer (HT-<NUM>) cell line, liver cancer (HepG2) cell line, pancreatic cancer (Panc-<NUM>) cell line, human glioma(U251) cell line, lung cancer (A-<NUM>), non-small cell lung cancer (NCI-H1299) cell line and prostate cancer (PC-<NUM>, Du-<NUM>) cell line were determined by the following method.

The inhibition of the compound on the proliferation of a variety of cancer cells was determined according to the MTT method and the IC<NUM> of the half inhibitory concentration of the compound against the cell proliferative activity was obtained.

The compound of Example <NUM> (I-<NUM>) and the marketed drug CDK4/<NUM> inhibitor Palbociclib were tested for a variety of cancer cell proliferative activities and the measured IC<NUM> values are shown in Table <NUM>. It can be seen that Compound I-<NUM> shows inhibitory activity against the proliferation of <NUM> cells including human breast cancer (MCF-<NUM>), triple negative breast cancer (MDA-MB-<NUM>) cell line, multiple myeloma (RPMI8226) cell line, leukemia (K562) cell line, gastric cancer (MGC-<NUM>) cell line, ovarian cancer (SK-OV-<NUM>) cell line, colon cancer (HT-<NUM>) cell line, liver cancer (HepG2) cell line, pancreatic cancer (Panc-<NUM>) cell line, human glioma(U251) cell line, lung cancer (A-<NUM>), non-small cell lung cancer (NCI-H1299) cell line and prostate cancer (PC-<NUM>, Du-<NUM>) cell line, and the inhibitory activities against the proliferation of the <NUM> cells were significantly stronger than the marketed drug CDK4/<NUM> inhibitor Palbociclib.

Test animals: ICR mice; <NUM>-<NUM>; half male and half female; in total <NUM>.

Dose settings of groups: (<NUM>) Control group: Rats were given the same amount of normal saline by gavage, once, for <NUM> mice, half male and half female in each group; (<NUM>) <NUM>/kg group: The drug was given by gavage to <NUM> mice, half male and half female, once. (<NUM>) <NUM>/kg group: The drug was given by gavage to <NUM> mice, half male and half female, once. (<NUM>) <NUM>/kg group: The drug was given by gavage to <NUM> mice, half male and half female, once.

Laboratory environment: room temperature <NUM>±<NUM>, relative humidity <NUM>~<NUM>%. Observation targets: The test drug (compound prepared in Example <NUM>) was administered once according to the dose shown in Table <NUM>, and the toxicity symptoms and death of the mice were recorded. The dead animals were necropsied. The observation period was <NUM> days. The results showed that no abnormality was found within <NUM> after administration in all groups. No animals died within <NUM> of dosing and no animals died after day <NUM> of dosing. No other obvious abnormalities were observed.

Body weight changes are shown in <FIG>. No significant toxic effects were observed when <NUM>/kg, <NUM>/kg, or <NUM>/kg were administered intragastrically as compared to the control group.

As shown in <FIG> by HE staining results, Compound (I-<NUM>) prepared in Example <NUM> showed no significant toxicity to heart, liver, spleen, lung, kidney and other major organs.

The tested compound was weighed and placed into a sterile vial, and <NUM>µL DMSO was added, followed by 10µL methanesulfonic acid. After dissolution, <NUM> of <NUM>% glucose injection was added, and mixed uniformly with ultrasound and shaking to prepare a tested compound solution of <NUM>/mL, which was used as a gavage drug preparation. In addition, <NUM> of <NUM>/mL test solution was added with <NUM> of <NUM>% glucose injection, and mixed with shaking to prepare <NUM>/mL test solution, which was used as an intravenous administration preparation.

Six SD rats were divided into two groups. One was administered via tail vein (<NUM>/kg) and the other was administered by gavage (<NUM>/kg) with Example <NUM>. blood samples of about <NUM> were collected from the posterior orbital venous plexus, in the intravenous injection group <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration, and in the gavage group <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> after administration. The concentrations of Example <NUM> in plasma samples from SD rats were determined by LC-MS/MS and pharmacokinetic parameters were calculated using WinNolin software, and the results are presented in Table <NUM>.

The results show that the Compound (I-<NUM>) of Example <NUM> of the invention has good metabolism in rats, good absorption and exposure and high bioavailability.

The drugs were Compound (I-<NUM>) prepared in Example <NUM> with the marketed drug CDK4/<NUM> inhibitor Palbociclib. The cell line, human non-small cell lung cancer cell line A-<NUM>, was cultured in RPMI-<NUM> medium containing <NUM>% fetal bovine serum. The test animals were SPF grade BALB/c nude mice; males; five for each group. Drug dose settings are shown in Table <NUM>.

Example <NUM> (<NUM>/kg): <NUM> of the compound powder to be tested was weighed, dissolved in <NUM> of normal saline, formulated as a <NUM>/mL drug, and administered orally by gavage in a volume of <NUM>/<NUM>.

Palbociclib (<NUM>/kg): <NUM> of the compound powder to be tested was weighed, dissolved in <NUM> of normal saline, and prepared into a <NUM>/mL drug for oral gavage administration in a volume of <NUM>/<NUM>.

Experimental method: A nude mouse model of human lung cancer xenografts was established by inoculating human lung cancer cell line A549 under the axillary skin of nude mice. A549 cells in logarithmic phase were inoculated subcutaneously at right axilla of <NUM> nude mice under sterile condition, and the inoculation amount of cells was <NUM>×<NUM><NUM> cells/mouse. The diameter of xenografts was measured with a vernier caliper. When the tumor grew to about <NUM><NUM>, <NUM> tumor-bearing nude mice in good growth condition and with uniform tumor size were selected and randomly divided into four groups, five for each group, i.e., the model group, the low-dose group of Example <NUM> (<NUM>/kg), the high-dose group of Example <NUM> (<NUM>/kg), and the positive drug Palbociclib (<NUM>/kg) group. Test Drug Example <NUM> and Palbociclib were intragastrically administered to the low-dose and high-dose groups and the positive drug group, once every <NUM> days. The model group was intragastrically administered with an equal volume of vehicle control. The antitumor effect of the test substance was dynamically observed by measuring the tumor diameter. Tumor diameters were measured every other day and nude mice were weighed while tumor diameters were measured. The mice were sacrificed on the 22nd day, and the tumor pieces removed by surgery were fixed with <NUM>% formaldehyde and stored in liquid nitrogen for later use.

The experimental results showed that compared with the model group, the relative tumor proliferation rates T/C(%) of the low-dose group of Example <NUM> (<NUM>/kg) and the high-dose group of Example <NUM> (<NUM>/kg) were <NUM>% and <NUM>%, respectively, and the tumor growth inhibition rates were <NUM>% and <NUM>%, respectively. When the positive drug Palbociclib was given by gavage at the dose of <NUM>/kg, the relative tumor proliferation rate T/C(%) and tumor inhibition rate were <NUM>% and <NUM>%, respectively.

Therefore, the test drug prepared in Example <NUM> had a significant inhibitory effect on the growth of xenografts of human lung cancer A549 in nude mice, and the effect was better than that of the positive control drug Palbociclib.

The drugs were Compound (I-<NUM>) prepared in example <NUM> with the marketed drug CDK4/<NUM> inhibitor Palbociclib. The cell strain was a human prostate cancer PC-<NUM> cell. The test animals were SPF grade BALB/c nude mice; Males; Eight for each group. Drug dose settings are shown in Table <NUM>.

Experimental method: A nude mouse model of human prostate cancer xenografts was established by inoculating human prostate cancer PC-<NUM> under the axillary skin of nude mice. PC-<NUM> cells in logarithmic phase were inoculated subcutaneously at right axilla of <NUM> nude mice under sterile condition, and the inoculation amount of cells was <NUM>×<NUM><NUM> cells/mouse. The diameter of xenografts was measured with a vernier caliper. When the tumor grew to about <NUM><NUM>, <NUM> tumor-bearing nude mice in good growth condition and with uniform tumor size were selected and randomly divided into four groups, eight for each group, i.e., the model group, the low-dose group of Example <NUM> (<NUM>/kg), the high-dose group of Example <NUM> (<NUM>/kg), and the positive drug Palbociclib (<NUM>/kg) group. Test Drug Example <NUM> and Palbociclib were intragastrically administered to the low-dose and high-dose groups and the positive drug group, once every day. The model group was intragastrically administered with an equal volume of vehicle control. The antitumor effect of the test substance was dynamically observed by measuring the tumor diameter. Tumor diameters were measured every other day and nude mice were weighed while tumor diameters were measured. The mice were sacrificed on the 29th day, and the tumor pieces removed by surgery were fixed with <NUM>% formaldehyde and stored in liquid nitrogen for later use.

Therefore, the test drug prepared in Example <NUM> had a significant inhibitory effect on the growth of xenografts of human prostate cancer PC3 in nude mice, and the effect was better than that of the positive control drug Palbociclib.

The drugs were the compound (I-<NUM>) prepared in example <NUM>, the marketed drug CDK4/<NUM> inhibitor Palbociclib and the first-line treatment drug for prostate cancer Enzalutamide. The cell strain is human prostate cancer Du-<NUM> cells. The test animals were SPF grade BALB/c nude mice; males; ten for each group. Drug dose settings are shown in Table <NUM>.

Enzalutamide (<NUM>/kg): <NUM> of the compound powder to be tested was weighed, dissolved in <NUM> of normal saline, and prepared into a <NUM>/mL drug for oral gavage administration in a volume of <NUM>/<NUM>.

Experimental method: A nude mouse model of human prostate cancer xenografts was established by inoculating human prostate cancer Du-<NUM> under the axillary skin of nude mice. Du-<NUM> cells in logarithmic phase were inoculated subcutaneously at right axilla of <NUM> nude mice under sterile condition, and the inoculation amount of cells was <NUM>×<NUM><NUM> cells/mouse. The diameter of xenografts was measured with a vernier caliper. When the tumor grew to about <NUM><NUM>, <NUM> tumor-bearing nude mice in good growth condition and with uniform tumor size were selected and randomly divided into five groups, ten for each group, i.e., the model group, the low-dose group of Example <NUM> (<NUM>/kg), the high-dose group of Example <NUM> (<NUM>/kg), the positive drug Palbociclib (<NUM>/kg) group, and the positive drug Enzalutamide (<NUM>/kg) group. Test Drug Example <NUM>, Palbociclib and Enzalutamide were intragastrically administered to the low-dose and high-dose groups and the positive drug group, once every day. The model group was intragastrically administered with an equal volume of vehicle control. The antitumor effect of the test substance was dynamically observed by measuring the tumor diameter. Tumor diameters were measured every other day and nude mice were weighed while tumor diameters were measured. On the 35th day, the mice of the control group were sacrificed, and the tumor pieces after surgical stripping were fixed with <NUM>% formaldehyde and stored in liquid nitrogen for later use. The remaining mice were sacrificed on the 49th day, and the tumor pieces after surgical stripping were fixed with <NUM>% formaldehyde and stored in liquid nitrogen for later use.

The experimental results are shown in <FIG>: the low dose group of test drug Example <NUM> (<NUM>/kg) exhibited better inhibition on tumor growth than the positive drug Palbociclib (<NUM>/kg) group; the low dose group of test drug Example <NUM> (<NUM>/kg) and the positive drug Enzalutamide (<NUM>/kg) had similar inhibition effects on tumor growth.

Example <NUM> (<NUM>/kg) the high dose group significantly inhibited tumor growth, better than the positive drug Palbociclib(<NUM>/kg) group and the positive drug Enzalutamide (<NUM>/kg) group, and started to reduce tumor volume on day <NUM>.

Claim 1:
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, characterized in that:
<CHM>
wherein,
X is C(O) or (CH<NUM>)n; n is <NUM> or <NUM>;
R<NUM> is hydrogen, C<NUM>-C<NUM> alkyl group or -NR<NUM>R<NUM>, wherein, R<NUM>, R<NUM> is selected from hydrogen, C<NUM>-C<NUM> alkyl group or C<NUM>-C<NUM> cycloalkyl group;
R<NUM> is F;
R<NUM> is hydrogen or C<NUM>-C<NUM> alkyl group.