Phenylthiazole amine pyrimidine derivatives, processes for their preparation and use

Abstract

The present application relates to phenyl thiazole amine pyrimidine derivatives and preparation method and application thereof, belong to the chemical technical field. The phenyl thiazole amine pyrimidine derivative of the present application includes the general formula of 4-methoxy phenyl thiazole amine compound containing pyrimidine ring, or its stereoisomer, hydrate or pharmaceutically acceptable salt. The beneficial effects of the present application are: the synthesis process of the provided phenyl thiazole amine pyrimidine derivative is simple, the reaction condition is mild, and the operation safety is high. Compared with the traditional aminopyrimidine inhibitor, the structure of the compound involved in the present application has innovation, which has significant anti-tumor clinical application potential, and is expected to play a potential role in the related tumor treatment field, and has broad prospects in drug research and development.

Description

Technical Field

[0001] This invention relates to phenylthiazolamine pyrimidine derivatives, their preparation methods, and applications, belonging to the field of chemical technology. Background Technology

[0002] Pyrimidine compounds, as an important class of nitrogen-containing heterocyclic compounds, exhibit diverse biological and pharmaceutical activities. Their derivatives demonstrate significant biological activities in antibacterial, antitumor, and insecticidal applications, leading to their widespread use in pesticides and pharmaceuticals. The biological activity potential of pyrimidine derivatives, particularly their antitumor activity, has attracted considerable attention. 5-Fluorouracil, a widely used antimetabolite and antitumor drug, has inhibitory effects on various tumors and has shown good clinical efficacy in treating colorectal cancer, gastric cancer, breast cancer, and other cancers. In the pesticide field, the pyrimidine ring plays a crucial role as the active structure in pesticide development. For example, Ferimzone and Dimethirimol, as commercially available pyrimidine amine fungicides, have shown specific efficacy in controlling gray mold. In recent years, significant progress has been made in the research of anticancer drugs. Pyrimidine amines are widely used in the treatment of various diseases, especially in cancer drugs, such as those targeting TNF-α (tumor necrosis factor α), Akt (protein kinase A), BCR-ABL tyrosine kinase, and JAK (Janus kinase). For example, a series of 4,6-diaminopyrimidine derivatives were designed and synthesized in 2019 as Janus kinase (JAK) inhibitors. JAKs play a crucial role in the proliferation, apoptosis, and differentiation of immune cells, and are therefore considered potential targets for the treatment of inflammatory and autoimmune diseases. The design and optimization of 4,6-diaminopyrimidine derivatives as selective JAK3 inhibitors, among which compound 16 exhibited excellent JAK3 inhibitory activity (IC50 = 2.1 nM) and high JAK kinase selectivity. The specific structure of the JAKs inhibitor is as follows: In the same year, a series of 4-piperazinyl-2-aminopyrimidine derivatives were successfully synthesized by combining the pharmacophores of momerlotinib and tandotinib using molecular hybridization techniques. Among these, compounds exhibiting potent enzymatic activity were tested for their antiproliferative activity against three cancer cell lines (HEL, MV4-11, and HL60). Structure-activity relationship studies were conducted by examining changes in the "A" and "B" benzene ring regions. Compound 26 showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2, IC50 = 27 nM; FLT3, IC50 = 30 nM), and it also demonstrated effective inhibition against the aforementioned test cell lines. In cellular terms, compound 26 induces apoptosis by arresting the cell cycle at the G0 / G1 phase and was selected as a promising dual inhibitor of JAK2 / FLT3. Its chemical structure is as follows: Based on the above literature, it was found that aminopyrimidine derivatives predominantly have substitutions at positions 2, 4, and 6, and exhibit rich activity, which is of guiding significance in drug development. They represent a promising area for development in anticancer drug research and can be applied to small molecule drug design. Based on the literature containing aminopyrimidine groups, it was found that when aminopyrimidines form long-chain amide structures, they possess antibacterial, insecticidal, and anticancer activities. When pyrimidines are linked to other amide groups via nitrogen atoms or to benzene rings or nitrogen-containing heterocycles, they exhibit good antitumor activity, providing new insights for the development of small molecule inhibitors. Summary of the Invention

[0003] The purpose of this invention is to address the shortcomings of existing technologies by proposing phenylthiazolamine pyrimidine derivatives, their preparation methods, and applications, in order to screen for compounds with higher efficacy and selectivity for the preparation of tumor suppressor drugs.

[0004] This invention solves the technical problem through the following technical solution: First, it provides the general formula of phenylthiazolamine pyrimidine derivatives, the chemical structural formula of which is as follows: The structure of R in equation (I) includes, but is not limited to, the following structures Pharmaceutically acceptable salts are those in which a basic group in a parent compound is converted into a salt form. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts containing basic groups such as amine (amino) groups. The pharmaceutically acceptable salts of this invention can be synthesized from a parent compound by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system. Suitable salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

[0005] In this invention, the basic groups of the compounds can form salts with acids. Examples of such acid salts include: salts formed with inorganic acids, especially hydrohalic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc.; salts formed with lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid; salts formed with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts formed with organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid, or succinic acid; and salts formed with amino acids, such as aspartic acid or glutamic acid.

[0006] The compounds and pharmaceutically acceptable salts of this invention also include solvated or hydrated forms. Generally, solvated or hydrated forms are equivalent to, and covered by, the unsolvated or unhydrated forms. Some compounds of this invention may exist in polycrystalline or amorphous forms. In general, all physical forms have equivalent use and are covered by the scope of this invention.

[0007] Furthermore, unless otherwise indicated, the structural formulas of the compounds in the pyrimidine-ring-containing 4-methoxyphenylthiazolamine class of the present invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of the present invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), are within the scope of the present invention.

[0008] The present invention further provides that the phenylthiazolamine pyrimidine derivative comprises one of the following structures:

[0009] (1) 5-Chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)-N4-phenylpyrimidine-2,4-diamine;

[0010] (2)(2-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-ylamino)pyrimidin-4-ylamino)phenyl)dimethylphosphine oxide;

[0011] (3) 5-Chloro-N4-(2-isopropylsulfonyl)phenyl-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0012] (4) 2-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-amino)-N,N-dimethylbenzenesulfonamide;

[0013] (5) 2-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidine-4-amino)-N-methylbenzamide;

[0014] (6) 5-Chloro-(N4-(2-dimethylamino)phenyl-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0015] (7) 5-Chloro-N4-(3-dimethylamino)phenyl-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0016] (8) 5-Chloro-N4-(2-methoxyphenyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0017] (9) 5-Chloro-N4-(3-methoxyphenyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0018] (10) 5-Chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)-N4-naphth-2-ylpyrimidin-2,4-diamine;

[0019] (11)N-(5-chloro-4-(1H-indol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine;

[0020] (12)N-(5-chloro-4-(5-methoxy-1H-indol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine;

[0021] (13)N-((4-bromo-1H-indol-1-yl)-5-chloropyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine;

[0022] (14)N-(5-chloro-4-(1H-indazol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine;

[0023] (15)N-(5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine;

[0024] (16)N-((4-benzo[1,2,3]triazol-1-yl)-5-chloropyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine;

[0025] (17)N-(5-chloro-4-(5-methylimidazol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine;

[0026] (18) N4-benzyl-(5-chloro-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0027] (19) 5-Chloro-N4-(2-fluorobenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0028] (20) 5-Chloro-(N4-(3-fluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0029] (21) 5-Chloro-(N4-(4-fluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0030] (22) 5-Chloro-(N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)-(N4-(4-trifluoromethoxy)benzyl)pyrimidin-2,4-diamine;

[0031] (23) 5-Chloro-(N4-(4-chlorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine;

[0032] (24)N4-(4-bromobenzyl)-5-chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0033] (25) 5-Chloro-N4-(2-methoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0034] (26) 5-Chloro-(N4-(3-methoxybenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0035] (27) 5-Chloro-N4-(4-methoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0036] (28) 5-Chloro-N4-(3,4-dimethoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0037] (29) 5-Chloro-N4-(3,4-difluorobenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0038] (30) 5-Chloro-(N4-(2,4-difluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0039] (31) 5-Chloro-N4-(3-Chloro-4-fluorobenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0040] (32) 5-Chloro-N4-(2,4-dimethoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0041] (33) 5-Chloro-(N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)-N4-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine;

[0042] (34) 5-Chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)-N4-phenylethylpyrimidine-2,4-diamine;

[0043] (35) 5-Chloro-(N4-(4-fluorophenylethyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0044] (36) 5-Chloro-(N4-(2-chlorophenylethyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0045] (37) 5-Chloro-(N4-(3-chlorophenylethyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0046] (38) 5-Chloro-(N4-(3,4-dimethoxyphenethyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine;

[0047] (39) 5-Chloro-(N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)-N4-propylpyrimidine-2,4-diamine;

[0048] (40) 5-Chloro-N4-(2-(dimethylamino)ethyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine hydrochloride;

[0049] (41)N-((5-chloro-4-piperidin-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine;

[0050] (42)N-(5-chloro-4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine;

[0051] (43)(R)-(1-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-ol;

[0052] (44)(R)-1-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-2-methanol;

[0053] (45)((5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)amino)ethylcarbamate tert-butyl ester;

[0054] (46)4-((5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-ylamino)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester;

[0055] (47)(1-((5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)piperidin-4-yl)tert-butyl methylcarbamate;

[0056] (48)((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)piperidine-4-carbamate tert-butyl ester;

[0057] (49) (S)-3-((5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester;

[0058] (50)(R)-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)piperidine-3-carbamate tert-butyl ester;

[0059] (51)(S)-((1-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)tert-butyl carbamate;

[0060] (52)(S)-(5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-ylamino)pyrimidin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester;

[0061] (53)(R)-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-carbamate tert-butyl ester;

[0062] (54)(S)-(((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate.

[0063] This invention further provides a method for preparing phenylthiazolamine pyrimidine derivatives, using 4-methoxyphenylacetone as raw material a, reacting raw material a with phenyltrimethylammonium tribromide in an α-bromination reaction to obtain intermediate b, and reacting intermediate b with thiourea in a condensation reaction to obtain intermediate compound c; using trichloropyrimidine d, aromatic amine and aliphatic amine e as raw materials, a nucleophilic substitution reaction is carried out under alkaline conditions to obtain intermediate f, and intermediate f and intermediate compound c are reacted with palladium as a catalyst in a Buchwald-Hartwig reaction to obtain target compound g; the preparation route is as follows. .

[0064] The present invention further provides a pharmaceutical composition comprising at least one effective therapeutic dose of a phenylthiazolidine derivative and a combination of a pharmaceutically acceptable excipient, adjuvant, or carrier.

[0065] The present invention further provides the use of the above-mentioned phenylthiazolidine derivatives or the pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment and / or adjuvant treatment of proliferative diseases, metabolic diseases, nervous system diseases, and tuberous sclerosis caused by kinase overactivation. The proliferative diseases include colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, hematological malignancies, or lymphoma, etc.

[0066] The use of the phenylthiazolamine pyrimidine derivative or the pharmaceutical composition in the preparation of a medicament for inhibiting the growth of cancer cells in vitro.

[0067] The beneficial effects of this invention are: the synthesis process of the provided phenylthiazolamine pyrimidine derivative is simple, the reaction conditions are mild, and the operation is highly safe. Compared with traditional aminopyrimidine inhibitors, the compound structure involved in this invention is innovative, possesses significant potential for anti-tumor clinical application, and is expected to play a potential role in related tumor treatment fields, showing broad prospects in drug development. Detailed Implementation

[0068] The terms used in this invention have the following meanings:

[0069] The term "alkyl" refers to a monovalent hydrocarbon group comprising 1-20 carbon atoms in a saturated straight or branched chain, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Some embodiments show that the alkyl group contains 1-10 carbon atoms, others show that it contains 1-8 carbon atoms, still others show that it contains 1-6 carbon atoms, and yet another embodiment shows that it contains 1-4 carbon atoms. Further embodiments of the alkyl group include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), and the like. The term "alkyl" and its prefix "alkane" are used here to refer to both straight-chain and branched saturated carbon chains.

[0070] The term "alkoxy" refers to the alkyl portion, which is the same as the aforementioned definition of "alkyl," formed by an oxygen atom attached to the main carbon chain of the alkyl group.

[0071] The terms "haloalkyl" or "haloalkoxy" indicate that the "alkyl" or "alkoxy" group can be substituted by one or more of the same or different halogen atoms. The alkyl and alkoxy groups have the meanings described above in this invention, and such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, etc.

[0072] The terms "hydroxyalkyl" or "hydroxyalkoxy" indicate that the "alkyl" or "alkoxy" group can be replaced by one or more hydroxyl groups. The "alkyl" and "alkoxy" groups have the meanings described above in this invention, and such examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxypropyl, hydroxymethoxy, 1-hydroxyethoxy, etc.

[0073] The terms “halogen,” “halogen atom,” or “halogen atom” include fluorine, chlorine, bromine, and iodine.

[0074] The term "heterocyclic group" can be carbon-based or heteroatom-based. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocyclic compounds include, but are not limited to, pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, thiaxyl, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, piperidinyl, homopiperidinyl, glycidyl, azirroheptanyl, oxacycloheptanyl, thioheptanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazaphenyl, diazaphenyl, thioazaphenyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2 H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazine, 1,1-dioxo-2-yl, quinazinyl, and N-pyridylurea, wherein the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), carboxyalkoxy, etc.

[0075] The term "effective therapeutic dose" refers to the amount of a general formula compound that is sufficient to effectively treat a mammal requiring such treatment. The effective therapeutic dose will vary depending on the specific activity of the therapeutic agent used, the patient's age, physiological condition, the presence of other disease states, and nutritional status. Furthermore, other drug treatments the patient may be receiving will affect the determination of the effective therapeutic dose to be administered.

[0076] The term “treatment” means any treatment of disease in a mammal, including: (i) preventing disease, i.e. causing the clinical symptoms of disease to not develop; (ii) suppressing disease, i.e. preventing the development of clinical symptoms; and / or (iii) alleviating disease, i.e. causing the clinical symptoms to subside.

[0077] The term "pharmaceutically acceptable excipient, adjuvant, or carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated.

[0078] The technical solution of the present invention will be further defined below with reference to specific embodiments, but the scope of protection is not limited to the description made.

[0079] Unless otherwise stated, all temperatures in the examples described below are in degrees Celsius. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Bailingwei Technology Co., Ltd., Aladdin Reagent Co., Ltd., and Beijing Coupling Technology Co., Ltd., and were used without further purification unless otherwise stated. Common reagents were purchased from Xilong Chemical Co., Ltd., Nanjing Chemical Reagent Co., Ltd., Sinopharm Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Co., Ltd., among others.

[0080] In the examples described below, silica gel columns were used. The silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Co., Ltd. Nuclear magnetic resonance spectroscopy was performed using CDCl3 or DMSO-d6 as solvents (in ppm), with TMS (0 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0081] In the embodiments described below, low-resolution mass spectrometry (MS) data were determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311B quaternary pump and a G1316BTCC (column temperature maintained at 30°C). A G1329B autosampler and a G1315CDAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0082] For ease of description, some raw materials will be described using their abbreviations in the examples described below. These abbreviations are explained in comparison with their full names as follows: DCM is CH2Cl2, i.e., dichloromethane; CDCl3 is deuterated chloroform; PE is petroleum ether; EtOAc and EA are both ethyl acetate; MeOH and CH3OH are both methanol; ClSO3H is chlorosulfonic acid; TEA and Et3N are triethylamine; DMSO-d6 is hexadeuterated dimethyl sulfoxide; THF is tetrahydrofuran; NaCl is sodium chloride; Na2SO4 is sodium sulfate; CDI is N,N-carbonyldiimidazole.

[0083] Example 1

[0084] The synthesis of 5-chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-phenylpyrimidine-2,4-diamine is as follows:

[0085] Step 1: 5-(4-methoxyphenyl)-4-methylthiazol-2-amine

[0086] Measure 0.16 g (1 mmol) of 4-methoxyphenylacetone, dissolve it in 5 mL of tetrahydrofuran solution and place it in a 50 mL round-bottom flask. Under ice bath conditions, slowly add 10 mL of tetrahydrofuran solution containing (0.41 g, 1.1 mmol) phenyltrimethylammonium tribromide to the above reaction solution. After the addition is completed, remove the ice bath and react at room temperature for 0.5 h until all the reactants are consumed. Purify intermediate b, 1-bromo-1-(4-methoxyphenyl)-2-propanone by silica gel column chromatography (PE:EA=20:1), 0.19 g of white solid, yield: 80%. 1 HNMR (400MHz, Chloroform- d )δ7.41-7.35(m,2H),6.95-6.89(m,2H),5.45(s,1H),3.84(s,3H),2.33(s,3H).

[0087] Weigh 0.24 g (1 mmol) of 1-bromo-1-(4-methoxyphenyl)-2-propanone, add 0.08 g (1.1 mmol) of thiourea, dissolve in 15 mL of acetone, heat under reflux for 0.5 h, and purify by silica gel column chromatography (DCM:MeOH = 30:1) to give intermediate (c), 5-(4-methoxyphenyl)-4-methylthiazol-2-amine. White solid, yield: 50%. 1 HNMR (300MHz, DMSO-) d 6) δ7.30-7.19(m,2H),7.00-6.90(m,2H),6.87(s,2H),3.76(s,3H),2.14(s,3H).

[0088] Step 2: (1) Synthesis of 5-chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-phenylpyrimidine-2,4-diamine, with the following structural formula: Weigh 0.18 g, 1 mmol of trichloropyrimidine and dissolve it in 15 mL of isopropanol in a 50 mL round-bottom flask. Add aniline (0.09 g, 1.05 mmol) and DIPEA (0.13 g, 1.4 mmol). Heat under reflux for 12 h. Concentrate the reaction solution under reduced pressure and slurry with Et2O to obtain intermediate 2,5-dichloro-N-phenylpyrimidin-4-amine, a white solid. No further purification is required; proceed directly to the next step. Add intermediate (c) (0.22 g, 1 mmol) and dissolve it in 15 mL of dioxane. Add K3PO4 (0.30 g, 1.4 mmol), Pd2(dba)3 (0.073 g, 0.08 mmol), and Xantphos (0.069 g, 0.12 mmol). Heat under reflux for 24 h and purify by silica gel column chromatography (PE:EA = 3:1). 90 mg of white solid was obtained; yield: 21%. 1 HNMR(300MHz,DMSO-d6)δ11.33(s,1H),9.09(s,1H),8.26(s,1H),7.65(m,2H),7.38(t ,J=7.7Hz,2H),7.22(t,J=8.1Hz,3H),7.01(d,J=8.7Hz,2H),3.80(s,3H),2.27(s,3H).

[0089] Example 2

[0090] The synthesis of (2-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-ylamino)pyrimidin-4-ylamino)phenyl)dimethylphosphine oxide, with its structural formula and synthetic steps, is as follows: Using (2-aminophenyl)dimethylphosphine oxide (0.17 g, 1 mmol) as the starting material, it was dissolved in DMF (15 mL), and trichloropyrimidine (0.27 g, 1.5 mmol) and K₂HPO₄ (0.52 g, 3 mmol) were added. The mixture was heated to 65 °C and stirred for 4 h. After cooling to room temperature, the mixture was filtered through EA and washed. The filtrate was collected, concentrated under reduced pressure, and then dissolved in EA. The mixture was extracted three times with saturated NaCl solution. The organic phase was collected, concentrated, and the intermediate (2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, a white solid, was obtained at 0.22 g. Yield: 69%. 1 HNMR (400MHz, Chloroform- d )δ11.86(s,1H),8.80(ddd, J =8.5, 4.5, 1.0 Hz, 1H), 8.08 (d, J =2.7Hz, 1H), 7.60(ddt, J=8.6,7.2,1.5Hz,1H),7.33–7.23(m,1H),7.17(tdd, J =7.6, 2.4, 1.0 Hz, 1H), 1.86 (d, J =13.1Hz, 6H). Replacing 2,5-dichloro-N-phenylpyrimidin-4-amine with (((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (0.316 g, 1 mmol), the remaining steps were the same as in step 2 of Example 1, yielding the target product, 0.2 g of white solid. Yield: 40%. 1 HNMR(300MHz,Chloroform-d)δ11.19(s,1H),8.66(s,1H),8.28(s,1H),7.66-6.91(m,8H),3.74(s,3H),2.24(s,3H),1.72(d,J=13.5Hz,6H).

[0091] Example 3

[0092] 5-Chloro-N 4 -(2-isopropylsulfonyl)phenyl-N 2 The synthesis of -(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, including its structural formula and synthetic steps, is as follows: Using 2-(isopropylthio)aniline (0.17 g, 1 mmol) as the starting material, it was dissolved in isopropanol (15 mL), and trichloropyrimidine (0.22 g, 1.2 mmol) and DIPEA (0.194 g, 1.5 mmol) were added. The mixture was heated to reflux for 24 h, and silica gel column chromatography (PE:DCM=4:1) was used to obtain the intermediate 2,5-dichloro-N-(2-(isopropylthio)phenyl)pyrimidine-4-amine, which was a white crystalline solid with a yield of 45%. Weigh 0.5 g (1.6 mmol) of 2,5-dichloro-N-(2-(isopropylthio)phenyl)pyrimidin-4-amine and add 5 mL of glacial acetic acid, 0.02 g of tungstic acid, and 30% H2O2 sequentially. React at room temperature for 1.5 h. For post-treatment, add 10 mL of EA, 10 mL of ammonia, 10 mL of water, 10 mL of saturated Na2SO3 solution, and 10 mL of 1 M hydrochloric acid solution sequentially to the reaction solution. Finally, extract with 10 mL of water, collect the organic phase, dry it with anhydrous Na2SO4, and perform silica gel column chromatography (PE:EA = 5:1) to obtain the intermediate 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine, 0.5 g of white crystals, yield: 91%. 1¹H NMR (300 MHz, Chloroform-d) δ 10.06 (s, 1H), 8.63 (dd, J = 8.5, 1.1 Hz, 1H), 8.30 (s, 1H), 7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.73 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.32 (ddd, J = 8.2, 7.4, 1.1 Hz, 1H), 3.30–3.15 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H). The intermediate 2,5-dioxane was weighed. Chloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (0.346 g, 1 mmol) was dissolved in 1,4-dioxane (15 mL), intermediate (c) (0.22 g, 1 mmol) was added, followed by K3PO4 (0.30 g, 1.4 mmol), Pd2(dba)3 (0.073 g, 0.08 mmol), and Xantphos (0.069 g, 0.12 mmol). The mixture was heated to reflux for 24 h and then subjected to silica gel column chromatography (PE:EA = 1:1) to give 0.359 g of a white solid, yield: 68%. 1HNMR(400MHz,Chloroform-d)δ9.79(s,1H),9.53(s,1H),8.43(d,J=8.4Hz,1H),8.35(s,1H),7.94(dd,J=8.0,1.6Hz,1H),7.66–7.58(m,1H) ,7.31(d,J=8.6Hz,2H),7.25(d,J=7.6Hz,1H),6.99–6.94(m,2H),3.88(s,3H),3.24(hept,J=6.9Hz,1H),2.38(s,3H),1.32(d,J=6.9Hz,6H).

[0093] Example 4

[0094] The synthesis of 2-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazol-2-amino)pyrimidine-4-amino)-N,N-dimethylbenzenesulfonamide, including its structural formula and synthetic steps, is as follows: Using 2-nitrobenzenesulfonyl chloride (0.22 g, 1 mmol) and dimethylamine (2.5 g, 5 mmol) as raw materials, the dimethylamine (2.5 g, 5 mmol) was dissolved in tetrahydrofuran (6 mL) at 0 °C. The 2-nitrobenzenesulfonyl chloride (0.22 g, 1 mmol) was dissolved in tetrahydrofuran (1 mL) and added to the dimethylamine. The mixture was stirred at room temperature for 4 h, heated to 50 °C, stirred overnight, and concentrated under reduced pressure to remove tetrahydrofuran. The mixture was extracted with DCM, water, and 1N NaOH solution, washed with saturated sodium chloride solution, and the organic phase was collected and concentrated to give the intermediate N,N-dimethyl-2-nitrobenzenesulfonamide, a yellow solid of 0.2 g, with a yield of 85%. The intermediate (0.23 g, 1 mmol) was dissolved in ethanol (10 mL), and zinc powder (0.3 g, 5.3 mmol) and ammonium chloride (0.27 g, 5 mmol) were added. The mixture was heated under reflux for 6 h to give 0.18 g of 2-amino-N,N-dimethylbenzenesulfonamide, a white solid, with a yield of 88%. 2-Amino-N,N-dimethylbenzenesulfonamide (0.2 g, 1 mmol) and NaH (0.12 g, 3 mmol) were weighed, protected with Ar, and activated in an ice bath with 10 mL of anhydrous DMF for 4 h. Trichloropyrimidine (0.37 g, 2 mmol) was injected, and the reaction was carried out at room temperature for 25 min. The reaction was quenched with ice water, ethyl acetate was added, and the mixture was extracted with water. The organic phase was collected and concentrated, and subjected to silica gel column chromatography (PE:EA = 10:1) to give 90 mg of 2-(2,5-dichloropyrimidine-4-amino)-N,N-dimethylbenzenesulfonamide, a pale yellow solid, with a yield of 25%. 1 HNMR (400MHz, DMSO-) d 6)δ9.66(s,1H),8.55(s,1H),8.28(d, J =8.3Hz,1H),7.90–7.76(m,2H),7.46(t, J =7.7 Hz, 1H), 2.65 s, 6H. Weigh the intermediate (0.694 g, 1 mmol), dissolve it in 1,4-dioxane (10 mL), add intermediate (c) (0.22 g, 1 mmol), add t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol), heat to reflux for 24 h, and then perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 0.359 g white solid, yield: 68%. 1 HNMR (400MHz, DMSO-) d 6) δ11.55(s,1H),9.36(s,1H),8.40(s,2H),7.85(dd, J =8.0, 1.7Hz, 1H), 7.74(ddd,J =8.6,7.3,1.6Hz,1H),7.42(t, J =7.7Hz, 1H), 7.26(d, J =5.5Hz,2H),7.05–7.00(m,2H),3.81(s,3H),2.63(s,6H),2.29(s,3H).

[0095] Example 5

[0096] The synthesis of 2-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidine-4-amino)-N-methylbenzamide, with its structural formula and synthetic steps, is as follows: 2-Amino-N-methylbenzamide (0.15 g, 1 mmol) and trichloropyrimidine (0.18 g, 1 mmol) were dissolved in acetonitrile (10 mL), and DIPEA (0.2585 g, 2 mmol) was added. The mixture was heated to reflux for 10 h, and then subjected to silica gel column chromatography (DCM:EA = 20:1) to give the intermediate 2-(2,5-dichloropyrimidine-4-amino)-N-methylbenzamide, 0.18 g of white solid, yield: 60%. The intermediate 2-(2,5-dichloropyrimidin-4-amino)-N-methylbenzamide (0.3 g, 1 mmol) and intermediate (c) (0.22 g, 1 mmol) were dissolved in 1,4-dioxane (10 mL), and K2CO3 (0.207 g, 1.5 mmol), Pd2(dba)3 (0.092 g, 0.1 mmol) and Xantphos (0.116 g, 0.2 mmol) were added. The mixture was heated under reflux for 24 h and then subjected to silica gel column chromatography (PE:EA = 1:1) to give 0.24 g of white solid, yield: 50%. 1 HNMR(300MHz,DMSO-d6)δ11.83(s,1H),11.59(s,1H),8.96(s,1H),8.80(d,J=4.9Hz,1H),8.38(s,1H),7.76(d,J=7.8Hz,1H),7.52(t ,J=7.9Hz,1H),7.36(d,J=8.3Hz,2H),7.19(t,J=7.5Hz,1H),7.01(d,J=8.5Hz,2H),3.80(s,3H),2.81(d,J=4.4Hz,3H),2.32(s,3H).

[0097] Example 6

[0098] The synthesis of 5-chloro-(N4-(2-dimethylamino)phenyl-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthetic method: Using N,N-dimethyl-o-phenylenediamine (0.14 g, 1 mmol) and trichloropyrimidine (0.18 g, 1 mmol) as starting materials, the solutions were dissolved in n-butanol (10 mL), and DIPEA (0.2585 g, 2 mmol) was added. The mixture was stirred at room temperature and reacted overnight. The reaction was then carried out by silica gel column chromatography (PE:EA = 40:1) to obtain the intermediate N1-(2,5-dichloropyrimidine-4-yl)-N 2 N 2 -Dimethylphenyl-1,2-diamine, white crystals, 0.15 g, yield: 52%. 1 HNMR (400MHz, Chloroform- d )δ9.16(s,1H),8.54(dd, J =8.1,1.5Hz,1H),8.20(s,1H),7.24(ddd, J =13.2,7.7,1.6Hz,2H),7.14(td, J =7.6, 1.6 Hz, 1H), 2.73 (s, 6H).

[0099] Weigh the intermediate (0.28 g, 1 mmol) and dissolve it in 1,4-dioxane (10 mL). Add intermediate (c) (0.22 g, 1 mmol) to t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol). Heat under reflux for 24 h and perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 0.16 g of white solid, yield: 35%. 1 HNMR(400MHz,Chloroform-d)δ10.19(s,1H),8.68(s,1H),8.49–8.44(m,1H),8.29(s,1H),7.39(d,J=8.7 Hz,2H),7.23–7.18(m,1H),7.13–7.05(m,2H),6.99–6.94(m,2H),3.88(s,3H),2.73(s,6H),2.42(s,3H).

[0100] Example 7

[0101] The synthesis of 5-chloro-N4-(3-dimethylamino)phenyl-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material N,N-dimethyl-o-phenylenediamine in Example 6 was replaced with N,N-dimethyl-m-phenylenediamine, and other steps and operations were the same as in Example 6; 0.14 g of white solid, yield: 30%. 1 HNMR (400MHz, Chloroform- d )δ9.63(s,1H),8.25(s,1H),7.30(d, J =8.4Hz,2H),7.24(t, J =8.1Hz, 1H), 7.12(s, 1H), 6.95(d, J =8.7Hz, 3H), 6.84(d, J =7.7Hz, 1H), 6.56(dd, J =8.3,2.5Hz,1H),3.88(s,3H),2.89(s,6H),2.39(s,3H).

[0102] Example 8

[0103] The synthesis of 5-chloro-N4-(2-methoxyphenyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthetic method: 2-Methoxyaniline (0.12 g, 1 mmol) and trichloropyrimidine (0.14 g, 1 mmol) were used as raw materials, dissolved in isopropanol (10 mL), and DIPEA (0.26 g, 2 mmol) was added. The mixture was heated under reflux for 8 h and then subjected to silica gel column chromatography (PE:EA = 10:1) to obtain the intermediate 2,5-dichloro-N-(2-methoxyphenyl)pyrimidine-4-amine, a white flocculent solid, 0.16 g, yield: 60%. Weigh the intermediate (0.3 g, 1 mmol) and dissolve it in 1,4-dioxane (10 mL). Add intermediate (c) (0.22 g, 1 mmol) to t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol). Heat under reflux for 24 h and perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 0.16 g of white solid, yield: 35%. 1HNMR(300MHz,DMSO-d6)δ11.29(s,1H),8.59(s,J=20.5Hz,1H),8.22(s,1H),7.78–7.30(m,1H),7.21(d,J=8. 5Hz,3H),7.10(d,J=8.2Hz,1H),7.00(dd,J=16.1,8.0Hz,3H),3.81(d,J=2.0Hz,3H),3.77(s,3H),2.26(s,3H).

[0104] Example 9

[0105] The synthesis of 5-chloro-N4-(3-methoxyphenyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material 2-methoxyaniline in Example 8 was replaced with 3-methoxyaniline, and other steps and operations were the same as in Example 8; 0.15 g of white solid, yield: 33%. 1 HNMR (400MHz, Chloroform- d )δ9.30(s,1H),8.25(s,1H),7.32(d, J =8.5Hz,2H),7.27(d, J =3.7Hz,2H),7.15(s,1H),7.06(dd, J =8.0, 1.3 Hz, 1H), 6.96 (d, J =8.7Hz,2H),6.74(dd, J =8.1,2.4Hz,1H),3.88(s,3H),3.76(s,3H),2.39(s,3H).

[0106] Example 10

[0107] The synthesis of 5-chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-naphth-2-ylpyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material 2-methoxyaniline in Example 8 was replaced with 2-naphthylamine, and other steps and operations were the same as in Example 8; 39 mg of white solid, yield: 8%. 1 HNMR (300MHz, DMSO-) d 6)δ11.44(s,1H),9.28(s,1H),8.31(s,1H),8.09–7.60(m,5H),7.49(d, J =4.2Hz,2H),6.88(d, J =39.8Hz,4H),3.77(s,3H),2.25(s,3H).

[0108] Example 11

[0109] The synthesis of N-(5-chloro-4-(1H-indol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the following structural formula and synthetic steps: Synthetic method: Indole (0.12 g, 1 mmol) and NaH (0.12 g, 3 mmol) were weighed, protected with Ar, placed in an ice bath, and injected with anhydrous DMF (10 mL) for 4 h. Trichloropyrimidine (0.37 g, 2 mmol) was injected, and the reaction was carried out at room temperature for 25 min. The reaction was quenched with ice water, ethyl acetate was added, and the mixture was extracted with water. The organic phase was collected and concentrated, and subjected to silica gel column chromatography (PE:EA = 50:1) to give the intermediate 1-(2,5-dichloropyrimidin-4-yl)-1H-indole, 0.12 g of white solid, yield 45%. Weigh 1-(2,5-dichloropyrimidin-4-yl)-1H-indole (0.26 g, 1 mmol), dissolve in 1,4-dioxane (15 mL), add intermediate (c) (0.22 g, 1 mmol), dissolve in dioxane (15 mL), add K3PO4 (0.30 g, 1.4 mmol), Pd2(dba)3 (0.073 g, 0.08 mmol) and Xantphos (0.069 g, 0.12 mmol), heat under reflux for 24 h, and perform silica gel column chromatography (PE:EA = 1:1) to give 0.22 g of pale yellow solid, yield: 50%. 1 HNMR (400MHz, DMSO-) d 6)δ12.09(s,1H),8.90(s,1H),7.93(d, J=8.7Hz, 1H), 7.89(d, J =3.5Hz, 1H), 7.67(d, J =7.6Hz,1H),7.36–7.31(m,2H),7.31–7.21(m,2H),6.99(d, J =8.7Hz,2H),6.83(d, J =3.5Hz,1H),3.79(s,3H),2.32(s,3H).

[0110] Example 12

[0111] The synthesis of N-(5-chloro-4-(5-methoxy-1H-indol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the following structural formula and synthetic steps: Synthesis method: The raw material indole in Example 11 was replaced with 5-methoxyindole, and other steps and operations were the same as in Example 11; 0.14 g of pale yellow solid, yield: 29%. 1 HNMR (300MHz, Chloroform- d )δ8.63(s,1H),7.89(d, J =9.0Hz,1H),7.82(d, J =3.6Hz, 1H), 7.35(d, J =8.6Hz,2H),7.12(d, J =2.5Hz,1H),6.99–6.91(m,4H),6.70(d, J =3.6Hz,1H),3.89(s,3H),3.87(s,3H),2.42(s,3H).

[0112] Example 13

[0113] The synthesis of N-((4-bromo-1H-indol-1-yl)-5-chloropyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the following structural formula and synthetic steps: Synthesis method: The indole raw material in Example 11 was replaced with 5-bromoindole, and other steps and operations were the same as in Example 11; 0.15 g of pale yellow solid, yield: 28%. 1 HNMR (300MHz, DMSO-) d 6)δ12.13(s,1H),8.91(s,1H),8.02–7.84(m,3H),7.49–7.40(m,1H),7.34(d, J =8.2Hz,2H),6.99(d, J=8.2Hz,2H),6.81(d, J =3.6Hz,1H),3.79(s,3H),2.32(s,3H).

[0114] Example 14

[0115] The synthesis of N-(5-chloro-4-(1H-indazol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the structural formula and synthetic steps are as follows: Synthesis method: The raw material indole in Example 11 was replaced with indazole, and other steps and operations were the same as in Example 11; 0.2 g of pale yellow solid, yield: 45%. 1 HNMR(300MHz,DMSO-d6)δ12.18(s,1H),8.88(s,1H),8.58(d,J=0.8Hz,2H),7.94(d,J=7.9Hz,1H),7.64– 7.57(m,1H),7.43(d,J=7.5Hz,1H),7.40–7.34(m,2H),7.01(d,J=8.6Hz,2H),3.79(s,3H),2.34(s,3H).

[0116] Example 15

[0117] The synthesis of N-(5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazolyl-2-amine, with the following structural formula and synthetic steps: Synthesis method: The raw material indole in Example 11 was replaced with 7-azaindole, and other steps and operations were the same as in Example 11; 0.19 g of pale yellow solid, yield: 42%. 1 HNMR (300MHz, DMSO-) d 6)δ12.16(s,1H),8.95(s,1H),8.38–8.28(m,1H),8.13(d, J =7.8Hz, 1H), 7.90(d, J =3.8Hz, 1H), 7.35(d, J =8.3Hz,2H),7.28(dd, J =8.0, 4.8Hz, 1H), 7.01(d, J =8.3Hz,2H),6.86(d, J =4.0Hz,1H),3.79(s,3H),2.31(s,3H).

[0118] Example 16

[0119] The synthesis of N-((4-benzo[1,2,3]triazol-1-yl)-5-chloropyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the following structural formula and synthetic steps: Synthesis method: The raw material indole in Example 11 was replaced with benzotriazole, and other steps and operations were the same as in Example 11; 0.2 g of yellow solid, yield: 44%. 1 HNMR (400MHz, DMSO-) d 6)δ12.35(s,1H),9.06(s,1H),8.52–8.41(m,1H),8.26(dt, J =8.4, 1.0 Hz, 1H), 7.77 (ddd, J =8.3,7.0,1.1Hz,1H),7.62(ddd, J =8.3,7.0,1.0Hz,1H),7.35(d, J =8.3Hz,2H),7.03–6.98(m,2H),3.79(s,3H),2.34(s,3H).

[0120] Example 17

[0121] The synthesis of N-(5-chloro-4-(5-methylimidazol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the following structural formula and synthetic steps: Synthesis method: The raw material N,N-dimethyl-o-phenylenediamine in Example 6 was replaced with 4-methylimidazole, and other steps and operations were the same as in Example 6; 0.27 g of yellow solid, yield: 65%. 1 HNMR(300MHz,DMSO-d6)δ12.15(s,1H),8.85(s,1H),8.45(s,1H),7.70(s,1H),7.4 4–7.37(m,2H),7.08–7.01(m,2H),3.80(s,3H),2.33(s,3H),2.20(d,J=1.2Hz,3H).

[0122] Example 18

[0123] The synthesis of N4-benzyl-(5-chloro-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with its structural formula and synthetic steps, is as follows: Using benzylamine (0.11 g, 1 mmol) and trichloropyrimidine (0.18 g, 1 mmol) as raw materials, the mixture was dissolved in isopropanol (10 mL), and DIPEA (0.19 g, 1.5 mmol) was added. The mixture was heated under reflux for 3 h and then subjected to silica gel column chromatography (PE:EA = 50:1) to obtain the intermediate N-benzyl-2,5-dichloropyrimidine-4-amine, a white solid of 0.2 g, with a yield of 80%. 1 HNMR (300MHz, DMSO-) d 6)δ8.55(s,1H),8.21(s,1H),7.40–7.27(m,4H),7.25(tt, J =7.4 (2.2 Hz, 1H), 4.59 (s, 2H).

[0124] Weigh the intermediate N-benzyl-2,5-dichloropyrimidin-4-amine (0.25 g, 1 mmol), dissolve it in 1,4-dioxane (15 mL), add intermediate (c) (0.22 g, 1 mmol), add K3PO4 (0.30 g, 1.4 mmol), Pd2(dba)3 (0.073 g, 0.08 mmol) and Xantphos (0.069 g, 0.12 mmol), heat to reflux for 24 h, and then perform silica gel column chromatography (PE:EA = 2:1) to give 90 mg of white solid, yield: 21%. 1 HNMR(300MHz,DMSO-d6)δ11.24(s,1H),8.09(s,2H),7.32(d,J=4.6Hz,4H),7.27–7 .15(m,3H),6.98(d,J=8.8Hz,2H),4.78(d,J=6.2Hz,2H),3.79(s,3H),2.26(s,3H).

[0125] Example 19

[0126] The synthesis of 5-chloro-N4-(2-fluorobenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthetic method: 2-Fluorobenzylamine (0.13 g, 1 mmol) and trichloropyrimidine (0.18 g, 1 mmol) were used as starting materials, dissolved in isopropanol (10 mL), and DIPEA (0.19 g, 1.5 mmol) was added. The mixture was heated under reflux for 3 h and then subjected to silica gel column chromatography (PE:EA = 10:1) to obtain the intermediate 2,5-dichloro-N-(2-fluorobenzyl)pyrimidine-4-amine, a white solid of 0.22 g, yield: 80%. Weigh the intermediate (0.27 g, 1 mmol) and dissolve it in 1,4-dioxane (10 mL). Add intermediate (c) (0.22 g, 1 mmol) to t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol). Heat under reflux for 24 h and perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 0.3 g of white solid, yield: 66%. 1 HNMR (300MHz, DMSO-) d 6)δ11.23(s,1H),8.12(s,1H),8.03(t, J =6.1Hz,1H),7.34–7.10(m,6H),7.05–6.95(m,2H),4.82(d, J =6.0Hz,2H),3.81(s,3H),2.24(s,3H).

[0127] Example 20

[0128] The synthesis of 5-chloro-(N4-(3-fluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material 2-fluorobenzylamine in Example 19 was replaced with 3-fluorobenzylamine, and other steps and operations were the same as in Example 19; 0.16 g of white solid, yield: 35%. 1 HNMR (300MHz, DMSO-) d 6)δ11.32(s,1H),8.16–8.08(m,2H),7.35(t, J =7.7Hz, 1H), 7.19(d, J =8.3Hz,4H),7.06(t, J =8.7Hz, 1H), 6.97(d, J =6.6Hz,2H),4.77(d, J =6.2Hz,2H),3.79(s,3H),2.26(s,3H).

[0129] Example 21

[0130] The synthesis of 5-chloro-(N4-(4-fluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material 2-fluorobenzylamine in Example 19 was replaced with 4-fluorobenzylamine, and other steps and operations were the same as in Example 19; 95 mg of white solid, yield: 21%. 1 HNMR (300MHz, DMSO-) d 6) δ 11.24 (s, 1H), 8.08 (d, J =6.2Hz,2H),7.38(t, J =7.0Hz,2H),7.25–7.07(m,4H),7.04–6.94(m,2H),4.74(d, J =6.2Hz,2H),3.80(s,3H),2.27(s,3H).

[0131] Example 22

[0132] The synthesis of 5-chloro-(N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)-(N4-(4-trifluoromethoxy)benzyl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material 2-fluorobenzylamine in Example 19 was replaced with 4-(trifluoromethoxy)benzylamine, and other steps and operations were the same as in Example 19; 0.19 g of white solid, yield: 36%. 1 HNMR (400MHz, Chloroform- d )δ10.11(s,1H),8.22(s,1H),7.40(d, J =8.5Hz,2H),7.24(dd, J =20.8,8.4Hz,4H),6.93(d, J =8.7Hz,2H),5.76(t, J =6.0Hz, 1H), 4.88(d, J =5.9Hz,2H),3.86(s,3H),2.41(s,3H).

[0133] Example 23

[0134] The synthesis of 5-chloro-(N4-(4-chlorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material 2-fluorobenzylamine in Example 19 was replaced with 4-chlorobenzylamine, and other steps and operations were the same as in Example 19; 0.26 g of white solid, yield: 54%. 1 HNMR (400MHz, DMSO-) d 6)δ11.26(s,1H),8.10(s,2H),7.36(d, J =5.0Hz, 4H), 7.16(d, J =8.3Hz,2H),7.03–6.95(m,2H),4.74(d, J =5.9Hz,2H),3.80(s,3H),2.26(s,3H).

[0135] Example 24

[0136] The synthesis of N4-(4-bromobenzyl)-5-chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, including its structural formula and synthetic steps, is as follows: Synthesis method: The raw material 2-fluorobenzylamine in Example 19 was replaced with 4-bromobenzylamine, and other steps and operations were the same as in Example 19; 0.15 g of white solid, yield: 29%. 1 HNMR(400MHz,DMSO-d6)δ11.25(s,1H),8.11(d,J=12.0Hz,1H),8.10(s,1H),7.55–7.46(m,2H),7.28(d, J=7.9Hz,2H),7.15(d,J=8.2Hz,2H),7.03–6.95(m,2H),4.72(d,J=6.1Hz,2H),3.80(s,3H),2.26(s,3H).

[0137] Example 25

[0138] The synthesis of 5-chloro-N4-(2-methoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Synthesis method: The raw material 2-fluorobenzylamine in Example 19 was replaced with 2-methoxybenzylamine. Other steps and operations were the same as in Example 19. 65 mg of white solid, yield: 14%. 1HNMR(400MHz,DMSO-d6)δ11.17(s,1H),8.10(s,1H),7.87(s,1H),7.26–7.17(m,1H),7.11(d,J=8.3Hz,2H),7.05–6.97(m,3 H),6.97(dd,J=8.2,1.1Hz,1H),6.87(td,J=7.4,1.1Hz,1H),4.72(d,J=6.1Hz,2H),3.80(s,3H),3.63(s,3H),2.21(s,3H).

[0139] Example 26

[0140] The synthesis of 5-chloro-(N4-(3-methoxybenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 3-methoxybenzylamine, and the other steps and operations were the same as in Example 19; 86 mg of white solid, yield: 18%. 1 HNMR (400MHz, DMSO-) d 6) δ 11.25 (s, 1H), 8.08 (d, J =9.5Hz,2H),7.27–7.17(m,3H),7.02–6.93(m,2H),6.89(d, J =5.9Hz,2H),6.80(ddd, J =8.2,2.5,1.0Hz,1H),4.75(d, J =6.2Hz,2H),3.79(s,3H),3.66(s,3H),2.26(s,3H).

[0141] Example 27

[0142] The synthesis of 5-chloro-N4-(4-methoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 4-methoxybenzylamine, and the other steps and operations were the same as in Example 19; 0.26 g of white solid, yield: 56%. 1 HNMR (400MHz, DMSO-) d 6)δ11.24(s,1H),8.08(s,1H),8.01(t, J =6.2Hz, 1H), 7.28(d, J =8.2Hz,2H),7.22(d, J=8.2Hz,2H),7.02–6.94(m,2H),6.91–6.83(m,2H),4.69(d, J =6.1Hz,2H),3.79(s,3H),3.70(s,3H),2.27(s,3H).

[0143] Example 28

[0144] The synthesis of 5-chloro-N4-(3,4-dimethoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 3,4-dimethoxybenzylamine, and the other steps and operations were the same as in Example 19; 0.15 g of white solid, yield: 30%. 1 HNMR (400MHz, DMSO-) d 6)δ11.25(s,1H),8.08(s,1H),8.01(t, J =6.2Hz, 1H), 7.22(d, J =8.2Hz,2H),7.03–6.93(m,3H),6.85(d, J =3.9Hz,2H),4.69(d, J =6.2Hz,2H),3.78(s,3H),3.69(s,3H),3.58(s,3H),2.27(s,3H).

[0145] Example 29

[0146] The synthesis of 5-chloro-N4-(3,4-difluorobenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 3,4-difluorobenzylamine, and other steps and operations were the same as in Example 19; 0.26 g of white solid, yield: 54%. 1 HNMR (400MHz, DMSO-) d 6)δ11.30(s,1H),8.11(s,2H),7.37(dt, J =10.8,8.4Hz,2H),7.21(d, J =8.7Hz, 3H), 6.98(d, J =8.8Hz,2H),4.70(s,2H),3.79(s,3H),2.27(s,3H).

[0147] Example 30

[0148] The synthesis of 5-chloro-(N4-(2,4-difluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 2,4-difluorobenzylamine, and other steps and operations were the same as in Example 19; 0.15 g of white solid, yield: 32%. 1 HNMR (300MHz, Chloroform- d )δ8.10(s,1H),7.43–7.36(m,1H),7.33(d, J =8.7Hz,2H),6.96(d, J =8.8Hz,2H),6.91–6.85(m,1H),6.85–6.77(m,1H),5.75(t, J =6.1Hz, 1H), 4.86(d, J =6.0Hz,2H),3.87(s,3H),2.39(s,3H).

[0149] Example 31

[0150] The synthesis of 5-chloro-N4-(3-chloro-4-fluorobenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 3-chloro-4-fluorobenzylamine, and the other steps and operations were the same as in Example 19; 0.14 g of white solid, yield: 29%. 1 HNMR (400MHz, DMSO-) d 6)δ11.30(s,1H),8.11(s,2H),7.37(dt, J =10.8,8.4Hz,2H),7.21(d, J =8.7Hz, 3H), 6.98(d, J =8.8Hz,2H),4.70(s,2H),3.79(s,3H),2.27(s,3H).

[0151] Example 32

[0152] The synthesis of 5-chloro-N4-(2,4-dimethoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 2,4-dimethoxybenzylamine, and other steps and operations were the same as in Example 19; 0.12 g of white solid, yield: 23%. 1 HNMR (400MHz, DMSO-) d 6)δ11.17(s,1H),8.08(s,1H),7.76(s,1H),7.15(d, J =8.3Hz,2H),7.03–6.97(m,2H),6.92(d, J =8.3Hz, 1H), 6.53(d, J =2.4Hz, 1H), 6.43(dd, J =8.4, 2.4 Hz, 1H), 4.64 (d, J =6.1Hz,2H),3.79(s,3H),3.70(s,3H),3.62(s,3H),2.22(s,3H).

[0153] Example 33

[0154] The synthesis of 5-chloro-(N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 2-fluorobenzylamine in Example 19 was replaced with 3,4,5-trimethoxybenzylamine, and the other steps and operations were the same as in Example 19; 0.14 g of white solid, yield: 26%. 1 HNMR (400MHz, DMSO-) d 6)δ11.26(s,1H),8.09(s,1H),8.02(t, J =6.3Hz, 1H), 7.25(d, J =8.5Hz,2H),7.01–6.93(m,2H),6.68(s,2H),4.68(d, J =6.1Hz,2H),3.78(s,3H),3.62(s,6H),3.59(s,3H),2.27(s,3H).

[0155] Example 34

[0156] The synthesis of 5-chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-phenylethylpyrimidine-2,4-diamine, with the following structural formula and synthetic steps: Using phenethylamine (0.12 g, 1 mmol) as the starting material, it was dissolved in methanol (10 mL). Et3N (0.11 g, 1.05 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 10 min. Trichloropyrimidine (0.18 g, 1 mmol) was slowly added dropwise. The mixture was then subjected to silica gel column chromatography (PE:EA = 15:1) to obtain the intermediate 2,5-dichlorophenylethylpyrimidine-4-amine, a transparent oily liquid, 0.18 g, yield: 50%. Weigh the intermediate (0.27 g, 1 mmol) and dissolve it in 1,4-dioxane (10 mL). Add intermediate (c) (0.22 g, 1 mmol) to t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol). Heat under reflux for 24 h and perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 0.18 g of white solid, yield: 40%. 1 HNMR (400MHz, Chloroform- d )δ8.07(s,1H),7.35(d, J =8.7Hz,2H),7.25(d, J =5.9Hz, 5H), 6.96(d, J =8.6Hz,2H),5.54(t, J =5.9Hz, 1H), 3.93(q, J =6.8Hz,2H),3.88(s,3H),3.02(t, J =7.3Hz,2H),2.42(s,3H).

[0157] Example 35

[0158] The synthesis of 5-chloro-(N4-(4-fluorophenylethyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl)pyrimidine-2,4-diamine, with its structural formula and synthetic steps, is as follows: Using 4-fluorophenylethylamine (0.14 g, 1 mmol) and trichloropyrimidine (0.18 g, 1 mmol) as raw materials, the mixture was dissolved in isopropanol (10 mL), and DIPEA (0.19 g, 1.5 mmol) was added. The mixture was heated under reflux for 3 h, and then subjected to silica gel column chromatography (PE:EA = 10:1) to obtain the intermediate 2,5-dichloro-N-(4-fluorophenylethyl)pyrimidine-4-amine, a white solid of 0.17 g, with a yield of 59%. Weigh the intermediate (0.29 g, 1 mmol), dissolve it in 1,4-dioxane (10 mL), and add intermediate (c) (0.22 g, 1 mmol) to t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol). Heat under reflux for 24 h, and then perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 95 mg of white solid, yield: 20%. 1 HNMR (300MHz, Chloroform- d )δ8.07(s,1H),7.32(d, J =8.7Hz,2H),7.18(dd, J =8.5,5.4Hz,2H),7.00–6.87(m,4H),5.53(s,1H),3.89(s,5H),2.99(t, J =7.4Hz,2H),2.41(s,3H).

[0159] Example 36

[0160] The synthesis of 5-chloro-(N4-(2-chlorophenylethyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 4-fluorophenylethylamine in Example 35 was replaced with 2-chlorophenylethylamine, and the other steps and operations were the same as in Example 35; 0.12 g of white solid, yield: 25%. 1 HNMR (400MHz, Chloroform- d )δ8.05(s,1H),7.36(d, J =8.7Hz,3H),7.26–7.05(m,3H),6.96(d, J =8.7Hz,2H),5.56(t, J =5.8Hz, 1H), 3.88(s, 5H), 3.15(t, J =7.1Hz,2H),2.41(s,3H).

[0161] Example 37

[0162] The synthesis of 5-chloro-(N4-(3-chlorophenylethyl)-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 4-fluorophenylethylamine in Example 35 was replaced with 3-chlorophenylethylamine, and the other steps and operations were the same as in Example 35; 0.26 g of white solid, yield: 53%. 1 HNMR (400MHz, Chloroform- d )δ8.06(s,1H),7.35–7.30(m,2H),7.25–7.20(m,2H),7.17(t, J =8.0Hz,1H),7.13–7.08(m,1H),6.98–6.93(m,2H),5.53(t, J =6.1Hz, 1H), 3.88(s, 5H), 3.00(t, J =7.2Hz,2H),2.41(s,3H).

[0163] Example 38

[0164] The synthesis of 5-chloro-(N4-(3,4-dimethoxyphenethyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine, with the following structural formula and synthetic steps: The raw material 4-fluorophenylethylamine in Example 35 was replaced with 3,4-dimethoxyphenylethylamine, and the other steps and operations were the same as in Example 35; 0.14 g of white solid, yield: 28%. 1 HNMR (400MHz, Chloroform- d )δ10.40(s,1H),8.19(s,1H),7.34(d, J =8.7Hz, 2H), 6.95(d, J =8.7Hz,2H),6.80–6.69(m,3H),5.55(t, J =6.0Hz,1H),3.87(s,8H),3.82(s,3H),2.96(t, J =7.1Hz,2H),2.44(s,3H).

[0165] Example 39

[0166] The synthesis of 5-chloro-(N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-propylpyrimidine-2,4-diamine, with its structural formula and synthetic steps, is as follows: Trichloropyrimidine (0.18 g, 1 mmol) was dissolved in anhydrous ethanol (10 mL), stirred at 0 °C, and n-propylamine (0.11 g, 1.82 mmol) was slowly added dropwise. The mixture was stirred at 0 °C for 3 h, and silica gel column chromatography (PE:EA = 15:1) was used to obtain the intermediate 2,5-dichloro-N-propylpyrimidine-4-amine, a transparent oily liquid, 0.12 g, yield: 58%. Weigh the intermediate (0.21 g, 1 mmol), dissolve it in 1,4-dioxane (10 mL), and add intermediate (c) (0.22 g, 1 mmol) to t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol). Heat under reflux for 24 h, and then perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 84 mg of white solid, yield: 21%. 1 HNMR (300MHz, DMSO-) d 6)δ11.22(s,1H),8.02(s,1H),7.58(s,1H),7.39–7.32(m,2H),7.05–6.98(m,2H),3.79(s,3H),3.47(q, J =6.8Hz,2H),2.29(s,3H),1.63(h, J =7.3Hz,2H),0.88(t, J =7.4Hz, 3H).

[0167] Example 40

[0168] The synthesis of 5-chloro-N4-(2-(dimethylamino)ethyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl)pyrimidine-2,4-diamine hydrochloride, with the following structural formula and synthetic steps: The raw material benzylamine in Example 18 was replaced with N,N-dimethylethylenediamine. Other steps and operations were the same as in Example 18. 0.1 g of white solid was obtained, with a yield of 22%. 1 HNMR (400MHz, DMSO-) d 6)δ11.29(s,1H),9.73(s,1H),8.12(s,1H),7.58(s,1H),7.38(d, J =8.6Hz,2H),7.01(d, J =8.6Hz,2H),3.79(s,5H),3.21(s,2H),2.72(s,6H),2.30(s,3H).

[0169] Example 41

[0170] The synthesis of N-((5-chloro-4-piperidin-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the following structural formula and synthetic steps: Synthetic method: Piperidine (0.08 g, 1 mmol) and trichloropyrimidine (0.18 g, 1 mmol) were used as raw materials, dissolved in n-butanol (10 mL), and DIPEA (0.15 g, 1.2 mmol) was added. After incubation at room temperature for 18 h, silica gel column chromatography (PE:EA = 10:1) was performed to obtain the intermediate 2,5-dichloro-4-piperidin-1-ylpyrimidine, 0.19 g of white solid, yield: 83%. Weigh the intermediate (0.23 g, 1 mmol) and dissolve it in 1,4-dioxane (10 mL). Add intermediate (c) (0.22 g, 1 mmol) to t-BuONa (0.192 g, 2 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and BINAP (0.06 g, 0.1 mmol). Heat under reflux for 24 h and perform silica gel column chromatography (PE:EA = 1:1) to obtain the target product, 0.17 g of white solid, yield: 41%. 1 HNMR (300MHz, DMSO-) d 6) δ11.38(s,1H),8.16(s,1H),7.40–7.33(m,2H),7.06–6.99(m,2H),3.79(s,3H),3.72(s,4H),2.30(s,3H),1.65(s,6H).

[0171] Example 42

[0172] The synthesis of N-(5-chloro-4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with N-methylpiperazine. Other steps and operations were the same as in Example 41. 70 mg of white solid was obtained, with a yield of 16%. 1 HNMR (400MHz, DMSO-) d 6)δ11.43(s,1H),8.20(s,1H),7.37(d, J =8.7Hz,2H),7.02(d, J =8.7Hz,2H),3.79(s,3H),3.74(t, J =4.9Hz,4H),2.46(t, J =4.7Hz,4H),2.30(s,3H),2.22(s,3H).

[0173] Example 43

[0174] The synthesis of (R)-(1-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-ol, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with (R)-3-pyrrolidone. Other steps and operations were the same as in Example 41. 90 mg of white solid was obtained, yield: 22%. [α]D 25 =-28.0 (c=0.075, CHCl3). 1 HNMR (300MHz, DMSO-) d 6)δ11.23(s,1H),8.04(s,1H),7.39–7.33(m,2H),7.02(d, J =8.7Hz,2H),5.05(d, J =3.3Hz,1H),4.40–4.33(m,1H),3.97–3.85(m,3H),3.79(s,3H),3.74(d, J =12.1Hz,1H),2.28(s,3H),1.99–1.82(m,2H).

[0175] Example 44

[0176] The synthesis of (R)-1-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-2-methanol, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with L-prolyl, and other steps and operations were the same as in Example 41. 0.14 g of white solid was obtained, with a yield of 32%. [α]D 25 =+32.7 (c=0.10, CHCl3). 1 HNMR (300MHz, Chloroform- d )δ10.21(s,1H),8.16(s,1H),7.41–7.34(m,2H),7.00–6.93(m,2H),4.92–4.81(m,1H),4.07(d, J =4.3Hz, 1H), 3.90(d, J =6.3Hz,1H),3.86(s,4H),3.82(dd, J =5.0,2.1Hz,2H),2.41(s,3H),2.16–2.08(m,2H),2.04(m,1H),1.97–1.89(m,1H).

[0177] Example 45

[0178] The synthesis of tert-butyl ((5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)amino)ethylcarbamate, the structural formula and synthetic steps are as follows: The raw material piperidine in Example 41 was replaced with tert-butyl (2-aminoethyl)carbamate. Other steps and operations were the same as in Example 41. 0.12 g of white solid was obtained, with a yield of 24%. 1 HNMR (400MHz, Chloroform- d )δ9.75(s,1H),8.09(s,1H),7.37(d, J =7.4Hz, 2H), 6.97(d, J =5.7Hz,2H),6.23(s,1H),4.90(s,1H),3.87(s,3H),3.73(s,2H),3.48(s,2H),2.39(s,3H),1.46(s,9H).

[0179] Example 46

[0180] The synthesis of tert-butyl 4-((5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-ylamino)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid is described below, along with its structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with 1-tert-butoxycarbonyl-4-aminomethylpiperidine. Other steps and operations were the same as in Example 41. 0.14 g of white solid was obtained, with a yield of 26%. 1 HNMR (400MHz, Chloroform- d )δ10.62(s,1H),8.21(s,1H),7.36(d, J =8.7Hz,2H),6.97(d, J =8.8Hz,2H),5.60(t, J =6.2Hz, 1H), 4.14(d, J =7.1Hz,2H),3.87(s,3H),3.58(t, J =6.7Hz,2H),2.70(t, J =12.9Hz,2H),2.44(s,3H),2.05–1.93(m,1H),1.77(d, J =13.0Hz,2H),1.47(s,9H),1.29–1.17(m,2H).

[0181] Example 47

[0182] The synthesis of tert-butyl (1-((5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)piperidin-4-yl)methylcarbamate, the structural formula and synthetic steps are as follows: The raw material piperidine in Example 41 was replaced with 4-Boc-aminomethylpiperidine. Other steps and operations were the same as in Example 41. 0.12 g of white solid was obtained, with a yield of 23%. 1 HNMR (300MHz, DMSO-) d 6)δ11.38(s,1H),8.16(s,1H),7.37(d, J =8.7Hz,2H),7.02(d, J =8.8Hz,2H),6.96–6.88(m,1H),4.44(d, J =12.5Hz,2H),3.79(s,3H),3.02(t, J =12.3Hz,2H),2.85(d, J =6.1Hz,2H),2.30(s,3H),1.72(d, J =11.8Hz,3H),1.36(s,9H),1.24(dt, J =8.7, 4.7 Hz, 2H).

[0183] Example 48

[0184] The synthesis of tert-butyl ((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)piperidine-4-carbamate, with its structural formula and synthetic steps, is as follows: The raw material piperidine in Example 41 was replaced with 4-tert-butoxycarbonylaminopiperidine. Other steps and operations were the same as in Example 41. 0.15 g of white solid was obtained, with a yield of 28%. 1 HNMR (400MHz, Chloroform- d )δ9.47(s,1H),8.18(s,1H),7.38(d, J =8.8Hz,2H),6.99(d, J =8.7Hz,2H),4.50(s,2H),4.46(s,1H),3.88(s,3H),3.77(s,1H),3.18(t, J =12.1Hz,2H),2.42(s,3H),2.10(d, J =11.4Hz,2H),1.58–1.52(m,2H),1.48(s,9H).

[0185] Example 49

[0186] The synthesis of (S)-3-((5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with (S)-1-tert-butoxycarbonyl-3-aminopiperidine. Other steps and operations were the same as in Example 41. 0.15 g of white solid was obtained, with a yield of 28%. [α]D 25 =-28.3 (c=0.11, CHCl3). 1 HNMR (300MHz, Chloroform- d )δ9.82(s,1H),8.15(s,1H),7.38(d, J =8.7Hz,2H),6.98(d, J =8.7Hz,2H),5.58(s,1H),4.39(s,1H),3.88(s,3H),3.77(s,2H),3.52(d, J =12.0Hz,1H),3.34–3.16(m,1H),2.43(s,3H),1.96(d, J =3.0Hz,2H),1.75(d, J =4.0Hz,2H),1.41(s,9H).

[0187] Example 50

[0188] The synthesis of (R)-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)piperidine-3-carbamate tert-butyl ester, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with (R)-3-Boc-aminopiperidine. Other steps and operations were the same as in Example 41. 0.24 g of white solid was obtained, yield: 45%. [α]D 25 =-14.0 (c=0.11, CHCl3). 1 HNMR (400MHz, Chloroform- d )δ9.41(s,1H),8.19(s,1H),7.41–7.36(m,2H),7.01–6.95(m,2H),4.83(s,1H),3.87(s,5H),3.69(d, J =4.6Hz,3H),2.42(s,3H),1.99–1.89(m,2H),1.78(d, J =5.2Hz,2H),1.44(s,9H).

[0189] Example 51

[0190] The synthesis of (S)-((1-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)tert-butyl carbamate, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with (S)-3-Boc-aminopiperidine, and other steps and operations were the same as in Example 41. 0.22 g of white solid was obtained, yield: 41%. [α]D 25 =-4.1 (c=0.073, CHCl3). 1 HNMR (400MHz, Chloroform- d )δ9.19(s,1H),8.17(s,1H),7.38(d, J =8.7Hz,2H),7.01–6.96(m,2H),4.82(s,1H),3.87(s,5H),3.68(d, J =8.1Hz,3H), 2.41(s,3H), 1.94(d, J =11.9Hz,2H),1.88–1.78(m,2H),1.44(s,9H).

[0191] Example 52

[0192] The synthesis of (S)-(5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-ylamino)pyrimidin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with (S)-1-Boc-3-aminopyrrolidine, and other steps and operations were the same as in Example 41. 0.23 g of white solid was obtained, yield: 44%. [α]D 25 =-51.5 (c=0.10, CHCl3). 1 HNMR (300MHz, Chloroform- d )δ10.03(s,1H),8.18(s,1H),7.41–7.34(m,2H),7.01–6.94(m,2H),5.44(d, J =7.0Hz,1H),4.93–4.79(m,1H),3.87(s,3H),3.85–3.75(m,1H),3.65–3.42(m,3H),3.35(d, J =11.8Hz,1H),2.43(s,3H),2.40–2.30(m,1H),1.49(s,9H).

[0193] Example 53

[0194] The synthesis of (R)-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-carbamate tert-butyl ester, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with (R)-3-tert-butoxycarbonylaminopyrrolidine. Other steps and operations were the same as in Example 41. 0.27 g of white solid was obtained, with a yield of 52%. [α]D 25 =-7.7 (c=0.13, CHCl3). 1 HNMR (300MHz, Chloroform- d )δ9.91(s,1H),8.12(s,1H),7.40–7.33(m,2H),7.01–6.94(m,2H),4.87(s,1H) ,4.41–4.26(m,1H),4.21–4.16(m,1H),4.07–3.94(m,2H),3.87(s,3H),3.83(d, J =11.5Hz,1H),2.40(s,3H),2.19(td, J =13.8,8.2Hz,1H),2.06–1.91(m,1H),1.47(s,9H).

[0195] Example 54

[0196] The synthesis of (S)-(((5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate, with the following structural formula and synthetic steps: The raw material piperidine in Example 41 was replaced with (R)-3-tert-butoxycarbonylaminopyrrolidine. Other steps and operations were the same as in Example 41. 0.14 g of white solid was obtained, with a yield of 27%. [α]D 25 =-11.8 (c=0.11, CHCl3). 1 HNMR (400MHz, Chloroform- d )δ9.30(s,1H),8.08(s,1H),7.39–7.35(m,2H),7.00–6.96(m,2H),4.78(s,1H),4.33(m,1H),4.16(dd, J =12.0, 5.9 Hz, 1H), 4.01(q, J =6.2,5.2Hz,2H),3.87(s,3H),3.84(d, J=11.9Hz,1H),2.39(s,3H),2.26–2.15(m,1H),1.98(dd, J =11.3,5.5Hz,1H),1.47(s,9H).

[0197] Example 55

[0198] The compounds in this invention have a certain inhibitory effect on the proliferation of human prostate cancer cells (PC-3) and human prostate cancer tumor cells (DU145).

[0199] (1) Cell inoculation: Prepare a single-cell suspension using a culture medium containing 10% fetal bovine serum, and inoculate 1000 PC-3 cells per well into a 96-well plate, with a volume of 100 μL per well;

[0200] (2) Preparation of the drug: Taking compound 40 as an example, the stock solution of Example 40 was prepared as 100mM (5.5mg, 120μL). 100μL of the stock solution was added to 200μL of LDMSO to prepare 33mM. The same method was used to prepare 100mM, 33mM, 10mM and 3.3mM respectively. Each concentration was then diluted 1000 times. The concentrations of the diluted solutions were 100μM, 33μM, 10μM and 3.3μM respectively.

[0201] (3) Drug administration: 24 hours after cell seeding, add 100 μL to each well and incubate for 4 days;

[0202] (4) Staining: After culturing for 4 days, add 10 μL MTT solution (5 mg / mL PBS, pH=7.4) to each well; continue incubation for 4 hours to terminate the culture, aspirate the culture supernatant from the well, centrifuge the suspended cells and aspirate the culture supernatant from the well; add 100 μL LDMSO to each well and shake for 10 minutes to completely dissolve the crystals;

[0203] (5) Colorimetric method: Select a wavelength of 570 nm, measure the absorbance of each well on an enzyme-linked immunosorbent assay (ELISA) instrument, record the results, process the data using GraphPad software, and list them in Table 1 below to obtain the IC50. 50 .

[0204] Example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 PC-3 >30 >30 >30 >30 >30 >30 DU145 >30 >30 >30 >30 8.74±0.41 >30 Example Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 PC-3 23.14±1.24 >30 >30 >30 >30 >30 DU145 >30 9.13±0.32 28.07±1.36 >30 >30 >30 Example Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 PC-3 >30 10.99±1.20 >30 >30 >30 16.60±1.80 DU145 >30 16.91±0.09 >30 >30 >30 28.82±2.43 Example Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 PC-3 >30 25.94±2.43 23.76±1.82 >30 NT NT DU145 10.79±1.33 >30 16.87±1.32 19.08±1.43 24.75±1.96 15.25±1.21 Example Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 PC-3 NT >30 NT NT >30 6.21±0.31 DU145 NT >30 28.06±1.30 NT >30 8.17±0.73 Example Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 PC-3 >30 >30 NT >30 >30 >30 DU145 >30 >30 NT >30 >30 >30 Example Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 PC-3 >30 20.23±2.30 >30 <1 >30 >30 DU145 >30 8.02±0.76 15.19±1.36 <1 >30 18.96±2.03 Example Example 43 Example 44 Example 45 Example 46 Example 47 Example 48 PC-3 6.02±0.53 13.75±1.45 >30 >30 >30 >30 DU145 3.23±0.31 12.44±1.36 17.28±2.03 >30 >30 10.71±1.23 Example Example 49 Example 50 Example 51 Example 52 Example 53 Example 54 PC-3 >30 27.63±2.63 25.48±2.02 >30 >30 >30 DU145 >30 9.72±0.83 16.84±1.72 >30 >30 20.67±1.67

[0205] Compounds with good activity selected from Table 1 were used to analyze the cell activity of human lung cancer cells (PC-9) and human non-small cell lung cancer cells (H1650). The results are shown in Table 2. ("NT" indicates not measured)

[0206] Table 2 shows the PC-9 and H1650 inhibitory activities (IC50) of some of the compounds in the examples. 50 (μM) .

[0207] In addition to the above-described embodiments, the present invention may have other implementations. All technical solutions formed by equivalent substitution or equivalent transformation fall within the protection scope claimed by the present invention.

Claims

1. A phenylthiazolamine pyrimidine derivative, characterized in that: The derivatives are selected from the following specific structures: (5) 2-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidine-4-amino)-N-methylbenzamide; (7) 5-Chloro-N4-(3-dimethylamino)phenyl-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (8) 5-Chloro-N4-(2-methoxyphenyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (9) 5-Chloro-N4-(3-methoxyphenyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (14) N-(5-chloro-4-(1H-indazol-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazol-2-amine; (18) N4-benzyl-5-chloro-N2-(5-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidine-2,4-diamine; (19) 5-Chloro-N4-(2-fluorobenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidin-2,4-diamine; (20) 5-Chloro-N4-(3-fluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (21) 5-Chloro-N4-(4-fluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (22) 5-Chloro-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-(4-trifluoromethoxy)benzyl)pyrimidine-2,4-diamine; (23) 5-Chloro-N4-(4-chlorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (24) N4-(4-bromobenzyl)-5-chloro-N2-(5-(4-methoxyphenyl)-4-methylthiazo-2-yl)pyrimidin-2,4-diamine; (27) 5-Chloro-N4-(4-methoxybenzyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (30) 5-Chloro-N4-(2,4-difluorobenzyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (38) 5-Chloro-N4-(3,4-dimethoxyphenethyl)-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; (39) 5-Chloro-N2-(5-methoxyphenyl)-4-methylthiazolyl-2-yl)-N4-propylpyrimidine-2,4-diamine; (40) 5-Chloro-N4-(2-(dimethylamino)ethyl)-N2-(5-(4-methoxyphenyl)-4-methylthiazolyl)pyrimidine-2,4-diamine hydrochloride; (42) N-(5-chloro-4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)-5-(4-methoxyphenyl)-4-methylthiazo-2-amine; (43) (R)-1-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-ol; (44) (R)-(1-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-2-methanol; (45) Tert-butyl (5-chloro-2-((5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)amino)ethyl)carbamate; (48) (5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)piperidine-4-carbamate tert-butyl ester; (50) (R)-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)piperidine-3-carbamate tert-butyl ester; (51) (S)-(1-(5-chloro-2-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)tert-butyl carbamate; (54) (S)-(5-(4-methoxyphenyl)-4-methylthiazolyl-2-amino)pyrimidin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate.

2. The method for preparing the phenylthiazolamine pyrimidine derivative as described in claim 1, characterized in that: Using 4-methoxyphenylacetone as starting material a, the starting material a undergoes an α-bromination reaction with phenyltrimethylammonium tribromide to obtain intermediate b. Intermediate b then undergoes a condensation reaction with thiourea to obtain intermediate compound c. Using trichloropyrimidine d, aromatic amine, and aliphatic amine e as starting materials, a nucleophilic substitution reaction is carried out under alkaline conditions to obtain intermediate f. Intermediate f and intermediate compound c undergo a Buchwald-Hartwig reaction using palladium as a catalyst to obtain the target compound g. The preparation route is as follows: ; The structure of R-NH in the formula is selected from .

3. The use of the phenylthiazolamine pyrimidine derivative as described in claim 1 in the preparation of a medicament for inhibiting the growth of cancer cells in vitro.

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