CN103483345A - Phosphoinositide 3-kinase (P13K) inhibitor, pharmaceutical composition containing P13K inhibitor, and application of phosphoinositide kinase inhibitor and pharmaceutical composition - Google Patents

Abstract

The invention discloses a phosphoinositide 3-kinase (P13K) inhibitor, a pharmaceutical composition containing the P13K inhibitor, and application of the P13K inhibitor and the pharmaceutical composition. The P13K inhibitor comprises a pyrimidine compound and a stereoisomer/hydrate/pharmaceutically-acceptable salt thereof. The pyrimidine compound has a general formula I of which the structure is shown in the specification. The P13K inhibitor and the pharmaceutical composition containing the same can be used for inhibiting PI3 Ks and treating proliferative diseases on which the PI3 Ks act. According to the invention, high-effectiveness and high-selectivity inhibitors for treating proliferative diseases on which PI3Ks act can be provided.

Description

PI3K kinase inhibitors, pharmaceutical compositions comprising them and uses thereof

technical field

The present invention relates to the technical field of medicine, and more specifically refers to a PI3K kinase inhibitor, a pharmaceutical composition containing it and applications thereof. the

Background technique

Malignant tumors are a type of disease that seriously threatens human life and health. Its morbidity and mortality are increasing year by year. Human mortality due to cancer ranks second only to cardiovascular and cerebrovascular diseases. At present, the clinical drugs for tumor treatment are divided into traditional cytotoxic drugs and new molecular targeted drugs. The former mainly acts on DNA, RNA, tubulin and other common components that are critical to cell life and death, non-specifically blocking cell division and causing cell death. While killing tumor cells, it also destroys normal cells in the human body, resulting in Low selectivity and high toxicity; while the latter usually has a relatively clear target, mainly acting on key molecules and their signal transduction pathways that regulate cell growth and proliferation that differ greatly in normal cells and tumor cells, and can inhibit tumor cell growth and reduce the effect on normal cells, thereby increasing the selectivity to tumors, reducing the toxicity to normal tissues, and greatly improving the level of treatment. the

Various pharmaceutical companies are accelerating the development of targeted anti-tumor drugs, coupled with the strong market demand for this category of anti-tumor drugs, molecular targeted drugs have become the fastest growing segment of the global anti-tumor drug market. Phosphoinositide 3-kinase (PI3K) is a key signaling molecule in many life activities. The PI3K-mediated signaling pathway (PI3K/Akt/m-TOR) controls many cell biological processes that are critical in tumorigenesis and development, including cell proliferation, apoptosis, transcription, translation, metabolism, angiogenesis, and cell cycle regulation etc. In human tumor cells, compared with other signaling pathways, this signaling pathway has a higher probability of gene changes such as gene mutation, gene amplification, and gene rearrangement, which is closely related to tumor development, metastasis, and drug resistance. Therefore, PI3K inhibitors have unique advantages in inhibiting tumor cell proliferation, inducing tumor cell apoptosis, and reversing drug resistance of tumor cells, and can be used alone or in combination with other targeted drugs. Antitumor drug research targeting key molecules in the PI3K signaling pathway has become one of the hotspots in targeted tumor therapy. the

PI3Ks are a class of phosphatidylinositol kinases with serine/threonine (Ser/Thr) kinase activity in cells, which can phosphorylate phosphatidylinositol (PtdIns), phosphatidylinositol-4-phosphate (PtdIns4P), The 3-hydroxyl group of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2). According to their structural characteristics and substrate specificity, the PI3Ks family can be divided into four categories: type I, type II, type III and type IV. So far, the most studied type I PI3K is divided into four subtypes according to the catalytic subunits: PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ (Nat. Rev. Drug Discov. 2009, 8, 627-644). Although the four subtypes of type I PI3K have high homology in structural composition and their physiological functions overlap to a certain extent, due to the difference in the peripheral structure of their active pockets, they play an important role in the function and the occurrence and development of cancer. with different effects. the

At present, nearly 20 compounds have entered the clinical trial stage, among which more than a dozen compounds are in the phase II clinical stage, and 4 compounds have entered the phase III clinical trial. The compounds entering Phase III clinical trials are Buparlisib (NVP-BKM120) with structural formula 1 developed by Novartis, Rigosertib (ON-01910) with structural formula 2 developed by Onconova Therapeutics, and Idelalisib with structural formula 3 developed by ICOS. (CAL-101, GS-1101) and Perifosine (KRX-0401) with structural formula 4 developed by ASTA Medica. Above-mentioned structural formula 1-4 is as follows:

However, there is no PI3K inhibitor on the market so far, and researchers still need to develop more PI3K kinase inhibitor molecules in order to select compounds with better efficacy and selectivity for the treatment of cancer. the

Contents of the invention

The present invention aims to provide a PI3K kinase inhibitor, a pharmaceutical composition containing it and applications thereof, so as to select compounds with better effectiveness and selectivity for the treatment of cancer. the

In order to achieve the above object, according to one aspect of the present invention, a PI3K kinase inhibitor is provided, including a pyrimidine compound having the general formula I, its stereoisomer, hydrate or pharmaceutically acceptable salt, the general formula The I structure is as follows:

In the general formula I: X, Y, Z, W are independently selected from N or -CH-; R ¹ , R ² are independently selected from H, C ₁ -C ₄ alkyl, containing one or more substituents C ₁ -C ₄ alkyl, C ₁ -C 4 alkoxy, C ₁ -C ₄ alkoxy containing one or more substituents, C ₃ -C ₆ heterocyclyl, containing one _or more substituents C ₃ -C ₆ heterocyclic group, C ₄ -C ₈ fused heterobicyclic group or C ₄ -C ₈ fused heterobicyclic group containing one or more substituents, the substituents are selected from fluorine, chlorine , bromine, iodine, hydroxy, amino, C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ - C ₄ alkoxy, hydroxy C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl; R ³ is selected from H, -CN, -CH ₃ , -CF ₃ or - SO ₂ NH ₂ ; R ⁴ is selected from H or halogen.

Further, the above R ³ is -CF ₃ ;

Further, the above-mentioned PI3K kinase inhibitors include pyrimidine compounds with general formula II and/or general formula III, stereoisomers, hydrates or pharmaceutically acceptable salts thereof; general formula II and general formula III have the following structures:

In the general formula II and general formula III: R ¹ and R ² are independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl containing one or more substituents, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy containing one _or more substituents, C 3 -C ₆ heterocyclic group, C ₃ -C ₆ heterocyclic group containing one or more substituents, C ₄ -C fused heterobicyclic group or C _{4 -C} fused heterobicyclic group containing one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C _{1 -C 4} alkyl, halo _{C 1} -C ₄ alkyl, hydroxy C ₁ -C 4 alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkane Oxy or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl.

Further, R ¹ and R ² in the above general formula I or in the general formulas II and III are independently selected from the following structures:

Wherein, A, B, C, D, E, F are independently selected from -CH ₂ -, -O-, -S- or -NR ¹¹ -; R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently selected from H, halogen, hydroxy, amino, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkane Oxygen, halogenated C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkoxy, or C ₁ -C ₄ alkylsulfonyl;

Further, R ^{1 and} R ² in the above general formula I, general formula II or general formula III are independently selected from the following structures:

Further, ^R in the above general formula I, general formula II or general formula III is selected from the following structures:

Further, R in the above general formula I, general formula II or general formula ^III is selected from the following structures:

Further, the above-mentioned pyrimidine compound is:

rac-5-(6-morpholin-2-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl)pyrimidine- 4-yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(2-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-morpholine pyrimidin-4-yl)-4-(trifluoro Methyl) pyridin-2-amine;

5-(2-((2R,6S)-2,6-dimethylmorpholine)-6-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(2-((4RS, 7SR)-dihydro-2H-[1,4]dioxa[2,3-c]pyrrole-6(3H,7H,7aH)-yl)-6-morpholine pyrimidine -4-yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(6-((2R,6S)-2,6-dimethylmorpholine)-2-((4SR,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c ]pyrrol-6(3H)-yl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(6-((2R,6S)-2,6-dimethylmorpholine)-2-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(2-morpholin-6-((4SR,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)pyrimidin-4-yl )-4-(trifluoromethyl)pyridin-2-amine;

rac-5-(2-morpholin-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)pyrimidine-4 -yl)-4-(trifluoromethyl)pyridin-2-amine;

rac-6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-[4,5 '-Bipyrimidine]-2'-amine

4-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(2-morpholineethyl)pyrimidin-2-amine;

4-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(4-morpholinephenyl)pyrimidin-2-amine;

(-)-5-(6-morpholine-2-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl) Pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine;

(+)-5-(6-morpholine-2-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl) Pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-morpholine-1,3,5-triazazine-2 -yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine;

5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-((2R,6S)-2,6-dimethyl Morpholine)-1,3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine;

rac-5-(4-morpholin-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-1, 3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine;

(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)- 1,3,5-Triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; or

(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)- 1,3,5-Triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine. the

According to another aspect of the present invention, a pharmaceutical composition is provided, which comprises at least one pharmaceutically acceptable excipient, adjuvant or carrier and an effective therapeutic dose of at least one of the above-mentioned PI3K kinase inhibitors. the

According to another aspect of the present invention, a use of the above-mentioned PI3K kinase inhibitor or the above-mentioned pharmaceutical composition in the treatment, prevention and/or treatment and/or auxiliary treatment of proliferative diseases caused by PI3K kinase is provided. the

Further, the proliferative diseases in which PI3K kinase acts in the above application are colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, neck cancer, CNS Cancer, glioblastoma, or myeloproliferative disease, and leukemia and lymphoma. the

According to another aspect of the present invention, there is provided an application of the above-mentioned PI3K kinase inhibitor or the above-mentioned pharmaceutical composition to inhibit the growth of cancer cells in vitro. the

Applying the technical scheme of the present invention, the PI3K kinase inhibitor provided by the present invention and the pharmaceutical composition containing it can be used for inhibiting PI3K kinase and proliferative diseases of PI3K kinase action, and can be used for the treatment of proliferative diseases of PI3K kinase action Provides inhibitors with better potency and selectivity. the

Detailed ways

The technical solution of the present invention will be described in detail below in conjunction with the embodiments of the present invention, but the following embodiments are only used to understand the present invention, and cannot limit the present invention. The present invention can be defined and covered by claims in many different ways implement. the

In order to provide compounds with more efficacy and better selectivity as pointed out in the background technology section for the treatment of tumors. In the present invention there is provided a PI3K kinase inhibitor. Such PI3K kinase inhibitors include pyrimidine compounds of general formula I, stereoisomers, hydrates or pharmaceutically acceptable salts thereof. Wherein, general formula I structure is as follows:

In the above general formula I, X, Y, Z, W are independently selected from N or -CH-. the

In the above general formula I, R ¹ and R ² are independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl containing one or more substituents, C ₁ -C ₄ alkoxy, containing C ₁ -C ₄ alkoxy group with one or more substituents, C ₃ -C ₆ heterocyclic group, C ₃ -C ₆ heterocyclic group with one or more substituents, C ₄ -C ₈ fused heterocyclic group Bicyclic group or C ₄ -C ₈ fused heterobicyclic group containing one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenated C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkoxy or C ₁ - C ₄ alkoxy C ₁ -C ₄ alkyl.

In the above general formula I, R ³ is selected from H, -CN, -CH ₃ , -CF ₃ or -SO ₂ NH ₂ ; wherein R ³ is preferably -CF ₃ .

In the above general formula I, R ⁴ is selected from H or halogen, preferably H.

In a preferred embodiment of the present invention, the above-mentioned PI3K kinase inhibitors include pyrimidine compounds with general formula II and/or general formula III, stereoisomers, hydrates or pharmaceutically acceptable salts thereof; General formula II and general formula III structures are as follows:

In the above general formula II and general formula III: R ¹ and R ² are independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl containing one or more substituents, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy containing one _or more substituents, C 3 -C ₆ heterocyclic group, C ₃ -C ₆ heterocyclic group containing one or more substituents, C ₄ -C fused heterobicyclic group or C _{4 -C} fused heterobicyclic group containing one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C _{1 -C 4} alkyl, halo _{C 1} -C ₄ alkyl, hydroxy C ₁ -C 4 alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkane Oxy or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl.

In a preferred embodiment of the present invention, in the above-mentioned PI3K kinase inhibitor, R ¹ and R ² in the general formula I, general formula II or general formula III are independently selected from the following structures:

Wherein, A, B, C, D, E, F are independently selected from -CH ₂ -, -O-, -S- or -NR ¹¹ -;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently selected from H, halogen, hydroxyl, amino, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ alkyl, Hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenated C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkoxy, or C ₁ -C ₄ alkylsulfonyl.

Preferably, R ¹ and R ² in the general formula I, general formula II or general formula III in the above-mentioned PI3K kinase inhibitor are independently selected from the following structures:

More preferably, ^R in the general formula I, general formula II or general formula III in the above-mentioned PI3K kinase inhibitor is selected from the following structures:

More preferably, in the above-mentioned PI3K kinase inhibitor, ^R in the general formula I, general formula II or general formula III is selected from the following structures:

More preferably, the pyrimidine compound in the above-mentioned PI3K kinase inhibitor is:

rac-5-(6-morpholin-2-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl)pyrimidine- 4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-04);

5-(2-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-morpholine pyrimidin-4-yl)-4-(trifluoro Methyl)pyridin-2-amine (hereinafter referred to as ZJQ-05);

5-(2-((2R,6S)-2,6-dimethylmorpholine)-6-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-06);

5-(2-((4RS, 7SR)-dihydro-2H-[1,4]dioxa[2,3-c]pyrrole-6(3H,7H,7aH)-yl)-6-morpholine pyrimidine -4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-13);

5-(6-((2R,6S)-2,6-dimethylmorpholine)-2-((4SR,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c ]pyrrol-6(3H)-yl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-14);

5-(6-((2R,6S)-2,6-dimethylmorpholine)-2-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-10);

5-(2-morpholin-6-((4SR,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)pyrimidin-4-yl )-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-19);

rac-5-(2-morpholin-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)pyrimidine-4 -yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-20);

(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxin)[2,3-c]pyrrol-6(3H)-yl )pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-22);

(+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydro)-2H-[1,4]dioxin)[2,3-c]pyrrol-6(3H)-yl )pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-23);

rac-6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-[4,5 '-Bipyrimidine]-2'-amine (hereinafter referred to as ZJQ-24);

5-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ- 26)

4-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(2-morpholineethyl)pyrimidin-2-amine (hereinafter referred to as ZJQ-27);

4-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(4-morpholinephenyl)pyrimidin-2-amine (hereinafter referred to as ZJQ-28);

5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-morpholine-1,3,5-triazazine-2 -yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-07);

5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-((2R,6S)-2,6-dimethyl Morpholine)-1,3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-08);

rac-5-(4-morpholin-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-1, 3,5-Triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-21);

(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)- 1,3,5-Triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-29); or

(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)- 1,3,5-Triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (hereinafter referred to as ZJQ-30). the

The PI3K kinase inhibitor provided by the present invention can be used for inhibiting PI3K kinase and proliferative diseases caused by PI3K kinase, and can provide an inhibitor with better effectiveness and selectivity for the treatment of proliferative diseases caused by PI3K kinase. the

The PI3K kinase inhibitors of the present invention may include pharmaceutically acceptable salts of pyrimidine compounds. A pharmaceutically acceptable salt refers to the form in which the basic group in the parent compound is converted into a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound by reacting the basic group in the parent compound with 1-4 equivalents of 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). the

In the present invention, the basic group of the compound can form a salt with an acid. Examples of these acid salts include: with an inorganic acid, especially a hydrohalic acid (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 arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts formed with organic acids, Such as salts of acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; salts with amino acids such as aspartic acid or glutamic acid. the

The compounds and pharmaceutically acceptable salts of the present invention also include solvated or hydrated forms. In general, solvated or hydrated forms are equivalent to unsolvated or unhydrated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent and are intended to be within the scope of the present invention. the

In addition, unless otherwise indicated, the structural formula of the pyrimidine compound in the PI3K enzyme inhibitor of the present invention described in the present invention includes all isomeric forms (such as enantiomerism, diastereoisomerism, and geometric isomerism ( or conformational isomerism)): such as R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention. the

Unless otherwise indicated, all tautomeric forms of the pyrimidine compounds in the PI3K kinase inhibitors of the present invention are included within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms. the

Exemplary embodiments of the present invention will be described in detail below. However, these embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention. the

As used herein, if to provide specific definitions, the terms of the present invention have the following meanings. the

The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group comprising 1-20 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, in other embodiments, the alkyl group contains 1-6 carbon atoms, and in other embodiments, the alkyl group contains 1-4 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ) and the like. The term "alkyl" and its prefix "alk" are used herein to include straight and branched saturated carbon chains.

The term "alkoxy" refers to the part of the alkyl group as defined above for the "alkyl group", which is formed by connecting an oxygen atom to the main carbon chain of the "alkyl group". the

The term "haloalkyl" or "haloalkoxy" means that the "alkyl" or "alkoxy" may be substituted by one or more of the same or different halogen atoms. Where the alkyl and alkoxy groups have the meanings previously defined herein, such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like. the

The term "hydroxyalkyl" or "hydroxyalkoxy" refers to the case where "alkyl" or "alkoxy" may be substituted by one or more hydroxy groups. Wherein "alkyl" and "alkoxy" groups have the meanings previously defined herein, such examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxy Propyl, hydroxymethoxy, 1-hydroxyethoxy, etc. the

The term "halogen", "halogen atom" or "halogen atom" includes fluorine, chlorine, bromine, iodine. the

The term "heterocyclyl" may be carbonyl or heteroatomyl. "Heterocyclyl" also includes the combination of a heterocyclic group and a saturated or partially unsaturated ring or heterocycle. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Thioxanyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, sulfur Heterocycloheptyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazine Base, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrole Lin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl , pyrazolinyl, dithianyl, dithianyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1 , 2,6-thiadiazinane, 1,1-dioxo-2-yl, quinazinyl and N-pyridyl urea. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkane Amino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O ), carboxyalkoxy, etc. the

The terms "fused bicyclic", "fused ring", "fused bicyclyl" or "fused cycloyl" denote saturated or unsaturated fused ring systems, referring to non-aromatic bicyclic ring systems. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics may serve as substituents thereon). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 7 -Azabicyclo[2.2.1]heptanyl, fused bicyclo[3.3.0]octyl, fused bicyclo[3.1.0]hexyl, 1,2,3,4,4a,5,8 , 8a-octahydronaphthyl, these are included in the fused bicyclic system. And the fused bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, halogen, hydroxyl, amino, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl radical, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc. the

The term "fused heterobicyclyl" denotes a saturated or unsaturated fused ring system, involving non-aromatic bicyclic ring systems. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics may serve as substituents thereon). And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , where S or P is optionally substituted with one or more oxygen atoms to obtain groups like SO, SO ₂ , PO, PO ₂ , such examples include, but are not limited to, hexahydro-2H-[1, 4] Dioxa[2,3-c]pyrrolyl, etc. And the fused heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, halogen, hydroxyl, amino, cyano, aryl, heteroaryl, alkoxyl, alkyl, Alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, etc.

The pyrimidine compounds in the above-mentioned PI3K inhibitors provided by the present invention can be prepared in various ways, and those skilled in the art can find an appropriate way to prepare under the inspiration of the structural formula provided in this application. For ease of understanding, the preparation methods for the above general formulas II and III are provided in this application. the

A method for preparing pyrimidine compounds with general formula II: using 2,4,6-trichloropyrimidine (A) as raw material, according to the difference in reactivity between the 2 and 4 positions of pyrimidine, nucleophilic substitution reaction occurs with R ¹ NH Obtain intermediate (B), then introduce R ² NH by substitution reaction to obtain intermediate (C), and finally undergo Suzuki coupling reaction with 2-amino-4-trifluoromethylpyridine-5-boronate to obtain The target compound (D) of the general structural formula II.

The reaction formula of the above method is as follows:

A method for preparing pyrimidine compounds with general formula III: similar to the synthesis of general formula II, by successively introducing R ¹ NH and R ² NH, and then reacting with pyrimidine boronate to obtain the target compound with structural general formula III (H).

The reaction formula of the above method is as follows:

The definition of each substituent R ¹ and R ² in formula A to formula H in the above preparation steps is the same as the substituent R ¹ and R ² in general formulas I, II and III.

At the same time, one embodiment of the present invention also provides a pharmaceutical composition, which comprises at least one pharmaceutically acceptable adjuvant, adjuvant or carrier; and an effective therapeutic dose of at least one of the above-mentioned PI3K kinase inhibitors. the

The term "therapeutically effective amount" refers to that amount of a compound of formula sufficient to be effective when administered to a mammal in need of such treatment. A therapeutically effective amount will vary depending on the particular activity of the therapeutic agent employed, the age, physiological condition, presence of other disease states, and nutritional status of the patient. In addition, other drug treatments that the patient may be receiving will affect the determination of a therapeutically effective amount of the therapeutic agent to be administered. the

The term "treatment" means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease to not develop; (ii) inhibiting the disease, that is, preventing the development of clinical symptoms; and/or ( iii) Alleviation of the disease, ie causing regression of clinical symptoms. the

The term "pharmaceutically acceptable excipients, adjuvants or carriers" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. the

The composition is preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active substance calculated to produce the required therapeutically effective and relevant suitable pharmaceutical excipients (eg tablets, capsules, ampoules). Pyrimidine compounds among PI3K kinase inhibitors are effective over a wide dosage range and are usually administered in a pharmaceutically effective amount. Preferably, each dosage unit comprises 10 mg to 2 g of the pyrimidine compound in a PI3K kinase inhibitor, more preferably 10 to 700 mg for oral administration, and preferably 10 to 700 mg of a PI3K kinase inhibitor for parenteral administration. Pyrimidine compounds, more preferably about 50 to 200 mg. However, it should be understood that the amount of pyrimidine compound actually administered in a PI3K kinase inhibitor will be determined by the physician based on the circumstances involved, including the condition to be treated, the route of administration chosen, the actual compound administered and its relative activity, the individual patient's Age, weight, and response, the severity of the patient's symptoms, etc. the

For the preparation of solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient (or carrier) to form a solid preformulation composition comprising a homogeneous mixture of the compounds of the invention. When these preformulated compositions are referred to as homogeneous, it means that the active ingredient is dispersed uniformly throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules . the

Tablets or pills of the invention may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to protect the tablet or pill from the acidic conditions of the stomach. For example, a tablet or pill may comprise an inner dosage and an outer dosage composition, the latter in the form of an outer skin over the former. The two components may be separated by an enteric layer, which serves to prevent disintegration in the stomach and to allow the inner component to enter the duodenum intact or be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. the

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutical excipients as described above. Preferably, these compositions are administered by the oral or nasal respiratory route for local or systemic effects. Compositions in preferably pharmaceutically acceptable solvents can be nebulized by use of inert gases. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from devices that deliver the dosage form in an appropriate manner, preferably orally or nasally. the

In another aspect, the present invention also provides a use of the above-mentioned P13K kinase inhibitor or the above-mentioned pharmaceutical composition in the treatment of drugs for the prevention and/or treatment and/or auxiliary treatment of proliferative diseases where PI3K kinase acts. A proliferative disease in which PI3K kinases act is cancer. This cancer includes solid cancers and forms of blood cancers. Preferably, the proliferative disease in which the PI3K kinase acts is colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, neck cancer, cancer of the CNS, Glioblastoma, or myeloproliferative disease, and leukemia and lymphoma. the

In another aspect, the present invention also provides an application of the above-mentioned P13K kinase inhibitor or the above-mentioned pharmaceutical composition to inhibit the growth of cancer cells in vitro. the

The following examples 1-24 further describe the present invention, however, these examples should not be regarded as limiting the scope of the present invention. the

In the examples described below all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Alfa Aesar Chemical Company, Bailingwei Technology Co., Ltd., Aladdin Reagent Co., Ltd., Beijing Coupling Technology Co., Ltd., etc., and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangzhou Chemical Reagent Factory, Tianjin Zhiyuan Chemical Reagent Co., Ltd. and Qingdao Haiyang Chemical Factory. the

In the examples described below, a silica gel column was used as the chromatographic column, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. The nuclear magnetic resonance spectrum uses CDCl ₃ or DMSO-d ₆ as the solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

The low-resolution mass spectrometry (MS) data in the embodiment described below is determined by the spectrometer of Agilent 6120 series LC-MS equipped with G1311B quaternary pump and G1316B TCC (column temperature is maintained at 30 ℃), G1329B automatic sampler and G1315C DAD detector is used for analysis, and ESI source is used for LC-MS spectrometer. the

In the examples described below the injection volume was determined by the sample concentration; the flow rate was 0.5 mL/min; the HPLC peaks were recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase is isopropanol/n-hexane (40:60). the

The examples described below are convenient for expression, and some raw materials will be described by their abbreviations. These abbreviations and their full names are explained as follows: DCM is CH ₂ Cl ₂ , i.e. dichloromethane; CHCl ₃ is chloroform, i.e. trichloromethane; CDCl ₃ is Deuterated chloroform; PE is petroleum ether; EtOAc and EA are ethyl acetate; MeOH and CH ₃ OH are methanol; EtOH and CH ₃ CH ₂ OH are ethanol; HCl is hydrochloric acid; AcOH and acetic acid are acetic acid; NH ₄ OH and NH ₃ ·H ₂ O are ammonia water; Et ₃ N and TEA are triethylamine; K ₂ CO ₃ is potassium carbonate; KI is potassium iodide; NBS is bromosuccinimide; NaHSO ₃ is sulfurous acid Sodium hydrogen; DIPEA is N,N-diisopropylethylamine; THF is tetrahydrofuran; Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ is [1,1′-bis(diphenylphosphino)ferrocene]di Palladium chloride dichloromethane complex; DMF is N,N-dimethylformamide; SOCl ₂ is thionyl chloride; POCl ₃ is phosphorus oxychloride; DMSO is dimethyl sulfoxide; DMSO-d ₆ is Hexadeuteriodimethylsulfoxide; H ₂ O is water; mL is milliliter; Rt is retention time.

Example 1: Synthesis of pyrimidine compound ZJQ-04. the

Step 1: Synthesis of 5-bromo-4-(trifluoromethyl)pyridin-2-amine. the

The structural formula of 5-bromo-4-(trifluoromethyl)pyridin-2-amine:

Synthesis method: 4-trifluoromethyl-2-aminopyridine (10g, 61.69mmol) was dissolved in CH ₂ Cl ₂ (100mL), and bromosuccinimide (NBS, 12.08g, 67.86 mmol), and react overnight at room temperature in the dark. The reaction system was diluted with CH ₂ Cl ₂ (100 mL), washed twice with saturated NaHSO ₃ , washed once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography, eluent: petroleum ether/ethyl acetate=4/1, to obtain 13.08 g of the target product as a brown solid, yield: 87.96%.

The NMR data of the product are ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.28 (s, 1H), 6.78 (s, 1H), 4.82 (s, 2H). Same as in ACS Med.Chem.Lett.2011, 2, 774-779. From the above data, it can be seen that the product prepared by the above method is the target product 5-bromo-4-(trifluoromethyl)pyridin-2-amine.

Step 2: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine. the

The structural formula of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine:

Synthetic method: 5-bromo-4-(trifluoromethyl) pyridin-2-amine (6.54g, 27.26mmol) synthesized in step 1 is dissolved in dioxane (100mL), then adds potassium acetate ( 8.03g, 81.77mmol), pinacol borate (7.62g, 29.98mmol), nitrogen replacement, and stirring at room temperature for 10min, adding Pd(dppf)Cl ₂ CH ₂ Cl ₂ (1.12g, 1.37mmol), Then the temperature was raised to 115°C for 24h. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. Concentration, separation and purification of the residue by column chromatography, eluent: petroleum ether/ethyl acetate = 3/1, a brown solid was obtained, the solid was resuspended in n-hexane, and filtered to obtain 6.60 g of the target product as a white solid. Rate: 84.04%.

The mass spectrum data of the product is LC-MS: 289 (M+H). Same as in ACS Med.Chem.Lett.2011, 2, 774-779. From the above data, it can be seen that the product prepared by the above method is the target product 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(tri Fluoromethyl)pyridin-2-amine. the

Step 3: Synthesis of benzyl 6-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate. the

The structural formula of benzyl 6-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate:

Synthetic method: 2,5-dihydropyrrolidine-1-carboxylic acid benzyl ester (10g, 49.24mmol) was dissolved in dichloromethane (30mL), slowly added dropwise to m-chloroperoxybenzoic acid (10.55g, 61.14mmol ) in dichloromethane (70 mL), stirred at room temperature for 16 h. After filtering, the filtrate was washed once with saturated sodium thiosulfate (100 mL) and saturated sodium bicarbonate (100 mL), once with saturated NaCl aqueous solution, and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was directly separated by column chromatography, eluent: EA/PE=1/3 to obtain 7.39 g of the target product, yield: 68.49%.

The nuclear magnetic data of the product is ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.41-7.29 (m, 5H), 5.16-5.04 (m, 2H), 3.86 (dd, J=19.1, 12.8Hz, 2H), 3.73- 3.63 (m, 2H), 3.38 (dd, J=12.7, 6.0 Hz, 2H). Same as in J.Med.Chem.2010, 53, 6730-6746. From the above data, it can be seen that the product prepared by the above method is the target product 6-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester.

Step 4: Synthesis of rac-(3RS,4RS)-3-(2-bromoethoxy)-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester. the

The structural formula of rac-(3RS, 4RS)-3-(2-bromoethoxy)-4-hydroxypyrrolidine-1-carboxylate benzyl ester:

Synthesis method: 6-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate benzyl ester (3.16g, 14.42mmol) synthesized in step 3 was dissolved in dry dichloromethane (20mL), added 2-Bromoethanol (1.97g, 15.87mmol) was added slowly at room temperature to a solution of boron trifluoride in ether (0.22g, 0.19mmol), and stirred overnight at room temperature. The reaction system was diluted with dichloromethane (30 mL), washed once with water, washed once with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and separated the residue by column chromatography, eluent: EA/PE=2/1 1.44 g of the product was obtained, yield: 29.03%. the

The nuclear magnetic data of the product is ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.32-7.16 (m, 5H), 5.03 (s, 2H), 4.16 (s, 1H), 3.78 (s, 1H), 3.73-3.66 ( m, 1H), 3.56(dd, J=14.9, 12.0Hz, 2H), 3.41(dd, J=23.8, 12.8Hz, 2H), 3.32(t, J=6.0Hz, 2H), 3.03(s, 2H ). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 155.66(s), 137.09(s), 128.50(s), 128.04(s), 127.82(s), 83.27(s), 82.52(s), 73.32(s) , 72.38(s), 69.38(s), 66.92(s), 30.35(s). From the above data, it can be seen that the product prepared by the above method is the target product rac-(3RS, 4RS)-3-(2-bromoethoxy)-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester.

Step 5: Synthesis of rac-(4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrole-6(3H)-carboxylic acid benzyl ester. the

The structural formula of rac-(4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrole-6(3H)-carboxylate benzyl ester:

Synthetic method: rac-(3RS, 4RS)-3-(2-bromoethoxy)-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester (1.43g, 4.17mmol) synthesized in step 4 was dissolved in anhydrous To ethanol (10 mL), a solution of potassium hydroxide (0.26 g, 4.59 mmol) in absolute ethanol (3 mL) was added, and then heated to reflux for 6 h. Filtration, the filter cake was rinsed with ethyl acetate (50 mL), the combined filtrates were evaporated to dryness under reduced pressure, and the residue was separated by column chromatography (eluent: EA/PE=1/1) to obtain 0.74 g of the product, yield: 67.27 %. the

The mass spectrum data of the product is LC-MS: 264.1 (M+H). NMR data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.35(d, J=4.6Hz, 5H), 5.13(d, J=3.1Hz, 2H), 3.92-3.70(m, 6H), 3.60(s , 2H), 3.15 (dd, J=9.5, 4.6Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 155.15(s), 136.40(s), 128.50(s), 128.08(s), 127.96(s), 77.90(s), 77.55(s), 76.56(s) , 67.13(s), 45.89(s). From the above data, it can be seen that the product prepared by the above method is the target product rac-(4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrole-6(3H)-carboxy benzyl ester.

Step 6: Synthesis of rac-(4RS,7RS)-hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole. the

The structural formula of rac-(4RS, 7RS)-hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole:

Synthesis method: rac-(4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrole-6(3H)-carboxylate benzyl ester (0.30g) synthesized in step 5 , 1.14mmol) was dissolved in dry THF (10mL), added with 10% Pd/C (0.10g), replaced by hydrogen twice, and hydrogenolyzed at room temperature for 6h. After filtration, the filtrate was evaporated to dryness to obtain the product, which was directly used for the reaction in the following step 8. the

The mass spectrum data of the product is LC-MS: 130 (M+H). Same as in WO 2004043472. It can be seen from the above data that the product prepared by the above method is the target product rac-(4RS, 7RS)-hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole. the

Step 7: Synthesis of 4-(2,6-dichloropyrimidin-4-yl)morpholine. the

The structural formula of 4-(2,6-dichloropyrimidin-4-yl)morpholine:

Synthesis method: Dissolve 2,4,6-trichloropyrimidine (1.0g, 5.45mmol) in dry dichloromethane (10mL), add DIPEA (0.74g, 0.95mL), cool to -5°C, drop slowly Morpholine (0.47 g, 5.45 mmol) was added. Slowly warm up to room temperature for 2h. Water was added to the system, the organic phase was separated, washed once with a saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography (eluent: EA/PE=1/4) to obtain 1.02 g of the product, yield: 65.81%. the

The nuclear magnetic data of the product is ¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.39 (d, J=4.5 Hz, 1H), 3.88-3.49 (m, 8H). Same as in WO 2006005918. It can be seen from the above data that the product prepared by the above method is the target product 4-(2,6-dichloropyrimidin-4-yl)morpholine.

Step 8: Synthesis of rac-(4RS,7RS)-6-(4-chloro-6-morpholinepyrimidin-2-yl)hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole . the

The structural formula of rac-(4RS, 7RS)-6-(4-chloro-6-morpholine pyrimidin-2-yl) hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole:

Synthesis method: 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42g, 1.80mmol) synthesized in step 7 was dissolved in THF/EtOH (1:1, 12mL), and added to step 6 rac-(4RS, 7RS)-hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole (1.64mmol), triethylamine (0.20g, 1.97mmol), iodide Sodium (246mg, 1.80mmol), heated to 60°C for 12h. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, separated and purified by column chromatography (eluent: EA/PE=1/5) to obtain 0.28 g of the product, yield: 52.34%. the

The mass spectrum data of the product is LC-MS: 327.10 (M+H). NMR data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 5.87(s, 1H), 3.96(s, 2H), 3.90-3.81(m, 5H), 3.77-3.64(m, 7H), 3.58-3.51( m, 4H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 163.26(s), 160.39(s), 159.46(s), 91.00(s), 78.14(s), 67.24(s), 66.31(s), 46.39(s) , 44.35(s). From the above data, it can be seen that the product prepared by the above method is the target product rac-(4RS, 7RS)-6-(4-chloro-6-morpholine pyrimidin-2-yl) hexahydro-2H-[1,4] Dioxa[2,3-c]pyrrole.

Step 9: Synthesis of the pyrimidine compound ZJQ-04 of the present invention. the

rac-5-(6-morpholin-2-((4RS,7RS)-tetrahydro)-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl)pyrimidine -4-yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-04:

Synthetic method: rac-(4RS, 7RS)-6-(4-chloro-6-morpholine pyrimidin-2-yl)hexahydro-2H-[1,4]dioxa[2,3 synthesized in step 8 -c] pyrrole (200mg, 0.61mmol) was dissolved in deoxygenated dioxane (3.9mL), and the 5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (0.35g, 1.23mmol), 2M potassium carbonate aqueous solution (1.05mL, 2.1mmol), nitrogen gas for 10min, Then Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (25mg, 0.031mmol) was added, sealed, and reacted by microwave at 150°C for 2.5h. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography, eluent: petroleum ether/ethyl acetate=3/1-1/2, to obtain a yellow solid. The solid was purified by secondary column chromatography, eluent: dichloromethane/methanol=50/1, to obtain 47 mg of the target product as a white solid, yield: 16.97%, purity: 98.20%.

The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z[M+H]+calcd.for[C ₂₀ H ₂₄ F ₃ N ₆ O ₃ ] ⁺ : 453.1856, found: 453.1852. NMR data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.25(s, 1H), 6.76(s, 1H), 5.95(s, 1H), 5.29(s, 1H), 4.82(s, 2H), 4.01 (s, 2H), 3.87 (s, 3H), 3.79-3.70 (m, 6H), 3.63-3.56 (m, 4H), 3.26 (t, J=10.0Hz, 2H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 163.01(s), 160.06(s), 159.08(s), 150.34(s), 138.07(s), 124.44(s), 121.87(s), 105.33(s) , 100.14(s), 93.04(s), 78.81(s), 67.75(s), 66.46(s), 46.75(s), 44.24(s). From the above data, it can be seen that the product prepared by the above method is the target product rac-5-(6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxin)[2 ,3-c]pyrrol-6(3H)-yl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-04.

Example 2: Synthesis of pyrimidine compound ZJQ-05. the

Step 1: (2R,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxy)tetrahydropyrrole-1,2-dicarboxylate synthesis. the

The structural formula of (2R,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxy)tetrahydropyrrole-1,2-dicarboxylate:

Synthetic method: Dissolve (2R,4R)-1-tert-butyl-2-methyl 4-hydroxytetrahydropyrrole-1,2-dicarbonate (5g, 20.40mmol) in dichloromethane (40mL), DIPEA (7.46mL, 44.87mmol) was cooled to -40°C, tert-butyldimethylsilyl triflate (5.63mL, 24.48mmol) was added dropwise and stirring was continued for 3h. A large amount of water was added to quench the reaction, and dichloromethane was added for extraction, dried over anhydrous sodium sulfate, concentrated, and purified by column, eluent: PE/EA=3/1, and 6.63 g of the target product was obtained with a yield of 90.45%. the

The mass spectrum data of the product is LC-MS: 360.2 (M+H). Same as in WO 2009137130. From the above data, it can be seen that the product prepared by the above method is the target product (2R, 4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxo) tetra Hydropyrrole-1,2-dicarboxylate. the

Step 2: Synthesis of (2R,4R)-tert-butyl-4-((tert-butyldimethylsilyl)oxo)-2-(hydroxymethyl)tetrahydropyrrole-1-carboxylate. the

The structural formula of (2R,4R)-tert-butyl-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)tetrahydropyrrole-1-carboxylate:

Synthesis method: (2R,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxo)tetrahydropyrrole-1 synthesized in step 1, 2-Dicarboxylate (6.63g, 18.46mmol) was dissolved in dry THF (50mL), cooled to 0°C, and lithium borohydride (1.0g, 46.14mmol) was added, then returned to room temperature and stirred overnight. Cool to 0°C and slowly add methanol to quench the reaction, then filter, concentrate the filtrate, and pass through a column for purification to obtain 3.80 g of the target product, a colorless oily liquid, yield: 62.19%. the

The mass spectrum data of the product is LC-MS: 276.2 (M-55). NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ: 4.60(s, 1H), 4.30(d, J=25.1Hz, 1H), 4.08-3.92(m, 1H), 3.86-45(m, 3H) , 3.32(d, J=11.6Hz, 1H), 3.16(dd, J=29.0, 8.0Hz, 1H), 2.13(s, 2H), 1.43(s, 8H), 0.85(s, 9H), 0.05( d, J=4.5Hz, 6H). Same as in US 20080081803. From the above data, it can be seen that the product prepared by the above method is the target product (2R, 4R)-tert-butyl-4-((tert-butyldimethylsilyl) oxo)-2-(hydroxymethyl) Tetrahydropyrrole-1-carboxylate.

Step 3: Synthesis of (2R,4R)-tert-butyl-4-hydroxy-2-((benzenesulfonyloxy)methyl)tetrahydropyrrole-1-carboxylate

The structural formula of (2R,4R)-tert-butyl-4-hydroxy-2-((benzenesulfonyloxy)methyl)tetrahydropyrrole-1-carboxylate:

Synthesis method: (2R,4R)-tert-butyl-4-((tert-butyldimethylsilyl)oxo)-2-(hydroxymethyl)tetrahydropyrrole-1- synthesized in step 2 Carboxylate (3.80g, 11.47mmol) was dissolved in dry dichloromethane (50mL), added DIPEA (3.80mL, 22.94mmol) and cooled to 0°C, added methanesulfonyl chloride (1.96g, 17.22mmol), then Return to room temperature and stir overnight. Water was added to quench the reaction, the organic phase was washed once with water, once with saturated NaHCO ₃ , then once with saturated NaCl, and dried over anhydrous sodium sulfate. Concentrate and proceed directly to the next step. Dissolve the above crude product in THF (25mL), add tetrabutylammonium fluoride (3.79g, 14.49mmol) and stir at room temperature for 1h, add water to quench the reaction, distill off the solvent under reduced pressure, add CH ₂ Cl ₂ (100mL) Extracted, washed the organic layer with water, washed once with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain 2.90 g of the target product as a white solid, yield: 88.14%.

The NMR data of the product are ¹ H NMR (400MHz, CDCl ₃ ) δ: 4.44(dd, J=9.1, 4.2Hz, 2H), 4.12(s, 1H), 3.55(s, 1H), 3.39(d, J= 12.0Hz, 1H), 3.02(s, 3H), 2.24-1.98(m, 4H), 1.46(s, 9H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 177.95(s), 69.86(s), 64.05(s), 55.47(s), 37.16(s), 36.07(s), 28.32(s), 27.90(s) , 18.78(s). From the above data, it can be seen that the product prepared by the above method is the target product (2R, 4R)-tert-butyl-4-hydroxyl-2-((benzenesulfonyloxy)methyl)tetrahydropyrrole-1-carboxylic acid ester.

Step 4: Synthesis of (1R,4R)-tert-butyl-2-oxa-5-heterobicyclo[2.2.1]-heptane-5-carboxylate. the

The structural formula of (1R,4R)-tert-butyl-2-oxa-5-heterobicyclo[2.2.1]-heptane-5-carboxylate:

Synthesis method: (2R, 4R)-tert-butyl-4-hydroxyl-2-((benzenesulfonyloxy)methyl)tetrahydropyrrole-1-carboxylate (1.28g, 4.33mmol) was dissolved in dry THF (20mL), cooled to -10°C, added 60% NaH (0.40g, 12.98mmol), then returned to room temperature and stirred for 24h, the mixture was cooled to 0°C, then slowly added water to quench Reaction, adding ethyl acetate for extraction, drying the organic layer with anhydrous sodium sulfate, concentrating, separating and purifying the residue by column chromatography, eluent: petroleum ether/ethyl acetate=5/1-3/1, to obtain 0.84g of the target Product, white solid, yield: 44.44%. the

The nuclear magnetic data of the product is ¹ H NMR (400MHz, CDCl ₃ ) δ: 4.58-4.38(m, 2H), 3.93-3.70(m, 2H), 3.49-3.18(m, 2H), 1.75(d, J=47.0 Hz, 2H), 1.45 (s, 9H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 154.19(s), 74.31(s), 57.43(s), 56.27(s), 54.68(s), 54.17(s), 36.47(s), 29.45(s) . It can be seen from the above data that the product prepared by the above method is the target product (1R,4R)-tert-butyl-2-oxa-5-heterobicyclo[2.2.1]-heptane-5-carboxylate.

Step 5: Synthesis of (1R,4R)-2-oxa-5-heterobicyclo[2.2.1]-heptane trifluoroacetate. the

The structural formula of (1R,4R)-2-oxa-5-heterobicyclo[2.2.1]-heptane trifluoroacetate:

Synthetic method: (1R,4R)-tert-butyl-2-oxa-5-heterobicyclo[2.2.1]-heptane-5-carboxylate (0.3g, 1.51mmol) synthesized in step 4 Dissolve in dry CH ₂ Cl ₂ (10 mL), add trifluoroacetic acid (1 mL) and stir at room temperature overnight. The solvent was distilled off under reduced pressure and used directly in the next reaction.

Step 6: Synthesis of (1R,4R)-5-(4-chloro-6-morpholinepyrimidin-2-yl)-2-oxo-5-azabicyclo[2.2.1]heptane. the

The structural formula of (1R,4R)-5-(4-chloro-6-morpholine pyrimidin-2-yl)-2-oxo-5-azabicyclo[2.2.1]heptane:

Synthetic method: 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.38g, 1.65mmol) was dissolved in THF/EtOH (1:1, 12mL), and the ( 1R, 4R)-2-oxa-5-heterobicyclo[2.2.1]-heptane trifluoroacetate (1.51mmol), triethylamine (0.36g, 3.32mmol), sodium iodide (227mg, 1.51mmol), heated to 60°C for 40h. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, separated and purified by column chromatography (eluent: EA/PE=1/5) to obtain 0.96 g of the target product, yield: 66.22%. the

The mass spectrum data of the product is LC-MS: 297.10 (M+H). NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ: 5.84(s, 1H), 4.96(s, 1H), 4.64(s, 1H), 3.84(s, 2H), 3.73(s, 4H), 3.54 (s, 6H), 1.89 (s, 2H). ¹³ CNMR (100MHz, CDCl ₃ ) δ: 163.29(s), 160.35(s), 159.75(s), 91.09(s), 73.92(s), 66.58(s), 56.90(s), 55.51(s), 44.31(s), 36.60(s). From the above data, it can be seen that the product prepared by the above method is the target product (1R, 4R)-5-(4-chloro-6-morpholine pyrimidin-2-yl)-2-oxo-5-azabicyclo[2.2 .1] Heptane.

Step 7: Synthesis of the pyrimidine compound ZJQ-05 of the present invention. the

5-(2-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-morpholine pyrimidin-4-yl)-4-(trifluoro Methyl)pyridin-2-amine, the structural formula of compound ZJQ-05:

Synthetic method: (1R, 4R)-5-(4-chloro-6-morpholine pyrimidin-2-yl)-2-oxo-5-azabicyclo[2.2.1]heptane ( 221 mg, 0.75 mmol) was dissolved in deoxygenated dioxane (4.8 mL), and the 5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (0.43g, 1.49mmol), 2M potassium carbonate aqueous solution (1.13mL, 2.26mmol), was blown into nitrogen for 10min, then Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (31mg, 0.0375mmol) was added, sealed and microwaved at 150°C for 2.5h. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography, eluent: petroleum ether: ethyl acetate = 3/1-1/2, to obtain a yellow solid. The solid was purified by secondary column chromatography, eluent: dichloromethane/methanol=50/1, to obtain 75 mg of the target product as a white solid, yield: 23.81%, purity: 93.71%.

The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z[M+H] ⁺ calcd.for[C ₁₉ H ₂₂ F ₃ N ₆ O ₂ ] ⁺ : 423.1751, found: 423.1772. NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.25(s, 1H), 6.76(s, 1H), 5.94(s, 1H), 4.99(s, 1H), 4.83(s, 2H), 4.64 (s, 1H), 3.87 (dd, J=20.0, 7.2 Hz, 2H), 3.81-3.66 (m, 5H), 3.62-3.56 (m, 5H), 1.90 (s, 2H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 162.99(s), 160.73(s), 158.77(s), 151.01(s), 147.41(s), 138.08(s), 124.43(s), 121.89(s) , 105.32(s), 92.07(s), 73.34(s), 67.15(s), 56.76(s), 55.50(s), 53.22(s), 44.79(s), 36.36(s). From the above data, it can be seen that the product prepared by the above method is the target product 5-(2-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6 -morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-05.

Example 3: Synthesis of pyrimidine compound ZJQ-22. the

(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxin)[2,3-c]pyrrol-6(3H)-yl )pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-22:

Synthesis method: resolve ZJQ-04 prepared in Example 1, separation conditions: reversed-phase chiral preparative column (Philomen's lu 5u cellose-2), mobile phase: methanol/water=95/5; purity: 99.90%; retention time: 13.94min, the resolution product ZJQ-22 was obtained. the

由上述数据可知，经上述方法所制备的产物为目标产物(-)-5-(6-吗啉-2-((4RS，7RS)-四氢)-2H-[1，4]二噁)[2，3-c]吡咯-6(3H)-基)嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺，即化合物ZJQ-22。  The high-resolution mass spectrometry data of the resolved product is HRMS (ESI): m/z[M+H] ⁺ calcd.for[C ₂₀ H ₂₄ F ₃ N ₆ O ₃ ] ⁺ : 453.1856, found: 453.1845. Optical rotation data is

From the above data, it can be seen that the product prepared by the above method is the target product (-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxin) [2,3-c]pyrrol-6(3H)-yl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-22.

Example 4: Synthesis of pyrimidine compound ZJQ-23. the

(+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydro)-2H-[1,4]dioxin)[2,3-c]pyrrol-6(3H)-yl )pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-23:

Synthesis method: resolve ZJQ-04 prepared in Example 1, separation conditions: reversed-phase chiral preparative column (Philomen's lu 5u cellose-2), mobile phase: methanol/water=95/5; purity: 99.07%; retention time: 14.67min, the resolution product ZJQ-23 was obtained. the

由上述数据可知，经上述方法所制备的产物为目标产物(+)-5-(6-吗啉-2-((4SR，7SR)-四氢)-2H-[1，4]二噁)[2，3-c]吡咯-6(3H)-基)嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺，即化合物ZJQ-23。  The high-resolution mass spectrometry data of the resolved product is HRMS (ESI): m/z[M+H] ⁺ calcd.for[C ₂₀ H ₂₄ F ₃ N ₆ O ₃ ] ⁺ : 453.1856, found: 453.1863. Optical rotation data is

From the above data, it can be seen that the product prepared by the above method is the target product (+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydro)-2H-[1,4]dioxin) [2,3-c]pyrrol-6(3H)-yl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-23.

Example 5: Synthesis of pyrimidine compound ZJQ-07. the

Step 1: Synthesis of 4-(4,6-dichloro-1,3,5-triazazin-2-yl)morpholine. the

The structural formula of 4-(4,6-dichloro-1,3,5-triazazin-2-yl)morpholine:

Synthesis method: Dissolve 2,4,6-trichloro-1,3,5-triazazine (5.0g, 27.33mmol) in CH ₂ Cl ₂ (100mL), cool to -5°C, and slowly add DIPEA dropwise (4.10 mL, 24.64 mmol) and morpholine (2.15 mL, 24.64 mmol) in CH ₂ Cl ₂ (20 mL) were reacted at low temperature for 1 h, then warmed to 0° C. for overnight. The reaction system was diluted with CH ₂ Cl ₂ (50 mL), washed twice with 1M HCl (50 mL×2), washed once with saturated NaCl, and dried over anhydrous sodium sulfate. Separation and purification by column chromatography, eluent: PE/EA=10/1-5/1, to obtain 4.59 g of the target product as a white solid, yield: 59.74%.

The NMR data of the product are ¹ H NMR (400 MHz, CDCl ₃ ) δ: 3.97-3.80 (m, 4H), 3.80-3.65 (m, 4H). Same as in WO 2011039735. From the above data, it can be seen that the product prepared by the above method is the target product 4-(4,6-dichloro-1,3,5-triazazin-2-yl)morpholine.

Step 2: (1R,4R)-5-(4-Chloro-6-morpholine-1,3,5-triazazin-2-yl)-2-oxo-5-azabicyclo[2.2.1] Synthesis of Heptane

(1R, 4R)-5-(4-chloro-6-morpholine-1,3,5-triazazin-2-yl)-2-oxo-5-azabicyclo[2.2.1]heptane Structural formula:

Synthetic method: 4-(4,6-dichloro-1,3,5-triazazin-2-yl)morpholine (0.36g, 1.51mmol) synthesized in step 1 was dissolved in THF (1:1 , 12mL), add (1R,4R)-2-oxa-5-heterobicyclo[2.2.1]-heptane trifluoroacetate (1.51mmol) synthesized in Step 5 of Example 2, potassium carbonate (0.32g, 2.27mmol), stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, separated and purified by column chromatography (eluent: EA/PE=1/5) to obtain 0.39 g of the product, yield: 84.46%. the

The mass spectrum data of the product is LC-MS: 298.2 (M+H). NMR data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 5.02(d, J=35.7Hz, 1H), 4.67(s, 1H), 3.94-3.64(m, 10H), 3.52(dt, J=27.2, 11.2Hz, 4H). ¹³ CNMR (100MHz, CDCl ₃ ) δ: 169.09(s), 164.57(s), 163.29(s), 76.13(s), 73.57(s), 66.84(s), 56.77(s), 55.22(s), 43.79(s), 36.73(s). From the above data, it can be seen that the product prepared by the above method is the target product (1R, 4R)-5-(4-chloro-6-morpholine-1,3,5-triazazin-2-yl)-2- Oxy-5-azabicyclo[2.2.1]heptane.

Step 3: Synthesis of pyrimidine compound ZJQ-07. the

5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-morpholine-1,3,5-triazazine-2 -yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-07:

Synthetic method: (1R,4R)-5-(4-chloro-6-morpholine-1,3,5-triazazin-2-yl)-2-oxo-5-nitrogen synthesized in step 2 Heterobicyclo[2.2.1]heptane (250mg, 0.84mmol) was dissolved in deoxygenated dioxane (4.0mL), and the 5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (0.49g, 1.69mmol), 2M potassium carbonate aqueous solution (1.26mL, 2.52 mmol), blow nitrogen gas for 10 min, then add Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (35 mg, 0.042 mmol), seal, and react with microwave at 150°C for 2.5 h. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography, eluent: petroleum ether/ethyl acetate=3/1-1/2, to obtain a brown solid. The solid was purified by secondary column chromatography, eluent: dichloromethane/methanol=50/1, to obtain 60 mg of the target product as a white solid, yield: 16.85%, purity: 95.32%.

The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z[M+H] ⁺ calcd.for[C ₁₈ H ₂₁ F ₃ N ₇ O ₂ ] ⁺ : 424.1703, found: 424.1692. NMR data are ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.71(s, 1H), 6.77(s, 1H), 5.06(d, J=35.4Hz, 1H), 4.95(s, 2H), 4.68(s , 1H), 3.93-3.46 (m, 12H), 1.92 (q, J = 10.0 Hz, 1H), 1.84 (s, 1H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 169.47(s), 164.57(s), 163.59(s), 159.39(s), 152.58(s), 138.38(s), 122.47(s), 121.50(s) , 105.32(s), 74.35(s), 66.80(s), 56.59(s), 54.90(s), 43.56(s), 36.59(s). From the above data, it can be seen that the product prepared by the above method is the target product 5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6 -Morpholine-1,3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-07.

Example 6: Synthesis of pyrimidine compound ZJQ-28. the

Step 1: Synthesis of 4-chloro-6-morpholine-N-(4-morpholinephenyl)pyrimidin-2-amine. the

The structural formula of 4-chloro-6-morpholine-N-(4-morpholinephenyl)pyrimidin-2-amine:

Synthetic method: 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.50g, 2.15mmol) synthesized in Step 7 of Example 1 was dissolved in n-butanol (20mL), and 4-morpholine was added Phenylaniline (0.38g, 2.15mmol), p-toluenesulfonic acid monohydrate (0.26g, 1.72mmol), heated to 100°C for 24h. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed once with saturated NaHCO ₃ aqueous solution, once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, separated and purified by column chromatography (eluent: EA/PE=1/1, DCM/CH3OH=10/1, gradient elution) to obtain 0.43 g of the product, yield: 53.54%.

The mass spectrum data of the product is LC-MS: 376.2 (M+H). NMR data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.45-7.36(m, 2H), 6.89(d, J=7.4Hz, 2H), 6.83(s, 1H), 5.97(d, J=1.5Hz , 1H), 3.89-3.82 (m, 4H), 3.78-3.72 (m, 4H), 3.57 (s, 4H), 3.14-3.07 (m, 4H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 163.66(s), 160.29(s), 159.10(s), 147.23(s), 132.18(s), 121.19(s), 116.44(s), 92.62(s) , 66.94(s), 66.44(s), 50.05(s), 44.53(s). It can be seen from the above data that the product prepared by the above method is the target product 4-chloro-6-morpholine-N-(4-morpholinephenyl)pyrimidin-2-amine.

Step 2: Synthesis of pyrimidine compound ZJQ-28. the

4-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(4-morpholinephenyl)pyrimidin-2-amine, the structural formula of compound ZJQ-28 :

Synthetic method: 4-chloro-6-morpholine-N-(4-morpholine phenyl) pyrimidin-2-amine (0.30g, 0.80mmol) synthesized in step 1 was dissolved in deoxygenated dioxane (3.60 mL), sequentially added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoro Methyl)pyridin-2-amine (0.27g, 1.20mmol), 2M potassium carbonate aqueous solution (1.20mL, 2.40mmol), was blown with nitrogen for 10min, then added Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (33mg, 0.04 mmol), sealed, and microwaved at 150°C for 43min. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography, eluent: dichloromethane/methanol=50/1, to obtain 38 mg of the target product as a white solid, yield: 9.50%, purity: 98.30%.

The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z[M+H] ⁺ calcd.for[C ₂₄ H ₂₇ F ₃ N ₇ O ₂ ] ⁺ : 502.2173, found: 502.2163. NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.27(s, 1H), 7.47(d, J=7.7Hz, 2H), 6.92-6.85(m, 3H), 6.76(s, 1H), 6.06 (s, 1H), 4.84 (s, 2H), 3.88-3.83 (m, 4H), 3.81-3.76 (m, 4H), 3.62 (d, J=4.0Hz, 4H), 3.13-3.07 (m, 4H ). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 163.27(s), 162.96(s), 159.62(s), 158.71(s), 151.02(s), 146.79(s), 137.71(s), 137.32(s) , 133.07(s), 123.94(s), 120.83(s), 116.61(s), 104.80(s), 94.66(s), 66.99(s), 66.66(s), 50.29(s), 44.40(s) . From the above data, it can be seen that the product prepared by the above method is the target product 4-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(4-morpholinebenzene Base) pyrimidin-2-amine, namely compound ZJQ-28.

Example 7: Synthesis of pyrimidine compound ZJQ-26. the

Step 1: Synthesis of 4-(6-chloro-2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)morpholine

The structural formula of 4-(6-chloro-2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)morpholine:

Synthetic method: 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.40 g, 1.72 mmol) synthesized in Step 7 of Example 1 was dissolved in THF/EtOH (1:1, 20 mL), Add N-methylsulfopiperazine (0.31g, 1.89mmol), DIPEA (0.34g, 2.58mmol), sodium iodide (258mg, 1.72mmol), and heat to 70°C for 24h. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (100 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, separated and purified by column chromatography (eluent: EA/PE=1/3-1/1) to obtain 0.31 g of the product, yield: 50.65%. the

The mass spectrum data of the product is LC-MS: 362.1 (M+H). NMR data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 5.89(d, J=2.8Hz, 1H), 3.90(d, J=3.6Hz, 4H), 3.80-3.70(m, 4H), 3.55(s , 4H), 3.24 (d, J=4.0Hz, 4H), 2.78 (d, J=2.8Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 163.51(s), 160.65(s), 160.47(s), 91.78(s), 66.83(s), 45.77(s), 44.47(s), 43.46(s) , 34.48(s). From the above data, it can be seen that the product prepared by the above method is the target product 4-(6-chloro-2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)morpholine.

Step 2: Synthesis of pyrimidine compound ZJQ-26. the

5-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, the compound ZJQ- The structural formula of 26:

Synthetic method: 4-(6-chloro-2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-4-yl)morpholine (0.25g, 0.69mmol) prepared in step 1 was dissolved In deoxygenated dioxane (3.0 mL), sequentially add the 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)-4-(trifluoromethyl)pyridin-2-amine (0.40g, 1.38mmol), 2M aqueous potassium carbonate solution (1.05mL, 2.07mmol), bubble nitrogen for 10min, then add Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (28mg, 0.035mmol), sealed and microwaved at 150°C for 2.5h. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (eluent: dichloromethane/methanol=50/1) to obtain 49 mg of the target product as a white solid, yield: 14.54%, purity: 97.34%.

The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z[MH] ^- calcd.for[C ₁₉ H ₂₄ F ₃ N ₇ O ₃ S] ⁺ : 486.1507, found: 486.1498. NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.23(s, 1H), 6.79(s, 1H), 5.98(s, 1H), 4.94(s, 2H), 3.99-3.89(m, 4H) , 3.84-3.74 (m, 4H), 3.66-3.53 (m, 4H), 3.31-3.20 (m, 4H), 2.77 (s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 163.32(s), 162.93(s), 160.91(s), 158.84(s), 150.69(s), 144.28(s), 137.71(s), 124.13(s) , 105.44(s), 92.70(s), 66.64(s), 45.77(s), 44.28(s), 43.57(s), 34.33(s). As can be seen from the above data, the product prepared by the above method is the target product 5-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)-4-( Trifluoromethyl) pyridin-2-amine, namely compound ZJQ-26.

Example 8: Synthesis of pyrimidine compound ZJQ-21. the

Step 1: rac-(4RS,7RS)-6-(4-chloro-6-morpholine-1,3,5-triazazin-2-yl)hexahydro-2H-[1,4]diox[ Synthesis of 2,3-c]pyrrole. the

rac-(4RS, 7RS)-6-(4-chloro-6-morpholine-1,3,5-triazazin-2-yl)hexahydro-2H-[1,4]dioxa[2,3 -c] The structural formula of pyrrole:

Synthetic method: 4-(4,6-dichloro-1,3,5-triazazin-2-yl)morpholine (0.27g, 1.14mmol) synthesized in Step 1 of Example 5 was dissolved in THF (10mL ), add rac-(4RS, 7RS)-hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole (0.18g, 1.14mmol), DIPEA (0.18g, 1.37mmol), room temperature Stir overnight. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, separated and purified by column chromatography (eluent: EA/PE=1/5) to obtain 0.31 g of product, yield: 82.23%. the

The mass spectrum data of the product is LC-MS: 328.1 (M+H). The nuclear magnetic data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 4.08-3.41 (m, 16H), 3.31-3.14 (m, 2H). ¹³ C NMR (100MHz, CDCl ₃ ) δ: 169.18(s), 164.17(s), 163.82(s), 77.77(s), 67.18(s), 66.62(s), 46.17(s), 43.82(s) . From the above data, it can be seen that the product prepared by the above method is the target product rac-(4RS, 7RS)-6-(4-chloro-6-morpholine-1,3,5-triazazin-2-yl)hexa Hydrogen-2H-[1,4]dioxa[2,3-c]pyrrole

Step 2: Synthesis of pyrimidine compound ZJQ-21. the

rac-5-(4-morpholin-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-1, 3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-21:

Synthetic method: rac-(4RS, 7RS)-6-(4-chloro-6-morpholine-1,3,5-triazazin-2-yl)hexahydro-2H-[1 , 4] Dioxa[2,3-c]pyrrole (250mg, 0.76mmol) was dissolved in deoxygenated dioxane (3.5mL), and the 5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (0.44g, 1.53mmol), 2M aqueous potassium carbonate ( 1.14mL, 2.28mmol), blow nitrogen for 10min, then add Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (31mg, 0.038mmol), seal, react with microwave at 150°C for 2.5h. The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed twice with water and once with saturated NaCl aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography, eluent: dichloromethane/methanol=50/1, to obtain 35 mg of the target product as a white solid, yield: 10.12%, purity: 90.49%.

The mass spectrum data of the product is LC-MS: 454.2 (M+H). NMR data is ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.72(s, 1H), 6.77(s, 1H), 4.90(s, 2H), 4.16-3.60(m, 16H), 3.26(dt, J= 14.9, 10.0Hz, 2H). ¹³ CNMR (100MHz, CDCl ₃ ) δ: 169.73(s), 164.52(s), 163.88(s), 159.75(s), 152.72(s), 138.10(s), 122.28(s), 105.32(s), 99.74(s), 78.01(s), 67.27(s), 66.80(s), 45.82(s), 43.58(s). From the above data, it can be seen that the product prepared by the above method is the target product rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3 -c] pyrrol-6(3H)-yl)-1,3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-21.

Example 9: Synthesis of pyrimidine compound ZJQ-29. the

(-)-(4-morpholine-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-1, 3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-29:

Synthesis method: split the prepared ZJQ-21, separation conditions: reversed-phase chiral preparative column (lu 5u cellose-2 from Pheromones), mobile phase: methanol/water=95/5; purity: 97.70%; Retention time: 12.25min, the resolution product ZJQ-29 was obtained. the

由上述数据可知，经上述方法所制备的产物为目标产物(-)-(4-吗啉-6-((4RS，7RS)-四氢-2H-[1，4]二噁[2，3-c]吡咯-6(3H)-基)-1，3，5-三氮嗪-2-基)-4-(三氟甲基)吡啶-2-胺，即化合物ZJQ-29。  The mass spectrum data of the product is LC-MS: 454.2 (M+H). Optical rotation data is

From the above data, it can be seen that the product prepared by the above method is the target product (-)-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3 -c] pyrrol-6(3H)-yl)-1,3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-29.

Example 10: Synthesis of pyrimidine compound ZJQ-30. the

(+)-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-1, 3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-30:

Synthetic method: the prepared ZJQ-21 is resolved, separation conditions: reversed-phase chiral preparative column (lu 5ucellose-2 of Pheromones), mobile phase: methanol/water=95/5; purity: 98.62%; Time: 14.25min, the resolution product ZJQ-30 was obtained. the

由上述数据可知，经上述方法所制备的产物为目标产物(+)-(4-吗啉-6-((4RS，7RS)-四氢-2H-[1，4]二噁[2，3-c]吡咯-6(3H)-基)-1，3，5-三氮嗪-2-基)-4-(三氟甲基)吡啶-2-胺，即化合物ZJQ-30。  The mass spectrum data of the product is LC-MS: 454.2 (M+H). Optical rotation data is

From the above data, it can be seen that the product prepared by the above method is the target product (+)-(4-morpholine-6-((4RS, 7RS)-tetrahydro-2H-[1,4]dioxa[2,3 -c] pyrrol-6(3H)-yl)-1,3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, namely compound ZJQ-30.

In the present invention, other compounds in the following Table 1 are also prepared, and the synthesis methods of these compounds refer to the above-mentioned methods. The characterization data of these compounds, including NMR data and high-resolution mass spectrometry data are shown in Table 1. the

Table 1

In vitro PI3Kα kinase inhibition test:

The compound of the present invention inhibits the activity of PI3Kα kinase, thereby inhibiting the transduction of the cell signal pathway, thereby affecting the cell cycle and cell proliferation. The inhibitory effect of these compounds on PI3Kα kinase was evaluated by the following Kinase-Glo Luminescent Kinase Assay method. the

Detection tools: Kinase-Glo Plus Luminescent Kinase Assay (Kinase Glo Plus kinase luminescent detection) kit is used to test the kinase inhibitory activity of the target compound. the

Detection principle: Kinase-Glo Plus Luminescent Kinase Assay is a homogeneous non-radioactive detection method, which quantitatively measures the activity of purified kinase by detecting the ATP content in the system after the kinase reaction. The determination of ATP content was quantified by the light intensity generated by the oxidation of Mg ²⁺ , ATP and oxygen-catalyzed beetle luciferin. Add a certain amount of ATP to the reaction system, the kinase reaction needs to consume ATP, and the remaining ATP can react with the firefly luciferase in the Kinase Glo reagent and then emit light, so that the amount of remaining ATP can be quantitatively detected, and the reaction kinase can be indirectly determined. active.

Detection method: the test compound was prepared with 100% dimethyl sulfoxide (DMSO) to a concentration of 100× of the highest reaction inhibitory concentration, and 100 μL was drawn into one well of a 96-well plate. Then 100% DMSO was used to perform 3-fold concentration gradient dilution well by well, and 10 concentrations were prepared. "Complete" and "blank" control wells were replaced with 100 μL of 100% DMSO. Among them, the "complete" control well is the no compound group, and the "blank" control well is the no kinase group. Subsequently, compound intermediate dilutions were prepared in 4% DMSO by adding 4 μL of compound and 96 μL of 1× Kinase Base Buffer to each well of the assay plate. Add 2.5 μL of intermediate dilutions of the above compounds to the reaction plate, and then add 2.5 μL of 4×kinase solution (add kinase to 1×kinase base buffer (50 mM HEPES, pH 7.5, 1 mM EGTA, 100 mM NaCl, 3 mM MgCl ₂ , 2 mM DTT, 0.03% CHAPS) was added to each well of the assay plate. Incubate at room temperature for 10 min. Add 5 μL of 2× substrate solution (prepared by adding PIP2 and ATP to 1× kinase base buffer) into each well of the assay plate. Incubate at room temperature for 1 h. Add 10 μL of stop solution (Kinase-Glo reagent) to stop the reaction. Shake, centrifuge for 1 min, shake at low speed for 15 min, then read the plate with Flexstation for detection, and finally calculate according to the RLU value and the readings of "complete" and "blank" control wells The inhibitory rate at each concentration of the compound was obtained, and the IC ₅₀ value was calculated according to the compound concentration.

Test results: see Table 2. the

Table 2 Inhibitory activity of target compounds on PI3Kα kinase in vitro

compound IC ₅₀ (nM) compound IC ₅₀ (nM) ZJQ-04 31 ZJQ-20 375 ZJQ-05 60 ZJQ-21 32 ZJQ-06 91 ZJQ-22 61 ZJQ-07 59 ZJQ-23 35 ZJQ-08 9530 ZJQ-24 128 ZJQ-10 224 ZJQ-26 twenty three ZJQ-13 117 ZJQ-27 568 ZJQ-14 5751 ZJQ-28 26 ZJQ-19 896 ZJQ-29 68 NVP-BKM120 28 ZJQ-30 38

It can be seen from the data in Table 2 that all the compounds protected by the invention have inhibitory activity on PI3Kα kinase, and most of them have obvious PI3Kα kinase inhibitory activity. Moreover, compared with Buparlisib (NVP-BKM120) with structural formula 1 developed by Novartis, a compound that has entered phase III clinical trials pointed out in the current background technology, the compounds ZJQ-04 provided by the present invention, ZJQ-21, ZJQ- 23. ZJQ-26, ZJQ-28 and compound ZJQ-30 have equivalent or slightly better inhibitory activity. It can be seen that the compound provided by the present invention has obvious inhibitory activity on PI3Kα kinase and has further development prospects. the

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention. the

Claims (11)

1. A PI3K kinase inhibitor, characterized in that it comprises a pyrimidine compound with general formula I, its stereoisomer, hydrate or pharmaceutically acceptable salt, and said general formula I has the following structure:

In the general formula I: X, Y, Z, W are independently selected from N or -CH-; R ¹ , R ² are independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl containing one or more substituents, C ₁ -C ₄ alkoxy, containing one or more substituents C ₁ -C ₄ alkoxy group, C ₃ -C ₆ heterocyclic group, C ₃ -C ₆ heterocyclic group containing one or more substituents, C ₄ -C ₈ fused heterobicyclic group or containing one or a C ₄ -C ₈ fused heterobicyclic group of multiple substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenated C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl; R ³ is selected from H, -CN, -CH ₃ , -CF ₃ or -SO ₂ NH ₂ ; ^R4 is selected from H or halogen. 2. The PI3K kinase inhibitor according to claim 1, wherein said R ³ is -CF ₃ . 3. The PI3K kinase inhibitor according to claim 2, characterized in that, the PI3K kinase inhibitor comprises pyrimidine compounds with general formula II and/or general formula III, stereoisomers, hydrates or pharmaceutically Acceptable salt; The structure of the general formula II and the general formula III is as follows:

In said general formula II and general formula III: R ¹ , R ² are independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl containing one or more substituents, C ₁ -C ₄ alkoxy, containing one or more substituents C ₁ -C ₄ alkoxy group, C ₃ -C ₆ heterocyclic group, C ₃ -C ₆ heterocyclic group containing one or more substituents, C ₄ -C ₈ fused heterobicyclic group or containing one or a C ₄ -C ₈ fused heterobicyclic group of multiple substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenated C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl. 4. The PI3K kinase inhibitor according to claim 1 or 3, characterized in that R ¹ and R ² in the general formula I, the general formula II or the general formula III are independently selected from the following structures:

Wherein, A, B, C, D, E, F are independently selected from -CH ₂ -, -O-, -S- or -NR ¹¹ -; R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are independently selected from H, halogen, hydroxyl, amino, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ alkyl, Hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogenated C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₄ alkoxy, or C ₁ -C ₄ alkylsulfonyl. 5. The PI3K kinase inhibitor according to claim 4, characterized in that R ¹ and R ² in the general formula I or in the general formulas II and III are independently selected from the following structures:

6. The PI3K kinase inhibitor according to claim 5, characterized in that, in the general formula I, the general formula II or the general formula III, R ¹ is selected from the following structures:

R ² is selected from the following structures:

7. The PI3K kinase inhibitor according to claim 1, wherein the pyrimidine compound is: rac-5-(6-morpholin-2-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl)pyrimidine- 4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(2-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-morpholinepyrimidin-4-yl)-4-(trifluoro Methyl)pyridin-2-amine; 5-(2-((2R,6S)-2,6-dimethylmorpholine)-6-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(2-((4RS,7SR)-dihydro-2H-[1,4]dioxa[2,3-c]pyrrole-6(3H,7H,7aH)-yl)-6-morpholine pyrimidine -4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(6-((2R,6S)-2,6-dimethylmorpholine)-2-((4SR,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c ]pyrrol-6(3H)-yl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(6-((2R,6S)-2,6-dimethylmorpholine)-2-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(2-morpholin-6-((4SR,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)pyrimidin-4-yl )-4-(trifluoromethyl)pyridin-2-amine; rac-5-(2-morpholin-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)pyrimidine-4 -yl)-4-(trifluoromethyl)pyridin-2-amine; rac-6-morpholine-2-((4RS,7RS)-tetrahydro)-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-[4,5 '-Bipyridinyl]-2'-amine 4-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(2-morpholineethyl)pyrimidin-2-amine; 4-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-N-(4-morpholinephenyl)pyrimidin-2-amine; (-)-5-(6-morpholine-2-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl) Pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; (+)-5-(6-morpholine-2-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa)[2,3-c]pyrrol-6(3H)-yl) Pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptan-5-yl)-6-morpholine-1,3,5-triazine-2 -yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl)-6-((2R,6S)-2,6-dimethyl Morpholine)-1,3,5-triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; rac-5-(4-morpholin-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)-1, 3,5-Triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; (-)-5-(4-morpholine-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)- 1,3,5-Triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; or (+)-5-(4-morpholine-6-((4RS,7RS)-tetrahydro-2H-[1,4]dioxa[2,3-c]pyrrol-6(3H)-yl)- 1,3,5-Triazazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine. 8. A pharmaceutical composition, characterized in that it comprises at least one pharmaceutically acceptable adjuvant, adjuvant or carrier and an effective therapeutic dose of at least one PI3K kinase inhibitor described in any one of claims 1 to 7 agent. 9. A PI3K kinase inhibitor according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the treatment of proliferative diseases of prevention and/or treatment and/or adjuvant treatment of PI3K kinase action application in medicine. 10. The application according to claim 9, wherein the proliferative disease on which the PI3K kinase acts is colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, Kidney cancer, brain tumor, neck cancer, cancer of the CNS, malignant glioma, or myeloproliferative disease, and leukemia and lymphoma. 11. The application of a PI3K kinase inhibitor according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in inhibiting the growth of cancer cells in vitro.