CN108191837A - PI3K α/mTOR bidifly enzyme inhibitors and its pharmaceutical composition and application - Google Patents

Abstract

The invention discloses a kind of PI3K α/mTOR bidifly enzyme inhibitor, its pharmaceutical composition and its applications.Wherein described PI3K α/mTOR bidifly enzyme inhibitors, including compound or its stereoisomer, geometric isomer, hydrate, solvate or pharmaceutically acceptable salt or prodrug shown in logical formula (I)：

Description

PI3Kα/mTOR dual kinase inhibitor and its pharmaceutical composition and application

field of invention

The invention relates to the technical field of medicine, and more specifically, the invention relates to a PI3Kα/mTOR dual kinase inhibitor and its pharmaceutical composition and application.

Background of the invention

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. The essence of carcinogenesis is that the molecular signals that regulate the physiological functions of cells are abnormal in the transduction process, disrupting the normal regulation of cells and proliferating indefinitely. Cell signal transduction is closely related to tumor occurrence, development, recurrence and metastasis. Traditional cytotoxic drugs for tumor treatment generally have disadvantages such as low selectivity, strong side effects and poor drug resistance, which promotes the transfer of anti-tumor drugs to targeted small molecule drugs. In recent years, the vigorous development of precision medicine has further accelerated the research and development of targeted small molecule anti-tumor drugs. In the past year alone, 6 small molecule kinase inhibitors including Palbociclib, Lenvatinib, Osimertinib, etc. have been approved by the FDA listed. It can be seen that the research and development of small-molecule inhibitors based on key protein kinases in cell signal transduction pathways has become a hot spot in the research of targeted anti-tumor innovative drugs (Nat. Rev. Drug Discovery 2017, 16, 73-76).

The phosphatidylinositol-3 kinase (PI3K)-protein kinase B (Akt)-target of rapamycin (mTOR) signaling pathway is one of the three main signaling pathways in cells, and it plays an important role in maintaining cell survival, growth, metastasis, apoptosis play an important role in death and protein synthesis. PI3Ks are a class of lipid kinases with serine/threonine (Ser/Thr) kinase activity, which can phosphorylate the 3-hydroxyl of the substrate, such as phosphorylating the substrate PI(4,5)P2 to generate phosphatidylinositol- 3,4,5-triphosphate (PI(3,4,5)P3), the latter can be used as an important second messenger to activate downstream effectors to regulate various life activities in cells (Nat.Rev.DrugDiscovery 2014, 13, 140-156). According to the structural characteristics, phosphorylation substrates and tissue distribution of PI3K, it can be divided into three categories. Among them, the research on class I PI3K is the most extensive and in-depth, and it is further subdivided into two subtypes, IA and IB, according to the type of receptor binding. Type IA PI3K includes three subtypes of PI3Kα, PI3Kβ, and PI3Kδ, while type IB PI3K only contains one subtype of PI3Kγ. The activated receptor tyrosine kinases (receptor tyrosine kinases, RTK) transmit the signal to the cell through PI3K, and activate the downstream protein Akt. After Akt is activated, it will inhibit GS3Kβ, thereby inhibiting the expression of cyclin D1, and then causing cell expansion. mTOR regulates cell growth and proliferation by monitoring effective nutrients, cell energy and molecular oxygen levels, and cell mitosis signals. mTOR exists in two different complexes: mTORC1 and mTORC2. The PI3K/Akt/mTOR signaling pathway is widely involved in the regulation and control of various physiological functions of cells, and the abnormality of this pathway is closely related to the occurrence and development of tumors.

Among the four subtypes of class I PI3K, PI3Kα is most closely related to the occurrence and development of tumors. Studies have found that PIK3CA mutation (the gene encoding PI3Kα) occurs in more than 30% of patients with various solid tumors. Among them, the proportion of PIK3CA gene mutations in breast cancer patients accounts for 18-40%, and the proportion of PIK3CA mutations in lung cancer patients accounts for more than 50% ^[4] . PI3Kβ and oncogenic Ras genes and tyrosine kinases play a key role in the formation of PTEN-deficient tumors (Nat. Rev. Drug Discovery. 2014, 13, 140-156.). PI3Kγ and δ are mainly expressed on leukocytes and play a role in lymphocyte activation, mast cell degranulation and leukocyte chemotaxis, so they are potential targets for immunosuppression and cancer therapy (Curr.Drug Discovery Technol.2014,11,113-126) . As a key site downstream of the PI3K-Akt-mTOR signaling pathway, mTOR is abnormally regulated in a variety of malignant tumors, such as breast cancer, prostate cancer, and lung cancer. Therefore, targeting PI3Kα/mTOR can effectively inhibit tumor development while reducing non-target-related side effects.

In recent years, the research on PI3K/mTOR dual-target inhibitors has made gratifying progress. There are dozens of candidate compounds in different clinical stages, and these compounds have various molecular structures. Among them, arylmorpholine PI3K/mTOR dual-target inhibitors have good development prospects, and the representative compounds are shown in the above structural formula. However, there are no drugs on the market so far, and the analysis may have the following problems: 1) There are many subtypes of protein kinases in the PI3K signaling pathway, and most of the PI3K/mTOR inhibitors reported so far are non-subtype-selective inhibition, and this non-specific inhibition will lead to from non-target related side effects. 2) Most of the candidate drug molecules entering clinical research have disadvantages such as large molecular weight and poor water solubility, and usually need to be administered by injection, resulting in poor patient compliance. Therefore, further research and development of novel PI3Kα/mTOR dual-target inhibitors is of great significance.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chiral" is a molecule that has the property of being nonsuperimposable to its mirror image, and "achiral" is a molecule that is superimposable to its mirror image.

"Enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other.

"Diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. The terms "optionally", "optionally" or "optionally" mean that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not or the situation, the term "optionally" whether or not preceding the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but not limited to, H, F, Cl, Br, I, N ₃ , -CN, -OH, -NO ₂ , -NH ₂ , oxo (=O), R ⁴ C (=O)NH-, R ⁴ C(=O)O-, N(R ⁴ R ^4a )-C(=O)-, R ⁴ OC(=O)-, R ⁴ ON=, C _1-4 Alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _1-4 dialkylamino , C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 hydroxyalkoxy, or C _1-4 alkoxy C _1-4 alkyl and so on.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention "each...independently are" can be interchanged with "...independently" and "...independently". It should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and it can also mean that in the same group, the specific options expressed between the same symbols do not affect each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C _1-4 alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, and C ₄ alkyl.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group.

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group can be any Optionally substituted with one or more substituents described herein. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in other embodiments, the alkyl group contains 1 - 4 carbon atoms; in still some embodiments, the alkyl group contains 1-3 carbon atoms. In other embodiments, the alkyl group contains 1-2 carbon atoms.

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, i-propyl, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl ( i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu , t-butyl, -C(CH ₃ ) ₃ ), n-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2- Butyl (-CH(CH ₃ ) CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl ( -CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3 -Methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ ) C(CH ₃ ) ₃ ), n-heptyl, n-octyl, etc.

The term "alkyl" and its prefix "alk", both include straight and branched saturated carbon chains.

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, trifluoromethoxy, etc.

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-20 carbon atoms. In some embodiments, the alkoxy group contains 1-10 carbon atoms; in other embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in other embodiments, the alkoxy group contains 1-3 carbon atoms.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy ( _-OCH2CH ( _CH3 ) _CH2CH3 ), and so _on . The alkoxy groups may independently be unsubstituted or substituted with one or more substituents described herein.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, the alkylamino group is a lower alkylamino group with one or two C _1-6 alkyl groups attached to the nitrogen atom; in other embodiments, the alkylamino group is one or two A lower alkylamino group with a C _1-3 alkyl group attached to a nitrogen atom. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.

The term "aminoalkyl" refers to an alkyl group substituted by one or more amino groups, wherein alkyl has the definition described herein, non-limiting examples of aminoalkyl include, but are not limited to, aminomethyl, amino Ethyl, aminopropyl, etc.

The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein to refer to monocyclic, bicyclic or tricyclic ring systems in which one or more atoms of the ring are independently optionally replaced by heterocyclic rings. Atoms substituted, rings may be fully saturated or contain one or more unsaturations, but are never aromatic, with one or more points of attachment (which may be carbon or nitrogen atoms) to other molecules. One or more ring hydrogen atoms may be independently unsubstituted or substituted with one or more substituents described herein. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a monocyclic ring consisting of 3-7 atoms (2-6 carbon atoms and selected from N, O, P, 1-3 heteroatoms of S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO ₂ , PO, PO ₂ , when the ring is three atoms When forming a ring, there is only one heteroatom in it), and some other embodiments are monocyclic rings composed of 3-8 atoms (2-7 carbon atoms and 1-3 heteroatoms selected from N, O, P, S Atoms, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO ₂ , PO, PO ₂ , when the ring is a ring composed of three atoms, only a heteroatom), or a bicyclic ring consisting of 7-10 atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by a Or a plurality of oxygen atoms are substituted to obtain groups like SO, SO ₂ , PO, PO ₂ ).

A heterocyclic group may be a carbon group or a heteroatom group. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Thioxanyl, Piperazinyl, Homopiperazinyl, Azetidinyl, Oxetanyl, Thietanyl, Homopiperidinyl, Glycidyl Base, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, Indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithianyl, di Hydrogen thienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl. Examples of the heterocyclic group also include pyrimidinedionyl and 1,1-dioxothiomorpholinyl in which two ring carbon atoms are substituted by oxygen (=O). The heterocyclyl groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heterocyclylalkyl" means that an alkyl group may be substituted by one or more heterocyclyl groups, wherein the alkyl and heterocyclyl groups have the meanings described herein. In some of these embodiments, a heterocyclylalkylene group refers to a "lower heterocyclylalkylene" group, ie a heterocyclyl group attached to a C _1-6 alkyl group. In some other embodiments, the heterocyclyl group is attached to a C _1-4 alkyl group. Such examples include, but are not limited to, 2-pyrrolidinylethyl and the like. The heterocyclylalkylene groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroatom" refers to O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl NR).

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "H" denotes a single hydrogen atom. Such atomic groups can be linked to other groups, such as oxygen atoms, to form hydroxyl groups.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

The term "arylalkyl" means that an alkyl group may be substituted by one or more aryl groups, wherein the alkyl and aryl groups have the meanings described herein, some of which are, aryl An alkylene group refers to a "lower arylalkylene" group, that is, an aryl group attached to a C _1-6 alkyl group; some other examples are, arylalkylene The group refers to a "phenylene alkylene" containing a C _1-4 alkyl group; in some other embodiments, an aryl alkylene group refers to an aryl group connected to a C _1-3 alkyl group ; In some other embodiments, the aryl alkylene group refers to that the aryl group is connected to a C _1-2 alkyl group. Specific examples thereof include benzyl, diphenylmethyl, phenethyl and the like. The arylalkylene groups can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least One ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the 5-6 atom heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Monocyclic examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxanyl Azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazole Base, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,2,4-thiodiazolyl, 1,3,4-thiodiazolyl Azolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuran Base, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyridyl Azolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2 ,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, and the like.

The term "heteroarylalkyl" means that an alkyl group may be substituted by one or more heteroaryl groups, wherein the alkyl and heteroaryl groups have the meanings described herein, some examples of which are , a heteroarylalkylene group refers to a "lower heteroarylalkylene" group, that is, a heteroaryl group attached to a C _1-6 alkyl group; some other examples are , the heteroaryl group is connected to the C _1-4 alkyl group; some other embodiments are, the heteroaryl group is connected to the C _1-3 alkyl group; some other embodiments are, the hetero The aryl group is attached to a C _1-2 alkyl group. Specific examples thereof include 2-pyridylmethyl, 3-furylethyl and the like. The heteroarylalkylene groups can be independently unsubstituted or substituted with one or more substituents described herein.

The terms "fused bicyclic", "fused ring", "fused bicyclic radical", "fused cycloyl" mean saturated or unsaturated fused or bridged ring systems, involving non-aromatic bicyclic or bridged ring systems, such as As shown in formula (a), ring A1 and ring A2 share a bond or an alkane chain, wherein j is 0, 1, 2, 3 or 4. 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, hexahydro-furo[3,2-b]furan, 2,3,3a,4 ,7,7a-hexahydro-1H-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, bicyclo[2.2 .1]heptane, 2-azabicyclo[2.2.1]heptane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, 2-oxa-5-azabicyclo[ 2.2.1] Heptane, hexahydro-2H-[1,4]dioxane[2,3-c]pyrrole, these are included in the system of fused bicyclic or bridged rings. And the fused bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, H, F, Cl, Br, I, N ₃ , -CN, -OH, -NO ₂ , - NH ₂ , oxo(=O), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, N(R ⁴ R ^4a )-C(=O)-, R ⁴ OC(= O)-, R ⁴ ON=, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _1-4 dialkylamino, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 Hydroxyalkoxy, or C _1-4 alkoxy C _1-4 alkyl and the like.

The term "fused heterobicyclyl" means a saturated or unsaturated fused or bridged ring system, involving a non-aromatic bicyclic or bridged ring system. 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 by one or more oxygen atoms to obtain groups such as SO, SO ₂ , PO, PO ₂ , such examples include, but are not limited to, hexahydro-furo[3, 2-b]furan, 7-azabicyclo[2.3.0]heptane, 2-azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, Hexahydro-2H-[1,4]dioxane[2,3-c]pyrrole, etc. And the fused heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, H, F, Cl, Br, I, N ₃ , -CN, -OH, -NO ₂ , -NH ₂ , oxo(=O), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, N(R ⁴ R ^4a )-C(=O)-, R ⁴ OC( =O)-, R ⁴ ON=, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _1-4 dialkylamino, C 1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, _{C 1-4 haloalkoxy} , C _{1-4 4} hydroxyalkoxy, or C _1-4 alkoxy C _1-4 alkyl and the like.

As used herein, the term "unsaturated" means that a group contains one or more degrees of unsaturation.

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 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.

As described in the present invention, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, Salts, drug stabilizers, binders, excipients, dispersants, lubricants, sweeteners, flavoring agents, coloring agents, or combinations thereof, these carriers are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The present invention aims to provide a new PI3Kα/mTOR dual kinase inhibitor, its pharmaceutical composition and application, so as to select more effective and selective compounds for the treatment of proliferative diseases, especially cancer.

In order to achieve the above object, according to one aspect of the present invention, a PI3Kα/mTOR dual kinase inhibitor is provided, including a compound represented by general formula (I), or its stereoisomer, geometric isomer, hydrate, Solvates, or pharmaceutically acceptable salts or prodrugs:

Wherein, X is selected from N or -CR ^a -;

R ¹ , R ² and R ^a are each independently selected from H, C ₁ -C ₄ alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C ₁ -C ₄ alkyl-C(=O )-, C _1-4 alkylsulfonyl, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, or C _4-9 fused Heterobicyclyl C _1-4 alkyl, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, and C _4-9 fused heterobicyclic Each C _1-4 alkyl group can be independently selected from one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _1-4 aminoalkyl, C _1-4 hydroxyalkoxy, or C _1-4 Substituents of alkoxy C ₁ -C ₄ alkyl;

R ³ is selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclic Base, C _4-9 fused heterobicyclyl C _1-4 alkyl, C _4-9 fused heterobicyclyl C _1-4 alkylamino, C _3-7 heterocyclyl C _1-4 alkyl, C _{3 -7} heterocyclyl C _1-4 alkylamino, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryl C _1-4 alkylamino, C _1-9 hetero Aryl, C _1-9 heteroaryl C _1-4 alkyl, or C _1-9 heteroaryl C _1-4 alkylamino, wherein the C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, C _3-7 hetero Cyclic C _1-4 alkylamino, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryl C _1-4 alkylamino, C _1-9 heteroaryl, C _1-9 heteroaryl C _1-4 alkyl, and C _1-9 heteroaryl C _1-4 alkylamino each independently can be selected from one or more of fluorine, chlorine, bromine, iodine, hydroxyl, amino , Oxo(=O), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, N(R ⁴ R ^4a )-C(=O)-, R ⁴ OC(=O) -, R ⁴ ON =, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkylamino, C _1-4 dialkylamino, C 1-4 aminoalkyl _, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 hydroxyalkoxy Oxygen, or a C _1-4 alkoxy C _1-4 alkyl substituent;

Each R ⁴ and R ^4a are independently selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl, C _1-4 alkyl, C _{1-4 9} heteroaryl, C _1-9 heteroaryl C _1-4 alkyl, C _4-7 heterocyclyl, or C _4-7 heterocyclyl C _1-4 alkyl, wherein the C _1-4 alkane C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _1-9 heteroaryl, C _1-9 heteroaryl C _1-4 alkyl , C _4-7 heterocyclyl, and C _4-7 heteroaryl C _1-4 alkyl each independently can be selected from one or more of fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo (= O), C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 hydroxyalkoxy, or C _1-4 alkoxy C Substituents of _1-4 alkyl groups.

In some embodiments, the compound represented by formula (I) has the structure represented by formula (II), or its stereoisomer, geometric isomer, hydrate, solvate, or pharmaceutically acceptable salt or prodrug :

X is selected from N or -CH-;

R ¹ is selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl , C _3-7 heterocyclyl, or C _4-9 fused heterobicyclyl, wherein the C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkane The group -C(=O)-, C _1-4 alkylsulfonyl, C _3-7 heterocyclyl, and C _4-9 fused heterobicyclyl can be independently selected from one or more of fluorine, chlorine , bromine, iodine, hydroxyl, amino, cyano, oxo (=O), C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy _, C _1-4 hydroxyalkoxy, C 1-4 alkylamino, C _1-4 aminoalkyl, R ⁴ C(=O)NH-, R ⁴ C(=O)O- , C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, or C _1-4 alkoxy C _1-4 alkyl substituents.

In other embodiments, R ³ is selected from R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, C _{3 -7} heterocyclyl C _1-4 alkylamino, C _6-10 aryl C _1-4 alkylamino, or C _1-9 heteroaryl C _1-4 alkylamino, wherein said R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, C _3-7 heterocyclyl C _1-4 alkylamino, C _6-10 aromatic Group C _1-4 alkylamino, and C _1-9 heteroaryl C _1-4 alkylamino each independently can be selected from one or more of fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo (=O ), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, N(R ⁴ R ^4a )-C(=O)-, R ⁴ OC(=O)-, R ⁴ ON= , C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _{1 -4} dialkylamino, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 hydroxyalkoxy, or C _{1 -4} alkoxy C _1-4 alkyl substituents;

Each R ⁴ and R ^4a are independently selected from H, C _1-4 alkyl, or C _1-4 haloalkyl.

In other embodiments, ^R represents the following substructure:

Wherein, A, B, C and D are each independently selected from -CH ₂ -, -O-, -S- or -NR ^b -; R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from From H, halogen, hydroxyl, amino, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _{1-4 4} hydroxyalkoxy, C _1-4 alkyl-C(=O)-, or C _1-4 alkylsulfonyl.

In other embodiments, ^R represents the following substructure:

In other embodiments, R ³ is selected from C _1-4 alkylamino, C _1-4 haloalkylamino, or C _3-7 heterocyclyl C _1-4 alkyl, or R ³ represents the following substructural formula:

In other embodiments, the compounds of the present invention comprise one of the following structures:

(1) 1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide;

(2) (S)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide;

(3) (R)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide;

(4) 1-(4-(3-(4-((2,6-dimorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)piperidine-2-carboxamide;

(5) (2S)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)-4-hydroxypyrrolidine-2 - Formamide;

(6) (S)-1-(4-(3-(4-(2-(4-methylpiperazin-1-yl)-6-morpholine pyrimidin-4-yl)phenyl)ureido) Benzoyl) pyrrolidine-2-carboxamide;

(7) (S)-1-(4-(3-(4-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)phenyl) ureido) benzoyl) pyrrolidine-2-carboxamide;

(8) (2S)-1-(4-(3-(4-(6-morpholine-2-(tetrahydro-2H-[1,4]dioxo[2,3-c]pyrrole-6( 3H)-yl)pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide;

(9) 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)azetidine- 2-formamide;

(10)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide;

(11)(R)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide;

(12) 1-(4-(3-(4-4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)piperidine-2- Formamide;

(13)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide;

(14) (S)-methyl 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzyl Acyl)pyrrolidine-2-carboxylic acid;

(15)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) -N-Methylpyrrolidine-2-carboxamide;

(16)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) -N,N-Dimethylpyrrolidine-2-carboxamide;

(17) 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4-hydroxy Pyrrolidine-2-carboxamide;

(18) 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4-oxo Pyrrolidine-2-carboxamide;

(19) 1-(4-(3-(4-(4,6-bimorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4-( Methoxyimino) pyrrolidine-2-carboxamide;

(20)4-Amino-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide;

(21) 4-Dimethylamino-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzyl Acyl)pyrrolidine-2-carboxamide;

(22)(S)-1-(4-(2-(aminomethyl)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4,6-bismorpholine-1,3,5 - Triazin-2-yl) phenyl) urea;

(23)(S)-1-(4-(3-(4-(4-(4-methylpiperazin-1-yl)-6-morpholine-1,3,5-triazine-2- Base) phenyl) urea) benzoyl) pyrrolidine-2-carboxamide;

(24)(S)-1-(4-(3-(4-(4-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine-1,3,5-triazine -2-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide;

(25)(2S)-1-(4-(3-(4-(4-morpholine-6-(tetrahydro-2H-[1,4]dioxo[2,3-c]pyrrole-6( 3H)-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide;

or a stereoisomer, geometric isomer, racemate, solvate, or pharmaceutically acceptable salt or prodrug thereof.

In another aspect, the present invention provides a pharmaceutical composition, comprising the compound described in the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

On the other hand, the present invention provides a proliferative agent for the prevention and/or treatment and/or adjuvant treatment of PI3Kα/mTOR dual kinase effect using the compound of the present invention or the pharmaceutical composition of the present invention. Use in medicines for diseases.

In some embodiments, the purposes of the present invention, wherein the proliferative diseases include 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, leukemia, or lymphoma.

In another aspect, the present invention provides an application of the PI3Kα/mTOR dual kinase inhibitor of the present invention or the pharmaceutical composition of the present invention to inhibit the growth of cancer cells in vitro.

Applying the technical scheme of the present invention, the PI3Kα/mTOR dual kinase inhibitor provided by the present invention, and its pharmaceutical composition can be used to inhibit PI3Kα/mTOR dual kinase and proliferative diseases that PI3Kα/mTOR dual kinase acts, and can be PI3Kα Treatment of proliferative diseases in which the /mTOR dual kinase acts provides more potent and selective inhibitors.

The PI3Kα/mTOR dual kinase inhibitor provided by the present invention can be used for inhibiting PI3Kα/mTOR dual kinase and proliferative diseases of PI3Kα/mTOR dual kinase, and can be used for the treatment of proliferative diseases of PI3K/Akt/mTOR dual kinase Provides inhibitors with better potency and selectivity.

The PI3Kα/mTOR dual 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).

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 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.

In addition, the present invention provides methods for preparing, isolating and purifying the compound represented by formula (I) or (II). 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 conformation) Isomers)): eg R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and conformational isomers of (Z), (E). 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.

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.

Composition Formulations of Compounds of the Invention

The pharmaceutical composition of the present invention includes the compound of the structure shown in formula (I) or (II) or the compound of the structure shown in formula 1-38, the compound listed in the present invention, or the compound of embodiment 1-25, or its stereo Isomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers , excipient, diluent, adjuvant, vehicle, or a combination thereof.

The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the present invention, their metabolites or their residues.

As described in the present invention, the pharmaceutically acceptable pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, which, as used in the present invention, includes any solvent, diluent Agents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, summarizing the literature herein, shows that different carriers can be used in the formulation of pharmaceutically acceptable pharmaceutical compositions and their known methods of preparation. Except to the extent that any conventional carrier medium is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable pharmaceutical composition, Their use is also contemplated by the present invention.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid, Potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive, corn, and soybean oils; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, sweeteners, flavors and fragrances, preservatives and antioxidants.

The compositions of the invention are 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.

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 .

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.

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.

Uses of the compounds and pharmaceutical compositions of the present invention

The compound of the present invention will be applied to, but not limited to, using the effective amount of the compound or pharmaceutical composition of the present invention to administer to the patient a drug for the prevention and/or treatment and/or adjuvant treatment of proliferative diseases of PI3K kinase action in the patient in the application. A proliferative disease in which PI3K kinases act is cancer. Such cancers include solid cancers and forms of blood cancers. Preferably, 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, and CNS cancer , malignant glioma, or myeloproliferative disease, and leukemia and lymphoma.

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.

In addition to their therapeutic benefits in humans, the compounds of the present invention are also useful in the veterinary treatment of pets, introduced breeds and farm animals, including mammals, rodents and the like. Examples of additional animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives.

General Synthesis Process

In order to describe the present invention, examples are listed below. However, it should be understood that the present invention is not limited to these examples, but only provides a method of practicing the present invention.

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I) or (II). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

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.

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 CDC1 ₃ or DMSO-d ₆ as the solvent (in ppm), and 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 G1316BTCC (column temperature is maintained at 30oC), G1329B autosampler and G1315C DAD The detector is used in the analysis, and the ESI source is used in the LC-MS spectrometer.

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 examples described below are convenient for expression, and some raw materials will be described by their abbreviations. These abbreviations and their full names are compared as follows: DCM is CH ₂ Cl ₂ , that is, dichloromethane; CHCl ₃ is chloroform, that is, chloroform; CDC1 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; DME is ethylene glycol dimethyl ether.

The PI3Kα/mTOR inhibitor compound 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 by the present invention. In order to facilitate understanding, the present invention provides the preparation method of the general formula (I) or (II) described in the present invention.

A method for preparing a compound represented by general formula (I) or (II): using 2,4,6-trichloropyrimidine or (A) as a raw material, according to the difference in reactivity between the 2 and 4 positions of pyrimidine, first react with The nucleophilic substitution reaction of the morphine gives the intermediate (B), and then the substitution reaction with the nitrogen-containing heterocyclic ring under basic conditions introduces R ¹ to obtain the intermediate (C). Coupling reaction to obtain intermediate (D), D is condensed with methyl 4-isocyanatobenzoate to obtain intermediate (E), E is hydrolyzed under alkaline conditions to obtain F, and F is condensed with different nitrogen-containing heterocyclic fragments The target compound (G) having the general structure II is obtained. It is also possible to start from 2,4,6-trichloro-1,3,5-triazoxide to obtain the target compound (G) with general structural formula II of X=N

The reaction formula of above-mentioned method is as follows:

In the above preparation steps, the substituents R ¹ and R ³ in formula A to formula G have the definitions described in the present invention.

Detailed ways

The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. Embodiment structure is as shown in table 1:

Example 1: 1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide (PT-1 )

Step 1: Synthesis of 4-(2,6-dichloropyrimidin-4-yl)morpholine

Synthesis method: Add 2,4,6-trichloropyrimidine (10.0g, 54.97mmol) into a 50mL reaction flask, dissolve CH ₂ Cl ₂ (100mL), add DIPEA (57.72mmol, 10.36mL), cool to -5 °C, followed by slow addition of morpholine (54.97 mmol, 4.79 g). The reaction solution was reacted at low temperature for 0.5h, and then warmed up to room temperature for 2h. After the reaction was complete as detected by TLC, H ₂ O (100 mL) was added, the CH ₂ Cl ₂ layer was separated, and the aqueous phase was extracted once with CH ₂ Cl ₂ (100 mL). The organic layers were combined, washed once with saturated NaCl (100 mL), and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE/EtOAc=4/1) to obtain 8.43 g of a white solid, yield: 65.81%; ESI-MS (m/z): 234.2 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ: 6.39 (d, J=4.5Hz, 1H), 3.88-3.49 (m, 8H).

Step 2: Synthesis of 6-chloro-2,4-bismorpholinopyrimidine

Synthetic method: after dissolving 4-(2,6-dichloropyrimidin-4-yl)morpholine (5.0g, 21.46mmol) synthesized in step 1 in THF/EtOH (50mL), add morpholine (1.87g, 21.46mmol), TEA (2.60g, 25.75mmol) and NaI (4.39g, 23.61mmol), then the reaction was heated to 65°C for 12h. After the reaction was complete as detected by TLC, the solvent was evaporated under reduced pressure, dissolved by adding EtOAc (50 mL), washed once with H ₂ O (50 mL) and saturated NaCl (50 mL), and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure to obtain a crude product, which was purified by column chromatography (PE/EtOAc=5/1) to obtain 3.93 g of an intermediate white solid, yield: 64.50%; ESI-MS (m/z): 285.2 [M+H ] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ: 5.86 (d, J = 1.1 Hz, 1H), 3.82-3.64 (m, 12H), 3.59-3.50 (m, 4H).

Step 3: Synthesis of 4-(2,6-bismorpholine pyrimidin-4-yl)aniline

Synthetic method: Dissolve 6-chloro-2,4-bismorpholinopyrimidine (3.50g, 12.32mmol) in DME (50mL), add Pd(PPh ₃ ) ₄ (0.14g, 0.12mmol), 2.0M Na ₂ CO ₃ solution (7.50 mL) and 4-aminophenylboronic acid pinacol ester (4.05 g, 18.48 mmol) were refluxed under N ₂ atmosphere for 24 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CH ₂ Cl ₂ (50 mL), washed twice with water (50 mL×2), once with saturated NaCl (30 mL), 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=1/1 to obtain 3.15 g of the target product, yield: 75.20%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₁₈ H ₂₄ N ₅ O ₂ ] ⁺ : 342.1925, measured value 342.1922.

Step 4: Synthesis of methyl 4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoate

Synthetic method: Dissolve 4-(2,6-bismorpholine pyrimidin-4-yl)aniline (2.0g, 5.86mmol) in CH ₂ Cl ₂ (20mL), add DMAP (36mg, 0.29mmol), then add Methyl 4-isocyanatobenzoate (1.30 g, 7.33 mmol) was stirred at room temperature for 48 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CH ₂ Cl ₂ (30 mL), washed twice with water (30 mL×2), once with saturated NaCl (30 mL), 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: DCM/MeOH=30/1 to obtain 2.49 g of the target product, yield: 82.0%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₂₇ H ₃₁ N ₆ O ₅ ] ⁺ : 519.2350, measured value 519.2351.

Step 5: Synthesis of 4-(3-(4-(2,6-bismorpholinepyrimidin-4-yl)phenyl)ureido)benzoic acid

Synthetic method: Methyl 4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoate (1.0g, 1.98mmol) was dissolved in CH ₃ OH/THF (10mL, 1/1) mixed solvent, add water (2.50mL), LiOH monohydrate solution (0.25g, 6.0mmol), heat to reflux for 12h. The low-boiling point solvent was evaporated under reduced pressure, added to water (10 mL), and the pH was adjusted to 5 with 2N HCl. After filtering, the filter cake was washed with water (10 mL), and dried to obtain 0.93 g of off-white solid, which was directly used in the next reaction, yield: 93.50%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₂₆ H ₂₉ N ₆ O ₅ ] ⁺ : 505.2194, measured value 505.2189.

Step 6: Synthesis of 1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide (PT- 1)

Synthetic method: Dissolve 4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoic acid (200mg, 0.40mmol) in DMF (10mL), add pyrrole in sequence Alkane-2-carboxamide (50mg, 0.44mmol), HBTU (182mg, 0.48mmol), heated to 80°C and stirred for 8h. After the reaction solution was cooled, it was poured into water (20 mL), heated to CH ₂ Cl ₂ (20 mL), stirred for 10 min, and the organic layer was separated. The aqueous layer was extracted once with CH ₂ Cl ₂ (10 mL), and the combined organic layers were washed once with saturated NaCl ( 30 mL), dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was directly separated by column chromatography, eluent: DCM/MeOH=10/1 to obtain 120 mg of the target product, yield: 50.0%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₇ N ₈ O ₅ ] ⁺ : 601.2881, measured value 60.1.2894. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.96 (t, J = 17.5Hz, 2H), 8.08 (d, J = 8.7Hz, 2H), 7.60-7.45 (m, 6H), 7.35 (dd,J=18.4,9.9Hz,1H),6.96(d,J=13.1Hz,1H),6.64(s,1H),4.33(m,1H),3.76-3.61(m,17H),3.48( dd, J = 10.3, 6.1 Hz, 1H), 2.18 (dd, J = 18.7, 7.2 Hz, 1H), 1.94-1.72 (m, 3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 173.5, 168.0, 162.9, 161.8, 161.2, 152.0, 141.5, 131.2, 129.5, 128.0, 127.5, 127.2, 118.1, 117.6, 88.2, 65.9, 65.9, 45.2, , 44.0, 28.5, 25.0.

Example 2: (S)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide (PT-2)

Synthetic method: Change the condensation fragment in step 6 in Example 1 to (S)-pyrrolidine-2-carboxamide, and other steps and operations are similar.

White solid, yield: 62.5%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₂₇ H ₃₁ N ₆ O ₅ ] ⁺ : 601.2881, measured value 601.2885. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.90(t, J=15.5Hz, 2H), 8.03(d, J=8.7Hz, 2H), 7.61-7.42(m, 6H), 7.33 (dd,J=13.6,9.9Hz,1H),6.92(d,J=12.5Hz,1H),6.60(s,1H),4.30-4.15(m,1H),3.76-3.61(m,16H), 3.56 (m, 1H), 3.44 (dd, J = 10.3, 6.1 Hz, 1H), 2.15 (m, 1H), 1.93-1.78 (m, 3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 173.9, 168.2, 163.6, 162.2, 161.2, 152.3, 141.2, 131.5, 129.7, 128.7, 127.8, 127.5, 117.6, 117.2, 88.0, 66.2, 66.0, 507.0, , 44.1, 29.1, 25.2.

Example 3: (R)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide (PT-3)

Synthetic method: Change the condensation fragment in step 6 in Example 1 to (R)-pyrrolidine-2-carboxamide, and other steps and operations are similar.

White solid, yield: 60.2%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₂₇ H ₃₁ N ₆ O ₅ ] ⁺ : 601.2881, measured value 601.2875. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.90-8.85(m, 2H), 7.98(d, J=8.7Hz, 2H), 7.60-7.45(m, 6H), 7.32-7.28( m,1H),6.95(d,J＝12.5Hz,1H),6.63(s,1H),4.25-4.17(m,1H),3.75-3.63(m,16H),3.52-3.48(m,1H) , 3.46 (dd, J = 10.3, 6.1 Hz, 1H), 2.13 (m, 1H), 1.90-1.82 (m, 3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 173.6, 168.4, 163.5, 162.0, 161.3, 152.5, 141.5, 131.6, 129.8, 128.6, 127.4, 127.1, 117.5, 117.0, 87.9, 66.1, 66.2, 55.3, , 44.0, 29.4, 25.0.

Example 4: 1-(4-(3-(4-((2,6-dimorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)piperidine-2-carboxamide (PT- 4)

Synthetic method: Change the condensation fragment in step 6 in Example 1 to piperidine-2-carboxamide, and the other steps and operations are similar.

White solid, yield: 55.6%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₂ H ₃₉ N ₈ O ₅ ] ⁺ : 615.3038, measured value 615.3045. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.93-8.87(m, 2H), 7.86(d, J=7.6Hz, 2H), 7.65-7.53(m, 5H), 7.50(s, 1H),7.30-7.26(m,1H),6.98(d,J＝12.5Hz,1H),6.61(s,1H),4.24-4.19(m,1H),3.74-3.65(m,16H),3.52 -3.48(m,1H),3.45-3.40(m,1H),2.18(m,2H),1.91-1.86(m,2H),1.61-1.34(m,2H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 172.8, 167.9, 163.9, 162.5, 160.8, 153.1, 140.8, 132.0, 129.5, 128.2, 127.5, 126.8, 117.6, 116.7, 88.1, 65.2, 66.2, 50.3, , 44.0, 25.2, 24.0, 21.1.

Example 5: (2S)-1-(4-(3-(4-(2,6-dimorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)-4-hydroxypyrrolidine- 2-Formamide (PT-5)

Synthetic method: Change the condensation fragment in step 6 in Example 1 to (2S)-4-hydroxypyrrolidine-2-carboxamide, and other steps and operations are similar.

Yield: 55.5%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₇ N ₈ O ₆ ] ⁺ : 616.2831, measured value 616.2842. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.91-8.82(m, 2H), 7.93(d, J=7.6Hz, 2H), 7.64-7.51(m, 6H), 7.28-7.22( m,1H),6.97-6.90(m,1H),6.61(s,1H),6.52(s,1H),4.22-4.16(m,1H),3.91(s,1H),3.71-3.62(m, 13H), 3.50-3.42(m, 1H), 3.39-3.32(m, 2H), 2.13(m, 1H), 1.90-1.82(m, 3H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 175.1, 169.3, 164.5, 162.5, 161.6, 151.7, 143.6, 133.1, 128.0, 129.1, 128.2, 126.9, 118.2, 117.6, 87.6, 69.1, 66.3, 63.0, 5 , 49.1, 36.5, 34.1, 29.3.

Example 6: (S)-1-(4-(3-(4-(2-(4-methylpiperazin-1-yl)-6-morpholine pyrimidin-4-yl)phenyl)ureido ) Benzoyl) pyrrolidine-2-carboxamide (PT-6)

Synthetic method: Change the condensed heterocyclic segment in step 2 in Example 1 to 1-methylpiperazine, and other steps and operations are similar to Example 2.

Yield: 58.6%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₂ H ₄₀ N ₉ O ₄ ] ⁺ : 614.3198, measured value 614.3190. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.20-8.96(m, 2H), 8.13(d, J=8.7Hz, 2H), 7.65-7.49(m, 6H), 7.36-7.32( m,1H),6.96(d,J＝12.5Hz,1H),6.58(s,1H),4.30-4.15(m,1H),3.76-3.61(m,16H),3.56(m,1H),3.44 (dd, J=10.3, 6.1 Hz, 1H), 2.63(s, 3H), 2.15(m, 1H), 1.93-1.78(m, 3H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 178.5, 169.3, 165.8, 163.1, 162.7, 150.4, 143.2, 136.6, 130.5, 128.0, 127.5, 127.1, 117.5, 116.8, 89.3, 71.2, 66.5, 65.0, 5 , 52.3, 50.1, 46.7, 29.2, 24.9.

Example 7: (S)-1-(4-(3-(4-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)phenyl ) ureido) benzoyl) pyrrolidine-2-carboxamide (PT-7)

Synthetic method: Change the condensed heterocyclic segment in step 2 of Example 1 to 1-methanesulfonylpiperazine, and other steps and operations are similar to Example 2.

Yield: 62.0%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₂ H ₄₀ N ₉ O ₆ S] ⁺ : 678.2817, measured value 678.2825. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.05-8.95(m, 2H), 8.10(d, J=7.5Hz, 2H), 7.62-7.43(m, 5H), 7.40(s, 1H),7.35-7.30(m,1H),6.90(d,J＝12.5Hz,1H),6.82(s,1H),4.28-4.17(m,1H),3.65-3.57(m,8H),3.51 (m,1H),3.44-3.40(m,1H),3.20-3.16(m,4H),2.83(s,3H),2.63-2.58(m,4H),2.15(m,1H),1.93-1.78 (m,3H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 176.2, 170.4, 166.9, 165.1, 163.6, 155.8, 144.5, 137.6, 131.0, 129.5, 128.7, 126.4, 116.8, 115.4, 89.5, 70.6, 66.4, 696.1, 5 , 53.5, 49.5, 46.7, 40.1, 29.0, 24.6.

Example 8: (2S)-1-(4-(3-(4-(6-morpholine-2-(tetrahydro-2H-[1,4]dioxo[2,3-c]pyrrole-6 (3H)-yl)pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide (PT-8)

Synthetic method: Change the condensed heterocyclic segment in step 2 in Example 1 to hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole (the synthetic method is the same as J.Med.Chem., 2016, 59,7268-7274), other steps and operations are similar to embodiment 2.

Yield: 32.4%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₃ H ₃₉ N ₈ O ₆ ] ⁺ : 643.2987, measured value 643.2975. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.98-8.89(m, 2H), 8.21(d, J=6.5Hz, 2H), 7.68-7.56(m, 5H), 7.43(s, 1H),7.38-7.35(m,1H),6.93(d,J＝12.5Hz,1H),6.83(s,1H),4.30-4.25(m,1H),3.90-3.81(m,6H),3.65 -3.57(m,8H),3.52-3.46(m,4H),3.53(m,1H),3.42-3.35(m,1H),2.63-2.58(m,3H),2.18(m,1H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 175.8, 170.9, 167.2, 163.0, 162.8, 153.9, 143.8, 136.5, 130.9, 129.1, 128.9, 125.8, 115.4, 115.0, 89.9, 78.1, 71.6, 67.2, , 66.5, 59.2, 53.5, 49.5, 46.4, 44.5, 28.6, 25.3.

Example 9: 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)azetidine -2-Carboxamide (PT-9)

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

Synthetic method: Add DIPEA (8.91mL, 49.70mmol), morpholine (4.33g, 49.70mmol), CH ₂ Cl ₂ (100mL) into a 50mL reaction flask, then add 2,4,6-trichloro-1, 3,5-Triazine (10.0g, 54.67mmol), cooled to -5°C, then slowly added the reaction liquid to react at low temperature for 0.5h, then raised the temperature to 0°C for 12h. After the reaction was complete as detected by TLC, H ₂ O (100 mL) was added, the CH ₂ Cl ₂ layer was separated, and the aqueous phase was extracted once with CH ₂ Cl ₂ (100 mL). The organic layers were combined, washed once with saturated NaCl (100 mL), and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE/EtOAc=5/1) to obtain 6.94 g of a white solid, yield: 59.7%; ESI-MS (m/z): 235.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 3.97-3.80 (m, 4H), 3.80-3.65 (m, 4H).

Step 2: Synthesis of 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)bismorpholine

Synthetic method: after dissolving 4-(2,6-dichloropyrimidin-4-yl)morpholine (5.0g, 21.37mmol) synthesized in step 1 in THF/EtOH (50mL), add morpholine (2.22g, 25.46mmol), potassium carbonate (4.42g, 32.06mmol), react at room temperature for 12h. After the reaction was complete as detected by TLC, the solvent was evaporated under reduced pressure, dissolved by adding EtOAc (50 mL), washed once with H ₂ O (50 mL) and saturated NaCl (50 mL), and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE/EtOAc=5/1) to obtain 5.01 g of an intermediate white solid, yield: 82.3%; ESI-MS (m/z): 286.2 [M+H ] ⁺ .

Step 3: Synthesis of 4-(4,6-bismorpholine 1,3,5-triazin-2-yl)aniline

Synthetic method: Dissolve 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)bismorpholine (3.0g, 10.52mmol) in DME (30mL), and add Pd(PPh ₃ ) ₄ (0.12g, 0.10mmol), 2.0M Na ₂ CO ₃ solution (6.40mL) and 4-aminophenylboronic acid pinacol ester (3.46g, 15.78mmol), reflux reaction under N ₂ atmosphere for 24h . The solvent was evaporated under reduced pressure, the residue was dissolved in CH ₂ Cl ₂ (50 mL), washed twice with water (50 mL×2), once with saturated NaCl (30 mL), 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=1/1 to obtain 2.65 g of the target product, yield: 73.50%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₁₇ H ₂₃ N ₆ O ₂ ] ⁺ : 343.1877, measured value 343.1880.

Step 4: Synthesis of methyl 4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoate

Synthetic method: Dissolve 4-(4,6-bismorpholine 1,3,5-triazin-2-yl)aniline (2.0g, 5.84mmol) in CH ₂ Cl ₂ (20mL), add DMAP (36mg , 0.29mmol), followed by the addition of methyl 4-isocyanatobenzoate (1.30g, 7.33mmol), and the reaction was stirred at room temperature for 48h. The solvent was evaporated under reduced pressure, the residue was dissolved in CH ₂ Cl ₂ (30 mL), washed twice with water (30 mL×2), once with saturated NaCl (30 mL), 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: DCM/MeOH=30/1 to obtain 2.29 g of the target product, yield: 75.6%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₂₆ H ₃₀ N ₇ O ₅ ] ⁺ : 520.2303, measured value 520.2309.

Step 5: Synthesis of 4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid

Synthetic method: Methyl 4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoate (1.0 g, 1.93 mmol) was dissolved in CH ₃ OH/THF (10mL, 1/1) mixed solvent, add water (2.50mL), LiOH monohydrate solution (0.25g, 6.0mmol), heat to reflux for 12h. The low-boiling point solvent was evaporated under reduced pressure, added to water (10 mL), and the pH was adjusted to 5 with 2N HCl. After filtration, the filter cake was washed with water (10 mL), and dried to obtain 0.92 g of off-white solid, which was directly used in the next reaction, yield: 95.0%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₂₅ H ₂₈ N ₇ O ₅ ] ⁺ : 506.2146, measured value 506.2150.

Step 6: 1-(4-(3-(4-(4,6-bimorpholin-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)azetidine- Synthesis of 2-formamide

Synthetic method: 4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (200mg, 0.40mmol) dissolved in DMF (10 mL), sequentially added pyrrolidine-2-carboxamide (50 mg, 0.44 mmol), HBTU (182 mg, 0.48 mmol), heated to 80° C. and stirred for 8 h. After the reaction solution was cooled, it was poured into water (20 mL), heated to CH ₂ Cl ₂ (20 mL), stirred for 10 min, and the organic layer was separated. The aqueous layer was extracted once with CH ₂ Cl ₂ (10 mL), and the combined organic layers were washed once with saturated NaCl ( 30 mL), dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was directly separated by column chromatography, eluent: DCM/MeOH=10/1 to obtain 136 mg of the target product, yield: 57.9%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₆ N ₉ O ₅ ] ⁺ : 588.2677, measured value 588.2689. The NMR data is ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 9.10(s,1H), 8.92(s,1H), 8.29(d, J=8.5Hz, 2H), 7.56-7.35(m,7H) ,6.92(s,1H),4.30-4.27(m,1H),3.83(s,8H),3.64(d,J＝4.0Hz,8H),3.60-3.52(m,2H),2.58(m,1H ),2.30(m,1H). ¹³ CNMR (100MHz, DMSO-d ₆ ) δ: 173.8, 169.0, 168.5, 165.1, 151.9, 142.8, 140.9, 130.2, 130.0, 129.6, 129.1, 127.6, 117.3, 67.2, 66.5, 50.1, 46.5, 21.6.

Example 10: (S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl ) pyrrolidine-2-carboxamide (PT-10)

Synthetic method: Change the condensed heterocyclic fragment in step 6 in Example 9 to (S)-pyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 67.0%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₆ N ₉ O ₅ ] ⁺ : 602.2834, measured value 602.2822. NMR data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 9.06(s,1H), 8.96(s,1H), 8.27(d, J=8.7Hz, 2H), 7.60-7.31(m,7H) ,6.93(s,1H),4.32(dd,J=28.8,22.5Hz,1H),3.82(s,8H),3.65(d,J=4.0Hz,8H),2.20-2.12(m,1H), 1.91-1.69(m,3H),1.28(s,1H),1.21(s,2H). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 174.3, 169.4, 168.6, 165.0, 152.5, 143.2, 141.5, 130.5, 130.2, 129.5, 129.1, 128.1, 117.7, 66.5, 60.6, 50.4, 43.7, 294.5, 25 .

Example 11: (R)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl ) pyrrolidine-2-carboxamide (PT-11)

Synthetic method: Change the condensed heterocyclic segment in step 6 in Example 9 to (R)-pyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 50.5%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₆ N ₉ O ₅ ] ⁺ : 602.2834, measured value 602.2829. The NMR data is ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 9.07(s,1H), 8.97(s,1H), 8.28(d, J=8.7Hz, 2H), 7.60-7.32(m,7H) ,6.93(s,1H),4.32(dd,J=28.8,22.5Hz,1H),3.82(s,8H),3.65(d,J=4.0Hz,8H),2.20-2.12(m,1H), 1.91-1.69 (m, 2H), 1.29 (s, 1H), 1.22 (s, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ: 173.8, 169.1, 168.5, 165.2, 152.3, 143.1, 142.2, 130.3, 129.7, 129.3, 129.0, 128.3, 117.1, 66.2, 59.9, 50.3, 43.2, 28.2, 25 .

Example 12: 1-(4-(3-(4-4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)piperidine-2 - Formamide (PT-12)

Synthetic method: Change the condensed heterocyclic segment in step 6 in Example 9 to piperidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 36.7%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₈ N ₉ O ₅ ] ⁺ : 616.2996, measured value 617.2993. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.99(t, J=17.5Hz, 2H), 8.11(d, J=8.7Hz, 2H), 7.63-7.48(m, 6H), 7.38 (dd, J=18.4,9.9Hz,1H),6.99(d,J=13.1Hz,1H),4.36(dd,J=36.1,29.7Hz,1H),3.80-3.65(m,17H),3.52( dd, J = 10.3, 6.1 Hz, 1H), 2.21 (dd, J = 18.7, 7.2 Hz, 1H), 1.97-1.74 (m, 3H), 1.53-1.47 (m, 2H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 174.1, 168.1, 165.9, 163.1, 154.1, 140.6, 140.4, 136.7, 131.5, 128.8, 126.5, 121.4, 119.7, 65.6, 57.3, 47.1, 42.8, 25.6, 25 , 22.3.

Example 13: (S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl ) pyrrolidine-2-carboxamide (PT-13)

Synthetic method: hydrolyze PT-12 under alkaline conditions to obtain the target compound.

Yield: 35.3%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₅ N ₈ O ₆ ] ⁺ : 603.2680, measured value 603.2687. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 12.3(s,1H),8.97(s,1H),8.86(s,1H),7.65-7.34(m,7H),6.95(s, 1H), 4.56(dd, J＝28.8, 22.5Hz, 1H), 3.93(s, 8H), 3.67(d, J＝4.0Hz, 8H), 2.23-2.15(m, 1H), 1.97-1.64(m ,1H), 1.34(s,2H), 1.19(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 175.2, 171.5, 165.9, 163.6, 154.1, 141.1, 140.8, 136.8, 131.6, 128.8, 126.6, 121.3, 119.7, 66.7, 62.4, 46.8, 45.8, 29.4, 2 .

Example 14: (S)-methyl 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzene Formyl)pyrrolidine-2-carboxylic acid (PT-14)

Synthetic method: change the condensed heterocyclic segment in step 6 in Example 9 to (R)-pyrrolidine-2-methyl carboxylate, other steps and operations are similar to

Example 9.

Yield: 43.2%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₇ N ₈ O ₆ ] ⁺ : 617.2836, measured value 617.2834. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.03(s,1H), 8.92(s,1H), 7.58-7.29(m,7H), 6.90(s,1H), 4.27(dd, J=28.8,22.5Hz,1H),3.79(s,8H),3.65(d,J=4.0Hz,8H),3.603(s,3H),2.23-2.14(m,1H),1.93-1.74(m ,1H), 1.26(s,2H), 1.23(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 171.7, 171.5, 165.9, 163.6, 154.1, 141.1, 140.8, 136.8, 131.5, 128.8, 126.6, 121.4, 119.7, 66.7, 61.1, 52.1, 46.8, 45.8, 28 , 24.9.

Example 15: (S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl )-N-methylpyrrolidine-2-carboxamide (PT-15)

Synthetic method: Change the condensed heterocyclic fragment in step 6 in Example 9 to (S)-N-methylpyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 36.2%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₈ N ₉ O ₅ ] ⁺ : 616.2996, measured value 616.2992. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.99(s,1H),8.92(s,1H),8.12(s,1H),7.42-7.25(m,7H),6.87(s, 1H), 4.24(dd, J=28.8, 22.5Hz, 1H), 3.73(s, 8H), 3.57(d, J=4.0Hz, 8H), 3.05(s, 3H), 2.28-2.16(m, 1H ), 1.95-1.64(m,2H), 1.33(s,1H), 1.12(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 173.0, 171.5, 165.9, 163.6, 154.1, 141.1, 140.8, 136.8, 131.5, 128.8, 126.6, 121.4, 119.7, 66.7, 59.9, 46.8, 45.9, 30.5, 2 , 24.9.

Example 16: (S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl )-N,N-Dimethylpyrrolidine-2-carboxamide (PT-16)

Synthetic method: Change the condensed heterocyclic fragment in step 6 in Example 9 to (S)-N,N-dimethylpyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 32.4%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₂ H ₄₀ N ₉ O ₅ ] ⁺ : 630.3152, measured value 630.3158. NMR data are ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.98(s,1H), 8.91(s,1H), 7.41-7.24(m,7H), 6.86(s,1H), 4.23(dd, J=28.8,22.5Hz,1H),3.72(s,8H),3.56(d,J=4.0Hz,8H),3.04(s,6H),2.27-2.15(m,1H),1.93-1.64(m ,2H), 1.35(s,1H), 1.16(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 172.1, 171.5, 165.9, 163.6, 154.7, 141.9, 140.8, 136.8, 131.5, 128.8, 126.2, 121.3, 119.7, 66.7, 60.5, 46.8, 45.8, 36.7, 3 , 24.9.

Example 17: 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4- Hydroxypyrrolidine-2-carboxamide (PT-17)

Synthetic method: Change the condensed heterocyclic segment in step 6 in Example 9 to 3-hydroxypyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 30.7%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₆ N ₉ O ₆ ] ⁺ : 618.2789, measured value 618.2787. NMR data: ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.13(s,1H), 8.94(s,1H), 8.25(d, J=8.7Hz, 2H), 7.58-7.31(m,7H) ,6.87(s,1H),4.28(dd,J=28.8,22.5Hz,1H),3.75(s,8H),3.64(d,J=4.0Hz,8H),3.55(d,J=3.6Hz, 1H), 3.05(s,1H), 2.19-2.12(m,1H), 1.89-1.67(m,1H), 1.23(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 174.7, 170.8, 165.9, 163.1, 154.1, 140.6, 140.4, 136.7, 131.5, 128.8, 126.5, 121.4, 119.7, 69.2, 65.6, 55.7, 48.2, 49.1, 38 .

Example 18: 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4- Oxypyrrolidine-2-carboxamide (PT-18)

Synthetic method: Change the condensed heterocyclic segment in step 6 in Example 9 to 3-oxopyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 32.4%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₄ N ₉ O ₆ ] ⁺ : 616.2632, measured value 616.2637. The NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 8.97(s,1H), 8.65(s,1H), 8.36(d, J=8.7Hz, 2H), 7.43-7.31(m,7H) ,6.69(s,1H),4.25(dd,J=28.8,22.5Hz,1H),3.97(s,8H),3.85(d,J=4.0Hz,8H),3.27-3.10(m,1H), 2.89(s,1H),2.53(m,2H). ¹³ CNMR (125MHz, DMSO-d ₆ ) δ: 165.9, 163.1, 154.1, 140.6, 140.3, 136.7, 131.5, 128.8, 126.5, 121.4, 119.7, 65.6, 57.2, 54.2, 47.1, 43.5, 33.1, 29.3, 25.4

Example 19: 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4- (Methoxyimino)pyrrolidine-2-carboxamide (PT-19)

Synthetic method: Change the condensed heterocyclic fragment in step 6 in Example 9 to 4-methoxyiminopyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 33.6%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₇ N ₁₀ O ₆ ] ⁺ : 645.2898, measured value 645.2891. NMR data: ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.05(s,1H), 8.76(s,1H), 8.54(d, J=8.7Hz, 2H), 7.46-7.38(m,7H) ,6.78(s,1H),4.20(dd,J=28.8,22.5Hz,1H),3.95(s,8H),3.83(d,J=4.0Hz,8H),3.78(s,3H),3.28- 3.13 (m, 1H), 2.84 (s, 1H), 2.64 (m, 2H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 173.9, 172.1, 165.9, 163.1, 161.1, 154.1, 140.6, 140.3, 136.7, 131.5, 128.8, 126.5, 121.6, 119.6, 65.5, 60.3, 57.8, 49.1.7, ,33.1.

Example 20: 4-Amino-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl ) pyrrolidine-2-carboxamide (PT-20)

Synthetic method: Change the condensed heterocyclic fragment in step 6 in Example 9 to 4-aminopyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 33.6%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₇ N ₁₀ O ₅ ] ⁺ : 617.2948, measured value 617.2943. The NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.08(s,1H), 8.97(s,1H), 8.30(d, J=8.7Hz, 2H), 7.65-7.36(m,7H) ,6.98(s,1H),5.11(s,2H),4.35(dd,J=28.8,22.5Hz,1H),3.84(s,8H),3.68(d,J=4.0Hz,8H),2.76( m, 1H), 2.24-2.12(m, 1H), 1.92-1.65(m, 2H), 1.47(s, 1H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 174.7, 170.8, 165.9, 163.1, 154.1, 140.6, 140.4, 136.7, 131.5, 128.8, 126.5, 121.4, 119.7, 65.6, 56.4, 52.3, 49.1, 47.1, 38 .

Example 21: 4-Dimethylamino-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzene Formyl)pyrrolidine-2-carboxamide (PT-21)

Synthetic method: Change the condensed heterocyclic fragment in step 6 in Example 9 to 4-dimethylaminopyrrolidine-2-carboxamide, and other steps and operations are similar to Example 9.

Yield: 34.2%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₂ H ₄₁ N ₁₀ O ₅ ] ⁺ : 645.3261, measured value 645.3266. The NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.03(s,1H), 8.95(s,1H), 8.28(d, J=8.7Hz, 2H), 7.63-7.36(m,7H) ,6.95(s,1H),4.32(dd,J=28.8,22.5Hz,1H),3.82(s,8H),3.66(d,J=4.0Hz,8H),2.79(m,1H),2.26( s,6H), 2.18-2.08(m,1H), 1.88-1.74(m,2H), 1.45(s,1H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 174.7, 170.8, 165.9, 163.6, 154.1, 140.6, 140.3, 136.7, 131.5, 128.8, 126.5, 121.3, 119.7, 65.9, 65.6, 57.4, 47.1, 44.9, 4 , 29.3.

Example 22: (S)-1-(4-(2-(aminomethyl)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4,6-bimorpholine-1,3, 5-Triazin-2-yl)phenyl)urea (PT-22)

Synthetic method: Change the condensed heterocyclic segment in step 6 in Example 9 to 2-aminomethylpyrrolidine, and other steps and operations are similar to Example 9.

Yield: 43.8%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₀ H ₃₈ N ₉ O ₄ ] ⁺ : 588.3047, measured value 588.3042. NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.10(s,1H), 9.03(s,1H), 7.75-7.68(m,7H), 6.86(s,1H), 5.15(d, J＝8.7Hz, 2H), 4.40(dd, J＝28.8, 22.5Hz, 1H), 3.96(s, 8H), 3.64(d, J＝4.0Hz, 8H), 2.96(m, 2H), 2.18- 2.10(m,1H),1.88-1.68(m,2H),1.46(s,1H),1.23(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 171.3, 165.9, 163.6, 154.7, 141.9, 140.8, 136.8, 131.6, 128.8, 126.6, 121.9, 119.7, 66.7, 59.3, 46.8, 45.6, 41.9, 29.8, 25. .

Example 23: (S)-1-(4-(3-(4-(4-(4-methylpiperazin-1-yl)-6-morpholine-1,3,5-triazine-2 -yl)phenyl)urea)benzoyl)pyrrolidine-2-carboxamide (PT-23)

Synthetic method: change the condensed heterocyclic segment in step 2 in Example 10 to methylpiperazine, and other steps and operations are similar to Example 10.

Yield: 40.6%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₉ N ₁₀ O ₄ ] ⁺ : 615.3156, measured value 615.3152. NMR data: ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.08(s,1H), 8.98(s,1H), 8.29(d, J=8.7Hz, 2H), 7.62-7.33(m,7H) ,6.95(s,1H),4.35(dd,J=28.8,22.5Hz,1H),3.87(s,8H),3.69(d,J=4.0Hz,8H),2.26(s,3H),2.18- 2.12(m,1H),1.94-1.69(m,2H),1.37(s,1H),1.27(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 173.9, 171.5, 165.9, 163.7, 154.1, 141.1, 140.8, 136.8, 131.6, 128.9, 126.6, 121.4, 119.7, 66.7, 65.9, 60.1, 54.1, 52.5, 4 , 45.9, 43.7, 30.8, 25.1.

Example 24: (S)-1-(4-(3-(4-(4-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine-1,3,5-tri Oxyzin-2-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide (PT-24)

Synthetic method: Change the condensed heterocyclic segment in step 2 of Example 10 to methanesulfonylpiperazine, and other steps and operations are similar to Example 10.

Yield: 29.6%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₁ H ₃₉ N ₁₀ O ₆ S] ⁺ : 679.2775, measured value 679.2779. The NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.05(s,1H), 8.95(s,1H), 8.24(d, J=8.7Hz, 2H), 7.61-7.30(m,7H) ,6.96(s,1H),4.38(dd,J=28.8,22.5Hz,1H),3.88(s,8H),3.66(d,J=4.0Hz,8H),2.94(s,3H),2.16- 2.08(m,1H),1.96-1.70(m,2H),1.40(s,1H),1.32(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ: 173.9, 171.5, 165.9, 163.6, 154.1, 141.1, 140.8, 136.8, 131.5, 128.8, 126.6, 121.3, 119.7, 66.7, 65.8, 60.0, 54.1, 46.8, 45 , 43.6, 39.5, 30.7, 24.9.

Example 25: (2S)-1-(4-(3-(4-(4-morpholine-6-(tetrahydro-2H-[1,4]dioxo[2,3-c]pyrrole-6 (3H)-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide (PT-25)

Synthetic method: Change the condensed heterocyclic fragment in step 2 in Example 10 to hexahydro-2H-[1,4]dioxa[2,3-c]pyrrole, and other steps and operations are similar to Example 10.

Yield: 37.3%. The high-resolution mass spectrometry data of the product is HRMS (ESI): m/z [M+H] ⁺ calculated value [C ₃₂ H ₃₈ N ₉ O ₆ ] ⁺ : 644.2945, measured value 644.2943. The NMR data is ¹ H NMR (500MHz, DMSO-d ₆ ) δ: 9.06(s,1H), 8.96(s,1H), 8.27(d, J=8.7Hz, 2H), 7.60-7.31(m,7H) ,6.93(s,1H),4.32(dd,J=28.8,22.5Hz,1H),3.82(s,8H),3.66-3.56(m,4H),3.26(m,2H),3.04-2.86(m ,4H), 2.20-2.12(m,1H), 1.91-1.69(m,2H), 1.28(s,1H), 1.21(s,2H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ: 173.9, 171.5, 166.8, 165.4, 154.7, 141.9, 140.3, 136.1, 131.7, 128.8, 126.2, 121.3, 119.7, 75.7, 66.7, 65.8, 60.6, 54.1, 4 , 45.9, 30.8, 24.9.

In vitro PI3Kα Kinase Inhibition Assay:

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.

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.

mTOR activity is measured by Lance Ultra fluorescence assay, the principle is similar to PI3Kα. The detection method is as follows: 50mM HEPES, pH 7.5, 1mM EGTA, 3mM MnCl ₂ , 10mM MgCl ₂ , 2mM DTT, 0.01% Tween-20, 100% DMSO as solvent. mTOR was added to the above buffer and diluted to a final concentration of 2.5nM, and 2.5 μL of the kinase solution was placed in a 384-well plate. At the same time, pretreated substrates ULight-4E-BP1 (Thr37/46, PE) (50 μM) and ATP (10.8 μM) were added to the plate to start the reaction. After reacting at room temperature for 1 hour, 10 μL of pretreated EDTA and Eu- The detection buffer of anti-phospho-4E-BP1 (Thr37/46, PE) antibody was centrifuged and equilibrated for 60 minutes, then the data was collected using Envision, and the absorbance value was measured at a wavelength of 665nm.

The test results are shown in Table 2. From the activity data in the following table, it can be seen that the compounds of the present invention can effectively inhibit PI3Kα and mTOR dual kinase, and have good inhibitory activity to it, that is, most of the compounds have inhibitory activity on PI3Kα and mTOR dual kinase. (IC50) are all at the nanomolar level, and compared with the phase II clinical candidate drug PF-05212384, it is surprisingly found that the compound of the present invention has comparable or even better inhibitory activity, while compared with the compound PI-103, it has obvious advantages , and the selectivity to these two kinases is higher, as in Example 10 and Example 21. Therefore, the compound of the present invention has active and predictable anti-proliferative diseases, especially anti-tumor clinical application value, and has good development prospects.

Table 2 Inhibitory activity of target compounds on PI3Kα and mTOR kinases in vitro

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.

Claims (10)

1. A compound having a structure as shown in formula (I), or a stereoisomer, a geometric isomer, a hydrate, a solvate, or a pharmaceutically acceptable salt of a structure as shown in formula (I) or prodrugs: Wherein, X is selected from N or -CR ^a -; R ¹ , R ² and R ^a are each independently selected from H, C ₁ -C ₄ alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C ₁ -C ₄ alkyl-C(=O )-, C _1-4 alkylsulfonyl, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, or C _4-9 fused Heterobicyclyl C _1-4 alkyl, wherein said C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, and C _4-9 fused heterobicyclic Each C _1-4 alkyl group can be independently selected from one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _1-4 aminoalkyl, C _1-4 hydroxyalkoxy, or C _1-4 Substituents of alkoxy C ₁ -C ₄ alkyl; R ³ is selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclic Base, C _4-9 fused heterobicyclyl C _1-4 alkyl, C _4-9 fused heterobicyclyl C _1-4 alkylamino, C _3-7 heterocyclyl C _1-4 alkyl, C _{3 -7} heterocyclyl C _1-4 alkylamino, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryl C _1-4 alkylamino, C _1-9 hetero Aryl, C _1-9 heteroaryl C _1-4 alkyl, or C _1-9 heteroaryl C _1-4 alkylamino, wherein the C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, C _3-7 hetero Cyclic C _1-4 alkylamino, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _6-10 aryl C _1-4 alkylamino, C _1-9 heteroaryl, C _1-9 heteroaryl C _1-4 alkyl, and C _1-9 heteroaryl C _1-4 alkylamino each independently can be selected from one or more of fluorine, chlorine, bromine, iodine, hydroxyl, amino , Oxo(=O), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, N(R ⁴ R ^4a )-C(=O)-, R ⁴ OC(=O) -, R ⁴ ON =, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkylamino, C _1-4 dialkylamino, C 1-4 aminoalkyl _, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 hydroxyalkoxy Oxygen, or a C _1-4 alkoxy C _1-4 alkyl substituent; Each R ⁴ and R ^4a are independently selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl, C _1-4 alkyl, C _{1-4 9} heteroaryl, C _1-9 heteroaryl C _1-4 alkyl, C _4-7 heterocyclyl, or C _4-7 heterocyclyl C _1-4 alkyl, wherein the C _1-4 alkane C _1-4 haloalkyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, C _1-9 heteroaryl, C _1-9 heteroaryl C _1-4 alkyl , C _4-7 heterocyclyl, and C _4-7 heteroaryl C _1-4 alkyl each independently can be selected from one or more of fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo (= O), C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 hydroxyalkoxy, or C _1-4 alkoxy C Substituents of _1-4 alkyl groups. 2. The compound according to claim 1, wherein the compound shown in formula (I) has a structure shown in formula (II), or its stereoisomer, geometric isomer, hydrate, solvate, or pharmaceutically Acceptable salts or prodrugs: X is selected from N or -CH-; R ¹ is selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl , C _3-7 heterocyclyl, or C _4-9 fused heterobicyclyl, wherein the C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkane The group -C(=O)-, C _1-4 alkylsulfonyl, C _3-7 heterocyclyl, and C _4-9 fused heterobicyclyl can be independently selected from one or more of fluorine, chlorine , bromine, iodine, hydroxyl, amino, cyano, oxo (=O), C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy _, C _1-4 hydroxyalkoxy, C 1-4 alkylamino, C _1-4 aminoalkyl, R ⁴ C(=O)NH-, R ⁴ C(=O)O- , C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, or C _1-4 alkoxy C _1-4 alkyl substituents. 3. The compound according to any one of claims 1-2, wherein R ³ is selected from R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 Heterocyclyl C _1-4 alkyl, C _3-7 heterocyclyl C _1-4 alkylamino, C _6-10 aryl C _1-4 alkylamino, or C _1-9 heteroaryl C _1-4 alkane Amino, wherein said R ⁴ -NH-, C _3-7 heterocyclyl, C _4-9 fused heterobicyclyl, C _3-7 heterocyclyl C _1-4 alkyl, C _3-7 heterocyclyl C _1-4 alkylamino, C _6-10 aryl C _1-4 alkylamino, and C _1-9 heteroaryl C _1-4 alkylamino can be independently selected from one or more of fluorine, chlorine, bromine , iodine, hydroxyl, amino, oxo (=O), R ⁴ C(=O)NH-, R ⁴ C(=O)O-, N(R ⁴ R ^4a )-C(=O)-, R ⁴ OC(=O)-, R ⁴ ON=, C _1-4 alkyl-C(=O)-, C _1-4 alkylsulfonyl, cyano, C _1-4 alkyl, C _1-4 Haloalkyl, C _1-4 alkylamino, C _1-4 dialkylamino, C _1-4 aminoalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, Substituents of C _1-4 hydroxyalkoxy or C _1-4 alkoxy C _1-4 alkyl; Each R ⁴ and R ^4a are independently selected from H, C _1-4 alkyl, or C _1-4 haloalkyl. 4. The compound according to claim 1, wherein ^R represents the following substructural formula: Wherein, A, B, C and D are each independently selected from -CH ₂ -, -O-, -S- or -NR ^b -; R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from From H, halogen, hydroxyl, amino, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _{1-4 4} hydroxyalkoxy, C _1-4 alkyl-C(=O)-, or C _1-4 alkylsulfonyl. 5. The compound according to claim 3, wherein ^R represents the following substructural formula: 6. The compound according to claim 1, wherein, R ³ is selected from C _1-4 alkylamino, C _1-4 haloalkylamino, or C _3-7 heterocyclyl C _1-4 alkyl, or R ³ represents The following substructure: 7. The compound according to claim 1, comprising one of the following structures: (1) 1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide; (2) (S)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide; (3) (R)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide; (4) 1-(4-(3-(4-((2,6-dimorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)piperidine-2-carboxamide; (5) (2S)-1-(4-(3-(4-(2,6-bismorpholine pyrimidin-4-yl)phenyl)ureido)benzoyl)-4-hydroxypyrrolidine-2 - Formamide; (6) (S)-1-(4-(3-(4-(2-(4-methylpiperazin-1-yl)-6-morpholine pyrimidin-4-yl)phenyl)ureido) Benzoyl) pyrrolidine-2-carboxamide; (7) (S)-1-(4-(3-(4-(2-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine pyrimidin-4-yl)phenyl) ureido) benzoyl) pyrrolidine-2-carboxamide; (8) (2S)-1-(4-(3-(4-(6-morpholine-2-(tetrahydro-2H-[1,4]dioxo[2,3-c]pyrrole-6( 3H)-yl)pyrimidin-4-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide; (9) 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)azetidine- 2-formamide; (10)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide; (11)(R)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide; (12) 1-(4-(3-(4-4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)piperidine-2- Formamide; (13)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide; (14) (S)-methyl 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzyl Acyl)pyrrolidine-2-carboxylic acid; (15)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) -N-Methylpyrrolidine-2-carboxamide; (16)(S)-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) -N,N-Dimethylpyrrolidine-2-carboxamide; (17) 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4-hydroxy Pyrrolidine-2-carboxamide; (18) 1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4-oxo Pyrrolidine-2-carboxamide; (19) 1-(4-(3-(4-(4,6-bimorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)-4-( Methoxyimino) pyrrolidine-2-carboxamide; (20)4-Amino-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl) Pyrrolidine-2-carboxamide; (21) 4-Dimethylamino-1-(4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzyl Acyl)pyrrolidine-2-carboxamide; (22)(S)-1-(4-(2-(aminomethyl)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4,6-bismorpholine-1,3,5 - Triazin-2-yl) phenyl) urea; (23)(S)-1-(4-(3-(4-(4-(4-methylpiperazin-1-yl)-6-morpholine-1,3,5-triazine-2- Base) phenyl) urea) benzoyl) pyrrolidine-2-carboxamide; (24)(S)-1-(4-(3-(4-(4-(4-(methylsulfonyl)piperazin-1-yl)-6-morpholine-1,3,5-triazine -2-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide; (25)(2S)-1-(4-(3-(4-(4-morpholine-6-(tetrahydro-2H-[1,4]dioxo[2,3-c]pyrrole-6( 3H)-yl)-1,3,5-triazin-2-yl)phenyl)ureido)benzoyl)pyrrolidine-2-carboxamide; or a stereoisomer, geometric isomer, racemate, solvate, or pharmaceutically acceptable salt or prodrug thereof. 8. A pharmaceutical composition, comprising the compound according to any one of claims 1-7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 9. A drug that uses the compound described in any one of claims 1-7 or the pharmaceutical composition described in claim 8 to prepare for the treatment, prevention and/or treatment and/or adjuvant treatment of PI3Kα/mTOR dual kinase Use in medicines for proliferative diseases. 10. The use according to claim 9, wherein said proliferative disease comprises colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, cervical cancer Carcinoma, cancer of the CNS, malignant glioma, or myeloproliferative disease, leukemia, or lymphoma.