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

PI3K α/mTOR bidifly enzyme inhibitors and its pharmaceutical composition and application Download PDF

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Publication number
CN108191837A
CN108191837A CN201810022227.4A CN201810022227A CN108191837A CN 108191837 A CN108191837 A CN 108191837A CN 201810022227 A CN201810022227 A CN 201810022227A CN 108191837 A CN108191837 A CN 108191837A
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alkyl
phenyl
alkoxy
morpholine
bis
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张吉泉
李述敏
徐晓倩
武婷婷
汤磊
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Guizhou Medical University
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Guizhou Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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

PI3K α/mTOR bidifly enzyme inhibitors and its pharmaceutical composition and application
Invention field
The present invention relates to pharmaceutical technology field, more particularly it relates to a kind of PI3K α/mTOR bidifly enzyme inhibitors And its pharmaceutical composition and application.
Background of invention
Malignant tumour is a kind of disease of serious threat human life and health, and morbidity and mortality are in what is risen year by year Trend, mankind's death rate caused by cancer are only second to cardiovascular and cerebrovascular disease and are at the second place.The essence of canceration is regulating cell There is exception in transductive process in the molecular signal of physiological function, has upset to the normal regulation of cell and unlimited hyperplasia.Cell Generation, development, recurrence and the transfer of signal transduction and tumour etc. are closely related.The cytotoxic drug of traditional treatment tumour is universal There is selectivity it is low, toxic side effect is strong and drug resistance is poor the shortcomings of, this facilitate antitumor drug to targeting small-molecule drug Research direction shifts.The booming of accurate medicine has also further speeded up grinding for targeting small molecule, anti-tumor drug in recent years Hair, only time in the previous year, small point of 6 including just having including Palbociclib, Lenvatinib, Osimertinib etc. Sub- kinase inhibitor is ratified to list by FDA.It can be seen that the small molecule based on key protein kinase in intracellular signal transduction pathway The research and development of inhibitor have become hot fields (the Nat.Rev.Drug Discovery of targeting anti-tumor innovation drug research 2017,16,73-76)。
Phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-rapamycin target protein (mTOR) signal path is One of intracellular three big primary signal pathways play in the synthesis for maintaining cell survival, growth, transfer, apoptosis and albumen Important function.PI3Ks is a kind of lipid kinase, has serine/threonine (Ser/Thr) kinase activity, phosphorylatable substrate 3 hydroxyls, as phosphorylated substrate PI (4,5) P2 generate phosphatidylinositols -3,4,5- triguaiacyl phosphates (PI (3,4,5) P3), after Person can activate the effector in downstream to adjust intracellular a variety of vital movement (Nat.Rev.Drug as important second messenger Discovery 2014,13,140-156).According to the difference of the structure feature of PI3K, phosphorylated substrate and Tissue distribution, can incite somebody to action It is divided into three classes.Wherein, the research of I classes PI3K is the most extensive, and IA is further subdivided into according to the acceptor type of combination And two kinds of hypotypes of IB.IA types PI3K includes tri- kinds of PI3K α, PI3K β, PI3K δ hypotypes, and IB types PI3K contains only mono- Asia of PI3K γ Type.The receptor tyrosine kinases (receptor tyrosine kinases, RTK) of activation are transmitted signal by PI3K To intracellular, activation downstream albumen Akt.After Akt is activated, GS3K β can be inhibited, so as to inhibit the expression of Cyclin D_1 gene, And then cell is caused to expand.MTOR is then by monitoring effective nutritional ingredient, cellular energy and molecular oxygen levels, cell mitogen Signal etc. comes regulating cell growth and proliferation.MTOR exists in the form of two kinds of different composite objects：MTORC1 and mTORC2.PI3K/ The adjusting and control of Akt/mTOR signal path wide participation cell items physiological functions, the abnormal generation with tumour of this access with Development is closely related.
In four kinds of hypotypes of I classes PI3K, PI3K α are associated with the closest with the occurrence and development of tumour.It is the study found that all kinds of About more than 30% occurs PIK3CA mutation (this gene code PI3K α) in solid tumor patient.Wherein, in patient with breast cancer The ratio of PIK3CA gene mutations accounts for 18-40%, and PIK3CA mutant proportions account for more than 50% in patients with lung cancer[4].PI3K β and tool Have in the neoplastic process that carcinogenicity Ras genes and tyrosine kinase lack in PTEN and play a crucial role (Nat.Rev.Drug Discovery.2014,13,140-156.).PI3K γ and δ are mainly expressed on the leukocytes, in lymph There is effect in cell activation, mast cell threshing and leukocyte chemotaxis, thus be immunosupress and the potential target for the treatment of of cancer Point (Curr.Drug Discovery Technol.2014,11,113-126).MTOR is as PI3K-Akt-mTOR signal paths The critical sites in downstream, dysregulation are found in Several Kinds of Malignancy, such as breast cancer, prostate cancer, lung cancer.Therefore, target It can effectively inhibit the generation of tumour, while reduce non-target spot related side effects to PI3K α/mTOR are acted on.
In recent years, the research of the bis- target spot inhibitor of PI3K/mTOR achieves gratifying progress, has dozens of candidate compound In clinical different phase, these molecular structure of compounds are various.Wherein, the bis- target spot inhibitor of aryl morpholine class PI3K/mTOR With preferable development prospect, shown in representative compound constituted above formula.However, so far there has been no drug listing, analysis can It can have the following problems：1) PI3K signaling pathway proteins kinase sub-families are numerous, and the PI3K/mTOR inhibitor reported at present is most Inhibit for non-subtype-selective, this non-specific inhibition can bring non-target spot related side effects.2) into the time of clinical research Selecting drug molecule, there are the drawbacks such as the big, poorly water-soluble of molecular weight mostly, it usually needs drug administration by injection, the compliance of patient are poor. Therefore, the bis- target spot inhibitor of novel PI3K α/mTOR are further researched and developed to be of great significance.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.In the one of document, patent and similar material combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
" stereoisomer " refers to there is identical chemical constitution, but the spatially different change of arrangement mode of atom or group Close object.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image cannot be overlapped property molecule, and " achirality " refer to can be overlapped with its mirror image Molecule.
" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
" diastereoisomer " refer to there are two or multiple chiral centers and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer mixes Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to detach by closing object.
Stereochemical definitions used in the present invention and rule 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 (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, 90% enantiomeric excess, at least at least 95% enantiomeric excess or 99% enantiomer It is excessive.
" solvate " of the present invention refers to the association that one or more solvent molecules are formed with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of included N is formed.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above or a kind of compound included as example special inside embodiment, subclass and the present invention. It should be appreciated that this term can exchange use to " optionally replacing " this term with " substituted or non-substituted ".Term is " optionally Ground ", " optional " or " optional " refer to the then described event or situation can with but may not occur, and the description is including wherein There is a situation where the event or situation and wherein there is a situation where the event or situations, and term " optionally " is whether Before term " substituted ", all represent that institute is replaced to one or more of structure hydrogen atom by specific substituent group.It removes Other non-aspects show that an optional substituent group can be taken there are one substituent group in each commutable position of group Generation.When more than one position can be replaced by one or more substituent groups selected from specific group in given structural formula, that Substituent group can replace in each position identical or differently.The wherein described substituent group can be, but be not limited to H, F, Cl、Br、I、N3、-CN、-OH、-NO2、-NH2, oxo (=O), R4C (=O) NH-, R4C (=O) O-, N (R4R4a)-C (=O)-, R4O-C (=O)-, R4ON=, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Halogenated alkyl, C1-4 Alkylamino, C1-4Dialkylamino, C1-4Aminoalkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy Base or C1-4Alkoxy C1-4Alkyl etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and should all be interpreted broadly, both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.
In each section of this specification, the substituent group that the present invention discloses compound is disclosed according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-4Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl and C4Alkyl.
In each section of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group " represented containing 1-20 carbon atom, saturated straight chain or The univalent hydrocarbyl group of branch, wherein, the substituent group that the alkyl group can be described optionally by one or more present invention Replaced.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains There is 1-12 carbon atom；In other embodiments, alkyl group contains 1-6 carbon atom；In other embodiment party In case, alkyl group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom.In addition In some embodiments, alkyl group contains 1-2 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr ,-CH2CH2CH3), isopropyl (i-Pr, i-propyl ,-CH (CH3)2), normal-butyl (n-Bu, n-butyl ,- CH2CH2CH2CH3), isobutyl group (i-Bu, i-butyl ,-CH2CH(CH3)2), sec-butyl (s-Bu, s-butyl ,-CH (CH3) CH2CH3), tertiary butyl (t-Bu, t-butyl ,-C (CH3)3), n-pentyl (n-pentyl ,-CH2CH2CH2CH2CH3), 2- amyls (- CH(CH3)CH2CH2CH3), 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- fourths Base (- CH (CH3)CH(CH3)2), 3- methyl-1s-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3) CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyls (- CH (CH3)CH (CH3)CH2CH3), 4- methyl -2- amyls (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyls (- C (CH3)(CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- diformazans Base -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " alkyl " and its prefix " alkane ", the saturated carbon chains all comprising straight chain and branch.
Term " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " represent alkyl, and alkenyl or alkoxy base are by one A or multiple halogen atoms are replaced, and such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-20 carbon atom.It is some of real Applying example is, alkoxy base contains 1-10 carbon atom；Other embodiment is that alkoxy base contains 1-8 carbon atom； Other embodiment is that alkoxy base contains 1-6 carbon atom；Other embodiment is that alkoxy base contains 1-4 A carbon atom；Other embodiment is that alkoxy base contains 1-3 carbon atom.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..The alkoxy base can be independently unsubstituted or by one or more institute of the present invention The substituent group of description is replaced.
Term " alkylamino " or " alkylamino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group Separately replaced by one or two alkyl group.Some of embodiments are that alkyl amino is one or two C1-6 Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms；Other embodiment is that alkyl amino is one or two A C1-3Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Suitable alkylamino group can be monoalkyl Amino or dialkyl amido, such example include, but is not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Term " aminoalkyl " refers to that alkyl group is replaced by one or more amino groups, and wherein alkyl has the present invention The definition, the non-limiting examples of aminoalkyl include, but are not limited to amino methyl, amino-ethyl, aminopropyl etc..
Term " heterocycle ", " heterocycle " or " heterocycle " are used interchangeably here, all referring to monocyclic, bicyclic or three ring bodies It is that one or more atoms are substituted individually optionally by hetero atom in middle ring, and ring can be fully saturated or comprising one A or multiple degrees of unsaturation, but definitely not aromatic, there are one or multiple tie points (can be carbon atom or nitrogen-atoms) even It is connected to other molecules up.One or more ring hydrogen atoms can be independently unsubstituted or by one or more present invention Described substituent group is replaced.Some of embodiments are " heterocycles ", and " heterocycle " or " heterocycle " group is 3-7 original It is molecular that monocyclic (2-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S is optionally one or more in this S or P Oxygen atom replaces to obtain as SO, SO2, PO, PO2Group, when the ring is the molecular ring of three originals, wherein only having One hetero atom), other embodiment is, 3-8 former molecular monocyclic (2-7 carbon atom and selected from N, O, P, the 1- of S 3 hetero atoms are optionally replaced to obtain picture SO, SO by one or more oxygen atoms in this S or P2, PO, PO2Group, work as institute When the ring stated is three originals molecular ring, only one of which hetero atom) or 7-10 former molecular bicyclic (4-9 is a Carbon atom and selected from N, O, P, the 1-3 hetero atom of S optionally replace to obtain picture in this S or P by one or more oxygen atoms SO, SO2, PO, PO2Group).
Heterocycle can be carbon-based or hetero atom base.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrochysene furan It mutters base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulphur For morpholinyl , thioxane bases, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, Glycidyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2- Pyrrolinyl, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxy amyl, Pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetra- Hydrogen isoquinoline base.The example of heterocyclic group further includes, the hybar X base and 1,1- that two carbon atoms are replaced by oxygen (=O) on ring Dioxidothiomorpholinyl.The heterocyclyl groups can be independently unsubstituted or described in the invention be taken by one or more Replaced for base.
Term " heterocyclylalkyl group " represents that alkyl group can be replaced by one or more heterocyclyl groups, wherein alkyl There is meaning as described in the present invention with heterocyclyl groups.Some of embodiments are that heterocycloalkylene group refers to " relatively low The heterocycloalkylene of grade " group, i.e. heterocyclyl groups are connected to C1-6Alkyl group on.Other embodiment is heterocycle Base group is connected to C1-4Alkyl group on.Such example includes, but is not limited to, 2- pyrrolidines ethyls etc..It is described miscellaneous Ring group alkylidene group can be independently unsubstituted or be replaced by one or more substituent groups described in the invention.
Term " hetero atom " refers to O, S, N, P and Si, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl replaced as N-).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " H " represents single hydrogen atom.Such atomic group can be connect with other groups, for example with oxygen atom phase Even, hydroxyl group is formed.
Term " aryl " represents monocyclic, double containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom The carbocyclic ring system of ring and tricyclic, wherein, at least one member ring systems are aromatic, and wherein each member ring systems includes 3-7 original Molecular ring, and there are one or multiple tie points be connected with the rest part of molecule.Term " aryl " can be with term " fragrance Ring ", which exchanges, to be used.The example of aryl group can include phenyl, naphthalene and anthryl.The aryl group can individually optionally Replaced by one or more substituent groups described in the invention.
Term " aryl alkyl " represents that alkyl group can be replaced by one or more aryl groups, wherein alkyl and virtue Base group has meaning as described in the present invention, and some of embodiments are that arylalkylene groups refer to the " aryl of lower level Alkylidene " group, i.e. aryl group are connected to C1-6Alkyl group on；Other embodiment is that arylalkylene groups are Refer to containing C1-4Alkyl " benzene alkylene "；Other embodiment is that arylalkylene groups refer to that aryl group is connected to C1-3 Alkyl group on；Other embodiment is that arylalkylene groups refer to that aryl group is connected to C1-2Alkyl group On.Wherein specific example includes benzyl, diphenyl methyl, phenethyl etc..The arylalkylene groups can independently not It is substituted or is replaced by one or more substituent groups described in the invention.
Term " heteroaryl " is represented containing 5-14 annular atom or 5-12 annular atom or 5-10 annular atom or 5-6 Monocyclic, the bicyclic and three-ring system of a annular atom, wherein at least one member ring systems are aromatic, and at least one member ring systems packets Containing one or more hetero atoms, wherein each member ring systems include 5-7 former molecular ring, and there are one or multiple tie points It is connected with molecule rest part.Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".Institute Heteroaryl groups are stated optionally by one or more substituent groups described in the invention to be replaced.In some embodiments, 5- 10 molecular heteroaryls of original include 1,2,3 or 4 hetero atom for being independently selected from O, S and N.In other embodiments, 5-6 former molecular heteroaryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.
The Monocyclic examples of heteroaryl groups include, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazoles Base, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- Evil Oxazolyl, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), three Oxazolyl (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2, 3- oxadiazolyls, 1,3,4- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2,3- sulphur For di azoly, 1,2,4- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, pyrazinyl, 1,3,5- triazines Base；Also include following bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, indoles Base (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolines Quinoline base, 3- isoquinolyls or 4- isoquinolyls), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1, 5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridyl group, etc..
Term " heteroaryl alkyl " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkyl There is meaning as described in the present invention with heteroaryl groups, some of embodiments are that heteroarylalkylenyl group refers to " relatively low The heteroarylalkylenyl of grade " group, i.e. heteroaryl groups are connected to C1-6Alkyl group on；Other embodiment is heteroaryl Base group is connected to C1-4Alkyl group on；Other embodiment is that heteroaryl groups are connected to C1-3Alkyl group on； Other embodiment is that heteroaryl groups are connected to C1-2Alkyl group on.Wherein specific example includes 2- picolyls, 3- furylethyls etc..The heteroarylalkylenyl group can be independently unsubstituted or be retouched by one or more present invention The substituent group stated is replaced.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base ", " condensed ring radical " represent saturated or unsaturated fused ring system Or bridged-ring system, be related to the bicyclic or bridged-ring system of non-aromatic, as shown in formula (a), i.e. ring A1 and ring A2 altogether there are one key or One alkane chain, wherein j are 0,1,2,3 or 4.Such system can include independent or conjugation undersaturated condition, but its core Core structure does not include aromatic rings or heteroaromatic (but aromatic series can be as substituent group thereon).Each in condensed-bicyclic Ring is either carbocyclic ring or is miscellaneous alicyclic, and such example includes, but is not limited to, hexahydro-furans simultaneously [3,2-b] furans, 2,3,3a, 4,7,7a- hexahydro -1H- indenes, 7- azabicyclos [2.3.0] heptane, condensed-bicyclic [3.3.0] octane, condensed-bicyclic [3.1.0] hexane, bicyclic [2.2.1] heptane, 2- azabicyclos [2.2.1] heptane, 1,2,3,4,4a, 5,8,8a- octahydro naphthalenes, 2- Oxa- -5- azabicyclos [2.2.1] heptane, hexahydro -2H- [Isosorbide-5-Nitrae] dioxane simultaneously [2,3-c] pyrroles, these are included in thick It closes within bicyclic or bridged ring system.And the condensed-bicyclic base can be substituted or unsubstituted, and wherein substituent group can be with It is, but is not limited to, H, F, Cl, Br, I, N3、-CN、-OH、-NO2、-NH2, oxo (=O), R4C (=O) NH-, R4C (=O) O-、N(R4R4a)-C (=O)-, R4O-C (=O)-, R4ON=, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkane Base, C1-4Halogenated alkyl, C1-4Alkylamino, C1-4Dialkylamino, C1-4Aminoalkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4It is halogenated Alkoxy, C1-4Hydroxy alkoxy base or C1-4Alkoxy C1-4Alkyl etc..
Term " condensing miscellaneous bicyclic group " represents saturated or unsaturated fused ring system or bridged-ring system, is related to non-aromatic Bicyclic system or bridged-ring system.Such system can include independent or conjugation undersaturated condition, but its nuclear structure is not Include aromatic rings or heteroaromatic (but aromatic series can be as substituent group thereon).And at least one member ring systems include one or Multiple hetero atoms, wherein each member ring systems include 3-7 round ringss, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 of S is a Hetero atom optionally replaces to obtain such as SO, SO in this S or P by one or more oxygen atoms2, PO, PO2Group, in this way Example include, but is not limited to hexahydro-furans simultaneously [3,2-b] furans, 7- azabicyclos [2.3.0] heptane, 2- azabicyclos [2.2.1] heptane, 2- oxa- -5- azabicyclos [2.2.1] heptane, hexahydro -2H- [Isosorbide-5-Nitrae] dioxane simultaneously [2,3-c] pyrroles Deng.And the condensed miscellaneous bicyclic group can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, H, F, Cl、Br、I、N3、-CN、-OH、-NO2、-NH2, oxo (=O), R4C (=O) NH-, R4C (=O) O-, N (R4R4a)-C (=O)-, R4O-C (=O)-, R4ON=, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Halogenated alkyl, C1-4 Alkylamino, C1-4Dialkylamino, C1-4Aminoalkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy Base or C1-4Alkoxy C1-4Alkyl etc..
Used term is " undersaturated " in the present invention represents in group containing one or more degrees of unsaturation.
Term " therapeutically effective amount " is referred to when giving the mammal for needing such treatment, it is sufficient to effectively be treated The amount of general formula compound.Therapeutically effective amount will be dependent on the age of the given activity of healing potion used, patient, physiology shape Condition, the presence of Other diseases state and nutrition condition and change.In addition, the other medicines that patient may just receive are treated shadow The therapeutically effective amount of the healing potion to be given of sound determines.
Term " treatment " means any treatment for disease in mammal body, including：(i) disease is prevented, that is, is made Clinical symptoms into disease do not develop；(ii) inhibit disease, that is, prevent the development of clinical symptoms；And/or (iii) mitigates disease, That is, cause the recession of clinical symptoms.
As described herein, term " pharmaceutically acceptable carrier " includes any solvent, decentralized medium, coating agents, Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizing agent, bonding Agent, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination object, these carriers are all affiliated technologies Known (such as Remington's Pharmaceutical Sciences, the 18th Ed.Mack of field technology personnel Printing Company, described in 1990, p1289-1329).In addition to any conventional carrier situation incompatible with active constituent Outside, cover its purposes in treatment or pharmaceutical composition.
The description of the compound of the present invention
The present invention is intended to provide a kind of new PI3K α/mTOR bidifly enzyme inhibitor, its pharmaceutical composition and its application, with Just selection is more effectively used for the treatment of proliferative diseases, especially cancer with the higher compound of selectivity.
To achieve these goals, according to an aspect of the invention, there is provided a kind of bis- kinase inhibitions of PI3K α/mTOR Agent, including having compound shown in logical formula (I) or its stereoisomer, geometric isomer, hydrate, solvate or pharmacy Upper acceptable salt or prodrug：
Wherein, X is selected from N or-CRa-；
R1、R2And RaIt is each independently selected from H, C1-C4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-C4Alkyl-C (= O)-、C1-4Alkyl sulphonyl, C3-7Heterocycle, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl or C4-9It is condensed miscellaneous bicyclic Base C1-4Alkyl, wherein described C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Alkyl-C (=O)-, C1-4Alkyl sulfonyl Base, C3-7Heterocycle, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl and C4-9Condense miscellaneous bicyclic group C1-4Alkyl is respectively only It on the spot can be by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), R4C (=O) NH-, R4C (=O) O-, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Hydroxyalkyl, C1-4Alcoxyl Base, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4Aminoalkyl, C1-4Hydroxy alkoxy base or C1-4Alkoxy C1-C4Alkyl takes Replaced for base；
R3Selected from H, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, R4-NH-、C3-7Heterocycle, C4-9It is condensed miscellaneous bicyclic Base, C4-9Condense miscellaneous bicyclic group C1-4Alkyl, C4-9Condense miscellaneous bicyclic group C1-4Alkylamino, C3-7Heterocycle C1-4Alkyl, C3-7Heterocycle C1-4Alkylamino, C6-10Aryl, C6-10Aryl C1-4Alkyl, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl, C1-9Heteroaryl C1-4Alkane Base or C1-9Heteroaryl C1-4Alkylamino, wherein the C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, R4-NH-、C3-7Heterocycle Base, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl, C3-7Heterocycle C1-4Alkylamino, C6-10Aryl, C6-10Aryl C1-4Alkane Base, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl, C1-9Heteroaryl C1-4Alkyl and C1-9Heteroaryl C1-4Alkylamino is respectively independent It ground can be by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo (=O), R4C (=O) NH-, R4C (=O) O-, N (R4R4a)-C (=O)-, R4O-C (=O)-, R4ON=, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkylamino, C1-4Dialkylamino, C1-4Aminoalkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Haloalkoxy Base, C1-4Hydroxy alkoxy base or C1-4Alkoxy C1-4The substituent group of alkyl is replaced；
Each R4And R4aSeparately it is selected from H, C1-4Alkyl, C1-4Halogenated alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl, C1-9Heteroaryl, C1-9Heteroaryl C1-4Alkyl, C4-7Heterocycle or C4-7Heterocycle C1-4Alkyl, wherein the C1-4Alkyl, C1-4Halogen Substituted alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl, C1-9Heteroaryl, C1-9Heteroaryl C1-4Alkyl, C4-7Heterocycle and C4-7Heteroaryl Base C1-4Alkyl each independently can be by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo (=O), C1-4Alkane Base-C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkylamino, C1-4Aminoalkyl, C1-4Hydroxyl Alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy base or C1-4Alkoxy C1-4The substituent group of alkyl is replaced.
Some embodiments wherein, compound shown in formula (I) have structure or its stereoisomer shown in formula (II), Geometric isomer, hydrate, solvate or pharmaceutically acceptable salt or prodrug：
X is selected from N or-CH-；
R1Selected from H, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C3-7Heterocycle or C4-9Miscellaneous bicyclic group is condensed, wherein the C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C3-7Heterocycle and C4-9Condensing miscellaneous bicyclic group can be selected each independently by one or more From fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), C1-4Alkyl, C1-4Halogenated alkyl, C1-4Hydroxyalkyl, C1-4Alcoxyl Base, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy base, C1-4Alkylamino, C1-4Aminoalkyl, R4C (=O) NH-, R4C (=O) O-, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl or C1-4Alkoxy C1-4The substituent group of alkyl is replaced.
In other embodiments, R3Selected from R4-NH-、C3-7Heterocycle, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkane Base, C3-7Heterocycle C1-4Alkylamino, C6-10Aryl C1-4Alkylamino or C1-9Heteroaryl C1-4Alkylamino, wherein the R4-NH-、 C3-7Heterocycle, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl, C3-7Heterocycle C1-4Alkylamino, C6-10Aryl C1-4Alkane ammonia Base and C1-9Heteroaryl C1-4Alkylamino each independently can be by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxygen Generation (=O), R4C (=O) NH-, R4C (=O) O-, N (R4R4a)-C (=O)-, R4O-C (=O)-, R4ON=, C1-4Alkyl-C (= O)-、C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkylamino, C1-4Dialkylamino, C1-4Aminoalkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy base or C1-4Alkoxy C1-4The substituent group institute of alkyl Substitution；
Each R4And R4aSeparately it is selected from H, C1-4Alkyl or C1-4Halogenated alkyl.
In other embodiments, R1Represent following subformula：
Wherein, A, B, C and D are each independently selected from-CH2,-O- ,-S- or-NRb-；R5、R6、R7、R8And R9It is respectively independent Ground is selected from H, halogen, hydroxyl, amino, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy base, C1-4Alkyl-C (=O)-or C1-4Alkyl sulphonyl.
In other embodiments, R1Represent following subformula：
In other embodiments, R3Selected from C1-4Alkylamino, C1-4Halogenated alkylamino or C3-7Heterocycle C1-4Alkyl or R3 Represent following subformula：
In other embodiments, compound of the present invention includes the structure of one of：
(1) 1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- formyls Amine；
(2) (S) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- first Amide；
(3) (R) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- first Amide；
(4) 1- (4- (3- (4- ((the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) piperidines -2- formamides；
(5) (2S) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) -4- hydroxyl pyrroles Cough up alkane -2- formamides；
(6) (S) -1- (4- (3- (4- (2- (4- methylpiperazine-1-yls) -6- morpholines pyrimidine-4-yl) phenyl) urea groups) benzene first Acyl group) pyrrolidines -2- formamides；
(7) (S) -1- (4- (3- (4- (2- (4- (mesyl) piperazine -1- bases) -6- morpholines pyrimidine-4-yl) phenyl) ureas Base) benzoyl) pyrrolidines -2- formamides；
(8) (2S) -1- (4- (3- (4- (6- morpholine -2s-(tetrahydrochysene -2H- [1,4] dioxy [2,3-c] pyrroles -6 (3H)-yls) Pyrimidine-4-yl) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides；
(9) 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) azetidine - 2- formamides；
(10) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrrole Cough up alkane -2- formamides；
(11) (R) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrrole Cough up alkane -2- formamides；
(12) 1- (4- (3- (the bis- morpholine -1,3,5- triazines -2- bases of 4-4,6-) phenyl) urea groups) benzoyl) piperidines -2- Formamide；
(13) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrrole Cough up alkane -2- formamides；
(14) (S)-methyl 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyls Base) pyrrolidines -2- formic acid；
(15) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl)-N- Methylpyrrolidin- 2- formamides；
(16) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl)-N, N- dimethyl pyrrolidine -2- formamides；
(17) 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) -4- hydroxyls Pyrrolidines -2- formamides；
(18) 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) -4- oxygen pyrroles Cough up alkane -2- formamides；
(19) 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) -4- (first Oxygen imido grpup) pyrrolidines -2- formamides；
(20) 4- amino -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) Pyrrolidines -2- formamides；
(21) 4- dimethylaminos -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzene first Acyl group) pyrrolidines -2- formamides；
(22) (S) -1- (4- (2- (aminomethyl) pyrrolidines -1- carbonyls) phenyl) -3- (4- (bis- morpholine -1,3,5- three of 4,6- Piperazine -2- bases) phenyl) urea；
(23) (S) -1- (4- (3- (4- (4- (4- methylpiperazine-1-yls) -6- morpholine -1,3,5- triazine -2- bases) phenyl) Urea) benzoyl) pyrrolidines -2- formamides；
(24) (S) -1- (4- (3- (4- (4- (4- (mesyl) piperazine -1- bases) -6- morpholine -1,3,5- triazine -2- bases) Phenyl) urea groups) benzoyl) pyrrolidines -2- formamides；
(25) (2S) -1- (4- (3- (4- (4- morpholines -6- (tetrahydrochysene -2H- [1,4] dioxy [2,3-c] pyrroles -6 (3H) - Base) -1,3,5- triazine -2- bases) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides；
Or its stereoisomer, geometric isomer, raceme, solvate or pharmaceutically acceptable salt or prodrug.
On the other hand, the present invention provides a kind of pharmaceutical composition, comprising compound of the present invention and pharmaceutically Acceptable carrier, excipient, diluent, adjuvant, medium or combination.
On the other hand, compound of the present invention or pharmaceutical composition of the present invention are used the present invention provides a kind of To prepare in the proliferative diseases of Prevention and/or treatment and/or auxiliary treatment PI3K α/mTOR bidifly enzyme effects Purposes in drug.
Some embodiments wherein, purposes of the present invention, wherein the proliferative diseases include colorectal cancer, stomach Cancer, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, carcinoma of urinary bladder, kidney, brain tumor, neck cancer, the cancer of CNS, Glioblastoma or myeloproliferative disease, leukaemia or lymph cancer.
On the other hand, the present invention provides a kind of PI3K α/mTOR bidifly enzyme inhibitor of the present invention or institutes of the present invention The pharmaceutical composition stated inhibits the application of cancer cell growth in vitro.
It applies the technical scheme of the present invention, PI3K α/mTOR bidifly enzyme inhibitor provided by the present invention and its medicine group Object is closed to can be used in inhibiting PI3K α/mTOR bidifly enzymes and the proliferative diseases of PI3K α/mTOR bidifly enzyme effects, Neng Gouwei The treatment of the proliferative diseases of PI3K α/mTOR bidifly enzyme effects provides validity and the better inhibitor of selectivity.
PI3K α/mTOR bidifly enzyme inhibitors provided by the present invention can be used in inhibit PI3K α/mTOR bidifly enzymes and The proliferative diseases of PI3K α/mTOR bidifly enzyme effects can be the proliferative diseases of PI3K/Akt/mTOR bidifly enzyme effects Treatment provides validity and the better inhibitor of selectivity.
PI3K α/mTOR bidifly enzyme inhibitor of the present invention can include pyrimidine compound pharmaceutically acceptable salt.Pharmacy Upper acceptable salt refers to the basic group in parent compound to be converted into the form of salt.Pharmaceutically acceptable salt includes, But it is not limited only to, the inorganic or organic acid salt of basic group such as amine (ammonia) base.Pharmaceutically acceptable salt of the present invention can be with It is synthesized by parent compound, i.e., the basic group in parent compound is reacted with the acid of 1-4 equivalents in a solvent system.It closes Suitable salt is enumerated in Remington ' s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, 66,2 (1977) In.
Compound basic group can be with acid into salt in the present invention, and the example of these acid into salt includes：With inorganic acid, especially hydrogen Hydracid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid formation salt；Lower alkanesulfonic acid, such as first Sulfonic acid, the salt that trifluoromethanesulfonic acid is formed；With aryl sulfonic acid, the salt formed such as benzene sulfonic acid or p-methyl benzenesulfonic acid；With organic acid, such as second The salt that acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid are formed；With amino acid, such as asparagus fern ammonia The salt that acid or glutamic acid are formed.
The compound of the present invention and pharmaceutically acceptable salt further include the form of solvate or hydrate.It is general next It says, the form of solvate or hydrate is equal with non-solvated or non-hydrated form, and covers in the scope of the present invention It is interior.Certain compounds in the present invention there may be polycrystal or unbodied form.Generally speaking, all physical forms With equal purposes, and cover within the scope of the invention.
In addition, the present invention provides the preparation of compound shown in formula (I) or (II), the method for separation and purifying.Unless its It is all same that its aspect shows that the structural formula of pyrimidine compound in the PI3K enzyme inhibitors of the present invention described in the invention includes Divide isomeric form (such as enantiomerism, diastereo-isomerism and geometrical isomerism (or conformational isomerism))：Such as contain asymmetric center R, S configurations, (Z) of double bond, (E) isomers and (Z), the rotamer of (E).Therefore, the compound of the present invention is single vertical The mixture of body chemical isomer or its enantiomter, diastereoisomer or geometric isomer (or rotamer) is all Belong to the scope of the present invention.
Unless other aspects show all tautomeric forms of pyrimidine compound in PI3K kinase inhibitors of the present invention all It is included within the scope of the present invention.In addition, unless other aspects show that the structural formula of compound described in the invention includes The enriched isotope of one or more different atoms.
The composite preparation of the compound of the present invention
The pharmaceutical composition of the present invention includes the change of structure shown in structural compounds shown in formula (I) or (II) or formula 1~38 Close object, the present invention listed by compound or Examples 1 to 25 compound or its stereoisomer, geometric isomer, mutually Tautomeric, racemic modification, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt are preceding Medicine and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or combination.
The compound of the present invention there are free form or it is suitable, as pharmaceutically acceptable derivates.According to this hair Bright, pharmaceutically acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt or energy of esters Other any adducts or derivative being directly or indirectly administered according to the needs of patient, other aspects of the present invention are described Compound, metabolite or his residue.
As described in the invention, the pharmaceutically acceptable pharmaceutical composition of the present invention further includes pharmaceutically acceptable Carrier, diluent, adjuvant or excipient, these as the present invention applied, including any solvent, diluent or other liquid Body excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or profit Lubrication prescription etc. is suitable for specific target formulation.As documents below is described：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, comprehensive document herein Content, show that different carriers can be applied to preparation and their well known preparation sides of pharmaceutically acceptable pharmaceutical composition Method.In addition to any conventional carrier medium range incompatible with the compound of the present invention, for example, it is generated any undesirable Biological effect or the interaction generated in harmful manner with any other component of pharmaceutically acceptable pharmaceutical composition, Their purposes is also the range that the present invention is considered.
It can be included, but is not limited to as the substance of pharmaceutically acceptable carrier, ion-exchanger, aluminium, aluminum stearate, ovum Phosphatide, such as haemocyanin, human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturation vegetable butter The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymerization Body, lanolin, sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose and its derivative Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Fat and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Object, such as propylene glycol and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethyl alcohol, phosphate buffer solution and other are nontoxic Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colorant, releasing agent, coating agents, sweetener, flavoring agent and perfume (or spice) Material, preservative and antioxidant.
This composition of the present invention is preferably formulated as unit dosage forms.Term " unit dosage forms " refer to being suitable for use as to The physical discrete unit of human experimenter and the single dose of other mammals is given, per unit, which contains, to be calculated to generate The scheduled amount and relevant suitable pharmaceutical excipient (such as tablet, capsule, peace of the required effective active material for the treatment of Small jar).Pyrimidine compound is effective in extensive dosage range and usually gives active drug in PI3K kinase inhibitors Amount.Preferably for oral medication, pyrimidine compound in PI3K kinase inhibitors of each dosage unit comprising 10mg to 2g, More preferably 10 to 700mg, and for parenteral administration, pyrimidine chemical combination in preferably 10 to 700mg PI3K kinase inhibitors Object, more preferably from about 50 to 200mg.It should be appreciated, however, that the amount of pyrimidine compound will in the PI3K kinase inhibitors actually given Determined by doctor according to related situation, including illness to be treated, the administration route of selection, the practical compound given with And its relative activity, age, weight and the reaction, the seriousness of patient symptom etc. of each patient.
In order to prepare solid composite such as tablet, main active component is mixed with drug excipient (or carrier) To form solid preformulation composition, it includes the homogeneous mixtures of the compound of the present invention.When these preformulation compositions of title When being uniform, it refers to that active component is dispersed in entire composition, so that composition can be easily thin It is divided into identical effective unit dosage forms such as tablet, pill and capsule.
The tablet or pill of the present invention can be applied or otherwise have extension effect by compound to provide one kind The dosage form of advantage protects tablet or pill from the effect of acid condition in stomach.For example, tablet or pill can include interior dose Amount and external dose ingredient, the latter have the form of the crust on the former.Two kinds of ingredients can be separated with enteric layer, wherein Enteric layer is used for preventing ingredient in disintegration and permission under one's belt completely to enter duodenum or be delayed by release.A variety of materials It can be used for such enteric layer or coating, above-mentioned material includes many polymer acids and polymer acid and such material such as The mixture of shellac, hexadecanol and cellulose acetate.
For inhalation or insufflation composition be included in pharmaceutically acceptable aqueous solvent or organic solvent or its Solution and suspension and powder in mixture.Liquid or solid composition can include suitable medicine as described above Use excipient.Preferably, these compositions are given by oral or nasal respiratory route to obtain locally or systemically effect.It can lead to Cross the composition being atomized in preferred pharmaceutically acceptable solvent using inert gas.It can directly be sucked from atomising device Atomized soln or atomising device can be connected to mask account shape object or intermittent positive pressure breathing machine.It can be by delivering in a suitable manner The device of dosage form, preferably oral or nose approach, gives solution, suspension or powder composite.
The purposes of the compounds of this invention and pharmaceutical composition
The compound of the present invention will be applied to, but be not limited to, and use the effective of the compound of the present invention or pharmaceutical composition Amount administers to a patient the medicine for the proliferative diseases for coming Prevention and/or treatment and/or auxiliary treatment patient's PI3K zymogenesis Application in object.Wherein the proliferative diseases of PI3K zymogenesis are cancer.Such cancer includes solid cancer and blood borne cancer The form of disease.Preferably, the proliferative diseases of the PI3K zymogenesis be colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, Prostate cancer, cancer of pancreas, thyroid cancer, carcinoma of urinary bladder, kidney, brain tumor, neck cancer, the cancer of CNS, glioblastoma or marrow increase Sick and leukaemia and lymph cancer.
The present invention also provides a kind of above-mentioned P13K kinase inhibitors or aforementioned pharmaceutical compositions to inhibit cancer cell in vitro The application of growth.
The compound of the present invention to human treatment in addition to beneficial to other than, applying also for veterinary treatment pet, introduced variety Animal and farm animal, including mammal, rodent etc..The example of other animal include horse, dog and Cat.Here, the compound of the present invention includes its pharmaceutically acceptable derivates.
General building-up process
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only The method that the practice present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or (II).Following reaction scheme and embodiment are for further citing Illustrate present disclosure.
The professional of fields will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention Within enclosing.It for example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as appropriate protection interference group, by using other known reagent in addition to described in the invention Or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
Unless other aspects show that all temperature are set to degree Celsius in the embodiments described below.Reagent is bought in quotient Product supplier such as Alfa Aesar Chemical Company, lark prestige Science and Technology Ltd., Aladdin reagent Co., Ltd, Beijing coupling Science and Technology Ltd. etc., all without by not being further purified during use, unless other aspects show.General reagent From Shantou Xi Long chemical plant, Guangzhou Chemical Reagent Factory, the purchases such as Tianjin Zhi Yuan chemical reagent Co., Ltd and Haiyang Chemical Plant, Qingdao It can buy.
Chromatographic column uses silicagel column in the embodiments described below, and silica gel (200-300 mesh) is purchased from Qingdao Haiyang chemical industry Factory.NMR spectrum is with CDC13Or DMSO-d6For solvent (as unit of ppm), with TMS (0ppm) or chloroform (7.26ppm) As reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is represented with hertz (Hz).
Algorithm (MS) data are by being equipped with G1311B quaternary pumps and G1316B in the embodiments described below The spectrometer of the 6120 series LC-MS of Agilent of TCC (column temperature is maintained at 30oC) measures, G1329B automatic samplers and G1315C DAD detectors are applied to analysis, and ESI sources are applied to LC-MS spectrometers.
Volume injected is determined by sample concentration in the embodiments described below；Flow velocity is 0.5mL/min；HPLC Peak value be that reading is recorded by the UV-Vis wavelength at 210nm and 254nm.Mobile phase is isopropanol/n-hexane (40：60).
Convenient for statement, part material can be described the embodiments described below with its abbreviation, these referred to as with its full name Control is described as follows：DCM is CH2Cl2, i.e. dichloromethane；CHCl3For chloroform, i.e. chloroform；CDC13For deuterochloroform；PE For petroleum ether；EtOAc and EA is ethyl acetate；MeOH and CH3OH is methanol；EtOH and CH3CH2OH is ethyl alcohol；HCl For hydrochloric acid；AcOH and acetic acid are acetic acid；NH4OH and NH3·H2O is ammonium hydroxide；Et3N and TEA is triethylamine；K2CO3For carbon Sour potassium；KI is potassium iodide；NBS is bromosuccinimide；NaHSO3For sodium hydrogensulfite；DIPEA is N, N- diisopropyl second Amine；THF is tetrahydrofuran；Pd(dppf)Cl2·CH2Cl2For [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane Alkane complex compound；DMF is N,N-dimethylformamide；SOCl2For thionyl chloride；POCl3For phosphorus oxychloride；DMSO is dimethyl sulfoxide； DMSO-d6For six deuterated dimethyl sulfoxides；DME is glycol dimethyl ether.
PI3K α/mTOR inhibitors compound provided by the present invention can be prepared in several ways, those skilled in the art Appropriate mode can be found under the inspiration of structural formula provided by the present invention to be prepared.In order to make it easy to understand, in the present invention In provide preparation method about logical formula (I) of the present invention or (II).
It is a kind of to prepare the method with compound shown in logical formula (I) or (II)：It is original with 2,4,6- trichloropyrimidines or (A) Material according to pyrimidine 2 and the difference of 4 reactivities, first occurs nucleophilic substitution with morpholine and obtains intermediate (B), then exist Substitution reaction is occurred to alkaline condition and nitrogen heterocyclic ring and introduces R1Intermediate (C) is obtained, C is sent out with 4- aminobenzenes pinacol borate Raw Suzuki coupling reactions obtain intermediate (D), and D is condensed to yield intermediate (E) with 4- isocyanate group methyl benzoates, and E is in alkali Property under the conditions of hydrolysis obtain F, F obtains the target compound with general formula II (G) from different nitrogen heterocyclic ring fragment condensations. Can set out from 2,4,6- tri- chloro- 1,3,5- tri- nitrogen piperazines, obtain X=N with the target compound (G) with general formula II
The reaction equation of the above method is as follows：
The substituent R in above-mentioned preparation process Chinese style A to formula G1、R3With definition of the present invention.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..Example structure such as 1 institute of table Show：
Embodiment 1：1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- Formamide (PT-1)
Step 1：The synthesis of 4- (2,6- dichloro pyrimidine -4- bases) morpholine
Synthetic method：2,4,6- trichloropyrimidines (10.0g, 54.97mmol), CH are added in 50mL reaction bulbs2Cl2 After (100mL) dissolving, DIPEA (57.72mmol, 10.36mL) is added in, -5 DEG C is cooled to, is then slowly added to morpholine (54.97mmol, 4.79g).Reaction solution reacts 0.5h at low temperature, then heats to room temperature reaction 2h.The reaction was complete for TLC detections Afterwards, H is added in2O (100mL), isolates CH2Cl2Layer, water phase CH2Cl2(100mL) extraction is primary.Merge organic layer, saturation NaCl (100mL) is washed once, anhydrous Na2SO4It is dry.Decompression boils off solvent and obtains crude product, column chromatography purifying (PE/EtOAc=4/ 1) white solid 8.43g, yield are obtained：65.81%；ESI-MS(m/z):234.2[M+H]+；1H NMR(400MHz,CDCl3) δ:6.39 (d, J=4.5Hz, 1H), 3.88-3.49 (m, 8H).
Step 2：The synthesis of the bis- morpholine yl pyrimidines of the chloro- 2,4- of 6-
Synthetic method：The 4- synthesized in step 1 (2,6- dichloro pyrimidine -4- bases) morpholine (5.0g, 21.46mmol) is dissolved After THF/EtOH (50mL), morpholine (1.87g, 21.46mmol), TEA (2.60g, 25.75mmol) and NaI are added in (4.39g, 23.61mmol), following reaction are warming up to 65 DEG C of reaction 12h.After the reaction was complete, decompression boils off solvent, adds for TLC detections Enter EtOAc (50mL) dissolvings, use H2O (50mL) and saturation NaCl (50mL) is respectively washed once, anhydrous Na2SO4It is dry.Decompression boils off Solvent obtains crude product, and column chromatography purifying (PE/EtOAc=5/1) obtains intermediate white solid 3.93g, yield：64.50%； ESI-MS(m/z):285.2[M+H]+；1H NMR(400MHz,CDCl3)δ:5.86 (d, J=1.1Hz, 1H), 3.82-3.64 (m, 12H),3.59-3.50(m,4H)。
Step 3：The synthesis of 4- (the bis- morpholine pyrimidine-4-yls of 2,6-) aniline
Synthetic method：The bis- morpholine yl pyrimidines (3.50g, 12.32mmol) of chloro- 2, the 4- of 6- are dissolved in DME (50mL), successively Add in Pd (PPh3)4(0.14g, 0.12mmol), 2.0M Na2CO3Solution (7.50mL) and 4- aminobenzene pinacol borates (4.05g, 18.48mmol), N2Back flow reaction is for 24 hours under atmosphere.Decompression boils off solvent, and residue is dissolved in CH2Cl2In (50mL), water It washes (50mL × 2) twice, saturation NaCl washes primary (30mL), anhydrous Na2SO4It is dry.Decompression boils off solvent, the direct column of residue Chromatography, eluant, eluent：EA/PE=1/1 obtains target product 3.15g, yield：75.20%.The high resolution mass spectrum data of product For HRMS (ESI)：m/z[M+H]+Calculated value [C18H24N5O2]+:342.1925 measured value 342.1922.
Step 4：The synthesis of 4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) methyl benzoate
Synthetic method：4- (2,6- bis- morpholine pyrimidine-4-yls) aniline (2.0g, 5.86mmol) is dissolved in CH2Cl2(20mL) In, DMAP (36mg, 0.29mmol) is added in, then adds in 4- isocyanate groups methyl benzoate (1.30g, 7.33mmol), room temperature Under be stirred to react 48h.Decompression boils off solvent, and residue is dissolved in CH2Cl2In (30mL), wash twice (30mL × 2), saturation NaCl Wash primary (30mL), anhydrous Na2SO4It is dry.Decompression boils off solvent, the direct column chromatography for separation of residue, eluant, eluent：DCM/MeOH =30/1 obtains target product 2.49g, yield：82.0%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+ Calculated value [C27H31N6O5]+:519.2350 measured value 519.2351.
Step 5：The synthesis of 4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoic acid
Synthetic method：By 4- (3- (4- (2,6- bis- morpholine pyrimidine-4-yls) phenyl) urea groups) methyl benzoate (1.0g, 1.98mmol) it is dissolved in CH3OH/THF (10mL, 1/1) in the mixed solvent adds in water (2.50mL), a hydration LiOH solution (0.25g, 6.0mmol), heating reflux reaction 12h.Decompression boils off low boiling point solvent, adds in water (10mL), 2N HCl tune pH To 5.Filtering, filter cake is washed with water (10mL), and dry off-white powder 0.93g is directly used in the next step, yield： 93.50%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C26H29N6O5]+:505.2194, it is real Measured value 505.2189.
Step 6：1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- first The synthesis (PT-1) of amide
Synthetic method：4- (3- (4- (2,6- bis- morpholine pyrimidine-4-yls) phenyl) urea groups) benzoic acid (200mg, It 0.40mmol) is dissolved in DMF (10mL), sequentially adds pyrrolidines -2- formamides (50mg, 0.44mmol), HBTU (182mg, 0.48mmol), 80 DEG C are heated to and is stirred to react 8h.Reaction solution cooling is fallen back in (20mL), heats CH2Cl2(20mL), is stirred Organic layer, water layer CH are separated after mixing 10min2Cl2(10mL) extraction is primary, merges organic layer, and saturation NaCl washes primary (30mL), Anhydrous Na2SO4It is dry.Decompression boils off solvent, the direct column chromatography for separation of residue, eluant, eluent：DCM/MeOH=10/1 obtains target Product 120mg, yield：50.0%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H37N8O5]+:601.2881 measured value 60.1.2894.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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, 6.1Hz, 1H), 2.18 (dd, J=18.7,7.2Hz, 1H), 1.94-1.72 (m, 3H).13C NMR(125MHz,DMSO-d6)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, 118.1,117.6,88.2,65.9,65.9,49.2,46.5,44.0,28.5,25.0。
Embodiment 2：(S) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrroles Alkane -2- formamides (PT-2)
Synthetic method：Segment will be condensed in step 6 in embodiment 1 and be changed to (S)-pyrrolidines -2- formamides, other steps and It operates similar.
White solid, yield：62.5%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C27H31N6O5]+:601.2881 measured value 601.2885.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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=10.3,6.1Hz, 1H), 2.15 (m, 1H), 1.93-1.78 (m, 3H).13C NMR(125MHz,DMSO-d6)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, 117.6,117.2,88.0,66.2,66.0,50.0,46.7,44.1,29.1,25.2。
Embodiment 3：(R) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrroles Alkane -2- formamides (PT-3)
Synthetic method：Segment will be condensed in step 6 in embodiment 1 and be changed to (R)-pyrrolidines -2- formamides, other steps and It operates similar.
White solid, yield：60.2%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C27H31N6O5]+:601.2881 measured value 601.2875.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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=10.3,6.1Hz, 1H), 2.13 (m, 1H), 1.90-1.82 (m, 3H).13C NMR(125MHz,DMSO-d6)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, 117.5,117.0,87.9,66.1,66.2,50.3,46.5,44.0,29.4,25.0。
Embodiment 4：1- (4- (3- (4- ((the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) piperidines -2- first Amide (PT-4)
Synthetic method：Segment will be condensed in step 6 in embodiment 1 and is changed to piperidines -2- formamides, other steps and operation class It is similar to.
White solid, yield：55.6%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C32H39N8O5]+:615.3038 measured value 615.3045.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz, DMSO-d6)δ：172.8,167.9,163.9,162.5,160.8,153.1,140.8,132.0,129.5,128.2,127.5, 126.8,117.6,116.7,88.1,65.2,66.2,50.3,49.3,44.0,25.2,24.0,21.1。
Embodiment 5：(2S) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) -4- hydroxyls Base pyrrolidines -2- formamides (PT-5)
Synthetic method：(2S) -4- hydroxyl pyrrolidine -2- formamides are changed to by segment is condensed in step 6 in embodiment 1, His step and operation are similar.
Yield：55.5%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H37N8O6 ]+:616.2831 measured value 616.2842.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 117.6,87.6,69.1,66.3,66.0,52.3,49.1,36.5,34.1,29.3。
Embodiment 6：(S) -1- (4- (3- (4- (2- (4- methylpiperazine-1-yls) -6- morpholines pyrimidine-4-yl) phenyl) ureas Base) benzoyl) pyrrolidines -2- formamides (PT-6)
Synthetic method：1- methyl piperazines are changed to by heterocyclic fragments are condensed in step 2 in embodiment 1, other steps and operation Similar to embodiment 2.
Yield：58.6%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C32H40N9O4 ]+:614.3198 measured value 614.3190.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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=10.3,6.1Hz, 1H), 2.63(s,3H),2.15(m,1H),1.93-1.78(m,3H)。13C NMR(125MHz,DMSO-d6)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, 71.2,66.5,66.0,58.5,52.3,50.1,46.7,29.2,24.9。
Embodiment 7：(S) -1- (4- (3- (4- (2- (4- (mesyl) piperazine -1- bases) -6- morpholines pyrimidine-4-yl) benzene Base) urea groups) benzoyl) pyrrolidines -2- formamides (PT-7)
Synthetic method：1- methanesulfonylpiperazins are changed to by heterocyclic fragments are condensed in step 2 in embodiment 1, other steps And operation is similar to embodiment 2.
Yield：62.0%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C32H40N9O6S]+:678.2817 measured value 678.2825.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)δ：176.2,170.4,166.9,165.1,163.6,155.8,144.5, 137.6,131.0,129.5,128.7,126.4,116.8,115.4,89.5,70.6,66.4,66.1,59.2,53.5,49.5, 46.7,40.1,29.0,24.6。
Embodiment 8：(2S) -1- (4- (3- (4- (6- morpholine -2s-(tetrahydrochysene -2H- [1,4] dioxy [2,3-c] pyrroles -6 (3H)-yl) pyrimidine-4-yl) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides (PT-8)
Synthetic method：Hexahydro -2H- [1,4] bis- Evil [2,3-c] pyrroles are changed to by heterocyclic fragments are condensed in step 2 in embodiment 1 It coughs up (synthetic method same J.Med.Chem., 2016,59,7268-7274), other steps and operation are similar to embodiment 2.
Yield：32.4%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C33H39N8O6 ]+:643.2987 measured value 643.2975.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR (125MHz,DMSO-d6)δ：175.8,170.9,167.2,163.0,162.8,153.9,143.8,136.5,130.9, 129.1,128.9,125.8,115.4,115.0,89.9,78.1,71.5,67.2,66.7,66.5,59.2,53.5,49.5, 46.4,44.5,28.6,25.3。
Embodiment 9：1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) a word used for translation Fourth pyridine -2- formamides (PT-9)
Step 1：The synthesis of 4- (bis- chloro- 1,3,5- triazines -2- bases of 4,6-) morpholine
Synthetic method：The addition DIPEA (8.91mL, 49.70mmol) in 50mL reaction bulbs, morpholine (4.33g, 49.70mmol), CH2Cl2After (100mL) dissolving, 2,4,6-, tri- chloro-1,3,5-triazines (10.0g, 54.67mmol), cooling are added in It to -5 DEG C, is then slowly added to reaction solution and reacts 0.5h at low temperature, then heat to 0 DEG C of reaction 12h.TLC detections have been reacted Quan Hou adds in H2O (100mL), isolates CH2Cl2Layer, water phase CH2Cl2(100mL) extraction is primary.Merge organic layer, saturation NaCl (100mL) is washed once, anhydrous Na2SO4It is dry.Decompression boils off solvent and obtains crude product, column chromatography purifying (PE/EtOAc=5/ 1) white solid 6.94g, yield are obtained：59.7%；ESI-MS(m/z):235.1[M+H]+；1H NMR(400MHz,CDCl3)δ: 3.97-3.80(m,4H),3.80-3.65(m,4H)。
Step 2：The synthesis of 4,4'- (the chloro- 1,3,5- triazines -2,4- diyls of 6-) double morpholines
Synthetic method：The 4- synthesized in step 1 (2,6- dichloro pyrimidine -4- bases) morpholine (5.0g, 21.37mmol) is dissolved After THF/EtOH (50mL), morpholine (2.22g, 25.46mmol), potassium carbonate (4.42g, 32.06mmol) are added in, room temperature is anti- Answer 12h.After the reaction was complete, decompression boils off solvent for TLC detections, adds in EtOAc (50mL) and dissolves, uses H2O (50mL) and saturation NaCl (50mL) is respectively washed once, anhydrous Na2SO4It is dry.Decompression boils off solvent and obtains crude product, column chromatography purifying (PE/EtOAc=5/ 1) intermediate white solid 5.01g, yield are obtained：82.3%；ESI-MS(m/z):286.2[M+H]+。
Step 3：The synthesis of 4- (the bis- morpholine 1,3,5- triazines -2- bases of 4,6-) aniline
Synthetic method：4,4'- (6- chloro-1,3,5-triazines -2,4- diyl) double morpholines (3.0g, 10.52mmol) are dissolved in In DME (30mL), Pd (PPh are sequentially added3)4(0.12g, 0.10mmol), 2.0M Na2CO3Solution (6.40mL) and 4- amino Phenyl boric acid pinacol ester (3.46g, 15.78mmol), N2Back flow reaction is for 24 hours under atmosphere.Decompression boils off solvent, and residue is dissolved in CH2Cl2In (50mL), twice (50mL × 2), saturation NaCl washes primary (30mL), anhydrous Na for washing2SO4It is dry.Decompression boils off Solvent, the direct column chromatography for separation of residue, eluant, eluent：EA/PE=1/1 obtains target product 2.65g, yield：73.50%.Production The high resolution mass spectrum data of object is HRMS (ESI)：m/z[M+H]+Calculated value [C17H23N6O2]+:343.1877, measured value 343.1880。
Step 4：The synthesis of 4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) methyl benzoate
Synthetic method：4- (4,6- bis- morpholine 1,3,5-triazines -2- bases) aniline (2.0g, 5.84mmol) is dissolved in CH2Cl2 In (20mL), add in DMAP (36mg, 0.29mmol), then add in 4- isocyanate groups methyl benzoates (1.30g, 7.33mmol), it is stirred to react 48h at room temperature.Decompression boils off solvent, and residue is dissolved in CH2Cl2In (30mL), washing is twice (30mL × 2), saturation NaCl wash primary (30mL), anhydrous Na2SO4It is dry.Decompression boils off solvent, residue direct column chromatography point From eluant, eluent：DCM/MeOH=30/1 obtains target product 2.29g, yield：75.6%.The high resolution mass spectrum data of product is HRMS(ESI)：m/z[M+H]+Calculated value [C26H30N7O5]+:520.2303 measured value 520.2309.
Step 5：The synthesis of 4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoic acid
Synthetic method：By 4- (3- (4- (2,6- bis- morpholine pyrimidine-4-yls) phenyl) urea groups) methyl benzoate (1.0g, 1.93mmol) it is dissolved in CH3OH/THF (10mL, 1/1) in the mixed solvent adds in water (2.50mL), a hydration LiOH solution (0.25g, 6.0mmol), heating reflux reaction 12h.Decompression boils off low boiling point solvent, adds in water (10mL), 2N HCl tune pH To 5.Filtering, filter cake is washed with water (10mL), and dry off-white powder 0.92g is directly used in the next step, yield：95.0%. The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C25H28N7O5]+:506.2146, measured value 506.2150。
Step 6：1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) azete The synthesis of pyridine -2- formamides
Synthetic method：4- (3- (4- (4,6- bis- morpholines -1,3,5-triazines -2- bases) phenyl) urea groups) benzoic acid (200mg, It 0.40mmol) is dissolved in DMF (10mL), sequentially adds pyrrolidines -2- formamides (50mg, 0.44mmol), HBTU (182mg, 0.48mmol), 80 DEG C are heated to and is stirred to react 8h.Reaction solution cooling is fallen back in (20mL), heats CH2Cl2(20mL), is stirred Organic layer, water layer CH are separated after mixing 10min2Cl2(10mL) extraction is primary, merges organic layer, and saturation NaCl washes primary (30mL), Anhydrous Na2SO4It is dry.Decompression boils off solvent, the direct column chromatography for separation of residue, eluant, eluent：DCM/MeOH=10/1 obtains target Product 136mg, yield：57.9%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H36N9O5]+:588.2677 measured value 588.2689.Nuclear magnetic data is1H NMR(400MHz,DMSO-d6)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).13C NMR(100MHz,DMSO-d6)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。
Embodiment 10：(S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyls Base) pyrrolidines -2- formamides (PT-10)
Synthetic method：(S)-pyrrolidines -2- formamides are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, other steps Rapid and operation is similar to embodiment 9.
Yield：67.0%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H36N9O5 ]+:602.2834 measured value 602.2822.Nuclear magnetic data is1H NMR(400MHz,DMSO-d6)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)。13C NMR(100MHz,DMSO-d6)δ：174.3,169.4,168.6,165.0,152.5,143.2, 141.5,130.5,130.2,129.5,129.1,128.1,117.7,66.5,60.6,50.4,43.7,29.5,25.4。
Embodiment 11：(R) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyls Base) pyrrolidines -2- formamides (PT-11)
Synthetic method：(R)-pyrrolidines -2- formamides are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, other steps Rapid and operation is similar to embodiment 9.
Yield：50.5%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H36N9O5 ]+:602.2834 measured value 602.2829.Nuclear magnetic data is1H NMR(400MHz,DMSO-d6)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)。13C NMR(100MHz,DMSO-d6)δ：173.8,169.1,168.5,165.2,152.3,143.1, 142.2,130.3,129.7,129.3,129.0,128.3,117.1,66.2,59.9,50.3,43.2,28.2,25.3。
Embodiment 12：1- (4- (3- (the bis- morpholine -1,3,5- triazines -2- bases of 4-4,6-) phenyl) urea groups) benzoyl) piperazine Pyridine -2- formamides (PT-12)
Synthetic method：Piperidines -2- formamides, other steps and behaviour are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9 Make to be similar to embodiment 9.
Yield：36.7%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H38N9O5 ]+:616.2996 measured value 617.2993.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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=10.3,6.1Hz, 1H), 2.21 (dd, J=18.7,7.2Hz, 1H), 1.97-1.74 (m, 3H), 1.53-1.47 (m, 2H).13C NMR(125MHz, DMSO-d6)δ：174.1,168.1,165.9,163.1,154.1,140.6,140.4,136.7,131.5,128.8,126.5, 121.4,119.7,65.6,57.3,47.1,42.8,26.6,25.5,22.3。
Embodiment 13：(S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyls Base) pyrrolidines -2- formamides (PT-13)
Synthetic method：PT-12 hydrolyzed under basic conditions is obtained into target compound.
Yield：35.3%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H35N8O6 ]+:603.2680 measured value 603.2687.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)δ：175.2,171.5,165.9,163.6,154.1,141.1,140.8,136.8, 131.6,128.8,126.6,121.3,119.7,66.7,62.4,46.8,45.8,29.4,24.9。
Embodiment 14：(S)-methyl 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzene Formoxyl) pyrrolidines -2- formic acid (PT-14)
Synthetic method：(R)-pyrrolidines -2- methyl formates are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, other Step and operation are similar to
Embodiment 9.
Yield：43.2%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H37N8O6 ]+:617.2836 measured value 617.2834.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)δ：171.7,171.5,165.9,163.6,154.1,141.1,140.8, 136.8,131.5,128.8,126.6,121.4,119.7,66.7,61.1,52.1,46.8,45.8,28.2,24.9。
Embodiment 15：(S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyls Base)-N- methylpyrrolidin- 2- formamides (PT-15)
Synthetic method：(S)-N- methylpyrrolidin- 2- formamides are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, Other steps and operation are similar to embodiment 9.
Yield：36.2%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H38N9O5 ]+:616.2996 measured value 616.2992.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)δ：173.0,171.5,165.9,163.6,154.1,141.1, 140.8,136.8,131.5,128.8,126.6,121.4,119.7,66.7,59.9,46.8,45.9,30.5,26.2,24.9。
Embodiment 16：(S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyls Base)-N, N- dimethyl pyrrolidine -2- formamides (PT-16)
Synthetic method：(S)-N, N- dimethyl pyrrolidine -2- first is changed to by heterocyclic fragments are condensed in step 6 in embodiment 9 Amide, other steps and operation are similar to embodiment 9.
Yield：32.4%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C32H40N9O5 ]+:630.3152 measured value 630.3158.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)δ：172.1,171.5,165.9,163.6,154.7,141.9,140.8,136.8, 131.5,128.8,126.2,121.3,119.7,66.7,60.5,46.8,45.8,36.7,30.4,24.9。
Embodiment 17：1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) - 4- hydroxyl pyrrolidine -2- formamides (PT-17)
Synthetic method：3- hydroxyl pyrrolidine -2- formamides are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, other Step and operation are similar to embodiment 9.
Yield：30.7%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H36N9O6 ]+:618.2789 measured value 618.2787.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 48.2,47.1,38.9。
Embodiment 18：1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) - 4- oxygen pyrrolidines -2- formamides (PT-18)
Synthetic method：3- oxygen pyrrolidines -2- formamides are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, other steps Rapid and operation is similar to embodiment 9.
Yield：32.4%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H34N9O6 ]+:616.2632 measured value 616.2637.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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).13C NMR(125MHz,DMSO-d6)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。
Embodiment 19：1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) - 4- (methoxy imino) pyrrolidines -2- formamides (PT-19)
Synthetic method：4- methoxy imino pyrrolidines -2- formyls are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9 Amine, other steps and operation are similar to embodiment 9.
Yield：33.6%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H37N10O6 ]+:645.2898 measured value 645.2891.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)δ：173.9,172.1,165.9,163.1,161.1,154.1,140.6, 140.3,136.7,131.5,128.8,126.5,121.6,119.6,65.5,60.3,57.8,49.7,47.1,33.1。
Embodiment 20：4- amino -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzene first Acyl group) pyrrolidines -2- formamides (PT-20)
Synthetic method：4- amino-pyrrolidine -2- formamides are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, other Step and operation are similar to embodiment 9.
Yield：33.6%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H37N10O5 ]+:617.2948 measured value 617.2943.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 47.1,38.7。
Embodiment 21：4- dimethylaminos -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) Benzoyl) pyrrolidines -2- formamides (PT-21)
Synthetic method：4- dimethylamino pyrrolidines -2- formamides are changed to by heterocyclic fragments are condensed in step 6 in embodiment 9, Other steps and operation are similar to embodiment 9.
Yield：34.2%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C32H41N10O5 ]+:645.3261 measured value 645.3266.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 44.9,41.6,29.3。
Embodiment 22：(S) -1- (4- (2- (aminomethyl) pyrrolidines -1- carbonyls) phenyl) -3- (4- (bis- morpholine -1 of 4,6-, 3,5- triazine -2- bases) phenyl) urea (PT-22)
Synthetic method：By in step 6 in embodiment 9 be condensed heterocyclic fragments be changed to 2- aminomethyl pyrrolidines, other steps and Operation is similar to embodiment 9.
Yield：43.8%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C30H38N9O4 ]+:588.3047 measured value 588.3042.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 29.8,25.3。
Embodiment 23：(S) -1- (4- (3- (4- (4- (4- methylpiperazine-1-yls) -6- morpholine -1,3,5- triazine -2- bases) Phenyl) urea) benzoyl) pyrrolidines -2- formamides (PT-23)
Synthetic method：Methyl piperazine is changed to by heterocyclic fragments are condensed in step 2 in embodiment 10, other steps and operation class It is similar to embodiment 10.
Yield:40.6%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H39N10O4 ]+:615.3156 measured value 615.3152.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 52.5,46.8,45.9,43.7,30.8,25.1。
Embodiment 24：(S) -1- (4- (3- (4- (4- (4- (mesyl) piperazine -1- bases) -6- morpholine -1,3,5- triazines - 2- yls) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides (PT-24)
Synthetic method：By in step 2 in embodiment 10 be condensed heterocyclic fragments be changed to methanesulfonylpiperazin, other steps and Operation is similar to embodiment 10.
Yield：29.6%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C31H39N10O6S]+:679.2775 measured value 679.2779.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 60.0,54.1,46.8,45.8,43.6,39.5,30.7,24.9。
Embodiment 25：(2S) -1- (4- (3- (4- (4- morpholines -6- (tetrahydrochysene -2H- [1,4] dioxy [2,3-c] pyrroles -6 (3H)-yl) -1,3,5- triazine -2- bases) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides (PT-25)
Synthetic method：Hexahydro -2H- [1,4] bis- Evil [2,3-c] are changed to by heterocyclic fragments are condensed in step 2 in embodiment 10 Pyrroles, other steps and operation are similar to embodiment 10.
Yield：37.3%.The high resolution mass spectrum data of product is HRMS (ESI)：m/z[M+H]+Calculated value [C32H38N9O6 ]+:644.2945 measured value 644.2943.Nuclear magnetic data is1H NMR(500MHz,DMSO-d6)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)。13C NMR(125MHz,DMSO-d6)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, 65.8,60.6,54.1,46.6,45.9,30.8,24.9。
External PI3K alpha kinases inhibit test：
The compounds of this invention inhibits PI3K alpha kinases activity, thus inhibits the transduction of cell-signaling pathways, so as to influence cell Period and cell Proliferation.Such compound passes through following Kinase-Glo Luminescent to the inhibiting effect of PI3K alpha kinases Kinase Assay methods are evaluated.
Testing principle：Kinase-Glo Plus Luminescent Kinase Assay are a kind of on-radiations of homogeneous Detection method, it is to quantitative determine the activity of purifying kinases by detecting the content of ATP in system after kinase reaction.ATP The measure of content is by by Mg2+, ATP and oxygen catalysis firefly luciferin (beetle luciferin) aoxidize after generate Luminous intensity come it is quantitative.A certain amount of ATP is added in the reaction system, and kinase reaction needs to consume ATP, and remaining ATP can To shine after reacting with the firefly luciferase in Kinase Glo reagents, so as to the quantitative remaining ATP of detection Amount, indirect determination react kinases activity.
Detection method：Test-compound is formulated as the 100 of highest response inhibition concentration with 100% dimethyl sulfoxide (DMSO) × concentration is drawn in 100 μ L to 96 orifice plate, one holes.Then 3 times of concentration gradient dilution is hole-specifically carried out with 100%DMSO, is prepared 10 concentration." complete " and " blank " control wells are replaced with the 100%DMSO of 100 μ L.Wherein, " complete " control wells are no chemical combination Object group, " blank " control wells are no kinases group.Then, prepare the compound intermediate diluent containing 4%DMSO, preparation method be to 4 μ L compounds and 96 μ L 1 × kinases basis buffers are added in each hole of detection plate.By 2.5 μ L above compound intermediate dilutes Object adds in reaction plate, then by 2.5 4 × kinase solutions of μ L (by kinases add in 1 × kinases basis buffer (50mM HEPES, pH 7.5、1mM EGTA、100mM NaCl、3mM MgCl2, 2mM DTT, 0.03%CHAPS be formulated) add in detection plate In each hole.It is incubated at room temperature 10min.By 5 μ L 2 × substrate solution (PIP2 and ATP is added in 1 × kinases basis buffer to prepare Into) add in each hole of detection plate.It is incubated at room temperature 1h.It adds in 10 μ L terminate liquids (Kinase-Glo reagent) and terminates reaction. Oscillation centrifuges 1min, low-speed oscillation 15min, and then Flexstation read plates are detected, finally according to RLU values and " complete " The reading of " blank " control wells calculates the inhibiting rate under each concentration of compound, and the mapping of binding compounds concentration calculates IC50Value.
MTOR activity is measured by Lance Ultra fluorescent tests, and principle is similar with PI3K α.Detection method is as follows： 50mM HEPES、pH 7.5、1mM EGTA、3mM MnCl2、10mM MgCl2, 2mM DTT, 0.01%Tween-20,100% DMSO is solvent.MTOR, which is added in above-mentioned buffer solution, is diluted to ultimate density as 2.5nM, and 2.5 μ L kinase solutions is taken to be placed in 384 In orifice plate.The substrate ULight-4E-BP1 (Thr37/46, PE) (50 μM) of pretreatment and ATP (10.8 μ is added in into plate simultaneously M it) is reacted to start, after reacting at room temperature 1h, add in 10 μ L pretreatments contains EDTA and Eu-anti-phospho-4E-BP1 The detection buffer solution of (Thr37/46, PE) antibody, 60min is balanced after centrifugation, then using Envision gathered datas, is selected 665nm wavelength measures light absorption value.
Result of the test is shown in Table 2, and the activity data from following table is it is found that compound of the present invention can effectively inhibit PI3K α With mTOR bidifly enzymes, to it with preferable inhibitory activity, i.e., most compound is to the inhibitory activity of PI3K α and mTOR bidifly enzymes (IC50) in nanomolar range, and compared with II phase clinical candidates PF-05212384, surprisingly it has been found that chemical combination of the present invention Object is suitable with its inhibitory activity, even better, and compared with compound PI-103, then it has a clear superiority, and both are swashed The selective higher of enzyme, such as embodiment 10 and embodiment 21.Therefore, compound of the present invention has positive and foreseeable anti- Proliferative diseases, especially antitumor clinical value, and with good development prospect.
2 target compound PI3K α of table and the external inhibitory activity of mTOR kinases
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, that is made any repaiies Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.

Claims (10)

1. a kind of compound, have as shown in formula (I) structure or as shown in formula (I) structure stereoisomer, geometrical isomerism Body, hydrate, solvate or pharmaceutically acceptable salt or prodrug：
Wherein, X is selected from N or-CRa-；
R1、R2And RaIt is each independently selected from H, C1-C4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-C4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C3-7Heterocycle, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl or C4-9Condense miscellaneous bicyclic group C1-4 Alkyl, wherein described C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C3-7 Heterocycle, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl and C4-9Condense miscellaneous bicyclic group C1-4Alkyl each independently may be used To be selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), R by one or more4C (=O) NH-, R4C (=O) O-, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4It is halogenated Alkoxy, C1-4Alkylamino, C1-4Aminoalkyl, C1-4Hydroxy alkoxy base or C1-4Alkoxy C1-C4The substituent group of alkyl is replaced；
R3Selected from H, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, R4-NH-、C3-7Heterocycle, C4-9Condense miscellaneous bicyclic group, C4-9 Condense miscellaneous bicyclic group C1-4Alkyl, C4-9Condense miscellaneous bicyclic group C1-4Alkylamino, C3-7Heterocycle C1-4Alkyl, C3-7Heterocycle C1-4Alkane Amino, C6-10Aryl, C6-10Aryl C1-4Alkyl, C6-10Aryl C1-4Alkylamino, C1-9Heteroaryl, C1-9Heteroaryl C1-4Alkyl or C1-9Heteroaryl C1-4Alkylamino, wherein the C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, R4-NH-、C3-7Heterocycle, C4-9 Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl, C3-7Heterocycle C1-4Alkylamino, C6-10Aryl, C6-10Aryl C1-4Alkyl, C6-10 Aryl C1-4Alkylamino, C1-9Heteroaryl, C1-9Heteroaryl C1-4Alkyl and C1-9Heteroaryl C1-4Alkylamino each independently can be by One or more is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo (=O), R4C (=O) NH-, R4C (=O) O-, N (R4R4a)-C (=O)-, R4O-C (=O)-, R4ON=, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Alkyl halide Base, C1-4Alkylamino, C1-4Dialkylamino, C1-4Aminoalkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxyl Base alkoxy or C1-4Alkoxy C1-4The substituent group of alkyl is replaced；
Each R4And R4aSeparately it is selected from H, C1-4Alkyl, C1-4Halogenated alkyl, C6-10Aryl, C6-10Aryl C1-4Alkyl, C1-9It is miscellaneous Aryl, C1-9Heteroaryl C1-4Alkyl, C4-7Heterocycle or C4-7Heterocycle C1-4Alkyl, wherein the C1-4Alkyl, C1-4Alkyl halide Base, C6-10Aryl, C6-10Aryl C1-4Alkyl, C1-9Heteroaryl, C1-9Heteroaryl C1-4Alkyl, C4-7Heterocycle and C4-7Heteroaryl C1-4Alkyl each independently can be by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo (=O), C1-4Alkyl- C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkylamino, C1-4Aminoalkyl, C1-4Hydroxyl alkane Base, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy base or C1-4Alkoxy C1-4The substituent group of alkyl is replaced.
2. compound according to claim 1, wherein, compound shown in formula (I) has structure shown in formula (II) or it is vertical Body isomers, geometric isomer, hydrate, solvate or pharmaceutically acceptable salt or prodrug：
X is selected from N or-CH-；
R1Selected from H, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C3-7It is miscellaneous Ring group or C4-9Miscellaneous bicyclic group is condensed, wherein the C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, C3-7Heterocycle and C4-9Condense miscellaneous bicyclic group each independently can by one or more selected from fluorine, chlorine, Bromine, iodine, hydroxyl, amino, cyano, oxo (=O), C1-4Alkyl, C1-4Halogenated alkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogen For alkoxy, C1-4Hydroxy alkoxy base, C1-4Alkylamino, C1-4Aminoalkyl, R4C (=O) NH-, R4C (=O) O-, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl or C1-4Alkoxy C1-4The substituent group of alkyl is replaced.
3. according to claim 1-2 any one of them compounds, wherein, R3Selected from R4-NH-、C3-7Heterocycle, C4-9It is condensed miscellaneous Bicyclic group, C3-7Heterocycle C1-4Alkyl, C3-7Heterocycle C1-4Alkylamino, C6-10Aryl C1-4Alkylamino or C1-9Heteroaryl C1-4Alkane Amino, wherein the R4-NH-、C3-7Heterocycle, C4-9Condense miscellaneous bicyclic group, C3-7Heterocycle C1-4Alkyl, C3-7Heterocycle C1-4Alkane Amino, C6-10Aryl C1-4Alkylamino and C1-9Heteroaryl C1-4Alkylamino each independently can by one or more selected from fluorine, Chlorine, bromine, iodine, hydroxyl, amino, oxo (=O), R4C (=O) NH-, R4C (=O) O-, N (R4R4a)-C (=O)-, R4O-C (= O)-、R4ON=, C1-4Alkyl-C (=O)-, C1-4Alkyl sulphonyl, cyano, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkylamino, C1-4Dialkylamino, C1-4Aminoalkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Hydroxy alkoxy base or C1-4 Alkoxy C1-4The substituent group of alkyl is replaced；
Each R4And R4aSeparately it is selected from H, C1-4Alkyl or C1-4Halogenated alkyl.
4. compound according to claim 1, wherein, R1Represent following subformula：
Wherein, A, B, C and D are each independently selected from-CH2,-O- ,-S- or-NRb-；R5、R6、R7、R8And R9It selects each independently From H, halogen, hydroxyl, amino, C1-4Alkyl, C1-4Halogenated alkyl, C1-4Hydroxyalkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4 Hydroxy alkoxy base, C1-4Alkyl-C (=O)-or C1-4Alkyl sulphonyl.
5. compound according to claim 3, wherein, R1Represent following subformula：
6. compound according to claim 1, wherein, R3Selected from C1-4Alkylamino, C1-4Halogenated alkylamino or C3-7Heterocycle C1-4Alkyl or R3Represent following subformula：
7. compound according to claim 1, the structure comprising one of：
(1) 1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides；
(2) (S) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- formyls Amine；
(3) (R) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) pyrrolidines -2- formyls Amine；
(4) 1- (4- (3- (4- ((the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) piperidines -2- formamides；
(5) (2S) -1- (4- (3- (4- (the bis- morpholine pyrimidine-4-yls of 2,6-) phenyl) urea groups) benzoyl) -4- hydroxyl pyrrolidines - 2- formamides；
(6) (S) -1- (4- (3- (4- (2- (4- methylpiperazine-1-yls) -6- morpholines pyrimidine-4-yl) phenyl) urea groups) benzoyls Base) pyrrolidines -2- formamides；
(7) (S) -1- (4- (3- (4- (2- (4- (mesyl) piperazine -1- bases) -6- morpholines pyrimidine-4-yl) phenyl) urea groups) benzene Formoxyl) pyrrolidines -2- formamides；
(8) (2S) -1- (4- (3- (4- (6- morpholine -2s-(tetrahydrochysene -2H- [1,4] dioxy [2,3-c] pyrroles -6 (3H)-yl) pyrimidine - 4- yls) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides；
(9) 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) azetidine -2- first Amide；
(10) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrrolidines - 2- formamides；
(11) (R) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrrolidines - 2- formamides；
(12) 1- (4- (3- (the bis- morpholine -1,3,5- triazines -2- bases of 4-4,6-) phenyl) urea groups) benzoyl) piperidines -2- formyls Amine；
(13) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrrolidines - 2- formamides；
(14) (S)-methyl 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrrole Cough up alkane -2- formic acid；
(15) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl)-N- methyl Pyrrolidines -2- formamides；
(16) (S) -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl)-N, N- bis- Methylpyrrolidin- 2- formamides；
(17) 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) -4- hydroxypyrroles Alkane -2- formamides；
(18) 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) -4- oxygen pyrroles Alkane -2- formamides；
(19) (methoxy is sub- by 1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) -4- Amido) pyrrolidines -2- formamides；
(20) 4- amino -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) pyrroles Alkane -2- formamides；
(21) 4- dimethylaminos -1- (4- (3- (4- (the bis- morpholine -1,3,5- triazines -2- bases of 4,6-) phenyl) urea groups) benzoyl) Pyrrolidines -2- formamides；
(22) (S) -1- (4- (2- (aminomethyl) pyrrolidines -1- carbonyls) phenyl) -3- (4- (the bis- morpholine -1,3,5- triazines of 4,6- - 2- yls) phenyl) urea；
(23) (S) -1- (4- (3- (4- (4- (4- methylpiperazine-1-yls) -6- morpholine -1,3,5- triazine -2- bases) phenyl) urea) benzene Formyl) pyrrolidines -2- formamides；
(24) (S) -1- (4- (3- (4- (4- (4- (mesyl) piperazine -1- bases) -6- morpholine -1,3,5- triazine -2- bases) benzene Base) urea groups) benzoyl) pyrrolidines -2- formamides；
(25) (2S) -1- (4- (3- (4- (4- morpholines -6- (tetrahydrochysene -2H- [1,4] dioxy [2,3-c] pyrroles -6 (3H)-yl) -1, 3,5- triazine -2- bases) phenyl) urea groups) benzoyl) pyrrolidines -2- formamides；
Or its stereoisomer, geometric isomer, raceme, solvate or pharmaceutically acceptable salt or prodrug.
8. a kind of pharmaceutical composition, comprising the compound as described in claim 1-7 any one and pharmaceutically acceptable Carrier, excipient, diluent, adjuvant, medium or combination.
9. a kind of compound using described in claim 1-7 any one or pharmaceutical composition according to any one of claims 8 are made It is ready for use on the drug of the proliferative diseases in Prevention and/or treatment and/or auxiliary treatment PI3K α/mTOR bidifly enzyme effects In purposes.
10. purposes according to claim 9, wherein the proliferative diseases include colorectal cancer, gastric cancer, breast cancer, lung Cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, carcinoma of urinary bladder, kidney, brain tumor, neck cancer, the cancer of CNS, glioblastoma, Or myeloproliferative disease, leukaemia or lymph cancer.
CN201810022227.4A 2018-01-10 2018-01-10 PI3K α/mTOR bidifly enzyme inhibitors and its pharmaceutical composition and application Pending CN108191837A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
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CN111153891A (en) * 2020-01-10 2020-05-15 贵州医科大学 Substituted benzimidazole PI3K α/mTOR double-target inhibitor and pharmaceutical composition and application thereof
CN113045559A (en) * 2021-03-15 2021-06-29 贵州医科大学 Diaryl urea PI3K alpha/mTOR double-target inhibitor and pharmaceutical composition and application thereof
CN114751899A (en) * 2022-04-24 2022-07-15 贵州医科大学 Diaryl urea mTOR kinase inhibitor and pharmaceutical composition and application thereof
CN115557908A (en) * 2022-09-28 2023-01-03 九江学院 Triazine derivative containing sulfur connecting bond and synthesis method and application thereof

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CN102939292A (en) * 2010-03-15 2013-02-20 巴塞尔大学 Spirocyclic compounds and their use as therapeutic agents and diagnostic probes
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Publication number Priority date Publication date Assignee Title
CN111153891A (en) * 2020-01-10 2020-05-15 贵州医科大学 Substituted benzimidazole PI3K α/mTOR double-target inhibitor and pharmaceutical composition and application thereof
CN111153891B (en) * 2020-01-10 2023-03-31 贵州医科大学 Substituted benzimidazole PI3K alpha/mTOR double-target inhibitor and pharmaceutical composition and application thereof
CN113045559A (en) * 2021-03-15 2021-06-29 贵州医科大学 Diaryl urea PI3K alpha/mTOR double-target inhibitor and pharmaceutical composition and application thereof
CN114751899A (en) * 2022-04-24 2022-07-15 贵州医科大学 Diaryl urea mTOR kinase inhibitor and pharmaceutical composition and application thereof
CN114751899B (en) * 2022-04-24 2024-03-29 贵州医科大学 Diaryl urea mTOR kinase inhibitor, and pharmaceutical composition and application thereof
CN115557908A (en) * 2022-09-28 2023-01-03 九江学院 Triazine derivative containing sulfur connecting bond and synthesis method and application thereof

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