CN105330699B - A kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt, pharmaceutical composition and its application - Google Patents

A kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt, pharmaceutical composition and its application Download PDF

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CN105330699B
CN105330699B CN201410397283.8A CN201410397283A CN105330699B CN 105330699 B CN105330699 B CN 105330699B CN 201410397283 A CN201410397283 A CN 201410397283A CN 105330699 B CN105330699 B CN 105330699B
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amino
pyrimidin
ones
methyl
cyclohexyl
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CN105330699A (en
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吕慧敏
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Shandong Huiruidi Biotechnology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

The present invention provides one kind phosphorous pyrido [2 as shown in formula (I), 3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt, preparation method, the pharmaceutical composition and its application comprising phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound for also disclosing the compound simultaneously.This kind of compound is protein kinase (such as PI3K) inhibitor, can be used for treating because protein kinase activity extremely caused by disease, such as tumour etc..

Description

A kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its can pharmaceutically connect Salt, pharmaceutical composition and its application received
Technical field
The present invention relates to organic chemistry and field of medicinal chemistry, and in particular to phosphorous pyrido [2,3-d] pyrimidin-7-ones class Compound or its pharmaceutically acceptable salt, pharmaceutical composition and its application containing the compound.
Background technique
Protein kinase is a kind of phosphotransferase, and effect is that γ-phosphate of ATP is transferred to the specific ammonia of substrate On base acid residue, make protein phosphorylation, plays its biochemical functions.Protein kinase is a kind of important kinases, in signal There are two aspects for main function in transduction: one is passing through the activity of phosphorylated regulation protein；The second is passing through protein Phosphorylation step by step amplifies signal step by step, causes cell effect.
The exception of protein kinase activity not only a series of signal with the proliferation of tumour, apoptosis, transfer etc. with intraor extracellular The exception of some part is closely related in conduction path, while being also to lead to that a series of other are related with inflammation or breeder reaction Human diseases, such as the main reason for rheumatoid arthritis, angiocarpy and the nervous system disease, asthma, psoriasis etc..At present It has been known that there is more than 400 kinds of human diseases are directly or indirectly related to protein kinase, this makes protein kinase become even after G- albumen Join another major class important drugs target after receptor.
Protein kinase big family is commonly divided into protein tyrosine kinase (protein by more than 500 a member compositions Tyrosine kinases or PTKs) and serine-threonine kinase (serine-threonine kinases) two classes.It presses According to kinases the location of in cell, and receptor kinase (receptor kinases) and non-receptor kinase can be divided into, also known as Intracellular kinases.Receptor kinase generally belongs to tyrosine kinase, also referred to as tyrosine receptor kinase (receptor tyrosine Kinases or RTKs), this kind of receptor kinase is by cell membrane exterior point, transmembrane region and cytoplasm internal grouping at catalysis Active kinases part is located in cytoplasm.The serine-threonine kinase overwhelming majority be located at it is intracellular, belong to non-receptor kinase or Claim cytoplasmic kinase (cytosolic kinases).
Typical Representative in RTKs family is growth factor receptors (growth factor receptors), is at least existed 19 subfamilies are several main subfamilies below:
(a) HER family tyrosine receptor kinase, including EGFR (epithelial growth factor receptor), HER2, HER3 and HER4.EGFR is the synthesized micromolecule medicine for treating non-small cell lung cancer And monoclonal AntibodyTarget.
(b) by insulin receptor (insulin receptor or IR), as the growth factor I receptor of insulin (insulin-like growth factor I receptor or IGF-1R) and receptor relevant to insulin receptor (insulin receptor-related receptor or IRR) composition.IGF-1R therein is generally acknowledged anticancer target, But since it is too similar to IR, especially intracellular kinases part, amino acid sequence is 100% identical, inhibits IGF-1R Activity, can generally also inhibit the activity of IR.Evidence show IR and effective anticancer targets, but because inhibiting IR to have causes The risk of blood glucose rise, IR inhibitor need to find the balance of benefit and security risk for anticancer.
(c) platelet-derived growth factor receptor (platelet-derived growth factor receptor or PDGFRs) family, including PDGFR- α, PDGFR- β, CSF1R, c-KIT and c-fms.Wherein c-KIT is also leukemia treating medicine ObjectMolecular target, for treating gastrointestinal stromal tumor.
(d) vascular endothelial growth factor receptor (vascular endothelial growth factor receptors Or VEGFRs) family, including FLT1 (Fms-like tyrosine kinase 1 or VEGFR1), KDR (or VEGFR-2) and FLT4 (or VEGFR3).Member therein isWithMolecular target.
(e) fibroblast growth factor acceptor (fibroblast growth factor receptors or FGFRs) family, including FGFR1, FGFR2, FGFR3 and FGFR4 and 7 ligands FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 And FGF7.Member therein as molecular target drug also in clinical trial.
(f) MET family, including c-Met or human Hepatocyte Growth's factor acceptor (human hepatocyte Growth factor receptor or hHGFR) and RON.Wherein c-Met plays the part of weight in the growth and transfer of initial tumor The role wanted.It goes through to treat non-small thin respectively as the drug Crizotinib and Cabozantinib of molecular target Born of the same parents' lung cancer and medullary carcinoma of thyroid gland.
(g) RET family, RET are the receptors of GDNF family member, and there are RET51, RET43 and RET9isoforms.It is made It has gone through to treat medullary carcinoma of thyroid gland for the drug Cabozantinib of molecular target.
(h) Eph family is maximum family in tyrosine receptor kinase, by 16 receptors (EPHA1, EPHA2, EPHA3, EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA9、EPHA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB5、 EPHB6 it) is formed with 9 ligands (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3).These members It plays an important role in the development of animal, some members figure in tumour.
There is no cell membrane exteriors point and transmembrane region part, entire kinases to be in cytoplasm for non-receptor kinase.Now Know that at least 24 kinds of non-receptor kinases are divided into 11 subfamilies, they be Src, Frk, Btk, CsK, Abl, Zap70, Fes, Fps, Fak, Jak and AcK subfamily.Wherein Src subfamily be maximum, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2 and Yrk kinases.More detailed information is shown in Neet, K.；Hunter,T.Genes to Cells 1996,1,147- 169 and this article reference document.Although there is several non-receptor kinase category tyrosine kinase, most non-receptor kinases belong to Serine-threonine kinase.Several members therein are medicament for treatment of leukemiaAndMolecular target.
PI3K (Phosphatidylinositide 3-kinase) is a kind of lipid kinase for participating in multinomial cell function Family.These functions include cell growth, proliferation, differentiation, motility, survival and intracellular transport etc. (J.A.Engelman, Nat.Rev.Cancer 2009,9,550).PI3K family according to primary structure, effect and is divided into the specificity of lipid substrates Three types: I type, II type and type III.Compared to II and type III, people are most complete to the understanding of I type at present, and I type mainly exists Figure in tumour.I type PI3K is further divided into IA and IB hypotype according to the similar figures of amino acid sequence, and IA is comprising one Regulator subunit p85 (regulatory subunit) and catalytic subunit p110 (catalytic subunit) it is miscellaneous Dimeric molecule.Regulator subunit p85 includes 5 mutation, and wherein p85 alpha expression is most.Mutation that there are three catalytic subunit p110, That is p110 α, p110 β and p110 δ, they are expressed by gene PIK3CA, PIK3CB and PIK3CD respectively.IB type PI3K is sub- by adjusting Unit p101 and catalytic subunit p110 γ composition, and expressed by PIK3CAG.P110 α and p110 β have in each cell Expression, but p110 δ mainly in leucocyte expression (C.L.Carpenter et al, J.Biol.Chem.1990,265, 19704.S.J.Leevers et al,Curr.Opin.Cell Biol.1999,11,219.K.Okkenhaug, Ann.Rev.Immunol.2013,31,675)。
PI3K receives the letter transmitted from tyrosine receptor kinase, G- G-protein linked receptor (GPCR) and RAS of activation etc. Number and be activated, p110, which then has an effect with immobilized artificial membrane, makes inositol PIP2 phosphorylation in phosphatidylinositols generate PIP3.This One process activates AKT and a variety of albumen for playing the part of most important role in tumour in downstream.The generation of PIP3 and how much quilts of amount Tumor suppressor protein, phosphatase and PTEN strict control (I.Brana and L.L.Siu BMC Med.2012,10,161).
Many tumours be all as PI3K signal transduction path it is out of control caused by.Common mechanism is the mutation of PI3KCA Or gene expression increase, tumor suppressor protein PTEN missing, pass through the expression of the height of tyrosine receptor kinase or activated mutant Caused by overactivity etc..PI3K- δ inhibitor Idelalisib ratifies the treatment white blood of chronic lymphocytic by FDA Sick (CLL), recurrent follicular B cell non-Hodgkin lymphoma and small lymphocyte lymthoma.
In addition to the effect in tumour, PI3K also plays an important role in immune function, PI3K- γ and PI3K- δ hypotype It is mainly expressed in immunocyte, to inflammation, immune and hematologic disease is related certainly.The active resistance of PI3K- γ and PI3K- δ Disconnected (the D.G.Winkler et al that will play a role to diseases such as treatment of arthritis, tracheitis, lupus erythematosus Chem.Biol.2013,20,1364 and the document of this article reference).
MTOR is a kind of serine/threonine kinase encoded by people's MTOR gene, belongs to PI3K kinase families.MTOR exists (N.Hay and is played regulatory role in cell growth, increment, movement, survival, protein synthesis and transcription N.Sonenberg,Genes Dev.2004,18,1926.).MTOR is mTORC1 and two kinds of mTORC2 answering with different structure Close the catalytic sub-units (S.Wullschleger et al, Cell2006,124,471.) of object.Several mTOR inhibitors by Approval for clinical anticancer (for example, temsirolimus, everolimus etc.), anti-organ-graft refection (that is, Rapamycin) etc..
WO2005113556A1 reports series of quinazoline ketone as people's PI3K- δ kinase inhibitor.WO2011146882A1 Report a series of isoquinoline-1-ketones as PI3K kinase inhibitor.WO2007084786A1 reports that a series of miazines PI3K swash Enzyme inhibitor.WO2006122806A2 reports a series of imidazoquinolies as PI3K/mTOR kinase inhibitor. WO2008032162A1 reports a series of pyrido [2,3-d] pyrimidones as PI3K/mTOR kinase inhibitor. WO2008144464A1 reports a series of quinolines as PI3K/mTOR kinase inhibitor.
As described above, receptor kinase and non-receptor kinase clinically and in practical application have been obtained as antitumor target It is proved to sufficient, several antineoplastics have been approved by listing treatment patient.Other than oncotherapy, inhibit receptor kinase and It includes but is not limited to following disease that the abnormal activity of non-receptor kinase, which can also be used in treatment: psoriasis or psoriasis, cirrhosis, Diabetes, lupus erythematosus, the disease for being related to angiogenesis, the disease for being related to restenosis, disease of eye, have with the age tracheitis The macular degeneration of pass, rheumatic arthritis and other inflammation, disease of immune system such as auto-immune disease, cardiovascular disease are for example Atherosclerosis, kidney trouble etc..Therefore the inhibitor for continuing to research and develop these kinases is very important.
Summary of the invention
The first object of the present invention is to provide one kind, and there is protein kinase (especially PI3K, mTOR etc.) inhibitory activity to contain Phosphorus pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt and its raceme or enantiomerism Body.
The second object of the present invention is to provide one kind and contains above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound Or the pharmaceutical composition of its pharmaceutically acceptable salt and its raceme or enantiomter.
Third object of the present invention is to provide above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its Pharmaceutically acceptable salt and its raceme or enantiomter disease caused by preparation treatment is because of protein kinase abnormal activity Application in the drug of disease.
To achieve the above object, the present invention adopts the following technical scheme:
A kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt, the compound Shown in molecular structural formula such as formula (I):
In formula,
Ar is aryl or heteroaryl, and the hydrogen in Ar can be by 1-5 identical or different G1Replace；
X is C-R1Or N；
A indicates C1-6Alkyl, C=O or covalent bond, and when A is C1-6When alkyl, hydrogen therein can be identical by 1-5 Or different G2Replace；
L indicates O, N-R2, S (=O)mAn or covalent bond；
J indicates C1-6Alkyl or a covalent bond, and the hydrogen in J can be by 1-5 identical or different G3Replace；
R and R ' separately indicates H, OH, halogen, C1-6Alkyl, C3-6Naphthenic base, C3-12Heteroalicyclyl, C1-6Alcoxyl Base, C3-6Cycloalkyloxy or C3-12Heterolipid epoxy group, and the hydrogen in R and R ' can be by 1-5 identical or different G4Replace, R and R ' Also C can be formed together with the phosphorus atoms being connected3-12Heterolipid ring, the C3-12Heterolipid ring can additionally comprise one or more O, N or S (=O)mHetero atom；
Wherein:
G1、G2、G3And G4Separately indicate H ,-CN ,-CF3、-OCF3、-NO2, halogen, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl, C6Aryl, C5-6Heteroaryl, C3-12Heteroalicyclyl, R3O-、R3R4N-、R3S (=O)m-、R3R4NS (= O)m-、R5C (=O)-, R3R4NC (=O)-, R3OC (=O)-, R5C (=O) O-, R3R4NC (=O) O-, R5C (=O) NR3-、 R3R4NC (=O) NR6-、R3OC (=O) NR6-、R3S (=O)mNR6-、R3R4NS (=O)mNR6-、R3R4NC (=NR7)NR6-、 R3R4NC (=CHNO2)NR6-、R3R4NC (=N-CN) NR6-、R3R4NC (=NR7)-、R3S (=O) (=NR7)NR6Or R3R4NS (=O) (=NR7)-；
R1、R2、R3、R4、R5、R6And R7Separately indicate H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base, C6Aryl, C5-6Heteroaryl or C3-12Heteroalicyclyl；Work as R3And R4When being connected on same nitrogen-atoms, can together with the nitrogen-atoms shape At a C3-12Heterolipid ring, this C3-12Heterolipid ring can also additionally comprise one or more O, N or S (=O)mHetero atom；And R1、 R2、R3、R4、R5、R6And R7In hydrogen can be by 1-5 identical or different halogen ,-CN ,-OH, C1-6Alkyl or C3-6Naphthenic base takes Generation；
M is 0,1 or 2.
Wherein, the structure such as formula (Ia) of preferably described phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound or (Ib) institute Show:
Described in formula,
R1Indicate hydrogen or C1-6Alkyl；
A indicates C1-6Alkyl, C=O or covalent bond, and when A is C1-6When alkyl, hydrogen therein can be identical by 1-5 Or different G2Replace；
L indicates O, N-R2Or S (=O)mAn or covalent bond；
J indicates C1-6Alkyl or a covalent bond, and the hydrogen in J can be by 1-5 identical or different G3Replace；
m、G1、G2、G3, R, R ' and R2It is defined as above.
Phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound structure such as formula (Ic) or (Id) shown in:
Described in formula,
G11Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy；
L indicates O or N-R2；
J indicates C1-6Alkyl, and the hydrogen in J can be by 1-5 identical or different G3Replace；
RR and R ' R ' separately expression-OH, halogen, C1-6Alkyl or C1-6Alkoxy, and the hydrogen in RR and R ' R ' can By 1-5 identical or different G4Replace, RR and R ' R ' can also be formed together C with the phosphorus atoms being connected3-12Heterolipid ring, it is described C3-12Heterolipid ring can also additionally comprise one or more O, N or S (=O)mHetero atom；
m、G3、G4And R2It is defined as above.
Again or shown in the structure such as formula (Ie) of the phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or (If):
Described in formula,
G11Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy；
A indicates C=O or C1-6Alkyl, and when A is C1-6When alkyl, hydrogen therein can be by 1-5 identical or different G2It takes Generation；
L indicates O or N-R2；
J indicates C1-6Alkyl, and the hydrogen in J can be by 1-5 identical or different G3Replace；
RR and R ' R ' separately expression-OH, halogen, C1-6Alkyl or C1-6Alkoxy, and the hydrogen in RR and R ' R ' can By 1-5 identical or different G4Replace, RR and R ' R ' can also be formed together C with the phosphorus atoms being connected3-12Heterolipid ring, it is described C3-12Heterolipid ring can also additionally comprise one or more O, N or S (=O)mHetero atom；
m、G2、G3、G4And R2It is defined as above.
And again or shown in the structure such as formula (Ig) of the phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound:
Described in formula,
G11Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy；
J indicates C1-6Alkyl, and the hydrogen in J can be by 1-5 identical or different G3Replace；
RR and R ' R ' separately expression-OH, halogen, C1-6Alkyl or C1-6Alkoxy, and the hydrogen in RR and R ' R ' can By 1-5 identical or different G4Replace, RR and R ' R ' can also be formed together C with the phosphorus atoms being connected3-12Heterolipid ring, it is described C3-12Heterolipid ring can additionally comprise one or more O, N or S (=O)mHetero atom；
m、G3And G4It is defined as above.
Wherein, various general formula compounds defined by the present invention, the pharmaceutically acceptable salt are the phosphorous pyrrole Simultaneously [2,3-d] pyrimidin-7-ones class compound and inorganic acid, organic acid, inorganic base, organic base are formed by chemical reaction for pyridine Salt.
Above-mentioned salt retains the bioactivity of compound of the present invention.The inorganic acid or organic acid can be with are as follows: hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, salicylic acid, Tartaric acid, methanesulfonic acid, ethanesulfonic acid, 2- ethylenehydrinsulfonic acid, benzene sulfonic acid, substituted benzene sulfonic acid (for example, p-methyl benzenesulfonic acid), different cigarette Acid, oleic acid, tannic acid, pantothenic acid, ascorbic acid, succinic acid, maleic acid, gentianic acid, fumaric acid, gluconic acid, uronic acid, glucose Diacid or sucrose acid, formic acid, benzoic acid, glutamic acid, pamoic acid, sorbic acid etc.；The inorganic base or organic base can be with are as follows: Sodium hydroxide, potassium hydroxide, lithium hydroxide, iron hydroxide, calcium hydroxide, barium hydroxide, aluminium hydroxide, magnesium hydroxide, hydrogen-oxygen Changing zinc, ammonium hydroxide, hydroxide organic quaternary ammonium salt, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, carbonating has Machine quaternary ammonium salt, sodium bicarbonate, saleratus, lithium bicarbonate, calcium bicarbonate, barium bicarbonate, magnesium bicarbonate, carbonic acid hydrogenate organic season Ammonium salt, methylamine, dimethylamine, trimethylamine, ethamine, diethylamine, triethylamine, trishydroxymethylaminomethane etc..
More preferable phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound or its pharmaceutically acceptable salt is Any one following compound:
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Cis- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
2- amino -8- [1- (diethoxy phosphoryl methyl) -4- piperidyl] -6- (6- methoxyl group -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- dimethylamino -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- dimethylamino -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- dimethylamino -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- dimethylamino -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -4- [2- amino -6- (6- dimethylamino -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine - 8- yl]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Cis- -4- [2- amino -6- (6- dimethylamino -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine - 8- yl]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- dimethylamino -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- dimethylamino -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
2- amino -8- [1- (diethoxy phosphoryl methyl) -4- piperidyl] -6- (6- dimethylamino -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methylamino -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methylamino -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methylamino -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methylamino -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (methyl) amino) cyclohexyl] -6- (6- methoxyl group -3- Pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (methyl) amino) cyclohexyl] -6- (6- methoxyl group -3- Pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (ethyl) amino) cyclohexyl] -6- (6- methoxyl group -3- Pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (ethyl) amino) cyclohexyl] -6- (6- methoxyl group -3- Pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (n-propyl) amino) cyclohexyl] -6- (6- methoxyl group - 3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (n-propyl) amino) cyclohexyl] -6- (6- methoxyl group - 3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (isopropyl) amino) cyclohexyl] -6- (6- methoxyl group - 3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (isopropyl) amino) cyclohexyl] -6- (6- methoxyl group - 3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (cyclopropyl) amino) cyclohexyl] -6- (6- methoxyl group - 3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (cyclopropyl) amino) cyclohexyl] -6- (6- methoxyl group - 3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans--[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyloxy] methyl-ethoxy-phosphoric acid；
Cis--[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyloxy] methyl-ethoxy-phosphoric acid；
Trans--[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyloxy] methyl-phosphoric acid；
Cis--[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyloxy] methyl-phosphoric acid；
Trans--[[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyl] amino] methyl-ethoxy-phosphoric acid；
Cis--[[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyl] amino] methyl-ethoxy-phosphoric acid；
Trans--[[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyl] amino] methyl-phosphoric acid or
Cis--[[[2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] is phonetic by 4- Pyridine -8- base] cyclohexyl] amino] methyl-phosphoric acid.
The phosphorous pyrido of any one above-mentioned [2,3-d] pyrimidin-7-ones class compound or it is pharmaceutically acceptable The raceme or enantiomter of salt are also technical solution of the present invention.
The phosphorous pyrido of any one above-mentioned [2,3-d] pyrimidin-7-ones class compound or it is pharmaceutically acceptable The cis or trans isomers of salt is also technical solution of the present invention.
The present invention simultaneously claimed above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its in pharmacy The raceme or enantiomter of upper acceptable salt, wherein phonetic having been able to phosphorous pyrido [2,3-d] is prepared Pyridine -7- ketone compounds or its pharmaceutically on the basis of acceptable salt, raceme and corresponding isomers can be using normal Technological means is advised to obtain, those skilled in the art simultaneously it can be envisaged that the raceme and corresponding isomers also have it is identical/ Similar activity.
The present invention also protects the synthetic intermediate of above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound (IIa), (IIb) or (IIc):
In formula,
Ar ' is aryl or heteroaryl, and the hydrogen in Ar ' can be by 1-5 identical or different R8Replace；
R2Indicate H, C1-6Alkyl, C3-6Naphthenic base or C3-12Heteroalicyclyl；And R2In hydrogen can be identical or different by 1-5 Halogen ,-CN ,-OH, C1-6Alkyl or C3-6Naphthenic base replaces；
R and R ' separately indicates H, OH, halogen, C1-6Alkyl, C3-6Naphthenic base, C3-12Heteroalicyclyl, C1-6Alcoxyl Base, C3-6Cycloalkyloxy or C3-12Heterolipid epoxy group, and the hydrogen in R and R ' can be by 1-5 identical or different R9Replace, R and R ' Also C can be formed together with the phosphorus atoms being connected3-12Heterolipid ring, the C3-12Heterolipid ring can additionally comprise one or more O, N or S (=O)mHetero atom；
Wherein:
R8And R9Separately indicate H ,-CN ,-CF3、-OCF3、-NO2, halogen, C1-6Alkyl, C3-6Naphthenic base, C3-12It is miscellaneous Alcyl, C1-6Alkoxy, C1-6Cycloalkyloxy, C3-12Heterolipid epoxy group or R10R11N-.Wherein, R10And R11Independently earth's surface Show H, C1-6Alkyl, C3-6Naphthenic base or C3-12Heteroalicyclyl.Work as R10And R11It, can be with the nitrogen-atoms when being connected on same nitrogen-atoms It is formed together a C3-12Heterolipid ring, this C3-12Heterolipid ring can also additionally comprise one or more O, N or S (=O)mHetero atom；
M is 0,1 or 2.
Or the synthetic intermediate as shown in structural formula (IIaa), (IIbb) or (IIcc):
Described in formula,
R2Indicate hydrogen, C1-6Alkyl, C3-6Naphthenic base or C3-12It is heteroalicyclyl, preferably hydrogen, methyl, ethyl, n-propyl, different Propyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, oxetanylmethoxy, azelidinyl, Tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, piperazinyl or morpholinyl, further preferably hydrogen, methyl, second Base, n-propyl, second propyl, cyclopropyl, oxetanylmethoxy, tetrahydrofuran base or THP trtrahydropyranyl are still more preferably hydrogen, first Base, ethyl, isopropyl, cyclopropyl, and these groups can be by 1-5 halogen ,-CN ,-OH or C1-6Alkyl replaces；
R88Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy, preferably halogen ,- OCF3、-OCH3、-OCH2CH3Or-NMe2, further preferably-OCH3Or-NMe2；
R12And R13Separately expression-OH, halogen, C1-6Alkyl or C1-6Alkoxy, preferably-OH or C1-6Alcoxyl Base, further preferably C1-6Alkoxy is still more preferably methoxyl group, ethyoxyl, positive propoxy or isopropoxy.
The present invention provides the systems of above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound and its synthetic intermediate Preparation Method, as an implementation, this method can the step shown in Scheme 1A and/or Scheme 1B form (such as Scheme 1A illustrates the preparation method of partially synthetic intermediate, and Scheme 1A+Scheme 1B illustrates the phosphorous pyridine in part And the preparation method of [2,3-d] pyrimidin-7-ones class compound, Scheme 1B are illustrated directly with the preparation of above-mentioned synthetic intermediate The method of phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound, similarly hereinafter):
Wherein, Ar, R and R ' it is defined as above (see the definition in logical formula (I) compound to each substituent group).M includes but not It is limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、 BF3K、Sn(Bu-n)4、SnMe4Deng.LG represents a leaving group, including but not limited to F, Cl, Br, I, MsO, p-TsO, TfO, PhSO3Deng.The meaning of Pd catalyst, Base and Solvent are shown in " term definition " part.Compound A-1 can basis WO2008032162 preparation.
The preparation method of another phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound, this method is by Scheme2A And/or the composition of step shown in Scheme 2B:
Wherein, Ar, R2, R and R ' be defined as above (see the definition in logical formula (I) compound to each substituent group).W represents ammonia Base or 2,5- dimethyl pyrrole -1- base.The meaning of Oxidant, Reductant, Base and Solvent are shown in " term definition " portion Point.
The preparation method of another phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound, this method is by Scheme3A And/or the composition of step shown in Scheme 3B:
Wherein, Ar, R2, R and R ' be defined as above (see the definition in logical formula (I) compound to each substituent group).M include but It is not limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、 BF3K、Sn(Bu-n)4、SnMe4Deng.Pd catalyst, Coupling Reagent, Base and Solvent meaning see " term Definition " part.
The preparation method of another phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound, this method is by Scheme4A And/or the composition of step shown in Scheme 4B:
Wherein, Ar, R and R ' it is defined as above (see the definition in logical formula (I) compound to each substituent group).M includes but not It is limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、 BF3K、Sn(Bu-n)4、SnMe4Deng.LG represents a leaving group, including but not limited to F, Cl, Br, I, MsO, p-TsO, TfO, PhSO3Deng.The meaning of Pd catalyst, Base and Solvent are shown in " term definition " part.
The preparation method of another phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound, this method is by Scheme5A And/or the composition of step shown in Scheme 5B:
Wherein, Ar, R and R ' it is defined as above (see the definition in logical formula (I) compound to each substituent group).M includes but not It is limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、 BF3K、Sn(Bu-n)4、SnMe4Deng.LG represents a leaving group, including but not limited to F, Cl, Br, I, MsO, p-TsO, TfO, PhSO3Deng.Pd catalyst, Acid, Base and Solvent meaning see " term definition " part.
The present invention also protect containing above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically The pharmaceutical composition of acceptable salt or its raceme or enantiomter.
Pharmaceutical composition of the present invention can be used for treating because of protein kinase abnormal activity caused by disease.Except above-mentioned work Property ingredient outside, pharmaceutical composition of the present invention further includes pharmaceutically acceptable one or more of carrier or diluent.
The dosage form of pharmaceutical composition of the present invention includes but is not limited to: oral agents, injection, anus suppository, nose Hole inhalant, eye drops or skin patch.
The pharmaceutical composition being made of compound of the present invention is for treating mammal, such as human patient, because of albumen Disease caused by the abnormal activity of kinases.
Compound (including raceme, enantiomter, cis-trans-isomer and other stereoisomer) of the present invention or Pharmaceutically acceptable salt, hydrate, solvate or prodrug are and suitable by preparation (formulation) process for it The pharmaceutical composition that pharmaceutically acceptable carrier and pharmaceutically common adjuvant are prepared into conducive to administration.
Specifically, the drug administration approach of compound of the present invention composition can be with are as follows: (1) take orally: such as tablet, glue Capsule etc.；(2) it injects: such as intravenous injection, subcutaneous injection, intramuscular injection, eyeball injection, intraperitoneal injection；(3) anus plug: such as Suppository, gelling agent etc.；(4) nostril sucks: such as spray, aerosol；(5) eye drops；(6) skin patch.It can also be used Drug delivery system, for example, liposome (liposome), slow release method etc., wherein the method preferentially selected is oral and injection, The method more preferably selected is oral.
The various dosage forms for the pharmaceutical composition that the present invention is made of the compound can be commonly square using medical industry Method preparation, for example, mixing, dissolution, granulation, grinding, emulsification, capsule, sugar-coat, freeze-drying, cryospray etc..
Content range of the compound in foregoing pharmaceutical composition in the present invention is 0.001-100%.The pharmaceutical composition The effective dose that object is applied to mammal including people is per kg body weight per day 0.1-500 milligrams, the dosage of optimization 1-100 milligrams are used for per kg body weight per day.In this effective dosage ranges, the compound in the present invention plays its suppression The pharmacological action of protein kinase activity processed and treatment because of disease (such as cancer) caused by abnormal protein kinase activity.
The frequency of use of drug of the present invention is according to used compound or its pharmaceutical composition and the disease of application and Change, the pharmaceutical composition in the present invention is usually to be administered daily 1-6 times, and the administration frequency of optimization is to be administered daily 1-3 times.
The packaging of drug of the present invention and preservation are similar with general drug, such as the drug of solid dosage forms can be directly loadable into Desiccant etc. is put into glass, plastics, papery or metal bottle, in bottle preferably to keep the quality of drug；The drug of liquid dosage form Generally it is fitted into glass, plastics or metal bottle or hose；The drug for the dosage form that hazes generally is packed into filling with pressure reducing valve etc. for pressure resistance In the metal or plastic containers set.
Invention further provides phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound or its pharmaceutically Acceptable salt or its raceme or enantiomter, or contain phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound Or its pharmaceutically the pharmaceutical composition of acceptable salt or its raceme or enantiomter treatment because protein kinase exception Application in disease caused by activity.
In above-mentioned application, the protein kinase is PI3K or mTOR, and the preferably protein kinase is PI3K, more into one Step is preferably PI3K- α, PI3K- β, PI3K- γ and PI3K- δ.
The compounds of this invention composition pharmaceutical composition application described in disease be psoriasis, cirrhosis, tracheitis, Rheumatic arthritis, lupus erythematosus, diabetes, the disease for being related to angiogenesis, disease of eye, disease of immune system, angiocarpy Disease, epilepsy, neurodegenerative disease, Alzheimer's disease, Huntington's disease or Parkinson's disease.
Disease caused by the abnormal activity of the present invention because of protein kinase is tumour, specifically includes solid tumor and liquid Tumor, more specifically include: lung cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, skin or intraocular melanoma, uterine cancer, oophoroma, The carcinoma of the rectum, anal region cancer, gastric cancer, colon cancer, breast cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical carcinoma, carcinoma of vagina, vaginal orifice cancer, Hodgkin's disease, cancer of the esophagus, carcinoma of small intestine, internal system cancer, thyroid cancer, parathyroid carcinoma, soft tissue sarcoma, carcinoma of urethra, yin Stem cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or carcinoma of ureter, kidney, nervous centralis cental system (CNS) Neoplasm, spinal column axis tumour, pituitary adenoma, gastrointestinal stromal, colorectal cancer, non-small cell lung cancer, Small Cell Lung Cancer, fertilizer One of mastocytosis, glioma, sarcoma, lymthoma or any several combination.
Proved by a series of test, phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound of the present invention or its in medicine Acceptable salt has the following beneficial effects: that (1) passes through the screening experiment of inhibition kinase activity on, it can be seen that of the present inventionization Closing object has very strong inhibiting effect to a series of protein kinases especially PI3K and mTOR；(2) pressed down by the tumour to animal System test it can be seen that, such phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt can To significantly inhibit tumour, and without apparent toxicity；(3) compound of the present invention can make jointly with other anti-tumor drugs With to play collaboration (synergistic) or adduction (additive) effect；(4) compound in the present invention can be with other Tumor therapy, such as radiotherapy, interventional therapy etc. be used together.It can be seen that a kind of phosphorous pyrido of the present invention [2, 3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt can be used as a kind of effectively treatment because of protein kinase exception The drug of disease caused by activity.
Compound of the present invention treat because protein kinase activity extremely caused by above-mentioned disease in, the kidney For adrenal, clear-cell carcinoma, carcinoma of renal pelvis；Glioma is brain stem glioma, neuroendocrine glia tumour, neuroglia Tumor.
Compound of the present invention treat because protein kinase activity extremely caused by disease in, can be in addition to tumour For psoriasis (or psoriasis), cirrhosis, tracheitis, rheumatic arthritis, lupus erythematosus, diabetes, it is related to angiogenesis Disease, be related to restenosis disease, disease of eye such as AMD, rheumatic arthritis and other inflammation, disease of immune system example Such as auto-immune disease (for example, AIDS), cardiovascular disease such as atherosclerosis, kidney trouble, epilepsy, neurological Property disease, such as Alzheimer's disease, Huntington's disease, Parkinson's disease etc..
The definition of term
The following are terms involved in the present invention to define.The variable groups being used in the present invention, such as Ra、Rb, m etc. It is only applicable to this trifle (i.e. " definition of term " part).
According to the common knowledge of those of ordinary skill in the art, chemical reaction needs to carry out in a solvent in most cases, Preparation the common solvent of the compound of the present invention (Solvent) include but is not limited to water, methanol, ethyl alcohol, isopropanol, normal propyl alcohol, N-butanol, isobutanol, the tert-butyl alcohol, 2-methyl cellosolve, 2,2,2 tfifluoroethyl alcohol, methylene chloride, 1,2- dichloroethanes, chloroform, THF, dioxane, DME, ethyl acetate, ether, methyl tertiary butyl ether, hexane, hexamethylene, toluene, acetonitrile, DMF, DMSO or this Two or more of mixtures etc. in a little solvents.
Chemical reaction needs to occur in the presence of sour (Acid) or alkali (Base) in some cases, the preparation present invention The common alkali of compound (Base) include but is not limited to Et3N、Me3N、i-Pr2NEt, pyridine, DBU, DABCO, tetramethylguanidine, NaOH、KOH、Cs2CO3、Na2CO3、K2CO3、NaHCO3、KF、CsF、K3PO3、K2HPO4、KH2PO4、NaH、n-BuLi、s-BuLi、 t-BuLi、NaN(SiMe3)2、LiN(SiMe3)2、KN(SiMe3)2Or two or more of mixtures in these alkali etc.；It is common Acid (Acid) include but is not limited to HCO2H, AcOH, TFA (trifluoracetic acid), HCl (hydrochloric acid), H2SO4、HNO3、H3PO4、p- TsOH、PhSO3H, CSA, MsOH etc. or Lewis acid ZnCl2、AlCl3、BF3.OEt2Deng.
Chemical reaction needs to occur in the presence of coupling reagent (Coupling Reagent) in some cases, makes Standby the common coupling reagent of the compound of the present invention (Coupling Reagent) include but is not limited to DCC, EDC, HATU, TBTU, PyBOP, HCTU, BOP, T3P, DIC, HOBt, HOAt, CDI, DEPBT etc..
Preparation some steps of the compound of the present invention are needed using reduction reaction (Reduction) and go back original reagent (Reductant), the go back original reagent includes but is not limited to H2+Pd/C、H2+Pd(OH)2、H2+PtO2、Ni、Ti (OPr-i)4+NaBH4、Ti(OPr-i)4+NaB(OAc)3H、Ti(OPr-i)4+NaBH3(CN)、Ti(OPr-i)4+H2、Ni、Mg+MeOH、Fe+AcOH、Fe+HCl、Zn+AcOH、Zn+HCl、Zn+NH4OAc、SnCl2、 LiAlH4、NaBH4、NaBH3(CN)、NaB(OAc)3H、BH3Deng.
Preparation some steps of the compound of the present invention are needed using oxidation reaction (Oxidation) and oxidising agent (Oxidant), the oxidising agent includes but is not limited to PCC (PyH.ClCrO3)、PDC(2Py.Cr2O7)、K2Cr2O7、 Na2Cr2O7、H2Cr2O7、CrO3、CrO3.2Py、O2、H2O2、mCPBA、DMSO+(COCl)2、NaClO2、NaClO、Dess-Martin reagent、KMnO4、OsO4、MnO2Deng.
Preparation some steps of the compound of the present invention are needed using palladium catalyst (Pd catalyst), the palladium catalyst Including but not limited to Pd/C, Pd (PPh3)4、Pd2(dba)3、PdCl2、Pd(OAc)2、Pd(O2CCF3)2、PdCl2(dppf)、PdCl2 (dppp)、Pd(PPh3)2Cl2、Pd(PhCN)2Cl2、Pd(OH)2Deng.
Preparation some steps of the compound of the present invention need Deprotection (Deprotection), when protecting group is Boc (or-CO2When Bu-t), common deprotecting regent includes but is not limited to HCl, TFA, H2SO4Deng, when protecting group be CBZ (or- CO2CH2When Ph), common deprotecting regent includes but is not limited to dense HCl, H2+ Pd/C etc., when protecting group is Bn (or-CH2Ph) When, common deprotecting regent includes but is not limited to H2+Pd/C、H2+Pd(OH)2、H2+ Pd/C+HCl etc..
Preparation the compound of the present invention reaction usually carry out at room temperature, but sometimes for be reduced to -78 DEG C or heating To 200 DEG C；Reaction usually carried out under the conditions of solvent above-mentioned and temperature and convention stir, but sometimes in micro-wave oven into Row；When the alkali, reagent, catalyst used is to water or oxygen sensitive, reaction need to carry out under the conditions of anhydrous and oxygen-free, in this feelings Under condition, protonic solvent cannot be used.
" solvate " refers to compound of the present invention and chemically common solvent with covalent bond, hydrogen bond, ionic bond, model The stable material of the formation such as De Huali, complexing, inclusion, the solvent can be with are as follows: methanol, ethyl alcohol, propyl alcohol, butanol, ethylene glycol, Propylene glycol, polyethylene glycol, acetone, acetonitrile, ether, methyl tertiary butyl ether etc..
" hydrate " refers to that solvate, solvent therein are water.
" prodrug ", which refers to, converts another compound for the compound in the present invention by the method for chemical synthesis or physics, And after giving the compound to mammal, it is converted to compound of the present invention in animal body.Utilize " prodrug " side Method is typically to overcoming medical compounds itself bad or not good enough physicochemical properties or druggability.
" raceme, enantiomter, cis-trans-isomer and other stereoisomer " refers to compound molecule having the same Formula and molecular weight, however different compounds is formed due to the different bonding patterns and arrangement space sequence between atom, this The compound of sample is isomers or stereoisomer.When these stereoisomers mirror each other, i.e., look the same, but It cannot be completely coincident, as left hand and the right hand, these compounds are enantiomter.The absolute configuration of enantiomter is usually used (R)-and (S)-or R- and S- indicate.The rule of the specific absolute configuration for determining enantiomter is shown in Chapter 4of “Advanced Organic Chemistry,”4th edition(by J.March,John Wiley and Sons,New York,1992).(R)-and (S)-enantiomter to polarised light have opposite turning effort, i.e., left-handed and dextrorotation.As (R)- And (S)-enantiomter in 1:1 ratio mixing or in the presence of, which does not have turning effort to polarised light, and at this moment this is mixed It closes object and is known as raceme.
Compound of the present invention there is likely to be tautomer (tautomers), rotational isomer (rotamers), Cis-trans-isomer etc., these concepts all can be in " the Advanced Organic Chemistry, " 4 of J.MarchthIn edition It finds and is understood.As long as these isomers have living with the same or similar inhibition protein kinase of compound of the present invention The effect of property, these isomers are also covered by the present invention.
After compound in the present invention is given mammal (such as people), according to the common sense of this field, it is possible in animal Various metabolites are metabolized to by different enzymes in vivo, if these metabolites have with as compounds of the present invention Inhibit the effect of protein kinase activity, these metabolites are also covered by the present invention.
" pharmaceutical composition " refers to one in compound of the present invention, multiple, pharmaceutically acceptable salt or solvent Close the system that object or hydrate or prodrug and other chemical component (such as pharmaceutically acceptable carrier or diluent) are mixed to prepare Agent.The purpose of pharmaceutical composition is the process for promoting to be administered to animal.In above-mentioned pharmaceutical composition, in addition to including pharmaceutically may be used Outside the carrier of receiving, common adjuvant in medicine (agent) can also be included in, such as: it is antibacterial agent, antifungal agent, antimicrobial Agent, preservative, toner, solubilizer, thickener, surfactant, complexing agent, protein, amino acid, fat, carbohydrate, dimension life Element, minerals, microelement, sweetener, pigment, essence or their combination etc..
" pharmaceutically acceptable carrier " or " diluent " refer to non-active ingredient in pharmaceutical composition, can be but unlimited In: calcium carbonate, calcium phosphate, various sugared (such as lactose, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, carbonic acid Magnesium, acrylate copolymer, methacrylate polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenation castor Sesame oil, more ethoxy aluminium castor oil, sesame oil, corn oil, peanut oil etc..
" alkyl " refers to the saturated hydrocarbon group with the linear chain or branched chain for specifying number carbon atom, such as C1-6Alkane Base refers to containing minimum 1, the linear chain or branched chain group of most 6 carbon atoms.C0Alkyl represents a covalent single bond.It is of the present invention Alkyl include but is not limited to: methyl, ethyl, propyl, butyl, isopropyl, neopentyl, 2- methyl-1-hexyl etc..Institute of the present invention The alkyl stated is sometimes referred to as alkylidene, i.e. alkyl loses the group that a hydrogen atom is formed.One in alkyl or alkylidene or Whole hydrogen atoms can be replaced by following groups: naphthenic base, aryl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano, nitre Base, carboxyl, sulfydryl, oxygroup (oxo), alkoxy, aryloxy group, alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C- amide groups, N- amide groups, O- ammonia carbonyloxy group, N- ammonia carbonyloxy group, the thio ammonia carbonyloxy group of O-, the thio ammonia carbonyloxy group of N-, C- ester group, O- ester group and- NRaRb, wherein RaAnd RbIt is respectively selected from: hydrogen, alkyl, naphthenic base, aryl, acetyl group, carbonyl, sulfonyl, trifyl Deng, and RaAnd Rb5- or 6- member heterolipid ring can be formed together with nitrogen-atoms.
" naphthenic base " or " cycloalkanes " refers to the single, double or polycyclic hydrocarbon group for specifying number carbon atom, double Ring or it is polycyclic when, with condensed (two rings or multiple rings share two adjacent carbon atoms) or can screw togather that (two rings are multiple Ring shares a carbon atom) form combine, such as C1-6Naphthenic base refers to containing minimum 1, most 6 single, double or polycyclic carbon Hydrogen compound group.C0Naphthenic base represents a covalent single bond.Unsaturated double or triple bonds can be contained in naphthenic base, but not Pi-electron system with total conjugated.Naphthenic base of the present invention is sometimes referred to as cycloalkylidene, i.e. naphthenic base loses a hydrogen The group that atom is formed.Naphthenic base of the present invention includes but is not limited to: cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, Cycloheptatriene base, adamantane etc. (citing such as Table A):
Table A
One or all hydrogen atom in naphthenic base or cycloalkanes can be replaced by following groups: alkyl, aryl, heteroaryl, miscellaneous Alicyclic ring, halogen, amino, hydroxyl, cyano, nitro, carboxyl, sulfydryl, oxygroup (oxo), alkoxy, aryloxy group, alkyl thiol, aryl Sulfydryl, carbonyl, thiocarbonyl group, C- amide groups, N- amide groups, O- ammonia carbonyloxy group, N- ammonia carbonyloxy group, the thio ammonia carbonyloxy group of O-, N- sulphur For ammonia carbonyloxy group, C- ester group, O- ester group and-NRaRb, wherein RaAnd RbIt is respectively selected from: hydrogen, alkyl, naphthenic base, aryl, acetyl Base, carbonyl, sulfonyl, trifyl etc., and RaAnd Rb5- or 6- member heterolipid ring can be formed together with nitrogen-atoms.
" heteroalicyclyl or heterolipid ring " refers to the monocycle being made of 3 to 12 non-hydrogen annular atoms, bicyclic or polycyclic system, wherein At least one annular atom is the hetero atom selected from O, N, S or P, remaining annular atom is carbon atom, for example, C8Heteroalicyclyl refers to The monocycle that is made of 8 non-hydrogen annular atoms, bicyclic or polycyclic moiety, wherein at least one annular atom are selected from O, N, S or P.It is this In ring in addition to singly-bound, it can also contain double bond or three key, but these double bonds or three key do not constitute the aromatic structure being all conjugated.These Monocycle, bicyclic or polycyclic system can exist in the form of condensed ring, bridged ring or loop coil.Heteroalicyclyl of the present invention is sometimes Refer to that sub- heteroalicyclyl, i.e. heteroalicyclyl lose the group that a hydrogen atom is formed.Heteroalicyclyl or heterolipid ring packet in the present invention It includes but is not limited to: (citing such as table such as piperidines, morpholine, piperazine, pyrrolidines, indoline, tetrahydropyridine, tetrahydrofuran, tropanol B):
Table B
One or all hydrogen atom in heteroalicyclyl or heterolipid ring can be replaced by following groups: alkyl, naphthenic base, virtue Base, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano, nitro, carboxyl, sulfydryl, oxygroup (oxo), alkoxy, aryloxy group, Alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C- amide groups, N- amide groups, O- ammonia carbonyloxy group, N- ammonia carbonyloxy group, O- are thio The thio ammonia carbonyloxy group of ammonia carbonyloxy group, N-, C- ester group, O- ester group and-NRaRb, wherein RaAnd RbIt is respectively selected from: hydrogen, alkyl, cycloalkanes Base, aryl, acetyl group, carbonyl, sulfonyl, trifyl etc., and RaAnd RbIt is miscellaneous that 5- or 6- member can be formed together with nitrogen-atoms Alicyclic ring.
" alkenyl " refers to the linear chain or branched chain hydrocarbon group containing at least two carbon atoms and a double bond, such as C2-6Alkenyl refers to containing minimum 2, unsaturated group of the linear chain or branched chain containing at least one double bond of most 6 carbon atoms.The present invention In alkenyl include but is not limited to: vinyl, 2- acrylic, 1- pentenyl etc..
" alkynyl " refers to the linear chain or branched chain hydrocarbon group containing at least two carbon atoms and three keys, such as C2-6Alkynyl refers to containing minimum 2, unsaturated group of the linear chain or branched chain containing at least one three key of most 6 carbon atoms.The present invention In alkynyl include but is not limited to: vinyl, 2- acrylic, 1- pentenyl etc..
" halogen " refers to fluorine, chlorine, bromine or iodine.
" alkoxy " refers to be connected by oxygen atom with other groups with the alkyl for specifying number carbon atom.In the present invention Alkoxy includes but is not limited to: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, new Amoxy, 2- methyl-1-hexyloxy etc..
" cycloalkyloxy " refers to be connected by oxygen atom with other groups with the naphthenic base for specifying number carbon atom.The present invention In cycloalkyloxy include but is not limited to: cyclopropyl alkoxy, cyclobutane oxygroup, hexamethylene alkoxy etc..
" heterolipid epoxy group " refers to that heteroalicyclyl is connected by oxygen atom with other groups.Heterolipid epoxy group packet in the present invention It includes but is not limited to: -4 base oxygroup of piperidines, oxetanes -3- base oxygroup etc..
" aryl " refers to that, by specifying number monocycle, the bicyclic or polycyclic moiety that carbon atom forms, wherein at least one ring has The pi-electron system of total conjugated simultaneously meets N+2 rule, that is, has armaticity, but entire group need not be all conjugated.For example, C6 Aryl means phenyl.Aryl can also occur in the form of arlydene, i.e., in heteroaryl structure with other groups there are two or it is above Tie point.Aryl in the present invention includes but is not limited to: phenyl, naphthalene, indenyl, indanyl, tetrahydronaphthalene etc..In aryl One or all hydrogen atom can be replaced by following groups: alkyl, naphthenic base, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, Cyano, nitro, carboxyl, sulfydryl, oxygroup (oxo), alkoxy, aryloxy group, alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C- Amide groups, N- amide groups, O- ammonia carbonyloxy group, N- ammonia carbonyloxy group, the thio ammonia carbonyloxy group of O-, the thio ammonia carbonyloxy group of N-, C- ester group, O- Ester group and-NRaRb, wherein RaAnd RbIt is respectively selected from: hydrogen, alkyl, naphthenic base, aryl, acetyl group, carbonyl, sulfonyl, fluoroform Sulfonyl etc., and RaAnd Rb5- or 6- member heterolipid ring can be formed together with nitrogen-atoms.
" heteroaryl " refers to by specifying number monocycle, the bicyclic or polycyclic moiety that non-hydrogen annular atom forms, wherein at least one Annular atom is the hetero atom selected from O, N, S or P, remaining annular atom is carbon atom, also, wherein at least one ring is with completely total The pi-electron system of yoke simultaneously meets N+2 rule, that is, has armaticity, but entire group need not be all conjugated, for example, C5Heteroaryl Refer to that the aromatic group being made of 5 non-hydrogen annular atoms, wherein at least one annular atom are selected from O, N, S or P.Heteroaryl Can occur in the form of inferior heteroaryl, i.e., in heteroaryl moieties with other groups there are two or above tie point.The present invention In heteroaryl include but is not limited to: arsenic pyridine, arsenic heavy stone used as an anchor ketone, tetrahydro arsenic heavy stone used as an anchor ketone, miaow pyridine, pyrazine, pyridazine, imidazoles, thiazole, thiophene, Furans, indoles, azaindole, benzimidazole, indoline, indolone, quinoline give repeated exhortations etc. (citing such as table C):
Table C
One or all hydrogen atom in heteroaryl can be replaced by following groups: alkyl, naphthenic base, aryl, heterolipid ring, halogen Element, amino, hydroxyl, cyano, nitro, carboxyl, sulfydryl, oxygroup (oxo), alkoxy, aryloxy group, alkyl thiol, aryl thiol, carbonyl Base, thiocarbonyl group, C- amide groups, N- amide groups, O- ammonia carbonyloxy group, N- ammonia carbonyloxy group, the thio ammonia carbonyloxy group of O-, the thio ammonia carbonyl oxygen of N- Base, C- ester group, O- ester group and-NRaRb, wherein RaAnd RbIt is respectively selected from hydrogen, alkyl, naphthenic base, aryl, acetyl group, carbonyl, sulphur Acyl group, trifyl etc., and RaAnd Rb5- or 6- member heterolipid ring can be formed together with nitrogen-atoms.
" aryloxy group " refers to that aryl is connected by oxygen atom with other groups.Aryloxy group in the present invention includes but is not limited to: Phenoxy group, naphthoxy etc..
" heteroaryloxy " refers to that heteroaryl is connected by oxygen atom with other groups.Heteroaryloxy in the present invention includes but not It is limited to: 4- arsenic pyridine oxygroup, 2- thiophene oxy etc..
" amino " refers to H2The N- or in which substituted H of hydrogen atom2N-, i.e. RaHN- and RaRbN-。
" oxo " or " oxygroup " refers to that=O, i.e. oxygen atom are connected by double bond with hetero atoms such as carbon or N, S, P.It is taken by oxygroup The example in generation includes but is not limited to substance shown in table D:
Table D
" hydroxyl " refers to-OH.
" nitro " refers to-NO2。
" carboxyl " refers to-CO2H。
" sulfydryl " refers to-SH.
" alkyl thiol " refers to alkyl-S-.
" aryl thiol " refers to aryl-S-.
" carbonyl " refers to-C (=O)-.
" thiocarbonyl group " refers to-C (=S)-.
" C- amide groups " refers to-C (=O) NRaRb。
" N- amide groups " refers to C (=O) NRa-。
" O- ammonia carbonyloxy group " refers to-O-C (=O) NRaRb。
" N- ammonia carbonyloxy group " refers to O-C (=O) NRa-。
" the thio ammonia carbonyloxy group of O- " refers to-O-C (=S) NRaRb。
" the thio ammonia carbonyloxy group of N- " refers to O-C (=S) NRa-。
" C- ester group " refers to-C (=O) ORa。
" N- ester group " refers to C (=O) O-.
" acetyl group " refers to CH3C (=O)-.
" sulfonyl " refers to-SO2Ra。
" trifyl " refers to CF3SO2-。
Detailed description of the invention
Tumor-inhibiting action curve control figure of the compounds of this invention described in Fig. 1 embodiment 1 to mouse A549 tumour；
Tumor-inhibiting action curve control figure of the compounds of this invention described in Fig. 2 embodiment 2-4b to mouse A549 tumour；
Tumor-inhibiting action curve control figure of the compounds of this invention described in Fig. 3 embodiment 3 to mouse A549 tumour；
Tumor-inhibiting action tumor weight comparative diagram of the compounds of this invention described in Fig. 4 embodiment 5 to mouse A549 tumour；
Tumor-inhibiting action curve control figure of the compounds of this invention described in Fig. 5 embodiment 2-4a to mouse PC3 tumour；
Tumor-inhibiting action curve control figure of the compounds of this invention described in Fig. 6 embodiment 2-4a to mouse U87MG tumour.
Specific embodiment
Below in conjunction with specific embodiment, invention is further described in detail, so that reader further understands institute of the present invention Compound, preparation method and beneficial effect etc. are stated, but a specific embodiment of the invention is to claimed content Without restriction effect.
The english abbreviation occurred in embodiment and corresponding Chinese meaning is listed below.If do not had in embodiment It is listed in this abbreviation, then represents generally accepted meaning.
DMSO: dimethyl sulfoxide
DMSO-d6: hexadeuterated dimethyl sulfoxide
TMS: tetramethylsilane
DCM: methylene chloride
CDCl3: deuterated chloroform
CD3OD: deuterated methanol
THF: tetrahydrofuran
EtOAc: ethyl acetate
MeOH: methanol
EtOH: ethyl alcohol
HCl: hydrogen chloride or hydrochloric acid
TLC: thin-layer chromatography
LC-MS: liquid chromatograph mass spectrography
G: gram
Mg: milligram
Mol: mole
Mmol: mM
μM: micromole
L: it rises
μ L: microlitre
NM: nanomole
[M+H]+: the molecular ion peak in mass spectrum
N: equivalent concentration
M/z: mass-to-charge ratio
δ: chemical shift
DMAP:4- dimethyl aminopyridine
DIPEA: diisopropyl ethyl amine
11 carbon -7- alkene of DBU:1,8- diazabicylo [5.4.0]
PCC: pyridine chlorochromate drone salt
Ti(OPr-i)4: tetra isopropyl titanate
Pd(PPh3)4: tetrakis triphenylphosphine palladium (0)
Pd(PPh3)2Cl2: double-(triphenylphosphine) palladium chloride (II)
NBS:N- bromosuccinimide
LiHMDS: double-(trimethyl silicon substrate) amine lithium
LiAlH4: Lithium Aluminium Hydride
DMA: dimethyl acetamide
Common experimental conditions:
Nuclear magnetic resonance spectroscopy and carbon spectrum on Varian 400MHz or Bruker 400MHz instrument obtain (deuterated DMSO, Deuterated chloroform, deuterated methanol etc. are solvent, and TMS is internal standard).Mass spectrum obtained by liquid chromatograph-mass spectrometer (using ESI or APCI ion source ZQ4000, Waters, US).Ultraviolet spectra by Hitachi, Japan UV-3010 uv-spectrophotometric It measures.Infrared spectroscopy uses NICOLET6700 infrared spectrometric analyzer (KBr tabletting).High performance liquid chromatography uses Waters 2695ZORBAX high performance liquid chromatograph (Bx-C85 150 × 4.6mm of μ chromatographic columns).The measurement of fusing point uses The digital melting point apparatus IA9100 of Electrothermal, and do not correct.
Starting material, reagent and solvent are bought from following supplier: Beta-Pharma；Shanghai PI Chemicals；AndaChem；Taiyuan；Shanghai FWD Chemicals；Sigma-Aldrich,Milwaukee,WI, USA；Acros,Morris Plains,NJ,USA；Frontier Scientific,Logan,Utah,USA；Alfa Aesar, Ward Hill, MA, USA etc. are synthesized using method reported in the literature.Unless otherwise indicated, solvent is generally without drying, and straight It connects using the product of supplier or through over-molecular sieve drying.
Embodiment 1A
Trans- -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-15) preparation, specific reaction equation is as follows:
Step 1: toward drop in the dichloromethane solution (4L) of the chloro- 6- methylpyrimidine -2- amine (1-1,100g, 0.70mol) of 4- Add bromine (134g, 0.84mol), generated suspension is stirred at room temperature 2 hours, methylene chloride (5L) dilution is added, with full It is washed with sodium bicarbonate solution (2x3L) and saturated salt solution (3L), magnesium sulfate is dry, filter, to be concentrated to get the bromo- 4- of product 5- chloro- 6- methylpyrimidine -2- amine (1-2) is white solid (120g, yield: 79%).
Step 2: the chloro- 6- methylpyrimidine -2- amine (1-2,120g, 0.54mol) of 5- bromine 4-, trans-4-amino cyclohexanol Dimethyl acetamide (4L) solution of (1-3,58g, 0.5mol) and diisopropyl ethyl amine (110g, 0.84mol) adds in 120 DEG C Thermal response 16 hours.Reaction mixture is diluted with methyl tertiary butyl ether(MTBE) (2.0L), with saturated ammonium chloride solution (2x3.0L) and is satisfied And brine It, anhydrous magnesium sulfate is dry, filters, is concentrated to dryness, residue column chromatographic purifying, methylene chloride/methanol Mixture (95/5) is used as eluant, eluent, obtains the trans- -4- of product [(the bromo- 6- methylpyrimidine -4- base of 2- amino -5-) amino] hexamethylene Alcohol (1-4) is pale red solid (100g, yield: 61%).Nuclear magnetic resonance spectroscopy result:1H-NMR(CD3OD,400MHz):δ 3.90(m,1H),3.56(m,1H),3.25(s,3H),1.99-1.94(m,4H),1.42-1.30(m,4H)。
Step 3: trans- -4- [(the bromo- 6- methylpyrimidine -4- base of 2- amino -5-) amino] cyclohexanol (1-4,50g, 0.166mol), ethyl acrylate (1-5,83g, 0.83mol), triethylamine (84g, 0.83mol) and Pd (PPh3)4(10g, DMF (500mL) solution 8.65mmol) reacts 16 hours in 130 DEG C of heating.Reaction mixture is cooled to room temperature and is concentrated, residual Object with methylene chloride (200mL) dilute, filtering, be dried to obtain product it is trans--(E) -3- [2- amino -4- [(4- hydroxy-cyclohexyl) Amino] -6- methylpyrimidine -5- base] -2- ethyl acrylate (1-6) is white solid (25g, yield: 46%).Mass spectral analysis knot Fruit: m/z:321.20 [M+H]+。
Step 4: trans--(E) -3- [2- amino -4- [(4- hydroxy-cyclohexyl) amino] -6- methylpyrimidine -5- base] -2- Ethyl acrylate (1-6,40g, 0.125mol), benzenethiol (14g, 0.13mol), benzenethiol sodium (33g, 0.25mol), DBU (1- 7,76g, 0.5mol) and the DMF solution (400mL) of diisopropyl ethyl amine (97g, 0.75mol) it is small in 120 DEG C of heating reaction 16 When.Reaction mixture is concentrated to dryness, and residue is purified with silica gel column chromatography, mixture (95/5) conduct of methylene chloride/methanol Eluant, eluent obtains product trans- -2- amino -8- (4- hydroxy-cyclohexyl) -4- picoline [2,3-d] pyrimidin-7-ones, is yellow Solid (1-8,29g, yield: 85%).Mass spectrometry results: m/z:275.20 [M+H]+。
Step 5: trans--(2- amino -8- (4- hydroxy-cyclohexyl) -4- picoline [2,3-d] pyrimidin-7-ones (1-8, 29g, 0.106mol) DMF (290mL) solution in NBS (23g, 0.13mol) is added, after being stirred at room temperature 1 hour, reaction is mixed It closes object to be concentrated to dryness, residue column chromatographic purifying, the mixture (95/5) of methylene chloride/methanol is used as eluant, eluent, is produced The trans- bromo- 8- of -2- amino -6- (4- hydroxy-cyclohexyl) -4- picoline [2, the 3-d] pyrimidin-7-ones (1-9) of object, it is solid for yellow Body (27g, yield: 71%).Mass spectrometry results: m/z:353.00 [M+H,79Br]+,355.00[M+H,81Br]+。
Step 6: in trans- -2- amino -6- bromo- 8- (4- hydroxy-cyclohexyl) -4- picoline [2,3-d] pyrimidin-7-ones (1-9,11g, 31.1mmol), potassium carbonate (13g, 93mmol) and 2- methoxypyridine -3- ylboronic acid (1-10,6.8g, 56mmol) in DMF/H2Drum nitrogen 5 minutes in mixture in O (5:1,24mL), Pd (PPh is added into the mixture3)2Cl2 (3g,4.28mmol).Gained mixture is in 100 DEG C of micro-wave oven heating stirring 2 hours.Reaction mixture is concentrated to dryness, residue Purified with silica gel column chromatography, the mixture (95/5) of methylene chloride/methanol is used as eluant, eluent, obtains the trans- -2- amino -8- of product (4- hydroxy-cyclohexyl) -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-11) are yellow Solid (6.64g, yield: 56%).Mass spectrometry results: m/z:382.30 [M+H]+。
Step 7: trans- -2- amino -8- (4- hydroxy-cyclohexyl) -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-11,1.5g, 3.93mmol), bis- hexanone of 2,5- (1-12,2.7g, 24mmol) and p-methyl benzenesulfonic acid Toluene (100mL) the solution heated overnight at reflux of (0.15g, 0.87mmol).Reaction mixture is cooled to room temperature, and is concentrated.It is residual Stay object column chromatographic purifying, the mixture (80/20) of petrol ether/ethyl acetate is used as eluant, eluent, obtain the trans- -2- of product (2, 5- dimethyl pyrrole -1- base) -8- (4- hydroxy-cyclohexyl) -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] is phonetic Pyridine -7- ketone (1-13) is white solid (1g, yield: 55%).
Step 8: at 0 DEG C, toward trans- -2- (2,5- dimethyl pyrrole -1- base) -8- (4- hydroxy-cyclohexyl) -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-13,1.1g, 2.39mmol) THF solution LiHMDS (THF solution of 1N, 4mL, 4mmol) is added in (20mL).Gained mixture is stirred at room temperature 1 hour, is cooled to 0 DEG C, it is added diethoxy phosphoryl methyl triflate (1-14,1.1g, 3.6mmol).The mixture is stirred at room temperature 5 hours, saturation NH is added4Cl solution is quenched, and is extracted with dichloromethane.Organic layer is dried and concentrated, and residue is pure with preparation TLC Change obtains compound trans -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) - 6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-15,0.61g, yield: 42%).Mass spectrum point Analyse result: m/z:610.20 [M+H]+。
Embodiment 1
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - The preparation of 4- picoline [2,3-d] pyrimidin-7-ones (1-16), specific reaction equation are as follows:
Trans- -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-15,0.61g, 1mmol, according to embodiment 1A system It is standby) and hydroxylamine hydrochloride (0.35g, 5mmol) be dissolved in ethanol/water (10:1,22mL), and be heated to being refluxed overnight.Reaction mixing Object is concentrated under reduced pressure, the trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) that residue is purified with HPLC is prepared Cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-16,210mg, yield: It 40%), is yellow solid.Nuclear magnetic resonance spectroscopy result:1H-NMR(CDCl3, 400MHz): δ 8.31 (d, J=2.8Hz, 1H), 7.96 (dd, J=2.4,8.4Hz, 1H), 7.74 (s, 1H), 6.80 (d, J=8.4Hz, 1H), 5.52 (m, 1H), 5.31 (s, 2H), 4.24-4.17 (m, 4H), 3.98 (s, 3H), 3.85 (d, J=9.2Hz, 2H), 3.51 (m, 1H), 2.82 (m, 1H), 2.60 (s, 3H), 2.23-2.20 (m, 2H), 1.73-1.70 (m, 2H), 1.54-1.43 (m, 2H), 1.37 (t, J=7.2Hz, 6H).Matter Spectrum analysis result: m/z:532.20 [M+H]+。
Can be described according to embodiment 1A and embodiment 1 identical of following compounds (but being not limited to these compounds) or Similar method synthesis:
Embodiment 2A
Cis/trans -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) - The preparation of 6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (2A), specific reaction equation are as follows:
Step 1: at 0 DEG C, toward trans- -2- (2,5- dimethyl pyrrole -1- base) -8- (4- hydroxy-cyclohexyl) -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (1-13,0.179g, 0.39mmol, according to embodiment 1A In the 7th step synthesis) and methylene chloride (5mL) solution of sodium acetate (64mg, 0.78mmol) in addition PCC (0.11g, 0.47mmol), after gained mixture is stirred at room temperature 4 hours, filtering is concentrated under reduced pressure, the purifying of crude product purified by silica gel column chromatography, Petrol ether/ethyl acetate mixture (70/30) is used as eluant, eluent, obtains compound 2- (2,5- dimethyl pyrrole -1- base) -6- (6- methoxyl group -3- pyridyl group) -4- methyl -8- (4- oxocyclohexyl) pyridine [2,3-d] pyrimidin-7-ones (2A-1,0.093g, Yield: 52%).Mass spectrometry results: m/z:458.32 [M+H]+。
Step 2: 2- (2,5- dimethyl pyrrole -1- base) -6- (6- methoxyl group -3- pyridyl group) -4- methyl -8- (4- oxo Cyclohexyl) pyridine [2,3-d] pyrimidin-7-ones (2A-1,0.092g, 0.2mmol) and triethylamine (0.060g, 0.59mmol) THF (5mL) solution is stirred at room temperature 1 hour, is added Ti (OPr-i)4(0.25mL) and diethoxy phosphoryl methylamine (2-2, 0.075g, 0.30mmol), gained mixture is stirred at room temperature 2 hours, stirs after sodium borohydride (0.038g, 1.0mmol) is added It mixes overnight.Reaction mixture is quenched with saturated aqueous ammonium chloride (5mL), methylene chloride (3x20mL) extraction, organic phase sulphur Sour magnesium is dry, filtering, is concentrated, and residue is purified to obtain 8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -2- with HPLC (2,5- dimethyl pyrrole -1- base) -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (2A, 38mg, yield: 31%), being trans/cis mixture.Mass spectrometry results: m/z:609.32 [M+H]+。
Embodiment 2
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones (2-4a) and trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) hexamethylene Base] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (2-4b) preparation, specific reaction equation is such as Under:
Step 1: at 0 DEG C, toward trans- -2- amino -8- (4- hydroxy-cyclohexyl) -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones (1-11,1.5g, 3.93mmol are synthesized according to the 6th step in embodiment 1) and acetic acid PCC (1.1g, 4.7mmol) is added in methylene chloride (15mL) solution of sodium (640mg, 7.8mmol), gained mixture is in room temperature After lower stirring 4 hours, filtering is concentrated under reduced pressure, the purifying of crude product purified by silica gel column chromatography, petrol ether/ethyl acetate mixture (70/ 30) it is used as eluant, eluent, obtains compound 2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -8- (4- oxocyclohexyl) Pyridine [2,3-d] pyrimidin-7-ones (2-1,1g, yield: 67%).Mass spectrometry results: m/z:380.30 [M+H]+。
Step 2: 2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -8- (4- oxocyclohexyl) pyridine [2,3- D] THF (15mL) solution of pyrimidin-7-ones (2-1,1.5g, 4.0mmol) and triethylamine (1.2g, 11.8mmol) stirs at room temperature It mixes 1 hour, is added Ti (OPr-i)4(5mL) and diethoxy phosphoryl methylamine (2-2,1.5g, 5.9mmol), gained mixture It is stirred at room temperature 2 hours, is stirred overnight after sodium borohydride (0.75g, 19.8mmol) is added.Reaction mixture saturation chlorination Aqueous ammonium (30mL) is quenched, methylene chloride (3x100mL) extraction, and organic phase is dry with magnesium sulfate, filtering, is concentrated, residue Purified to obtain 2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridine with HPLC Base) (2-3,400mg, yield: 19%), being trans/cis mixture, further to -4- picoline [2,3-d] pyrimidin-7-ones With supercritical fluid chromatography (SFC) isolated 226mg is cis- and 50mg trans product.
Cis-product (2-4a): nuclear magnetic resonance spectroscopy result:1H-NMR(CDCl3, 400MHz): δ 8.32 (t, J=2.0Hz, 1H), 7.99 (dd, J=2.4,8.4Hz, 1H), 7.75 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 5.51 (m, 1H), 5.21 (s, 2H), 4.24-4.14 (m, 4H), 3.99 (s, 3H), 3.06 (d, J=13.6Hz, 2H), 2.88 (s, 2H), 2.84-2.58 (m,4H),2.10-2.07(m,2H),1.72-1.61(m,3H),1.39-1.34(m,8H).Mass spectrometry results: m/z: 531.30[M+H]+。
Trans product (2-4b): nuclear magnetic resonance spectroscopy result:1H-NMR(CDCl3, 400MHz): δ 8.35 (d, J=2.8Hz, 1H), 8.00 (dd, J=2.4,8.4Hz, 1H), 7.75 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 5.44 (m, 1H), 4.29- 4.19 (m, 4H), 3.99 (s, 3H), 3.12-3.06 (m, 2H), 3.01 (d, J=14.4Hz, 2H), 2.90 (s, 1H), 2.58 (s, 3H),2.02-1.99(m,2H),1.88(m,1H),1.61-1.51(m,4H),1.41-1.37(m,6H).Mass spectrometry results: m/z:531.30[M+H]+。
The same or similar method that following compounds (but being not limited to these compounds) can be described according to embodiment 2 Synthesis:
Embodiment 3A
Trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base] hexahydrobenzoid acid (3-7) preparation, specific reaction equation is as follows:
Step 1: the chloro- 6- methylpyrimidine -2- amine (1-2,109g, 0.49mol) of the bromo- 4- of 5-, trans-4-amino cyclohexyl Dimethyl acetamide (1L) solution of Ethyl formate (3-1,102g, 0.5mol) and diisopropyl ethyl amine (194g, 1.5mol) It flows back 12 hours in 130 DEG C.Mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride (1L), with water (2x500mL) and Saturated salt solution (2x500mL) washing.Organic phase sodium sulphate is dry, filters, is concentrated to get crude product trans- -4- [(2- ammonia The bromo- 6- methylpyrimidine -4- base of base -5-) amino] cyclohexyl ethyl formate (3-2), it is directly used in without purifying and reacts in next step.
Step 2: trans- -4- [(the bromo- 6- methylpyrimidine -4- base of 2- amino -5-) amino] cyclohexyl ethyl formate (3-2, 90g, 251.9mmol), ethyl acrylate (1-5,126g, 1.26mol), Pd (PPh3)4(30g) and triethylamine (127g, 1.26mol) DMF (1.5 liters) mixture at 130 DEG C heating stirring 12 hours.Mixture is concentrated under reduced pressure, residue is molten Solution is washed in methylene chloride (500mL) with water (200mL) and saturated salt solution (200mL).Organic phase sodium sulphate drying, It filters, being concentrated to get the trans- -4- of crude product, [[2- amino -5- [(E) -3- ethyoxyl -3- oxygroup propyl- 1- alkenyl] -6- methyl is phonetic Pyridine -4- base] amino] cyclohexyl ethyl formate (3-3), it is directly used in without purifying and reacts in next step.
Step 3: trans- -4- [[2- amino -5- [(E) -3- ethyoxyl -3- oxygroup propyl- 1- alkenyl] -6- methylpyrimidine -4- Base] amino] cyclohexyl ethyl formate (3-3,80g, 212.51mmol), benzenethiol (23g, 213mmol), benzenethiol sodium (34g, 255mmol), DBU (1-7,130g, 852mmol) and diisopropyl ethyl amine (165g, 12.8mol) are mixed in DMF (1.2L) Close object in 130 DEG C heating stirring 8 hours.Mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride (1L), uses water The washing of (400mL) and saturated salt solution (400mL).Organic phase sodium sulphate is dry, filters, is concentrated to get crude product, passes through silicon Rubber column gel column chromatogram purification obtains trans- -4- (2- amino -4- methyl -7- oxygroup pyrrole with the dichloromethane for containing 5% methanol Pyridine [2,3-d] pyrimidine -8- base) cyclohexyl ethyl formate (3-4,25g, 3 step gross production rate: 35%).
Step 4: toward trans- -4- (2- amino -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- base) hexahydrobenzoid acid NBS (12.8g, 72mmol) is added in DMF (250mL) solution of ethyl ester (3-4,25g, 75.67mmol), the mixture is in room temperature Lower stirring 2 hours.Mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride (200mL), is eaten with water (50mL) and saturation Salt water (50mL) washing.Organic phase sodium sulphate is dry, filters, is concentrated to get crude product, by silica gel chromatography, with containing The dichloromethane of 5% methanol, obtaining trans- -4-, (the bromo- 4- methyl -7- oxygroup pyridine [2,3-d] of 2- amino -6- is phonetic Pyridine -8- base) cyclohexyl ethyl formate (3-5,15g, yield: 48%).
Step 5: trans- -4- (bromo- 4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- base of 2- amino -6-) cyclohexyl first Acetoacetic ester (3-5,22g, 53.75mmol), potassium carbonate (14.9g, 108mmol), 2- methoxypyridine -3- ylboronic acid (1-10, 12.4g, 81mmol) and Pd (PPh3)4(4g) is in DMF/H2It is small that mixture in O (5:1,260 milliliters) stirs 2 at 100 DEG C When.Mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride (200mL), with water (50mL) and saturated salt solution (50mL) washing.Organic phase sodium sulphate is dry, filters, is concentrated to get crude product, by silica gel chromatography, with containing 5% The dichloromethane of methanol obtains trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup Pyridine [2,3-d] pyrimidine -8- base] cyclohexyl ethyl formate (3-6,3.5g, yield: 15%).
Step 6: trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] Pyrimidine -8- base] cyclohexyl ethyl formate (3-6,1.1g, 2.5mmol) and lithium hydroxide (210mg, 5mmol) be in H2O(10mL) After stirring 3 hours at room temperature in the mixed solution of EtOH (10mL), concentration, and use H2O (10mL) dilution, ethyl acetate extraction (2x20mL).Water layer 1N salt acid for adjusting pH to 5, is extracted with ethyl acetate (3x50mL), merges organic phase, dry with sodium sulphate Dry, filtering is concentrated to get trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] Pyrimidine -8- base] hexahydrobenzoid acid (3-7), it is not necessarily to purifying, is directly used in and reacts in next step.Mass spectrometry results: m/z:411.20 [M+H]+。
Embodiment 3
Trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide (3-8) preparation, specific reaction equation is as follows:
Trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base] hexahydrobenzoid acid (3-7,1g, 2.44mmol, the crude product synthesized according to the 6th step of embodiment 3A), diethoxy phosphinylidyne Base methylamine (2-2,720mg, 2.8mmol), hydroxybenzotriazole (HOBT, 513mg, 3.8mmol), 1- ethyl -3- (3- dimethyl Aminopropyl) phosphinylidyne diimine) (EDCI, 730mg, 3.8mmol) and N-methylmorpholine (NMM, 2g, 20mmol) methylene chloride Solution stirs 8 hours at room temperature.Reaction mixture is concentrated under reduced pressure, residue is dissolved in ethyl acetate (100mL), uses water The washing of (30mL) and saturated salt solution (30mL).Organic phase sodium sulphate is dry, filters, is concentrated to get crude product, and it is pure to lead to HPLC Change obtains trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide (3-8,203mg, 15%).1H-NMR(CDCl3,400MHz):δ 8.23 (d, J=2.4Hz, 1H), 7.88 (dd, J=2.4,8.8Hz, 1H), 7.66 (s, 1H), 6.73 (d, J=8.8Hz, 1H), 5.93 (s, 1H), 5.52 (m, 1H), 5.24 (s, 2H), 4.12-4.04 (m, 4H), 3.90 (s, 3H), 3.66 (dd, J=6.0, 12.0Hz,2H),2.75-2.69(m,2H),2.53(s,3H),2.24(m,1H),1.97-1.94(m,2H),1.71-1.62(m, 4H), 1.27 (t, J=6.8Hz, 6H).Mass spectrometry results: m/z:559.30 [M+H]+。
Can be described according to embodiment 3A and embodiment 3 identical of following compounds (but being not limited to these compounds) or Similar method synthesis:
Embodiment 4A
Trans- -2- (2,5- dimethyl pyrrole -1- base) -8- [4- (methylol) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones (4-9) preparation, specific reaction equation is as follows:
Step 1: the ethanol solution (500mL) of trans-4-amino hexahydrobenzoid acid hydrochloride (4-1,50g, 0.28mol) Middle addition SOCl2(100mL), gained mixture stir 8 hours in 100 DEG C.Solvent is removed under reduced pressure and obtains trans-4-amino hexamethylene Base carboxvlate hvdrochloride (4-2,58g, yield: 100%).
Step 2: at 0 DEG C, toward trans-4-amino cyclohexyl ethyl formate hydrochloride (4-2,53.3g, 257mmol) LiAlH is carefully added portionwise in THF (1L) solution4(11.4g, 309mmol), gained mixture, which is stirred at room temperature 3 hours, to react It completes.Reaction mixture is carefully quenched with ethyl alcohol, filtering, filtrate decompression be concentrated to give trans--(4- aminocyclohexyl) methanol (4-3, 28g, yield: 85%).
Step 3: the chloro- 6- methylpyrimidine -2- amine (1-2,57g, 256.2mmol) of the bromo- 4- of 5-, trans--(4- aminocyclohexyl Base) mixture of methanol (4-3,33g, 257mmol) and DIPEA (66g, 514mmol) in DMA (1.5L) in 130 DEG C stir Reflux 12 hours.Mixture is concentrated under reduced pressure, and with DCM (500mL) dilution, with water (200mL) and saturated salt solution (200mL) Washing.Organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, the residue silica gel chromatography (dichloromethane of 5% methanol Alkane solution elution) obtain trans--[4- [(the bromo- 6- methylpyrimidine -4- base of 2- amino -5-) amino] cyclohexyl] methanol (4-4, 58g, yield: 72%).
Step 4: trans--[4- [(the bromo- 6- methylpyrimidine -4- base of 2- amino -5-) amino] cyclohexyl] methanol (4-4, 70g, 222mmol), ethyl acrylate (1-5,111.5g, 1.12mol), Pd (PPh3)4(20g) and triethylamine (112g, Heating stirring 12 hours at 130 DEG C of DMF (1L) mixture 1.12mol).Mixture is concentrated under reduced pressure, and uses DCM (300mL) dilution is washed with water (100mL) and saturated salt solution (100mL).Organic phase is dry with anhydrous sodium sulfate, filters, is dense Contracting, residue obtain trans--(E) -3- [2- amino -4- with silica gel chromatography (dichloromethane of 5% methanol) [[4- (methylol) cyclohexyl] amino] -6- methylpyrimidine -5- base] propyl- 2- olefin(e) acid ethyl ester (4-5,48g, yield: 65%).
Step 5: trans--(E) -3- [2- amino -4- [[4- (methylol) cyclohexyl] amino] -6- methylpyrimidine -5- base] Propyl- 2- olefin(e) acid ethyl ester (4-5,48g, 143.5mmol), benzenethiol (15.8g, 143mmol), benzenethiol sodium salt (22.7g, 172mmol), the DMF solution (1L) of DBU (1-7,43g, 286mmol) and diisopropyl ethyl amine (55g, 429mmol) is in 130 DEG C heating reaction 8 hours.Mixture is concentrated under reduced pressure, and with DCM (300mL) dilution, with water (100mL) and saturated salt solution (100mL) washing.Organic phase is dried, filtered with anhydrous sodium sulfate, concentration, residue with silica gel chromatography (5% methanol Dichloromethane) obtain trans- -2- amino -8- [4- (methylol) cyclohexyl] -4- picoline [2,3-d] pyrimidine - 7- ketone (4-6,8.6g, yield: 21%).
Step 6: trans- -2- amino -8- [4- (methylol) cyclohexyl] -4- picoline [2,3-d] pyrimidin-7-ones (4- 6,8.6g, 29.8mmol) DMF (200mL) solution in be added NBS (5.3g, 30mmol), after being stirred at room temperature 2 hours, reaction Mixture is concentrated under reduced pressure, and is diluted with DCM (100mL), is washed with water (50mL) and saturated salt solution (50mL).Organic phase nothing Aqueous sodium persulfate is dry, filtering, is concentrated, and residue is obtained with silica gel chromatography (dichloromethane of 5% methanol) (4-7,9.0g are produced the bromo- 8- of trans- -2- amino -6- [4- (methylol) cyclohexyl] -4- picoline [2,3-d] pyrimidin-7-ones Rate: 82%).
Step 7: the bromo- 8- of trans- -2- amino -6- [4- (methylol) cyclohexyl] -4- picoline [2,3-d] pyrimidine -7- Ketone (4-7,9g, 24.5mmol), potassium carbonate (6.9g, 50mmol) and 2- methoxypyridine -3- ylboronic acid (1-10,3.7g, 30mmol) in DMF/H2Drum nitrogen 5 minutes in mixture in O (5:1,100mL), Pd (PPh is added into the mixture3)4 (2g).Gained mixture in 100 DEG C heating stirring 2 hours.Reaction mixture is concentrated under reduced pressure, and is diluted with DCM (80mL), uses water The washing of (40mL) and saturated salt solution (40mL).Organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, residue silicagel column Chromatogram purification (dichloromethane of 5% methanol) obtains trans- -2- amino -8- [4- (methylol) cyclohexyl] -6- (6- Methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (4-8,4.0g, yield: 41%).
Step 8: trans- -2- amino -8- [4- (methylol) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- methyl Pyridine [2,3-d] pyrimidin-7-ones (4-8,4.8g, 12.1mmol), 2,5- bis- hexanones (1-12,7g, 61mmol) and to toluene sulphur Toluene (100mL) the solution heated overnight at reflux of sour (0.46g).Reaction mixture is cooled to room temperature, and is concentrated.Residue column Chromatographic purifying, the mixture of petrol ether/ethyl acetate (1:1) obtain trans- -2- (2,5- dimethyl pyrrole -1- as eluant, eluent Base) -8- [4- (methylol) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (4- It 9), is white solid (2.5g, yield: 43%).Mass spectrometry results: m/z:474.32 [M+H]+。
Embodiment 4
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones (4-11) preparation, specific reaction equation is as follows:
Step 1: at -78 DEG C, toward trans- -2- (2,5- dimethyl pyrrole -1- base) -8- [4- (methylol) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (4-9,1.3g, 2.7mmol, according to embodiment 4A In the 7th step preparation) and trifluoromethanesulfonic acid (diethoxy phosphoryl methyl) ester (1-14,1.7g, 5.6mmol) THF The THF solution (5.6mL, 5.6mmol) of 1M LiHMDS is added dropwise in (50mL) solution.Gained mixture is small in -78 DEG C of stirrings 0.5 When, it is warmed to room temperature and continues stirring 0.5 hour.Reaction mixture is quenched with saturated ammonium chloride solution (30mL), and is extracted with DCM (50mL x3).Organic layer merges, and with anhydrous sodium sulfate drying, filtering, concentration, residue preparation HPLC is purified, and obtains anti- Formula -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -2- (2,5- dimethyl pyrrole -1- base) -6- (6- methoxy Base -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (4-10,100mg, yield: 5.8%).
Step 2: trans- -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -2- (2,5- dimethyl pyrrole - 1- yl) -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (4-10,100mg, 0.16mmol) and Hydroxylamine hydrochloride (35mg, 0.5mmol) heated overnight at reflux in the mixed solution (10:1,5mL) of ethanol/water.Reaction is mixed Object concentration is closed, residue purifies to obtain trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) with preparation HPLC Cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (4-11,8mg, yield: 9%). Nuclear magnetic resonance spectroscopy result:1H-NMR(CDCl3, 400MHz): δ 8.32 (d, J=2.0Hz, 1H), 7.99 (dd, J=2.4, 8.4Hz, 1H), 7.75 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 5.48 (m, 1H), 5.27 (s, 2H), 4.24-4.17 (m, 4H), 3.99 (s, 3H), 3.81 (d, J=8.4Hz, 2H), 3.46 (d, J=6.0Hz, 1H), 2.81-2.77 (m, 2H), 2.62 (s, 3H), 2.03-1.97 (m, 2H), 1.72-1.70 (m, 2H), 1.38 (t, J=6.8Hz, 6H), 1.30-1.12 (m, 3H).Matter Spectrum analysis result: m/z:546.20 [M+H]+。
Can be described according to embodiment 4 and embodiment 4A identical of following compounds (but being not limited to these compounds) or Similar method synthesis:
Embodiment 5
2- amino -8- [1- (diethoxy phosphoryl methyl) -4- piperidyl] -6- (6- methoxyl group -3- pyridyl group) -4- first The preparation of yl pyridines [2,3-d] pyrimidin-7-ones (5-9), specific reaction equation is as follows:
Step 1: the chloro- 6- methylpyrimidine -2- amine (1-2,200g, 0.9mol) of the bromo- 4- of 5-, 4- amino piperidine -1- formic acid uncle Dimethyl acetamide (1L) solution of butyl ester (5-1,217g, 1.08mol) and diisopropyl ethyl amine (232.6g, 1.8mol) in 120 DEG C of heating reactions are overnight.Reaction mixture concentration, and DCM (5L) and saturated salt solution (5L) is added, organic phase separation, nothing Aqueous sodium persulfate is dry, filters, is concentrated to dryness to obtain brown solid, is beaten with ethyl acetate (500mL), 4- [(2- ammonia is obtained by filtration The bromo- 6- methylpyrimidine -4- base of base -5-) amino] piperidines -1- t-butyl formate (5-2,250g, yield: 70%).Mass spectral analysis knot Fruit: m/z:386.20 [M+H,79Br]+,388.20[M+H,81Br]+.Silica gel thin-layer chromatography: Rf=0.4 (DCM/MeOH=20: 1)。
Step 2: under nitrogen, 4- [(the bromo- 6- methylpyrimidine -4- base of 2- amino -5-) amino] piperidines -1- t-butyl formate (5-2,150g, 0.39mol), ethyl acrylate (1-5,194g, 1.94mol), triethylamine (300mL) and Pd (PPh3)4(45g, 38mmol) mixture in DMF (500mL) reacts 48 hours in 120 DEG C of heating.Reaction mixture is cooled to room temperature and is concentrated, Residue column chromatographic purifying, the mixture of methylene chloride/methanol obtain product 4- [[2- amino -5- [(E)-as eluant, eluent 3- ethyoxyl -3- oxo propyl- 1- alkenyl] -6- methylpyrimidine -4- base] amino] piperidines -1- t-butyl formate (5-3) is yellow Solid (50g, yield: 30%).Mass spectrometry results: m/z:406.30 [M+H]+.Silica gel thin-layer chromatography: Rf=0.35 (DCM/ MeOH=20:1).
Step 3: 4- [[2- amino -5- [(E) -3- ethyoxyl -3- oxo propyl- 1- alkenyl] -6- methylpyrimidine -4- base] ammonia Base] piperidines -1- t-butyl formate (5-3,115g, 0.28mol), benzenethiol (31.23g, 0.28mol), benzenethiol sodium salt (37.48g, 0.28mol), the DMF of DBU (1-7,172.6g, 1.13mol) and diisopropyl ethyl amine (219.78g, 1.7mol) Solution (1L) is stayed overnight in 110 DEG C of heating reactions.Reaction mixture is concentrated, and DCM (500mL) and water (300mL) are added in residue. Organic phase separation is concentrated to get crude product, is added ethyl acetate (200mL), white product 4- (2- amino -4- first is collected by filtration Base -7- oxo pyridine [2,3-d] pyrimidine -8- base) piperidines -1- t-butyl formate (5-4,56g, yield: 56%).Mass spectral analysis knot Fruit: m/z:360.20 [M+H]+.Silica gel thin-layer chromatography: Rf=0.45 (DCM/MeOH=20:1).
Step 4: 4- (2- amino -4- methyl -7- oxo pyridine [2,3-d] pyrimidine -8- base) piperidines -1- t-butyl formate NBS (11.83g, 66mmol) is added in DMF (300mL) solution of (5-4,20g, 55mmol), after being stirred at room temperature 1 hour, instead It answers mixture to be concentrated to dryness, ethyl acetate (300mL) and saturated sodium bicarbonate solution (300mL) is added in residue.Organic phase It separates, be concentrated to get crude product 4- (bromo- 4- methyl -7- oxo pyridine [2,3-d] pyrimidine -8- base of 2- amino -6-) piperidines -1- first Tert-butyl acrylate (5-5,19g) is brown solid, is directly used in without purifying and reacts in next step.Mass spectrometry results: m/z: 438.20[M+H,79Br]+,440.20[M+H,81Br]+.Silica gel thin-layer chromatography: Rf=0.5 (DCM/MeOH=20:1).
Step 5: 4- (bromo- 4- methyl -7- oxo pyridine [2,3-d] pyrimidine -8- base of 2- amino -6-) piperidines -1- formic acid uncle Butyl ester (5-5,19g, 43mmol), potassium carbonate (18g, 130mmol) and 2- methoxypyridine -3- ylboronic acid (1-10,9.98g, 66mmol) in DMF/H2Drum nitrogen 5 minutes in mixture in O (5:1,240mL), Pd (PPh is added into the mixture3)2Cl2(3.00g).Gained mixture is stayed overnight in 100 DEG C of heating stirrings.Reaction mixture is concentrated to dryness, residue silica gel column layer Analysis purifying, the mixture of methylene chloride/methanol (95/5) obtain product 4- (2- amino -6- (6- methoxyl group -3- as eluant, eluent Pyridyl group) -4- methyl -7- oxo pyridine [2,3-d] pyrimidine -8- base) piperidines -1- t-butyl formate (5-6) is brown solid (8g, yield: 40%).Mass spectrometry results: m/z:467.30 [M+H]+.Silica gel thin-layer chromatography: Rf=0.4 (DCM/MeOH= 20:1)。
Step 6: 4- (2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxo pyridine [2,3-d] pyrimidine - 8- yl) piperidines -1- t-butyl formate (5-6,4.5g, 9.6mmol) is dissolved in the saturation methanol (50mL) of HCl, the mixture It is stirred at room temperature 4 hours, depressurizes lower concentration, dissolve the residue in water, and washed with ethyl acetate, discard organic layer.Water layer is used It protects and sodium bicarbonate solution adjusts pH=8-9, then extracted 3 times with DCM.Organic layer is merged, with sodium sulphate drying, is concentrated, Obtain product 2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -8- (4- piperidyl) pyridine [2,3-d] pyrimidin-7-ones (5-7,4g, yield: 90%), being greenish yellow solid.Silica gel thin-layer chromatography: Rf=0.1 (DCM/MeOH=5:1).
Step 7: toward 2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -8- (4- piperidyl) pyridine [2,3-d] Diethyl phosphite (HPO (OEt) is added in dioxanes (200mL) solution of pyrimidin-7-ones (5-7,2.5g, 6.82mmol)2, 5-8,1.9g, 13.66mmol), paraformaldehyde (0.2g, 6.83mmol) and acetic acid (0.41g, 6.83mmol).Gained mixture After return stirring 5 hours, solution is concentrated, crude product purifies to obtain product 2- amino -8- [1- (diethoxy with preparation HPLC Phosphoryl methyl) -4- piperidyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (5-9, 1.0g, yield: 28%, purity 95%), it is yellow solid.Further purified to obtain 220mg pure products with SFC, purity is 99%, it is yellow solid.Silica gel thin-layer chromatography: Rf=0.6 (DCM/MeOH=20:1).1H-NMR(CDCl3,400MHz):δ 8.32 (dd, J=0.4,2.4Hz, 1H), 7.98 (dd, J=2.4,8.8Hz, 1H), 7.75 (s, 1H), 6.82 (dd, J=0.4, 8.4Hz, 1H), 5.47 (s, br, 2H), 4.23-4.18 (m, 4H), 3.99 (s, 3H), 3.25-3.23 (m, 3H), 2.89 (d, J= 11.6Hz, 2H), 2.60 (s, 3H), 2.47-2.41 (m, 2H), 1.92 (s, 2H), 1.61-1.59 (m, 2H), 1.38 (t, J= 6.4Hz,6H).Mass spectrometry results: m/z:517.30 [M+H]+。
The same or similar method that following compounds (but being not limited to these compounds) can be described according to embodiment 5 Synthesis:
Embodiment 6
Inhibit the screening experiment of kinases:
This example is compound ds -2- amino -8- [4- (the diethoxy phosphoryl methylamino) ring prepared in embodiment 2 Hexyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones (2-4a) are in DiscoveRx company The KinomeScan of (4215Sorrento Valley Blvd, San Diego, CA 92121)TM (www.kinomescan.com) in system in the case where 100nM compound concentration for the suppression result of 98 kinases such as Shown in table 1:
The details of the screening technique is shown in Fabian, M.A.et al, Nat., Biotechnol.2005,23,329 and Karaman,M.W.et al,Nat.,Biotechnol.2008,26,127.In terms of the above representative result, in the present invention Compound has the kinases such as including mTOR, PIK3C2B, PIK3CA, PIK3CG, TYK2, DYRK1B and its mutant significant Inhibiting effect.
Table 1
Embodiment 7
To the biochemical inhibitory activity of several kinases and its hypotype: this example is the compound ds -2- ammonia prepared in embodiment 2 Base -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] Pyrimidin-7-ones (2-4a) are by Reaction Biology Corporation company (Reaction Biology Corp., One Great Valley Parkway,Suite 2,Malvern,PA 19355,USA.http:// Www.reactionbiology.com/webapps/main/pages/kinase.aspx) measurement to mTOR, PI3K- α, PI3K- β, PI3K- γ, PI3K- δ, DYRK1B, TYK2 kinases and its active inhibition of hypotype.Specific step is as follows:
Compound of the present invention is dissolved in dimethyl sulfoxide (DMSO), the stoste of 10mM is configured to, from 10mM Start to be serially diluted according to 3- times, does 10 different dosage.When measuring the inhibitory activity of four kinds of PI3K hypotypes, surveyed using HTRF Determine method, ATP concentration is 10 μM.When other three kinds of kinases (mTOR, DYRK1B, TYK2) measurements, ATP concentration is that they are corresponding Km value.
Measurement result
The compound 2-4a prepared in the embodiment of the present invention 2 inhibits the IC of 7 kinds of kinases and hypotype enzyme50Value be shown in Table 2:
Table 2
It can be seen that by above-mentioned data, COMPOUNDS EXAMPLE 2-4a of the present invention has strong to four kinds of hypotypes of PI3K Inhibitory activity, IC50Value respectively reaches 100nM or less.Compound 2a is also obvious to the inhibition of mTOR, IC50Value is 670nM. The compound is then weaker to the inhibitory activity of DYRK1B and TYK2.
Embodiment 8
Anti-tumor experiment: this example is using trans- -2- amino -8- [4- (the diethoxy phosphoryl first prepared in embodiment 1 Oxygroup) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2,3-d] pyrimidin-7-ones are thin in A549 Human Lung Cancer The method and result of anti-tumor experiment are as follows in born of the same parents' xenograft nude mice animal model:
Experimental material
4~5 SPF grades of week old female BAl BIcs/c-nu/nu mouse, 16~20g of weight are purchased from Guangdong Province's Experimental Animal Center, Quality certification number: NO:0072659.A549 lung carcinoma cell is purchased from Shanghai life science institute cell resource center.DMEM cell Culture medium, fetal calf serum (FBS) and tryptic digestive juice come from Gibco company.Various antibiotic are purchased from Sigma company.
Experimental method
First carry out A549 lung carcinoma cell culture: A549 cell strain be inoculated in containing 10%FBS, 100U/ml penicillin, In the DMEM culture solution of 100U/ml streptomysin, in 37 DEG C, 5%CO2, 100% humidity carbon dioxide incubator in cultivate, connect About 48h cell covers with bottom of bottle after kind.Then the A549 cell dissociation at culture bottle bottom 80%, 1000r/min centrifugation will have been covered with Cell precipitation is collected after 3min, and cell is diluted to 1 × 108/ mL, armpit is subcutaneous before the nude mice right side is only inoculated in by 0.1mL/.Inoculation Tumour cell starts to weigh to tumor bearing nude mice after the 12nd day, measures tumor size and by tumor size in 150~200mm3Range Mouse be uniformly divided into solvent group (Vehicle, aqueous hydrochloric acid solution, pH 3) and pyridine [2,3-d] pyrimidin-7-ones class at random Close one of object trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones (1-16) (being dissolved in Vehicle, concentration 1.0mg/mL), every group of 4 mouse； Thereafter it weighs daily to nude mice and (10mg/kg qd via p.o.) is administered orally by stomach-filling method by 0.1mL/10g weight, The size of the every animal tumor of measurement in every two days, after 18 days, tumor-bearing mice cervical dislocation is put to death, and is taken out tumour and is weighed.Suppression Ratio of outflow (Tumor Growth Inhibition or TGI) calculation method: experimental data is indicated with mean ± SD；Tumour inhibiting rate (TGI) =[(VSolvent group–VTreatment group)÷VSolvent group] × 100%.VSolvent groupFor solvent group mouse tumor volume；VTreatment groupFor treatment group's mouse tumor body Product.
Experimental result
Tumor-inhibiting action of the compounds of this invention treatment group to mouse tumor described in embodiment 1: solvent group and treatment group's difference It feeds solvent and after drug solution 18 days, the tumor average volume of solvent group and treatment group animal is respectively 1179.7 ± 420.6mm3 (n=4) and 550.8 ± 76.2 (n=4)；Therefore, the tumour inhibiting rate (TGI) for the treatment of group is 53%.Compared with primary tumor volume, Treatment group tumors have apparent diminution.Fig. 1 is shown in empirical curve control.
From the point of view of above-mentioned inhibiting tumor assay result, the representative compound in the present invention is in xenograft nude mice animal model It shows significant tumor inhibition effect, is administered orally, 10mg/kg, once a day, tumor control rate is up to 53% after 18 days.It controls The weight of animals for the treatment of group varies less, this illustrates that drug does not have apparent toxicity.
Embodiment 9
Anti-tumor experiment: the identical method of embodiment 8 is used, the compound that this example uses is prepared in embodiment 2-4b Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- methyl pyrrole Pyridine [2,3-d] pyrimidin-7-ones.Tumor model is A549 Human Lung Cancer cell xenograft Nude mice model.
Experimental result
Fig. 2 sees to the tumor-inhibiting action of mouse tumor in the compounds of this invention treatment group described in embodiment 2-4b.From above-mentioned tumor suppression From the point of view of experimental result, the representative compound in the present invention shows that tumor suppression is made in xenograft nude mice animal model With.
Embodiment 10
Anti-tumor experiment: use the identical method of embodiment 8, the compound that this example uses be prepared in embodiment 3 it is anti- Formula -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- base]-N- (diethyl Oxygroup phosphoryl methyl) cyclohexyl formamide.Tumor model is A549 Human Lung Cancer cell xenograft Nude mice model.
Experimental result
Fig. 3 sees to the tumor-inhibiting action of mouse tumor in the compounds of this invention treatment group described in embodiment 3.From above-mentioned inhibiting tumor assay As a result from the point of view of, the representative compound in the present invention shows tumor inhibition effect in xenograft nude mice animal model.
Embodiment 11
Anti-tumor experiment: the identical method of embodiment 8 is used, the compound that this example uses is the 2- prepared in embodiment 5 Amino -8- [1- (diethoxy phosphoryl methyl) -4- piperidyl] -6- (6- methoxyl group -3- pyridyl group) -4- picoline [2, 3-d] pyrimidin-7-ones.Tumor model is A549 Human Lung Cancer cell xenograft Nude mice model.
Experimental result
Fig. 4 sees to the tumor-inhibiting action of mouse tumor in the compounds of this invention treatment group described in embodiment 5.Experiment carries out 18 days Afterwards, tumour is taken out after putting to death animal, administration group is shown in Fig. 4 and solvent control group tumor weight compares.It is real from above-mentioned tumor suppression It tests from the point of view of result, the representative compound in the present invention shows tumor inhibition effect in xenograft nude mice animal model.
Embodiment 12
Anti-tumor experiment: using the similar method of embodiment 8, the compound that this example uses is prepared in embodiment 2-4a Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- methyl pyrrole Pyridine [2,3-d] pyrimidin-7-ones.Tumor model is PC3 human prostate cell xenograft Nude mice model.
Experimental result
Fig. 5 sees to the tumor-inhibiting action of mouse tumor in the compounds of this invention treatment group described in embodiment 2-4a.From above-mentioned tumor suppression From the point of view of experimental result, the representative compound in the present invention shows significant tumour suppression in xenograft nude mice animal model Production is used, oral administration, 10mg/kg, and once a day, tumor control rate is up to 73% after 21 days.The weight of animals for the treatment of group changes Very little, this illustrates that drug does not have apparent toxicity.
Embodiment 13
Anti-tumor experiment: using the similar method of embodiment 8, the compound that this example uses is prepared in embodiment 2-4a Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- methyl pyrrole Pyridine [2,3-d] pyrimidin-7-ones.Tumor model is U87MG human microglia blastoma cell xenograft Nude mice model.
Experimental result
Fig. 6 sees to the tumor-inhibiting action of mouse tumor in the compounds of this invention treatment group described in embodiment 2-4a.From above-mentioned tumor suppression From the point of view of experimental result, the representative compound in the present invention shows significant tumour suppression in xenograft nude mice animal model Production is used, oral administration, 2.5mg/kg, and once a day, tumor control rate is up to 64% after 14 days.The weight of animals for the treatment of group changes Very little, this illustrates that drug does not have apparent toxicity.
Embodiment 14:
Tablet (milli gram/piece)
Compound prepared by embodiment 1: 100；Lactose, Ph EUR:182.75；
Sodium carboxymethylcellulose: 12.0；Corn starch liquid (5w/v%): 2.25；
Magnesium stearate: 3.0.
Embodiment 15:
Tablet (milli gram/piece)
Compound prepared by embodiment 5: 100, other materials content is the same as embodiment 14.
Embodiment 16:
Tablet (milli gram/piece)
The compound of embodiment 2-4a preparation: 50；Lactose, Ph EUR:223.75；
Sodium carboxymethylcellulose: 6.0；Cornstarch: 15.0；
Polyvinylpyrrolidone (5w/v%): 2.25；Magnesium stearate: 3.0.
Embodiment 17:
Tablet (milli gram/piece)
The compound of embodiment 2-4a preparation: 50, other materials content is identical as embodiment 16.Embodiment 18:
Tablet (milli gram/piece)
Compound prepared by embodiment 3: 1.0；Lactose, Ph EUR:93.25；
Sodium carboxymethylcellulose: 4.0；Corn starch liquid (5w/v%): 0.75；
Magnesium stearate: 76.
Embodiment 19:
Tablet (milli gram/piece)
Compound prepared by embodiment 3: 1.0, other materials content is identical as embodiment 18.
Embodiment 20:
Capsule (milligram/capsule)
The compound of embodiment 2-4a preparation: 10.0；Lactose, Ph EUR:488.5；
Magnesium: 1.5.
Embodiment 21:
Drug composition and preparation
Capsule (milligram/capsule)
The compound of embodiment 2-4a preparation: 10.0, other materials content is identical as embodiment 20.
Embodiment 22:
Drug composition and preparation
Injection (50 mg/ml)
Compound prepared by embodiment 4: 5%；1M sodium hydroxide solution: 15%；
0.1M hydrochloric acid solution (adjusts pH=7.6)；Polyethylene glycol 400: 5%；
Water for injection is adjusted to 100%.
Embodiment 23:
Drug composition and preparation
Injection (50 mg/ml)
The compound of embodiment 2-4b preparation: 5%, other materials content is identical as embodiment 22, finally uses water for injection It is adjusted to 100%.
Embodiment 24:
Drug composition and preparation
Injection (10 mg/ml)
The compound of embodiment 2-4a preparation: 1%；Disodium hydrogen phosphate BP:3.6%；
0.1M sodium hydroxide solution: 15%；Water for injection is adjusted to 100%.
Embodiment 25:
Drug composition and preparation
Injection (10 mg/ml)
Compound prepared by embodiment 5: 1%, other materials content is identical as embodiment 32, and water for injection is adjusted to 100%.
Embodiment 26:
Drug composition and preparation
Injection (1 mg/ml) (pH is adjusted to 6)
Compound prepared by embodiment 1: 0.1%；Disodium hydrogen phosphate BP:2.26%；
Citric acid: 0.38%；Polyethylene glycol 400: 3.5%；
Water for injection is adjusted to 100%；
Embodiment 27:
Drug composition and preparation
Injection (1 mg/ml) (pH is adjusted to 6)
The compound of embodiment 2-4a preparation: 0.1%, the content of other materials is identical as embodiment 26, finally with injection Water use regulation is to 100%.
Embodiment 28:
Drug composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 1: 10；Sorbitan monooleate: 13.5；
Trichlorofluoromethane: 910.0；Dicholorodifluoromethane: 490.0.
Embodiment 29:
Drug composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 3: 10, other materials content is identical as embodiment 28.
Embodiment 30:
Drug composition and preparation
Aerosol (mg/ml)
The compound of embodiment 2-4a preparation: 0.2；Sorbitan monooleate: 0.27；
Trichlorofluoromethane: 70.0；Dicholorodifluoromethane: 280.0；
Dichlorotetra-fluoroethane: 1094.0.
Embodiment 31:
Drug composition and preparation
Aerosol (mg/ml)
The compound of embodiment 2-4a preparation: 0.2, other materials content is identical as embodiment 30.Embodiment 32:
Drug composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 5: 2.5；Sorbitan monooleate: 3.38；
Trichlorofluoromethane: 67.5；Dicholorodifluoromethane: 1086.0；
Dichlorotetra-fluoroethane: 191.60.
Embodiment 33:
Drug composition and preparation
Aerosol (mg/ml)
The compound of embodiment 2-4b preparation: 2.5, other materials content is identical as embodiment 32.Embodiment 34:
Drug composition and preparation
Aerosol (mg/ml)
The compound of embodiment 2-4a preparation: 2.5；Soybean lecithin: 2.7；
Trichlorofluoromethane: 67.5；Dicholorodifluoromethane: 1086.0；
Dichlorotetra-fluoroethane: 191.60.
Embodiment 35:
Drug composition and preparation
Aerosol (mg/ml)
The compound of embodiment 2-4a preparation: 2.5, other materials content is identical as embodiment 34.
Embodiment 36:
Drug composition and preparation
Ointment (/ milliliter)
The compound of embodiment 2-4a preparation: 40 milligrams；Ethyl alcohol: 300 microlitres；
Water: 300 microlitres；1- azone: 50 microlitres；
Propylene glycol: to 1 milliliter.
Embodiment 37:
Ointment (/ milliliter)
The compound of embodiment 2-4a preparation: 40 milligrams, other materials content is identical as embodiment 36.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any In the technical scope disclosed by the present invention, any changes or substitutions that can be easily thought of by those familiar with the art, all answers It is included within the scope of the present invention.Therefore, protection scope of the present invention should be with the scope of protection of the claims It is quasi-.

Claims (25)

1. a kind of pyrido [2,3-d] pyrimidin-7-ones class compound phosphorous as shown in formula (Ic) or (Id) or its pharmaceutically Acceptable salt:
Described in formula,
G11Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy；
L indicates O or N-R2；
J indicates C1-6Alkyl；
RR and R ' R ' separately expression-OH, C1-6Alkyl or C1-6Alkoxy；
R2Indicate H or C1-6Alkyl.
2. a kind of pyrido [2,3-d] pyrimidin-7-ones class compound phosphorous as shown in formula (Ie) or (If) or its pharmaceutically Acceptable salt:
Described in formula,
G11Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy；
A indicates C=O or C1-6Alkyl；
L indicates O or N-R2；
J indicates C1-6Alkyl；
RR and R ' R ' separately expression-OH, C1-6Alkyl or C1-6Alkoxy；
R2Indicate H or C1-6Alkyl.
3. a kind of pyrido [2,3-d] pyrimidin-7-ones class compound phosphorous as shown in formula (Ig) or its be pharmaceutically subjected to Salt:
Described in formula,
G11Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy；
J indicates C1-6Alkyl；
RR and R ' R ' separately expression-OH, C1-6Alkyl or C1-6Alkoxy.
4. a kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt, it is characterised in that The compound or its pharmaceutically acceptable salt be any one following compound:
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Trans- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- base] - N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Cis- -4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- base] - N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- methoxyl group -3- pyridyl group) - 4- picoline [2,3-d] pyrimidin-7-ones；
2- amino -8- [1- (diethoxy phosphoryl methyl) -4- piperidyl] -6- (6- methoxyl group -3- pyridyl group) -4- methyl pyrrole Pyridine [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- dimethylamino -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- dimethylamino -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- dimethylamino -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- dimethylamino -3- pyridyl group) -4- Picoline [2,3-d] pyrimidin-7-ones；
Trans- -4- [2- amino -6- (6- dimethylamino -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Cis- -4- [2- amino -6- (6- dimethylamino -3- pyridyl group) -4- methyl -7- oxygroup pyridine [2,3-d] pyrimidine -8- Base]-N- (diethoxy phosphoryl methyl) cyclohexyl formamide；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- dimethylamino -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy ylmethyl) cyclohexyl] -6- (6- dimethylamino -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
2- amino -8- [1- (diethoxy phosphoryl methyl) -4- piperidyl] -6- (6- dimethylamino -3- pyridyl group) -4- methyl Pyridine [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- methyl Pyridine [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- methyl Pyridine [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- methyl Pyridine [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- ethyl -3- pyridyl group) -4- methyl Pyridine [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methylamino -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methoxy base) cyclohexyl] -6- (6- methylamino -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methylamino -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methylamino) cyclohexyl] -6- (6- methylamino -3- pyridyl group) -4- first Yl pyridines [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (methyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (methyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (ethyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (ethyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyridine Base) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (n-propyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (n-propyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (isopropyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (isopropyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans- -2- amino -8- [4- (diethoxy phosphoryl methyl (cyclopropyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
Cis- -2- amino -8- [4- (diethoxy phosphoryl methyl (cyclopropyl) amino) cyclohexyl] -6- (6- methoxyl group -3- pyrrole Piperidinyl) -4- picoline [2,3-d] pyrimidin-7-ones；
Trans--[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyloxy] methyl-ethoxy-phosphoric acid；
Cis--[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyloxy] methyl-ethoxy-phosphoric acid；
Trans--[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyloxy] methyl-phosphoric acid；
Cis--[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyloxy] methyl-phosphoric acid；
Trans--[[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyl] amino] methyl-ethoxy-phosphoric acid；
Cis--[[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyl] amino] methyl-ethoxy-phosphoric acid；
Trans--[[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyl] amino] methyl-phosphoric acid or
Cis--[[4- [2- amino -6- (6- methoxyl group -3- pyridyl group) -4- methyl -7- oxygroup-pyrido [2,3-d] pyrimidine -8- Base] cyclohexyl] amino] methyl-phosphoric acid.
5. any one of according to claim 1~4 phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound or its in pharmacy Upper acceptable salt, it is characterised in that the pharmaceutically acceptable salt is phosphorous pyrido [2,3-d] the pyrimidin-7-ones class The salt that compound and inorganic acid, organic acid, inorganic base, organic base are formed by chemical reaction.
6. any one of Claims 1 to 5 phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically may be used The raceme or enantiomter of the salt of receiving.
7. a kind of pyrido [2,3-d] pyrimidin-7-ones class compound phosphorous as shown in formula (IIaa), (IIbb) or (IIcc):
Described in formula,
R2Indicate hydrogen or C1-6Alkyl；
R88Indicate hydrogen, halogen ,-OCF3、-CF3、-CN、-NMe2、C1-6Alkyl or C1-6Alkoxy；
R12And R13Separately expression-OH, halogen, C1-6Alkyl or C1-6Alkoxy.
8. phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound according to claim 7, it is characterised in that R2It indicates Hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl.
9. phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound according to claim 7, it is characterised in that R2It indicates Hydrogen, methyl, ethyl, n-propyl or isopropyl.
10. phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound according to claim 7, it is characterised in that R88It indicates Halogen ,-OCF3、-OCH3、-OCH2CH3Or-NMe2。
11. phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound according to claim 7, it is characterised in that R88Table Show-OCH3Or-NMe2。
12. phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound according to claim 7, it is characterised in that R12And R13 Separately expression-OH or C1-6Alkoxy.
13. phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound according to claim 7, it is characterised in that R12And R13 Separately indicate methoxyl group, ethyoxyl, positive propoxy or isopropoxy.
14. comprising any one of Claims 1 to 5 phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound or its in pharmacy It goes up phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound described in acceptable salt or claim 6 or it pharmaceutically may be used The raceme of the salt of receiving or the pharmaceutical composition of enantiomter.
15. pharmaceutical composition described in claim 14, it is characterised in that described pharmaceutical composition also includes one or more of medicines Acceptable carrier or diluent on.
16. the pharmaceutical composition as described in claims 14 or 15, it is characterised in that the dosage form of described pharmaceutical composition are as follows: Oral agents, injection, anus suppository, nostril inhalant, eye drops or skin patch.
17. any one of claim 1-5 phosphorous pyrido [2,3-d] the pyrimidin-7-ones class compound or its pharmaceutically may be used Phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound described in the salt or claim 6 of receiving or its be pharmaceutically subjected to Salt raceme or any one of enantiomter or claim 14-16 described pharmaceutical composition preparation treatment because of albumen Application in the drug of disease caused by kinases abnormal activity.
18. application described in claim 17, it is characterised in that the protein kinase is PI3K or mTOR.
19. application according to claim 18, it is characterised in that the protein kinase is PI3K- α, PI3K- β, PI3K- γ and PI3K- δ.
20. application described in claim 17, it is characterised in that the disease is psoriasis, cirrhosis, tracheitis, glycosuria Disease, disease, disease of eye, disease of immune system, cardiovascular disease, epilepsy or the neurodegenerative disease for being related to angiogenesis.
21. application described in claim 20, it is characterised in that the disease of immune system is rheumatic arthritis or erythema wolf Sore.
22. application described in claim 20, it is characterised in that the neurodegenerative disease is Alzheimer's disease, the prosperous court of a feudal ruler Dun Shi disease or Parkinson's disease.
23. application described in claim 17, it is characterised in that the disease is tumour, and the tumour is selected from solid tumor and liquid Body tumor.
24. application described in claim 23, it is characterised in that the tumour is selected from: lung cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, Head and neck cancer, intraocular melanoma, uterine cancer, oophoroma, the carcinoma of the rectum, anal region cancer, gastric cancer, colon cancer, breast cancer, carcinoma of fallopian tube, Carcinoma of endometrium, cervical carcinoma, carcinoma of vagina, vaginal orifice cancer, Hodgkin's disease, cancer of the esophagus, carcinoma of small intestine, internal system cancer, soft tissue meat Tumor, carcinoma of urethra, carcinoma of penis, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or carcinoma of ureter, nervous centralis maincenter system One of the neoplasm, spinal column axis tumour, gastrointestinal stromal, mastocytosis, glioma, sarcoma and lymthoma of uniting or Any several combination.
25. application described in claim 24, it is characterised in that the cutaneum carcinoma is cutaneous melanoma；The endocrine system System cancer is pituitary adenoma, thyroid cancer or parathyroid carcinoma；The lung cancer is non-small cell lung cancer or Small Cell Lung Cancer.
CN201410397283.8A 2014-08-13 2014-08-13 A kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones class compound or its pharmaceutically acceptable salt, pharmaceutical composition and its application Expired - Fee Related CN105330699B (en)

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PCT/CN2015/081854 WO2016023401A1 (en) 2014-08-13 2015-06-18 Phosphorus-containing pyrido pyrimidone compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and use thereof
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