CN105330699A - Phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound or pharmaceutically acceptable salt, pharmaceutical composition and application thereof - Google Patents

Phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound or pharmaceutically acceptable salt, pharmaceutical composition and application thereof Download PDF

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CN105330699A
CN105330699A CN201410397283.8A CN201410397283A CN105330699A CN 105330699 A CN105330699 A CN 105330699A CN 201410397283 A CN201410397283 A CN 201410397283A CN 105330699 A CN105330699 A CN 105330699A
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amino
pyrimidin
ones
pyridyl
cyclohexyl
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CN105330699B (en
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吕慧敏
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Shandong Huiruidi Biotechnology Co Ltd
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    • 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 Table
    • 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

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Abstract

The invention provides a phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound as shown in the formula (I) or its pharmaceutically acceptable salt, and also discloses a preparation method of the compound, a pharmaceutical composition containing the phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound and an application thereof. The compound is a protein kinase (such as PI3K) inhibitor and can be used in treating diseases caused by abnormal protein kinase activities, such as tumour, etc.

Description

A kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmacy acceptable salt, pharmaceutical composition and application thereof
Technical field
The present invention relates to organic chemistry and medicinal chemistry art, be specifically related to phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmacy acceptable salt, pharmaceutical composition containing this compound and application thereof.
Background technology
Protein kinase is a class phosphotransferase, and its effect is transferred on the specific amino-acid residue of substrate by the γ-phosphate of ATP, makes protein phosphorylation, play its biochemical functions.Protein kinase is the important kinases of a class, and in signal transduction, Main Function has in two: the first is by the activity of phosphorylated regulation protein; It two is phosphorylations step by step by protein, signal is amplified step by step, causes cell response.
The exception of protein kinase activity is not only closely related with the exception of certain link in a series of signal conduction path of intraor extracellular with the propagation, apoptosis, transfer etc. of tumour, also be simultaneously cause other human diseasess relevant with inflammation or proliferative response a series of, the such as major cause of rheumatoid arthritis, cardiovascular and nervous system disorders, asthma, psoriatic etc.There will be a known more than 400 kind of human diseases at present directly or indirectly relevant to protein kinase, this makes protein kinase become another large class important drugs target after G-protein linked receptor.
Protein kinase extended family, by more than 500 member compositions, can be divided into protein tyrosine kinase (proteintyrosinekinasesorPTKs) and serine-threonine kinase (serine-threoninekinases) two class usually.According to the position that kinases is residing in cell, receptor kinase (receptorkinases) and non-receptor kinase can be divided into again, also known as intracellular kinases.Receptor kinase generally belongs to Tyrosylprotein kinase, also tyrosine receptor kinase (receptortyrosinekinasesorRTKs) is claimed, this kind of receptor kinase is divided by cell membrane exterior, cross-film district and tenuigenin inside are grouped into, and the kinases part with catalytic activity is positioned at tenuigenin.The serine-threonine kinase overwhelming majority is positioned at cell, belongs to non-receptor kinase or claims cytoplasmic kinase (cytosolickinases).
Typical Representative in RTKs family is growth factor receptors (growthfactorreceptors), and at least there are 19 subfamilies, is below several main subfamilies:
A () HER family tyrosine receptor kinase, comprises EGFR (epithelialgrowthfactorreceptor), HER2, HER3 and HER4.EGFR is the synthesized micromolecule medicine for the treatment of nonsmall-cell lung cancer and monoclonal antibody target.
B () is by insulin receptor (insulinreceptororIR), form as the growth factors I receptor (insulin-likegrowthfactorIreceptororIGF-1R) of Regular Insulin and the acceptor relevant to insulin receptor (insulinreceptor-relatedreceptororIRR).IGF-1R is wherein generally acknowledged anticancer target, but due to it and IR too similar, especially intracellular kinases part, its aminoacid sequence is 100% identical, suppresses the activity of IGF-1R, usually also can suppress the activity of IR.Evidence show that IR is also effective anticancer target, but because suppress IR to have the risk causing blood sugar increasing, IR inhibitor needs for anticancer the balance finding benefit and security risk.
C () platelet-derived growth factor receptor (platelet-derivedgrowthfactorreceptororPDGFRs) family, comprises PDGFR-α, PDGFR-β, CSF1R, c-KIT and c-fms.Wherein c-KIT is also medicament for treatment of leukemia molecular target, be used for the treatment of gastrointestinal stromal tumors (GISTs).
D () vascular endothelial growth factor receptor (vascularendothelialgrowthfactorreceptorsorVEGFRs) family, comprises FLT1 (Fms-liketyrosinekinase1 or VEGFR1), KDR (or VEGFR-2) and FLT4 (or VEGFR3).Member is wherein with molecular target.
E () fibroblast growth factor acceptor (fibroblastgrowthfactorreceptorsorFGFRs) family, comprises FGFR1, FGFR2, FGFR3 and FGFR4 and 7 parts FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7.Member wherein as the medicine of molecular target also at clinical trial.
F () MET family, comprises c-Met or claims human Hepatocyte Growth's factor acceptor (humanhepatocytegrowthfactorreceptororhHGFR) and RON.Wherein c-Met plays the part of important role in the growth and transfer of initial tumor.Its medicine Crizotinib and Cabozantinib as molecular target has gone through to treat nonsmall-cell lung cancer and medullary thyroid carcinoma respectively.
G () RET family, RET is the acceptor of GDNF family member, there is RET51, RET43 and RET9isoforms.Its medicine Cabozantinib as molecular target has gone through to treat medullary thyroid carcinoma.。
H () Eph family is family maximum in tyrosine receptor kinase, be made up of 16 acceptors (EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6) and 9 parts (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3).These members play an important role in the growth of animal, some member figure in tumour.
There is not cell membrane exterior and divide and cross-film district part in non-receptor kinase, whole kinases is in cytoplasm.Now known have at least 24 kinds of non-receptor kinases to be divided into 11 subfamilies, and they are Src, Frk, Btk, CsK, Abl, Zap70, Fes, Fps, Fak, Jak and AcK subfamilies.Wherein Src subfamily is maximum, comprises Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2 and Yrk kinases.More detailed data is shown in Neet, K.; Hunter, T.GenestoCells1996, the document that 1,147-169 and this article are quoted.Although there is several non-receptor kinase to belong to Tyrosylprotein kinase, most non-receptor kinase belongs to serine-threonine kinase.Several members are wherein medicament for treatment of leukemia and molecular target.
PI3K (Phosphatidylinositide3-kinase) is the lipid kinase family that a class participates in multinomial cell function.These functions comprise (J.A.Engelman, Nat.Rev.Cancer2009,9,550) such as Growth of Cells, propagation, differentiation, mobility, survival and intracellular transport.PI3K family is divided into three types according to primary structure, effect and the specificity to lipid substrates: I type, II type and type III.Compared to II and type III, the understanding of current people to I type is the most complete, and I type is figure in tumour mainly.I type PI3K is further divided into IA and IB hypotype according to the similar figures of aminoacid sequence, and IA is the assorted dimeric molecule comprising a regulator subunit p85 (regulatorysubunit) and a catalytic subunit p110 (catalyticsubunit).Regulator subunit p85 comprises 5 mutation, and wherein p85 alpha expression is maximum.Catalytic subunit p110 has three mutation, i.e. p110 α, p110 β and p110 δ, and they are expressed by gene PIK3CA, PIK3CB and PIK3CD respectively.IB type PI3K is made up of regulator subunit p101 and catalytic subunit p110 γ, and is expressed by PIK3CAG.P110 α and p110 β has expression in each cell, but p110 δ mainly expresses (C.L.Carpenteretal in white corpuscle, J.Biol.Chem.1990,265,19704.S.J.Leeversetal, Curr.Opin.CellBiol.1999,11,219.K.Okkenhaug, Ann.Rev.Immunol.2013,31,675).
PI3K receives the signal that transmits such as RAS from tyrosine receptor kinase, G-protein linked receptor (GPCR) and activation and is activated, and makes the inositol PIP2 phosphorylation in phosphatidylinositols produce PIP3 so p110 and immobilized artificial membrane are had an effect.The multiple albumen of playing the part of most important role in tumour of this procedure activation AKT and downstream.The generation of PIP3 and the number of amount are strictly controlled (I.BranaandL.L.SiuBMCMed.2012,10,161) by tumor suppressor protein, Phosphoric acid esterase and PTEN.
Many tumours are all by out of control the causing in PI3K intracellular signaling path.Common mechanism is the sudden change of PI3KCA or genetic expression increase, the disappearance of tumor suppressor protein PTEN, the overactivity etc. that height is expressed or activated mutant causes by tyrosine receptor kinase.PI3K-δ inhibitor Idelalisib is by FDA approval treatment lymphocytic leukemia (CLL), recurrent follicular B cell non-Hodgkin lymphoma and small lymphocyte lymphoma.
Except the effect in tumour, PI3K also plays an important role in immunologic function, and PI3K-γ and PI3K-δ hypotype are mainly expressed in immunocyte, relevant to inflammation, certainly immunity and hematologic disease.The blocking-up of PI3K-γ and PI3K-δ activity will play a role to diseases such as treatment of arthritis, trachitis, lupus erythematosus (D.G.WinkleretalChem.Biol.2013,20,1364 and the document quoted of this article).
MTOR is by a kind of serine/threonine kinase of people MTOR genes encoding, belongs to PI3K kinase families.MTOR plays regulatory role in Growth of Cells, increment, motion, survival, protein synthesis and transcription (N.HayandN.Sonenberg, GenesDev.2004,18,1926.).MTOR is the catalytic sub-units (S.Wullschlegeretal, Cell2006,124,471.) that mTORC1 and mTORC2 two kinds has the mixture of different structure.Several mTOR inhibitors has been approved for clinical anticancer (such as, temsirolimus, everolimus etc.), anti-organ-graft refection (that is, rapamycin) etc.
WO2005113556A1 reports that series of quinazoline ketone is as people PI3K-δ kinase inhibitor.WO2011146882A1 reports that a series of isoquinoline-1-ketone is as PI3K kinase inhibitor.WO2007084786A1 reports a series of miazines PI3K kinase inhibitor.WO2006122806A2 reports that a series of imidazoquinoline is as PI3K/mTOR kinase inhibitor.WO2008032162A1 reports that a series of pyrido [2,3-d] pyrimidone is as PI3K/mTOR kinase inhibitor.WO2008144464A1 reports that a series of quinolines is as PI3K/mTOR kinase inhibitor.
As mentioned above, receptor kinase and non-receptor kinase are proved clinically and in practical application fully as antitumor target, and listing treatment patient ratified by several antitumour drug.Except oncotherapy, suppress the abnormal activity of receptor kinase and non-receptor kinase also to can be used for treatment and include but not limited to following disease: psoriatic or title psoriasis, liver cirrhosis, diabetes, trachitis, lupus erythematosus, the disease relating to angiogenesis, the disease relating to restenosis, disease of eye, the macular degeneration relevant with the age, rheumatic arthritis and other inflammation, disease of immune system such as auto-immune disease, cardiovascular disorder such as atherosclerosis, kidney disease etc.Therefore continue these kinase whose inhibitor of research and development to be very important.
Summary of the invention
The first object of the present invention is to provide the phosphorous pyrido [2 that one has protein kinase (especially PI3K, mTOR etc.) inhibit activities, 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, and its raceme or enantiomer.
The second object of the present invention is to provide a kind of containing above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, and the pharmaceutical composition of its raceme or enantiomer.
3rd object of the present invention is to provide above-mentioned phosphorous pyrido [2; 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, and the application in the medicine of disease that causes because of protein kinase abnormal activity in preparation treatment of its raceme or enantiomer.
For achieving the above object, the present invention adopts following technical scheme:
A kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, this molecular structure of compounds formula is such as formula shown in (I):
In formula,
Ar is aryl or heteroaryl, and the hydrogen in Ar can by the individual identical or different G of 1-5 1replace;
X is C-R 1or N;
A represents C 1-6alkyl, a C=O or covalent linkage, and when A is C 1-6during alkyl, hydrogen wherein can by the individual identical or different G of 1-5 2replace;
L represents O, N-R 2, S (=O) mor a covalent linkage;
J represents C 1-6alkyl or a covalent linkage, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
R and R ' separately represents H, OH, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 3-12heteroalicyclyl, C 1-6alkoxyl group, C 3-6cycloalkyloxy or C 3-12heterolipid epoxy group(ing), and the hydrogen in R and R ' can by the individual identical or different G of 1-5 4replace, R with R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring can comprise one or more O, N or S (=O) in addition mheteroatoms;
Wherein:
G 1, G 2, G 3and G 4separately represent H ,-CN ,-CF 3,-OCF 3,-NO 2, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 6aryl, C 5-6heteroaryl, C 3-12heteroalicyclyl, R 3o-, R 3r 4n-, R 3s (=O) m-, R 3r 4nS (=O) m-, R 5c (=O)-, R 3r 4nC (=O)-, R 3oC (=O)-, R 5c (=O) O-, R 3r 4nC (=O) O-, R 5c (=O) NR 3-, R 3r 4nC (=O) NR 6-, R 3oC (=O) NR 6-, R 3s (=O) mnR 6-, R 3r 4nS (=O) mnR 6-, R 3r 4nC (=NR 7) NR 6-, R 3r 4nC (=CHNO 2) NR 6-, R 3r 4nC (=N-CN) NR 6-, R 3r 4nC (=NR 7)-, R 3s (=O) (=NR 7) NR 6-or R 3r 4nS (=O) (=NR 7)-;
R 1, R 2, R 3, R 4, R 5, R 6and R 7separately represent H, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-6cycloalkyl, C 6aryl, C 5-6heteroaryl or C 3-12heteroalicyclyl; Work as R 3and R 4when being connected on same nitrogen-atoms, a C can be formed together with this nitrogen-atoms 3-12heterolipid ring, this C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms; And R 1, R 2, R 3, R 4, R 5, R 6and R 7in hydrogen can by the identical or different halogen of 1-5 ,-CN ,-OH, C 1-6alkyl or C 3-6cycloalkyl substituted;
M is 0,1 or 2.
Wherein, the structure of preferred described phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds is such as formula shown in (Ia) or (Ib):
Described in formula,
R 1represent hydrogen or C 1-6alkyl;
A represents C 1-6alkyl, a C=O or covalent linkage, and when A is C 1-6during alkyl, hydrogen wherein can by the individual identical or different G of 1-5 2replace;
L represents O, N-R 2or S (=O) mor a covalent linkage;
J represents C 1-6alkyl or a covalent linkage, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
M, G 1, G 2, G 3, R, R ' and R 2definition the same.
Or the structure of described phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds is such as formula shown in (Ic) or (Id):
Described in formula,
G 11represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group;
L represents O or N-R 2;
J represents C 1-6alkyl, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
RR and R ' R ' separately represents-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, and the hydrogen in RR and R ' R ' can by the individual identical or different G of 1-5 4replace, RR with R ' R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms;
M, G 3, G 4and R 2definition the same.
Again or the structure of described phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds such as formula shown in (Ie) or (If):
Described in formula,
G 11represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group;
A represents C=O or C 1-6alkyl, and when A is C 1-6during alkyl, hydrogen wherein can by the individual identical or different G of 1-5 2replace;
L represents O or N-R 2;
J represents C 1-6alkyl, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
RR and R ' R ' separately represents-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, and the hydrogen in RR and R ' R ' can by the individual identical or different G of 1-5 4replace, RR with R ' R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms;
M, G 2, G 3, G 4and R 2definition the same.
And again or the structure of described phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds such as formula shown in (Ig):
Described in formula,
G 11represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group;
J represents C 1-6alkyl, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
RR and R ' R ' separately represents-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, and the hydrogen in RR and R ' R ' can by the individual identical or different G of 1-5 4replace, RR with R ' R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring can comprise one or more O, N or S (=O) in addition mheteroatoms;
M, G 3and G 4definition the same.
Wherein, the various general formula compounds that the present invention limits, pharmacy acceptable salt described in it is the salt that described phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds and mineral acid, organic acid, mineral alkali, organic bases are formed by chemical reaction.
Above-mentioned salt retains the biological activity of compound of the present invention.Described mineral acid or organic acid can be: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, oxysuccinic acid, Whitfield's ointment, tartrate, methylsulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the Phenylsulfonic acid replaced (such as, p-methyl benzenesulfonic acid), γ-picolinic acid, oleic acid, tannic acid, pantothenic acid, xitix, succinic acid, toxilic acid, gentisinic acid, fumaric acid, gluconic acid, uronic acid, glucaric acid or sucrose acid, formic acid, phenylformic acid, L-glutamic acid, pamoic acid, Sorbic Acid etc., described mineral alkali or organic bases can be: sodium hydroxide, potassium hydroxide, lithium hydroxide, ironic hydroxide, calcium hydroxide, hydrated barta, aluminium hydroxide, magnesium hydroxide, zinc hydroxide, ammoniacal liquor, hydroxide organic quaternary ammonium salt, sodium carbonate, salt of wormwood, Quilonum Retard, calcium carbonate, barium carbonate, magnesiumcarbonate, carbonating organic quaternary ammonium salt, sodium bicarbonate, saleratus, lithium bicarbonate, Calcium hydrogen carbonate, barium bicarbonate, Magnesium hydrogen carbonate, carbonic acid hydrogenation organic quaternary ammonium salt, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, Tutofusin tris etc.
More preferably described phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt be any one compound following:
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Cis-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
2-amino-8-[1-(diethoxy phosphoryl methyl)-4-piperidyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-4-[2-amino-6-(6-dimethylamino-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Cis-4-[2-amino-6-(6-dimethylamino-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
2-amino-8-[1-(diethoxy phosphoryl methyl)-4-piperidyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (methyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (methyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (ethyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (ethyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (n-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (n-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (sec.-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (sec.-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (cyclopropyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (cyclopropyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-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)-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)-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)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-ethoxy-phosphoric acid;
Cis-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-ethoxy-phosphoric acid;
Trans-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-phosphoric acid;
Cis-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-phosphoric acid;
Trans-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] is amino] methyl-ethoxy-phosphoric acid;
Cis-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] is amino] methyl-ethoxy-phosphoric acid;
Trans-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] amino] methyl-phosphoric acid or
Cis-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] is amino] methyl-phosphoric acid.
Any one above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmaceutically the raceme of acceptable salt or enantiomer are also technical scheme of the present invention.
Any one above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmaceutically the cis of acceptable salt or trans-isomer(ide) are also technical scheme of the present invention.
The present invention's simultaneously also claimed above-mentioned phosphorous pyrido [2; 3-d] pyrimidin-7-ones compounds or its pharmaceutically raceme of acceptable salt or enantiomer; wherein; can prepare phosphorous pyrido [2; 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt basis on; its raceme and corresponding isomer can adopt routine techniques means to obtain, and those skilled in the art also can predict described raceme simultaneously and corresponding isomer also possesses identical/close activity.
The present invention also protects synthetic intermediate (IIa), (IIb) or (IIc) of above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds:
In formula,
Ar ' is aryl or heteroaryl, and the hydrogen in Ar ' can by the individual identical or different R of 1-5 8replace;
R 2represent H, C 1-6alkyl, C 3-6cycloalkyl or C 3-12heteroalicyclyl; And R 2in hydrogen can by the identical or different halogen of 1-5 ,-CN ,-OH, C 1-6alkyl or C 3-6cycloalkyl substituted;
R and R ' separately represents H, OH, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 3-12heteroalicyclyl, C 1-6alkoxyl group, C 3-6cycloalkyloxy or C 3-12heterolipid epoxy group(ing), and the hydrogen in R and R ' can by the individual identical or different R of 1-5 9replace, R with R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring can comprise one or more O, N or S (=O) in addition mheteroatoms;
Wherein:
R 8and R 9separately represent H ,-CN ,-CF 3,-OCF 3,-NO 2, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 3-12heteroalicyclyl, C 1-6alkoxyl group, C 1-6cycloalkyloxy, C 3-12heterolipid epoxy group(ing) or R 10r 11n-.Wherein, R 10and R 11separately represent H, C 1-6alkyl, C 3-6cycloalkyl or C 3-12heteroalicyclyl.Work as R 10and R 11when being connected on same nitrogen-atoms, a C can be formed together with this nitrogen-atoms 3-12heterolipid ring, this C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms;
M is 0,1 or 2.
Or the synthetic intermediate as shown in structural formula (IIaa), (IIbb) or (IIcc):
Described in formula,
R 2represent hydrogen, C 1-6alkyl, C 3-6cycloalkyl or C 3-12heteroalicyclyl, be preferably hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanylmethoxy, azelidinyl, tetrahydrofuran base, pyrrolidyl, THP trtrahydropyranyl, piperidyl, piperazinyl or morpholinyl, more preferably hydrogen, methyl, ethyl, n-propyl, second propyl group, cyclopropyl, oxetanylmethoxy, tetrahydrofuran base or THP trtrahydropyranyl, further be preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, and these groups can by 1-5 halogen,-CN,-OH or C 1-6alkyl replaces,
R 88represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group, is preferably halogen ,-OCF 3,-OCH 3,-OCH 2cH 3or-NMe 2, more preferably-OCH 3or-NMe 2;
R 12and R 13separately represent-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, is preferably-OH or C 1-6alkoxyl group, more preferably C 1-6alkoxyl group, is further preferably methoxyl group, oxyethyl group, positive propoxy or isopropoxy.
The invention provides above-mentioned phosphorous pyrido [2, 3-d] preparation method of pyrimidin-7-ones compounds and synthetic intermediate thereof, as a kind of embodiment, the method can be made up of the step shown in Scheme1A and/or Scheme1B (as Scheme1A illustrates the preparation method of partial synthesis intermediate, Scheme1A+Scheme1B illustrates the phosphorous pyrido [2 of part, 3-d] preparation method of pyrimidin-7-ones compounds, Scheme1B illustrates and directly prepares phosphorous pyrido [2 with above-mentioned synthetic intermediate, 3-d] method of pyrimidin-7-ones compounds, lower same):
Wherein, the definition of Ar, R and R ' the same (see in general formula (I) compound to each substituent definition).M includes but not limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH) 2, B (OMe) 2, B (OEt) 2, B (pinacolato), BF 3k, Sn (Bu-n) 4, SnMe 4deng.LG represents a leavings group, includes but not limited to F, Cl, Br, I, MsO, p-TsO, TfO, PhSO 3deng.The implication of Pdcatalyst, Base and Solvent is shown in " term definition " part.Compd A-1 can be prepared according to WO2008032162.
The preparation method of another kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds, the method is made up of the step shown in Scheme2A and/or Scheme2B:
Wherein, Ar, R 2, R and R ' definition the same (see in general formula (I) compound to each substituent definition).W represents amino or 2,5-dimethyl pyrrole-1-base.The implication of Oxidant, Reductant, Base and Solvent is shown in " term definition " part.
The preparation method of another kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds, the method is made up of the step shown in Scheme3A and/or Scheme3B:
Wherein, Ar, R 2, R and R ' definition the same (see in general formula (I) compound to each substituent definition).M includes but not limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH) 2, B (OMe) 2, B (OEt) 2, B (pinacolato), BF 3k, Sn (Bu-n) 4, SnMe 4deng.The implication of Pdcatalyst, CouplingReagent, Base and Solvent is shown in " term definition " part.
The preparation method of another kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds, the method is made up of the step shown in Scheme4A and/or Scheme4B:
Wherein, the definition of Ar, R and R ' the same (see in general formula (I) compound to each substituent definition).M includes but not limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH) 2, B (OMe) 2, B (OEt) 2, B (pinacolato), BF 3k, Sn (Bu-n) 4, SnMe 4deng.LG represents a leavings group, includes but not limited to F, Cl, Br, I, MsO, p-TsO, TfO, PhSO 3deng.The implication of Pdcatalyst, Base and Solvent is shown in " term definition " part.
The preparation method of another kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds, the method is made up of the step shown in Scheme5A and/or Scheme5B:
Wherein, the definition of Ar, R and R ' the same (see in general formula (I) compound to each substituent definition).M includes but not limited to Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B (OH) 2, B (OMe) 2, B (OEt) 2, B (pinacolato), BF 3k, Sn (Bu-n) 4, SnMe 4deng.LG represents a leavings group, includes but not limited to F, Cl, Br, I, MsO, p-TsO, TfO, PhSO 3deng.The implication of Pdcatalyst, Acid, Base and Solvent is shown in " term definition " part.
The present invention also protects containing above-mentioned phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, or the pharmaceutical composition of its raceme or enantiomer.
Pharmaceutical composition of the present invention can be used for treatment because of the disease caused by protein kinase abnormal activity.Except above-mentioned activeconstituents, pharmaceutical composition of the present invention also comprises one or more carriers pharmaceutically acceptable or thinner.
The dosage form of pharmaceutical composition of the present invention includes but not limited to: oral preparation, injection, anus suppository, nostril inhalation, eye drops or skin patch.
The pharmaceutical composition be made up of compound of the present invention is used for the treatment of Mammals, as human patient, and the disease that the abnormal activity because of protein kinase causes.
Compound of the present invention (comprising raceme, enantiomer, cis-trans-isomer and other steric isomer) or its pharmaceutically acceptable salt, hydrate, solvate or prodrug by preparation (formulation) process, are prepared into the pharmaceutically acceptable carrier be applicable to and pharmaceutically conventional assistant agent the pharmaceutical composition being beneficial to administration.
Specifically, the drug administration approach of compound composition of the present invention can be: (1) is oral: such as tablet, capsule etc.; (2) inject: such as intravenous injection, subcutaneous injection, intramuscular injection, eyeball injection, abdominal injection etc.; (3) anus plug: such as suppository, gelifying agent etc.; (4) nostril sucks: such as sprays, aerosol etc.; (5) eye drops; (6) skin patch.Also can use drug delivery system, such as, liposome (liposome), slow release method etc., the method wherein preferentially selected is oral and injection, and the method more preferably selected is oral.
The various formulations of the pharmaceutical composition that the present invention is made up of described compound can adopt the method that medicine industry is conventional to prepare, such as, and mixing, dissolving, granulation, grinding, emulsification, capsule, sugar-coat, lyophilize, cryospray etc.
The content range of compound in the present invention in foregoing pharmaceutical composition is 0.001-100%.It is per kg body weight per day 0.1-500 milligram that this pharmaceutical composition is applied to the mammiferous effective dose comprising people, and the dosage of optimization is that per kg body weight per day uses 1-100 milligram.In this effective dosage ranges, the compound in the present invention plays the pharmacological action of the disease (such as cancer) that its arrestin kinase activity and treatment cause because of abnormal protein kinase activity.
The frequency of utilization of medicine of the present invention is complied with the disease of used compound or its pharmaceutical composition and application and changes to some extent, and the pharmaceutical composition in the present invention normally daily 1-6 time, the administration frequency of optimization is daily 1-3 time.
The packaging of medicine of the present invention and preserve and general medicine similar, the medicine of such as solid dosage can directly load in glass, plastics, papery or metal bottle, preferably puts into the quality to keep medicine such as siccative in bottle; The medicine of liquid dosage form generally loads in glass, plastics or metal bottle or flexible pipe; The medicine of the formulation that hazes generally loads in the withstand voltage metal with devices such as reducing valve or plastic containers.
Invention further provides described phosphorous pyrido [2; 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt; or its raceme or enantiomer; or containing described phosphorous pyrido [2; 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, or the pharmaceutical composition of its raceme or enantiomer in treatment because of the application in the disease caused by protein kinase abnormal activity.
In above-mentioned application, described protein kinase is PI3K or mTOR, and preferably described protein kinase is PI3K, is further preferably PI3K-α, PI3K-β, PI3K-γ and PI3K-δ.
The disease described in application of the pharmaceutical composition of the compounds of this invention composition is psoriatic, liver cirrhosis, trachitis, rheumatic arthritis, lupus erythematosus, diabetes, the disease relating to angiogenesis, disease of eye, disease of immune system, cardiovascular disorder, epilepsy, nerve degenerative diseases, Alzheimer, Huntington's disease or Parkinson's disease.
Of the present invention because of the disease caused by protein kinase abnormal activity be tumour, specifically comprise solid tumor and liquid tumor, more specifically comprise: lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head and neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, anal region cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, vaginal orifice cancer, Hodgkin, esophagus cancer, carcinoma of small intestine, endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or carcinoma of ureter, kidney, nervus centralis cental system (CNS) vegetation, spinal column axis tumour, pituitary adenoma, gastrointestinal stromal, colorectal carcinoma, nonsmall-cell lung cancer, small cell lung cancer, mastocytosis, glioma, sarcoma, a kind of or several arbitrarily combination in lymphoma.
Prove through a series of test, the phosphorous pyrido [2 of the present invention, 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt there is following beneficial effect: (1), by suppressing the screening experiment of kinase activity, can find out that the compounds of this invention has very strong restraining effect to a series of protein kinase especially PI3K and mTOR; (2) by seeing the test of the tumor suppression of animal, such phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt can remarkable Tumor suppression, and there is no obvious toxicity; (3) compound of the present invention jointly can use with other antitumor drugs thus play collaborative (synergistic) or adduction (additive) effect; (4) compound in the present invention can with other tumor therapy, such as radiotherapy, interventional therapy etc. together use.As can be seen here, a kind of phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds of the present invention or its pharmaceutically acceptable salt can as the medicine of a kind of effective treatment because of the disease caused by protein kinase abnormal activity.
Compound of the present invention is in treatment because of in the abnormal caused above-mentioned disease of protein kinase activity, and described kidney is adrenal carcinoma, renal cell carcinoma, carcinoma of renal pelvis; Glioma is brain stem glioma, neuroendocrine glia tumour, neurospongioma.
Compound of the present invention is being treated because of in the abnormal caused disease of protein kinase activity, can also be psoriatic (or claiming psoriasis) except tumour, liver cirrhosis, trachitis, rheumatic arthritis, lupus erythematosus, diabetes, relate to the disease of angiogenesis, relate to the disease of restenosis, disease of eye is AMD such as, rheumatic arthritis and other inflammation, such as auto-immune disease is (such as disease of immune system, AIDS etc.), cardiovascular disorder is atherosclerosis such as, kidney disease, epilepsy, nerve degenerative diseases, such as Alzheimer, Huntington's disease, Parkinson's disease etc.
The definition of term
It is below term definition involved in the present invention.The variable groups used in the present invention, such as R a, R b, m etc. is only applicable to this trifle (i.e. " definition of term " part).
According to the common practise of those of ordinary skill in the art, chemical reaction in most cases needs to carry out in a solvent, the solvent (Solvent) preparing compound of the present invention conventional includes but not limited to water, methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 2-methyl cellosolve, 2, 2, 2-trifluoroethanol, methylene dichloride, 1, 2-ethylene dichloride, chloroform, THF, dioxane, DME, ethyl acetate, ether, methyl tert-butyl ether, hexane, hexanaphthene, toluene, acetonitrile, DMF, two or more mixture etc. in DMSO or these solvents.
Chemical reaction needs to occur when acid (Acid) or alkali (Base) exist in some cases, and the alkali (Base) preparing compound of the present invention conventional includes but not limited to Et 3n, Me 3n, i-Pr 2nEt, pyridine, DBU, DABCO, tetramethyl guanidine, NaOH, KOH, Cs 2cO 3, Na 2cO 3, K 2cO 3, NaHCO 3, KF, CsF, K 3pO 3, K 2hPO 4, KH 2pO 4, NaH, n-BuLi, s-BuLi, t-BuLi, NaN (SiMe 3) 2, LiN (SiMe 3) 2, KN (SiMe 3) 2or two or more the mixture etc. in these alkali; Conventional acid (Acid) includes but not limited to HCO 2h, AcOH, TFA (trifluoracetic acid), HCl (hydrochloric acid), H 2sO 4, HNO 3, H 3pO 4, p-TsOH, PhSO 3h, CSA, MsOH etc. or Lewis acid ZnCl 2, AlCl 3, BF 3.oEt 2deng.
Chemical reaction needs to occur when coupling reagent (CouplingReagent) exists in some cases, and the coupling reagent (CouplingReagent) preparing compound of the present invention conventional includes but not limited to DCC, EDC, HATU, TBTU, PyBOP, HCTU, BOP, T3P, DIC, HOBt, HOAt, CDI, DEPBT etc.
Prepare some step of compound of the present invention to need use reduction reaction (Reduction) and go back original reagent (Reductant), described reduction reagent includes but not limited to H 2+ Pd/C, H 2+ Pd (OH) 2, H 2+ PtO 2, ni, Ti (OPr-i) 4+ NaBH 4, Ti (OPr-i) 4+ NaB (OAc) 3h, Ti (OPr-i) 4+ NaBH 3(CN), Ti (OPr-i) 4+ H 2, ni, Mg+MeOH, Fe+AcOH, Fe+HCl, Zn+AcOH, Zn+HCl, Zn+NH 4oAc, SnCl 2, LiAlH 4, NaBH 4, NaBH 3(CN), NaB (OAc) 3h, BH 3deng.
Prepare some step of compound of the present invention to need to use oxidizing reaction (Oxidation) and oxidising agent (Oxidant), described oxidising agent includes but not limited to PCC (PyH.ClCrO 3), PDC (2Py.Cr 2o 7), K 2cr 2o 7, Na 2cr 2o 7, H 2cr 2o 7, CrO 3, CrO 3.2Py, O 2, H 2o 2, mCPBA, DMSO+ (COCl) 2, NaClO 2, NaClO, Dess-Martinreagent, KMnO 4, OsO 4, MnO 2deng.
Prepare some step of compound of the present invention to need to use palladium catalyst (Pdcatalyst), described palladium catalyst includes but not limited to Pd/C, Pd (PPh 3) 4, Pd 2(dba) 3, PdCl 2, Pd (OAc) 2, Pd (O 2cCF 3) 2, PdCl 2(dppf), PdCl 2(dppp), Pd (PPh 3) 2cl 2, Pd (PhCN) 2cl 2, Pd (OH) 2deng.
Prepare some step of compound of the present invention and need Deprotection (Deprotection), when protecting group is Boc (or-CO 2bu-t), time, conventional deprotecting regent includes but not limited to HCl, TFA, H 2sO 4deng, when protecting group is CBZ (or-CO 2cH 2ph), time, conventional deprotecting regent includes but not limited to dense HCl, H 2+ Pd/C etc., when protecting group is Bn (or-CH 2ph), time, conventional deprotecting regent includes but not limited to H 2+ Pd/C, H 2+ Pd (OH) 2, H 2+ Pd/C+HCl etc.
The reaction preparing compound of the present invention is at room temperature carried out usually, but sometimes needs to be reduced to-78 DEG C or be heated to 200 DEG C; Reaction is carried out usually under aforesaid solvent and temperature and convention stir condition, but sometimes needs to carry out in microwave oven; When the alkali used, reagent, catalyzer are to water or oxygen sensitive, reaction need be carried out under anhydrous and oxygen-free condition, in this case, can not use protic solvent.
" solvate " refers to the stable material that compound of the present invention is formed with covalent linkage, hydrogen bond, ionic linkage, Van der Waals force, complexing, inclusion etc. with chemically conventional solvent, and described solvent can be: methyl alcohol, ethanol, propyl alcohol, butanols, ethylene glycol, propylene glycol, polyoxyethylene glycol, acetone, acetonitrile, ether, methyl tert-butyl ether etc.
" hydrate " refers to solvate, and solvent is wherein water.
" prodrug " to refer to the converting compounds in the present invention by the method for chemosynthesis or physics is another kind of compound, and after giving Mammals by this compound, is converted to compound of the present invention in animal body." prodrug " method of utilization is normally in order to overcome the bad or not good enough physicochemical property of medical compounds itself or druggability.
" raceme, enantiomer, cis-trans-isomer and other steric isomer " refers to that compound has identical molecular formula and molecular weight, but forming different compounds due to the different bonding pattern between atom and arrangement space order, such compound is on isomer or claim steric isomer.When these steric isomers mirror each other, namely look the same, but can not overlap completely, and as left hand and the right hand, these compounds are enantiomer.The absolute configuration of enantiomer uses (R)-and (S)-or R-and S-to indicate usually.Specifically determine that the rule of the absolute configuration of enantiomer is shown in Chapter4of " AdvancedOrganicChemistry, " 4 thedition (byJ.March, JohnWileyandSons, NewYork, 1992).(R)-and (S)-enantiomer to polarized light, there is contrary turning effort, i.e. left-handed and dextrorotation.When (R)-and (S)-enantiomer are in the ratio mixing of 1:1 or when existing, this mixture does not have turning effort to polarized light, at this moment this mixture is called raceme.
Also may there are tautomer (tautomers), rotational isomer (rotamers), cis-trans-isomer etc. in compound of the present invention, these concepts all can at " AdvancedOrganicChemistry, " 4 of J.March thfind in edition and be understood.As long as these isomer have the effect of the same or similar arrestin kinase activity with compound of the present invention, these isomer are also covered by the present invention.
After compound in the present invention is given Mammals (such as people), according to the general knowledge of this area, likely become various meta-bolites by different enzymes metabolisms in animal body, as long as these meta-bolitess have the effect with arrestin kinase activity like compounds of the present invention, these meta-bolitess are also covered by the present invention.
" pharmaceutical composition " refers in compound of the present invention, multiple, pharmacy acceptable salt or solvate or hydrate or prodrug to mix obtained preparation with other chemical composition (such as pharmaceutically acceptable carrier or thinner).The object of pharmaceutical composition promotes to the process of animals administer.In above-mentioned pharmaceutical composition, except comprising pharmaceutically acceptable carrier, assistant agent conventional in medicine (agent) can also be included in, such as: antibacterial agent, anti-mycotic agent, biocide, preservative, toning agent, solubilizing agent, thickening material, tensio-active agent, complexing agent, protein, amino acid, fat, carbohydrate, VITAMIN, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.
" pharmaceutically acceptable carrier " or " thinner " refer in pharmaceutical composition non-active ingredient, can for but be not limited to: calcium carbonate, calcium phosphate, various sugar (such as lactose, N.F,USP MANNITOL etc.), starch, cyclodextrin, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, acrylate copolymer, methacrylate polymer, gel, water, polyoxyethylene glycol, propylene glycol, ethylene glycol, Viscotrol C, hydrogenated castor oil, many ethoxy aluminium Viscotrol C, sesame oil, Semen Maydis oil, peanut wet goods.
" alkyl " refers to have the saturated hydrocarbon group of the straight or branched specifying number carbon atom, such as C 1-6alkyl refers to containing minimum 1, the straight or branched group of maximum 6 carbon atoms.C 0alkyl represents a covalent single bond.Alkyl of the present invention includes but not limited to: methyl, ethyl, propyl group, butyl, sec.-propyl, neo-pentyl, 2-methyl isophthalic acid-hexyl etc.Alkyl of the present invention also refers to alkylidene group sometimes, and namely alkyl loses the group that a hydrogen atom is formed.One or all hydrogen atom in alkyl or alkylidene group can be replaced by following groups: cycloalkyl, aryl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR ar b, wherein, R aand R bbe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aand R b5-or 6-unit heterolipid ring can be formed together with nitrogen-atoms.
" cycloalkyl " or " cycloalkanes " refers to have the hydrocarbon group specifying number the single, double of carbon atom or many rings, when dicyclo or many rings, can combine with the form condensing (two rings or multiple ring share two adjacent carbon atoms) or screw togather (two rings or multiple ring share a carbon atom), such as C 1-6cycloalkyl refers to containing minimum 1, the hydrocarbon group of single, double or many rings of maximum 6.C 0cycloalkyl represents a covalent single bond.Can undersaturated double bond or triple bond be contained in cycloalkyl, but not there is the π-electron system of total conjugated.Cycloalkyl of the present invention also refers to cycloalkylidene sometimes, and namely cycloalkyl loses the group that a hydrogen atom is formed.Cycloalkyl of the present invention includes but not limited to: cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatriene base, diamantane etc. (citing is as Table A):
Table A
One or all hydrogen atom in cycloalkyl or cycloalkanes can be replaced by following groups: alkyl, aryl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR ar b, wherein, R aand R bbe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aand R b5-or 6-unit heterolipid ring can be formed together with nitrogen-atoms.
" heteroalicyclyl or heterolipid ring " refers to the monocycle, dicyclo or the polycyclic system that are made up of 3 to 12 non-hydrogen annular atomses, and wherein at least one annular atoms is the heteroatoms being selected from O, N, S or P, and all the other annular atomses are carbon atom, such as, and C 8heteroalicyclyl refers to the monocycle, dicyclo or the polycyclic moiety that are made up of 8 non-hydrogen annular atomses, and wherein at least one annular atoms is selected from O, N, S or P.In this ring except singly-bound, also double bond or three key can be contained, but these double bonds or three key do not form the aromatic structure of whole conjugation.These monocycles, dicyclo or polycyclic system can exist with the form of condensed ring, bridged ring or volution.Heteroalicyclyl of the present invention also refers to sub-heteroalicyclyl sometimes, and namely heteroalicyclyl loses the group that a hydrogen atom is formed.Heteroalicyclyl in the present invention or heterolipid ring include but not limited to: piperidines, morpholine, piperazine, tetramethyleneimine, indoline, tetrahydropyridine, tetrahydrofuran (THF), tropanol etc. (citing is as table B):
Table B
One or all hydrogen atom in heteroalicyclyl or heterolipid ring can be replaced by following groups: alkyl, cycloalkyl, aryl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR ar b, wherein, R aand R bbe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aand R b5-or 6-unit heterolipid ring can be formed together with nitrogen-atoms.
" thiazolinyl " refers to the straight or branched hydrocarbon group containing at least two carbon atoms and a double bond, such as C 2-6thiazolinyl refers to containing minimum 2, and the straight or branched of maximum 6 carbon atoms contains the unsaturated group of at least one double bond.Thiazolinyl in the present invention includes but not limited to: vinyl, 2-propenyl, 1-pentenyl etc.
" alkynyl " refers to the straight or branched hydrocarbon group containing at least two carbon atoms and a triple bond, such as C 2-6alkynyl refers to containing minimum 2, and the straight or branched of maximum 6 carbon atoms contains the unsaturated group of at least one triple bond.Alkynyl in the present invention includes but not limited to: vinyl, 2-propenyl, 1-pentenyl etc.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" alkoxyl group " is referred to have the alkyl specifying number carbon atom and is connected with other groups by Sauerstoffatom.Alkoxyl group in the present invention includes but not limited to: methoxyl group, oxyethyl group, propoxy-, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentyl oxygen, 2-methyl isophthalic acid-hexyloxy etc.
" cycloalkyloxy " is referred to have the cycloalkyl specifying number carbon atom and is connected with other groups by Sauerstoffatom.Cycloalkyloxy in the present invention includes but not limited to: cyclopropane oxygen base, tetramethylene oxygen base, hexamethylene alkoxyl group etc.
" heterolipid epoxy group(ing) " refers to that heteroalicyclyl is connected with other groups by Sauerstoffatom.Heterolipid epoxy group(ing) in the present invention includes but not limited to: piperidines-4 base oxygen base, trimethylene oxide-3-base oxygen base etc.
" aryl " refers to that wherein at least one ring has the π-electron system of total conjugated and meets N+2 rule, namely has aromaticity by monocycle, dicyclo or the polycyclic moiety specifying number carbon atom and form, but whole group need not whole conjugation.Such as, C 6aryl means phenyl.Aryl also can occur with the form of arylidene, namely has two or more tie points with other groups in heteroaryl structure.Aryl in the present invention includes but not limited to: phenyl, naphthyl, indenyl, indanyl, tetraline etc.One or all hydrogen atom in aryl can be replaced by following groups: alkyl, cycloalkyl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR ar b, wherein, R aand R bbe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aand R b5-or 6-unit heterolipid ring can be formed together with nitrogen-atoms.
" heteroaryl " refers to by the monocycle, dicyclo or the polycyclic moiety that specify number non-hydrogen annular atoms and form, wherein at least one annular atoms is the heteroatoms being selected from O, N, S or P, all the other annular atomses are carbon atom, and, wherein at least one ring has the π-electron system of total conjugated and meets N+2 rule, namely has aromaticity, but whole group need not whole conjugation, such as, C 5heteroaryl refers to the aromatic group be made up of 5 non-hydrogen annular atomses, and wherein at least one annular atoms is selected from O, N, S or P.Heteroaryl also can occur with the form of inferior heteroaryl, namely has two or more tie points with other groups in heteroaryl moieties.Heteroaryl in the present invention includes but not limited to: arsenic pyridine, arsenic heavy stone used as an anchor ketone, tetrahydrochysene arsenic heavy stone used as an anchor ketone, miaow pyridine, pyrazine, pyridazine, imidazoles, thiazole, thiophene, furans, indoles, azaindole, benzoglyoxaline, indoline, indolone, quinoline are given repeated exhortations etc. (citing is as table C):
Table C
One or all hydrogen atom in heteroaryl can be replaced by following groups: alkyl, cycloalkyl, aryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl thiol, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR ar b, wherein, R aand R bbe selected from hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc. respectively, and R aand R b5-or 6-unit heterolipid ring can be formed together with nitrogen-atoms.
" aryloxy " refers to that aryl is connected with other groups by Sauerstoffatom.Aryloxy in the present invention includes but not limited to: phenoxy group, naphthyloxy etc.
" heteroaryloxy " refers to that heteroaryl is connected with other groups by Sauerstoffatom.Heteroaryloxy in the present invention includes but not limited to: 4-arsenic pyridine oxygen base, 2-thiophene oxy etc.
" amino " refers to H 2the H that N-or wherein hydrogen atom are substituted 2n-, i.e. R ahN-and R ar bn-.
" oxo " or " oxygen base " refers to=O, and namely Sauerstoffatom is connected with the heteroatoms such as carbon or N, S, P by double bond.Material shown in table D is included but not limited to by the example that oxygen base replaces:
Table D
" hydroxyl " refers to-OH.
" nitro " refers to-NO 2.
" carboxyl " refers to-CO 2h.
" sulfydryl " refers to-SH.
" alkyl thiol " refers to alkyl-S-.
" aryl thiol " refers to aryl-S-.
" carbonyl " refer to-C (=O)-.
" thiocarbonyl group " refer to-C (=S)-.
" C-amide group " refers to-C (=O) NR ar b.
" N-amide group " refers to C (=O) NR a-.
" O-ammonia carbonyl oxygen base " refers to-O-C (=O) NR ar b.
" N-ammonia carbonyl oxygen base " refers to O-C (=O) NR a-.
" O-sulfo-ammonia carbonyl oxygen base " refers to-O-C (=S) NR ar b.
" N-sulfo-ammonia carbonyl oxygen base " refers to O-C (=S) NR a-.
" C-ester group " refers to-C (=O) OR a.
" N-ester group " refers to C (=O) O-.
" ethanoyl " refers to CH 3c (=O)-.
" alkylsulfonyl " refers to-SO 2r a.
" trifyl " refers to CF 3sO 2-.
Accompanying drawing explanation
The compounds of this invention described in Fig. 1 embodiment 1 is to the tumor-inhibiting action curve control figure of mouse A549 tumour;
The compounds of this invention described in Fig. 2 embodiment 2-4b is to the tumor-inhibiting action curve control figure of mouse A549 tumour;
The compounds of this invention described in Fig. 3 embodiment 3 is to the tumor-inhibiting action curve control figure of mouse A549 tumour;
The compounds of this invention described in Fig. 4 embodiment 5 is to the tumor-inhibiting action tumor weight contrast figure of mouse A549 tumour;
The compounds of this invention described in Fig. 5 embodiment 2-4a is to the tumor-inhibiting action curve control figure of mouse PC3 tumour;
The compounds of this invention described in Fig. 6 embodiment 2-4a is to the tumor-inhibiting action curve control figure of mouse U87MG tumour.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail; so that reader understands compound of the present invention, its preparation method and beneficial effect etc. further, but the specific embodiment of the present invention does not have restriction to the content that application claims is protected.
List the english abbreviation and corresponding Chinese implication that occur in an embodiment below.If there is the abbreviation of not listing in this in embodiment, then represent generally accepted implication.
DMSO: dimethyl sulfoxide (DMSO)
DMSO-d 6: hexadeuterated dimethyl sulfoxide
TMS: tetramethylsilane
DCM: methylene dichloride
CDCl 3: deuterochloroform
CD 3oD: deuterated methanol
THF: tetrahydrofuran (THF)
EtOAc: ethyl acetate
MeOH: methyl alcohol
EtOH: ethanol
HCl: hydrogenchloride or hydrochloric acid
TLC: thin-layer chromatography
LC-MS: liquid chromatograph mass spectrography
G: gram
Mg: milligram
Mol: mole
Mmol: mmole
μM: micromole
L: rise
μ L: microlitre
NM: nmole
[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
DBU:1,8-diazabicylo [5.4.0] 11 carbon-7-alkene
PCC: pyridinium chlorochromate drone salt
Ti (OPr-i) 4: tetra isopropyl titanate
Pd (PPh 3) 4: tetrakis triphenylphosphine palladium (0)
Pd (PPh 3) 2cl 2: two-(triphenylphosphine) Palladous chloride (II)
NBS:N-bromo-succinimide
LiHMDS: two-(trimethyl silicon based) amine lithium
LiAlH 4: Lithium Aluminium Hydride
DMA: N,N-DIMETHYLACETAMIDE
Common experimental conditions:
Proton nmr spectra and carbon are composed and obtain (deuterated methanol etc. are solvent for deuterated DMSO, deuterochloroform, and TMS is interior mark) on Varian400MHz or Bruker400MHz instruments.Mass spectrum is obtained (adopting ESI or APCI ion source ZQ4000, Waters, US) by liquid chromatograph-mass spectrometer.UV spectrum is recorded by the UV-3010 ultraviolet spectrophotometer of HIT.Infrared spectra uses NICOLET6700 infrared spectrometric analyzer (KBr compressing tablet).High performance liquid chromatography uses Waters2695ZORBAX high performance liquid chromatograph (Bx-C 85 μ 150 × 4.6mm chromatographic columns).The mensuration of fusing point uses the digital melting point apparatus IA9100 of Electrothermal, and does not correct.
Starting raw material, reagent and solvent are bought from following supplier: Beta-Pharma; ShanghaiPIChemicals; AndaChem; Taiyuan; ShanghaiFWDChemicals; Sigma-Aldrich, Milwaukee, WI, USA; Acros, MorrisPlains, NJ, USA; FrontierScientific, Logan, Utah, USA; AlfaAesar, WardHill, MA, USA etc. or utilize the method for bibliographical information to synthesize.Unless otherwise indicated, solvent generally not drying, and directly use supplier product or through 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)-4-picoline [2; 3-d] preparation of pyrimidin-7-ones (1-15), concrete reaction formula is as follows:
The first step: toward the chloro-6-methylpyrimidine of 4--2-amine (1-1,100g, bromine (134g is dripped in dichloromethane solution (4L) 0.70mol), 0.84mol), the suspension produced at room temperature stirs 2 hours, add methylene dichloride (5L) dilution, wash with saturated sodium bicarbonate solution (2x3L) and saturated aqueous common salt (3L), dried over mgso, filtration, concentrated obtain the bromo-4-of product 5-chloro-6-methylpyrimidine-2-amine (1-2), for white solid (120g, productive rate: 79%).
Second step: the chloro-6-methylpyrimidine of 5-bromine 4--2-amine (1-2,120g, 0.54mol), trans-4-amino hexalin (1-3,58g, 0.5mol) and the N,N-DIMETHYLACETAMIDE of diisopropyl ethyl amine (110g, 0.84mol) (4L) solution in 120 DEG C of reacting by heating 16 hours.Reaction mixture methyl tertiary butyl ether (2.0L) dilutes, with saturated ammonium chloride solution (2x3.0L) and saturated common salt water washing, anhydrous magnesium sulfate drying, filter, be concentrated into dry, residue column chromatography purification, the mixture (95/5) of methylene chloride/methanol is as eluent, obtain the trans-4-of product [(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] hexalin (1-4), for pale red solid (100g, productive rate: 61%).Nuclear magnetic resonance spectroscopy result: 1h-NMR (CD 3oD, 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).
3rd step: trans-4-[(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] hexalin (1-4,50g, 0.166mol), ethyl propenoate (1-5,83g, 0.83mol), triethylamine (84g, 0.83mol) and Pd (PPh 3) 4dMF (500mL) solution of (10g, 8.65mmol) was in 130 DEG C of reacting by heating 16 hours.Reaction mixture is chilled to room temperature and concentrates, residue methylene dichloride (200mL) dilutes, filter, drying obtains product trans-(E)-3-[2-amino-4-[(4-hydroxy-cyclohexyl) is amino]-6-methylpyrimidine-5-base]-2-ethyl propenoate (1-6), for white solid (25g, productive rate: 46%).Mass spectrometry results: m/z:321.20 [M+H] +.
4th step: trans-(E)-3-[2-amino-4-[(4-hydroxy-cyclohexyl) is amino]-6-methylpyrimidine-5-base]-2-ethyl propenoate (1-6,40g, 0.125mol), thiophenol (14g, 0.13mol), thiophenol sodium (33g, 0.25mol), DBU (1-7,76g, 0.5mol) and the DMF solution (400mL) of diisopropyl ethyl amine (97g, 0.75mol) in 120 DEG C of reacting by heating 16 hours.Reaction mixture is concentrated into dry, residue purification by silica gel column chromatography, the mixture (95/5) of methylene chloride/methanol is as eluent, obtain the trans-2-amino of product-8-(4-hydroxy-cyclohexyl)-4-picoline [2,3-d] pyrimidin-7-ones, for yellow solid (1-8,29g, productive rate: 85%).Mass spectrometry results: m/z:275.20 [M+H] +.
5th step: trans-(2-amino-8-(4-hydroxy-cyclohexyl)-4-picoline [2, 3-d] pyrimidin-7-ones (1-8, 29g, NBS (23g is added in DMF (290mL) solution 0.106mol), 0.13mol), in stirring at room temperature after 1 hour, reaction mixture is concentrated into dry, residue column chromatography purification, the mixture (95/5) of methylene chloride/methanol is as eluent, obtain product trans-2-amino-6-bromo-8-(4-hydroxy-cyclohexyl)-4-picoline [2, 3-d] pyrimidin-7-ones (1-9), for yellow solid (27g, productive rate: 71%).Mass spectrometry results: m/z:353.00 [M+H, 79br] +, 355.00 [M+H, 81br] +.
6th step: in the bromo-8-of trans-2-amino-6-(4-hydroxy-cyclohexyl)-4-picoline [2,3-d] pyrimidin-7-ones (1-9,11g, 31.1mmol), salt of wormwood (13g, 93mmol) and 2-methoxypyridine-3-ylboronic acid (1-10,6.8g, 56mmol) at DMF/H 2in mixture in O (5:1,24mL), drum nitrogen 5 minutes, adds Pd (PPh in this mixture 3) 2cl 2(3g, 4.28mmol).Gained mixture was in microwave oven 100 DEG C of heated and stirred 2 hours.Reaction mixture is concentrated into dry, residue purification by silica gel column chromatography, the mixture (95/5) of methylene chloride/methanol is as eluent, obtain the trans-2-amino of product-8-(4-hydroxy-cyclohexyl)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (1-11), for yellow solid (6.64g, productive rate: 56%).Mass spectrometry results: m/z:382.30 [M+H] +.
7th step: trans-2-amino-8-(4-hydroxy-cyclohexyl)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (1-11,1.5g, 3.93mmol), 2,5-bis-hexanone (1-12,2.7g, 24mmol) and toluene (100mL) vlil of tosic acid (0.15g, 0.87mmol) spend the night.Reaction mixture is cooled to room temperature, and concentrated.Residue column chromatography purification, the mixture (80/20) of petrol ether/ethyl acetate is as eluent, obtain the trans-2-(2 of product, 5-dimethyl pyrrole-1-base)-8-(4-hydroxy-cyclohexyl)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (1-13), for white solid (1g, productive rate: 55%).
8th step: at 0 DEG C, toward trans-2-(2,5-dimethyl pyrrole-1-base)-8-(4-hydroxy-cyclohexyl)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (1-13,1.1g, 2.39mmol) THF solution (20mL) in add LiHMDS (the THF solution of 1N, 4mL, 4mmol).Gained mixture at room temperature stirs 1 hour, is cooled to 0 DEG C, adds diethoxy phosphoryl methyl triflate (1-14,1.1g, 3.6mmol).This mixture at room temperature stirs 5 hours, adds saturated NH 4the cancellation of Cl solution, uses dichloromethane extraction.Organic layer is dry and concentrated; resistates preparation TLC purifying obtains compound trans-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-2-(2; 5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (1-15; 0.61g, productive rate: 42%).Mass spectrometry results: m/z:610.20 [M+H] +.
Embodiment 1
The preparation of trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (1-16), concrete reaction formula is as follows:
Trans-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-2-(2; 5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (1-15; 0.61g; 1mmol, according to embodiment 1A preparation) and oxammonium hydrochloride (0.35g, 5mmol) be dissolved in ethanol/water (10:1; 22mL), and be heated to backflow and spend the night.Reaction mixture concentrating under reduced pressure; trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-the pyridyl)-4-picoline [2 that resistates preparative HPLC purifying obtains; 3-d] pyrimidin-7-ones (1-16; 210mg; productive rate: 40%) is yellow solid.Nuclear magnetic resonance spectroscopy result: 1h-NMR (CDCl 3, 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).Mass spectrometry results: m/z:532.20 [M+H] +.
The same or similar method synthesis that following compounds (but being not limited to these compounds) can describe according to embodiment 1A and embodiment 1:
Embodiment 2A
Cis/trans-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-2-(2; 5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] preparation of pyrimidin-7-ones (2A), concrete reaction formula is as follows:
The first step: at 0 DEG C, toward trans-2-(2, 5-dimethyl pyrrole-1-base)-8-(4-hydroxy-cyclohexyl)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2, 3-d] pyrimidin-7-ones (1-13, 0.179g, 0.39mmol, according to the 7th step synthesis in embodiment 1A) and sodium-acetate (64mg, PCC (0.11g is added in methylene dichloride (5mL) solution 0.78mmol), 0.47mmol), after gained mixture at room temperature stirs 4 hours, filter, concentrating under reduced pressure, crude product purified by silica gel purification by column chromatography, petrol ether/ethyl acetate mixture (70/30) is as eluent, obtain compound 2-(2, 5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl) pyridine [2, 3-d] pyrimidin-7-ones (2A-1, 0.093g, productive rate: 52%).Mass spectrometry results: m/z:458.32 [M+H] +.
Second step: 2-(2,5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl) pyridine [2,3-d] pyrimidin-7-ones (2A-1,0.092g, 0.2mmol) with triethylamine (0.060g, THF (5mL) solution 0.59mmol) at room temperature stirs 1 hour, adds Ti (OPr-i) 4(0.25mL) and diethoxy phosphoryl methylamine (2-2,0.075g, 0.30mmol), gained mixture at room temperature stirs 2 hours, adds sodium borohydride (0.038g, 1.0mmol) and stirs afterwards and spend the night.Reaction mixture saturated aqueous ammonium chloride (5mL) cancellation; methylene dichloride (3x20mL) extracts; organic phase dried over mgso, filtration, concentrated; residue HPLC purifying obtains 8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-2-(2; 5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (2A; 38mg; productive rate: 31%) is 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)-4-picoline [2; 3-d] pyrimidin-7-ones (2-4a) and trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] preparation of pyrimidin-7-ones (2-4b), concrete reaction formula is as follows:
The first step: at 0 DEG C, toward trans-2-amino-8-(4-hydroxy-cyclohexyl)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2, 3-d] pyrimidin-7-ones (1-11, 1.5g, 3.93mmol, according to the 6th step synthesis in embodiment 1) and sodium-acetate (640mg, PCC (1.1g is added in methylene dichloride (15mL) solution 7.8mmol), 4.7mmol), after gained mixture at room temperature stirs 4 hours, filter, concentrating under reduced pressure, crude product purified by silica gel purification by column chromatography, petrol ether/ethyl acetate mixture (70/30) is as eluent, obtain compound 2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl) pyridine [2, 3-d] pyrimidin-7-ones (2-1, 1g, productive rate: 67%).Mass spectrometry results: m/z:380.30 [M+H] +.
Second step: 2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl) pyridine [2,3-d] pyrimidin-7-ones (2-1,1.5g, 4.0mmol) with triethylamine (1.2g, THF (15mL) solution 11.8mmol) at room temperature stirs 1 hour, adds Ti (OPr-i) 4(5mL) and diethoxy phosphoryl methylamine (2-2,1.5g, 5.9mmol), gained mixture at room temperature stirs 2 hours, adds sodium borohydride (0.75g, 19.8mmol) and stirs afterwards and spend the night.Reaction mixture saturated aqueous ammonium chloride (30mL) cancellation; methylene dichloride (3x100mL) extracts; organic phase dried over mgso, filtration, concentrated; residue HPLC purifying obtains 2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (2-3; 400mg; productive rate: 19%); for trans/cis mixture, use supercritical fluid chromatography (SFC) to be separated further and obtain 226mg cis and 50mg trans product.
Cis-product (2-4a): nuclear magnetic resonance spectroscopy result: 1h-NMR (CDCl 3, 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 (CDCl 3, 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 synthesis that following compounds (but being not limited to these compounds) can describe according to embodiment 2:
Embodiment 3A
The preparation of trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base] hexahydrobenzoic acid (3-7), concrete reaction formula is as follows:
The chloro-6-methylpyrimidine of the bromo-4-of the first step: 5--2-amine (1-2,109g, 0.49mol), trans-4-amino cyclohexyl ethyl formate (3-1,102g, 0.5mol) reflux 12 hours in 130 DEG C with N,N-DIMETHYLACETAMIDE (1L) solution of diisopropyl ethyl amine (194g, 1.5mol).By mixture concentrating under reduced pressure, residue is dissolved in methylene dichloride (1L), with water (2x500mL) and saturated aqueous common salt (2x500mL) washing.Organic phase with sodium sulfate is dry, filter, concentratedly obtain the trans-4-of crude product [(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] cyclohexyl ethyl formate (3-2), is directly used in next step reaction without the need to purifying.
Second step: trans-4-[(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] cyclohexyl ethyl formate (3-2,90g, 251.9mmol), ethyl propenoate (1-5,126g, 1.26mol), Pd (PPh 3) 4(30g) and the mixture of DMF (1.5 liters) of triethylamine (127g, 1.26mol) heated and stirred 12 hours at 130 DEG C.By mixture concentrating under reduced pressure, residue is dissolved in methylene dichloride (500mL), with water (200mL) and saturated aqueous common salt (200mL) washing.Organic phase with sodium sulfate is dry, filter, concentratedly obtain the trans-4-of crude product [[2-amino-5-[(E)-3-oxyethyl group-3-oxygen base third-1-thiazolinyl]-6-methylpyrimidine-4-base] is amino] cyclohexyl ethyl formate (3-3), is directly used in next step reaction without the need to purifying.
3rd step: trans-4-[[2-amino-5-[(E)-3-oxyethyl group-3-oxygen base third-1-thiazolinyl]-6-methylpyrimidine-4-base] is amino] cyclohexyl ethyl formate (3-3,80g, 212.51mmol), thiophenol (23g, 213mmol), thiophenol sodium (34g, 255mmol), DBU (1-7,130g, 852mmol) and the mixture of diisopropyl ethyl amine (165g, 12.8mol) in DMF (1.2L) in 130 DEG C of heated and stirred 8 hours.By mixture concentrating under reduced pressure, residue is dissolved in methylene dichloride (1L), with water (400mL) and saturated aqueous common salt (400mL) washing.Organic phase with sodium sulfate is dry, filter, concentratedly obtain crude product, pass through silica gel chromatography, with the dichloromethane containing 5% methyl alcohol, obtain trans-4-(2-amino-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base) cyclohexyl ethyl formate (3-4,25g, 3 step overall yields: 35%).
4th step: toward trans-4-(2-amino-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base) cyclohexyl ethyl formate (3-4,25g, NBS (12.8g is added in DMF (250mL) solution 75.67mmol), 72mmol), this mixture at room temperature stirs 2 hours.By mixture concentrating under reduced pressure, residue is dissolved in methylene dichloride (200mL), with water (50mL) and saturated aqueous common salt (50mL) washing.Organic phase with sodium sulfate is dry, filter, concentratedly obtain crude product, pass through silica gel chromatography, with the dichloromethane containing 5% methyl alcohol, obtain trans-4-(the bromo-4-methyl of 2-amino-6--7-oxygen yl pyridines [2,3-d] pyrimidine-8-base) cyclohexyl ethyl formate (3-5,15g, productive rate: 48%).
5th step: trans-4-(the bromo-4-methyl of 2-amino-6--7-oxygen yl pyridines [2,3-d] pyrimidine-8-base) cyclohexyl ethyl formate (3-5,22g, 53.75mmol), salt of wormwood (14.9g, 108mmol), 2-methoxypyridine-3-ylboronic acid (1-10,12.4g, 81mmol) and Pd (PPh 3) 4(4g) at DMF/H 2mixture in O (5:1,260 milliliters) stirs 2 hours at 100 DEG C.By mixture concentrating under reduced pressure, residue is dissolved in methylene dichloride (200mL), with water (50mL) and saturated aqueous common salt (50mL) washing.Organic phase with sodium sulfate is dry, filter, concentratedly obtain crude product, pass through silica gel chromatography, with the dichloromethane containing 5% methyl alcohol, obtain trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base] cyclohexyl ethyl formate (3-6,3.5g, productive rate: 15%).
6th step: trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base] cyclohexyl ethyl formate (3-6,1.1g, 2.5mmol) and lithium hydroxide (210mg, 5mmol) in H 2in the mixing solutions of O (10mL) and EtOH (10mL), stirred at ambient temperature is after 3 hours, concentrated, and uses H 2o (10mL) dilutes, extraction into ethyl acetate (2x20mL).Water layer 1N salt acid for adjusting pH to 5, be extracted with ethyl acetate (3x50mL), merge organic phase, by dried over sodium sulfate, filter, concentrate and obtain trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base] hexahydrobenzoic acid (3-7), without the need to purifying, be directly used in next step reaction.Mass spectrometry results: m/z:411.20 [M+H] +.
Embodiment 3
Trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2; 3-d] pyrimidine-8-base] preparation of-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide (3-8), concrete reaction formula is as follows:
Trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2, 3-d] pyrimidine-8-base] hexahydrobenzoic acid (3-7, 1g, 2.44mmol, thick product according to the 6th step synthesis of embodiment 3A), diethoxy phosphoryl methylamine (2-2, 720mg, 2.8mmol), hydroxybenzotriazole (HOBT, 513mg, 3.8mmol), 1-ethyl-3-(3-dimethylaminopropyl) phosphinylidyne diimine) (EDCI, 730mg, 3.8mmol) with N-methylmorpholine (NMM, 2g, dichloromethane solution 20mmol) was in stirred at ambient temperature 8 hours.By reaction mixture concentrating under reduced pressure, residue is dissolved in ethyl acetate (100mL), with water (30mL) and saturated aqueous common salt (30mL) washing.Organic phase with sodium sulfate is dry, filter, concentratedly obtain crude product; logical HPLC purifying obtains trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2; 3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide (3-8; 203mg, 15%). 1H-NMR(CDCl 3,400MHz):δ8.23(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] +.
The same or similar method synthesis that following compounds (but being not limited to these compounds) can describe according to embodiment 3A and embodiment 3:
Embodiment 4A
Trans-2-(2,5-dimethyl pyrrole-1-base)-8-[4-(methylol) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] preparation of pyrimidin-7-ones (4-9), concrete reaction formula is as follows:
The first step: add SOCl in the ethanolic soln (500mL) of trans-4-amino hexahydrobenzoic acid hydrochloride (4-1,50g, 0.28mol) 2(100mL), gained mixture stirs 8 hours in 100 DEG C.Removal of solvent under reduced pressure obtains trans-4-amino cyclohexyl ethyl formate hydrochloride (4-2,58g, productive rate: 100%).
Second step: at 0 DEG C, in THF (1L) solution of trans-4-amino cyclohexyl ethyl formate hydrochloride (4-2,53.3g, 257mmol), portion-wise with caution adds LiAlH 4(11.4g, 309mmol), gained mixture has reacted in stirring at room temperature for 3 hours.The careful cancellation of reaction mixture ethanol, filter, filtrate reduced in volume obtains trans-(4-aminocyclohexyl) methyl alcohol (4-3,28g, productive rate: 85%).
The chloro-6-methylpyrimidine of the bromo-4-of 3rd step: 5--2-amine (1-2,57g, 256.2mmol), trans-(4-aminocyclohexyl) methyl alcohol (4-3,33g, 257mmol) and the mixture of DIPEA (66g, 514mmol) in DMA (1.5L) in 130 DEG C of stirring and refluxing 12 hours.By mixture concentrating under reduced pressure, and dilute with DCM (500mL), wash with water (200mL) and saturated aqueous common salt (200mL).Organic phase anhydrous sodium sulfate drying, filtration, concentrated, residue over silica gel purification by column chromatography (dichloromethane of 5% methyl alcohol) obtains trans-[4-[(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] cyclohexyl] methyl alcohol (4-4,58g, productive rate: 72%).
4th step: trans-[4-[(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] cyclohexyl] methyl alcohol (4-4,70g, 222mmol), ethyl propenoate (1-5,111.5g, 1.12mol), Pd (PPh 3) 4(20g) and DMF (1L) mixture of triethylamine (112g, 1.12mol) heated and stirred 12 hours at 130 DEG C.By mixture concentrating under reduced pressure, and dilute with DCM (300mL), wash with water (100mL) and saturated aqueous common salt (100mL).Organic phase anhydrous sodium sulfate drying, filtration, concentrated, residue over silica gel purification by column chromatography (dichloromethane of 5% methyl alcohol) obtains trans-(E)-3-[2-amino-4-[[4-(methylol) cyclohexyl] is amino]-6-methylpyrimidine-5-base] the third-2-olefin(e) acid ethyl ester (4-5,48g, productive rate: 65%).
5th step: trans-(E)-3-[2-amino-4-[[4-(methylol) cyclohexyl] is amino]-6-methylpyrimidine-5-base] the third-2-olefin(e) acid ethyl ester (4-5,48g, 143.5mmol), thiophenol (15.8g, 143mmol), thiophenol sodium salt (22.7g, 172mmol), DBU (1-7,43g, 286mmol) and the DMF solution (1L) of diisopropyl ethyl amine (55g, 429mmol) in 130 DEG C of reacting by heating 8 hours.By mixture concentrating under reduced pressure, and dilute with DCM (300mL), wash with water (100mL) and saturated aqueous common salt (100mL).Organic phase anhydrous sodium sulfate drying, filter, concentrated, residue over silica gel purification by column chromatography (dichloromethane of 5% methyl alcohol) obtains trans-2-amino-8-[4-(methylol) cyclohexyl]-4-picoline [2,3-d] pyrimidin-7-ones (4-6,8.6g, productive rate: 21%).
6th step: trans-2-amino-8-[4-(methylol) cyclohexyl]-4-picoline [2,3-d] pyrimidin-7-ones (4-6,8.6g, NBS (5.3g is added in DMF (200mL) solution 29.8mmol), 30mmol), in stirring at room temperature after 2 hours, reaction mixture concentrating under reduced pressure, and with DCM (100mL) dilution, with water (50mL) and saturated aqueous common salt (50mL) washing.Organic phase anhydrous sodium sulfate drying, filtration, concentrated, residue over silica gel purification by column chromatography (dichloromethane of 5% methyl alcohol) obtains the bromo-8-of trans-2-amino-6-[4-(methylol) cyclohexyl]-4-picoline [2,3-d] pyrimidin-7-ones (4-7,9.0g, productive rate: 82%).
7th step: the bromo-8-of trans-2-amino-6-[4-(methylol) cyclohexyl]-4-picoline [2,3-d] pyrimidin-7-ones (4-7,9g, 24.5mmol), salt of wormwood (6.9g, 50mmol) and 2-methoxypyridine-3-ylboronic acid (1-10,3.7g, 30mmol) at DMF/H 2in mixture in O (5:1,100mL), drum nitrogen 5 minutes, adds Pd (PPh in this mixture 3) 4(2g).Gained mixture was in 100 DEG C of heated and stirred 2 hours.Reaction mixture concentrating under reduced pressure, and dilute with DCM (80mL), wash with water (40mL) and saturated aqueous common salt (40mL).Organic phase anhydrous sodium sulfate drying, filtration, concentrated, residue over silica gel purification by column chromatography (dichloromethane of 5% methyl alcohol) obtains trans-2-amino-8-[4-(methylol) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (4-8,4.0g, productive rate: 41%).
8th step: trans-2-amino-8-[4-(methylol) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (4-8,4.8g, 12.1mmol), 2, toluene (100mL) vlil of 5-bis-hexanone (1-12,7g, 61mmol) and tosic acid (0.46g) is spent the night.Reaction mixture is cooled to room temperature, and concentrated.Residue column chromatography purification, the mixture of petrol ether/ethyl acetate (1:1) is as eluent, obtain trans-2-(2,5-dimethyl pyrrole-1-base)-8-[4-(methylol) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (4-9), for white solid (2.5g, productive rate: 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-pyridyl)-4-picoline [2; 3-d] preparation of pyrimidin-7-ones (4-11), concrete reaction formula is as follows:
The first step: at-78 DEG C; toward trans-2-(2; 5-dimethyl pyrrole-1-base)-8-[4-(methylol) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (4-9; 1.3g; 2.7mmol; the 7th step preparation according in embodiment 4A) and trifluoromethanesulfonic acid (diethoxy phosphoryl methyl) ester (1-14; 1.7g; the THF solution (5.6mL, 5.6mmol) of 1MLiHMDS is dripped in THF (50mL) solution 5.6mmol).Gained mixture stirs 0.5 hour in-78 DEG C, rises to room temperature and continues stirring 0.5 hour.Reaction mixture saturated ammonium chloride solution (30mL) cancellation, and extract (50mLx3) with DCM.Organic layer merges; with anhydrous sodium sulfate drying, filtration, concentrate; resistates preparative HPLC is purified; obtain trans-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-2-(2; 5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (4-10,100mg, productive rate: 5.8%).
Second step: trans-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-2-(2; 5-dimethyl pyrrole-1-base)-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (4-10; 100mg; 0.16mmol) with hydroxylamine hydrochloride (35mg; 0.5mmol) heated overnight at reflux in the mixing solutions (10:1,5mL) of ethanol/water.Reaction mixture is concentrated; resistates preparative HPLC purifying obtains trans-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (4-11; 8mg, productive rate: 9%).Nuclear magnetic resonance spectroscopy result: 1h-NMR (CDCl 3, 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).Mass spectrometry results: m/z:546.20 [M+H] +.
The same or similar method synthesis that following compounds (but being not limited to these compounds) can describe according to embodiment 4 and embodiment 4A:
Embodiment 5
The preparation of 2-amino-8-[1-(diethoxy phosphoryl methyl)-4-piperidyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (5-9), concrete reaction formula is as follows:
The chloro-6-methylpyrimidine of the bromo-4-of the first step: 5--2-amine (1-2,200g, 0.9mol), 4-amino piperidine-1-t-butyl formate (5-1,217g, 1.08mol) and the N,N-DIMETHYLACETAMIDE of diisopropyl ethyl amine (232.6g, 1.8mol) (1L) solution spend the night in 120 DEG C of reacting by heating.Reaction mixture concentrates, and add DCM (5L) and saturated aqueous common salt (5L), organic phase is separated, anhydrous sodium sulfate drying, filter, be concentrated into and dryly obtain brown solid, pull an oar by ethyl acetate (500mL), filtration obtains 4-[(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] piperidines-1-t-butyl formate (5-2,250g, productive rate: 70%).Mass spectrometry results: m/z:386.20 [M+H, 79br] +, 388.20 [M+H, 81br] +.Silica gel thin-layer chromatography: R f=0.4 (DCM/MeOH=20:1).
Second step: under nitrogen, 4-[(the bromo-6-methylpyrimidine of 2-amino-5--4-base) is amino] piperidines-1-t-butyl formate (5-2,150g, 0.39mol), ethyl propenoate (1-5,194g, 1.94mol), triethylamine (300mL) and Pd (PPh 3) 4(45g, 38mmol) mixture in DMF (500mL) was in 120 DEG C of reacting by heating 48 hours.Reaction mixture is chilled to room temperature and concentrates, residue column chromatography purification, the mixture of methylene chloride/methanol is as eluent, obtain product 4-[[2-amino-5-[(E)-3-oxyethyl group-3-oxo third-1-thiazolinyl]-6-methylpyrimidine-4-base] is amino] piperidines-1-t-butyl formate (5-3), for yellow solid (50g, productive rate: 30%).Mass spectrometry results: m/z:406.30 [M+H] +.Silica gel thin-layer chromatography: R f=0.35 (DCM/MeOH=20:1).
3rd step: 4-[[2-amino-5-[(E)-3-oxyethyl group-3-oxo third-1-thiazolinyl]-6-methylpyrimidine-4-base] is amino] piperidines-1-t-butyl formate (5-3,115g, 0.28mol), thiophenol (31.23g, 0.28mol), thiophenol sodium salt (37.48g, 0.28mol), DBU (1-7,172.6g, 1.13mol) spend the night in 110 DEG C of reacting by heating with the DMF solution (1L) of diisopropyl ethyl amine (219.78g, 1.7mol).Reaction mixture concentrates, and adds DCM (500mL) and water (300mL) in residue.Organic phase is separated, concentrated obtain crude product, add ethyl acetate (200mL), collecting by filtration white product 4-(2-amino-4-methyl-7-oxo pyridine [2,3-d] pyrimidine-8-base) piperidines-1-t-butyl formate (5-4,56g, productive rate: 56%).Mass spectrometry results: m/z:360.20 [M+H] +.Silica gel thin-layer chromatography: R f=0.45 (DCM/MeOH=20:1).
4th step: 4-(2-amino-4-methyl-7-oxo pyridine [2,3-d] pyrimidine-8-base) piperidines-1-t-butyl formate (5-4,20g, NBS (11.83g is added in DMF (300mL) solution 55mmol), 66mmol), in stirring at room temperature after 1 hour, reaction mixture is concentrated into dry, adds ethyl acetate (300mL) and saturated sodium bicarbonate solution (300mL) in residue.Organic phase is separated, concentrated obtain crude product 4-(the bromo-4-methyl of 2-amino-6--7-oxo pyridine [2,3-d] pyrimidine-8-base) piperidines-1-t-butyl formate (5-5,19g), be brown solid, be directly used in next step reaction without purifying.Mass spectrometry results: m/z:438.20 [M+H, 79br] +, 440.20 [M+H, 81br] +.Silica gel thin-layer chromatography: R f=0.5 (DCM/MeOH=20:1).
5th step: 4-(the bromo-4-methyl of 2-amino-6--7-oxo pyridine [2,3-d] pyrimidine-8-base) piperidines-1-t-butyl formate (5-5,19g, 43mmol), salt of wormwood (18g, 130mmol) and 2-methoxypyridine-3-ylboronic acid (1-10,9.98g, 66mmol) at DMF/H 2in mixture in O (5:1,240mL), drum nitrogen 5 minutes, adds Pd (PPh in this mixture 3) 2cl 2(3.00g).Gained mixture spends the night in 100 DEG C of heated and stirred.Reaction mixture is concentrated into dry, residue purification by silica gel column chromatography, the mixture of methylene chloride/methanol (95/5) is as eluent, obtain product 4-(2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxo pyridine [2,3-d] pyrimidine-8-base) piperidines-1-t-butyl formate (5-6), for brown solid (8g, productive rate: 40%).Mass spectrometry results: m/z:467.30 [M+H] +.Silica gel thin-layer chromatography: R f=0.4 (DCM/MeOH=20:1).
6th step: 4-(2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxo pyridine [2,3-d] pyrimidine-8-base) piperidines-1-t-butyl formate (5-6,4.5g, 9.6mmol) be dissolved in the saturated methyl alcohol (50mL) of HCl, this mixture at room temperature stirs 4 hours, and concetrated under reduced pressure is water-soluble by residue, and wash by ethyl acetate, discard organic layer.Water layer is protected and sodium hydrogen carbonate solution regulates pH=8-9, then extracts 3 times with DCM.Organic layer is merged, by dried over sodium sulfate, concentrates, obtain product 2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-8-(4-piperidyl) pyridine [2,3-d] pyrimidin-7-ones (5-7,4g, productive rate: 90%) is greenish yellow solid.Silica gel thin-layer chromatography: R f=0.1 (DCM/MeOH=5:1).
7th step: toward 2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-8-(4-piperidyl) pyridine [2,3-d] pyrimidin-7-ones (5-7, diethyl phosphite (HPO (OEt) is added in 2.5g, 6.82mmol) diox (200mL) solution 2, 5-8,1.9g, 13.66mmol), paraformaldehyde (0.2g, 6.83mmol) and acetic acid (0.41g, 6.83mmol).Gained mixture return stirring is after 5 hours; solution is concentrated; crude product preparative HPLC purifying obtains product 2-amino-8-[1-(diethoxy phosphoryl methyl)-4-piperidyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2; 3-d] pyrimidin-7-ones (5-9; 1.0g; productive rate: 28%, purity 95%), be yellow solid.Purify with SFC further and obtain 220mg pure products, purity is 99%, is yellow solid.Silica gel thin-layer chromatography: R f=0.6 (DCM/MeOH=20:1). 1H-NMR(CDCl3,400MHz):δ8.32(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 synthesis that following compounds (but being not limited to these compounds) can describe according to embodiment 5:
Embodiment 6
Suppress kinase whose screening experiment:
This example is compound ds-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-the pyridyl)-4-picoline [2 of preparation in embodiment 2; 3-d] pyrimidin-7-ones (2-4a) is at DiscoveRx company (4215SorrentoValleyBlvd; SanDiego, CA92121) KinomeScan tM(www.kinomescan.com) as shown in table 1 for 98 kinase whose suppression results when 100nM compound concentration in system:
The details of this triage techniques is shown in Fabian, M.A.etal, Nat., Biotechnol.2005,23,329 and Karaman, M.W.etal, Nat., Biotechnol.2008,26,127.From above representational result, the compound in the present invention is to comprising the kinases such as mTOR, PIK3C2B, PIK3CA, PIK3CG, TYK2, DYRK1B and mutant has significant restraining effect.
Table 1
Embodiment 7
Biochemical inhibit activities to a few kinases and hypotype thereof: this example is compound ds-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-the pyridyl)-4-picoline [2 of preparation in embodiment 2, 3-d] pyrimidin-7-ones (2-4a) is by ReactionBiologyCorporation company (ReactionBiologyCorp., OneGreatValleyParkway, Suite2, Malvern, PA19355, measure mTOR USA.http: //www.reactionbiology.com/webapps/main/pages/kinase.aspx), PI3K-α, PI3K-β, PI3K-γ, PI3K-δ, DYRK1B, the suppression of TYK2 kinases and hypotype activity thereof.Concrete steps are as follows:
By compound dissolution of the present invention in dimethyl sulfoxide (DMSO) (DMSO), be mixed with the stoste of 10mM, according to 3-times of serial dilution from 10mM, do 10 different dosage.When measuring the inhibit activities of four kinds of PI3K hypotypes, adopt HTRF measuring method, ATP concentration is 10 μMs.When other three kinds of kinases (mTOR, DYRK1B, TYK2) measure, its ATP concentration is their corresponding Km values.
Measurement result
In the embodiment of the present invention 2, the compound 2-4a of preparation suppresses the IC of 7 kinds of kinases and hypotype enzyme 50value in table 2:
Table 2
Can be found out by above-mentioned data, COMPOUNDS EXAMPLE 2-4a of the present invention has strong inhibit activities, IC to four of PI3K kinds of hypotypes 50value reaches below 100nM respectively.Compound 2a is also obvious to the suppression of mTOR, IC 50value is 670nM.This compound is then more weak to the inhibit activities of DYRK1B and TYK2.
Embodiment 8
Anti-tumor experiment: method and the result of trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] the pyrimidin-7-ones anti-tumor experiment in A549 Human Lung Cancer cell xenograft Nude mice model prepared in this example employing embodiment 1 are as follows:
Experiment material
4 ~ 5 week age SPF level female BAl BIc/c-nu/nu mouse, body weight 16 ~ 20g, purchased from Guangdong Province's Experimental Animal Center, conformity certification number: NO:0072659.A549 lung carcinoma cell is purchased from life science institute cellular resources center, Shanghai.DMEM cell culture medium, foetal calf serum (FBS) and tryptic digestive juice are from Gibco company.The equal available from Sigma of various microbiotic.
Experimental technique
First carry out the cultivation of A549 lung carcinoma cell: A549 cell strain is inoculated in the DMEM nutrient solution containing 10%FBS, 100U/ml penicillin, 100U/ml Streptomycin sulphate, at 37 DEG C, 5%CO 2, 100% humidity carbonic acid gas incubator in cultivate, at the bottom of after inoculation, about 48h cell covers with bottle.Then will cover with the A549 cell dissociation of at the bottom of culturing bottle 80%, collecting cell precipitation after the centrifugal 3min of 1000r/min, by cell dilution to 1 × 10 8/ mL, is only inoculated in the right front armpit of nude mice by 0.1mL/ subcutaneous.Inoculated tumour cell starts after the 12nd day to weigh to tumor bearing nude mice, measure tumor size and by tumor size at 150 ~ 200mm 3the mouse of scope is evenly divided into group of solvents (Vehicle at random, aqueous hydrochloric acid, pH is 3) and pyridine [2,3-d] one of pyrimidin-7-ones compounds trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones (1-16) (is dissolved in Vehicle, concentration is 1.0mg/mL), often organize 4 mouse; Thereafter weigh to nude mice every day and by 0.1mL/10g body weight by gavage method oral administration (10mg/kgqdviap.o.), within every two days, measure the size of every animal tumor, after 18 days, tumor-bearing mice cervical dislocation being put to death, take out tumour and weigh.Tumour inhibiting rate (TumorGrowthInhibition or TGI) method of calculation: experimental data represents with mean ± SD; Tumour inhibiting rate (TGI)=[(V group of solvents– V treatment group) ÷ V group of solvents] × 100%.V group of solventsfor group of solvents mouse tumor volume; V treatment groupfor treatment group mouse tumor volume.
Experimental result
Described in embodiment 1, the compounds of this invention treatment group is to the tumor-inhibiting action of mouse tumor: hello solvent and drug solution are after 18 days respectively for group of solvents and treatment group, and the tumor average volume of group of solvents and treatment group animal is respectively 1179.7 ± 420.6mm 3(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 has and significantly reduces.Fig. 1 is shown in empirical curve contrast.
From above-mentioned inhibiting tumor assay result, the representative compound in the present invention demonstrates significant tumor inhibition effect in xenograft nude mice animal model, oral administration, 10mg/kg, and once a day, after 18 days, tumor control rate reaches 53%.The weight of animals change for the treatment of group is very little, and this illustrates that medicine does not have obvious toxicity.
Embodiment 9
Anti-tumor experiment: adopt the method that embodiment 8 is identical; the compound that this example uses is trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2, the 3-d] pyrimidin-7-ones prepared in embodiment 2-4b.Tumor model is A549 Human Lung Cancer cell xenograft Nude mice model.
Experimental result
Described in embodiment 2-4b, the tumor-inhibiting action of the compounds of this invention treatment group to mouse tumor is shown in Fig. 2.From above-mentioned inhibiting tumor assay result, the representative compound in the present invention demonstrates tumor inhibition effect in xenograft nude mice animal model.
Embodiment 10
Anti-tumor experiment: adopt the method that embodiment 8 is identical; the compound that this example uses is trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) the cyclohexyl methane amide of preparation in embodiment 3.Tumor model is A549 Human Lung Cancer cell xenograft Nude mice model.
Experimental result
Described in embodiment 3, the tumor-inhibiting action of the compounds of this invention treatment group to mouse tumor is shown in Fig. 3.From above-mentioned inhibiting tumor assay result, the representative compound in the present invention demonstrates tumor inhibition effect in xenograft nude mice animal model.
Embodiment 11
Anti-tumor experiment: adopt the method that embodiment 8 is identical; the compound that this example uses is 2-amino-8-[1-(diethoxy phosphoryl methyl)-4-piperidyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2, the 3-d] pyrimidin-7-ones of preparation in embodiment 5.Tumor model is A549 Human Lung Cancer cell xenograft Nude mice model.
Experimental result
Described in embodiment 5, the tumor-inhibiting action of the compounds of this invention treatment group to mouse tumor is shown in Fig. 4.After experiment carries out 18 days, take out tumour after putting to death animal, what Fig. 4 showed is that administration group and solvent control group tumor weight contrast.From above-mentioned inhibiting tumor assay result, the representative compound in the present invention demonstrates tumor inhibition effect in xenograft nude mice animal model.
Embodiment 12
Anti-tumor experiment: adopt the method that embodiment 8 is similar; the compound that this example uses is cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2, the 3-d] pyrimidin-7-ones prepared in embodiment 2-4a.Tumor model is PC3 human prostate cell xenograft Nude mice model.
Experimental result
Described in embodiment 2-4a, the tumor-inhibiting action of the compounds of this invention treatment group to mouse tumor is shown in Fig. 5.From above-mentioned inhibiting tumor assay result, the representative compound in the present invention demonstrates significant tumor inhibition effect in xenograft nude mice animal model, oral administration, 10mg/kg, and once a day, after 21 days, tumor control rate reaches 73%.The weight of animals change for the treatment of group is very little, and this illustrates that medicine does not have obvious toxicity.
Embodiment 13
Anti-tumor experiment: adopt the method that embodiment 8 is similar; the compound that this example uses is cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2, the 3-d] pyrimidin-7-ones prepared in embodiment 2-4a.Tumor model is U87MG human microglia blastoma cell xenograft Nude mice model.
Experimental result
Described in embodiment 2-4a, the tumor-inhibiting action of the compounds of this invention treatment group to mouse tumor is shown in Fig. 6.From above-mentioned inhibiting tumor assay result, the representative compound in the present invention demonstrates significant tumor inhibition effect in xenograft nude mice animal model, oral administration, 2.5mg/kg, and once a day, after 14 days, tumor control rate reaches 64%.The weight of animals change for the treatment of group is very little, and this illustrates that medicine does not have obvious toxicity.
Embodiment 14:
Tablet (milli gram/piece)
Compound prepared by embodiment 1: 100; Lactose, PhEUR:182.75;
Xylo-Mucine: 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 substances content is with embodiment 14.
Embodiment 16:
Tablet (milli gram/piece)
Compound prepared by embodiment 2-4a: 50; Lactose, PhEUR:223.75;
Xylo-Mucine: 6.0; W-Gum: 15.0;
Polyvinylpyrrolidone (5w/v%): 2.25; Magnesium Stearate: 3.0.
Embodiment 17:
Tablet (milli gram/piece)
Compound prepared by embodiment 2-4a: 50, other substances content is identical with embodiment 16.Embodiment 18:
Tablet (milli gram/piece)
Compound prepared by embodiment 3: 1.0; Lactose, PhEUR:93.25;
Xylo-Mucine: 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 substances content is identical with embodiment 18.
Embodiment 20:
Capsule (milligram/capsule)
Compound prepared by embodiment 2-4a: 10.0; Lactose, PhEUR:488.5;
Magnesium: 1.5.
Embodiment 21:
Medicine composition and preparation
Capsule (milligram/capsule)
Compound prepared by embodiment 2-4a: 10.0, other substances content is identical with embodiment 20.
Embodiment 22:
Medicine composition and preparation
Injection (50 mg/ml)
Compound prepared by embodiment 4: 5%; 1M sodium hydroxide solution: 15%;
0.1M hydrochloric acid soln (regulating pH=7.6); Poly(oxyethylene glycol) 400: 5%;
Water for injection is adjusted to 100%.
Embodiment 23:
Medicine composition and preparation
Injection (50 mg/ml)
Compound prepared by embodiment 2-4b: 5%, other substances content is identical with embodiment 22, is finally adjusted to 100% with water for injection.
Embodiment 24:
Medicine composition and preparation
Injection (10 mg/ml)
Compound prepared by embodiment 2-4a: 1%; Sodium phosphate dibasic BP:3.6%;
0.1M sodium hydroxide solution: 15%; Water for injection is adjusted to 100%.
Embodiment 25:
Medicine composition and preparation
Injection (10 mg/ml)
Compound prepared by embodiment 5: 1%, other substances content is identical with embodiment 32, and water for injection is adjusted to 100%.
Embodiment 26:
Medicine composition and preparation
Injection (1 mg/ml) (pH regulator to 6)
Compound prepared by embodiment 1: 0.1%; Sodium phosphate dibasic BP:2.26%;
Citric acid: 0.38%; Poly(oxyethylene glycol) 400: 3.5%;
Water for injection is adjusted to 100%;
Embodiment 27:
Medicine composition and preparation
Injection (1 mg/ml) (pH regulator to 6)
Compound prepared by embodiment 2-4a: 0.1%, the content of other material is identical with embodiment 26, is finally adjusted to 100% with water for injection.
Embodiment 28:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 1: 10; Sorbitan monooleate: 13.5;
Trichlorofluoromethane: 910.0; Refrigerant 12: 490.0.
Embodiment 29:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 3: 10, other substances content is identical with embodiment 28.
Embodiment 30:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 2-4a: 0.2; Sorbitan monooleate: 0.27;
Trichlorofluoromethane: 70.0; Refrigerant 12: 280.0;
Dichloro tetrafluoro ethane: 1094.0.
Embodiment 31:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 2-4a: 0.2, other substances content is identical with embodiment 30.Embodiment 32:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 5: 2.5; Sorbitan monooleate: 3.38;
Trichlorofluoromethane: 67.5; Refrigerant 12: 1086.0;
Dichloro tetrafluoro ethane: 191.60.
Embodiment 33:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 2-4b: 2.5, other substances content is identical with embodiment 32.Embodiment 34:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 2-4a: 2.5; Soybean lecithin: 2.7;
Trichlorofluoromethane: 67.5; Refrigerant 12: 1086.0;
Dichloro tetrafluoro ethane: 191.60.
Embodiment 35:
Medicine composition and preparation
Aerosol (mg/ml)
Compound prepared by embodiment 2-4a: 2.5, other substances content is identical with embodiment 34.
Embodiment 36:
Medicine composition and preparation
Ointment (/ milliliter)
Compound prepared by embodiment 2-4a: 40 milligrams; Ethanol: 300 microlitres;
Water: 300 microlitres; 1-azone: 50 microlitres;
Propylene glycol: to 1 milliliter.
Embodiment 37:
Ointment (/ milliliter)
Compound prepared by embodiment 2-4a: 40 milligrams, other substances content is identical with embodiment 36.
The above; be only the specific embodiment of the present invention, but protection scope of the present invention is not limited thereto, is anyly familiar with those skilled in the art in the technical scope that the present invention discloses; the change that can expect easily or replacement, all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain of described claim.

Claims (18)

1. phosphorous pyrido [2, a 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, this molecular structure of compounds formula is such as formula shown in (I):
In formula,
Ar is aryl or heteroaryl, and the hydrogen in Ar can by the individual identical or different G of 1-5 1replace;
X is C-R 1or N;
A represents C 1-6alkyl, a C=O or covalent linkage, and when A is C 1-6during alkyl, hydrogen wherein can by the individual identical or different G of 1-5 2replace;
L represents O, N-R 2, S (=O) mor a covalent linkage;
J represents C 1-6alkyl or a covalent linkage, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
R and R ' separately represents H, OH, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 3-12heteroalicyclyl, C 1-6alkoxyl group, C 3-6cycloalkyloxy or C 3-12heterolipid epoxy group(ing), and the hydrogen in R and R ' can by the individual identical or different G of 1-5 4replace, R with R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring can comprise one or more O, N or S (=O) in addition mheteroatoms;
Wherein:
G 1, G 2, G 3and G 4separately represent H ,-CN ,-CF 3,-OCF 3,-NO 2, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 6aryl, C 5-6heteroaryl, C 3-12heteroalicyclyl, R 3o-, R 3r 4n-, R 3s (=O) m-, R 3r 4nS (=O) m-, R 5c (=O)-, R 3r 4nC (=O)-, R 3oC (=O)-, R 5c (=O) O-, R 3r 4nC (=O) O-, R 5c (=O) NR 3-, R 3r 4nC (=O) NR 6-, R 3oC (=O) NR 6-, R 3s (=O) mnR 6-, R 3r 4nS (=O) mnR 6-, R 3r 4nC (=NR 7) NR 6-, R 3r 4nC (=CHNO 2) NR 6-, R 3r 4nC (=N-CN) NR 6-, R 3r 4nC (=NR 7)-, R 3s (=O) (=NR 7) NR 6-or R 3r 4nS (=O) (=NR 7)-;
R 1, R 2, R 3, R 4, R 5, R 6and R 7separately represent H, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-6cycloalkyl, C 6aryl, C 5-6heteroaryl or C 3-12heteroalicyclyl; Work as R 3and R 4when being connected on same nitrogen-atoms, a C can be formed together with this nitrogen-atoms 3-12heterolipid ring, this C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms; And R 1, R 2, R 3, R 4, R 5, R 6and R 7in hydrogen can by the identical or different halogen of 1-5 ,-CN ,-OH, C 1-6alkyl or C 3-6cycloalkyl substituted;
M is 0,1 or 2.
2. phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds according to claim 1 or its pharmaceutically acceptable salt, is characterized in that X is C-R when Ar is substituted pyridinyl 1or during N, the structure of described compound is such as formula shown in (Ia) or (Ib):
Described in formula,
R 1represent hydrogen or C 1-6alkyl;
A represents C 1-6alkyl, a C=O or covalent linkage, and when A is C 1-6during alkyl, hydrogen wherein can by the individual identical or different G of 1-5 2replace;
L represents O, N-R 2or S (=O) mor a covalent linkage;
J represents C 1-6alkyl or a covalent linkage, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
M, G 1, G 2, G 3, R, R ' and R 2definition with claim 1.
3. phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds (Ia) according to claim 2 or its pharmaceutically acceptable salt, is characterized in that when substituted pyridinyl is pyridin-3-yl, its substituting group G 1for G 11, R 1for hydrogen, R is RR, R ' for R ' R ', A be a covalent linkage time, the structure of described compound is such as formula shown in (Ic) or (Id):
Described in formula,
G 11represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group;
L represents O or N-R 2;
J represents C 1-6alkyl, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
RR and R ' R ' separately represents-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, and the hydrogen in RR and R ' R ' can by the individual identical or different G of 1-5 4replace, RR with R ' R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms;
M, G 3, G 4and R 2definition with claim 1.
4. phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds (Ia) according to claim 2 or its pharmaceutically acceptable salt, is characterized in that when substituted pyridinyl is pyridin-3-yl, its substituting group G 1for G 11, R 1for hydrogen, R is RR, R ' for R ' R ' time, the structure of described compound is such as formula shown in (Ie) or (If):
Described in formula,
G 11represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group;
A represents C=O or C 1-6alkyl, and when A is C 1-6during alkyl, hydrogen wherein can by the individual identical or different G of 1-5 2replace;
L represents O or N-R 2;
J represents C 1-6alkyl, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
RR and R ' R ' separately represents-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, and the hydrogen in RR and R ' R ' can by the individual identical or different G of 1-5 4replace, RR with R ' R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms;
M, G 2, G 3, G 4and R 2definition with claim 1.
5. phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds (Ib) according to claim 2 or its pharmaceutically acceptable salt, is characterized in that when substituted pyridinyl is pyridin-3-yl, its substituting group G 1for G 11, R is RR, R ' for R ' R ' time, the structure of described compound is such as formula shown in (Ig):
Described in formula,
G 11represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group;
J represents C 1-6alkyl, and the hydrogen in J can by the individual identical or different G of 1-5 3replace;
RR and R ' R ' separately represents-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, and the hydrogen in RR and R ' R ' can by the individual identical or different G of 1-5 4replace, RR with R ' R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring can comprise one or more O, N or S (=O) in addition mheteroatoms;
M, G 3and G 4definition with claim 1.
6. phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds according to claim 1 or its pharmaceutically acceptable salt, it is characterized in that described compound or its pharmaceutically acceptable salt be any one compound following:
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Cis-4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
2-amino-8-[1-(diethoxy phosphoryl methyl)-4-piperidyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-4-[2-amino-6-(6-dimethylamino-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Cis-4-[2-amino-6-(6-dimethylamino-3-pyridyl)-4-methyl-7-oxygen yl pyridines [2,3-d] pyrimidine-8-base]-N-(diethoxy phosphoryl methyl) cyclohexyl methane amide;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy ylmethyl) cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
2-amino-8-[1-(diethoxy phosphoryl methyl)-4-piperidyl]-6-(6-dimethylamino-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methoxy base) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methylamino-) cyclohexyl]-6-(6-methylamino--3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (methyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (methyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (ethyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (ethyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (n-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (n-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (sec.-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (sec.-propyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-2-amino-8-[4-(diethoxy phosphoryl methyl (cyclopropyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-4-picoline [2,3-d] pyrimidin-7-ones;
Cis-2-amino-8-[4-(diethoxy phosphoryl methyl (cyclopropyl) is amino) cyclohexyl]-6-(6-methoxyl group-3-pyridyl)-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)-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)-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)-4-picoline [2,3-d] pyrimidin-7-ones;
Trans-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-ethoxy-phosphoric acid;
Cis-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-ethoxy-phosphoric acid;
Trans-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-phosphoric acid;
Cis-[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyloxy] methyl-phosphoric acid;
Trans-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] is amino] methyl-ethoxy-phosphoric acid;
Cis-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] is amino] methyl-ethoxy-phosphoric acid;
Trans-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] amino] methyl-phosphoric acid or
Cis-[[4-[2-amino-6-(6-methoxyl group-3-pyridyl)-4-methyl-7-oxygen base-pyrido [2,3-d] pyrimidine-8-base] cyclohexyl] is amino] methyl-phosphoric acid.
7. phosphorous pyrido [2 according to any one of claim 1 ~ 6,3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, it is characterized in that described pharmacy acceptable salt is the salt that described phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds and mineral acid, organic acid, mineral alkali, organic bases are formed by chemical reaction.
8. phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds described in any one of claim 1 ~ 7 or its pharmaceutically raceme of acceptable salt or enantiomer.
9. phosphorous pyrido [2, a 3-d] pyrimidin-7-ones compounds, this molecular structure of compounds formula is such as formula (IIa), (IIb) or (IIc):
In formula,
Ar ' is aryl or heteroaryl, and the hydrogen in Ar ' can by the individual identical or different R of 1-5 8replace;
R 2represent H, C 1-6alkyl, C 3-6cycloalkyl or C 3-12heteroalicyclyl, and R 2in hydrogen can by the identical or different halogen of 1-5 ,-CN ,-OH, C 1-6alkyl or C 3-6cycloalkyl substituted;
R and R ' separately represents H, OH, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 3-12heteroalicyclyl, C 1-6alkoxyl group, C 3-6cycloalkyloxy or C 3-12heterolipid epoxy group(ing), and the hydrogen in R and R ' can by the individual identical or different R of 1-5 9replace, R with R ' also can form C together with the phosphorus atom be connected 3-12heterolipid ring, described C 3-12heterolipid ring can comprise one or more O, N or S (=O) in addition mheteroatoms;
Wherein:
R 8and R 9separately represent H ,-CN ,-CF 3,-OCF 3,-NO 2, halogen, C 1-6alkyl, C 3-6cycloalkyl, C 3-12heteroalicyclyl, C 1-6alkoxyl group, C 1-6cycloalkyloxy, C 3-12heterolipid epoxy group(ing) or R 10r 11n-; Wherein, R 10and R 11separately represent H, C 1-6alkyl, C 3-6cycloalkyl or C 3-12heteroalicyclyl; Work as R 10and R 11when being connected on same nitrogen-atoms, a C can be formed together with this nitrogen-atoms 3-12heterolipid ring, this C 3-12heterolipid ring also can comprise one or more O, N or S (=O) in addition mheteroatoms;
M is 0,1 or 2.
10. phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds (IIa) according to claim 9, (IIb) or (IIc), is characterized in that when Ar ' is for pyridin-3-yl, its substituent R 8for R 88, R is RR, R ' for R ' R ' time, the structure of described compound is such as formula shown in (IIaa), (IIbb) or (IIcc):
Described in formula,
R 2represent hydrogen, C 1-6alkyl, C 3-6cycloalkyl or C 3-12heteroalicyclyl, be preferably hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanylmethoxy, azelidinyl, tetrahydrofuran base, pyrrolidyl, THP trtrahydropyranyl, piperidyl, piperazinyl or morpholinyl, more preferably hydrogen, methyl, ethyl, n-propyl, second propyl group, cyclopropyl, oxetanylmethoxy, tetrahydrofuran base or THP trtrahydropyranyl, further be preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, and these groups can by 1-5 halogen,-CN,-OH or C 1-6alkyl replaces,
R 88represent hydrogen, halogen ,-OCF 3,-CF 3,-CN ,-NMe 2, C 1-6alkyl or C 1-6alkoxyl group, is preferably halogen ,-OCF 3,-OCH 3,-OCH 2cH 3or-NMe 2, more preferably-OCH 3or-NMe 2;
R 12and R 13separately represent-OH, halogen, C 1-6alkyl or C 1-6alkoxyl group, is preferably-OH or C 1-6alkoxyl group, more preferably C 1-6alkoxyl group, is further preferably methoxyl group, oxyethyl group, positive propoxy or isopropoxy.
11. comprise phosphorous pyrido [2 described in any one of claim 1 ~ 7,3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt, or phosphorous pyrido [2,3-d] pyrimidin-7-ones compounds described in claim 8 or its pharmaceutically raceme of acceptable salt or the pharmaceutical composition of enantiomer.
12. pharmaceutical compositions according to claim 11, is characterized in that described pharmaceutical composition also comprises one or more pharmaceutically acceptable carrier or thinners.
13. pharmaceutical compositions as described in claim 11 or 12, is characterized in that the dosage form of described pharmaceutical composition is: oral preparation, injection, anus suppository, nostril inhalation, eye drops or skin patch.
Phosphorous pyrido [2 described in 14. any one of claim 1-7; 3-d] pyrimidin-7-ones compounds or its pharmaceutically acceptable salt; or phosphorous pyrido [2 described in claim 8; 3-d] pyrimidin-7-ones compounds or its pharmaceutically raceme of acceptable salt or enantiomer, or pharmaceutical composition described in any one of claim 11-13 in treatment because of the application in the disease caused by protein kinase abnormal activity.
15. application according to claim 14, is characterized in that described protein kinase is PI3K or mTOR, are preferably PI3K, are further preferably PI3K-α, PI3K-β, PI3K-γ and PI3K-δ.
16. application according to claim 14, is characterized in that described disease is psoriatic, liver cirrhosis, trachitis, rheumatic arthritis, lupus erythematosus, diabetes, the disease relating to angiogenesis, disease of eye, disease of immune system, cardiovascular disorder, epilepsy, nerve degenerative diseases, Alzheimer, Huntington's disease or Parkinson's disease.
17. application according to claim 14, it is characterized in that described disease is tumour, described tumour comprises solid tumor and liquid tumor.
18. application according to claim 17, it is characterized in that described tumour comprises: lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head and neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, anal region cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, vaginal orifice cancer, Hodgkin, esophagus cancer, carcinoma of small intestine, endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or carcinoma of ureter, kidney, nervus centralis cental system vegetation, spinal column axis tumour, pituitary adenoma, gastrointestinal stromal, colorectal carcinoma, nonsmall-cell lung cancer, small cell lung cancer, mastocytosis, glioma, a kind of or several arbitrarily combination in sarcoma and lymphoma.
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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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106905315A (en) * 2017-03-02 2017-06-30 北京工业大学 Tetrahydropyridine simultaneously [3,4 d] pyrimidines and its preparation method and application
CN109280014A (en) * 2018-09-05 2019-01-29 成都百事兴科技实业有限公司 Trans-4-amino-cyclohexanecarboxylic acid carbethoxy hydrochloride preparation method
WO2021139775A1 (en) * 2020-01-10 2021-07-15 江苏先声药业有限公司 Pyridone compound and application

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022109001A1 (en) 2020-11-18 2022-05-27 Deciphera Pharmaceuticals, Llc Gcn2 and perk kinase inhibitors and methods of use thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1863774A (en) * 2003-10-08 2006-11-15 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN101031569A (en) * 2004-05-13 2007-09-05 艾科斯有限公司 Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2008144464A1 (en) * 2007-05-18 2008-11-27 Smithkline Beecham Corporation Quinoline derivatives as p13 kinase inhibitors
CN101389622A (en) * 2006-01-20 2009-03-18 诺瓦提斯公司 Pyrimidine derivatives used as pi-3 kinase inhibitors
CN101495477A (en) * 2005-05-20 2009-07-29 诺瓦提斯公司 Imidazoquinolines as lipid kinase inhibitors
CN101573358A (en) * 2006-09-15 2009-11-04 辉瑞产品公司 Pyrido (2, 3-D) pyrimidin0ne compounds and their use as PI3 inhibitors
CN103002738A (en) * 2010-05-21 2013-03-27 英特利凯恩有限责任公司 Chemical compounds, compositions and methods for kinase modulation
CN103491962A (en) * 2011-02-23 2014-01-01 因特利凯有限责任公司 Combination of kanase inhibitors and uses threof
CN103596951A (en) * 2011-04-08 2014-02-19 阿弗拉克西斯控股股份有限公司 8-ethyl-6-(aryl)pyrido [2,3-d]pyrimidin-7(8h)-ones for the treatment of nervous system disorders and cancer

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1863774A (en) * 2003-10-08 2006-11-15 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN101031569A (en) * 2004-05-13 2007-09-05 艾科斯有限公司 Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
CN101495477A (en) * 2005-05-20 2009-07-29 诺瓦提斯公司 Imidazoquinolines as lipid kinase inhibitors
CN101389622A (en) * 2006-01-20 2009-03-18 诺瓦提斯公司 Pyrimidine derivatives used as pi-3 kinase inhibitors
CN101573358A (en) * 2006-09-15 2009-11-04 辉瑞产品公司 Pyrido (2, 3-D) pyrimidin0ne compounds and their use as PI3 inhibitors
WO2008144464A1 (en) * 2007-05-18 2008-11-27 Smithkline Beecham Corporation Quinoline derivatives as p13 kinase inhibitors
CN103002738A (en) * 2010-05-21 2013-03-27 英特利凯恩有限责任公司 Chemical compounds, compositions and methods for kinase modulation
CN103491962A (en) * 2011-02-23 2014-01-01 因特利凯有限责任公司 Combination of kanase inhibitors and uses threof
CN103596951A (en) * 2011-04-08 2014-02-19 阿弗拉克西斯控股股份有限公司 8-ethyl-6-(aryl)pyrido [2,3-d]pyrimidin-7(8h)-ones for the treatment of nervous system disorders and cancer

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106905315A (en) * 2017-03-02 2017-06-30 北京工业大学 Tetrahydropyridine simultaneously [3,4 d] pyrimidines and its preparation method and application
CN106905315B (en) * 2017-03-02 2019-09-27 北京工业大学 Tetrahydropyridine simultaneously [3,4-d] pyrimidines and its preparation method and application
CN109280014A (en) * 2018-09-05 2019-01-29 成都百事兴科技实业有限公司 Trans-4-amino-cyclohexanecarboxylic acid carbethoxy hydrochloride preparation method
WO2021139775A1 (en) * 2020-01-10 2021-07-15 江苏先声药业有限公司 Pyridone compound and application

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