WO2016023401A1 - 一种含磷吡啶并嘧啶酮类化合物或其药学上可接受的盐、药物组合物及其应用 - Google Patents

一种含磷吡啶并嘧啶酮类化合物或其药学上可接受的盐、药物组合物及其应用 Download PDF

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WO2016023401A1
WO2016023401A1 PCT/CN2015/081854 CN2015081854W WO2016023401A1 WO 2016023401 A1 WO2016023401 A1 WO 2016023401A1 CN 2015081854 W CN2015081854 W CN 2015081854W WO 2016023401 A1 WO2016023401 A1 WO 2016023401A1
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amino
pyrimidin
pyridyl
group
cyclohexyl
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PCT/CN2015/081854
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English (en)
French (fr)
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吕慧敏
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山东汇睿迪生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic 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

Definitions

  • the present invention relates to the field of organic chemistry and medicinal chemistry, and in particular to a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use thereof.
  • Protein kinases are a class of phosphotransferases that transfer the ⁇ -phosphate group of ATP to specific amino acid residues of the substrate to phosphorylate proteins and exert their physiological and biochemical functions. Protein kinases are an important class of kinases that play a major role in signal transduction: one is to regulate the activity of proteins through phosphorylation; the other is to scale the signal step by step through the phosphorylation of proteins. Cellular response.
  • Abnormal protein kinase activity is not only closely related to tumor proliferation, apoptosis, metastasis, etc., but also to a series of other human diseases related to inflammation or proliferative response. For example, rheumatoid arthritis, cardiovascular and nervous system diseases, asthma, psoriasis and the like. More than 400 human diseases are known to be directly or indirectly related to protein kinases, making protein kinases another important class of drug targets following G-protein coupled receptors.
  • the protein kinase family consists of more than 500 members and is usually classified into protein tyrosine kinases (PTKs) and serine-threonine kinases. According to the position of the kinase in the cell, it can be further divided into receptor kinases and non-receptor kinases, also known as intracellular kinases.
  • Receptor kinases are generally tyrosine kinases, also known as receptor tyrosine kinases (RTKs), which are composed of extracellular, transmembrane, and intracytoplasmic, catalytically active kinases. Part of it is located in the cytoplasm. Most serine-threonine kinases are located in cells and are non-receptor kinases or cytosolic kinases.
  • Typical representatives of the RTKs family are growth factor receptors, with at least 19 subfamilies, and the following are several major subfamilies:
  • HER family tyrosine receptor kinases including EGFR (epithelial growth factor receptor), HER2, HER3 and HER4.
  • EGFR epidermal growth factor receptor
  • HER2 epidermal growth factor receptor
  • HER3 epidermal growth factor receptor
  • HER4 epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • IGF-1R insulin-like growth factor I receptor
  • IRR insulin receptor-related receptor
  • IGF-1R insulin receptor-like growth factor I receptor
  • IRR insulin receptor-related receptor Receptor
  • c a family of platelet-derived growth factor receptors (PDGFRs), including PDGFR- ⁇ , PDGFR- ⁇ , CSF1R, c-KIT, and c-fms.
  • PDGFRs platelet-derived growth factor receptors
  • c-KIT is also a leukemia treatment drug.
  • VEGFRs vascular endothelial growth factor receptors
  • FLT1 Fms-like tyrosine kinase 1 or VEGFR1
  • KDR or VEGFR-2
  • FLT4 or VEGFR3
  • FGFRs fibroblast growth factor receptors
  • FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7 members of the drug as molecular targets are still in clinical trials.
  • CMOS hepatocyte growth factor receptor
  • RON RON
  • c-Met plays an important role in the growth and metastasis of initial tumors. Its molecular targets, Crizotinib and Cabozantinib, have been approved for the treatment of non-small cell lung cancer and medullary thyroid carcinoma, respectively.
  • RET is a receptor for members of the GDNF family
  • RET51, RET43 and RET9isoforms are present.
  • Its drug, Bobozantinib has been approved for the treatment of medullary thyroid carcinoma. .
  • Eph family is the largest family of tyrosine receptor kinases, consisting of 16 receptors (EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4 , EPHB5, EPHB6) and 9 ligands (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3). These members play an important role in the development of animals, and some members play a role in the tumor.
  • Non-receptor kinases are absent from the extramembranous and transmembrane regions of the cell, and the entire kinase is in the cytoplasm. At least 24 non-receptor kinases are now known to be divided into 11 subfamilies, which are the Src, Frk, Btk, CsK, Abl, Zap70, Fes, Fps, Fak, Jak and AcK subfamilies.
  • the Src subfamily is the largest, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2, and Yrk kinase. For more detailed information, see Neet, K.; Hunter, T.
  • non-receptor kinase tyrosine kinases Although there are several non-receptor kinase tyrosine kinases, most non-receptor kinases belong to the serine-threonine kinase. Several of them are leukemia treatments and Molecular targets.
  • PI3K Phosphatidylinositide 3-kinase
  • the PI3K family is divided into three types based on primary structure, function, and specificity for lipid substrates: Type I, Type II, and Type III. Compared with type II and III, people have the most complete understanding of type I, and type I plays a major role in tumors.
  • Type I PI3K is further divided into IA and IB subtypes based on the similarity of amino acid sequences, and IA is a package.
  • a heterodimeric molecule comprising a regulatory subunit p85 (regulatory subunit) and a catalytic subunit p110 (catalytic subunit).
  • the regulatory subunit p85 includes 5 variants, of which p85 ⁇ is most expressed.
  • Type IB PI3K consists of the regulatory subunit p101 and the catalytic subunit p110 ⁇ and is expressed by PIK3CAG.
  • P110 ⁇ and p110 ⁇ are expressed in every cell, but p110 ⁇ is mainly expressed in leukocytes (CL Carpenter et al, J. Biol. Chem. 1990, 265, 19704. SJ Leevers et al, Curr. Opin. Cell Biol. 1999 , 11, 219. K. Okkenhaug, Ann. Rev. Immunol. 2013, 31, 675).
  • PI3K is activated by signals from tyrosine receptor kinases, G-protein coupled receptors (GPCRs), and activated RAS. P110 then interacts with phospholipid membranes to induce inositol PIP2 in phosphatidylinositol. Phosphorylation produces PIP3. This process activates AKT and downstream proteins that play a vital role in tumors. The production and amount of PIP3 are strictly controlled by tumor suppressor proteins, phosphatases and PTEN (I. Brana and L. L. Siu BMC Med. 2012, 10, 161).
  • PI3K-delta inhibitor Idelalisib has been approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL), recurrent follicular B-cell non-Hodgkin's lymphoma and small lymphocytic lymphoma.
  • PI3K In addition to its role in tumors, PI3K also plays an important role in immune function. PI3K- ⁇ and PI3K- ⁇ subtypes are mainly expressed in immune cells and are associated with a variety of inflammation, autoimmune and blood diseases. Blockade of PI3K-[gamma] and PI3K-[delta] activity will play a role in the treatment of diseases such as arthritis, bronchitis, lupus erythematosus (D. G. Winkler et al Chem. Biol. 2013, 20, 1364 and the literature cited therein).
  • mTOR is a serine/threonine kinase encoded by the human MTOR gene and belongs to the PI3K kinase family. mTOR plays a regulatory role in cell growth, proliferation, movement, survival, protein synthesis, and transcription (N. Hay and N. Sonenberg, Genes Dev. 2004, 18, 1926.). mTOR is a catalytic subunit of two complexes of different structures, mTORC1 and mTORC2 (S. Wullschleger et al, Cell 2006, 124, 471.). Several mTOR inhibitors have been approved for clinical treatment of cancer (eg, temsirolimus, everolimus, etc.), anti-organ transplant rejection (ie, rapamycin), and the like.
  • cancer eg, temsirolimus, everolimus, etc.
  • anti-organ transplant rejection ie, rapamycin
  • WO2005113556A1 reports a series of quinazolinones as human PI3K-delta kinase inhibitors.
  • WO2011146882A1 reports a series of isoquinolin-1-ones as PI3K kinase inhibitors.
  • WO2007084786A1 reports a series of pyrimidine PI3K kinase inhibitors.
  • WO2006122806A2 reports a series of imidazoquinolines as PI3K/mTOR kinase inhibitors.
  • WO2008032162A1 reports a series of pyrido[2,3-d]pyrimidinones as PI3K/mTOR kinase inhibitors.
  • WO2008144464A1 reports a series of quinoline compounds as PI3K/mTOR kinase inhibitors.
  • receptor kinases and non-receptor kinases have been used as anti-tumor targets in clinical and practical applications. Sufficient proof that several antineoplastic agents have been approved for market treatment of patients.
  • inhibition of the aberrant activity of receptor kinases and non-receptor kinases can also be used to treat diseases including, but not limited to, psoriasis or psoriasis, cirrhosis, diabetes, bronchitis, lupus erythematosus, involving angiogenesis.
  • a first object of the present invention is to provide a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound having a protein kinase (especially PI3K, mTOR, etc.) inhibitory activity or a pharmaceutically acceptable compound thereof a salt, as well as a racemate or enantiomer thereof.
  • a protein kinase especially PI3K, mTOR, etc.
  • a second object of the present invention is to provide a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, and a racemate or enantiomer thereof Body pharmaceutical composition.
  • a third object of the present invention is to provide a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, and a racemate or an enantiomer thereof.
  • the present invention adopts the following technical solutions:
  • Ar is an aryl or heteroaryl group, and the hydrogen in Ar may be substituted by 1 to 5 identical or different G 1 ;
  • X is CR 1 or N
  • J represents a C 1-6 alkyl group or a covalent bond, and the hydrogen in J may be substituted by 1 to 5 identical or different G 3 ;
  • R and R' each independently represent H, OH, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 heteroalicyclic, C 1-6 alkoxy, C 3-6 a cycloalkoxy group or a C 3-12 heteroaliphatic epoxy group, and the hydrogen in R and R′ may be substituted by 1 to 5 identical or different G 4 , and R and R′ may also form together with the connected phosphorus atom.
  • n 0, 1, or 2.
  • the structure of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound is as shown in the formula (Ia) or (Ib):
  • R 1 represents hydrogen or C 1-6 alkyl
  • J represents a C 1-6 alkyl group or a covalent bond, and the hydrogen in J may be substituted by 1 to 5 identical or different G 3 ;
  • G 1 , G 2 , G 3 , R, R' and R 2 are as defined above.
  • G 11 represents hydrogen, halogen, -OCF 3 , -CF 3 , -CN, -NMe 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • L represents O or NR 2 ;
  • J represents a C 1-6 alkyl group, and the hydrogen in J may be substituted by 1 to 5 identical or different G 3 ;
  • RR and R'R' independently represent -OH, halogen, C 1-6 alkyl or C 1-6 alkoxy, respectively, and the hydrogens in RR and R'R' may be the same or different from 1 to 5
  • G 3 , G 4 and R 2 are as defined above.
  • G 11 represents hydrogen, halogen, -OCF 3 , -CF 3 , -CN, -NMe 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • L represents O or NR 2 ;
  • J represents a C 1-6 alkyl group, and the hydrogen in J may be substituted by 1 to 5 identical or different G 3 ;
  • RR and R'R' independently represent -OH, halogen, C 1-6 alkyl or C 1-6 alkoxy, respectively, and the hydrogens in RR and R'R' may be the same or different from 1 to 5
  • G 2 , G 3 , G 4 and R 2 are as defined above.
  • G 11 represents hydrogen, halogen, -OCF 3 , -CF 3 , -CN, -NMe 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • J represents a C 1-6 alkyl group, and the hydrogen in J may be substituted by 1 to 5 identical or different G 3 ;
  • RR and R'R' independently represent -OH, halogen, C 1-6 alkyl or C 1-6 alkoxy, respectively, and the hydrogens in RR and R'R' may be the same or different from 1 to 5
  • G 3 and G 4 are as defined above.
  • the pharmaceutically acceptable salt of the various formulae defined by the present invention is the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound and an inorganic acid or an organic acid, A salt formed by a chemical reaction of an inorganic base or an organic base.
  • the above salts retain the biological activity of the compounds described herein.
  • the inorganic or organic acid may be: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, salicylic acid, tartaric acid.
  • the inorganic base or organic base may be: sodium hydroxide, potassium hydroxide, lithium hydroxide, iron hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water, organic hydroxide Quaternary ammonium salt, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbon
  • the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof is any one of the following compounds:
  • the present invention also claims a racemic or enantiomer of the above-mentioned phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, wherein
  • the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof can be prepared, and the racemate and the corresponding isomer can be obtained by a conventional technique. It is also foreseen by those skilled in the art that the racemates and corresponding isomers also have the same/similar activity.
  • the present invention also protects the above synthetic intermediate (IIa), (IIb) or (IIc) of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound:
  • Ar' is an aryl or heteroaryl group, and the hydrogen in Ar' may be substituted with 1 to 5 identical or different R 8 ;
  • R 2 represents H, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-12 heteroalicyclic; and the hydrogen in R 2 may be 1 to 5 identical or different halogen, -CN, -OH, C 1-6 alkyl or C 3-6 cycloalkyl substituted;
  • R and R' each independently represent H, OH, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 heteroalicyclic, C 1-6 alkoxy, C 3-6 a cycloalkoxy group or a C 3-12 heteroaliphatic epoxy group, and the hydrogen in R and R′ may be substituted by 1 to 5 identical or different R 9 , and R and R′ may also form together with the connected phosphorus atom.
  • R 8 and R 9 each independently represent H, -CN, -CF 3 , -OCF 3 , -NO 2 , halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-12 heteroalicyclic ring a group, a C 1-6 alkoxy group, a C 1-6 cycloalkoxy group, a C 3-12 heteroaliphatic group or R 10 R 11 N-.
  • R 10 and R 11 each independently represent H, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-12 heteroalicyclic.
  • n 0, 1, or 2.
  • R 2 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-12 heteroalicyclic, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperazine Pyridyl, piperazinyl or morpholinyl, further preferably hydrogen, methyl, ethyl, n-propyl, propyl, cyclopropyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, Further preferred are hydrogen, methyl, ethyl, isopropyl, cycl
  • R 88 represents hydrogen, halogen, -OCF 3 , -CF 3 , -CN, -NMe 2 , C 1-6 alkyl or C 1-6 alkoxy, preferably halogen, -OCF 3 , -OCH 3 , - OCH 2 CH 3 or -NMe 2 , further preferably -OCH 3 or -NMe 2 ;
  • R 12 and R 13 each independently represent -OH, halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably -OH or C 1-6 alkoxy, further preferably C 1-6 alkane
  • the oxy group is still more preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the present invention provides a method for preparing the above-mentioned phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound and a synthetic intermediate thereof as an embodiment, which can be represented by Scheme 1A and/or Scheme 1B.
  • the composition of the steps (such as Scheme 1A shows the preparation of some synthetic intermediates, Scheme 1A + Scheme 1B shows the preparation of some phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compounds, Scheme 1B
  • a method for preparing a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound directly from the above synthetic intermediate the same as:
  • M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) 2 , B(OMe) 2 , B(OEt) 2 , B (pinacolato), BF 3 K, Sn ( Bu-n) 4 , SnMe 4, etc.
  • LG represents a leaving group including, but not limited to, F, Cl, Br, I, MsO, p-TsO, TfO, PhSO 3, and the like.
  • the meaning of Pd catalyst, Base and Solvent can be found in the "Definition of Terms" section.
  • Compound A-1 can be prepared according to WO2008032162.
  • W represents an amino group or a 2,5-dimethylpyrrol-1-yl group.
  • M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) 2 , B(OMe) 2 , B(OEt) 2 , B (pinacolato), BF 3 K, Sn ( Bu-n) 4 , SnMe 4, etc.
  • Pd catalyst, Coupling Reagent, Base and Solvent can be found in the "Definition of Terms" section.
  • M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) 2 , B(OMe) 2 , B(OEt) 2 , B (pinacolato), BF 3 K, Sn ( Bu-n) 4 , SnMe 4, etc.
  • LG represents a leaving group including, but not limited to, F, Cl, Br, I, MsO, p-TsO, TfO, PhSO 3, and the like.
  • M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) 2 , B(OMe) 2 , B(OEt) 2 , B (pinacolato), BF 3 K, Sn ( Bu-n) 4 , SnMe 4, etc.
  • LG represents a leaving group including, but not limited to, F, Cl, Br, I, MsO, p-TsO, TfO, PhSO 3, and the like.
  • the present invention also protects a pharmaceutical composition
  • a pharmaceutical composition comprising the above phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, or a racemate or an enantiomer thereof .
  • the pharmaceutical composition of the present invention can be used for the treatment of diseases caused by abnormal activities of protein kinases.
  • the pharmaceutical compositions of the present invention also include one or more carriers or diluents which are pharmaceutically acceptable.
  • Formulation forms of the pharmaceutical compositions of the present invention include, but are not limited to, oral, injection, anal sputum, nasal inhalation, eye drops or skin patches.
  • the pharmaceutical composition consisting of the compound of the present invention is useful for treating a disease caused by abnormal activity of a protein kinase in a mammal, such as a human patient.
  • the compounds of the invention (including racemates, enantiomers, cis and trans isomers and other stereoisomers) or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof
  • a formulation process, prepared with a suitable pharmaceutically acceptable carrier and a pharmaceutically acceptable adjuvant, is a pharmaceutical composition that facilitates administration.
  • the drug administration route composed of the compound of the present invention may be: (1) oral: such as tablets, capsules, etc.; (2) injection: for example, intravenous injection, subcutaneous injection, intramuscular injection, eye injection, intraperitoneal injection (3) anal plug: for example, suppository, gel, etc.; (4) nostril inhalation: for example, spray, aerosol, etc.; (5) eye drops; (6) skin patch.
  • Drug release systems such as liposomes, sustained release techniques, and the like, may also be used, with the preferred methods being oral and injectable, with the preferred method being oral.
  • compositions of the present invention consisting of the compounds can be prepared by methods commonly used in the pharmaceutical industry, for example, mixing, dissolving, granulating, grinding, emulsifying, capsule, sugar coating, freeze drying, reconstituted spray, and the like.
  • the content of the compound of the present invention in the aforementioned pharmaceutical composition ranges from 0.001 to 100%.
  • the pharmaceutical composition is administered to a mammal, including a human, at an effective dose of from 0.1 to 500 mg per kilogram of body weight per day, and an optimized dose of from 1 to 100 mg per kilogram of body weight per day.
  • the compounds of the invention exert their pharmacological effects of inhibiting protein kinase activity and treating diseases (e.g., cancer) caused by abnormal protein kinase activity.
  • the frequency of use of the medicament of the present invention varies depending on the compound to be used or a pharmaceutical composition thereof and the disease to be applied.
  • the pharmaceutical composition of the present invention is usually administered 1-6 times a day, and the optimized administration frequency is per Dosing 1-3 times a day.
  • a solid dosage form of the medicament can be directly loaded into a glass, a plastic, a paper or a metal bottle, and a desiccant or the like is preferably placed in the bottle to maintain the quality of the drug;
  • the dosage form of the drug is generally contained in a glass, plastic or metal bottle or hose;
  • the aerosolized type of drug is generally contained in a metal or plastic container with a pressure-resistant device such as a pressure reducing valve.
  • the present invention further provides the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, or a racemate or enantiomer thereof, or a A pharmaceutical composition comprising a phosphorus pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, or a racemate or an enantiomer thereof, for treating a protein kinase abnormality Application in diseases caused by activity.
  • the protein kinase is PI3K or mTOR, and preferably the protein kinase is PI3K, and further preferably PI3K- ⁇ , PI3K- ⁇ , PI3K- ⁇ and PI3K- ⁇ .
  • the diseases described in the application of the pharmaceutical composition comprising the compound of the present invention are psoriasis, cirrhosis, bronchitis, rheumatoid arthritis, lupus erythematosus, diabetes, diseases involving angiogenesis, eye diseases, immune system diseases, heart Vascular disease, epilepsy, neurodegenerative disease, Alzheimer's disease, Huntington's disease or Parkinson's disease.
  • the diseases caused by the abnormal activity of the protein kinase of the present invention are tumors, and specifically include solid tumors and liquid tumors, and more specifically: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, Uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine Systemic cancer, thyroid cancer, parathyroid carcinoma, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or Ureteral cancer, renal cancer, central nervous system (CNS) neoplasm, spinal axis tumor, pituitary adenoma, gastrointestinal stromal tumor, colorectal cancer, non-small cell lung cancer, small cell lung cancer,
  • the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound of the present invention or a pharmaceutically acceptable salt thereof has the following beneficial effects: (1) screening by inhibiting kinase activity In the experiment, it can be seen that the compound of the present invention has a strong inhibitory effect on a series of protein kinases, especially PI3K and mTOR; (2) it can be seen by the tumor inhibition test on animals that the phosphorus-containing pyridine is [2,3- d] pyrimidine-7-one compound or a pharmaceutically acceptable salt thereof can significantly inhibit tumor without obvious toxicity; (3) the compound of the present invention can be used together with other antitumor drugs to cooperate (synergistic) or additive effect; (4) The compound of the present invention can be used together with other tumor therapies such as radiation therapy, interventional therapy and the like. Thus, a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof can be used
  • the compound of the present invention is used for treating the above-mentioned diseases caused by abnormal protein kinase activity, wherein the kidney cancer is adrenal cancer, renal cell carcinoma, renal pelvic cancer; glioma is brain stem glioma, neuroendocrine gel Tumor, glioma.
  • the compound of the present invention may treat psoriasis (or psoriasis), cirrhosis, bronchitis, rheumatoid arthritis, lupus erythematosus, diabetes, in addition to tumors in the treatment of diseases caused by abnormal protein kinase activity.
  • Angiogenesis diseases diseases involving restenosis, eye diseases such as AMD, rheumatoid arthritis and other inflammations, immune system diseases such as autoimmune diseases (eg, AIDS, etc.), cardiovascular diseases such as atherosclerosis, kidney diseases , epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.
  • variable groups used in the present invention such as R a , R b , m, etc., are only applicable to this subsection (ie, the "Definition of Terms” section).
  • the chemical reaction needs to be carried out in a solvent in many cases
  • the solvent (Solvent) commonly used in the preparation of the compound of the present invention includes, but is not limited to, water, methanol, ethanol, isopropanol, n-propanol, n-Butanol, isobutanol, tert-butanol, 2-methoxyethanol, 2,2,2-trifluoroethanol, dichloromethane, 1,2-dichloroethane, chloroform, THF, dioxane , DME, ethyl acetate, diethyl ether, methyl tert-butyl ether, hexane, cyclohexane, toluene, acetonitrile, DMF, DMSO or a mixture of two or more of these solvents, and the like.
  • the chemical reaction sometimes needs to occur in the presence of an acid or a base.
  • the bases commonly used in the preparation of the compounds of the present invention include, but are not limited to, Et 3 N, Me 3 N, i-Pr 2 NEt. , pyridine, DBU, DABCO, tetramethylguanidine, NaOH, KOH, Cs 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KF, CsF, K 3 PO 3 , K 2 HPO 4 , KH 2 PO 4 , NaH, n-BuLi, s-BuLi, t-BuLi, NaN(SiMe 3 ) 2 , LiN(SiMe 3 ) 2 , KN(SiMe 3 ) 2 or a mixture of two or more of these bases, etc.
  • Commonly used acids include, but are not limited to, HCO 2 H, AcOH, TFA (trifluoroacetic acid), HCl (hydrochloric acid), H 2 SO 4 , HNO 3 , H 3 PO 4 , p-TsOH, PhSO 3 H, CSA, MsOH, etc. or Lewis acid ZnCl 2 , AlCl 3 , BF 3 .OEt 2 and the like.
  • the chemical reaction sometimes needs to occur in the presence of a coupling reagent (Coupling Reagent), and the coupling reagents (Coupling Reagent) commonly used in the preparation of the compound of the present invention include, but are not limited to, DCC, EDC, HATU, TBTU, PyBOP, HCTU, BOP, T3P, DIC, HOBt, HOAt, CDI, DEPBT, etc.
  • a coupling reagent Coupling Reagent
  • the coupling reagents (Coupling Reagent) commonly used in the preparation of the compound of the present invention include, but are not limited to, DCC, EDC, HATU, TBTU, PyBOP, HCTU, BOP, T3P, DIC, HOBt, HOAt, CDI, DEPBT, etc.
  • Some steps in the preparation of the compounds of the invention require the use of reduction and reductant reagents including, but not limited to, H 2 + Pd/C, H 2 + Pd(OH) 2 , H 2 + PtO 2 H 2 + Ni, Ti(OPr-i) 4 + NaBH 4 , Ti(OPr-i) 4 + NaB(OAc) 3 H, Ti(OPr-i) 4 + NaBH 3 (CN), Ti(OPr-i) 4 + H 2 , H 2 NNH 2 + Ni, Mg + MeOH, Fe + AcOH, Fe + HCl, Zn + AcOH, Zn + HCl, Zn + NH 4 OAc, SnCl 2, LiAlH 4, NaBH 4, NaBH 3 (CN), NaB (OAc) 3 H, BH 3 and so on.
  • reduction and reductant reagents including, but not limited to, H 2 + Pd/C, H 2 + Pd(OH) 2 , H 2 + PtO 2 H 2 + Ni, Ti(
  • the preparation of the compounds of the present invention requires the use of an oxidation reaction (Oxidation) and an oxidizing reagent (Oxidant) including, but not limited to, PCC (PyH.ClCrO 3 ), PDC (2Py.Cr 2 O 7 ), K 2 Cr. 2 O 7, Na 2 Cr 2 O 7, H 2 Cr 2 O 7, CrO 3, CrO 3 .2Py, O 2, H 2 O 2, mCPBA, DMSO + (COCl) 2, NaClO 2, NaClO, Dess-Martin Reagent, KMnO 4 , OsO 4 , MnO 2 , etc.
  • an oxidation reaction Oxidation
  • Oxidant oxidizing reagent
  • a pd catalyst including but not limited to Pd/C, Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , PdCl 2 , Pd(OAc) 2 Pd(O 2 CCF 3 ) 2 , PdCl 2 (dppf), PdCl 2 (dppp), Pd(PPh 3 ) 2 Cl 2 , Pd(PhCN) 2 Cl 2 , Pd(OH) 2 and the like.
  • a pd catalyst including but not limited to Pd/C, Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , PdCl 2 , Pd(OAc) 2 Pd(O 2 CCF 3 ) 2 , PdCl 2 (dppf), PdCl 2 (dppp), Pd(PPh 3 ) 2 Cl 2 , Pd(PhCN) 2 Cl 2 , Pd(OH) 2 and the like.
  • deprotecting agents include, but are not limited to, HCl, TFA, H 2 SO 4 , and the like.
  • the protecting group is CBZ (or -CO 2 CH 2 Ph)
  • commonly used deprotecting reagents include, but are not limited to, concentrated HCl, H 2 + Pd/C, etc.
  • the protecting group is Bn (or -CH 2 Ph)
  • Common deprotection reagents include, but are not limited to, H 2 + Pd/C, H 2 + Pd(OH) 2 , H 2 + Pd/C + HCl, and the like.
  • the reaction for preparing the compound of the present invention is usually carried out at room temperature, but sometimes it is required to be lowered to -78 ° C or heated to 200 ° C; the reaction is usually carried out under the aforementioned solvent and temperature under ordinary stirring conditions, but sometimes it is required to carry out in a microwave oven; When the base, reagent, or catalyst used is sensitive to water or oxygen, the reaction is carried out under anhydrous and anaerobic conditions. In this case, a protic solvent cannot be used.
  • Solvate means a stable substance formed by a compound of the present invention and a chemically used solvent by covalent bond, hydrogen bond, ionic bond, van der Waals force, complexation, inclusion, etc., and the solvent may be: methanol. , ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, acetonitrile, diethyl ether, methyl tert-butyl ether and the like.
  • Hydrophilrate means a solvate wherein the solvent is water.
  • Prodrug means the conversion of a compound of the invention to another compound by chemical synthesis or physical means, and after administration of the compound to a mammal, is converted in the animal to the compound of the invention.
  • the “prodrug” method is generally used to overcome the poor or poor physicochemical properties or drug-forming properties of the drug compound itself.
  • Racemate, enantiomer, cis-trans isomer and other stereoisomers means that the compounds have the same molecular formula and molecular weight, but differ in the manner of different bonding modes and spatial arrangement between the atoms.
  • Compounds, such compounds are called isomers or stereoisomers. When these stereoisomers are mirror images of each other, they look alike, but they do not completely coincide, as with the left and right hands.
  • These compounds are called enantiomers.
  • the absolute configuration of the enantiomers is usually indicated by (R)- and (S)- or R- and S-.
  • Tautomers tautomer
  • rotamers rotamers
  • cis-trans isomers of these concepts can be in J.March “Advanced Organic Chemistry,” 4 th edition Found and understood.
  • isomers are also encompassed by the present invention as long as these isomers have the same or similar effects of inhibiting protein kinase activity as the compounds of the present invention.
  • a mammal e.g., a human
  • a mammal e.g., a human
  • the effect of inhibiting protein kinase activity, these metabolites are also encompassed by the present invention.
  • “Pharmaceutical composition” refers to one or more, pharmaceutically acceptable salts or solvates or hydrates or prodrugs of the compounds described herein, and other chemical ingredients (eg, pharmaceutically acceptable carriers or dilutions) (mixture) prepared by mixing the preparation.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the animal.
  • the above pharmaceutical composition may include, in addition to a pharmaceutically acceptable carrier, an auxiliary agent commonly used in medicine, for example, an antibacterial agent, an antifungal agent, an antimicrobial agent, a quality agent, a tone. Colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, colors, flavors or combinations thereof.
  • “Pharmaceutically acceptable carrier” or “diluent” means an inactive ingredient in a pharmaceutical composition which may be, but is not limited to, calcium carbonate, calcium phosphate, various sugars (eg, lactose, mannitol, etc.), starch, rings Dextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer, methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenated castor oil, polyethoxylate Hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
  • a pharmaceutical composition which may be, but is not limited to, calcium carbonate, calcium phosphate, various sugars (eg, lactose, mannitol, etc.), starch, rings Dextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer, methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene
  • Alkyl means a straight or branched saturated hydrocarbon group having the indicated number of carbon atoms, for example, C1-6 alkyl means a straight or branched chain group containing at least 1 and up to 6 carbon atoms. . C 0 alkyl represents a covalent single bond.
  • the alkyl groups described in the present invention include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like.
  • the alkyl group of the present invention sometimes also refers to an alkylene group, that is, a group in which an alkyl group loses one hydrogen atom.
  • One or all of the hydrogen atoms in the alkyl or alkylene group may be substituted by a cycloalkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a fluorenyl group.
  • R a and R b are each selected from the group consisting of hydrogen and an alkane A group, a cycloalkyl group, an aryl group, an acetyl group, a carbonyl group, a sulfonyl group, a trifluoromethanesulfonyl group or the like, and R a and R b together with a nitrogen atom may form a 5- or 6-membered heteroalicyclic ring.
  • Cycloalkyl or “cycloalkane” refers to a mono-, di- or polycyclic hydrocarbon group having the indicated number of carbon atoms, which may be fused when bicyclic or polycyclic (two rings or multiple rings share two) a combination of an adjacent carbon atom or a splicing (two or more rings sharing a carbon atom), for example, a C 1-6 cycloalkyl group containing a minimum of one and a maximum of six single, double or multiple a hydrocarbon group of the ring.
  • the C 0 cycloalkyl group represents a covalent single bond.
  • the cycloalkyl group may contain an unsaturated double or triple bond, but does not have a fully conjugated ⁇ -electron system.
  • the cycloalkyl group of the present invention sometimes also refers to a cycloalkylene group, that is, a group in which a cycloalkyl group loses one hydrogen atom.
  • the cycloalkyl group of the present invention includes, but is not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatrienyl, adamantane, etc. (for example, Table A):
  • One or all of the hydrogen atoms in the cycloalkyl or cycloalkane may be substituted by an alkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a fluorenyl group, Oxy (oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy And O-thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester, O-ester and -NR a R b , wherein R a and R b are each selected from the group consisting of hydrogen and alkyl A cycloalkyl
  • Heteroalicyclic or heteroalicyclic means a monocyclic, bicyclic or polycyclic ring system consisting of 3 to 12 non-hydrogen ring atoms, wherein at least one ring atom is a hetero atom selected from O, N, S or P, The remaining ring atoms are carbon atoms.
  • a C 8 heteroalicyclic group refers to a monocyclic, bicyclic or polycyclic group composed of 8 non-hydrogen ring atoms, wherein at least one ring atom is selected from O, N, S or P.
  • heteroalicyclic group of the present invention sometimes also refers to a heteroalicyclic group, that is, a group in which a heteroalicyclic group loses one hydrogen atom.
  • heteroalicyclic or heteroalicyclic ring in the present invention includes, but is not limited to, piperidine, morpholine, piperazine, pyrrolidine, porphyrin, tetrahydropyridine, tetrahydrofuran, tropinol, etc. (for example, Table B):
  • One or all of the hydrogen atoms in the heteroalicyclic or heteroalicyclic ring may be substituted by an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitrate Base, carboxyl, sulfhydryl, oxo, alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester, O-ester and -NR a R b , wherein R a and R b are respectively selected From: hydrogen, alkyl, cycloalkyl
  • alkenyl means a straight or branched hydrocarbon group containing at least two carbon atoms and one double bond, for example, C 2-6 alkenyl means a straight or branched chain containing at least 2 and up to 6 carbon atoms. An unsaturated group having at least one double bond in the chain.
  • the alkenyl group in the present invention includes, but is not limited to, a vinyl group, a 2-propenyl group, a 1-pentenyl group, and the like.
  • Alkynyl means a straight or branched hydrocarbon group containing at least two carbon atoms and a triple bond, for example C 2-6 alkynyl refers to a straight or branched chain containing at least 2 and up to 6 carbon atoms. The chain contains at least one triple bond of an unsaturated group.
  • the alkynyl group in the present invention includes, but is not limited to, an ethynyl group, a 3-propynyl group, a 1-pentynyl group and the like.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Alkoxy means an alkyl group having the indicated number of carbon atoms attached to the other group through an oxygen atom.
  • Alkoxy groups in the present invention include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentyloxy, 2- Methyl-1-hexyloxy and the like.
  • Cycloalkoxy means a cycloalkyl group having the indicated number of carbon atoms attached to the other group through an oxygen atom.
  • the cycloalkoxy group in the present invention includes, but is not limited to, a cyclopropoxy group, a cyclobutoxy group, a cyclohexaneoxy group, and the like.
  • Heteroaliphatic means that a heteroalicyclic group is attached to another group through an oxygen atom.
  • the heteroaliphatic epoxy group in the present invention includes, but is not limited to, piperidin-4-yloxy, oxetan-3-yloxy and the like.
  • Aryl means a monocyclic, bicyclic or polycyclic group consisting of a specified number of carbon atoms, wherein at least one of the rings has a fully conjugated ⁇ -electron system and conforms to the N+2 rule, ie is aromatic, but the entire group Not necessarily all conjugates.
  • C 6 aryl refers to phenyl.
  • the aryl group may also be present in the form of an arylene group, that is, two or more points of attachment to other groups in the aryl structure.
  • the aryl group in the present invention includes, but is not limited to, a phenyl group, a naphthyl group, an anthracenyl group, an indanyl group, a tetrahydronaphthalene or the like.
  • One or all of the hydrogen atoms in the aryl group may be substituted with an alkyl group, a cycloalkyl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group ( Oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O- a thioaminocarbonyloxy group, an N-thioaminocarbonyloxy group, a C-ester group, an O-ester group, and -NR a R b , wherein R a and R b are each selected from the group consisting of hydrogen, an alky
  • Heteroaryl means a monocyclic, bicyclic or polycyclic group consisting of a specified number of non-hydrogen ring atoms, wherein at least one of the ring atoms is a heteroatom selected from O, N, S or P, and the remaining ring atoms are carbon atoms. And wherein at least one of the rings has a fully conjugated ⁇ -electron system and conforms to the N+2 rule, ie, has aromaticity, but the entire group does not have to be fully conjugated, for example, C 5 heteroaryl refers to 5 non- An aromatic ring group composed of a hydrogen ring atom, wherein at least one ring atom is selected from O, N, S or P.
  • the heteroaryl group may also be present in the form of a heteroarylene group having two or more points of attachment to other groups in the heteroaryl structure.
  • the heteroaryl group in the present invention includes, but is not limited to, acridine, anthrone, tetrahydrofurfurone, imidazole, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, anthracene, azaindole, Benzimidazole, porphyrin, fluorenone, quinone, etc. (for example, Table C):
  • One or all of the hydrogen atoms in the heteroaryl group may be substituted with an alkyl group, a cycloalkyl group, an aryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group ( Oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O- a thioaminocarbonyloxy group, an N-thioaminocarbonyloxy group, a C-ester group, an O-ester group, and -NR a R b , wherein R a and R b are each selected from the group consisting of hydrogen, alkyl,
  • Aryloxy means that the aryl group is attached to the other group through an oxygen atom.
  • the aryloxy group in the present invention includes, but is not limited to, a phenoxy group, a naphthyloxy group and the like.
  • Heteroaryloxy means a heteroaryl group attached to another group through an oxygen atom.
  • the heteroaryloxy group in the present invention includes, but is not limited to, 4-acridinyloxy group, 2-thienyloxy group and the like.
  • Amino refers to H 2 N- wherein a hydrogen atom or a substituted H 2 N-, i.e., R a HN- and R a R b N-.
  • substitution by an oxy group include, but are not limited to, those shown in Table D:
  • Niro means -NO 2 .
  • Carboxyl means -CO 2 H.
  • Alkyl fluorenyl means alkyl-S-.
  • Aryl indenyl refers to aryl-S-.
  • Trifluoromethanesulfonyl refers to CF 3 SO 2 -.
  • Figure 1 is a comparison chart of the anti-tumor effect of the compound of the present invention on the mouse A549 tumor described in Example 1;
  • Figure 2 is a comparison diagram of the anti-tumor effect of the compound of the present invention on the mouse A549 tumor described in Example 2-4b;
  • Figure 3 is a comparison chart of the anti-tumor effect of the compound of the present invention on the mouse A549 tumor described in Example 3;
  • Figure 4 is a comparison diagram of the tumor weight of the compound of the present invention in the mouse A549 tumor described in Example 5;
  • Figure 5 is a graph showing the anti-tumor effect of the compound of the present invention on the tumor of mouse PC3 as described in Example 2-4a;
  • Figure 6 is a graph showing the anti-tumor effect of the compound of the present invention on the mouse U87MG tumor described in Example 2-4a.
  • DIPEA Diisopropylethylamine
  • PCC Pyridinium chlorochromate
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium (0)
  • Pd(PPh 3 ) 2 Cl 2 bis-(triphenylphosphine)palladium(II) chloride
  • NBS N-bromosuccinimide
  • LiHMDS lithium bis-(trimethylsilyl)amide
  • LiAlH 4 lithium tetrahydrogenate
  • Nuclear magnetic resonance spectroscopy and carbon spectrum 400MHz or Obtained on a 400 MHz instrument deuterated DMSO, deuterated chloroform, deuterated methanol, etc. as solvent, TMS as internal standard.
  • Mass spectrometry was obtained by liquid chromatography-mass spectrometry (using ESI or APCI ion source ZQ4000, USA) the company).
  • the ultraviolet spectrum was measured by a UV-3010 ultraviolet spectrophotometer from Hitachi, Japan.
  • High performance liquid chromatography 2695ZORBAX high performance liquid chromatography Bx-C 8 5 ⁇ 150 ⁇ 4.6mm column). The melting point was determined using an Electrothermal digital melting point apparatus IA9100 and was uncorrected.
  • bromine 134 g, 0.84 mol was added dropwise to a solution of 4-chloro-6-methylpyrimidin-2-amine (1-1, 100 g, 0.70 mol) in dichloromethane (4 L). The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane (5 L), washed with saturated sodium hydrogen sulfate (2 ⁇ 3L) and brine (3L) -Chloro-6-methylpyrimidin-2-amine (1-2) as a white solid (120 g, yield: 79%).
  • the second step 5-bromo 4-chloro-6-methylpyrimidin-2-amine (1-2, 120 g, 0.54 mol), trans-4-aminocyclohexanol (1-3, 58 g, 0.5 mol) and A solution of diisopropylethylamine (110 g, 0.84 mol) in dimethylacetamide (4 L) was heated at 120 ° C for 16 hours. The reaction mixture was diluted with methyl t-butyl ether (2.0 L), washed with aq.
  • the third step trans-4-[(2-amino-5-bromo-6-methylpyrimidin-4-yl)amino]cyclohexanol (1-4, 50 g, 0.166 mol), ethyl acrylate (1 -5,83 g, 0.83 mol), a solution of triethylamine (84 g, 0.83 mol) and Pd(PPh 3 ) 4 (10 g, 8.65 mmol) in DMF (500 mL).
  • the reaction mixture was cooled to room temperature and concentrated, the ⁇ Ethyl-6-methylpyrimidin-5-yl]-2-propenoate (1-6) as a white solid (25 g, yield: 46%).
  • Mass spectrometry analysis m/z: 321.20 [M+H] + .
  • the fourth step trans-(E)-3-[2-amino-4-[(4-hydroxycyclohexyl)amino]-6-methylpyrimidin-5-yl]-2-propenoic acid ethyl ester (1- 6,40 g, 0.125 mol), thiophenol (14 g, 0.13 mol), sodium thiophenolate (33 g, 0.25 mol), DBU (1-7, 76 g, 0.5 mol) and diisopropylethylamine (97 g) The 0.75 mol) DMF solution (400 mL) was heated at 120 ° C for 16 hours. The reaction mixture was concentrated to dryness.
  • the fifth step trans-(2-amino-8-(4-hydroxycyclohexyl)-4-methylpyridine [2,3-d]pyrimidin-7-one (1-8, 29 g, 0.106 mol)
  • NBS 23 g, 0.13 mol
  • DMF 290 mL
  • Deprotection gives the product trans-2-amino-6-bromo-8-(4-hydroxycyclohexyl)-4-methylpyridine [2,3-d]pyrimidin-7-one (1-9) as as a yellow solid (27g, yield: 71%) mass analysis:.
  • m / z 353.00 [ m + H, 79 Br] +, 355.00 [m + H, 81 Br] +.
  • Step 6 trans-2-amino-6-bromo-8-(4-hydroxycyclohexyl)-4-methylpyridine [2,3-d]pyrimidin-7-one (1-9, 11 g, 31.1 mmol), a mixture of potassium carbonate (13 g, 93 mmol) and 2-methoxypyridin-3-ylboronic acid (1-10, 6.8 g, 56 mmol) in DMF / H 2 O (5:1, 24 mL) Nitrogen gas was bubbled for 5 minutes, and Pd(PPh 3 ) 2 Cl 2 (3 g, 4.28 mmol) was added to the mixture. The resulting mixture was stirred and heated in a microwave oven at 100 ° C for 2 hours. The reaction mixture was concentrated to dryness.
  • Step 7 trans-2-amino-8-(4-hydroxycyclohexyl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine
  • 2,3-d]pyrimidine- 7-ketone (1-11, 1.5 g, 3.93 mmol
  • 2,5-dihexanone (1-12, 2.7 g, 24 mmol)
  • p-toluenesulfonic acid (0.15 g, 0.87 mmol) in toluene (100 mL) Heat to reflux overnight. The reaction mixture was cooled to room temperature and concentrated.
  • Step 8 trans-2-(2,5-dimethylpyrrol-1-yl)-8-(4-hydroxycyclohexyl)-6-(6-methoxy-3) at 0 °C
  • pyridine 1N in THF, 4 mL, pyridine solution
  • 1,3-d)-pyrimidin-7-one (1-13, 1.1 g, 2.39 mmol) in THF (20 mL) 4mmol.
  • the resulting mixture was stirred at room temperature for 1 hour, cooled to 0.degree. C. and diethoxyphosphorylmethyl trifluoromethanesulfonate (1-14, 1.1 g, 3.6 mmol).
  • Second step 2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl a solution of pyridine [2,3-d]pyrimidin-7-one (2A-1, 0.092 g, 0.2 mmol) and triethylamine (0.060 g, 0.59 mmol) in THF (5 mL) Ti(OPr-i) 4 (0.25 mL) and diethoxyphosphorylmethylamine (2-2, 0.075 g, 0.30 mmol), the mixture was stirred at room temperature for 2 hrs, sodium borohydride (0.038 g, 1.0) After stirring, it was stirred overnight.
  • Second step 2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl)pyridine [2,3-d]pyrimidine-7-
  • a solution of the ketone (2-1, 1.5 g, 4.0 mmol) and triethylamine (1.2 g, 11.8 mmol) in THF (15 mL) was stirred at room temperature for 1 hour, then Ti(OPr-i) 4 (5 mL) and The oxyphosphorylmethylamine (2-2, 1.5 g, 5.9 mmol) was stirred at room temperature for 2 hr, and sodium borohydride (0.75 g, 19.8 mmol) was added and stirred overnight.
  • the second step trans-4-[(2-amino-5-bromo-6-methylpyrimidin-4-yl)amino]cyclohexylcarboxylate (3-2, 90 g, 251.9 mmol), ethyl acrylate (1-5, 126 g, 1.26 mol), a mixture of Pd(PPh 3 ) 4 (30 g) and triethylamine (127 g, 1.26 mol) in DMF (1.5 L) was stirred and stirred at 130 ° C for 12 hours. The mixture was concentrated under reduced pressure. EtOAc m.
  • the third step trans-4-[[2-amino-5-[(E)-3-ethoxy-3-oxyprop-1-enyl]-6-methylpyrimidin-4-yl] Amino]ethyl cyclohexylcarboxylate (3-3, 80 g, 212.51 mmol), thiophenol (23 g, 213 mmol), sodium thiophenolate (34 g, 255 mmol), DBU (1-7, 130 g, 852 mmol) and diisopropyl
  • DMF 1-7, 130 g, 852 mmol
  • diisopropyl A mixture of ethyl ethylamine (165 g, 12.8 mol) in DMF (1.2 L) was stirred and stirred at 130 ° C for 8 hours. The mixture was concentrated under reduced pressure.
  • Step 4 To trans-4-(2-amino-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl)cyclohexylcarboxylate (3-4, 25 g, NBS (12.8 g, 72 mmol) was added to a solution of 75.67 mmol. The mixture was concentrated under reduced pressure and the residue was crystalljjjjjj Wash with saturated brine (50 mL). The organic phase is dried over sodium sulfate, filtered and evaporated tolululululululululululululu Ethyl methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl)cyclohexylcarboxylate (3-5, 15 g, yield: 48%).
  • the fifth step trans-4-(2-amino-6-bromo-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl)cyclohexylcarboxylic acid ethyl ester (3-5 , 22g, 53.75mmol), potassium carbonate (14.9g, 108mmol), 2-methoxypyridin-3-ylboronic acid (1-10, 12.4g, 81mmol) and Pd(PPh 3 ) 4 (4g) in DMF/
  • the mixture in H 2 O (5:1, 260 mL) was stirred at 100 ° C for 2 hr. The mixture was concentrated under reduced pressure. EtOAc m.
  • Step 6 trans-4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxypyridine [2,3-d]pyrimidine-8- After stirring at room temperature for 3 hours, a mixture of ethyl cyclohexylcarboxylate (3-6, 1.1 g, 2.5 mmol) and lithium hydroxide (210 mg, 5 mmol) in H 2 O (10 mL) and EtOH (10 mL) concentrated, and diluted with H 2 O (10mL), extracted with ethyl acetate (2x 20mL).
  • Step 2 Carefully add LiAlH 4 (11.4 g) to a solution of trans-4-aminocyclohexylcarboxylic acid ethyl ester hydrochloride (4-2, 53.3 g, 257 mmol) in THF (1 L). 309 mmol), the resulting mixture was stirred at room temperature for 3 hours and the reaction was completed. The reaction mixture was carefully quenched with EtOAc (EtOAc)EtOAc.EtOAc.
  • the third step 5-bromo-4-chloro-6-methylpyrimidin-2-amine (1-2, 57 g, 256.2 mmol), trans-(4-aminocyclohexyl)methanol (4-3, 33 g, A mixture of 257 mmol) and DIPEA (66 g, 514 mmol) The mixture was concentrated under reduced pressure and washed with EtOAc EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. mjjjjjjjjjjjjjj -Methylpyrimidin-4-yl)amino]cyclohexyl]methanol (4-4, 58 g, yield: 72%).
  • the fourth step trans-[4-[(2-amino-5-bromo-6-methylpyrimidin-4-yl)amino]cyclohexyl]methanol (4-4, 70 g, 222 mmol), ethyl acrylate ( 1-5, 111.5 g, 1.12 mol), a mixture of Pd(PPh 3 ) 4 (20 g) and triethylamine (112 g, 1.12 mol) in DMF (1 L) was stirred and stirred at 130 ° C for 12 hours. The mixture was concentrated under reduced pressure and washed with EtOAc EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.
  • the fifth step trans-(E)-3-[2-amino-4-[[4-(hydroxymethyl)cyclohexyl]amino]-6-methylpyrimidin-5-yl]prop-2-ene Ethyl ester (4-5, 48 g, 143.5 mmol), thiophenol (15.8 g, 143 mmol), sodium thiophenolate (22.7 g, 172 mmol), DBU (1-7, 43 g, 286 mmol) and diisopropyl
  • a solution of the ethylamine (55 g, 429 mmol) in DMF (1 L) was heated at 130 ° C for 8 hours. The mixture was concentrated under reduced pressure and washed with EtOAc EtOAc. The organic phase was dried over anhydrous sodium sulfate (MgSO4) Cyclohexyl]-4-methylpyridine [2,3-d]pyrimidin-7-one (4-6, 8.6 g, yield: 21%).
  • Step 6 trans-2-amino-8-[4-(hydroxymethyl)cyclohexyl]-4-methylpyridine [2,3-d]pyrimidin-7-one (4-6, 8.6 g, To a solution of 29.8 mmol) in EtOAc (EtOAc (EtOAc) (EtOAc). washing. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. mjjjjjjjj Hydroxymethyl)cyclohexyl]-4-methylpyridine [2,3-d]pyrimidin-7-one (4-7, 9.0 g, yield: 82%).
  • Step 7 trans-2-amino-6-bromo-8-[4-(hydroxymethyl)cyclohexyl]-4-methylpyridine [2,3-d]pyrimidin-7-one (4-7 , 9g, 24.5mmol), potassium carbonate (6.9g, 50mmol) and 2-methoxypyridin-3-ylboronic acid (1-10, 3.7g, 30mmol) in DMF/H 2 O (5:1, 100mL) Nitrogen was bubbled through the mixture for 5 minutes, and Pd(PPh 3 ) 4 (2 g) was added to the mixture. The resulting mixture was stirred with heating at 100 ° C for 2 hours. The reaction mixture was concentrated with EtOAc EtOAc m.
  • Step 8 trans-2-amino-8-[4-(hydroxymethyl)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3- d]pyrimidin-7-one (4-8, 4.8 g, 12.1 mmol), 2,5-dihexanone (1-12, 7 g, 61 mmol) and p-toluenesulfonic acid (0.46 g) in toluene (100 mL) Heat to reflux overnight. The reaction mixture was cooled to room temperature and concentrated.
  • the second step trans-8-[4-(diethoxyphosphorylmethoxymethyl)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6 -Methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one (4-10,100 mg, 0.16 mmol) and hydroxylamine hydrochloride (35 mg, 0.5 mmol) in ethanol
  • the mixed solution of water/water (10:1, 5 mL) was heated to reflux overnight.
  • Step 2 4-[(2-Amino-5-bromo-6-methylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (5-2, 150 g, 0.39 mol), Ethyl acrylate (1-5, 194 g, 1.94 mol), a mixture of triethylamine (300 mL) and Pd (PPh 3 ) 4 (45 g, 38 mmol) in DMF (500 mL). The reaction mixture is cooled to room temperature and concentrated.
  • Third step 4-[[2-amino-5-[(E)-3-ethoxy-3-oxoprop-1-enyl]-6-methylpyrimidin-4-yl]amino]piperidin Tert-butyl-1-carboxylic acid (5-3,115 g, 0.28 mol), thiophenol (31.23 g, 0.28 mol), sodium thiophenolate (37.48 g, 0.28 mol), DBU (1-7, 172.6 g, 1.13) Mol) and diisopropylethylamine (219.78 g, 1.7 mol) in DMF (1 L) were heated at 110 ° C overnight.
  • Step 4 4-(2-Amino-4-methyl-7-oxopyridyl[2,3-d]pyrimidin-8-yl)piperidine-1-carboxylic acid tert-butyl ester (5-4, 20 g, After adding NBS (11.83 g, 66 mmol) to a solution of EtOAc (EtOAc) (EtOAc) . The organic phase is separated and concentrated to give the crude 4-(2-amino-6-bromo-4-methyl-7-oxopyridine [2,3-d]pyrimidin-8-yl)piperidine-1-carboxylic acid tert-butyl The ester (5-5, 19 g) was obtained as a brown solid which was used in the next step without purification.
  • Step 5 4-(2-Amino-6-bromo-4-methyl-7-oxopyridine [2,3-d]pyrimidin-8-yl)piperidine-1-carboxylic acid tert-butyl ester (5- 5,19 g, 43 mmol), potassium carbonate (18 g, 130 mmol) and 2-methoxypyridin-3-ylboronic acid (1-10, 9.98 g, 66 mmol) in DMF / H 2 O (5:1, 240 mL) A nitrogen gas was bubbled through the mixture for 5 minutes, and Pd(PPh 3 ) 2 Cl 2 (3.00 g) was added to the mixture. The resulting mixture was stirred with heating at 100 ° C overnight. The reaction mixture was concentrated to dryness.
  • Step 6 4-(2-Amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxopyridine [2,3-d]pyrimidin-8-yl)peri
  • Step 7 To 2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-piperidinyl)pyridine [2,3-d]pyrimidine-7- A solution of ketone (5-7, 2.5 g, 6.82 mmol) in dioxane (200 mL) was added diethyl phosphite (HPO(OEt) 2 , 5-8, 1.9 g, 13.66 mmol), paraformaldehyde (0.2) g, 6.83 mmol) and acetic acid (0.41 g, 6.83 mmol).
  • HPO(OEt) 2 diethyl phosphite
  • This example is the compound prepared in Example 2, cis-2-amino-8-[4-(diethoxyphosphorylmethylamino)cyclohexyl]-6-(6-methoxy-3-pyridyl) -4-methyl-pyridine [2,3-d] pyrimidin-7-one (2-4a) in DiscoveRx Corporation (4215Sorrento Valley Boulevard, San Diego, CA92121) of KinomeScan TM (www.kinomescan.com) in the system
  • the inhibition results for 98 kinases at 100 nM compound concentration are shown in Table 1:
  • the compounds of the present invention have a significant inhibitory effect on kinases including mTOR, PIK3C2B, PIK3CA, PIK3CG, TYK2, DYRK1B and the like and mutants thereof.
  • Biochemical inhibitory activity against several kinases and their subtypes is the compound prepared in Example 2, cis-2-amino-8-[4-(diethoxyphosphorylmethylamino)cyclohexyl]-6- (6-Methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one (2-4a) by Reaction Biology Corp., One Great Valley Parkway , Suite 2, Malvern, PA19355, USA.
  • the compound of the present invention was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, and 10-fold serial dilutions were made from 10 mM to make 10 different doses.
  • DMSO dimethyl sulfoxide
  • the ATP concentration was 10 ⁇ M using the HTRF assay.
  • the other three kinases mTOR, DYRK1B, TYK2
  • their ATP concentrations were their corresponding Km values.
  • IC 50 ( ⁇ M) mTOR 50 0.67 PI3K- ⁇ 10 0.0051 PI3K- ⁇ 10 0.0156 PI3K- ⁇ 10 0.0992 PI3K- ⁇ 10 0.00237 DYRK1B 20 >10 TYK2 15 >10
  • the compound examples 2-4a of the present invention have strong inhibitory activity against the four subtypes of PI3K, and the IC 50 values are respectively below 100 nM.
  • Compound 2a also showed significant inhibition of mTOR with an IC 50 value of 670 nM.
  • the inhibitory activity of this compound against DYRK1B and TYK2 was weak.
  • mice Female BALB/c-nu/nu mice of 4 to 5 weeks old, weighing 16-20 g, were purchased from Guangdong Experimental Animal Center, and the certificate number was NO: 0072659.
  • A549 lung cancer cells were purchased from the Cell Resource Center of the Shanghai Institute of Biological Sciences.
  • DMEM cell culture medium, fetal bovine serum (FBS) and trypsin digest were from Gibco.
  • Various antibiotics were purchased from Sigma.
  • A549 cell line was inoculated in DMEM medium containing 10% FBS, 100 U/ml penicillin, 100 U/ml streptomycin, and incubated at 37 ° C, 5% CO 2 , 100% humidity carbon dioxide. The cells were cultured in the box, and the cells were full at the bottom of the bottle about 48 hours after inoculation.
  • A549 cells which had been overgrown with 80% of the bottom of the culture flask were digested, centrifuged at 1000 r/min for 3 min, and the cell pellet was collected, and the cells were diluted to 1 ⁇ 10 8 /mL, and inoculated into the right anterior tibia of the nude mouse at 0.1 mL/min.
  • the tumor-bearing nude mice were weighed, the tumor size was measured, and the mice with the tumor size in the range of 150-200 mm 3 were randomly divided into a solvent group (Vehicle, aqueous hydrochloric acid, pH 3) and pyridine
  • a solvent group Vehicle, aqueous hydrochloric acid, pH 3
  • pyridine a solvent group
  • One of the 2,3-d]pyrimidin-7-one compounds trans-2-amino-8-[4-(diethoxyphosphorylmethoxy)cyclohexyl]-6-(6-methoxy -3-pyridyl)-4-methylpyridine
  • 2,3-d]pyrimidin-7-one (1-16) dissolved in Vehicle at a concentration of 1.0 mg/mL
  • mice per group Thereafter, the nude mice were weighed daily and orally administered by intragastric administration (10 mg/kg qd via po) at 0.1 mL/10 g body weight, and the tumor size of each animal was measured
  • the V solvent group was the solvent group mouse tumor volume; the V treatment group was the treatment group mouse tumor volume.
  • the representative compounds of the present invention showed significant tumor inhibition in the xenograft nude mouse animal model, orally administered, 10 mg/kg once daily, and the tumor inhibition rate reached 53 after 18 days. %. Animals in the treatment group had little change in body weight, indicating that the drug had no significant toxicity.
  • Example 8 In the same manner as in Example 8, the compound used in this example was trans-2-amino-8-[4-(diethoxyphosphorylmethylamino)cyclohexyl prepared in Example 2-4b. -6-(6-Methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one.
  • the tumor model was an A549 human lung cancer cell xenograft nude mouse model.
  • the antitumor effect of the compound of the present invention in the treatment group of the present invention on the tumor of the mouse as shown in Example 2-4b is shown in Fig. 2. From the results of the above tumor inhibition experiments, representative compounds of the present invention showed tumor suppressive effects in an xenograft nude mouse animal model.
  • Example 8 In the same manner as in Example 8, the compound used in this example was trans-4-[2-amino-6-(6-methoxy-3-pyridyl)-4 prepared in Example 3. -Methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl]-N-(diethoxyphosphorylmethyl)cyclohexylcarboxamide.
  • the tumor model was an A549 human lung cancer cell xenograft nude mouse model.
  • the compound used in this example was 2-amino-8-[1-(diethoxyphosphorylmethyl)-4-piperidinyl] prepared in Example 5.
  • the tumor model was an A549 human lung cancer cell xenograft nude mouse model.
  • Fig. 4 shows the tumor weight of the drug-administered group and the vehicle control group. From the results of the above tumor inhibition experiments, representative compounds of the present invention showed tumor suppressive effects in an xenograft nude mouse animal model.
  • the compound used in this example is cis-2-amino-8-[4-(diethoxyphosphorylmethylamino)cyclohexyl prepared in Example 2-4a.
  • the tumor model was an animal model of PC3 human prostate cancer cell xenograft nude mice.
  • the anti-tumor effect of the compound of the present invention in the treatment group of the present invention as described in Example 2-4a on the tumor of the mouse is shown in FIG. From the results of the above tumor inhibition experiments, the representative compounds of the present invention showed significant tumor inhibition in the xenograft nude mouse animal model, orally administered, 10 mg/kg once daily, and the tumor inhibition rate reached 73 after 21 days. %. Animals in the treatment group had little change in body weight, indicating that the drug had no significant toxicity.
  • the compound used in this example is cis-2-amino-8-[4-(diethoxyphosphorylmethylamino)cyclohexyl prepared in Example 2-4a.
  • the tumor model was a U87MG human glioblastoma cell xenograft nude mouse model.
  • the antitumor effect of the therapeutic group of the compound of the present invention on the tumor of the mouse described in Example 2-4a is shown in Fig. 6. From the results of the above tumor inhibition experiments, the representative compounds of the present invention showed significant tumor inhibition in the xenograft nude mouse animal model, orally administered, 2.5 mg/kg once daily, and the tumor inhibition rate was reached after 14 days. 64%. Animals in the treatment group had little change in body weight, indicating that the drug had no significant toxicity.
  • Magnesium stearate 3.0.
  • Example 5 100, other materials were the same as in Example 14.
  • Polyvinylpyrrolidone (5 w/v%): 2.25; magnesium stearate: 3.0.
  • Example 2-4a 50, the other substance content was the same as in Example 16.
  • Magnesium stearate 76.
  • Example 3 The compound prepared in Example 3: 1.0, the other substance content was the same as in Example 18.
  • Example 2-4a The compound prepared in Example 2-4a: 10.0, the other substance content was the same as that of Example 20.
  • the water for injection was adjusted to 100%.
  • Example 2-4b The compound prepared in Example 2-4b: 5%, the other substance content was the same as in Example 22, and finally adjusted to 100% with water for injection.
  • Example 5 The compound prepared in Example 5: 1%, the other substance content was the same as in Example 32, and the water for injection was adjusted to 100%.
  • Citric acid 0.38%; polyethylene glycol 400: 3.5%;
  • the water for injection is adjusted to 100%;
  • Example 2-4a 0.1%, the content of other substances was the same as in Example 26, and finally adjusted to 100% with water for injection.
  • Example 2 The compound prepared in Example 1 : 10; sorbitan oleate: 13.5;
  • Example 3 The compound prepared in Example 3: 10, the other substance content was the same as in Example 28.
  • Example 2-4a The compound prepared in Example 2-4a: 0.2, the other substance content was the same as in Example 30.
  • Example 2-4b The compound prepared in Example 2-4b: 2.5, the other substance content was the same as in Example 32.
  • Example 2-4a The compound prepared in Example 2-4a: 2.5, the other substance content was the same as in Example 34.
  • Propylene glycol to 1 ml.
  • Example 2-4a 40 mg, the other substance content was the same as that of Example 36.
  • the invention discloses a phosphorus-containing pyridopyrimidinone compound or a pharmaceutically acceptable salt thereof, and also discloses a preparation method of the compound, comprising the phosphorus-containing pyrido[2,3-d]pyrimidine- A pharmaceutical composition of a 7-keto compound and use thereof.
  • Such compounds are protein kinase (eg, PI3K) inhibitors that can be used to treat diseases caused by abnormal protein kinase activity, such as tumors, in addition to tumors, psoriasis (or psoriasis), cirrhosis, bronchitis, Rheumatoid arthritis, lupus erythematosus, diabetes, diseases involving angiogenesis, immune system diseases, kidney diseases, epilepsy, neurodegenerative diseases and the like, and the present invention has strong industrial applicability.

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Abstract

本发明提供了一类如式（I）所示的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，同时还公开了该化合物的制备方法、包含所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的药物组合物及其应用。这类化合物是蛋白激酶（例如PI3K）抑制剂，可用于治疗因蛋白激酶活性异常所引起的疾病，例如肿瘤等。

Description

一种含磷吡啶并嘧啶酮类化合物或其药学上可接受的盐、药物组合物及其应用 技术领域
本发明涉及有机化学及药物化学领域，具体涉及含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其药学上可接受的盐、含有该化合物的药物组合物及其应用。
背景技术
蛋白质激酶是一类磷酸转移酶，其作用是将ATP的γ-磷酸基转移到底物特定的氨基酸残基上，使蛋白质磷酸化，发挥其生理生化功能。蛋白激酶是一类重要的激酶，在信号转导中主要作用有两个方面：其一是通过磷酸化调节蛋白质的活性；其二是通过蛋白质的逐级磷酸化，使信号逐级放大，引起细胞反应。
蛋白激酶活性的异常不仅与肿瘤的增殖、凋亡、转移等与细胞内外的一系列信号传导通路中某个环节的异常密切相关，同时也是导致一系列其他与炎症或增殖反应有关的人类疾病，例如类风湿性关节炎、心血管和神经系统疾病、哮喘、银屑病等的主要原因。目前已知有四百多种人类疾病与蛋白激酶直接或间接相关，这使得蛋白激酶成为继G－蛋白偶联受体之后的另一大类重要药物靶标。
蛋白激酶大家庭由500多个成员组成，通常可分为蛋白酪氨酸激酶(protein tyrosine kinases or PTKs)及丝氨酸-苏氨酸激酶(serine-threonine kinases)两类。按照激酶在细胞中所处的位置，又可分为受体激酶(receptor kinases)及非受体激酶，又称细胞内激酶。受体激酶一般属酪氨酸激酶，也称酪氨酸受体激酶(receptor tyrosine kinases or RTKs)，这类受体激酶由细胞膜外部分、跨膜区及细胞质内部分组成，具有催化活性的激酶部分位于细胞质内。丝氨酸-苏氨酸激酶绝大多数位于细胞内，属非受体激酶或称细胞质激酶(cytosolic kinases)。
RTKs家族中的典型代表为生长因子受体(growth factor receptors)，至少存在19个亚家族，以下是几个主要的亚家族：
(a)HER家族酪氨酸受体激酶，包括EGFR(epithelial growth factor receptor)、HER2、HER3及HER4。EGFR为治疗非小细胞肺癌的合成小分子药
Figure PCTCN2015081854-appb-000001
及单克隆抗体
Figure PCTCN2015081854-appb-000002
的靶标。
(b)由胰岛素受体(insulin receptor or IR)、像胰岛素的生长因子I型受体(insulin-like growth factor I receptor or IGF-1R)及与胰岛素受体相关的受体(insulin receptor-related receptor or IRR)组成。其中的IGF-1R是公认的抗癌靶标，但由于它与IR太相似，尤其是细胞内的激酶部分，其氨基酸序列为100％相同，抑制IGF-1R的活性，通常也会抑制IR的活性。有证据显示IR也是有效的抗癌靶标，但因为抑制IR有导致血糖升高的风险，IR 抑制剂用于抗癌需要找到效益与安全风险的平衡。
(c)血小板源生长因子受体(platelet-derived growth factor receptor or PDGFRs)家族，包括PDGFR-α、PDGFR-β、CSF1R、c-KIT及c-fms。其中c-KIT也是白血病治疗药物
Figure PCTCN2015081854-appb-000003
的分子靶标，用于治疗胃肠间质瘤。
(d)血管内皮生长因子受体(vascular endothelial growth factor receptors or VEGFRs)家族，包括FLT1(Fms-like tyrosine kinase 1或VEGFR1)、KDR(或VEGFR-2)及FLT4(或VEGFR3)。其中的成员为
Figure PCTCN2015081854-appb-000004
和
Figure PCTCN2015081854-appb-000005
的分子靶标。
(e)成纤维细胞生长因子受体(fibroblast growth factor receptors or FGFRs)家族，包括FGFR1、FGFR2、FGFR3及FGFR4及7个配体FGF1、FGF2、FGF3、FGF4、FGF5、FGF6及FGF7。其中的成员作为分子靶标的药物还在临床实验阶段。
(f)MET家族，包括c-Met或称人类肝细胞生长因子受体(human hepatocyte growth factor receptor or hHGFR)及RON。其中c-Met在初始肿瘤的生长及转移中扮演重要的角色。其作为分子靶标的药物Crizotinib及Cabozantinib已经分别被批准治疗非小细胞肺癌及甲状腺髓样癌。
(g)RET家族，RET是GDNF家族成员的受体，存在RET51、RET43和RET9isoforms。其作为分子靶标的药物Cabozantinib已经被批准治疗甲状腺髓样癌。。
(h)Eph家族是酪氨酸受体激酶中最大的家族，由16个受体(EPHA1、EPHA2、EPHA3,EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA9、EPHA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB5、EPHB6)和9个配体(EFNA1、EFNA2、EFNA3、EFNA4、EFNA5、EFNB1、EFNB2、EFNB3)组成。这些成员在动物的发育中起重要作用，有些成员在肿瘤中扮演角色。
非受体激酶不存在细胞膜外部分及跨膜区部分，整个激酶处于细胞浆中。现在已知至少有24种非受体激酶分为11个亚家族，它们是Src、Frk、Btk、CsK、Abl、Zap70、Fes、Fps、Fak、Jak及AcK亚家族。其中Src亚家族为最大，包括Src、Yes、Fyn、Lyn、Lck、Blk、Hck、Fgr、AUR1、AUR2及Yrk激酶。更详细的资料见Neet,K.；Hunter,T.Genes to Cells 1996,1,147-169及该文引用的文献。虽然有几个非受体激酶属酪氨酸激酶，但绝大多数非受体激酶属于丝氨酸-苏氨酸激酶。其中的几个成员是白血病治疗药物
Figure PCTCN2015081854-appb-000006
及
Figure PCTCN2015081854-appb-000007
的分子靶标。
PI3K(Phosphatidylinositide 3-kinase)是一类参与多项细胞功能的脂质激酶家族。这些功能包括细胞生长、增殖、分化、运动性、存活和细胞内运输等(J.A.Engelman,Nat.Rev.Cancer 2009,9,550)。PI3K家族根据一级结构、作用及对脂质底物的特异性分为三种类型：I型、II型及III型。相比于II及III型，目前人们对I型的了解最完整，I型主要在肿瘤中扮演角色。I型PI3K根据氨基酸序列的相似形进一步分为IA及IB亚型，IA是包 含一个调节亚单位p85(regulatory subunit)及一个催化亚单位p110(catalytic subunit)的杂二聚分子。调节亚单位p85包括5个变种，其中p85α表达最多。催化亚单位p110有三个变种，即p110α、p110β及p110δ，它们分别由基因PIK3CA、PIK3CB及PIK3CD表达。IB型PI3K由调节亚单位p101及催化亚单位p110γ组成，并由PIK3CAG表达。p110α和p110β在每一个细胞中都有表达，但p110δ主要在白细胞中表达(C.L.Carpenter et al,J.Biol.Chem.1990,265,19704.S.J.Leevers et al,Curr.Opin.Cell Biol.1999,11,219.K.Okkenhaug,Ann.Rev.Immunol.2013,31,675)。
PI3K接收来自酪氨酸受体激酶、G-蛋白偶联受体(GPCR)及活化的RAS等传来的信号而被激活，p110于是与磷脂膜发生作用使磷脂酰肌醇中的肌醇PIP2磷酸化产生PIP3。这一过程激活AKT及下游多种在肿瘤中扮演至关重要角色的蛋白。PIP3的产生及量的多少被肿瘤抑制蛋白、磷酸酶及PTEN严格控制(I.Brana and L.L.Siu BMC Med.2012,10,161)。
许多肿瘤都是由PI3K信号传导路径的失控而引起的。常见的机理为PI3KCA的突变或基因表达增加、肿瘤抑制蛋白PTEN的缺失、通过酪氨酸受体激酶的高度表达或激活突变而引起的过度活化等。PI3K-δ抑制剂Idelalisib已经被FDA批准治疗慢性淋巴细胞性白血病(CLL)、复发性滤泡性B细胞非霍奇金淋巴瘤及小淋巴细胞淋巴瘤。
除了在肿瘤中的作用，PI3K也在免疫功能中扮演重要角色，PI3K-γ及PI3K-δ亚型主要在免疫细胞中表达，与多种炎症、自免疫及血液疾病相关。PI3K-γ及PI3K-δ活性的阻断将对治疗关节炎、气管炎、红斑狼疮等疾病发挥作用(D.G.Winkler et al Chem.Biol.2013,20,1364及该文引用的文献)。
mTOR是由人MTOR基因编码的一种丝氨酸/苏氨酸激酶，属于PI3K激酶家族。mTOR在细胞生长、增值、运动、存活、蛋白质合成及转录过程中起调节作用(N.Hay and N.Sonenberg,Genes Dev.2004,18,1926.)。mTOR是mTORC1及mTORC2两种具有不同结构的复合物的催化亚单元(S.Wullschleger et al,Cell 2006,124,471.)。几个mTOR抑制剂已经被批准用于临床治疗癌症(例如，temsirolimus,everolimus等)、抗器官移植排斥(即，rapamycin)等。
WO2005113556A1报道一系列喹唑啉酮作为人PI3K-δ激酶抑制剂。WO2011146882A1报道一系列异喹啉-1-酮作为PI3K激酶抑制剂。WO2007084786A1报道一系列嘧啶类PI3K激酶抑制剂。WO2006122806A2报道一系列咪唑并喹啉作为PI3K/mTOR激酶抑制剂。WO2008032162A1报道一系列吡啶并[2,3-d]嘧啶酮作为PI3K/mTOR激酶抑制剂。WO2008144464A1报道一系列喹啉类化合物作为PI3K/mTOR激酶抑制剂。
如上所述，受体激酶及非受体激酶作为抗肿瘤靶标已经在临床上及实际应用中得到 充分的证明，几个抗肿瘤药已经批准上市治疗病人。除了肿瘤治疗以外，抑制受体激酶及非受体激酶的异常活性还可用于治疗包括但不限于以下疾病：银屑病或称牛皮癣、肝硬化、糖尿病、气管炎、红斑狼疮、涉及血管新生的疾病、涉及再狭窄的疾病、眼睛疾病、与年龄有关的黄斑退化、风湿性关节炎及别的炎症、免疫系统疾病例如自免疫疾病、心血管疾病例如动脉粥样硬化、肾脏疾病等。因此继续研发这些激酶的抑制剂是非常必要的。
发明内容
本发明的第一目的是提供一种具有蛋白激酶(尤其是PI3K、mTOR等)抑制活性的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，以及其消旋体或对映异构体。
本发明的第二目的是提供一种含有上述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，以及其消旋体或对映异构体的药物组合物。
本发明的第三个目的是提供上述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，以及其消旋体或对映异构体在制备治疗因蛋白激酶异常活性引起的疾病的药物中的应用。
为实现上述目的，本发明采用如下技术方案：
一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，该化合物分子结构式如式(I)所示：
Figure PCTCN2015081854-appb-000008
式中，
Ar为芳基或杂芳基，且Ar中的氢可被1-5个相同或不同的G1取代；
X为C-R1或N；
A表示C1-6烷基、C＝O或一个共价键，且当A为C1-6烷基时，其中的氢可被1-5个相同或不同的G2取代；
L表示O、N-R2、S(＝O)m或一个共价键；
J表示C1-6烷基或一个共价键，且J中的氢可被1-5个相同或不同的G3取代；
R和R’分别独立地表示H、OH、卤素、C1-6烷基、C3-6环烷基、C3-12杂脂环基、C1-6 烷氧基、C3-6环烷氧基或C3-12杂脂环氧基，且R和R’中的氢可被1-5个相同或不同的G4取代，R和R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环可另外包含一个或多个O、N或S(＝O)m杂原子；
其中：
G1、G2、G3及G4分别独立地表示H、-CN、-CF3、-OCF3、-NO2、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C6芳基、C5-6杂芳基、C3-12杂脂环基、R3O-、R3R4N-、R3S(＝O)m-、R3R4NS(＝O)m-、R5C(＝O)-、R3R4NC(＝O)-、R3OC(＝O)-、R5C(＝O)O-、R3R4NC(＝O)O-、R5C(＝O)NR3-、R3R4NC(＝O)NR6-、R3OC(＝O)NR6-、R3S(＝O)mNR6-、R3R4NS(＝O)mNR6-、R3R4NC(＝NR7)NR6-、R3R4NC(＝CHNO2)NR6-、R3R4NC(＝N-CN)NR6-、R3R4NC(＝NR7)-、R3S(＝O)(＝NR7)NR6-或R3R4NS(＝O)(＝NR7)-；
R1、R2、R3、R4、R5、R6及R7分别独立地表示H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C6芳基、C5-6杂芳基或C3-12杂脂环基；当R3和R4连接于同一氮原子上时，可与该氮原子一起形成一个C3-12杂脂环，这个C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；且R1、R2、R3、R4、R5、R6及R7中的氢可被1-5个相同或不同的卤素、-CN、-OH、C1-6烷基或C3-6环烷基取代；
m为0、1或2。
其中，优选所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的结构如式(Ia)或(Ib)所示：
Figure PCTCN2015081854-appb-000009
式中所述，
R1表示氢或C1-6烷基；
A表示C1-6烷基、C＝O或一个共价键，且当A为C1-6烷基时，其中的氢可被1-5个相同或不同的G2取代；
L表示O、N-R2或S(＝O)m或一个共价键；
J表示C1-6烷基或一个共价键，且J中的氢可被1-5个相同或不同的G3取代；
m、G1、G2、G3、R、R’和R2的定义同上。
或所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的结构如式(Ic)或(Id)所示：
Figure PCTCN2015081854-appb-000010
式中所述，
G11表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基；
L表示O或N-R2；
J表示C1-6烷基，且J中的氢可被1-5个相同或不同的G3取代；
RR和R’R’分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，且RR和R’R’中的氢可被1-5个相同或不同的G4取代，RR和R’R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；
m、G3、G4和R2的定义同上。
又或所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的结构如式(Ie)或(If)所示：
Figure PCTCN2015081854-appb-000011
式中所述，
G11表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基；
A表示C＝O或C1-6烷基，且当A为C1-6烷基时，其中的氢可被1-5个相同或不同的G2取代；
L表示O或N-R2；
J表示C1-6烷基，且J中的氢可被1-5个相同或不同的G3取代；
RR和R’R’分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，且RR和R’R’中的氢可被1-5个相同或不同的G4取代，RR和R’R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；
m、G2、G3、G4和R2的定义同上。
以及又或所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的结构如式(Ig)所示：
Figure PCTCN2015081854-appb-000012
式中所述，
G11表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基；
J表示C1-6烷基，且J中的氢可被1-5个相同或不同的G3取代；
RR和R’R’分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，且RR和R’R’中的氢可被1-5个相同或不同的G4取代，RR和R’R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环可另外包含一个或多个O、N或S(＝O)m杂原子；
m、G3和G4的定义同上。
其中，本发明所限定的各种通式化合物，其所述药学上可接受的盐为所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物与无机酸、有机酸、无机碱、有机碱通过化学反应形成的盐。
上述盐保留本发明所述化合物的生物活性。所述的无机酸或有机酸可以为：盐酸、氢溴酸、氢碘酸、硫酸、硝酸、碳酸、磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、2-羟基乙磺酸、苯磺酸、取代的苯磺酸(例如，对甲基苯磺酸)、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸或蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸、山梨酸等；所述的无机碱或有机碱可以为：氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸钾、碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢钙、碳酸氢钡、碳酸氢镁、碳酸氢化有机季铵盐、甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、三羟甲基氨基甲烷等。
更优选所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐为下列任意一种化合物：
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
顺式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
2-氨基-8-[1-(二乙氧基磷酰基甲基)-4-哌啶基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-4-[2-氨基-6-(6-二甲氨基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
顺式-4-[2-氨基-6-(6-二甲氨基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-二甲氨基-3-吡啶基)-4- 甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
2-氨基-8-[1-(二乙氧基磷酰基甲基)-4-哌啶基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(甲基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(甲基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(乙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(乙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(正丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(正丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(异丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(异丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(环丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(环丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-8-[4-(二乙氧基磷酰基甲氧基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
顺式-8-[4-(二乙氧基磷酰基甲氧基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-8-[4-(二乙氧基磷酰基甲氨基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
反式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-乙氧基-磷酸；
顺式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-乙氧基-磷酸；
反式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-磷酸；
顺式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-磷酸；
反式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-乙氧基-磷酸；
顺式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-乙氧基-磷酸；
反式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-磷酸或
顺式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-磷酸。
上述的任意一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的消旋体或对映异构体也为本发明的技术方案。
上述的任意一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的顺 式或反式异构体也为本发明的技术方案。
本发明同时也要求保护上述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的消旋体或对映异构体，其中，在已经能够制备得到含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的基础上，其消旋体和对应异构体可以采用常规技术手段获得，本领域技术人员同时也可以预见所述消旋体和对应异构体也具备相同/相近的活性。
本发明还保护了上述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的合成中间体(IIa)、(IIb)或(IIc)：
Figure PCTCN2015081854-appb-000013
式中，
Ar’为芳基或杂芳基，且Ar’中的氢可被1-5个相同或不同的R8取代；
R2表示H、C1-6烷基、C3-6环烷基或C3-12杂脂环基；且R2中的氢可被1-5个相同或不同的卤素、-CN、-OH、C1-6烷基或C3-6环烷基取代；
R和R’分别独立地表示H、OH、卤素、C1-6烷基、C3-6环烷基、C3-12杂脂环基、C1-6烷氧基、C3-6环烷氧基或C3-12杂脂环氧基，且R和R’中的氢可被1-5个相同或不同的R9取代，R和R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环可另外包含一个或多个O、N或S(＝O)m杂原子；
其中：
R8及R9分别独立地表示H、-CN、-CF3、-OCF3、-NO2、卤素、C1-6烷基、C3-6环烷基、C3-12杂脂环基、C1-6烷氧基、C1-6环烷氧基、C3-12杂脂环氧基或R10R11N-。其中，R10及R11分别独立地表示H、C1-6烷基、C3-6环烷基或C3-12杂脂环基。当R10和R11连接于同一氮原子上时，可与该氮原子一起形成一个C3-12杂脂环，这个C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；
m为0、1或2。
或如结构式(IIaa)、(IIbb)或(IIcc)所示的合成中间体：
Figure PCTCN2015081854-appb-000014
式中所述，
R2表示氢、C1-6烷基、C3-6环烷基或C3-12杂脂环基，优选为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基或吗啉基，进一步优选为氢、甲基、乙基、正丙基、乙丙基、环丙基、氧杂环丁基、四氢呋喃基或四氢吡喃基，更进一步优选为氢、甲基、乙基、异丙基、环丙基，且这些基团可被1-5个卤素、-CN、-OH或C1-6烷基取代；
R88表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基，优选为卤素、-OCF3、-OCH3、-OCH2CH3或-NMe2，进一步优选为-OCH3或-NMe2；
R12和R13分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，优选为-OH或C1-6烷氧基，进一步优选为C1-6烷氧基，更进一步优选为甲氧基、乙氧基、正丙氧基或异丙氧基。
本发明提供了上述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物及其合成中间体的制备方法，作为一种实施方式，该方法可由Scheme 1A和/或Scheme 1B所示的步骤组成(如Scheme 1A示意了部分合成中间体的制备方法，Scheme 1A+Scheme 1B示意了部分含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的制备方法，Scheme 1B示意了直接以上述合成中间体制备含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的方法，下同)：
Figure PCTCN2015081854-appb-000015
其中，Ar、R及R’的定义同上(见通式(I)化合物中对各取代基的定义)。M包括但不限于Li、Zn、ZnCl、ZnBr、ZnI、MgCl、MgBr、MgI、B(OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、BF3K、Sn(Bu-n)4、SnMe4等。LG代表一个离去基团，包括但不限于F、Cl、Br、I、MsO、p-TsO、TfO、PhSO3等。Pd catalyst、Base及Solvent的含义见”术语定义”部分。化合物A-1可以根据WO2008032162制备。
另一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的制备方法，该方法由Scheme 2A和/或Scheme 2B所示的步骤组成：
Figure PCTCN2015081854-appb-000016
其中，Ar、R2、R及R’的定义同上(见通式(I)化合物中对各取代基的定义)。W代表氨基或2,5-二甲基吡咯-1-基。Oxidant、Reductant、Base及Solvent的含义见”术语定义”部分。
另一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的制备方法，该方法由Scheme 3A和/或Scheme 3B所示的步骤组成：
Figure PCTCN2015081854-appb-000017
Figure PCTCN2015081854-appb-000018
其中，Ar、R2、R及R’的定义同上(见通式(I)化合物中对各取代基的定义)。M包括但不限于Li、Zn、ZnCl、ZnBr、ZnI、MgCl、MgBr、MgI、B(OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、BF3K、Sn(Bu-n)4、SnMe4等。Pd catalyst、Coupling Reagent、Base及Solvent的含义见”术语定义”部分。
另一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的制备方法，该方法由Scheme 4A和/或Scheme 4B所示的步骤组成：
Figure PCTCN2015081854-appb-000019
其中，Ar、R及R’的定义同上(见通式(I)化合物中对各取代基的定义)。M包括但不限于Li、Zn、ZnCl、ZnBr、ZnI、MgCl、MgBr、MgI、B(OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、BF3K、Sn(Bu-n)4、SnMe4等。LG代表一个离去基团，包括但不限于F、Cl、Br、I、MsO、p-TsO、TfO、PhSO3等。Pd catalyst、Base及Solvent的含义见”术语定义”部分。
另一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的制备方法，该方法由Scheme 5A和/或 Scheme 5B所示的步骤组成：
Figure PCTCN2015081854-appb-000020
其中，Ar、R及R’的定义同上(见通式(I)化合物中对各取代基的定义)。M包括但不限于Li、Zn、ZnCl、ZnBr、ZnI、MgCl、MgBr、MgI、B(OH)2、B(OMe)2、B(OEt)2、B(pinacolato)、BF3K、Sn(Bu-n)4、SnMe4等。LG代表一个离去基团，包括但不限于F、Cl、Br、I、MsO、p-TsO、TfO、PhSO3等。Pd catalyst、Acid、Base及Solvent的含义见”术语定义”部分。
本发明还保护了含有上述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，或其消旋体或对映异构体的药物组合物。
本发明所述药物组合物可用于治疗因蛋白激酶异常活性所引起的疾病。除上述活性成分外，本发明所述药物组合物还包括药学上可接受的一种或几种载体或稀释剂。
本发明所述的药物组合物的制剂形式包括但不限于：口服剂、注射剂、肛塞剂、鼻孔吸入剂、滴眼剂或皮肤贴剂。
由本发明所述化合物组成的药物组合物用于治疗哺乳动物，如人类病人，因蛋白激酶的异常活性引起的疾病。
本发明所述化合物(包括消旋体、对映异构体、顺反异构体及别的立体异构体)或其在药学上可接受的盐、水合物、溶剂合物或前药通过制剂(formulation)过程，与适合的药学上可接受的载体及药学上常用的辅剂制备成利于给药的药物组合物。
具体而言，本发明所述化合物组成的药物给药途径可以为：(1)口服：例如片剂、胶囊等；(2)注射：例如静脉注射、皮下注射、肌肉注射、眼球注射、腹腔注射等；(3)肛塞：例如栓剂、凝胶剂等；(4)鼻孔吸入：例如喷雾剂、气雾剂等；(5)滴眼剂；(6)皮肤贴剂。也可使用药物释放系统，例如，脂质体(liposome)、缓释技术等，其中优先选用的方法为口服及注射，更优先选用的方法为口服。
本发明由所述化合物组成的药物组合物的各种剂型可以采用医药工业常用的方法制备，例如，混合、溶解、制粒、研磨、乳化、胶囊、糖衣、冷冻干燥、冷冻喷雾等。
本发明中的化合物在前述药物组合物中的含量范围为0.001－100％。该药物组合物施用于包括人在内的哺乳动物的有效剂量为每日每千克体重0.1－500毫克，优化的剂量为每日每千克体重使用1－100毫克。在这个有效剂量范围内，本发明中的化合物发挥其抑制蛋白激酶活性及治疗因异常蛋白激酶活性引起的疾病(例如癌症)的药理作用。
本发明药物的使用频率依所使用的化合物或其药物组合物及应用的疾病而有所变化，本发明中的药物组合物通常是每日给药1－6次，优化的给药频率为每日给药1－3次。
本发明所述药物的包装和保存和一般药物类似，例如固体剂型的药物可直接装入玻璃、塑料、纸质或金属瓶中，瓶内最好放入干燥剂等以保持药物的质量；液体剂型的药物一般装入玻璃、塑料或金属瓶或软管中；起雾剂型的药物一般装入耐压的附有减压阀等装置的金属或塑料容器中。
本发明进一步提供了所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，或其消旋体或对映异构体，或含所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，或其消旋体或对映异构体的药物组合物在治疗因蛋白激酶异常活性所引起的疾病中的应用。
上述应用中，所述的蛋白激酶为PI3K或mTOR，优选所述的蛋白激酶为PI3K，更进一步优选为PI3K-α、PI3K-β、PI3K-γ及PI3K-δ。
本发明化合物组成的药物组合物的应用中所述的疾病为银屑病、肝硬化、气管炎、风湿性关节炎、红斑狼疮、糖尿病、涉及血管新生的疾病、眼睛疾病、免疫系统疾病、心血管疾病、癫痫、神经退行性疾病、阿尔茨海默氏病、亨廷顿氏病或帕金森氏症。
本发明所述因蛋白激酶异常活性所引起的疾病为肿瘤，具体包括实体瘤和液体瘤，更具体包括：肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、膀胱癌、肾或 输尿管癌、肾癌、中枢神经中枢系统(CNS)赘生物、脊柱轴肿瘤、垂体腺瘤、胃肠间质肿瘤、结肠直肠癌、非小细胞肺癌、小细胞肺癌、肥大细胞增多症、胶质瘤、肉瘤、淋巴瘤中的一种或任意几种的组合。
经过一系列的试验证明，本发明含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐具有如下有益效果：(1)通过抑制激酶活性的筛选实验，可以看出本发明化合物对一系列蛋白激酶尤其是PI3K及mTOR具有很强的抑制作用；(2)通过对动物的肿瘤抑制试验可以看到，该类含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐可以显著抑制肿瘤，且没有明显的毒性；(3)本发明所述的化合物可与其他抗肿瘤药物共同使用从而起到协同(synergistic)或加合(additive)效应；(4)本发明中的化合物可以与其他的肿瘤疗法，例如放射线疗法、介入疗法等一同使用。由此可见，本发明一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐可以作为一种有效治疗因蛋白激酶异常活性所引起的疾病的药物。
本发明所述化合物在治疗因蛋白激酶活性异常所引起的上述疾病中，所述的肾癌为肾上腺癌、肾细胞癌、肾盂癌；胶质瘤为脑干神经胶质瘤、神经内分泌胶质肿瘤、神经胶质瘤。
本发明所述化合物在治疗因蛋白激酶活性异常所引起的疾病中，除肿瘤外还可以为银屑病(或称牛皮癣)、肝硬化、气管炎、风湿性关节炎、红斑狼疮、糖尿病、涉及血管新生的疾病、涉及再狭窄的疾病、眼睛疾病例如AMD、风湿性关节炎及别的炎症、免疫系统疾病例如自免疫疾病(例如，爱滋病等)、心血管疾病例如动脉粥样硬化、肾脏疾病、癫痫、神经退行性疾病，比如阿尔茨海默氏病、亨廷顿氏病、帕金森氏症等。
术语的定义
以下为本发明中所涉及的术语定义。在本发明中使用的可变基团，例如Ra、Rb、m等只适用于本小节(即“术语的定义”部分)。
根据本领域普通技术人员的公知常识，化学反应多数情况下需要在溶剂中进行，制备本发明的化合物常用的溶剂(Solvent)包括但不限于水、甲醇、乙醇、异丙醇、正丙醇、正丁醇、异丁醇、叔丁醇、2-甲氧基乙醇、2,2,2-三氟乙醇、二氯甲烷、1,2-二氯乙烷、氯仿、THF、二氧六环、DME、乙酸乙酯、乙醚、甲基叔丁醚、己烷、环己烷、甲苯、乙腈、DMF、DMSO或这些溶剂中的两种或多种的混合物等。
化学反应有些情况下需要在酸(Acid)或碱(Base)存在的情况下发生，制备本发明的化合物常用的碱(Base)包括但不限于Et3N、Me3N、i-Pr2NEt、吡啶、DBU、DABCO、四甲基胍、NaOH、KOH、Cs2CO3、Na2CO3、K2CO3、NaHCO3、KF、CsF、K3PO3、K2HPO4、KH2PO4、NaH、n-BuLi、s-BuLi、t-BuLi、NaN(SiMe3)2、LiN(SiMe3)2、KN(SiMe3)2或这 些碱中的两种或多种的混合物等；常用的酸(Acid)包括但不限于HCO2H、AcOH、TFA(三氟醋酸)、HCl(盐酸)、H2SO4、HNO3、H3PO4、p-TsOH、PhSO3H、CSA、MsOH等或Lewis酸ZnCl2、AlCl3、BF3.OEt2等。
化学反应有些情况下需要在偶联试剂(Coupling Reagent)存在的情况下发生，制备本发明的化合物常用的偶联试剂(Coupling Reagent)包括但不限于DCC、EDC、HATU、TBTU、PyBOP、HCTU、BOP、T3P、DIC、HOBt、HOAt、CDI、DEPBT等。
制备本发明的化合物有些步骤需要使用还原反应(Reduction)及还原试剂(Reductant)，所述还原试剂包括但不限于H2+Pd/C、H2+Pd(OH)2、H2+PtO2、H2+
Figure PCTCN2015081854-appb-000021
Ni、Ti(OPr-i)4+NaBH4、Ti(OPr-i)4+NaB(OAc)3H、Ti(OPr-i)4+NaBH3(CN)、Ti(OPr-i)4+H2、H2NNH2+
Figure PCTCN2015081854-appb-000022
Ni、Mg+MeOH、Fe+AcOH、Fe+HCl、Zn+AcOH、Zn+HCl、Zn+NH4OAc、SnCl2、LiAlH4、NaBH4、NaBH3(CN)、NaB(OAc)3H、BH3等。
制备本发明的化合物有些步骤需要使用氧化反应(Oxidation)及氧化试剂(Oxidant)，所述氧化试剂包括但不限于PCC(PyH.ClCrO3)、PDC(2Py.Cr2O7)、K2Cr2O7、Na2Cr2O7、H2Cr2O7、CrO3、CrO3.2Py、O2、H2O2、mCPBA、DMSO+(COCl)2、NaClO2、NaClO、Dess-Martin reagent、KMnO4、OsO4、MnO2等。
制备本发明的化合物有些步骤需要使用钯催化剂(Pd catalyst)，所述钯催化剂包括但不限于Pd/C、Pd(PPh3)4、Pd2(dba)3、PdCl2、Pd(OAc)2、Pd(O2CCF3)2、PdCl2(dppf)、PdCl2(dppp)、Pd(PPh3)2Cl2、Pd(PhCN)2Cl2、Pd(OH)2等。
制备本发明的化合物有些步骤需要脱保护基(Deprotection)，当保护基是Boc(或-CO2Bu-t)时，常用的脱保护试剂包括但不限于HCl、TFA、H2SO4等,当保护基是CBZ(或-CO2CH2Ph)时，常用的脱保护试剂包括但不限于浓HCl、H2+Pd/C等,当保护基是Bn(或-CH2Ph)时，常用的脱保护试剂包括但不限于H2+Pd/C、H2+Pd(OH)2、H2+Pd/C+HCl等。
制备本发明的化合物的反应通常在室温下进行，但有时需要降低至-78℃或加热至200℃；反应通常在前述的溶剂及温度及常规搅拌条件下进行，但有时需要在微波炉中进行；当使用的碱、试剂、催化剂对水或氧气敏感时，反应需在无水无氧条件下进行，在这种情况下，不能使用质子性溶剂。
“溶剂合物”指本发明所述化合物与化学上常用的溶剂以共价键、氢键、离子键、范德华力、络合、包合等形成的稳定物质，所述的溶剂可以为：甲醇、乙醇、丙醇、丁醇、乙二醇、丙二醇、聚乙二醇、丙酮、乙腈、乙醚、甲基叔丁醚等。
“水合物”指溶剂合物，其中的溶剂为水。
“前药”指通过化学合成或物理的方法将本发明中的化合物转化为另一种化合物，并将该化合物给予哺乳动物后，在动物体内被转化成本发明所述的化合物。利用“前药”方法通常是为了克服药物化合物本身不良或欠佳的物理化学性质或成药性。
“消旋体、对映异构体、顺反异构体及别的立体异构体”指化合物具有相同的分子式及分子量，然而由于原子之间的不同键合方式及空间安排顺序而形成不同的化合物，这样的化合物叫异构体或称立体异构体。当这些立体异构体互为镜像关系，即看起来很像，却不能完全重合，就如左手与右手，这些化合物叫对映异构体。对映异构体的绝对构型通常用(R)-及(S)-或R-及S-来标示。具体确定对映异构体的绝对构型的规则见Chapter 4 of“Advanced Organic Chemistry,”4th edition(by J.March,John Wiley and Sons,New York,1992)。(R)-及(S)-对映异构体对偏振光具有相反的旋转作用，即左旋和右旋。当(R)-及(S)-对映异构体按1:1的比例混合或存在时，该混合物对偏振光没有旋转作用，这时该混合物称为消旋体。
本发明所述化合物还可能存在互变异构体(tautomers)、旋转异构体(rotamers)、顺反异构体等，这些概念都可在J.March的“Advanced Organic Chemistry,”4th edition中找到并得到理解。只要这些异构体具有与本发明所述化合物相同或类似的抑制蛋白激酶活性的作用，这些异构体也涵盖于本发明中。
本发明中的化合物被给予哺乳动物(例如人)后，据本领域的常识，有可能在动物体内被不同的酶代谢成各种代谢产物，只要这些代谢产物具有与本发明所述化合物类似的抑制蛋白激酶活性的作用，这些代谢产物也涵盖于本发明中。
“药物组合物”指将本发明所述化合物中的一个、多个、药学上可接受的盐或溶剂合物或水合物或前药与别的化学成分(例如药学上可接受的载体或稀释剂)混合制得的制剂。药物组合物的目的是促进给动物给药的过程。上述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
“药学上可接受的载体”或”稀释剂”指药物组合物中的非活性成分，可以为但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物、甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油、氢化蓖麻油、多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
“烷基”指具有指定数目碳原子的直链或支链的饱和碳氢化合物基团，例如C1-6烷基指含最少1个，最多6个碳原子的直链或支链基团。C0烷基代表一个共价单键。本发明所述的烷基包括但不限于：甲基、乙基、丙基、丁基、异丙基、新戊基、2-甲基-1-己基等。本发明所述的烷基有时也指亚烷基，即烷基失去一个氢原子形成的基团。烷基或亚烷基中的一个或全部氢原子可被下列基团取代：环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N- 硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“环烷基”或“环烷”指具有指定数目碳原子的单、双或多环的碳氢化合物基团，双环或多环时，可以以稠合(两个环或多个环共用两个相邻的碳原子)或螺合(两个环或多个环共用一个碳原子)的形式结合，例如C1-6环烷基指含最少1个，最多6个的单、双或多环的碳氢化合物基团。C0环烷基代表一个共价单键。环烷基中可以含有不饱和的双键或三键，但不具有完全共轭的π电子体系。本发明所述的环烷基有时也指亚环烷基，即环烷基失去一个氢原子形成的基团。本发明所述的环烷基包括但不限于：环丙基、环丁基、环己基、环戊烯基、环庚三烯基、金刚烷等(举例如表A)：
表A
Figure PCTCN2015081854-appb-000023
环烷基或环烷中的一个或全部氢原子可被下列基团取代：烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“杂脂环基或杂脂环”指由3至12个非氢环原子组成的单环、双环或多环体系，其中至少一个环原子为选自O、N、S或P的杂原子，其余环原子为碳原子，例如，C8杂脂环基指的是由8个非氢环原子构成的单环、双环或多环基团，其中至少一个环原子选自O、N、S或P。这种环中除单键外，还可含有双键或叁键，但这些双键或叁键不构成全部共轭的芳香结构。这些单环、双环或多环体系可以以稠环、桥环或螺环的形式存在。本发明所述的杂脂环基有时也指亚杂脂环基，即杂脂环基失去一个氢原子形成的基团。本发明中的杂脂环基或杂脂环包括但不限于：哌啶、吗啉、哌嗪、吡咯烷、吲哚啉、四氢吡啶、四氢呋喃、托品醇等(举例如表B)：
表B
Figure PCTCN2015081854-appb-000024
杂脂环基或杂脂环中的一个或全部氢原子可被下列基团取代：烷基、环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“烯基”指含有至少两个碳原子及一个双键的直链或支链碳氢化合物基团，例如C2-6烯基指含最少2个，最多6个碳原子的直链或支链含至少一个双键的不饱和基团。本发明中的烯基包括但不限于：乙烯基、2-丙烯基、1-戊烯基等。
“炔基”指含有至少两个碳原子及一个三键的直链或支链碳氢化合物基团，例如C2-6炔基指含最少2个，最多6个碳原子的直链或支链含至少一个三键的不饱和基团。本发明中的炔基包括但不限于：乙炔基、3-丙炔基、1-戊炔基等。
“卤素”指氟、氯、溴或碘。
“烷氧基”指具有指定数目碳原子的烷基通过氧原子与其他基团相连。本发明中的烷氧基包括但不限于：甲氧基、乙氧基、丙氧基、丁氧基、环戊氧基、环己氧基、异丙氧基、新戊氧基、2-甲基-1-己氧基等。
“环烷氧基”指具有指定数目碳原子的环烷基通过氧原子与其他基团相连。本发明中的环烷氧基包括但不限于：环丙烷氧基、环丁烷氧基、环己烷氧基等。
“杂脂环氧基”指杂脂环基通过氧原子与其他基团相连。本发明中的杂脂环氧基包括但不限于：哌啶-4基氧基、氧杂环丁烷-3-基氧基等。
“芳基”指由指定数目碳原子组成的单环、双环或多环基团，其中至少一个环具有完全共轭的π电子体系并符合N+2规则，即具有芳香性，但整个基团不必全部共轭。例如，C6芳基指苯基。芳基也可以以亚芳基的形式出现，即芳基结构中与其他基团有两个或以上的连接点。本发明中的芳基包括但不限于：苯基、萘基、茚基、二氢化茚基、四氢化萘等。芳基中的一个或全部氢原子可被下列基团取代：烷基、环烷基、杂芳基、杂脂环、卤素、 氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“杂芳基”指由指定数目非氢环原子组成的单环、双环或多环基团，其中至少一个环原子为选自O、N、S或P的杂原子，其余环原子为碳原子，并且，其中至少一个环具有完全共轭的π电子体系并符合N+2规则，即具有芳香性，但整个基团不必全部共轭，例如，C5杂芳基指的是由5个非氢环原子构成的芳香环基团，其中至少一个环原子选自O、N、S或P。杂芳基也可以以亚杂芳基的形式出现，即杂芳基结构中与其他基团有两个或以上的连接点。本发明中的杂芳基包括但不限于：砒啶、砒碇酮、四氢砒碇酮、咪啶、吡嗪、哒嗪、咪唑、噻唑、噻吩、呋喃、吲哚、氮杂吲哚、苯并咪唑、吲哚啉、吲哚酮、喹咛等(举例如表C)：
表C
Figure PCTCN2015081854-appb-000025
杂芳基中的一个或全部氢原子可被下列基团取代：烷基、环烷基、芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“芳氧基”指芳基通过氧原子与其他基团相连。本发明中的芳氧基包括但不限于：苯氧基、萘氧基等。
“杂芳氧基”指杂芳基通过氧原子与其他基团相连。本发明中的杂芳氧基包括但不限于：4-砒啶氧基、2-噻吩氧基等。
“氨基”指H2N-或其中氢原子被取代的H2N-，即RaHN-及RaRbN-。
“oxo”或“氧基”指＝O，即氧原子通过双键与碳或N、S、P等杂原子相连接。被氧基取代的例子包括但不限于表D中所示物质：
表D
Figure PCTCN2015081854-appb-000026
“羟基”指-OH。
“硝基”指-NO2。
“羧基”指-CO2H。
“巯基”指-SH。
“烷基巯基”指烷基-S-。
“芳基巯基”指芳基-S-。
“羰基”指-C(＝O)-。
“硫羰基”指-C(＝S)-。
“C-酰胺基”指-C(＝O)NRaRb。
“N-酰胺基”指C(＝O)NRa-。
“O-氨羰氧基”指-O-C(＝O)NRaRb。
“N-氨羰氧基”指O-C(＝O)NRa-。
“O-硫代氨羰氧基”指-O-C(＝S)NRaRb。
“N-硫代氨羰氧基”指O-C(＝S)NRa-。
“C-酯基”指-C(＝O)ORa。
“N-酯基”指C(＝O)O-。
“乙酰基”指CH3C(＝O)-。
“磺酰基”指-SO2Ra。
“三氟甲磺酰基”指CF3SO2-。
附图说明
图1实施例1所述本发明化合物对小鼠A549肿瘤的抑瘤作用曲线对照图；
图2实施例2-4b所述本发明化合物对小鼠A549肿瘤的抑瘤作用曲线对照图；
图3实施例3所述本发明化合物对小鼠A549肿瘤的抑瘤作用曲线对照图；
图4实施例5所述本发明化合物对小鼠A549肿瘤的抑瘤作用瘤体重量对照图；
图5实施例2-4a所述本发明化合物对小鼠PC3肿瘤的抑瘤作用曲线对照图；
图6实施例2-4a所述本发明化合物对小鼠U87MG肿瘤的抑瘤作用曲线对照图。
具体实施方式
以下结合具体实施例对本发明作进一步详细说明，以便读者进一步理解本发明所述化合物、其制备方法及有益效果等，但本发明的具体实施方式对本发明要求保护的内容不具有限制作用。
下面列出在实施例中出现的英文缩写及相应的中文含义。如果实施例中出现没有列于此的缩写，则代表普遍接受的含义。
DMSO：二甲基亚砜
DMSO-d6：六氘代二甲基亚砜
TMS：四甲基硅烷
DCM：二氯甲烷
CDCl3：氘代氯仿
CD3OD：氘代甲醇
THF：四氢呋喃
EtOAc：乙酸乙酯
MeOH：甲醇
EtOH：乙醇
HCl：氯化氢或盐酸
TLC：薄层色谱
LC-MS：液相色谱-质谱联用
g：克
mg：毫克
mol：摩尔
mmol：毫摩尔
μM：微摩尔
L：升
μL：微升
nM：纳摩尔
[M+H]+：质谱中的分子离子峰
N：当量浓度
m/z：质荷比
δ：化学位移
DMAP：4-二甲基氨基吡啶
DIPEA：二异丙基乙基胺
DBU：1,8-二氮杂二环[5.4.0]十一碳-7-烯
PCC：氯铬酸吡啶嗡盐
Ti(OPr-i)4：四异丙基钛酸酯
Pd(PPh3)4：四(三苯基膦)钯(0)
Pd(PPh3)2Cl2：双-(三苯基膦)氯化钯(II)
NBS：N-溴代琥珀酰亚胺
LiHMDS：双-(三甲基硅基)胺锂
LiAlH4：四氢铝锂
DMA：二甲基乙酰胺
一般实验条件：
核磁共振氢谱及碳谱于
Figure PCTCN2015081854-appb-000027
400MHz或
Figure PCTCN2015081854-appb-000028
400MHz仪器上获得(氘代DMSO，氘代氯仿，氘代甲醇等为溶剂，TMS为内标)。质谱由液相色谱-质谱联用仪获得(采用ESI或APCI离子源ZQ4000，美国
Figure PCTCN2015081854-appb-000029
公司)。紫外光谱由日本日立公司的UV-3010紫外分光光度计测得。红外光谱使用
Figure PCTCN2015081854-appb-000030
6700红外光谱分析仪(KBr压片)。高效液相色谱使用
Figure PCTCN2015081854-appb-000031
2695ZORBAX高效液相色谱仪(Bx-C8 5μ150×4.6mm色谱柱)。熔点的测定使用Electrothermal数字式熔点仪IA9100，并且未校正。
起始原料、试剂及溶剂从下列供应商购买：Beta-Pharma；Shanghai PI Chemicals；AndaChem；Taiyuan；Shanghai FWD Chemicals；Sigma-Aldrich,Milwaukee,WI,USA；Acros,Morris Plains,NJ,USA；Frontier Scientific,Logan,Utah,USA；Alfa Aesar,Ward Hill,MA,USA等或利用文献报道的方法合成。除非特别指出，溶剂一般不经干燥，而直接使用供应商的产品或经过分子筛干燥。
实施例1A
反式-8-[4-(二乙氧基磷酰基甲氧基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-15)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000032
第一步：往4-氯-6-甲基嘧啶-2-胺(1-1,100g，0.70mol)的二氯甲烷溶液(4L)中滴加溴(134g，0.84mol)，所产生的悬浮液在室温下搅拌2小时，加入二氯甲烷(5L)稀释，用饱和碳酸氢钠溶液(2x 3L)和饱和食盐水(3L)洗，硫酸镁干燥、过滤、浓缩得到产物5-溴-4-氯-6-甲基嘧啶-2-胺(1-2)，为白色固体(120g，产率：79％)。
第二步：5-溴4-氯-6-甲基嘧啶-2-胺(1-2,120g，0.54mol)，反式-4-氨基环己醇(1-3,58g，0.5mol)及二异丙基乙基胺(110g，0.84mol)的二甲基乙酰胺(4L)溶液于120℃加热反应16小时。反应混合物用甲基叔丁基醚(2.0L)稀释，用饱和氯化铵溶液(2x 3.0L)及饱和食盐水洗涤，无水硫酸镁干燥、过滤、浓缩至干，残留物用柱层析纯化，二氯甲烷/甲醇的混合物(95/5)作为洗脱剂，得到产物反式-4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]环己醇(1-4)，为浅红色固体(100g,产率：61％)。核磁共振分析结果：1H-NMR(CD3OD,400MHz):δ3.90(m,1H),3.56(m,1H),3.25(s,3H),1.99-1.94(m,4H),1.42-1.30(m,4H)。
第三步：反式-4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]环己醇(1-4,50g，0.166mol)，丙烯酸乙酯(1-5,83g，0.83mol)，三乙胺(84g，0.83mol)和Pd(PPh3)4(10g,8.65mmol)的DMF(500mL)溶液于130℃加热反应16小时。反应混合物冷至室温并浓缩，残留物用二氯甲烷(200mL)稀释，过滤，干燥得到产物反式-(E)-3-[2-氨基-4-[(4-羟基环己基)氨基]-6-甲基嘧啶-5-基]-2-丙烯酸乙酯(1-6)，为白色固体(25g，产率：46％)。质谱分析结果：m/z:321.20[M+H]+。
第四步：反式-(E)-3-[2-氨基-4-[(4-羟基环己基)氨基]-6-甲基嘧啶-5-基]-2-丙烯酸乙酯(1-6,40g,0.125mol)，苯硫酚(14g，0.13mol)，苯硫酚钠(33g，0.25mol)，DBU(1-7,76g，0.5mol)和二异丙基乙基胺(97g,0.75mol)的DMF溶液(400mL)于120℃加热反应16小时。反应混合物浓缩至干，残留物用硅胶柱层析纯化，二氯甲烷/甲醇的混合物(95/5)作为洗脱剂，得到产物反式-2-氨基-8-(4-羟基环己基)-4-甲基吡啶[2,3-d]嘧啶-7-酮，为黄色固体(1-8,29g，产率：85％)。质谱分析结果：m/z:275.20[M+H]+。
第五步：反式-(2-氨基-8-(4-羟基环己基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-8,29g，0.106mol)的DMF(290mL)溶液中加入NBS(23g，0.13mol)，于室温搅拌1小时后，反应混合物浓缩至干，残留物用柱层析纯化，二氯甲烷/甲醇的混合物(95/5)作为洗脱剂，得到产物反式-2-氨基-6-溴-8-(4-羟基环己基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-9)，为黄色固体(27g，产率：71％)。质谱分析结果：m/z:353.00[M+H,79Br]+,355.00[M+H,81Br]+。
第六步：于反式-2-氨基-6-溴-8-(4-羟基环己基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-9,11g,31.1mmol)，碳酸钾(13g,93mmol)及2-甲氧基吡啶-3-基硼酸(1-10,6.8g,56mmol)在DMF/H2O(5:1，24mL)中的混合物中鼓氮气5分钟，往该混合物中加入Pd(PPh3)2Cl2(3g,4.28mmol)。所得混合物于微波炉100℃加热搅拌2小时。反应混合物浓缩至干，残留物用硅胶柱层析纯化，二氯甲烷/甲醇的混合物(95/5)作为洗脱剂，得到产物反式-2-氨基-8-(4-羟基环己基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-11)，为黄色固体(6.64g，产率：56％)。质谱分析结果：m/z:382.30[M+H]+。
第七步：反式-2-氨基-8-(4-羟基环己基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-11,1.5g,3.93mmol)、2,5-二己酮(1-12,2.7g,24mmol)和对甲苯磺酸(0.15g,0.87mmol)的甲苯(100mL)溶液加热回流过夜。反应混合物冷却至室温，并浓缩。残留物用柱层析纯化，石油醚/乙酸乙酯的混合物(80/20)作为洗脱剂，得到产物反式-2-(2,5-二甲基吡咯-1-基)-8-(4-羟基环己基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-13)，为白色固体(1g，产率：55％)。
第八步：在0℃下，往反式-2-(2,5-二甲基吡咯-1-基)-8-(4-羟基环己基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-13,1.1g,2.39mmol)的THF溶液(20mL)中加入LiHMDS(1N的THF溶液，4mL,4mmol)。所得混合物在室温下搅拌1小时，冷却至0℃，加入二乙氧基磷酰基甲基三氟甲磺酸酯(1-14,1.1g,3.6mmol)。该混合物在室温下搅拌5小时，加入饱和NH4Cl溶液淬灭，用二氯甲烷萃取。有机层干燥并浓缩，残余物用制备TLC纯化得到化合物反式-8-[4-(二乙氧基磷酰基甲氧基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6- 甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-15,0.61g，产率：42％)。质谱分析结果：m/z:610.20[M+H]+。
实施例1
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-16)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000033
反式-8-[4-(二乙氧基磷酰基甲氧基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-15,0.61g,1mmol，根据实施例1A制备)和盐酸羟胺(0.35g,5mmol)溶解于乙醇/水(10:1,22mL)，并加热至回流过夜。反应混合物减压浓缩，残余物用制备HPLC纯化得到的反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-16,210mg，产率：40％)，为黄色固体。核磁共振分析结果：1H-NMR(CDCl3,400MHz):δ8.31(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)。质谱分析结果：m/z:532.20[M+H]+。
下列化合物(但不局限于这些化合物)可以按照实施例1A及实施例1描述的相同或类似的方法合成：
Figure PCTCN2015081854-appb-000034
Figure PCTCN2015081854-appb-000035
实施例2A
顺式/反式-8-[4-(二乙氧基磷酰基甲氨基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(2A)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000036
第一步：在0℃下，往反式-2-(2,5-二甲基吡咯-1-基)-8-(4-羟基环己基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-13,0.179g，0.39mmol，根据实施例1A中第七步合成)和醋酸钠(64mg，0.78mmol)的二氯甲烷(5mL)溶液中加入PCC(0.11g，0.47mmol)，所得混合物在室温下搅拌4小时后，过滤、减压浓缩，粗产物用硅胶柱色谱纯化，石油醚/乙酸乙酯混合物(70/30)作为洗脱剂，得到化合物2-(2,5-二甲基吡咯-1-基)-6-(6-甲 氧基-3-吡啶基)-4-甲基-8-(4-氧代环己基)吡啶[2,3-d]嘧啶-7-酮(2A-1,0.093g，产率：52％)。质谱分析结果：m/z:458.32[M+H]+。
第二步：2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基-8-(4-氧代环己基)吡啶[2,3-d]嘧啶-7-酮(2A-1,0.092g，0.2mmol)和三乙胺(0.060g，0.59mmol)的THF(5mL)溶液在室温下搅拌1小时，加入Ti(OPr-i)4(0.25mL)和二乙氧基磷酰基甲胺(2-2,0.075g，0.30mmol)，所得混合物在室温下搅拌2小时，加入硼氢化钠(0.038g，1.0mmol)后搅拌过夜。反应混合物用饱和氯化铵水溶液(5mL)淬灭，二氯甲烷(3x 20mL)萃取，有机相用硫酸镁干燥、过滤、浓缩，残留物用HPLC纯化得到8-[4-(二乙氧基磷酰基甲氨基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(2A,38mg，产率：31％)，为反式/顺式混合物。质谱分析结果：m/z:609.32[M+H]+。
实施例2
顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(2-4a)和反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(2-4b)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000037
第一步：在0℃下，往反式-2-氨基-8-(4-羟基环己基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-11,1.5g，3.93mmol，根据实施例1中第六步合成)和醋酸钠(640mg，7.8mmol)的二氯甲烷(15mL)溶液中加入PCC(1.1g，4.7mmol)，所得混合物在室温下搅拌4小时后，过滤、减压浓缩，粗产物用硅胶柱色谱纯化，石油醚/乙酸乙酯混合物(70/30)作为洗脱剂，得到化合物2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-8-(4-氧代环己基)吡啶[2,3-d]嘧啶-7-酮(2-1,1g，产率：67％)。质谱分析结果：m/z:380.30[M+H]+。
第二步：2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-8-(4-氧代环己基)吡啶[2,3-d]嘧啶-7-酮(2-1,1.5g，4.0mmol)和三乙胺(1.2g，11.8mmol)的THF(15mL)溶液在室温下搅拌1小时，加入Ti(OPr-i)4(5mL)和二乙氧基磷酰基甲胺(2-2,1.5g，5.9mmol)，所得混合物在室温下搅拌2小时，加入硼氢化钠(0.75g，19.8mmol)后搅拌过夜。反应混合物用饱和氯化铵水溶液(30mL)淬灭，二氯甲烷(3x 100mL)萃取，有机相用硫酸镁干燥、过滤、浓缩，残留物用HPLC纯化得到2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(2-3,400mg，产率：19％)，为反式/顺式混合物，进一步用超临界流体色谱(SFC)分离得到226mg顺式及50mg反式产物。
顺式产物(2-4a)：核磁共振分析结果：1H-NMR(CDCl3,400MHz):δ8.32(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)。质谱分析结果：m/z:531.30[M+H]+。
反式产物(2-4b)：核磁共振分析结果：1H-NMR(CDCl3,400MHz):δ8.35(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)。质谱分析结果：m/z:531.30[M+H]+。
下列化合物(但不局限于这些化合物)可以按照实施例2描述的相同或类似的方法合成：
Figure PCTCN2015081854-appb-000038
Figure PCTCN2015081854-appb-000039
Figure PCTCN2015081854-appb-000040
实施例3A
反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]环己基甲酸(3-7)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000041
第一步：5-溴-4-氯-6-甲基嘧啶-2-胺(1-2,109g，0.49mol)，反式-4-氨基环己基甲酸乙酯(3-1,102g，0.5mol)和二异丙基乙基胺(194g，1.5mol)的二甲基乙酰胺(1L)溶液于130℃回流12小时。将混合物减压浓缩，残留物溶解于二氯甲烷(1L)中，用水(2x 500mL)及饱和食盐水(2x 500mL)洗涤。有机相用硫酸钠干燥、过滤、浓缩得到粗产物反式-4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]环己基甲酸乙酯(3-2)，无需纯化直接用于下一步反应。
第二步：反式-4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]环己基甲酸乙酯(3-2,90g，251.9mmol)，丙烯酸乙酯(1-5,126g，1.26mol)，Pd(PPh3)4(30g)和三乙基胺(127g，1.26mol)的DMF(1.5升)的混合物于130℃下加热搅拌12小时。将混合物减压浓缩，残留物溶解于二氯甲烷(500mL)中，用水(200mL)及饱和食盐水(200mL)洗涤。有机相用硫酸钠干燥、过滤、浓缩得到粗产物反式-4-[[2-氨基-5-[(E)-3-乙氧基-3-氧基丙-1-烯基]-6-甲基嘧啶-4-基]氨基]环己基甲酸乙酯(3-3)，无需纯化直接用于下一步反应。
第三步：反式-4-[[2-氨基-5-[(E)-3-乙氧基-3-氧基丙-1-烯基]-6-甲基嘧啶-4-基]氨基]环己基甲酸乙酯(3-3,80g，212.51mmol)，苯硫酚(23g，213mmol)，苯硫酚钠(34g，255mmol)，DBU(1-7,130g，852mmol)和二异丙基乙基胺(165g，12.8mol)在DMF(1.2L)中的混合物于130℃加热搅拌8小时。将混合物减压浓缩，残留物溶解于二氯甲烷(1L)中，用水(400mL)及饱和食盐水(400mL)洗涤。有机相用硫酸钠干燥、过滤、浓缩得到粗产物，通过硅胶柱色谱纯化，用含5％甲醇的二氯甲烷溶液洗脱，得到反式-4-(2-氨基-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基)环己基甲酸乙酯(3-4,25g，3步总产率：35％)。
第四步：往反式-4-(2-氨基-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基)环己基甲酸乙酯(3-4,25g，75.67mmol)的DMF(250mL)溶液中加入NBS(12.8g，72mmol)，该混合物在室温下搅拌2小时。将混合物减压浓缩，残留物溶解于二氯甲烷(200mL)中，用水(50mL) 及饱和食盐水(50mL)洗涤。有机相用硫酸钠干燥、过滤、浓缩得到粗产物，通过硅胶柱色谱纯化，用含5％甲醇的二氯甲烷溶液洗脱，得到反式-4-(2-氨基-6-溴-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基)环己基甲酸乙酯(3-5,15g，产率：48％)。
第五步：反式-4-(2-氨基-6-溴-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基)环己基甲酸乙酯(3-5,22g，53.75mmol)，碳酸钾(14.9g，108mmol)，2-甲氧基吡啶-3-基硼酸(1-10,12.4g，81mmol)和Pd(PPh3)4(4g)在DMF/H2O(5:1，260毫升)中的混合物于100℃下搅拌2小时。将混合物减压浓缩，残留物溶解于二氯甲烷(200mL)中，用水(50mL)及饱和食盐水(50mL)洗涤。有机相用硫酸钠干燥、过滤、浓缩得到粗产物，通过硅胶柱色谱纯化，用含5％甲醇的二氯甲烷溶液洗脱，得到反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]环己基甲酸乙酯(3-6,3.5g，产率：15％)。
第六步：反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]环己基甲酸乙酯(3-6,1.1g，2.5mmol)和氢氧化锂(210mg，5mmol)于H2O(10mL)和EtOH(10mL)的混合溶液中室温下搅拌3小时后，浓缩，并用H2O(10mL)稀释，乙酸乙酯萃取(2x 20mL)。水层用1N盐酸调节pH至5，用乙酸乙酯萃取(3x 50mL)，合并有机相，用硫酸钠干燥，过滤，浓缩得到反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]环己基甲酸(3-7)，无需纯化，直接用于下一步反应。质谱分析结果：m/z:411.20[M+H]+。
实施例3
反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺(3-8)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000042
反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]环己基甲酸(3-7,1g，2.44mmol，根据实施例3A的第六步合成的粗产品)，二乙氧基磷酰基甲胺(2-2,720mg，2.8mmol)，羟基苯并三唑(HOBT，513mg，3.8mmol)，1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺)(EDCI,730mg，3.8mmol)和N-甲基吗啉(NMM， 2g，20mmol)的二氯甲烷溶液于室温下搅拌8小时。将反应混合物减压浓缩，残留物溶解于乙酸乙酯(100mL)中，用水(30mL)及饱和食盐水(30mL)洗涤。有机相用硫酸钠干燥、过滤、浓缩得到粗产物，通HPLC纯化得到反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺(3-8,203mg，15％)。1H-NMR(CDCl3,400MHz):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)。质谱分析结果：m/z:559.30[M+H]+。
下列化合物(但不局限于这些化合物)可以按照实施例3A和实施例3描述的相同或类似的方法合成：
Figure PCTCN2015081854-appb-000043
Figure PCTCN2015081854-appb-000044
实施例4A
反式-2-(2,5-二甲基吡咯-1-基)-8-[4-(羟甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基 吡啶[2,3-d]嘧啶-7-酮(4-9)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000045
第一步：反式-4-氨基环己基甲酸盐酸盐(4-1,50g,0.28mol)的乙醇溶液(500mL)中加入SOCl2(100mL)，所得混合物于100℃搅拌8小时。减压除去溶剂得到反式-4-氨基环己基甲酸乙酯盐酸盐(4-2,58g，产率：100％)。
第二步：在0℃下，往反式-4-氨基环己基甲酸乙酯盐酸盐(4-2,53.3g,257mmol)的THF(1L)溶液中小心分批加入LiAlH4(11.4g,309mmol)，所得混合物于室温搅拌3小时反应完成。反应混合物用乙醇小心淬灭，过滤，滤液减压浓缩得反式-(4-氨基环己基)甲醇(4-3,28g，产率：85％)。
第三步：5-溴-4-氯-6-甲基嘧啶-2-胺(1-2,57g,256.2mmol)，反式-(4-氨基环己基)甲醇(4-3,33g,257mmol)和DIPEA(66g,514mmol)在DMA(1.5L)中的混合物于130℃搅拌回流12小时。将混合物减压浓缩，并用DCM(500mL)稀释、用水(200mL)和饱和食盐水(200mL)洗涤。有机相用无水硫酸钠干燥、过滤、浓缩，残余物用硅胶柱色谱纯化(5％甲醇的二氯甲烷溶液洗脱)得到反式-[4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]环己基]甲醇(4-4,58g，产率：72％)。
第四步：反式-[4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]环己基]甲醇(4-4,70g,222mmol)，丙烯酸乙酯(1-5,111.5g,1.12mol)，Pd(PPh3)4(20g)和三乙胺(112g,1.12mol)的DMF(1L)混合物于130℃下加热搅拌12小时。将混合物减压浓缩，并用DCM(300mL)稀释、用水(100mL)和饱和食盐水(100mL)洗涤。有机相用无水硫酸钠干燥、过滤、浓缩，残余物用硅胶柱色谱纯化(5％甲醇的二氯甲烷溶液洗脱)得到反式-(E)-3-[2-氨基-4-[[4-(羟甲基)环己基]氨基]-6-甲基嘧啶-5-基]丙-2-烯酸乙酯(4-5,48g，产率：65％)。
第五步：反式-(E)-3-[2-氨基-4-[[4-(羟甲基)环己基]氨基]-6-甲基嘧啶-5-基]丙-2-烯酸乙酯(4-5,48g,143.5mmol)，苯硫酚(15.8g,143mmol)，苯硫酚钠盐(22.7g,172mmol)，DBU(1-7,43g,286mmol)和二异丙基乙基胺(55g,429mmol)的DMF溶液(1L)于130℃加热反应8小时。将混合物减压浓缩，并用DCM(300mL)稀释、用水(100mL)和饱和食盐水(100mL)洗涤。有机相用无水硫酸钠干燥，过滤，浓缩，残余物用硅胶柱色谱纯化(5％甲醇的二氯甲烷溶液洗脱)得到反式-2-氨基-8-[4-(羟甲基)环己基]-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-6,8.6g，产率：21％)。
第六步：反式-2-氨基-8-[4-(羟甲基)环己基]-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-6,8.6g,29.8mmol)的DMF(200mL)溶液中加入NBS(5.3g，30mmol)，于室温搅拌2小时后，反应混合物减压浓缩，并用DCM(100mL)稀释，用水(50mL)和饱和食盐水(50mL)洗涤。有机相用无水硫酸钠干燥、过滤、浓缩，残余物用硅胶柱色谱纯化(5％甲醇的二氯甲烷溶液洗脱)得到反式-2-氨基-6-溴-8-[4-(羟甲基)环己基]-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-7,9.0g，产率：82％)。
第七步：反式-2-氨基-6-溴-8-[4-(羟甲基)环己基]-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-7,9g,24.5mmol)、碳酸钾(6.9g,50mmol)及2-甲氧基吡啶-3-基硼酸(1-10,3.7g,30mmol)在DMF/H2O(5:1，100mL)中的混合物中鼓氮气5分钟，往该混合物中加入Pd(PPh3)4(2g)。所得混合物于100℃加热搅拌2小时。反应混合物减压浓缩，并用DCM(80mL)稀释、用水(40mL)和饱和食盐水(40mL)洗涤。有机相用无水硫酸钠干燥、过滤、浓缩，残余物用硅胶柱色谱纯化(5％甲醇的二氯甲烷溶液洗脱)得到反式-2-氨基-8-[4-(羟甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-8,4.0g，产率：41％)。第八步：反式-2-氨基-8-[4-(羟甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-8,4.8g,12.1mmol)，2,5-二己酮(1-12,7g,61mmol)和对甲苯磺酸(0.46g)的甲苯(100mL)溶液加热回流过夜。反应混合物冷却至室温，并浓缩。残留物用柱层析纯化，石油醚/乙酸乙酯(1:1)的混合物作为洗脱剂，得到反式-2-(2,5-二甲基吡咯-1-基)-8-[4-(羟甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-9)，为白色固体(2.5g，产率：43％)。质谱分析结果：m/z:474.32[M+H]+。
实施例4
反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-11)的制备，具体反应式如下：
Figure PCTCN2015081854-appb-000046
第一步：-78℃下，往反式-2-(2,5-二甲基吡咯-1-基)-8-[4-(羟甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-9,1.3g,2.7mmol，根据实施例4A中的第七步制备)及三氟甲磺酸(二乙氧基磷酰基甲基)酯(1-14,1.7g,5.6mmol)的THF(50mL)溶液中滴加1M LiHMDS的THF溶液(5.6mL,5.6mmol)。所得混合物于-78℃搅拌0.5小时，升至室温继续搅拌0.5小时。反应混合物用饱和氯化铵溶液(30mL)淬灭，并用DCM萃取(50mL x 3)。有机层合并，用无水硫酸钠干燥、过滤、浓缩，残余物用制备HPLC纯化，得到反式-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-10,100mg,产率：5.8％)。
第二步：反式-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-10,100mg,0.16mmol)和羟胺盐酸盐(35mg,0.5mmol)在乙醇/水的混合溶液(10:1,5mL)中加热回流过夜。将反应混合物浓缩，残余物用制备HPLC纯化得到反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(4-11,8mg，产率：9％)。核磁共振分析结果：1H-NMR(CDCl3,400MHz):δ8.32(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)。质谱分析结果：m/z:546.20[M+H]+。
下列化合物(但不局限于这些化合物)可以按照实施例4和实施例4A描述的相同或类似的方法合成：
Figure PCTCN2015081854-appb-000047
Figure PCTCN2015081854-appb-000048
实施例5
2-氨基-8-[1-(二乙氧基磷酰基甲基)-4-哌啶基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(5-9)的制备，，具体反应式如下：
Figure PCTCN2015081854-appb-000049
第一步：5-溴-4-氯-6-甲基嘧啶-2-胺(1-2,200g,0.9mol)，4-氨基哌啶-1-甲酸叔丁酯(5-1,217g,1.08mol)及二异丙基乙基胺(232.6g，1.8mol)的二甲基乙酰胺(1L)溶液于120℃加热反应过夜。反应混合物浓缩，并加入DCM(5L)及饱和食盐水(5L)，有机相分离，无水硫酸钠干燥、过滤、浓缩至干得到棕色固体，用乙酸乙酯(500mL)打浆，过滤得到4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]哌啶-1-甲酸叔丁酯(5-2,250g,产率：70％)。质谱分析结果：m/z:386.20[M+H,79Br]+,388.20[M+H,81Br]+。硅胶薄层色谱：Rf＝0.4(DCM/MeOH＝20:1)。
第二步：氮气下，4-[(2-氨基-5-溴-6-甲基嘧啶-4-基)氨基]哌啶-1-甲酸叔丁酯(5-2,150g,0.39mol)，丙烯酸乙酯(1-5,194g,1.94mol)，三乙胺(300mL)和Pd(PPh3)4(45g,38mmol)在DMF(500mL)中的混合物于120℃加热反应48小时。反应混合物冷至室温并浓缩，残留物用柱层析纯化，二氯甲烷/甲醇的混合物作为洗脱剂，得到产物4-[[2-氨基-5-[(E)-3-乙氧基-3-氧代丙-1-烯基]-6-甲基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5-3)，为黄色固体(50g，产率：30％)。质谱分析结果：m/z:406.30[M+H]+。硅胶薄层色谱：Rf＝0.35(DCM/MeOH＝20:1)。
第三步：4-[[2-氨基-5-[(E)-3-乙氧基-3-氧代丙-1-烯基]-6-甲基嘧啶-4-基]氨基]哌啶-1-甲酸叔丁酯(5-3,115g,0.28mol)，苯硫酚(31.23g，0.28mol)，苯硫酚钠盐(37.48g，0.28mol)，DBU(1-7,172.6g，1.13mol)和二异丙基乙基胺(219.78g,1.7mol)的DMF溶液(1L)于110℃加热反应过夜。反应混合物浓缩，残留物中加入DCM(500mL)及 水(300mL)。有机相分离、浓缩得到粗产物，加入乙酸乙酯(200mL)，过滤收集白色产物4-(2-氨基-4-甲基-7-氧代吡啶[2,3-d]嘧啶-8-基)哌啶-1-甲酸叔丁酯(5-4,56g，产率：56％)。质谱分析结果：m/z:360.20[M+H]+。硅胶薄层色谱：Rf＝0.45(DCM/MeOH＝20:1)。
第四步：4-(2-氨基-4-甲基-7-氧代吡啶[2,3-d]嘧啶-8-基)哌啶-1-甲酸叔丁酯(5-4,20g，55mmol)的DMF(300mL)溶液中加入NBS(11.83g，66mmol)，于室温搅拌1小时后，反应混合物浓缩至干，残留物中加入乙酸乙酯(300mL)及饱和碳酸氢钠溶液(300mL)。有机相分离、浓缩得到粗产物4-(2-氨基-6-溴-4-甲基-7-氧代吡啶[2,3-d]嘧啶-8-基)哌啶-1-甲酸叔丁酯(5-5,19g)，为棕色固体，不经过纯化直接用于下一步反应。质谱分析结果：m/z:438.20[M+H,79Br]+,440.20[M+H,81Br]+。硅胶薄层色谱：Rf＝0.5(DCM/MeOH＝20:1)。
第五步：4-(2-氨基-6-溴-4-甲基-7-氧代吡啶[2,3-d]嘧啶-8-基)哌啶-1-甲酸叔丁酯(5-5,19g,43mmol)，碳酸钾(18g,130mmol)及2-甲氧基吡啶-3-基硼酸(1-10,9.98g,66mmol)在DMF/H2O(5:1，240mL)中的混合物中鼓氮气5分钟，往该混合物中加入Pd(PPh3)2Cl2(3.00g)。所得混合物于100℃加热搅拌过夜。反应混合物浓缩至干，残留物用硅胶柱层析纯化，二氯甲烷/甲醇(95/5)的混合物作为洗脱剂，得到产物4-(2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧代吡啶[2,3-d]嘧啶-8-基)哌啶-1-甲酸叔丁酯(5-6)，为棕色固体(8g，产率：40％)。质谱分析结果：m/z:467.30[M+H]+。硅胶薄层色谱：Rf＝0.4(DCM/MeOH＝20:1)。
第六步：4-(2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧代吡啶[2,3-d]嘧啶-8-基)哌啶-1-甲酸叔丁酯(5-6,4.5g,9.6mmol)溶解于HCl的饱和甲醇(50mL)中，该混合物在室温下搅拌4小时，减压下浓缩，将残留物溶于水，并用乙酸乙酯洗，弃去有机层。水层用保和碳酸氢钠溶液调节pH＝8-9，然后用DCM萃取3次。将有机层合并，用硫酸钠干燥、浓缩，得到产物2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-8-(4-哌啶基)吡啶[2,3-d]嘧啶-7-酮(5-7,4g，产率：90％)，为黄绿色固体。硅胶薄层色谱：Rf＝0.1(DCM/MeOH＝5:1)。
第七步：往2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-8-(4-哌啶基)吡啶[2,3-d]嘧啶-7-酮(5-7,2.5g,6.82mmol)的二噁烷(200mL)溶液中加入亚磷酸二乙酯(HPO(OEt)2,5-8,1.9g,13.66mmol)，多聚甲醛(0.2g,6.83mmol)和乙酸(0.41g,6.83mmol)。所得混合物回流搅拌5小时后，将溶液浓缩，粗产物用制备HPLC纯化得到产物2-氨基-8-[1-(二乙氧基磷酰基甲基)-4-哌啶基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(5-9,1.0g，产率：28％，纯度95％)，为黄色固体。进一步用SFC纯化得到220mg纯产物，纯度为99％，为黄 色固体。硅胶薄层色谱：Rf＝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)。质谱分析结果：m/z:517.30[M+H]+。
下列化合物(但不局限于这些化合物)可以按照实施例5描述的相同或类似的方法合成：
Figure PCTCN2015081854-appb-000050
Figure PCTCN2015081854-appb-000051
实施例6
抑制激酶的筛选实验：
本例为实施例2中制备的化合物顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(2-4a)在DiscoveRx公司(4215Sorrento Valley Blvd,San Diego,CA92121)的KinomeScanTM(www.kinomescan.com)的体系 中在100nM化合物浓度的情况下对于98个激酶的抑制结果如表1所示：
该筛选技术的细节见Fabian,M.A.et al,Nat.,Biotechnol.2005,23,329和Karaman,M.W.et al,Nat.,Biotechnol.2008,26,127。从以上代表性的结果看，本发明中的化合物对包括mTOR、PIK3C2B、PIK3CA、PIK3CG、TYK2、DYRK1B等激酶及其突变体具有显著的抑制作用。
表1
Figure PCTCN2015081854-appb-000052
Figure PCTCN2015081854-appb-000053
实施例7
对几激酶及其亚型的生化抑制活性：本例为实施例2中制备的化合物顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(2-4a)由Reaction Biology Corporation公司(Reaction Biology Corp.,One Great Valley Parkway,Suite 2,Malvern,PA19355,USA.http://www.reactionbiology.com/webapps/main/pages/kinase.aspx)测定对mTOR、PI3K-α、PI3K-β、PI3K-γ、PI3K-δ、DYRK1B、TYK2激酶及其亚型活性的抑制。具体步骤如下：
将本发明所述的化合物溶解于二甲基亚砜(DMSO)中，配制成10mM的原液，从10mM开始按照3-倍系列稀释，做10个不同的剂量。测定四种PI3K亚型的抑制活性时，采用HTRF测定方法，ATP浓度为10μM。其他三种激酶(mTOR、DYRK1B、TYK2)测定时，其ATP浓度为它们相应的Km值。
测定结果
本发明实施例2中制备的化合物2-4a抑制7种激酶及亚型酶的IC50的值见表2：
表2
激酶 ATP浓度 实施例2-4a中制备的化合物
    IC50(μM)
mTOR 50 0.67
PI3K-α 10 0.0051
PI3K-β 10 0.0156
PI3K-γ 10 0.0992
PI3K-δ 10 0.00237
DYRK1B 20 >10
TYK2 15 >10
由上述数据可看出，本发明所述的化合物实施例2-4a对PI3K的四种亚型具有强的抑制活性，IC50值分别达到100nM以下。化合物2a对mTOR的抑制也比较明显，IC50值为670nM。该化合物对DYRK1B及TYK2的抑制活性则比较弱。
实施例8
抗肿瘤实验：本例采用实施例1中制备的反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮于A549人体肺癌细胞异种移植裸鼠动物模型中抗肿瘤实验的方法和结果如下：
实验材料
4～5周龄SPF级雌性BALB/c-nu/nu小鼠，体重16～20g，购自广东省实验动物中心，合格证编号：NO:0072659。A549肺癌细胞购自上海生命科学研究院细胞资源中心。DMEM细胞培养基、胎牛血清(FBS)及胰蛋白酶消化液来自Gibco公司。各种抗生素均购自Sigma公司。
实验方法
先进行A549肺癌细胞的培养：A549细胞株接种于含10％FBS、100U/ml青霉素、100U/ml链霉素的DMEM培养液中,在37℃、5％CO2、100％湿度的二氧化碳孵育箱中培养,接种后约48h细胞长满瓶底。然后将已长满培养瓶底80％的A549细胞消化，1000r/min离心3min后收集细胞沉淀，将细胞稀释至1×108/mL，按0.1mL/只接种于裸鼠右前腋皮下。接种肿瘤细胞第12天后开始给荷瘤裸鼠称重、测量肿瘤大小并将肿瘤大小在150～200mm3范围的小鼠随机均匀分为溶剂组(Vehicle，盐酸水溶液，pH为3)和吡啶[2,3-d]嘧啶-7-酮类化合物之一反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮(1-16)(溶解于Vehicle中，浓度为1.0mg/mL)，每组4只小鼠；其后每天给裸鼠称重并按0.1mL/10g体重通过灌胃方法口服给药(10mg/kg qd via p.o.)，每两天测量每只动物肿瘤的大小，18天后，将荷瘤小鼠颈椎脱臼处死， 取出肿瘤并称重。抑瘤率(Tumor Growth Inhibition或TGI)计算方法：实验数据以mean±SD表示；抑瘤率(TGI)＝[(V溶剂组–V治疗组)÷V溶剂组]×100％。V溶剂组为溶剂组小鼠肿瘤体积；V治疗组为治疗组小鼠肿瘤体积。
实验结果
实施例1所述本发明化合物治疗组对小鼠肿瘤的抑瘤作用：溶剂组和治疗组分别喂溶剂和药物溶液18天后，溶剂组和治疗组动物的肿瘤平均体积分别为1179.7±420.6mm3(n＝4)和550.8±76.2(n＝4)；因此，治疗组的抑瘤率(TGI)为53％。与初始肿瘤体积相比，治疗组肿瘤有明显的缩小。实验曲线对照见图1。
从上述抑瘤实验结果来看，本发明中的代表性化合物在异种移植裸鼠动物模型中显示出显著的肿瘤抑制作用，口服给药，10mg/kg，每天一次，18天后肿瘤抑制率达53％。治疗组的动物体重变化很小，这说明药物没有明显的毒性。
实施例9
抗肿瘤实验：采用实施例8相同的方法，本例使用的化合物是实施例2-4b中制备的反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮。肿瘤模型为A549人体肺癌细胞异种移植裸鼠动物模型。
实验结果
实施例2-4b所述本发明化合物治疗组对小鼠肿瘤的抑瘤作用见图2。从上述抑瘤实验结果来看，本发明中的代表性化合物在异种移植裸鼠动物模型中显示出肿瘤抑制作用。
实施例10
抗肿瘤实验：采用实施例8相同的方法，本例使用的化合物是实施例3中制备的反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺。肿瘤模型为A549人体肺癌细胞异种移植裸鼠动物模型。
实验结果
实施例3所述本发明化合物治疗组对小鼠肿瘤的抑瘤作用见图3。从上述抑瘤实验结果来看，本发明中的代表性化合物在异种移植裸鼠动物模型中显示出肿瘤抑制作用。
实施例11
抗肿瘤实验：采用实施例8相同的方法，本例使用的化合物是实施例5中制备的2-氨基-8-[1-(二乙氧基磷酰基甲基)-4-哌啶基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮。肿瘤模型为A549人体肺癌细胞异种移植裸鼠动物模型。
实验结果
实施例5所述本发明化合物治疗组对小鼠肿瘤的抑瘤作用见图4。实验进行18天后，处死动物后取出肿瘤，图4显示的是给药组与溶剂对照组肿瘤重量对比。从上述抑瘤实验结果来看，本发明中的代表性化合物在异种移植裸鼠动物模型中显示出肿瘤抑制作用。
实施例12
抗肿瘤实验：采用实施例8类似的方法，本例使用的化合物是实施例2-4a中制备的顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮。肿瘤模型为PC3人体前列腺癌细胞异种移植裸鼠动物模型。
实验结果
实施例2-4a所述本发明化合物治疗组对小鼠肿瘤的抑瘤作用见图5。从上述抑瘤实验结果来看，本发明中的代表性化合物在异种移植裸鼠动物模型中显示出显著的肿瘤抑制作用，口服给药，10mg/kg，每天一次，21天后肿瘤抑制率达73％。治疗组的动物体重变化很小，这说明药物没有明显的毒性。
实施例13
抗肿瘤实验：采用实施例8类似的方法，本例使用的化合物是实施例2-4a中制备的顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮。肿瘤模型为U87MG人体胶质母细胞瘤细胞异种移植裸鼠动物模型。
实验结果
实施例2-4a所述本发明化合物治疗组对小鼠肿瘤的抑瘤作用见图6。从上述抑瘤实验结果来看，本发明中的代表性化合物在异种移植裸鼠动物模型中显示出显著的肿瘤抑制作用，口服给药，2.5mg/kg，每天一次，14天后肿瘤抑制率达64％。治疗组的动物体重变化很小，这说明药物没有明显的毒性。
实施例14：
片剂(毫克/片)
实施例1制备的化合物：100；乳糖，Ph EUR：182.75；
羧甲基纤维素钠：12.0；玉米淀粉浆(5w/v％)：2.25；
硬脂酸镁：3.0。
实施例15：
片剂(毫克/片)
实施例5制备的化合物：100，其它物质含量同实施例14。
实施例16：
片剂(毫克/片)
实施例2-4a制备的化合物：50；乳糖，Ph EUR：223.75；
羧甲基纤维素钠：6.0；玉米淀粉：15.0；
聚乙烯吡咯烷酮(5w/v％)：2.25；硬脂酸镁：3.0。
实施例17：
片剂(毫克/片)
实施例2-4a制备的化合物：50，其它物质含量与实施例16相同。
实施例18：
片剂(毫克/片)
实施例3制备的化合物：1.0；乳糖，Ph EUR：93.25；
羧甲基纤维素钠：4.0；玉米淀粉浆(5w/v％)：0.75；
硬脂酸镁：76。
实施例19：
片剂(毫克/片)
实施例3制备的化合物：1.0，其它物质含量与实施例18相同。
实施例20：
胶囊(毫克/胶囊)
实施例2-4a制备的化合物：10.0；乳糖，Ph EUR：488.5；
镁：1.5。
实施例21：
药物组成及制剂
胶囊(毫克/胶囊)
实施例2-4a制备的化合物：10.0，其它物质含量与实施例20相同。
实施例22：
药物组成及制剂
注射剂(50毫克/毫升)
实施例4制备的化合物：5％；1M氢氧化钠溶液:15％；
0.1M盐酸溶液(调节pH＝7.6)；聚乙二醇400：5％；
注射用水调节至100％。
实施例23：
药物组成及制剂
注射剂(50毫克/毫升)
实施例2-4b制备的化合物：5％，其它物质含量与实施例22相同，最后用注射用水调节至100％。
实施例24：
药物组成及制剂
注射剂(10毫克/毫升)
实施例2-4a制备的化合物：1％；磷酸氢二钠BP：3.6％；
0.1M氢氧化钠溶液：15％；注射用水调节至100％。
实施例25：
药物组成及制剂
注射剂(10毫克/毫升)
实施例5制备的化合物：1％，其它物质含量与实施例32相同，注射用水调节至100％。
实施例26：
药物组成及制剂
注射剂(1毫克/毫升)(pH调节至6)
实施例1制备的化合物：0.1％；磷酸氢二钠BP：2.26％；
柠檬酸：0.38％；聚乙二醇400：3.5％；
注射用水调节至100％；
实施例27：
药物组成及制剂
注射剂(1毫克/毫升)(pH调节至6)
实施例2-4a制备的化合物：0.1％，其它物质的含量与实施例26相同，最后用注射用水调节至100％。
实施例28：
药物组成及制剂
气雾剂(毫克/毫升)
实施例1制备的化合物：10；失水山梨醇油酸酯：13.5；
三氯氟甲烷：910.0；二氯二氟甲烷：490.0。
实施例29：
药物组成及制剂
气雾剂(毫克/毫升)
实施例3制备的化合物：10，其它物质含量与实施例28相同。
实施例30：
药物组成及制剂
气雾剂(毫克/毫升)
实施例2-4a制备的化合物：0.2；失水山梨醇油酸酯：0.27；
三氯氟甲烷：70.0；二氯二氟甲烷：280.0；
二氯四氟乙烷：1094.0。
实施例31：
药物组成及制剂
气雾剂(毫克/毫升)
实施例2-4a制备的化合物：0.2，其它物质含量与实施例30相同。
实施例32：
药物组成及制剂
气雾剂(毫克/毫升)
实施例5制备的化合物：2.5；失水山梨醇油酸酯：3.38；
三氯氟甲烷：67.5；二氯二氟甲烷：1086.0；
二氯四氟乙烷：191.60。
实施例33：
药物组成及制剂
气雾剂(毫克/毫升)
实施例2-4b制备的化合物：2.5，其它物质含量与实施例32相同。
实施例34：
药物组成及制剂
气雾剂(毫克/毫升)
实施例2-4a制备的化合物：2.5；大豆卵磷脂：2.7；
三氯氟甲烷：67.5；二氯二氟甲烷：1086.0；
二氯四氟乙烷：191.60。
实施例35：
药物组成及制剂
气雾剂(毫克/毫升)
实施例2-4a制备的化合物：2.5，其它物质含量与实施例34相同。
实施例36：
药物组成及制剂
软膏(/毫升)
实施例2-4a制备的化合物：40毫克；乙醇：300微升；
水：300微升；1-十二烷基氮杂环庚酮：50微升；
丙二醇：至1毫升。
实施例37：
软膏(/毫升)
实施例2-4a制备的化合物：40毫克，其它物质含量与实施例36相同。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。
工业实用性
本发明公开了一种含磷吡啶并嘧啶酮类化合物或其在药学上可接受的盐，同时还公开了该化合物的制备方法、包含所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物的药物组合物及其应用。这类化合物是蛋白激酶(例如PI3K)抑制剂，可用于治疗因蛋白激酶活性异常所引起的疾病，例如肿瘤，除肿瘤外还可以为银屑病(或称牛皮癣)、肝硬化、气管炎、风湿性关节炎、红斑狼疮、糖尿病、涉及血管新生的疾病、免疫系统疾病、肾脏疾病、癫痫、神经退行性疾病等，本发明具有很强的工业实用性。

Claims (18)

  1. 一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，该化合物分子结构式如式(I)所示：
    Figure PCTCN2015081854-appb-100001
    式中，
    Ar为芳基或杂芳基，且Ar中的氢可被1-5个相同或不同的G1取代；
    X为C-R1或N；
    A表示C1-6烷基、C＝O或一个共价键，且当A为C1-6烷基时，其中的氢可被1-5个相同或不同的G2取代；
    L表示O、N-R2、S(＝O)m或一个共价键；
    J表示C1-6烷基或一个共价键，且J中的氢可被1-5个相同或不同的G3取代；
    R和R’分别独立地表示H、OH、卤素、C1-6烷基、C3-6环烷基、C3-12杂脂环基、C1-6烷氧基、C3-6环烷氧基或C3-12杂脂环氧基，且R和R’中的氢可被1-5个相同或不同的G4取代，R和R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环可另外包含一个或多个O、N或S(＝O)m杂原子；
    其中：
    G1、G2、G3及G4分别独立地表示H、-CN、-CF3、-OCF3、-NO2、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C6芳基、C5-6杂芳基、C3-12杂脂环基、R3O-、R3R4N-、R3S(＝O)m-、R3R4NS(＝O)m-、R5C(＝O)-、R3R4NC(＝O)-、R3OC(＝O)-、R5C(＝O)O-、R3R4NC(＝O)O-、R5C(＝O)NR3-、R3R4NC(＝O)NR6-、R3OC(＝O)NR6-、R3S(＝O)mNR6-、R3R4NS(＝O)mNR6-、R3R4NC(＝NR7)NR6-、R3R4NC(＝CHNO2)NR6-、R3R4NC(＝N-CN)NR6-、R3R4NC(＝NR7)-、R3S(＝O)(＝NR7)NR6-或R3R4NS(＝O)(＝NR7)-；
    R1、R2、R3、R4、R5、R6及R7分别独立地表示H、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C6芳基、C5-6杂芳基或C3-12杂脂环基；当R3和R4连接于同一氮原子上 时，可与该氮原子一起形成一个C3-12杂脂环，这个C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；且R1、R2、R3、R4、R5、R6及R7中的氢可被1-5个相同或不同的卤素、-CN、-OH、C1-6烷基或C3-6环烷基取代；
    m为0、1或2。
  2. 根据权利要求1所述的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，其特征在于当Ar为取代吡啶基，X为C-R1或N时，所述化合物的结构如式(Ia)或(Ib)所示：
    Figure PCTCN2015081854-appb-100002
    式中所述，
    R1表示氢或C1-6烷基；
    A表示C1-6烷基、C＝O或一个共价键，且当A为C1-6烷基时，其中的氢可被1-5个相同或不同的G2取代；
    L表示O、N-R2或S(＝O)m或一个共价键；
    J表示C1-6烷基或一个共价键，且J中的氢可被1-5个相同或不同的G3取代；
    m、G1、G2、G3、R、R’和R2的定义同权利要求1。
  3. 根据权利要求2所述的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物(Ia)或其在药学上可接受的盐，其特征在于当取代吡啶基为吡啶-3-基，其取代基G1为G11，R1为氢，R为RR，R’为R’R’，A为一个共价键时，所述化合物的结构如式(Ic)或(Id)所示：
    Figure PCTCN2015081854-appb-100003
    式中所述，
    G11表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基；
    L表示O或N-R2；
    J表示C1-6烷基，且J中的氢可被1-5个相同或不同的G3取代；
    RR和R’R’分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，且RR和R’R’中的氢可被1-5个相同或不同的G4取代，RR和R’R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；
    m、G3、G4和R2的定义同权利要求1。
  4. 根据权利要求2所述的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物(Ia)或其在药学上可接受的盐，其特征在于当取代吡啶基为吡啶-3-基，其取代基G1为G11，R1为氢，R为RR，R’为R’R’时，所述化合物的结构如式(Ie)或(If)所示：
    Figure PCTCN2015081854-appb-100004
    式中所述，
    G11表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基；
    A表示C＝O或C1-6烷基，且当A为C1-6烷基时，其中的氢可被1-5个相同或不同的G2取代；
    L表示O或N-R2；
    J表示C1-6烷基，且J中的氢可被1-5个相同或不同的G3取代；
    RR和R’R’分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，且RR和R’R’中的氢可被1-5个相同或不同的G4取代，RR和R’R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；
    m、G2、G3、G4和R2的定义同权利要求1。
  5. 根据权利要求2所述的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物(Ib)或其在药学上可接受的盐，其特征在于当取代吡啶基为吡啶-3-基，其取代基G1为G11，R为RR，R’为R’R’时，所述化合物的结构如式(Ig)所示：
    Figure PCTCN2015081854-appb-100005
    式中所述，
    G11表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基；
    J表示C1-6烷基，且J中的氢可被1-5个相同或不同的G3取代；
    RR和R’R’分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，且RR和R’R’中的氢可被1-5个相同或不同的G4取代，RR和R’R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环可另外包含一个或多个O、N或S(＝O)m杂原子；
    m、G3和G4的定义同权利要求1。
  6. 根据权利要求1所述的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，其特征在于所述化合物或其在药学上可接受的盐为下列任意一种化合物：
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡 啶[2,3-d]嘧啶-7-酮；
    反式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
    顺式-4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    2-氨基-8-[1-(二乙氧基磷酰基甲基)-4-哌啶基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-4-[2-氨基-6-(6-二甲氨基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
    顺式-4-[2-氨基-6-(6-二甲氨基-3-吡啶基)-4-甲基-7-氧基吡啶[2,3-d]嘧啶-8-基]-N-(二乙氧基磷酰基甲基)环己基甲酰胺；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基甲基)环己基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    2-氨基-8-[1-(二乙氧基磷酰基甲基)-4-哌啶基]-6-(6-二甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-乙基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氧基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲氨基)环己基]-6-(6-甲氨基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(甲基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(甲基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(乙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(乙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(正丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(正丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(异丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(异丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-2-氨基-8-[4-(二乙氧基磷酰基甲基(环丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-2-氨基-8-[4-(二乙氧基磷酰基甲基(环丙基)氨基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-8-[4-(二乙氧基磷酰基甲氧基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3- 吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    顺式-8-[4-(二乙氧基磷酰基甲氧基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-8-[4-(二乙氧基磷酰基甲氨基)环己基]-2-(2,5-二甲基吡咯-1-基)-6-(6-甲氧基-3-吡啶基)-4-甲基吡啶[2,3-d]嘧啶-7-酮；
    反式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-乙氧基-磷酸；
    顺式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-乙氧基-磷酸；
    反式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-磷酸；
    顺式-[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己氧基]甲基-磷酸；
    反式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-乙氧基-磷酸；
    顺式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-乙氧基-磷酸；
    反式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-磷酸或
    顺式-[[4-[2-氨基-6-(6-甲氧基-3-吡啶基)-4-甲基-7-氧基-吡啶并[2,3-d]嘧啶-8-基]环己基]氨基]甲基-磷酸。
  7. 根据权利要求1～6任一项所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，其特征在于所述药学上可接受的盐为所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物与无机酸、有机酸、无机碱、有机碱通过化学反应形成的盐。
  8. 权利要求1～7任一项所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的消旋体或对映异构体。
  9. 一种含磷吡啶并[2,3-d]嘧啶-7-酮类化合物，该化合物分子结构式如式(IIa)、(IIb)或(IIc)：
    Figure PCTCN2015081854-appb-100006
    式中，
    Ar’为芳基或杂芳基，且Ar’中的氢可被1-5个相同或不同的R8取代；
    R2表示H、C1-6烷基、C3-6环烷基或C3-12杂脂环基，且R2中的氢可被1-5个相同或不同的卤素、-CN、-OH、C1-6烷基或C3-6环烷基取代；
    R和R’分别独立地表示H、OH、卤素、C1-6烷基、C3-6环烷基、C3-12杂脂环基、C1-6烷氧基、C3-6环烷氧基或C3-12杂脂环氧基，且R和R’中的氢可被1-5个相同或不同的R9取代，R和R’还可与相连的磷原子一起形成C3-12杂脂环，所述C3-12杂脂环可另外包含一个或多个O、N或S(＝O)m杂原子；
    其中：
    R8及R9分别独立地表示H、-CN、-CF3、-OCF3、-NO2、卤素、C1-6烷基、C3-6环烷基、C3-12杂脂环基、C1-6烷氧基、C1-6环烷氧基、C3-12杂脂环氧基或R10R11N-；其中，R10及R11分别独立地表示H、C1-6烷基、C3-6环烷基或C3-12杂脂环基；当R10和R11连接于同一氮原子上时，可与该氮原子一起形成一个C3-12杂脂环，这个C3-12杂脂环还可另外包含一个或多个O、N或S(＝O)m杂原子；
    m为0、1或2。
  10. 根据权利要求9所述的含磷吡啶并[2,3-d]嘧啶-7-酮类化合物，其特征在于所述化合物的结构如式(IIaa)、(IIbb)或(IIcc)所示：
    Figure PCTCN2015081854-appb-100007
    R2表示氢、C1-6烷基、C3-6环烷基或C3-12杂脂环基，优选为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基或吗啉基，进一步优选为氢、甲基、乙基、正丙基、乙丙基、环丙基、氧杂环丁基、四氢呋喃基或四氢吡喃基，更进一步优选为氢、甲基、乙基、异丙基、环丙基，且这些基团可被1-5个卤素、-CN、-OH或C1-6烷基取代；
    R88表示氢、卤素、-OCF3、-CF3、-CN、-NMe2、C1-6烷基或C1-6烷氧基，优选为卤素、-OCF3、-OCH3、-OCH2CH3或-NMe2，进一步优选为-OCH3或-NMe2；
    R12和R13分别独立地表示-OH、卤素、C1-6烷基或C1-6烷氧基，优选为-OH或C1-6烷氧基，进一步优选为C1-6烷氧基，更进一步优选为甲氧基、乙氧基、正丙氧基或异丙氧基。
  11. 包含权利要求1～7任一项所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，或权利要求8所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的消旋体或对映异构体的药物组合物。
  12. 权利要求11所述的药物组合物，其特征在于所述药物组合物除了包含权利要求1～7任一项所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，或权利要求8所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的消旋体或对映异构体以外，还包含一种或几种药学上可接受的载体或稀释剂。
  13. 如权利要求11或12所述的药物组合物，其特征在于所述药物组合物的制剂形式为：口服剂、注射剂、肛塞剂、鼻孔吸入剂、滴眼剂或皮肤贴剂。
  14. 权利要求1-7任一项所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐，或权利要求8所述含磷吡啶并[2,3-d]嘧啶-7-酮类化合物或其在药学上可接受的盐的消旋体或对映异构体，或权利要求11-13任一项所述药物组合物在治疗因蛋白激酶异常活性所引起的疾病中的应用。
  15. 权利要求14所述的应用，其特征在于所述的蛋白激酶为PI3K或mTOR，优选为PI3K，更进一步优选为PI3K-α、PI3K-β、PI3K-γ及PI3K-δ。
  16. 权利要求14所述的应用，其特征在于所述的疾病为银屑病、肝硬化、气管炎、风湿性关节炎、红斑狼疮、糖尿病、涉及血管新生的疾病、眼睛疾病、免疫系统疾病、心血管疾病、癫痫、神经退行性疾病、阿尔茨海默氏病、亨廷顿氏病或帕金森氏症。
  17. 权利要求14所述的应用，其特征在于所述的疾病为肿瘤，所述肿瘤包括实体瘤和液体瘤。
  18. 权利要求17所述的应用，其特征在于所述的肿瘤包括：肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃 癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、膀胱癌、肾或输尿管癌、肾癌、中枢神经中枢系统赘生物、脊柱轴肿瘤、垂体腺瘤、胃肠间质肿瘤、结肠直肠癌、非小细胞肺癌、小细胞肺癌、肥大细胞增多症、胶质瘤、肉瘤和淋巴瘤中的一种或任意几种的组合。
PCT/CN2015/081854 2014-08-13 2015-06-18 一种含磷吡啶并嘧啶酮类化合物或其药学上可接受的盐、药物组合物及其应用 WO2016023401A1 (zh)

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