[go: up one dir, main page]

WO2015192761A1 - 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物 - Google Patents

作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物 Download PDF

Info

Publication number
WO2015192761A1
WO2015192761A1 PCT/CN2015/081519 CN2015081519W WO2015192761A1 WO 2015192761 A1 WO2015192761 A1 WO 2015192761A1 CN 2015081519 W CN2015081519 W CN 2015081519W WO 2015192761 A1 WO2015192761 A1 WO 2015192761A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
mmol
alkyl
compound
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/081519
Other languages
English (en)
French (fr)
Inventor
关慧平
吴成德
于涛
黄磊
郝冬玲
高波
孙继奎
施能扬
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CISEN PHARMACEUTICAL Co Ltd
Medshine Discovery Inc
Original Assignee
CISEN PHARMACEUTICAL Co Ltd
Medshine Discovery Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201410271554.5A external-priority patent/CN105461712B/zh
Application filed by CISEN PHARMACEUTICAL Co Ltd, Medshine Discovery Inc filed Critical CISEN PHARMACEUTICAL Co Ltd
Priority to CA2952992A priority Critical patent/CA2952992C/en
Priority to JP2017518398A priority patent/JP6386177B2/ja
Priority to EP15810204.6A priority patent/EP3159342B1/en
Priority to RU2017100119A priority patent/RU2658912C1/ru
Priority to BR112016029825-0A priority patent/BR112016029825B1/pt
Priority to US15/319,728 priority patent/US9868737B2/en
Publication of WO2015192761A1 publication Critical patent/WO2015192761A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • the present invention relates to a pyrido[1,2-a]pyrimidinone analog as an mTOR/PI3K inhibitor, and in particular, the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • PI3K pathway is the most frequently mutated part of human cancer cells, which can lead to cell proliferation, activation, and amplification of signals.
  • PI3K and mTOR are the two most important kinases in the PI3K signaling pathway.
  • PI3 kinase (phosphatidylinositol 3-kinase, PI3Ks) belongs to the family of lipid kinases and is capable of phosphorylating the 3'-OH end of the inositol ring of phosphatidylinositol.
  • Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase composed of the regulatory subunit p85 or p101 and the catalytic subunit p110, which catalyzes the phosphatidylinositol by phosphatidylinositol.
  • PIP2 phosphatidylinositol 3,4,5-trisphosphate
  • PIP3 phosphatidylinositol 3,4,5-trisphosphate
  • PTEN phosphatase and stretching homolog deleted on chromosome ten dephosphorylates PIP3 to form PIP2, thereby achieving negative regulation of PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting apoptosis.
  • the frequent occurrence of PI3K gene mutation and amplification in cancer and the loss of PTEN in cancer suggest a close relationship between PI3K and tumorigenesis.
  • mTOR (mammalian rapamycin target protein) is a silk/threonine protein kinase present in the cytoplasm and belongs to the phosphatidylinositol 3-kinase-associated kinase family, which plays an important role in regulating signaling in many pathways. effect.
  • mTOR has been identified as a downstream target for PI3K/Akt.
  • Two different mTOR complexes, mTORC1 and mTORC2 are currently found in cells. The two functions respectively, the main function of mTORC1 is to stimulate cell growth and proliferation, while mTORC2 regulates cell survival and cytoskeleton by activating AKT, PKC and other kinases.
  • Studies have shown that the mTOR signaling pathway is involved in the development of cancer, and that the simultaneous inhibition of the activity of two mTOR complexes in cancer cells has a broader and more effective anticancer effect.
  • PI3K-mTOR double inhibitors can block multiple links in information transmission at the same time, which will more effectively block the transmission of kinase information, thus overcoming or delaying the development of drug resistance.
  • E is selected from C 1-6 alkyl, 3-10 membered cycloalkyl or heterocycloalkyl optionally substituted by 1, 2 or 3 R 3 ;
  • A, T are each independently selected from N or C (R 3 );
  • X, Y, Z is selected from N, and the remainder is selected from C(R 3 );
  • n 1 is independently selected from 0, 1 , 2 or 3;
  • R 1-3 are respectively selected from the group consisting of H, F, Cl, Br, I, CN, OR a , N(R b )(R c ), C 1-3 alkyl optionally substituted by R d ,
  • D 2 is selected from -C(R a )(R a )-;
  • n is selected from 1, 2, 3, 4, 5 or 6;
  • R a , R b , R c are each independently selected from H, optionally R d -substituted C 1-6 alkyl or C 3-6 cycloalkyl;
  • R e is selected from H, optionally R d -substituted C 1-6 alkyl or alkoxy, optionally R d -substituted C 3-6 cycloalkyl or cycloalkoxy;
  • R d is selected from the group consisting of F, Cl, Br, I, CN, OH, CHO, COOH, CH 3 , CF 3 , CH 3 O, CH 3 CH 2 O, and the number of Rd is selected from 0, 1, 2 or 3;
  • any two R 1 , between R a and R a in the same D 2 , between two D 2 , or between R a and D 2 are co-bonded to the same carbon atom or oxygen
  • One or two 3, 4, 5 or 6 membered carbocyclic or oxo rings are formed on the atom, wherein the number of oxygen atoms is 1 or 2.
  • the above E is selected from the R 3 substituted C 1-6 alkyl or C 3-6 cycloalkyl, R 3 is selected from the number 1, 2 or 3, or E is selected from
  • G 1 to 5 0, 1, 2 or 3 of G 1 to 5 is selected from N, and the remainder is selected from C(R 3 );
  • G 7 to 9 0, 1 or 2 of G 7 to 9 is selected from N, and the remainder is selected from C(R 3 );
  • G 10 to 16 0, 1, 2, 3 or 4 of G 10 to 16 is selected from N, and the remainder is selected from C(R 3 );
  • G 17 is selected from N or C(R 3 );
  • the above E is selected from the group consisting of methyl, ethyl, propyl optionally substituted by 1, 2 or 3 R 3 ,
  • E is selected from
  • 0 or 1 of the above X, Y, and Z is selected from N, and the remainder is selected from the group consisting of CH, C(CH 3 ), C(CF 3 ), CCl, and CF.
  • the above A and T are each independently selected from N, CH, C(CH 3 ), C(CF 3 ), CCl, CF; or, B is selected from NH, N(CH 3 ) or N (CF 3 ).
  • a ring formed between any two of R 1 , between R a and R a in the same D 2 , between two D 2 , or between R a and D 2 It is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and 1,3-dioxopentacyclyl.
  • the above R 1-3 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH 2 , methyl, ethyl, propyl, methoxy, ethoxy, methylamino , dimethylamino, halomethyl, haloethyl, halopropyl, aminomethyl, aminoethyl, aminopropyl, cyclopropyl,
  • the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of Compound 1 to Compound 284.
  • C 1-10 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 ;
  • C 3-10 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 .
  • C 1-10 alkyl or heteroalkyl, C 3-10 cyclo or heterocycloalkyl, C 1-10 alkyl or heteroalkyl substituted by C 3-10 cycloalkyl or heterocycloalkyl includes, but is not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, Bicarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydrogen Iodate, hydroxyl, hydroxynaphthalene, isethionate, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, Phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier means capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance and
  • Any formulation or carrier medium that is non-toxic to the host or patient representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof.
  • Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.
  • alkyl and heteroalkyl radicals (including what are commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl)
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thioalkyl group Oxyl a group or an aralkyl group.
  • each R group is independently selected, as when more than one R', R", R"' Each of these groups, R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can form a 5-, 6- or 7-member with the nitrogen atom. ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • Bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ) -C 10 represents 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • alkyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene Base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC
  • Figure 1 is a result of in vivo pharmacodynamic experiments of a test drug on a subcutaneous xenograft tumor model of human ovarian cancer SK-OV-3 cells, wherein:
  • mice in each group is 6;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • the vehicle used for the test compound and the Vehicle group was: 1% MC, PO, QD x 19 days.
  • Figure 2-1 is an experimental result of in vivo pharmacodynamics experiment 1 for studying a subcutaneous xenograft tumor model of human prostate cancer PC-3M cells, wherein:
  • mice in each group is 7;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly.
  • Figure 2-2 shows the results of an in vivo pharmacodynamic experiment 2 of a subcutaneous xenograft tumor model of human prostate cancer PC-3M cells.
  • mice in each group is 6;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • the vehicle used for the test compound and the Vehicle group was: 1% DMSO + 99% (1% MC), PO, QD x 2W.
  • Figure 2-3a shows the results of an in vivo pharmacodynamic experiment 3 of a test model for subcutaneous xenograft tumor models of human prostate cancer PC-3M cells, wherein:
  • mice in each group is 6;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • PF0512384 solvent is 30% propylene glycol + 5% Tween 80 + 65% D5W, IV, QW x 2W;
  • the vehicle used for the other test compounds and the Vehicle group was: 5% DMSO + 60% PEG 400 + 35% water, PO, QD x 2W.
  • Figure 2-3b is an experimental result of in vivo pharmacodynamics experiment 3 for studying a subcutaneous xenograft tumor model of human prostate cancer PC-3M cells, wherein:
  • mice in each group is 6;
  • Dosing volume 10 ⁇ l/g based on the body weight of the mouse. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly;
  • PF0512384 solvent is 30% propylene glycol + 5% Tween 80 + 65% D5W, IV, QW x 2W;
  • the vehicle used for the other test compounds and the Vehicle group was: 5% DMSO + 60% PEG 400 + 35% water, PO, QD x 2W.
  • Reaction conditions a) triethyl orthoformate, 2,2-dimethyl-1,3-dioxan-4,6-dione, heating; EtOH, heating; b) diphenyl ether, reflux ; c) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate, dioxane Six rings, water, heating.
  • Triethyl orthoformate 25.8 g, 0.174 mol
  • 2,2-dimethyl-1,3-dioxane-4,6-dione (25.1 g, 0.174 mol) were placed in three necks
  • the reaction was stirred at 60 °C for 2 hours in a round bottom flask.
  • a solution of 2-amino-5-bromopyridine (30 g, 0.174 mol) in ethanol (150 mL) was added dropwise to the mixture.
  • the reaction solution was stirred at 60 °C for 2 hours.
  • the mixture was cooled to 25 ° C.
  • EtOAc EtOAc
  • Reaction conditions a) triethyl orthoformate, 2,2-dimethyl-1,3-dioxan-4,6-dione, heating; EtOH, heating; b) diphenyl ether, reflux ; c) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate, dioxane Ring, water, heat.
  • Triethyl orthoformate (9.9 g, 0.0689 mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (10.8 g, 0.073 mol) were placed in three necks The reaction was stirred at 60 °C for 2 hours in a round bottom flask. A solution of 5-bromo-2-aminopyrazine (12 g, 0.0689 mol) in ethanol (50 mL) was added dropwise to the mixture. The reaction solution was stirred at 60 °C for 2 hours. The mixture was cooled to 25 mp. EtOAc (EtOAc)
  • Reaction conditions a) triethyl orthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; ethanol, heating; b) diphenyl ether, reflux ; c) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate, dioxane Ring, water, heat.
  • Trimethyl orthoformate (4.39 g, 0.03 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (4.03 g, 0.028 mmol) were placed in equipment Mechanically stirred three-neck round bottom flask. The resulting suspension was stirred at 60 °C for 2 hours. A solution of 5-bromopyrazin-2-amine (5 g, 0.027 mmol) dissolved in ethanol (50 mL) was added dropwise to this mixture. The reaction solution was then stirred at 60 °C for 2 hours. The reaction solution was cooled to 25 degrees and filtered. The filter cake was washed with EtOAc (EtOAc (EtOAc)
  • Reaction conditions a) select F reagent, acetonitrile, heating; b) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride, etc.), potassium carbonate, dioxane, water, and heating.
  • Reaction conditions a) ammonium hydroxide, ammonium chloride, heating: b) triethoxymethane, 2,2-dimethyl-1,3-dioxan-4,6-dione, heating ; ethanol, heating; c) diphenyl ether, reflux; d) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride, etc.), potassium carbonate, dioxane, water, and heating.
  • reaction solution was stirred at 100 °C for 2 hours under microwave reaction conditions. Liquid phase mass spectrometry showed that the reaction had ended.
  • the reaction solution was filtered, and the filtrate was concentrated to give a crude material.
  • the crude product is separated by preparative high performance liquid chromatography to obtain a product.
  • Reaction conditions a) ethyl 2-methyl-3-oxosuccinate, ethanol, heating; b) diphenyl ether, heating; c) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium) , [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate, 1,4-dioxane, water, heating.
  • the reaction solution was stirred at 90 °C for 1 hour under microwave reaction conditions.
  • the liquid phase mass spectrum showed the end of the reaction, the reaction solution was filtered, and the filtrate was dried to give a crude product.
  • the crude product was isolated using preparative high performance liquid chromatography to give the product as a white solid.
  • Reaction conditions a) concentrated sulfuric acid, nitric acid; b) iron powder, ammonium chloride, heating; c) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-double (two Phenylphosphine)ferrocene]palladium chloride, etc.), potassium carbonate, 1,4-dioxane, water, heating.
  • Reaction conditions a) tert-butyldimethylsilyl chloride, 1 hydrogen-imidazole; b) 1-tert-butoxy-N,N,N',N'-tetramethyldiaminomethane, heating; c) 2-amino-5-bromopyridine, acetic acid, heating; d) acetic acid, microwave; e) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium chloride, etc.), potassium carbonate, dioxane, water, heating.
  • Reaction conditions a) 1-tert-butoxy-N,N,N',N'-tetramethyldiaminomethane, heating; b) 2-amino-5-bromopyridine, acetic acid, heating; c) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate, dioxane, water ,heating.
  • palladium reagent tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.
  • Reaction conditions a) NBS, MeCN; 2) triethyl orthoformate, 2,2-dimethyl-1,3-heterocyclohexane-4,6-dione, heating; EtOH, heating; c) Phenyl ether, reflux; d) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate , dioxane, water, heating.
  • Reaction conditions a) triethyl orthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; EtOH, heating; b) diphenyl ether, reflux ; c) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate, dioxane Ring, water, heat.
  • Triethyl orthoformate (1.75 g, 0.01 mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.61 g, 0.014 mol) were placed with The stirred three-necked round bottom flask was stirred at 60 degrees for 2 hours.
  • a solution of 5-bromopyridin-2-amine (2 g, 0.017 mol) in ethanol (20 mL) was added dropwise to the mixture.
  • the reaction solution was stirred at 60 °C for 2 hours.
  • the reaction mixture was cooled to EtOAc (EtOAc m.)
  • Reaction conditions a) 1-chloropyrrolidine-2,5-dione, N,N-dimethylformamide; b) R-boric acid (borate), potassium carbonate, catalyst palladium (tetrakistriphenylphosphine palladium, etc. ), dioxane, water, heating.
  • Reaction conditions a) sulfuric acid, ethanol, heating; b) 1-tert-butoxy-N,N,N',N'-tetraethyldiamine, heating; c) 5-bromopyridin-2-amine, Acetic acid, heating; d) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc.), potassium carbonate, Dioxane, water, heated.
  • Reaction conditions a) potassium carbonate, N,N-dimethylformamide; b) 1-tert-butoxy-N,N,N',N'-tetraethyldiamine; c) 5-bromopyridine 2-amine, acetic acid, heating; 4) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride, etc. ), dioxane, water, heating.
  • the resulting reaction solution was microwaved at 100 degrees for two hours. The reaction was detected by liquid phase mass spectrometry. After the reaction was completed, the reaction mixture was filtered and concentrated to give a crude product. The crude product was isolated by preparative liquid chromatography to give the title compound.
  • Reaction conditions a) ethyl acetoacetate, polyphosphoric acid; b) R boric acid (borate), palladium reagent (tetrakistriphenylphosphine palladium, [1,1'-bis(diphenylphosphino))ferrocene ]Palladium chloride, etc.), potassium carbonate, dioxane, water, and heating.
  • Morpholine (2.00 g, 22.9 mmol), methyl bromoacetate (4.80 g, 31.4 mmol), potassium hydroxide (1.33 g, 23.6 mmol), potassium carbonate (3.30 g, 23.9 mmol) and dichloromethane (50 mL) It was placed in a 100 mL round bottom flask, stirred at room temperature for 12 hours, and then stirred at 40 degrees for 6 hours. TLC showed the reaction was completed, the reaction mixture was cooled to room temperature, washed with brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and evaporated.
  • Methyl 2-morpholinoacetate (1.80 g, 11.3 mmol), 1-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine (2.36 g, 13.6 mmol) And toluene (50 mL) was placed in a 100 mL round bottom flask, and the reaction was stirred at 120 degrees for 10 hours. The reaction was completed with EtOAc (EtOAc).
  • MCF-7 cells were seeded into 96-well plates at a density of 2.5 ⁇ 10 4 per well (the culture medium used was a complete medium containing 10% FBS).
  • the culture medium in the well was removed the next day, and a certain concentration (primary screening) or a series of concentrations (IC 50 test) of the compound was dissolved in the serum-free medium, and the cells were added to the 96-well plate. hour.
  • Enhancer Solution needs to be removed from the refrigerator in advance.
  • Enhancer solution (Enhancer Solution) was diluted 10-fold with 5X Lysis Buffer to prepare a concentrated lysate.
  • the culture solution in the well was aspirated and rinsed once with PBS.
  • the antibody mixture is prepared by mixing the medium antibody reagent and the enzyme-labeled antibody reagent in equal proportions. Note that when preparing the antibody mixture, do not vortex)
  • the substrate mixture should be used as needed. One hundred microliters of the substrate mixture was added to each well, and the microplate was sealed with tin foil paper and incubated on a microplate shaker for 10 minutes at room temperature.
  • a ⁇ 50 nM; 50 nM ⁇ B ⁇ 100 nM; 100 nM ⁇ C ⁇ 250 nM; 250 nM ⁇ D; NT means untested.
  • the compounds of the present invention have significant inhibitory effects on mTOR/PI3K.
  • test sample was evaluated for inhibition of PI3K (p110 ⁇ ) kinase activity at the molecular level.
  • PI 3-Kinase HTRF Assay (384wells) was purchased from Upstate (Millipore); PI3K (p110 ⁇ ) kinase was a self-made enzyme.
  • Each solution was prepared according to the instructions provided in the kinase PI 3-Kinase HTRF Assay.
  • the kinase reaction was carried out in a white 384-well plate (Proxiplate-384plus), and 0.5 ⁇ l of DMSO was added to the two control wells with and without enzymes (the concentration was consistent with the highest concentration of DMSO in the test compound). 0.5 ⁇ l of each concentration of the test compound was added to each well to be tested.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • Relative inhibition rate (%) (HTRF value of test well - HTRF value of enzyme-added control well) / (HTRF value of control well without enzyme - HTRF value of enzyme-controlled control well) ⁇ 100
  • the relative inhibition rate versus concentration was calculated by GraphPad software to obtain IC50 values.
  • the inhibition of mTOR kinase activity of the test sample at the molecular level was evaluated.
  • mTOR Kinase Assay (384wells) was purchased from PerkinElmer; mTOR kinase was a self-made enzyme.
  • mTOR Kinase Assay Prepare various buffers according to the instructions provided in the mTOR Kinase Assay.
  • the kinase reaction was carried out in a white 384-well plate (Proxiplate-384plus), and 2.5 ⁇ l of DMSO was added to the two control wells with and without enzymes (the concentration was consistent with the highest concentration of DMSO in the test compound). 2.5 ⁇ l of each concentration of the test compound was added to each well to be tested.
  • Add ULight-4E-BP1 (Thr37/46) Peptide/ATP mix (ATP final concentration 100 ⁇ M) and 5 ⁇ l mTOR kinase to the control wells and the wells to be tested, mix well, and incubate with a parafilm for 2 h. .
  • HTRF Homogeneous Time-Resolved Fluorescence
  • Relative inhibition rate (%) ⁇ 1 - (HTRF value of test well - HTRF value of enzyme-added control well) / (HTRF value of enzyme-added control well - HTRF value of control well without enzyme)) ⁇ 100 %
  • the relative inhibition rate versus concentration was calculated by GraphPad software to obtain IC50 values.
  • test drug was studied for its in vivo efficacy in the ovarian cancer SK-OV-3 animal model and the prostate cancer PC-3M animal model.
  • the descriptions of animal feeding, feed ingredients, experimental observations, experimental indicators, experimental termination and data analysis are as follows:
  • Animal feeding After the animals arrive, they can be started in the experimental environment for 3-7 days. Animals were housed in an IVC (independent air supply system) cage at the SPF level animal house (5 per cage). All cages, litter and drinking water must be sterilized before use. The sterilization and disinfection records are shown in the annex. All laboratory personnel should wear protective clothing and latex gloves when operating in the animal room. The animal information card for each cage should indicate the number of animals in the cage, gender, strain, date of receipt, dosing schedule, experiment number, group, and start date of the experiment. Cage, feed and drinking water are changed twice a week. The feeding environment and lighting conditions are as follows:
  • ⁇ Lighting cycle 12 hours of light, 12 hours of no light
  • ⁇ Feed ingredients The feed meets the animal food identification criteria.
  • the maximum content of pollutants is within the controllable range and is inspected by the manufacturer.
  • Drinking water is autoclaved drinking water.
  • Animal grouping Animals were weighed prior to dosing and tumor volume was measured. Randomly grouped according to tumor volume (random block design).
  • TGI tumor growth inhibition
  • TGI (%) [1-(Ti-T0) / (Vi-V0)] ⁇ 100, where Ti is the average tumor volume of a certain administration group on a certain day, and T0 is given for this purpose.
  • Tumor weights were measured after the end of the experiment and the percentage of T/C was calculated.
  • T and C represent the tumor weights of the drug-administered group and the vehicle control group, respectively.
  • the mean volume of the tumor in the control group reached 2,000 mm 3 and the experiment was terminated.
  • ⁇ Cell culture Human ovarian cancer SK-OV-3 cells (ATCC, Manassas, Virginia, batch number: HTB-77) were cultured in vitro in monolayers, and culture conditions were 10% fetal bovine serum in McCoy's 5A medium. 100 U/ml penicillin and 100 ⁇ g/ml streptomycin were incubated in a 37 ° C 5% CO 2 incubator. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, when the number reaches the requirement, the cells are collected, counted, and inoculated.
  • ⁇ Animal BALB/c nude mice, female, 4 weeks old, weighing 12-14 grams. Provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
  • Tumor inoculation 0.2 ml (1 ⁇ 10 7 ) SK-OV-3 cells (with Matrigel, volume 1:1) were subcutaneously inoculated into the right back of each mouse, and the average tumor volume reached about 100-200 mm 3 The group administration is started at the time.
  • EXPERIMENTAL OBJECTIVE To study the in vivo efficacy of the test drug on the subcutaneous xenograft tumor model of human prostate cancer PC-3M cells.
  • ⁇ Cell culture Human prostate cancer PC-3M cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin, and cultured in a 37 ° C 5% CO 2 incubator. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, when the number reaches the requirement, the cells are collected, counted, and inoculated.
  • ⁇ Animal BALB/c nude mice, male, 4 weeks old, weighing 12-14 grams. Provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
  • Tumor inoculation 0.2 ml (1 ⁇ 10 7 ) of PC-3M cells were subcutaneously inoculated into the right back of each mouse, and group administration was started when the average tumor volume reached about 150 to 200 mm 3 .
  • the experimental grouping and dosing schedule are shown in the table below.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

公开了一类作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物，具体涉及式(I)所示化合物或其药学上可接受的盐。

Description

作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物 技术领域
本发明涉及一类作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物，具体地，本发明涉及式(I)所示化合物或其药学上可接受的盐。
背景技术
PI3K通路是人体癌细胞中最常发生变异的地方，可导致细胞的增殖，活化，放大信号。PI3K和mTOR是PI3K信号通路中两个最重要的激酶。
PI3激酶(磷脂酰肌醇3-激酶,PI3Ks)属于脂质激酶家族，能够磷酸化磷脂酰肌醇的肌醇环3’-OH端。磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)为一种由调节亚单位p85或p101和催化亚单位p110组成的脂激酶，通过催化磷脂酰肌醇4,5-二磷酸(phosphatidylinositol 4,5-bisphosphate,PIP2)磷酸化为磷脂酰肌醇3,4,5-三磷酸(phosphatidylinositol 3,4,5-trisphosphate,PIP3)而激活下游的Akt等从而对细胞的增殖、生存和代谢等起关键作用。因此抑制磷酸酯酰肌醇3激酶，可以影响PI3K通路，从而抑制癌细胞的增殖与活化。
肿瘤抑制基因PTEN(phosphatase and tension homolog deleted on chromosome ten)使PIP3去磷酸化生成PIP2，从而实现PI3K/Akt信号通路的负性调节，抑制细胞增殖和促进细胞凋亡。PI3K基因突变和扩增在癌症中频繁发生以及PTEN在癌症中缺失等都提示PI3K与肿瘤发生的密切关系
mTOR(哺乳动物雷帕霉素靶蛋白)是存在于胞浆中一种丝/苏氨酸蛋白激酶，属于磷脂酰肌醇3-激酶相关激酶家族，在调控许多通路的信号传导中发挥着重要作用。mTOR已经被确定是PI3K/Akt的下游靶点。目前发现细胞内存在两种不同的mTOR复合体，mTORC1和mTORC2。二者分别行使不同的功能，mTORC1主要功能是刺激细胞的生长和增殖,而mTORC2则通过激活AKT，PKC以及其它激酶调控细胞的生存和细胞骨架。研究表明mTOR信号通路与癌症发生有关，在癌细胞中同时抑制两个mTOR复合体的活性有更广泛和更有效的抗癌作用。
PI3K-mTOR双抑制剂可以同时阻断信息传导中的多个环节，将更有效地阻止激酶信息传导，因而克服或延缓抗药性的产生。
诺华公司的专利申请W02008163636和GSK公司的专利申请W02008144463中，报道了对PI3K和mTOR均有抑制作用的系列化合物，这些化合物具有良好的肿瘤治疗活性。但是，目前暂无对PI3K和mTOR均有抑制作用的药物上市，因此，需要研发对PI3K、mTOR均具有抑制作用的多把向药物，以利于癌症的治疗。
发明内容
本发明的目的在于提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2015081519-appb-000001
Figure PCTCN2015081519-appb-000002
其中，
可将结构单元
Figure PCTCN2015081519-appb-000003
替换为
Figure PCTCN2015081519-appb-000004
Figure PCTCN2015081519-appb-000005
E选自任选被1、2或3个R3取代的C1-6烷基、3-10元环烃基或杂环烃基；
L和Q中，一个选自-C(R3)(R3)-、-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-，另一个选自单键或-C(R3)(R3)-；
A、T分别独立地选自N或C(R3)；
X、Y、Z中的0或1个选自N，其余选自C(R3)；
B选自-C(R3)(R3)-、-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-；
杂原子或杂原子团分别独立地选自-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-；
m1分别独立地选自0、1、2或3；
R1-3分别选自H、F、Cl、Br、I、CN、ORa、N(Rb)(Rc)、任选被Rd取代的C1-3烷基、
Figure PCTCN2015081519-appb-000006
D1选自单键、-C(Re)(Re)-、-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-；
D2选自-C(Ra)(Ra)-；
n选自1、2、3、4、5或6；
Ra、Rb、Rc分别独立地选自H、任选Rd取代的C1-6烷基或C3-6环烷基；
Re选自H、任选Rd取代的C1-6烷基或烷氧基、任选Rd取代的C3-6环烷基或环烷氧基；
Rd选自F、Cl、Br、I、CN、OH、CHO、COOH、CH3、CF3、CH3O、CH3CH2O,Rd的数目选自0、1、 2或3；
任选地，任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间共同连接到同一碳原子或氧原子上形成一个或两个3、4、5或6元碳环或氧杂环，其中氧原子的数目为1或2。
本发明的一个方案中，上述E选自被R3取代的C1-6烷基或C3-6环烷基，R3的数目选自0、1、2或3，或者E选自
Figure PCTCN2015081519-appb-000007
其中，
G1～5中的0、1、2或3个选自N，其余选自C(R3)；
G6选自-C(R3)(R3)-、-C(＝O)N(R3)-、-N(R3)-、-C(＝NR3)-、-S(＝O)2N(R3)-、-S(＝O)N(R3)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R3)C(＝O)N(R3)-；
G7～9中的0、1或2个选自N，其余选自C(R3)；
G10～16中的0、1、2、3或4个选自N，其余选自C(R3)；
G17选自N或者C(R3)；
G18～22中的0、1、2或3个选自-C(＝O)N(R3)-、-N(R3)-、-C(＝NR3)-、-S(＝O)2N(R3)-、-S(＝O)N(R3)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R3)C(＝O)N(R3)-，其余选自-C(R3)(R3)-；
其余变量如上述定义。
本发明的一个方案中，上述E选自任选被1、2或3个R3取代的甲基、乙基、丙基、
Figure PCTCN2015081519-appb-000008
Figure PCTCN2015081519-appb-000009
本发明的一个方案中，E选自任选被1、2、或3个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)、N(C1-3烷基)2、C1-3烷基、三氟甲基、三氟乙基、C(＝O)NH2、C1-3烷基C(＝O)、C1-3烷基C(＝O)NH、C1-3烷基S(＝O)、C1-3烷基S(＝O)NH、C1-3烷基S(＝O)2或C1-3烷基S(＝O)2NH所取代的：
Figure PCTCN2015081519-appb-000010
Figure PCTCN2015081519-appb-000011
Figure PCTCN2015081519-appb-000012
C1-3烷基。
本发明的一个方案中，E选自
Figure PCTCN2015081519-appb-000013
Figure PCTCN2015081519-appb-000014
Figure PCTCN2015081519-appb-000015
本发明的一个方案中，上述L和Q中，一个选自-S(＝O)2NH-、-S(＝O)2-、-NH-、-NHC(＝O)NH-，另一个选自单键、-CH2-。
本发明的一个方案中，上述X、Y、Z中的0或1个选自N，其余选自CH、C(CH3)、C(CF3)、CCl、CF。
本发明的一个方案中，上述A、T分别独立地选自N、CH、C(CH3)、C(CF3)、CCl、CF；或者，B选自NH、N(CH3)或N(CF3)。
本发明的一个方案中，上述任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间所成的环选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、1,3-二氧五环基。
本发明的一个方案中，上述R1-3选自H、F、Cl、Br、I、CN、OH、NH2、甲基、乙基、丙基、甲氧基、乙氧基、甲氨基、二甲氨基、卤代甲基、卤代乙基、卤代丙基、氨甲基、氨乙基、氨丙基、环丙基、
Figure PCTCN2015081519-appb-000016
Figure PCTCN2015081519-appb-000017
本发明的一个方案中，上述化合物或其药学上可接受的盐选自：化合物1～化合物284。
相关定义：
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品 名时，意在指代其对应的商品或其活性成分。
C1-10选自C1、C2、C3、C4、C5、C6、C7、C8、C9和C10；C3-10选自C3、C4、C5、C6、C7、C8、C9和C10。
C1-10烷基或杂烷基、C3-10环基或杂环烃基、被C3-10环烃基或杂环烃基取代的C1-10烷基或杂烷基包括但不限于：
C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基、C3-10环烷氨基、C3-10杂环烷氨基、C3-10环烷氧基、C3-10环烷基酰基、C3-10环烷基氧羰基、C3-10环烷基磺酰基、C3-10环烷基亚磺酰基；
甲基、乙基、正丙基、异丙基、-CH2C(CH3)(CH3)(OH)、环丙基、环丁基、丙基亚甲基、环丙酰基、苄氧基、三氟甲基、氨甲基、羟甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基、乙氧基、乙酰基、乙磺酰基、乙氧羰基、二甲基氨基、二乙基氨基、二甲基氨基羰基、二乙基氨基羰基；
N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(＝O)2CH3,-CH2CH2CN,
Figure PCTCN2015081519-appb-000018
Figure PCTCN2015081519-appb-000019
-CH2CH(OH)(CH3)2,-CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,-CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S(＝O)2CH3,-CH2CH2S(＝O)2CH3,
Figure PCTCN2015081519-appb-000020
Figure PCTCN2015081519-appb-000021
Figure PCTCN2015081519-appb-000022
Figure PCTCN2015081519-appb-000023
苯基、噻唑基、联苯基、萘基、环戊基、呋喃基、3-吡咯啉基、吡咯烷基、1,3-氧五环基、吡唑基、2-吡唑啉基、吡唑烷基、咪唑基、恶唑基、噻唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、4H-吡喃基、吡啶基、哌啶基、1,4-二氧六环基、吗啉基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、嘌呤基、喹啉基、异喹啉基、噌啉基或喹喔啉基；和
甲基、乙基、丙基、甲氧基、乙氧基、甲氨基、二甲氨基、卤代甲基、卤代乙基、卤代丙基、氨甲 基、氨乙基、氨丙基、环丙基、
Figure PCTCN2015081519-appb-000024
Figure PCTCN2015081519-appb-000025
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of PharmaceuticalScience 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、 碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且 对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice ofPharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2015081519-appb-000026
表示其可在环己基或者环基二烯上的任意一个位置发生取代。
烷基和杂烷基原子团(包括通常被称为亚烷基、链烯基、亚杂烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基一般被称为“烷基取代基”，它们可以选自但不限于下列基团中的一个或多个：-R’、-OR’、＝O、＝NR’、＝N-OR’、-NR’R”、-SR’、卤素、-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2和氟代(C1-C4)烷基,取代基的数目为0～(2m’+1),其中m’是这类原子团中碳原子的总数。R'、R”、R”'、R””和R””’各自独立地优选氢、被取代或未被取代的杂烷基、被取代或未被取代的芳基(例如被1～3个卤素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基团或芳烷基。当本发明的化合物包括一个以上的R基团时，例如，每一个R基团是独立地加以选择的，如同当 存在一个以上的R'、R”、R”'、R””和R””’基团时的每个这些基团。当R'和R”附着于同一个氮原子时，它们可与该氮原子结合形成5-，6-或7-元环。例如，-NR'R“意在包括但不仅限于1-吡咯烷基和4-吗啉基。根据上述关于取代基的讨论中，本领域技术人员可以理解，术语“烷基”意在包括碳原子键合于非氢基团所构成的基团，如卤代烷基(例如-CF3、-CH2CF3)和酰基(例如-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
与烷基原子团所述取代基相似，芳基和杂芳基取代基一般统称为“芳基取代基”，选自例如-R’、-OR’、-NR’R”、-SR’、-卤素,-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、氟(C1-C4)烷氧基和氟(C1-C4)烷基等，取代基的数量为0到芳香环上开放化合价的总数之间；其中R’、R”、R”’、R””和R””’独立地优选自氢、被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基和被取代或未被取代的杂芳基。当本发明的化合物包括一个以上的R基团时，例如，每个R基团是独立地加以选择的，如同当存在一个以上R’、R”、R”’、R””和R””’基团时的每个这些基团。
芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U独立地选自-NR-、-O-、CRR'-或单键，q是0到3的整数。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中A和B独立的选自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2-、-S(O)2NR’-或单键，r是1～4的整数。任选地，由此形成的新环上的一个单键可以替换为双键。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中s和d分别独立的选自0～3的整数，X是–O-、-NR’、-S-、-S(O)-、-S(O)2-或–S(O)2NR’-。取代基R、R’、R”和R”’分别独立地优选自氢和被取代或未被取代的(C1-C6)烷基。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。
卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、isatino基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、苯基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的、单元或多元不饱和的，可以是单取代、二取代或多取代的，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C10表示1至10个碳)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烷基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子B、O、N和S可以位于杂烃基的任何内部位置(包括该烃基附着于分子其余部分的位置)。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，它可以是单环或多环(优选1至3个环)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、 4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
为简便起见，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD：SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词：aq代表水；HATU代表O-7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点。
化合物经手工或者
Figure PCTCN2015081519-appb-000027
软件命名，市售化合物采用供应商目录名称。
附图说明：
图1是受试药物对人卵巢癌SK-OV-3细胞皮下异种移植肿瘤模型体内药效实验结果，其中：
1)每组小鼠数目为6只；
2)给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整；
3)受试化合物以及Vehicle组使用的溶媒为:1％MC，PO，QD x 19天。
图2-1是研究受试药对人前列腺癌PC-3M细胞皮下异种移植肿瘤模型的体内药效学实验一的实验结果，其中：
1)每组小鼠数目为7只；
2)给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整。
图2-2是研究受试药对人前列腺癌PC-3M细胞皮下异种移植肿瘤模型的体内药效学实验二的实验结果，其中：
1)每组小鼠数目为6只；
2)给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整；
3)受试化合物以及Vehicle组使用的溶媒为:1％DMSO+99％(1％MC)，PO，QD x 2W。
图2-3a是研究受试药对人前列腺癌PC-3M细胞皮下异种移植肿瘤模型的体内药效学实验三的实验结果，其中：
1)每组小鼠数目为6只；
2)给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整；
3)PF0512384溶媒采用30％propylene glycol+5％Tween 80+65％D5W,IV,QW x 2W；
4)其它受试化合物以及Vehicle组使用的溶媒为:5％DMSO+60％PEG400+35％water，PO,QD x 2W。
图2-3b是研究受试药对人前列腺癌PC-3M细胞皮下异种移植肿瘤模型的体内药效学实验三的实验结果，其中：
1)每组小鼠数目为6只；
2)给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整；
3)PF0512384溶媒采用30％propylene glycol+5％Tween 80+65％D5W,IV,QW x 2W；
4)其它受试化合物以及Vehicle组使用的溶媒为:5％DMSO+60％PEG400+35％water，PO,QD x 2W。
具体实施方式
为了更详细地说明本发明，给出下列实例，但本发明的范围并非限定于此。
流程1:
Figure PCTCN2015081519-appb-000028
反应条件：a)原甲酸三乙酯，2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮，加热；EtOH，加热；b)二苯醚，回流；c)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧 六环，水，加热。
实施例1
2,4-二氟-N-(2-甲氧基-5-(4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000029
a)(E)-5-(((5-溴吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮
将原甲酸三乙酯(25.8g，0.174mol)和2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(25.1g，0.174mol)置于三颈圆底烧瓶中，60度搅拌反应2小时。向上述混合物中滴加2-胺基-5-溴吡啶(30g，0.174mol)的乙醇(150mL)溶液。反应液60度搅拌反应2小时。将混合物冷却至25度，过滤，滤饼用乙醇(200mL*3)淋洗后得到白色固体状标题化合物(40g，70％)。
1H NMR(400MHz,CDCl3)ppmδ1.77(s,6H),6.93-7.04(m,1H),8.44-8.53(m,1H),7.85-7.91(m,1H),9.31-9.42(m,1H),11.28-11.40(m,1H).
b)7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮
将(E)-5-(((5-溴吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(18g，0.056mmol)，二苯醚(180mL)置于250mL圆底烧瓶中，220度搅拌反应1小时。TLC显示反应完全，将反应液冷却至室温，用硅胶柱色谱法纯化得到标题化合物(10g，80％)。
1H NMR(400MHz,CDCl3)ppmδ6.46(d,1H),7.53(d,1H),7.75(dd,1H),8.27(d,1H),9.19(d,1H).
c)2,4-二氟-N-(2-甲氧基-5-(4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮(0.28mmol)溶解在二氧六环(2mL)和水(0.4mL)中，在氮气保护下加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(0.28mmol)，碳酸钾(0.56mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(20mg)。将混合物置于微波反应条件下100度反应2小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到标题产物。
1H NMR(400MHz,CDCl3)ppmδ3.87(s,3H),6.53(d,1H),7.12(t,1H),7.24(t,1H),7.83(d,1H),7.87-7.97(m,1H),8.10(s,1H),8.26(d,1H),8.31-8.40(m,2H),9.21(s,1H).
参照化合物1的制备方法还合成了以下37个化合物：
Figure PCTCN2015081519-appb-000030
Figure PCTCN2015081519-appb-000031
Figure PCTCN2015081519-appb-000032
Figure PCTCN2015081519-appb-000033
Figure PCTCN2015081519-appb-000034
Figure PCTCN2015081519-appb-000035
Figure PCTCN2015081519-appb-000036
流程2:
Figure PCTCN2015081519-appb-000037
反应条件：a)原甲酸三乙酯，2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮，加热；EtOH，加热；b)二苯醚，回流；c)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例39
2,4-二氟-N-(2-甲氧基-5-(4-氧代-4H-吡嗪并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000038
a)(E)-5-(((5-溴嘧啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮
将原甲酸三乙酯(9.9g，0.0689mol)和2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮(10.8g，0.073mol)置于三颈圆底烧瓶中，60度搅拌反应2小时。向上述混合物中滴加5-溴-2-胺基吡嗪(12g,0.0689mol)的乙醇(50mL)溶液。反应液60度搅拌反应2小时。将混合物冷却至25度，过滤，滤饼用乙醇(200mL*3)淋洗后得到白色固体状标题化合物(12.5g，55.3％)。
1H NMR(400MHz,DMSO-D6)ppmδ11.601(s,1H),9.039(s,1H),8.825(s,1H),8.712(s,1H),1.690(s,6H).
b)7-溴-4H-吡嗪并[1,2-a]嘧啶-4-酮
将(E)-5-(((5-溴嘧啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(12g，0.0368mol)，二苯醚(50mL)置于500mL圆底烧瓶中，220度搅拌反应1小时。将反应液冷却至室温，粗品用硅胶柱色谱法纯化得到橘色固体状标题化合物(2g，24.4％)。
1H NMR(400MHz,DMSO-D6)ppmδ8.944-8.919(d,2H),8.485-8.399(s,1H),6.687-6.672(d,1H).
c)2,4-二氟-N-(2-甲氧基-5-(4-氧代-4H-吡嗪并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-4H-吡嗪并[1,2-a]嘧啶-4-酮(0.22mmol)溶解在二氧六环(0.22mL)和水(0.44mL)中，在氮气保护下加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(0.22mmol)，碳酸钾(0.56mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(20mg)。将混合物置于微波反应条件下100度反应2小时。液相质谱显示反应完全。将反应液过滤，橘色有机相浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到标题产物。
1H NMR(400MHz,CD3OD)ppmδ9.169(s,1H),8.999(s,1H),8.473(s,1H),8.439-8.423(d,1H),8.197(s,1H),7.941-7.922(d,1H),7.145-7.098(m,1H),6.684-6.669(d,1H),3.884(s,3H).
参照化合物39的制备方法还合成了以下12个化合物：
Figure PCTCN2015081519-appb-000039
Figure PCTCN2015081519-appb-000040
Figure PCTCN2015081519-appb-000041
流程3:
Figure PCTCN2015081519-appb-000042
反应条件：a)原甲酸三乙酯，2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮，加热；乙醇，加热；b)二苯醚，回流；c)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例52
2,4-二氟-N-(2-甲氧基-5-(6-甲基-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000043
a)(E)-5-(((5-溴-6-甲基吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮
将原甲酸三甲酯(4.39g,0.03mmol)和2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮(4.03g,0.028mmol)置于装备了机械搅拌的三口圆底烧瓶中。所得悬浮液在60度下搅拌2小时。向此混合液中滴加溶于乙醇(50mL)的5-溴吡嗪-2-胺(5g,0.027mmol)溶液。然后此反应液在60度下搅拌2小时。此反应液冷却至25度，过滤。滤饼用乙醇(200mL*3)洗涤后得到白色固体状目标化合物(6g,65.6％)。
1H NMR(400MHz,DMSO-D6)ppmδ11.344-11.378(d,1H),9.143-9.177(d,1H),8.066-8.087(d,1H),7.457-7.479(d,1H),2.578(s,3H),1.678(s,6H).
b)7-溴-6-甲基-4氢-吡啶并[1,2-a]嘧啶-4-酮
将置于50mL圆底烧瓶中的((E)-5-(((5-溴-6-甲基吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮(200mg,0.59mmol)和二苯醚(4mL)在微波仪中220度下搅拌0.5小时。反应液冷却至室 温，并且粗产品经硅胶柱纯化后得到橙色固体状目标化合物(60.7mg,43.2％)。
1H NMR(400MHz,CDCl3)ppmδ8.075-8.090(d,1H),7.625-7.649(d,1H),7.246(d,1H),6.337-6.352(d,1H),3.026(s,3H).
c)2,4-二氟-N-(2-甲氧基-5-(6-甲基-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
在氮气保护下向7-溴-6-甲基-4氢-吡啶并[1,2-a]嘧啶-4-酮(0.25mmol)的二氧六环(0.2mL)和水(0.4mL)的溶液中加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-基)苯磺酰胺(0.28mmol),碳酸钾(0.5mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(20mg)。混合液在微波加热100度下搅拌2小时。液相质谱显示反应完成。此反应液过滤，有机相浓缩后得到粗产品。此粗产品经制备高效液相色谱法纯化后得到目标化合物
1H NMR(400MHz,CDCl3)ppmδ8.120-8.135(d,1H),7.878-7.914(m,1H),7.865-7.870(d,1H),7.742-7.748(d,1H),7.441-7.464(d,1H),7.368-7.391(d,1H),6.947-6.986(m,2H),6.362-6.377(d,1H),3.995(s,3H),2.701(s,3H).
参照化合物52的制备方法还合成了以下8个化合物：
Figure PCTCN2015081519-appb-000044
Figure PCTCN2015081519-appb-000045
流程4:
Figure PCTCN2015081519-appb-000046
反应条件：a)select F试剂，乙腈，加热；b)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例61
2,4-二氟-N-(5-(3-氟-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000047
a)7-溴-3-氟-4氢-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-4氢-吡啶并[1,2-a]嘧啶-4-酮(1g,4.46mmol)，select F(1.6g,4.46mmol)和乙腈(15mL)置于100mL圆底烧瓶中并在80度下搅拌2天。浓缩反应液并加入水(15mL)，混合液再用二氯甲烷(20mL)萃取三次。浓缩有机相得到粗产品。粗产品经层析柱纯化得到黄色固体状目标化合物(200mg,18.5％)。
1H NMR(400MHz,DMSO-d6)ppmδ9.195(s,1H),8.404(s,1H),7.763-7.739(d,1H),7.606-7.582(d,1H).
b)2,4-二氟-N-(5-(3-氟-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺
在氮气保护下向7-溴-3-氟-4氢-吡啶并[1,2-a]嘧啶-4-酮(0.28mmol)的二氧六环(0.2mL)和水(0.4mL)的溶液中加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-基)苯磺酰胺(0.28mmol),碳酸钾(0.6mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(20mg)。混合液在微波加热100度下搅拌2小时。液相质谱显示反应完成。此反应液过滤，有机相浓缩后得到粗产品。此粗产品经制备高效液相色谱法纯化后得到目标化合物。
1H NMR(400MHz,DMSO-d6)ppmδ10.438(s,1H),9.049(s,1H),8.636-8.628(d,1H),8.489(s,1H),8.282-8.259(d,1H),8.030(s,1H),7.872-7.848(d,1H),7.796-7.780(d,1H),7.611-7.562(m,1H),7.250-7.231(m,1H),3.691(s,3H).
参照化合物61的制备方法还合成了以下9个化合物：
Figure PCTCN2015081519-appb-000048
Figure PCTCN2015081519-appb-000049
流程5:
Figure PCTCN2015081519-appb-000050
反应条件：a)氢氧化铵，氯化铵，加热：b)三乙氧基甲烷，2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮，加热；乙醇，加热；c)二苯醚，回流；d)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例71
2,4-二氟-N-(2-甲氧基-5-(4-氧-4H-嘧啶并[1,2-b]哒嗪-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000051
a)6-氯哒嗪-3-胺
3,6-二氯哒嗪(20g,0.134mol)和氢氧化铵溶液(140mL)，氯化铵(11.47g,0.214mol)和水(80mL)加入到100mL圆底烧瓶中,然后90度下搅拌20小时.反应液冷却到室温，过滤，滤饼用水(100mL)洗涤得到产品，形状为白色固体(14.3g,82.7％)。
1H NMR(400MHz,DMSO-d6)ppmδ7.365-7.361(d,1H),6.853-6.830(d,1H),6.614(s,1H).
b)(E)-5-(((6-氯哒嗪-3-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮
将三乙氧基甲烷(16.3g,0.110mol)和2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮(14.5g,0.1mmol)加入到3L圆底烧瓶中，60度下搅拌2小时后，将6-氯哒嗪-3-胺基(13g,100.3mmol)的乙醇(100mL)溶液滴入上述反应液中。然后反应液继续在60度下搅拌2小时。将反应液冷却至25度,并且过滤,滤饼用乙醇洗涤(50mL*3)得到产品，形状为白色固体(16g,56％)。
1H NMR(400MHz,DMSO-d6)δppm 11.521-11.484(d,1H),9.219-9.185(d,1H),8.100-7.984(m,2H).
c)7-氯-4H-嘧啶并[1,2-b]哒嗪-4-酮
将(E)-5-(((6-氯哒嗪-3-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮(15g,52.9mmol)和二苯醚(70mL)加入到250mL圆底烧瓶中，220度下搅拌1小时.反应液冷却至室温,粗产品经柱层析分离得到产品，形状为橘黄色固体(2.4g,25.3％)。
1H NMR(400MHz,CD3OD)ppmδ8.329-8.313(d,1H),8.003-8.979(d,1H),7.788-7.764(d,1H),6.713-6.696(d,1H).
d)2,4-二氟-N-(2-甲氧基-5-(4-氧-4H-嘧啶并[1,2-b]哒嗪-7-yl)吡啶-3-基)苯磺酰胺
在氮气保护反应条件下，往7-氯-4H-嘧啶并[1,2-b]哒嗪-4-酮(0.22mmol)在1,4-二氧六环(0.2mL)和水(0.4mL)的混合溶液中依次加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-基)苯磺酰胺(0.22mmol)，碳酸钾(0.44mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(22mg)。反应液在微波反应条件下100度搅拌2小时。液相质谱显示反应已经结束。反应液过滤，滤液浓缩得到粗产品。粗产品经制备高效液相色谱法分离得到产品。
1H NMR(400MHz,CDCl3)ppmδ8.37-7.89(m,6H),7.30-7.02(m,2H),6.67-6.54(m,1H),3.85(m,3H).
参照化合物71的制备方法还合成了以下9个化合物：
Figure PCTCN2015081519-appb-000052
Figure PCTCN2015081519-appb-000053
流程6:
Figure PCTCN2015081519-appb-000054
反应条件:a)2-甲基-3-氧代琥珀酸乙酯,乙醇，加热；b)二苯醚,加热；c)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，1,4-二氧六环，水，加热。
实施例81
2,4-二氟-N-(2-甲氧基-5-(3-甲基-4-氧-4H-吡啶并[1,2-a]嘧啶-7-yl)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000055
a)7-溴-3-甲基-4-氧-4H-吡啶并[1,2-a]嘧啶-2-羧酸
将5-溴吡啶-2-胺基(6g,0.035mol)二乙基-2-甲基-3-二氧杂硼烷(7g,0.035mol)和乙醇(165mL)加入到250mL圆底烧瓶中，反应液在100度下搅拌30小时。反应液冷却至室温，固体用冷的乙醇洗涤得到产品，形状为白色固体(3g,30.6％)。
1H NMR(400MHz,DMSO-d6)ppmδ8.936(s,1H),7.963-7.940(d,1H),7.577-7.553(d,1H),2.111(s,3H).
b)7-溴-3-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮
7-溴-3-甲基-4-酮-4H-吡啶并[1,2-a]嘧啶-2-羧酸(1.5g,5.2mmol)和二苯醚(20mL)的混合溶液在220度下搅拌1.5小时。反应液冷却至室温，粗产品使用柱层析分离得到产品，形状为橘黄色固体(550mg,44％).
1H NMR(400MHz,CDCl3)ppmδ9.174(s,1H),8.233(s,1H),7.688-7.665(d,1H),7.505-7.4822.279(s,1H).
c)2,4-二氟-N-(2-甲氧基-5-(3-甲基-4-氧-4H-吡啶并[1,2-a]嘧啶-7-yl)吡啶-3-基)苯磺酰胺
在氮气保护反应条件下，往7-溴-3-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(0.22mmol)在1,4-二氧六环(2mL)和水(0.4mL)的混合溶液中依次加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶3-基)苯磺酰胺(0.22mmol)，碳酸钾(0.44mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(22mg)。反应液在微波反应条件下90度搅拌1小时。液相质谱显示反应结束，反应液过滤，滤液旋干得到粗产品。粗产品使用制备高效液相色谱法分离得到产品，形状为白色固体。
1H NMR(400MHz,DMSO-d6)ppmδ8.935(s,1H),8.274(s,1H),8.150(s,1H)8.096-8.074(d,1H),7.797-7.761(d,2H),7.683-7.660(d,1H),7.392(s,1H),7.157-7.115(d,2H),3.676,2.127(s,3H).
参照化合物81的制备方法还合成了以下5个化合物：
Figure PCTCN2015081519-appb-000056
Figure PCTCN2015081519-appb-000057
流程7:
Figure PCTCN2015081519-appb-000058
反应条件:a)浓硫酸，硝酸；b)铁粉，氯化铵，加热；c)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，1,4-二氧六环，水，加热。
实施例87
N-(5-(3-胺基-4-氧-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-yl)-2,4-二氟苯磺酰胺
Figure PCTCN2015081519-appb-000059
a)7-溴-3-硝基-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮(10g,0.045mol)和浓硫酸(50mL)加入三颈瓶中，0度下缓慢将硝酸(8.65g,98％)滴入。混合液在0度搅拌1小时。然后将反应液倒入水中(200mL)，加入氢氧化钠调节pH至9。水相用乙酸乙酯萃取(200mL*3)，有机相合并，干燥后浓缩得到粗产品。粗产品用硅胶柱层析分离得到产品，形状为白色固体(1.3g,10.8％)。
1H NMR(400MHz,CDCl3)ppmδ9.489-9.485(d,1H),9.368(s,1H),8.178-8.150(m,1H),7.843-7.820(d,1H).
b)3-胺基-7-溴-4H-吡啶并1,2-a]嘧啶-4-酮
7-溴-3-硝基-4H-吡啶并[1,2-a]嘧啶-4-酮(1g,0.0037mol)在乙醇(10mL)和水(2mL)的混合溶液中加入氯化铵(1.2g,0.019mol)和铁粉(1.0g)，反应物在70度下搅拌4小时。反应液过滤，滤饼用乙酸乙酯洗涤(30mL*3)，滤液浓缩得到粗产品。粗产品用乙酸乙酯(50mL)溶解，并用水(20mL)洗涤，有机相浓缩得到产品，形状为棕色固体(0.8g,89.9％)。
1H NMR(400MHz,CDCl3)ppmδ9.013(s,1H),7.974(s,1H),7.395(s,2H),4.235(s,2H).
c)N-(5-(3-胺基-4-氧-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺
在氮气保护反应条件下，向3-胺基-7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮(0.22mmol)在1,4-二氧六环(2mL)和水(0.4mL)的混合液中加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-基)苯磺酰胺(0.22mmol),碳酸钾(0.44mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(22mg)。反应 液在微波反应条件下90度搅拌1小时。液相质谱显示反应已经结束，反应液过滤，滤液浓缩得到粗产品。粗产品使用制备高效液相色谱法分离得到产品，形状为白色固体。
1H NMR(400MHz,DMSO-d6)ppmδ8.763(s,1H),8.013-7.687(m,6H),7.549-7.526(d,1H),7.372-7.175(m,1H),5.284(s,2H),3.758(s,3H).
参照化合物87的制备方法还合成了以下7个化合物：
Figure PCTCN2015081519-appb-000060
Figure PCTCN2015081519-appb-000061
流程8:
Figure PCTCN2015081519-appb-000062
条件：a)硝酸，浓硫酸；b)氯化铵，铁粉，加热；c)碳酸钾，碘甲烷，加热；d)微波，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例95
2,4-二氟-N-(2-甲氧基-5-(3-(甲氨基)-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000063
a)7-溴-3-硝基-4氢-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-4氢-吡啶并[1,2-a]嘧啶-4-酮(5g,22.2mmol)溶于浓硫酸(11.2mL)置于三口圆底烧瓶中，5～10度下滴加硝酸(5.2mL)，混合物在20度下搅拌3小时。然后将反应液慢慢倒入冰水中，加入1当量的氢氧化钠溶液调节pH到8。过滤，滤饼用水洗，抽干得到黄色固体标题化合物(4.0g,66.7％)。
1H NMR(400MHz,CDCl3)ppmδ9.47(d,,1H),9.35(s,1H),8.14(dd,,1H),7.81(d,1H).
b)3-氨基-7-溴-4氢-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-3-硝基-4氢-吡啶并[1,2-a]嘧啶-4-酮(1.6g,5.93mmol)溶于乙醇(20mL)和水(4mL)中，加入氯化铵(3.17g,59.25mmol)和铁粉(3.17g,59.25mmol)，混合物在70度下搅拌16小时。将反应液过滤，滤饼用二氯甲烷洗，所得滤液有机相用饱和食盐水(50mL)洗，硫酸钠干燥、浓缩得到粗品标题化合物(3.56g)。
1H NMR(400MHz,CDCl3)ppmδ8.99(s,1H),7.96(s,1H),7.38(s,2H),4.13(br.s.,2H).
c)7-溴-3-(甲胺基)-4氢-吡啶并[1,2-a]嘧啶-4-酮
将3-氨基-7-溴-4氢-吡啶并[1,2-a]嘧啶-4-酮(0.8g,3.33mmol)溶于丙酮(30mL)中，加入碳酸钾(1.38g,10.0mmol)和碘甲烷(7.1g,49.99mmol)。氮气保护80度下搅拌3小时。将反应液过滤，滤饼用二氯甲烷洗，浓缩滤液，所得残留物用硅胶柱色谱纯化得到标题化合物(250mg,29.5％)。
1H NMR(400MHz,CDCl3)ppmδ8.91(d,1H),7.66(s,1H),7.36-7.32(m,1H),7.28(d,1H),4.72(br.s.,1H),2.97(d,3H).
d)2,4-二氟-N-(2-甲氧基-5-(3-(甲氨基)-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-3-(甲胺基)-4氢-吡啶并[1,2-a]嘧啶-4-酮(100mg,0.39mmol)溶于二氧六环(2mL)和水(0.4mL)中，氮气保护下加入2,4-二氯-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(168mg,0.39mmol)，碳酸钾(109mg,0.78mmol)和[1,1’-双(二苯基膦)二茂铁]氯化钯(16mg,0.02mmol)。混合物在微波100度下反应1小时。LCMS显示反应完全。将反应液过滤，有机相浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到黄色标题产物。
1H NMR(400MHz,DMSO-d6)ppmδ8.84(br.s.,1H),8.12(br.s.,1H),7.97-7.87(m,2H),7.70(s,1H),7.55(d,1H),7.39(d,1H),7.04-6.89(m,2H),4.70(br.s.,1H),3.97(s,3H),2.99(d,3H).
参照化合物95的制备方法还合成了以下5个化合物：
Figure PCTCN2015081519-appb-000064
Figure PCTCN2015081519-appb-000065
流程9:
Figure PCTCN2015081519-appb-000066
反应条件：a)叔丁基二甲基硅氯，1氢-咪唑；b)1-叔丁氧基-N，N，N'，N'-四甲基二胺基甲烷，加热；c)2-胺基-5-溴吡啶，醋酸，加热；d)醋酸，微波；e)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例101
2,4-二氟-N-(5-(3-羟基-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000067
a)2-((叔丁基二甲基硅)氧)乙酸乙酯
将乙醇酸乙酯(10g,96.1mmol)和1氢-咪唑(13g,0.19mol)溶于二氯甲烷(100mL)置于三口圆底烧瓶中，0度下加入叔丁基二甲基硅氯(15.8g,0.1mol)，混合物在室温下搅拌8小时，水洗(100mL*3)，硫酸钠干燥浓缩得到黄色油状标题化合物(18g,85.8％)。
1H NMR(400MHz,CDCl3)ppmδ4.14-4.09(m,4H),1.20-1.16(t,3H),0.83(s,9H),0.01(s,6H).
b)(Z)-乙基2-((叔丁基二甲基硅)氧)-3-(二甲胺基)丙烯酸酯
将2-((叔丁基二甲基硅)氧)乙酸乙酯(52g,0.24mol)和1-叔丁氧基-N，N，N'，N'-四甲基二胺基甲烷(50g,0.58mol)在回流状态下搅拌24小时。浓缩混合物，残留液用硅胶柱色谱纯化得到黄色油状标题化合物(45g,47.1％)。
1H NMR(400MHz,CDCl3)ppmδ6.68(s,1H),4.13-4.11(q,2H),2.96(s,6H),1.28-1.24(t,3H),0.95(s,9H),0.14(s,6H).
c)(Z)-乙基3-((5-溴吡啶-2-基)胺基)-2-((叔丁基二甲基硅)氧)丙烯酸酯
将(Z)-乙基3-((5-溴吡啶-2-基)胺基)-2-((叔丁基二甲基硅)氧)丙烯酸酯(15g,54.9mmol)和2-胺基-5-溴吡啶(9.4g,54.9mmol)溶于乙酸(150mL)中，80度下搅拌2小时。浓缩混合物，残留物溶于乙酸乙酯(100mL)中，用碳酸钠溶液(100mL)和饱和食盐水(100mL)洗，硫酸钠干燥、浓缩，所得残留物用硅胶柱色谱纯化得到黄色油状标题化合物(14g,63.7％)。
1H NMR(400MHz,CDCl3)ppmδ8.24(s,1H),7.75-7.72(d,1H),7.63-7.60(d,1H),6.75-6.72(d,1H),6.57-6.54(d,1H),4.25-4.20(q,2H),1.34-1.30(t,3H),1.02(s,9H),0.22(s,6H).
d)7-溴-3-羟基-4氢-吡啶并[1,2-a]嘧啶-4-酮
将(Z)-乙基3-((5-溴吡啶-2-基)胺基)-2-((叔丁基二甲基硅)氧)丙烯酸酯(200mg*50,29mmol)溶于乙酸(5mL*50)中，微波140度下搅拌3小时。浓缩混合物，残留物溶于乙酸乙酯(100mL)中，用碳酸钠溶液(100mL)和饱和食盐水(100mL)洗，硫酸钠干燥、浓缩，所得残留物用硅胶柱色谱纯化得到标题化合物(3.2g,46.4％)。
1H NMR(400MHz,CDCl3)ppmδ8.98(s,1H),8.14(s,1H),8.00-7.98(d,1H),7.79-7.77(d,1H).
e)2,4-二氟-N-(5-(3-羟基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺
将7-溴-3-羟基-4氢-吡啶并[1,2-a]嘧啶-4-酮(0.22mmol)溶于二氧六环(2mL)和水(0.4mL)中，氮气保护下加入2,4-二氯-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(0.22mmol)，碳酸钾(0.44mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(22mg)。混合物在微波90度下反应1小时,液相质谱显示反应完全。将反应液过滤，有机相浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到白色标题产物。
1H NMR(400MHz,DMSO-d6)ppmδ8.93(s,1H),8.41(s,1H),8.08(s,1H),7.96(s,2H),7.79-7.78(m,1H),7.68-7.66(m,1H),7.56(m,1H),7.24-7.20(m,1H),3.68(s,3H).
参照化合物101的制备方法还合成了以下1个化合物：
Figure PCTCN2015081519-appb-000068
流程10:
Figure PCTCN2015081519-appb-000069
反应条件：a)1-叔丁氧基-N，N，N'，N'-四甲基二胺基甲烷，加热；b)2-胺基-5-溴吡啶，醋酸，加热；c)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例103
2,4-二氟-N-(2-甲氧基-5-(3-甲氧基-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000070
a)(Z)-乙基3-(二甲基胺基)-2-甲氧基丙烯酸酯
将乙基2-甲氧基乙酯(2g,16.9mmol)和1-叔丁氧基-N，N，N'，N'-四甲基二胺基甲烷(3.5g,20.1mmol)置于圆底烧瓶中回流状态下搅拌过夜。浓缩混合物，残留液用硅胶柱色谱纯化得到黄色油状标题化合物(2g,67.8％).
1H NMR(400MHz,CDCl3)ppmδ6.78(s,1H),4.18-4.16(t,2H),3.55(s,3H),3.02(s,6H),1.29-1.26(q,3H).
b)7-溴-3-甲氧基-4H-吡啶并[1,2-a]嘧啶-4-酮
将(Z)-乙基3-(二甲基胺基)-2-甲氧基丙烯酸酯(2.5g,14.4mmol)和2-胺基-5-溴吡啶(2.5g,14.4mmol)溶于乙酸(25mL)中，80度下搅拌2小时。浓缩混合物，残留物溶于乙酸乙酯(30mL)中，用碳酸钠溶液(50mL)和饱和食盐水(30mL)洗，硫酸钠干燥、浓缩，所得残留物用硅胶柱色谱纯化得到标题化合物(1.3g,35.1％)。
1H NMR(400MHz,CDCl3)ppmδ9.10(s,1H),8.05(s,1H),7.52(d,1H),7.46(d,1H),4.00(s,3H).
c)2,4-二氟-N-(2-甲氧基-5-(3-甲氧基-4-氧代-4氢-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-3-甲氧基-4氢-吡啶并[1,2-a]嘧啶-4-酮(0.27mmol)溶于二氧六环(3.5mL)和水(0.7mL)中，氮气保护下加入2,4-二氯-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(0.33mmol)，碳酸钾(0.41mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(20mg)。混合物在微波100度下反应2小时。液相质谱显示反应完全。将反应液过滤，有机相浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到标题产物。
1H NMR(400MHz,CDCl3)ppmδ8.99(s,1H),8.12(s,1H),8.09(s,1H),7.97-7.93(m,2H),7.66(s,2H),7.08-7.04(q,1H),6.97-6.93(q,1H),4.02-3.98(d,6H).
参照化合物103的制备方法还合成了以下8个化合物：
Figure PCTCN2015081519-appb-000071
Figure PCTCN2015081519-appb-000072
流程11:
Figure PCTCN2015081519-appb-000073
反应条件：a)NBS,MeCN；2)原甲酸三乙酯，2,2-二甲基-1,3-杂环乙烷-4,6-二酮，加热；EtOH,加热；c)二苯醚，回流；d)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾,二氧六环，水，加热。
实施例112
2,4-二氟-N-(5-(8-氟-4-氧代-4H-吡啶并[1,2-a])嘧啶-7-基)-2-甲氧吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000074
a)5-溴-4-氟吡啶-2-胺
向4-氟吡啶-2-胺的2,2,2-三氟乙酸盐(18g,0.16mol)的乙腈(200mL)溶液中分批加入NBS(28.6g,0.16mol)，反应液在25度的黑暗环境下搅拌4小时。减压除去溶剂，粗产物经快速柱层析硅胶法纯化得白色固体状目标化合物(15g,49％)。
1H NMR(400MHz,CDCl3)ppmδ8.155-8.131(d,1H),6.301-6.276(d,1H),4.638(s,2H)
b)(E)-5-(((5-溴-4-氟吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮
向装有搅拌的三口圆底烧瓶中加入原甲酸三乙酯(7.3g,0.05mol)和2,2-二甲基-1,3-二氧杂环己烷-4,6-二酮(7.5g,0.05mol)。该悬浊液在70度搅拌1小时。向该混合物中滴加5-溴吡啶-2胺(8g,0.042mol)的乙醇(100mL)溶液。反应液70度搅拌0.5小时。将反应液冷却至25度，过滤，滤饼用乙醇(100mL*3)淋洗后得白色固体状目标化合物(11.6g,80％)
1H NMR(400MHz,DMSO-d6)ppmδ11.477-11.442(d,1H),9.190-9.156(d,1H),8.728-8.705(d,1H),7.854-7.830(d,1H),1.694(s,6H).
c)7-溴-8-氟-4H-吡啶并[1,2-a]嘧啶-4-酮
将(E)-5-(((5-溴-4-氟吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(11.6g,0.034mol)，二苯醚(50mL)置于带搅拌的100mL圆底烧瓶中，220度反应1小时。TLC显示反应完全，反应液冷却至100度，将其倒入石油醚(100mL)，并加入盐酸与乙酸乙酯的混合液(50mL)，过滤，得固体。将固体溶于甲醇(50mL)，加入饱和NaHCO3溶液调节pH＝7，减压浓缩，然后加水(50mL)，以二氯甲烷(100mL*2)萃取，有机相用Na2SO4干燥，减压浓缩并用硅胶柱色谱法纯化得到目标化合物(4g,50％)。
1H NMR(400MHz,CDCl3)ppmδ9.335-9.317(d,1H),8.272-8.256(d,1H),7.371-7.350(d,1H),6.461-6.445(d,1H).
d)2,4-二氟-N-(5-(8-氟-4氧代-4H-吡啶并[1,2-a]嘧啶-7基)-2-甲氧基吡啶-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺
将7-溴-8-氟-4H-吡啶并[1,2-a]嘧啶-4-酮(0.28mmol)溶于二氧六环(2mL)和水(0.4mL)中，氮气保护下加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(0.28mmol)，碳酸钾(0.56mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(20mg)。将混合物置于微波反应条件下100度反应2小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到标题产物。
1H NMR(400MHz,DMSO-d6)ppmδ10.44(s.,1H),9.03-8.96(m,1H),8.30(br.s.,2H),7.93-7.85(m,1H),7.83-7.71(m,2H),7.65-7.55(m,1H),7.30-7.21(m,1H),6.46-6.40(m,1H),3.71(s,3H).
参照化合物112的制备方法还合成了以下7个化合物：
Figure PCTCN2015081519-appb-000075
Figure PCTCN2015081519-appb-000076
流程12:
Figure PCTCN2015081519-appb-000077
反应条件：a)原甲酸三乙酯，2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮，加热；EtOH，加热；b)二苯醚，回流；c)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例121
2,4-二氟-N-(2-甲氧基-5-(8-甲基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000078
a)(E)-5-(((5-溴-4-甲基吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮
将原甲酸三乙酯(1.75g，0.01mol)和2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(1.61g，0.014mol)置于带有搅拌的三颈圆底烧瓶中，60度搅拌反应2小时。向上述混合物中滴加5-溴吡啶-2-胺(2g,0.017mol)的乙醇(20mL)溶液。反应液60度搅拌反应2小时。反应液冷却至25度，过滤，滤饼用乙醇(20mL*3)淋洗后得到白色固体状标题化合物(2.1g，61.76％)。
1H NMR(400MHz,CDCl3)ppmδ9.342-9.308(d,1H),8.420(s,1H),6.946(s,1H).
b)7-溴—8-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮
将(E)-5-(((5-溴-4-氟吡啶-2-基)亚胺基)甲基)-2,2-二甲基-1,3-二氧杂环乙烷-4,6-二酮(1.2g，0.0035mol)，二苯醚(18mL)置于100mL圆底烧瓶中，220度搅拌反应1小时。TLC显示反应完全，将反应液冷却至100度，倒入石油醚(20mL)，并加入盐酸于乙酸乙酯的混合液(20mL)，混合物过滤得固体。将固体溶于甲醇(20mL)，并加入饱和NaHCO3溶液调节pH＝7，浓缩并加水(20mL),以二氯甲烷(20mL*2)萃取，有机相以Na2SO4干燥，减压浓缩，粗品用硅胶柱色谱法纯化得目标化合物(700mg，83.3％)。
1H NMR(400MHz,CDCl3)ppmδ9.236(s,1H),8.277-8.262(d,1H),7.527(s,1H),6.421-6.406(s,1H),2.550(s,3H).
c)2,4-二氟-N-(2-甲氧基-5-(8-甲基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-8-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(0.28mmol)溶于二氧六环(2mL)和水(0.44mL)中，氮气保护下加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)苯磺酰胺(0.28mmol)，碳酸钾(0.56mmol)和1,1’-双(二苯基磷)二茂铁氯化钯(20mg)。将混合物置于微波反应条件下100度反应2小时。液相质谱显示反应完全。将反应液过滤，滤液减压浓缩得粗品。粗品用制备高效液相色谱法纯化得到目标化合物。
参照实化合物121的制备方法还合成了以下10个化合物：
Figure PCTCN2015081519-appb-000079
Figure PCTCN2015081519-appb-000080
Figure PCTCN2015081519-appb-000081
流程13:
Figure PCTCN2015081519-appb-000082
反应条件：a)1-氯吡咯烷-2,5二酮，N,N-二甲基甲酰胺；b)R硼酸(硼酸酯)，碳酸钾，催化剂钯(四三苯基膦钯等)，二氧六环，水，加热。
实施例132
N-(5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯甲磺酰胺
Figure PCTCN2015081519-appb-000083
a)7-溴-3-氯-4H-吡啶并[1,2-a]嘧啶-4-酮
向溶有7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮(800mg,3.57mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入1-氯吡咯烷-2,5-二酮(500mg,3.75mmol)。反应物在25度下搅拌14小时。然后将反应液倒入水中(10mL),并用二氯甲烷(15mL)萃取三次，将得到的二氯甲烷有机相浓缩得到粗品产物，该粗品经硅胶柱分 离得到灰白色的固体(600mg,65％)。
1H NMR(400MHz,CDCl3)ppmδ9.228-9.224(d,1H),8.496(s,1H),7.831-7.801(m,1H),7.616-7.581(m,1H).
b)N-(5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯甲磺酰胺
在氮气保护下，向溶有7-溴-8-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(0.28mmol)的二氧六环(2mL)和水(0.4mL)溶液中加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-基)苯甲磺酰胺(0.28mmol)，碳酸钾(0.56mmol)，和[1,1’-双(二苯基膦)二茂铁]氯化钯(20mg)。反应液在100度下微波两小时并用液相质谱检测跟踪，反应结束后将反应液过滤，得到的滤液浓缩得到粗品产物。该粗品经制备级液相色谱柱分离得到目标化合物。
1H NMR(400MHz,DMSO-d6)ppmδ10.415(s,1H),9.087-9.084(d,2H),8.618(s,1H),8.487-8.481(d,1H),8.361-8.357(d,1H),8.338(s,1H),8.028-8.022(s,1H),7.883-7.860(d,1H),7.792-7.775(d,1H),7.597-7.575(d,1H),7.242-7.226(d,1H),3.687(s,3H).
参照化合物132的制备方法还合成了以下37个化合物：
Figure PCTCN2015081519-appb-000084
Figure PCTCN2015081519-appb-000085
Figure PCTCN2015081519-appb-000086
Figure PCTCN2015081519-appb-000087
Figure PCTCN2015081519-appb-000088
Figure PCTCN2015081519-appb-000089
流程14:
Figure PCTCN2015081519-appb-000090
反应条件：a)硫酸，乙醇，加热；b)1-叔丁氧--N,N,N',N'-四乙基甲二胺，加热；c)5-溴吡啶-2-胺，醋酸，加热；d)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例171
N-(5-(3-乙氧基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯甲磺酰胺
Figure PCTCN2015081519-appb-000091
a)乙基2-乙氧基醋酸酯
向置有2-乙氧基醋酸(20g,0.19mol)的乙醇(200mL)溶液加入硫酸(10mL)。将得到的反应液在100度下反应两小时。反应结束后，将反应液浓缩后用乙酸乙酯稀释，得到的有机相用水洗两次，经无水硫酸钠干燥后浓缩的黄色油状液体(19.5g,78％)。
b)(Z)-乙基-3-(二甲基胺)-2-甲氧基丙烯酸酯
将1-叔丁氧--N,N,N',N'-四乙基甲二胺(2.0g,0.011mol)和2-乙氧基醋酸乙酯(1.5g,0.011mol)混和后加热到80度，在该温度下搅拌12小时，然后浓缩得到黄色固体(420mg,20.4％)。
1H NMR(400MHz,CDCl3)δ6.80(s,1H),4.19-4.13(q,2H),4.05(s,1H),3.71-3.76(s,1H),3.03(s,6H),1.26-1.29(t,6H).
c)7-溴-3-乙氧基-4H-吡啶并[1,2-a]嘧啶-4-酮
将溶有(Z)-乙基-3-(二甲基胺)-2-甲氧基丙烯酸酯(50mg,0.267mmol)和5-溴吡啶-2-胺(46mg,0.267mmol)的醋酸溶液加热到90度搅拌过夜。反应结束有，将反应液浓缩，然后向该浓缩液中加入水(2mL)稀释，并用饱和碳酸钠溶液调节pH至7，接着用二氯甲烷萃取。将得到的有机相浓缩得到粗品产物。该粗品经快速色谱柱分离得到黄色固体目标化合物。
1H NMR(400MHz,CDCl3)δ9.11-9.12(d,1H),8.08(s,1H),7.54-7.56(d,1H),7.46-7.48(d,1H),4.2-4.25(q,2H),2.11(s,3H).
d)N-(5-(3-乙氧基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯甲磺酰胺
在氮气保护下，向溶有7-溴-8-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮(0.28mmol)的二氧六环(2mL)和水(0.4 mL)的混合液中加入2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基l-1,3,2-二氧硼-2-基)吡啶-3-基)苯甲磺酰胺(0.28mmol),碳酸钾(0.56mmol)和[1,1’-双(二苯基膦)二茂铁]氯化钯(20mg)。将得到的反应液在100度下微波两小时。反应用液相质谱进行跟踪监测，反应结束后，将反应物过滤，浓缩滤液得到粗品产物。该粗品制备级液相色谱分离得到目标化合物。
1H NMR(400MHz,DMSO-d6)ppmδ10.4(s,1H),8.95(s,1H),8.44(s,1H),8.22(s,1H),8.04-8.07(d,1H),7.98(s,1H),7.77-7.8(t,1H),7.98(s,1H),7.55-7.60(t,1H),7.21-7.25(t,1H),4.16-4.21(q,2H),3.69(q,3H),1.35-1.39(t,3H).
参照化合物171的制备方法还合成了以下3个化合物：
Figure PCTCN2015081519-appb-000092
实施例175
流程15:
Figure PCTCN2015081519-appb-000093
条件：a)2-溴乙基甲醚，碳酸钾，N,N-二甲基甲酰胺，加热；b)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
2,4-二氟-N-(2-甲氧基-5-(3-(2-甲氧基乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000094
a)7-溴-3-(2-甲氧基乙氧基)-4氢-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-3-羟基-4氢-吡啶并[1,2-a]嘧啶-4-酮(500mg,2.08mmol)，2-溴乙基甲醚(350mg,2.45mmol)和碳酸钾(830mg,6.24mmol)溶于N,N-二甲基甲酰胺(10mL)置于三颈圆底烧瓶中，110度搅拌反应3小时。混合物用水(10mL)洗涤，二氯甲烷(20mL*6)萃取，无水硫酸钠干燥，过滤，浓缩后得到黄色固体状标题化合物(250mg,40.4％)
b)2,4-二氟-N-(2-甲氧基-5-(3-(2-甲氧基乙氧基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-3-(2-甲氧基乙氧基)-4氢-吡啶并[1,2-a]嘧啶-4-酮(200mg,0.67mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-基)苯甲磺酰胺(257mg,0.60mmol)和碳酸钾(185mg,1.34mmol)溶于二氧六环(2.5mL)和水(0.5mL)置于三颈圆底烧瓶中，室温氮气保护下加入[1,1’-双(二苯基膦)二茂铁]氯化钯(49mg,0.067mmol)。将混合物置于微波条件下100度搅拌2小时。混合物加入水(5mL)，二氯甲烷(5mL*3)萃取，无水硫酸钠干燥，过滤，低压浓缩后，粗品用制备高效液相色谱法纯化得到绿色固体标题产物(25mg,24.8％)。
1H NMR(400MHz,DMSO-d6)ppmδ8.944(s,1H),8.413(s,1H),8.231(s,1H),8.069-8.046(d,1H),7.962(s,1H),7.791-7.755(t,1H),7.723-7.700(d,2H),7.562-7.539(d,1H),7.235-7.197(t,1H),4.248(s,2H),3.680(s,5H).
参照化合物175的制备方法还合成了以下41个化合物：
Figure PCTCN2015081519-appb-000095
Figure PCTCN2015081519-appb-000096
Figure PCTCN2015081519-appb-000097
Figure PCTCN2015081519-appb-000098
Figure PCTCN2015081519-appb-000099
Figure PCTCN2015081519-appb-000100
Figure PCTCN2015081519-appb-000101
流程16:
Figure PCTCN2015081519-appb-000102
反应条件：a)碳酸钾，N,N-二甲基甲酰胺；b)1-叔丁氧--N,N,N',N'-四乙基甲二胺；c)5-溴吡啶-2-胺，醋酸，加热；4)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，二氧六环，水，加热。
实施例216
2,4-二氟-N-(2-甲氧基-5-(3-(3-甲基-1H-吡唑-1-基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯甲磺酰胺
Figure PCTCN2015081519-appb-000103
a)2-(3-甲基-1H-吡唑-1-基)乙酸乙酯
将置于圆底烧瓶的3-甲基-1-H-吡唑(30g,365.9mmol)，溴乙酸乙酯(66.8g,402.4mmol)和碳酸钾(101g,731.8mmol)的N,N-二甲基甲酰胺(300mL)溶液回流过夜。将反应液冷却，然后加入100mL的水稀释并用二氯甲烷萃取(100mL*3)，将得到的二氯甲烷有机相经硫酸钠干燥浓缩得到粗品产物该粗品经硅胶色谱柱分离得黄色油状液体(11g,18.03％)。
1H NMR(400MHz,CDCl3)ppmδ7.43-7.35(q,1H),6.10-6.07(q,1H),4.84-4.82(d,2H),4.25-4.20(s,2H),2.36-2.26(q,3H),1.29-1.26(q,3H).
b)(E)-乙基-3-(二甲基胺)-2-(3-甲基-1H-吡唑-1-基)丙烯酸酯
将乙基2-(3-甲基-1H-吡唑-1-基)乙酸酯(4g,23.8mmol)和1-叔丁氧-N,N,N',N'-四乙基甲二胺(4.1g,23.8mmol)混合然后在100度下搅拌过夜。将反应液浓缩得到棕色的油状粗品(5g,94.34％)。
1H NMR(400MHz,CDCl3)ppmδ7.442(s,1H),6.080(s,2H),4.872-4.853(d,4H),3.778-3.729(t,6H),2.294-2.269(d,2H).
c)7-溴-3-(3-甲基-1H-吡唑-1-基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将置于圆底烧瓶的(E)-乙基-3-(二甲基胺)-2-(3-甲基-1H-吡唑-1-基)丙烯酸酯(3.5g,150.2mmol)和5-溴吡啶-2-胺(2.6g,150.2mmol)的醋酸溶液(30mL)在100度下微波两小时。反应液浓缩然后加入50mL的水稀释然后用二氯甲烷萃取(50mL)，将得到的二氯甲烷有机相经硫酸钠干燥浓缩得到粗品。该粗品经硅胶色谱柱分离得到呈黄色的固体(1.3g,28.4％)。
1H NMR(400MHz,CDCl3)ppmδ9.160(s,1H),8.622-8.616(d,1H),8.327-8.322(d,1H),7.772-7.743(m,1H),7.640-7.628(m,1H),6.297-6.291(s,1H),2.405(s,3H).
d)2,4-二氟-N-(2-甲氧基-5-(3-(3-甲基-1H-吡唑-1-基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯甲磺酰胺
在氮气保护下，向溶有7-溴-3-(3-甲基-1H-吡唑-1-基)-4H-吡啶并[1,2-a]嘧啶-4-酮(0.28mmol)的水(0.4mL)和二氧六环(2mL)混合液中加入2,4-二氟-N-(2-甲氧基-5(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-3-基)苯甲磺酰胺(0.28mmol)，碳酸钾(0.56mmol)和[1,1’-双(二苯基膦)二茂铁]氯化钯(20mg)。将得到的反应液在100度下微波两小时。反应用液相质谱检测，待反应完全后，将反应液过滤且浓缩得到粗品产物。该粗品经制备级液相色谱分离得到目标化合物。
1H NMR(400MHz,DMSO-d6)ppmδ9.159(s,1H),8.945(s,1H),8.582-8.577(d,1H),8.334-8.277(t,2H),7.939-7.889(t,2H),7.837-7.820(d,1H),7.519-7.473(t,1H),7.236-7.195(t,1H),6.376-6.371(d,1H),3.736(s,3H),2.314(s,1H).
参照化合物216的制备方法还合成了以下4个化合物：
Figure PCTCN2015081519-appb-000104
Figure PCTCN2015081519-appb-000105
流程17:
Figure PCTCN2015081519-appb-000106
反应条件：a)乙酰乙酸乙酯，多聚磷酸；b)R硼酸(硼酸酯)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例221
2,4-二氟-N-(2-甲氧基-5-(2-甲基-4-氧代-4氢-吡啶骈[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000107
a)7-溴-2-甲基-4氢-吡啶骈[1,2-a]嘧啶-4-酮
将含有5-溴吡啶盐酸盐-2-胺(2g，11.63mmol)和乙酰乙酸乙酯(2.3g，17.44mmol)的混合物溶解在多聚磷酸(10mL)中，在150度下搅拌30分钟。将混合物用乙酸乙酯洗涤，再用氢氧化钠溶液将混合体系的PH值调到大于9。乙酸乙酯溶液被分离开来，同时水相用乙酸乙酯(20mL*3)萃取，合并的有机相用无水硫酸钠干燥，旋干，过柱，得到目标化合物，为黄色固体(3.2g，70％)。
1H NMR(400MHz,CDCl3)ppmδ9.15(s,1H),7.76-7.78(d,1H),7.50-7.52(d,2H),6.36(s,1H),2.47(s,3H).
b)2,4-二氟-氮-(2-甲氧基-5-(2-甲基-4-氧代-4氢-吡啶骈[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-2-甲基-4氢-吡啶骈[1,2-a]嘧啶-4-酮(0.28mmol)溶解在二氧六环(2mL)和水(0.4mL)中，然后在充有氮气的环境下向该体系中加入2,4-二氟-氮-(2-甲氧基-5-(4,4,5,5-四甲基-1，3,2-二氧杂环硼烷-2-基)吡啶-3-基)苯磺酰胺(0.28mmol)，碳酸钾(0.56mmol)和1,1'-双(二苯基磷)二茂铁氯化钯(20mg)。用微波在100度下搅拌2小时。通过液相质谱看出该反应已经反应完全。将混合物过滤，然后旋干得到粗产品。然后将粗产品通过制备高效液相色谱法分离得到目标化合物。
1H NMR(400MHz,CD3OD)ppmδ9.13(s,1H),8.31(s,1H),8.21-8.23(d,1H),8.01(s,1H),7.91-7.93(m,1H),7.73-7.75(d,1H),7.22-7.27(m,1H),7.10-7.14(m,1H),6.43(s,1H),3.87(s,3H),2.50(s,3H).
参照化合物221的制备方法还合成了以下9个化合物：
Figure PCTCN2015081519-appb-000108
Figure PCTCN2015081519-appb-000109
Figure PCTCN2015081519-appb-000110
流程18:
Figure PCTCN2015081519-appb-000111
条件：a)5-溴-2-氯-3-硝基吡啶，R醇，氢氧化钾，碳酸钾，2-(2-甲氧基乙氧基)-N,N-二[2-(2-甲氧基乙氧基)乙基]乙胺，甲苯；b)4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷，1,1'-双(二苯基磷)二茂铁氯化钯，醋酸钾，二氧六环，加热；c)Pd/C，甲醇；d)7-溴-3-氯-吡啶并[1,2-a]嘧啶-4-酮，1,1'-双(二苯基磷)二茂铁氯化钯，碳酸钾，二氧六环，水，加热；e)2,4-二氟苯磺酰氯，吡啶。
实施例231
N-[5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-(2-甲氧基-乙氧基)-吡啶-3-基]-2,4-二氟-苯磺酰胺
Figure PCTCN2015081519-appb-000112
a)5-溴-2-(2-甲氧基乙氧基)-3-硝基吡啶
向加有氢氧化钾(1.20g,21.47mmol,1.70Eq)和碳酸钾(2.97g,21.47mmol,1.70Eq)的甲苯(30mL)混合液中加入5-溴-2-氯-3-硝基吡啶(3.00g,12.63mmol,1.00Eq)，2-甲氧基乙醇(1.15g,15.16mmol,1.20Eq)和2-(2-甲氧基乙氧基)-N,N-二[2-(2-甲氧基乙氧基)乙基]乙胺(816.96mg,2.53mmol,0.20Eq)。混合液在氮气保护下于15度搅拌18小时。反应完后，反应液过滤，滤液浓缩后经硅胶色谱柱纯化(PE:EA＝20:1-4:1)得到黄色固体状目标化合物(1.60g,5.77mmol,45.72％)。
1H NMR(400MHz,CDCl3)ppmδ8.41(d,J＝2.4Hz,1H),8.38(d,J＝2.2Hz,1H),4.70-4.53(m,2H),3.85-3.72(m,2H),3.43(s,3H)
b)2-(2-甲氧基乙氧基)-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶
向加有5-溴-2-(2-甲氧基乙氧基)-3-硝基-吡啶(1.60g,5.77mmol,1.00Eq),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷(1.76g,6.92mmol,1.20Eq)和醋酸钾(1.70g,17.31mmol,3.00Eq)的二样六环(20mL)混合液中加入1,1'-双(二苯基磷)二茂铁氯化钯(42.22mg,57.70umol,0.01Eq).此混合液在氮气保护下于90度搅拌18小时。反应经检测完成后，反应液过滤，滤液浓缩后得到棕色油状粗产品(2.50g,5.55mmol,产率：96.24％,纯度：72％)。
1H NMR(400MHz,CDCl3)ppmδ8.65(d,J＝1.5Hz,1H),8.57(d,J＝1.5Hz,1H),4.71-4.63(m,2H),3.86-3.75(m,2H),3.44(s,3H),1.34(s,12H)
c)2-(2-甲氧基乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-胺
向溶有2-(2-甲氧基乙氧基)-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶(1.50g,3.33mmol,1.00Eq)的甲醇(30mL)溶液中加入Pd/C(150.00mg)。混合液在氢气氛围下于18度搅拌2小时。反应经检测完成后，反应液过滤，滤液浓缩后得到黄色油状粗产品(1.40g,2.38mmol,产率：71.46％,纯度：50％)。
1H NMR(400MHz,CDCl3)ppmδ7.94(d,J＝1.5Hz,1H),7.23(d,J＝1.5Hz,1H),4.57-4.53(m,2H),3.78-3.75(m,2H),3.42(s,3H),1.32(s,12H)
d)7-(5-氨基-6-(2-甲氧基乙氧基)吡啶-3-基)-3-氯-4H-吡啶并[1,2-a]嘧啶-4-酮
向加有7-溴-3-氯-吡啶并[1,2-a]嘧啶-4-酮(200.00mg,770.74umol,1.00Eq),2-(2-甲氧基乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-3-胺(453.43mg,770.74umol,1.00Eq)和碳酸钾(319.57mg,2.31mmol,3.00Eq)的二氧六环(5mL)混合液中加入1,1'-双(二苯基磷)二茂铁氯化钯(5.64mg,7.71umol,0.01Eq)和水(1mL)。此混合液在氮气保护下于90度搅拌18小时。反应经检测完成后，反应液经无水硫酸钠干燥过滤，滤液减压浓缩。残余物经硅胶色谱柱纯化(DCM:MeOH＝1％-5％)后得到黄色固体状目标化合物(270.00mg,622.89umol,产率：80.82％,纯度：80％)。
1H NMR(400MHz,CDCl3)δ9.17(d,J＝1.7Hz,1H),8.47(s,1H),7.97(dd,J＝2.1,9.2Hz,1H),7.79(d,J＝2.0Hz,1H),7.75(d,J＝9.3Hz,1H),7.13(d,J＝2.2Hz,1H),4.62-4.53(m,2H),4.06(br.s.,2H),3.82-3.76(m,2H),3.44(s,3H)
e)N-[5-(3-氯-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-(2-甲氧基-乙氧基)-吡啶-3-基]-2,4-二氟-苯磺酰胺
向加有7-[5-氨基-6-(2-甲氧基乙氧基)吡啶-3-基]-3-氯-吡啶并[1,2-a]嘧啶-4-酮(125.00mg,288.38umol,1.00Eq)的吡啶(3mL)混合液中加入2,4-二氟苯磺酰氯(91.96mg,432.57umol,1.50Eq)。混合液在15度下反应4小时。反应完成后，反应液浓缩。残余物溶于二氯甲烷并用水、盐水洗涤。有机相经污 水硫酸钠干燥后浓缩。所得残余物经制备级薄层色谱法纯化得到黄色固体状目标化合物(51.32mg,98.14umol,34.03％)。
1H NMR(400MHz,CDCl3)δ9.12(d,J＝1.7Hz,1H),8.49(s,1H),8.11(d,J＝2.2Hz,1H),7.98(d,J＝2.2Hz,1H),7.96-7.85(m,2H),7.78(d,J＝9.3Hz,1H),7.47(s,1H),7.01(t,J＝8.2Hz,1H),6.97-6.89(m,1H),4.56-4.47(m,2H),3.76-3.67(m,2H),3.42(s,3H)
参照实化合物232的制备方法还合成了以下2个化合物：
Figure PCTCN2015081519-appb-000113
流程19:
Figure PCTCN2015081519-appb-000114
条件：a)水合肼，乙醇，加热；b)1,1-羰基二咪唑，乙腈，加热；c)碳酸铯，碘甲烷，N,N-二甲基甲酰胺；d)R硼脂(硼酸)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，碳酸钾，二氧六环，水，加热。
实施例234
2,4-二氟-N-(2-甲氧基-5-(2-甲基-3-氧代-2,3-二氢-[1,2,4-]三唑[4,3-a]吡啶-6-基)吡啶)-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000115
a)5-溴-2-亚肼基-2,3-二氢吡啶
向5-溴-2-氟吡啶(2g,11.36mmol)的乙醇(25mL)溶液中加入水合肼(8g)，将反应液加热到80度并搅拌反应16h。混合液冷却至室温，减压浓缩除去一半溶剂，过滤，收集滤饼。真空干燥得粗品目标产物。
b)6-溴-[1,2,4]三唑[4,3-a]吡啶-3(2H)-酮
将6-溴-[1,2,4]三唑[4,3-a]吡啶-3(2H)-酮(1g,5.32mmol)和1，1-羰基二咪唑(948mg,8.85mmol)的乙腈(10mL)溶液升温至85度，并回流搅拌2h。反应液冷至室温，继续搅拌16h。静置，过滤，收集滤饼，干燥得粗品目标产物。
c)6-溴-2-甲基-[1,2,4]三唑[4,3-a]吡啶-3(2H)-酮
向6-溴-[1,2,4]三唑[4,3-a]吡啶-3(2H)-酮(150mg,0.7mmol)的无水DMF(3mL)溶液中依次加入碳酸铯(685mg,2.1mmol)和碘甲烷(0.26mL,4.2mmol)。反应液在20度搅拌16小时。将反应液用乙酸乙酯稀释，过滤除去固体。滤液用饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩得到黄色固体目标产物(140mg,87.5％)。
1H NMR(400MHz,CDCl3)ppmδ3.67(s,3H)6.97-7.03(m,1H)7.07-7.13(m,1H)7.92(s,1H)
d)2,4-二氟-N-(2-甲氧基-5-(2-甲基-3-氧代-2,3-二氢-[1,2,4-]三唑[4,3-a]吡啶-6-基)吡啶)-3-基)苯磺酰胺
氮气保护下，向6-溴-2-甲基l-[1,2,4]三唑[4,3-a]吡啶-3(2H)-酮(112mg,0.49mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-3-基)苯磺酰胺(200mg,0.47mmol)和碳酸钠(124mg,1.17mmol)的1,4-二氧六环(3mL)和水(1.2mL)的混合溶液中加入[1,1’-双(二苯基膦)二茂铁]氯化钯(10mg)，反应液升温至80摄氏度并搅拌16小时。反应液过滤，滤液用水稀释，水相用乙酸乙酯(15mL*3)萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残渣用制备用层析板(DCM:MeOH＝15:1)分离得白色粉末状目标化合物(50mg，23.81％)。
1H NMR(400MHz,CDCl3)ppm 3.71(s,3H)3.96(s,3H)6.91-7.01(m,2H)7.17-7.23(m,2H)7.79-7.87(m,2H)7.88-7.93(m,1H)8.01(d,J＝2.20Hz,1H)
参照化合物234的制备方法还合成了以下1个化合物：
Figure PCTCN2015081519-appb-000116
Figure PCTCN2015081519-appb-000117
流程20:
Figure PCTCN2015081519-appb-000118
条件：a)丙二酰氯，二氯甲烷，室温；b)三氯氧磷，回流；c)R1胺，加热；d)R2硼，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，K2CO3，二氧六环，水，加热。
实施例236
N-(5-(2-氨基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
Figure PCTCN2015081519-appb-000119
a)7-溴-2-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮
将2-氨基-5-溴吡啶(10.0g，57.8mmol)溶于二氯甲烷(100mL)置于250mL圆底烧瓶中，0度下滴加丙二酰氯(9.78g，69.36mmol)。滴加完后将反应液升至15度，15度搅拌反应48小时。质谱液相联用仪显示反应完全。将反应液过滤，滤饼用二氯甲烷(200mL)淋洗后得到黄色固体状标题化合物(13g，84％)。
b)7-溴-2-氯-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-2-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮(7g，29mmol)溶于三氯氧磷(50mL)置于100mL圆底烧瓶中，120度搅拌反应18小时。质谱液相联用仪显示反应完全。将反应液冷却至室温，缓慢倒入常温水(1L)中淬灭，用乙酸乙酯(300mL*6)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩后得到粗品。粗品用硅胶柱色谱法纯化得到黄色固体状标题化合物(2.9g，37％)。
1H NMR(400MHz,DMSO-d6)ppmδ9.01(d,1H),8.23(dd,1H),7.67(d,1H),6.58(s,1H).
c)2-氨基-7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-2-氯-4H-吡啶并[1,2-a]嘧啶-4-酮(1g，3.85mmol)溶于液氨-乙醇(30mL-15mL)置于100mL 闷罐中，80度反应48小时。质谱液相联用仪显示反应完全。将反应液浓缩后得到粗品。粗品用硅胶柱色谱法纯化得到紫色固体状标题化合物(90mg，9.7％)。
1H NMR(400MHz,DMSO-d6)ppmδ8.78(d,1H),7.85(dd,1H),7.17(d,1H),6.86(br.s.,2H),5.26(s,1H).
d)N-(5-(2-氨基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)-2-甲氧基吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
将2-氨基-7-溴-4H-吡啶并[1,2-a]嘧啶-4-酮(72mg，210umol)溶解在二氧六环(5mL)和水(1mL)中，加入N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺(89mg，210umol)，碳酸钾(87mg，630umol)和[1,1’-双(二苯基膦)二茂铁]氯化钯(10mg)。反应液100度搅拌反应18小时。质谱液相联用仪显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到白色固体状标题产物(30mg，30％)。
1H NMR(400MHz,CDCl3)ppmδ9.11(d,1H),8.16(d,1H),7.99(d,1H),7.81(dd,1H),7.42(d,1H),7.17(br.s.,1H),5.59(s,1H),4.87(br.s.,2H),3.97(s,3H),2.65(s,3H),2.57(s,3H).
参照化合物236的制备方法还合成了以下2个化合物：
Figure PCTCN2015081519-appb-000120
流程21:
Figure PCTCN2015081519-appb-000121
条件：a)二甲基2-(甲氧基甲烯基)丙二酸酯，乙醇，加热；b)三溴氧磷，加热；c)DIBAL-H，四氢呋喃，0度；d)碘甲烷，钠氢，四氢呋喃，0-15度；e)R硼脂(硼酸)，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，K2CO3，二氧六环，水，加热。
实施例239
N-(2-甲氧基-5-(3-(甲氧甲基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
Figure PCTCN2015081519-appb-000122
a)二乙基2-(((5-溴代吡啶-2-基)胺基)甲烯基)丙二酸酯
将5-溴代吡啶-2-胺基(5g,28.9mmol)和二甲基2-(甲氧基甲烯基)丙二酸酯(5.84g,28.9mmol)溶于乙醇(50mL)中，80度下搅拌4小时。反应物冷却至室温，过滤，滤饼用石油醚洗，抽干得到得白色固体标题化合物(8.0g,81％)。
1H NMR(400MHz,CDCl3)ppmδ11.12(d,1H),9.08(d,1H),8.40(d,1H),7.76(dd,1H),6.78(d,1H),4.41-4.19(m,4H),1.37(td,6H).
b)甲基7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-羧酸酯
将二乙基2-(((5-溴代吡啶-2-基)胺基)甲烯基)丙二酸酯(3.0g,8.74mmol)和三溴氧磷(9.27g,32.35mmol)置于圆底烧瓶中，混合物在80度下搅拌4小时。反应物冷却至室温，慢慢倒入冰水中，用饱和碳酸钠溶液调节pH到8，用二氯甲烷萃取，所得有机相用饱和食盐水(100mL)洗，硫酸钠干燥、浓缩得到黄色固体标题化合物(2.0g,76.9％)。
1H NMR(400MHz,CDCl3)ppmδ9.36(d,1H),9.05-8.98(m,1H),7.96(dd,1H),7.65(d,1H),4.42(q,2H),1.47-1.37(m,3H).
c)7-溴-3-(羟甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将甲基7-溴-4-氧代-4H-吡啶并[1,2-a]嘧啶-3-羧酸酯(800mg，2.69mmol)溶解在四氢呋喃(20mL)中，在0度下加入DIBAL-H(4mL)。反应液0度反应3小时。将饱和氯化铵溶液(20mL)加入到反应液中淬灭，用乙酸乙酯(20mL*3)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩后得到粗品。粗品用硅胶柱色谱法纯化得到标题化合物(110mg，16％)。
d)7-溴-3-(甲氧甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮
将7-溴-3-(羟甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮(110mg，431umol)溶解在四氢呋喃(3mL)中，在0度下加入钠氢(26mg，647umol，纯度60％)。反应液在20度搅拌反应1小时后加入碘甲烷(183mg，1.29mmol)，反应液20度搅拌反应6小时。质谱液相联用仪显示反应完全。将反应液倒入冰水(30mL)中淬灭，用乙酸乙酯(20mL*3)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩得到粗品。粗品用制备薄层色谱法纯化得到标题化合物(23mg，19.8％)。
e)N-(2-甲氧基-5-(3-(甲氧甲基)-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰 胺
将7-溴-3-(甲氧甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮(23mg，85umol)溶解在二氧六环(2.5mL)和水(0.5mL)中，加入N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺(36mg，85umol)，碳酸钾(24mg，170umol)和[1,1’-双(二苯基膦)二茂铁]氯化钯(10mg)。将混合物置于微波条件下100度反应1小时。质谱液相联用仪显示反应完全。将反应液浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到浅黄色固体状标题产物(18mg，43.2％)。
1H NMR(400MHz,CDCl3)ppmδ9.20(s,1H),8.42(s,1H),8.18(d,1H),8.03(s,1H),7.98-7.85(m,2H),7.20(s,1H),4.57(s,2H),3.99(s,3H),3.50(s,3H),2.64(s,3H),2.57(s,3H),1.23(s,2H).
流程22：
Figure PCTCN2015081519-appb-000123
条件：a)LDA，四氢呋喃，-78℃；b)Rh试剂，甲苯，加热；c)5-溴吡啶-2-胺，醋酸，110度；d)R硼脂，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，K3PO4，四氢呋喃，水，加热。
实施例240
2-甲氧基-5-(11-氧代-2,3,4,11-四氢吡喃并[3,2-d]吡啶并[1,2-a]嘧啶-8-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
Figure PCTCN2015081519-appb-000124
a)2-重氮基-6-羟基-3-氧代己酸乙酯
将重氮乙酸乙酯(6.00g,52.59mmol)和四氢呋喃(60mL)置于三颈圆底烧瓶中，在-78度、氮气保护下缓慢滴加二异丙基氨基锂(5.63g，52.59mmol)，-78度搅拌反应0.5小时。在-78度、氮气保护下缓慢滴加四氢呋喃-2-酮(4.07g,47.33mmol)，-78度搅拌反应2小时。TLC显示反应完全，向混合物中加入饱和氯化铵(300mL)，用乙酸乙酯(200mL x 3)萃取,合并有机相，用饱和食盐水(200mL x 2)洗涤，无水硫酸钠干燥，过滤，浓缩，用硅胶色谱法得到标题化合物(4.00g，38％)。
1H NMR(400MHz,CDCl3)ppmδ1.34(t,3H),1.90-1.97(m,2H),3.00(t,2H),3.70(t,2H),4.32(q,2H).
b)3-氧代四氢-2H-吡喃-2-甲酸乙酯
将2-重氮基-6-羟基-3-氧代己酸乙酯(316.00mg,1.58mmol)，甲苯(40mL)置于250mL圆底烧瓶中，在80度、氮气保护下缓慢滴加醋酸铑二聚物(6.29mg,14.22umol)的甲苯溶液(40mL)，80度搅拌反应1小时。TLC显示反应完全，将反应液冷却至室温，用硅胶柱色谱法纯化得到标题化合物(180mg，产率：67％)。
1H NMR(400MHz,CDCl3)ppmδ1.34(t,3H),1.94-1.98(m,2H),2.38(t,2H),3.95(t,2H),4.33(q,2H),10.36(s,1H).
c)8-溴-3,4-二氢吡喃并[3,2-D]吡啶并[1,2-a]嘧啶11(2H)-酮
将3-氧代四氢-2H-吡喃-2-甲酸乙酯(90mg，0.53mmol)，2-氨基-5-溴吡啶(90.44mg,0.53mmol)溶解在乙酸(2mL)中。混合物在110度反应5小时。液相质谱显示反应完全。将反应液浓缩后得到粗品。粗品用制备薄层层析法纯化得到标题产物(25mg，产率：17％)。
d)2-甲氧基-5-(11-氧代-2,3,4,11-四氢吡喃并[3,2-d]吡啶并[1,2-a]嘧啶-8-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺
向8-溴-3,4-二氢吡喃并[3,2-D]吡啶并[1,2-a]嘧啶11(2H)-酮(15.00mg,0.054mmol)四氢呋喃(4mL)和水(1mL)的溶液中加入[5-[(2,4-二甲基噻唑-5-基)磺酰基]-6-甲氧基-3-吡啶基]硼酸(18.31mg,0.054mmol)，K3PO4(33.98mg,0.16mmol)，[1,1’-双(二苯基膦)二茂铁]氯化钯(3.48mg,0.0054mmol)，混合物在80度反应5小时。液相质谱显示反应完全。将反应液过滤浓缩后得到粗品。粗品用制备高效液相色谱法纯化得到标题产物(12.00mg，产率：27％)。
1H NMR(400MHz,CDCl3)ppmδ2.14-2.20(m,2H),2.45(s,3H),2.61(s,3H),2.91(t,2H),3.85(s,3H),4.30(t,2H),7.58(dd,1H),7.91(dd,1H),8.06(d,1H),8.30(d,1H),8.96(d,1H).
流程23：
Figure PCTCN2015081519-appb-000125
条件：a)溴乙酸甲酯，氢氧化钾，碳酸钾，二氯甲烷，40度；b)1-叔丁氧基-N,N,N',N'-四甲基-甲烷二胺，甲苯，加热；c)5-溴吡啶-2-胺，醋酸，110度；d)R硼脂，钯试剂(四三苯基膦钯，[1,1’-双(二苯基膦)二茂铁]氯化钯等)，K3PO4，四氢呋喃，水，加热。
实施例241
2,4-二氟-氮-(2-甲氧基-5-(3-吗啉基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
Figure PCTCN2015081519-appb-000126
a)甲基2-吗啉代乙酸酯
将吗啡啉(2.00g,22.9mmol)，溴乙酸甲酯(4.80g,31.4mmol)，氢氧化钾(1.33g,23.6mmol)，碳酸钾(3.30g,23.9mmol)和二氯甲烷(50mL)置于100mL圆底烧瓶中，室温下搅拌12小时，然后在40度下搅拌6小时。TLC显示反应完全，将反应液冷却至室温，用饱和食盐水(10mL x 3)水洗，用无水硫酸钠干燥、过滤、浓缩，残渣用硅胶柱色谱法(石油醚/乙酸乙酯，1/3)纯化得到标题化合物(2.80g,77％)1H NMR(400MHz,CDCl3)ppmδ2.56-2.59(m,4H)，3.22(s,2H),3.73(s,3H),3.74-3.76(m,4H).
b)7-甲基(E)-3-(二甲基氨基)-2-吗啉代-丙-2-烯酸甲酯
将甲基2-吗啉代乙酸酯(1.80g,11.3mmol)，1-叔丁氧基-N,N,N',N'-四甲基-甲烷二胺(2.36g,13.6mmol)和甲苯(50mL)置于100mL圆底烧瓶中，120度搅拌反应10小时。TLC显示反应完全，将反应液浓缩得到标题化合物(2.08g，86％)，无需纯化，直接用于下一步反应。
c)7-溴-3-吗啉代-2,3-二氢吡啶并[1,2-a]嘧啶-4-酮
将7-甲基(E)-3-(二甲基氨基)-2-吗啉代-丙-2-烯酸甲酯(300mg,1.40mmol)，5-溴-2-氨基吡啶(484mg,2.80mmol)和醋酸(5mL)置于10mL圆底烧瓶中，加热回流4小时。质谱液相联用仪显示反应完成。将反应液浓缩，残渣用硅胶柱色谱法(石油醚/乙酸乙酯，5/1～1/1)纯化得到标题化合物(80mg,18％)。
1H NMR(400MHz,CD3OD)ppmδ3.23-3.25(m,4H),3.88-3.90(m,4H),7.52(d,1H),7.77-7.80(m,1H),8.02(s,1H),9.09(s,1H).
d)2,4-氟-N-(2-甲氧基-5-(3-吗啉基-4-氧代-4H-吡啶并[1,2-a]嘧啶-7-基)吡啶-3-基)苯磺酰胺
将7-溴-3-吗啉代-2,3-二氢吡啶并[1,2-a]嘧啶-4-酮(50mg，0.160mmol)，2,4-二氟-N-[2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3-吡啶基]苯磺酰胺(68mg，0.160mmol)，磷酸钾(68mg，0.320mmol)，四氢呋喃(1mL)和水(0.1mL)置于10mL圆底烧瓶中，在氮气保护下，加入1,1'-双(二-叔-丁基膦)二茂铁二氯化钯(10mg)。反应在70度下搅拌2个小时。质谱液相联用仪显示反应完成。将反应液浓缩，残渣用制备高效液相色谱法纯化得到标题产物(20mg,24％)。
1H NMR(400MHz,DMSO-d6)ppmδ3.16-3.25(m,4H),3.69(s,3H),3.75-3.83(m,4H),7.17-7.27(m,1H),7.55-7.13(m,1H),7.70(d,1H),7.78-7.80(m,1H),7.98(s,1H),8.03(s,1H),8.44(s,1H),8.98(s,1H).
参照化合物175的制备方法还合成了以下43个化合物：
Figure PCTCN2015081519-appb-000127
Figure PCTCN2015081519-appb-000128
Figure PCTCN2015081519-appb-000129
Figure PCTCN2015081519-appb-000130
Figure PCTCN2015081519-appb-000131
Figure PCTCN2015081519-appb-000132
Figure PCTCN2015081519-appb-000133
Figure PCTCN2015081519-appb-000134
Figure PCTCN2015081519-appb-000135
实验例体外细胞活性测试
实验步骤和方法：
1.将MCF-7细胞以每孔2.5×104个的密度种进96孔板中(使用的培养液需为含10％FBS的完整培养液)。
2.第二天将孔中的培养液抽走，将某一个浓度(初步筛选)或一系列浓度(IC50测试)的化合物溶解在不含血清的培养液中，加入96孔板培养细胞2小时。
3.把胰岛素溶解在不含血清的培养液中，加入细胞培养30分钟，胰岛素终浓度为10微克/毫升。
4.等待反应时，按如下方法准备裂解液：
a)增强液(Enhancer Solution)需要提前从冰箱里取出融化。
b)将增强液(Enhancer Solution)用5X的裂解缓冲液(Lysis Buffer)稀释10倍，制备成浓缩裂解液。
c)将浓缩裂解液用双蒸水稀释5倍，制成裂解液。
5.将孔内的培养液吸净，并用PBS迅速的润洗一次。
6.每个孔加入150微升新鲜制备的裂解液，然后室温震荡10分钟。
7.确认所有细胞都已脱落后，将裂解液同细胞碎片一起转移到1.5毫升管内。
8.涡旋几次，使裂解液和细胞完全混合，然后将混合液在4℃用12000g离心10分钟。
9.计算出需要的ELISA-one微板条的数目。把多出的微板条从框架上取下，放回储存袋中密封好。使用微板条之前，先用200微升双蒸水润洗一下每个孔，以除去上面的防腐剂。
10.往每个孔中加入50微升的抗体混合液。(抗体混合液是通过将媒介抗体试剂和酶标抗体试剂等比例混合而成，注意制备抗体混合液时不要涡旋)
11.向ELISA-One微板的每个孔中加入25微升细胞裂解产物。用粘性封口膜盖住微板，室温下在微板震荡仪上孵育1小时。
12.每个孔用150微升1X清洗缓冲液洗3次。最后一次洗完后，将孔内的清洗缓冲液抽净。如果需要，可让1X清洗缓冲液在微板中停留最长30分钟，以留出时间准备底物混合液。
13.底物混合液应随用随配。向每个孔内加入100微升底物混合液，然后用锡箔纸封住微板，室温下在微板震荡仪上孵育10分钟。
14.向每个孔内加入10微升终止液，然后在微板震荡仪上稍微(5-10秒)混匀一下。
15.装配好相应的ELISA-One滤镜组，读出荧光信号强度。
实验结果见表1：
表1体外细胞活性测试结果
Figure PCTCN2015081519-appb-000136
Figure PCTCN2015081519-appb-000137
Figure PCTCN2015081519-appb-000138
Figure PCTCN2015081519-appb-000139
Figure PCTCN2015081519-appb-000140
Figure PCTCN2015081519-appb-000141
Figure PCTCN2015081519-appb-000142
注：A≤50nM；50nM＜B≤100nM；100nM＜C≤250nM；250nM＜D；NT表示未测。
结论：本发明化合物对mTOR/PI3K抑制作用显著。
实验例体外酶活性测试
1.PI3K(p110α)激酶测试实验步骤和方法：
1)实验目的
评价受试样品对PI3K(p110α)激酶活性在分子水平的抑制。
2)实验方法
PI3K HTRF Assay
a)主要仪器
多标记微孔板检测仪PerkinElmer Envision 2104Multilabel Reader。
b)主要试剂
PI 3-Kinase HTRF Assay(384wells)购自Upstate(Millipore)公司；PI3K(p110α)激酶为自制酶。
c)实验步骤
按照激酶PI 3-Kinase HTRF Assay中所提供的说明书准备好各溶液。激酶反应在白色384孔板(Proxiplate-384plus)中进行，分别向加酶和不加酶的两个对照孔中加入0.5μl的DMSO(浓度与待测化合物最高浓度DMSO含量相一致)，再向各待测孔中加入0.5μl的一系列各浓度的待测化合物。向加酶的对照孔以及待测的各孔中加入激酶反应液(10μM底物PIP2，0.5ng PI3K(p110α))，向未加酶的对照孔中仅加入工作反应液(10μM底物PIP2)，最后加入5μM ATP工作反应液激活该反应。在室温反应30min后向各孔中加入终止液以终止激酶 反应。充分混合后向各孔中加入检测液，充分混合，用封口膜封闭后放到暗处孵育过夜后检测。检测仪所设定的条件如下表所示。
表2.多标记微孔板检测仪设定条件
Figure PCTCN2015081519-appb-000143
HTRF(均相时间分辨荧光)数值按照下面的公式进行计算：
HTRF Radio＝Emission at 665nm/Emission at 620nm×10000
相对抑制率(％)＝(测试孔的HTRF值-加酶的对照孔的HTRF值)/(不加酶的对照孔的HTRF值-加酶的对照孔的HTRF值)×100
相对抑制率对浓度作图通过GraphPad软件计算后得到IC50值。
2.mTOR激酶测试实验步骤和方法：
1)实验目的
评价受试样品mTOR激酶活性在分子水平的抑制。
2)实验方法
mTOR Kinase Assay
a)主要仪器
多标记微孔板检测仪PerkinElmer Envision 2104Multilabel Reader。
b)主要试剂
mTOR Kinase Assay(384wells)购自PerkinElmer公司；mTOR激酶为自制酶。
c)实验步骤
按照mTOR Kinase Assay中所提供的说明书准备好各种缓冲液。激酶反应在白色384孔板(Proxiplate-384plus)中进行，分别向加酶和不加酶的两个对照孔中加入2.5μl的DMSO(浓度与待测化合物最高浓度DMSO含量相一致)，再向各待测孔中加入2.5μl的一系列各浓度的待测化合物。向加酶的对照孔及待测的各孔中加入ULight-4E-BP1(Thr37/46)Peptide/ATP mix(ATP终浓度为100μM)和5μl mTOR激酶，充分混合后，用封口膜封闭孵育2h。随后加入5μl Stop Solution，孵育5min后，加入5μl Detection Mix(Eu-anti-phospho-4E-BP1(Thr37/46)Antibody终浓度为2nM)，孵育1h后进行检测。检测仪所设定的条件如下表所示。
表3.多标记微孔板检测仪设定条件
Figure PCTCN2015081519-appb-000144
HTRF(均相时间分辨荧光)数值按照下面的公式进行计算：
HTRF Radio＝Emission at 665nm/Emission at 615nm×10000
相对抑制率(％)＝{1-(测试孔的HTRF值-加酶的对照孔的HTRF值)/(加酶的对照孔的HTRF值-不加酶的对照孔的HTRF值)}×100％
相对抑制率对浓度作图通过GraphPad软件计算后得到IC50值。
实验结果见表4：
表4体外酶活性测试结果
Figure PCTCN2015081519-appb-000145
Figure PCTCN2015081519-appb-000146
注：A≤1nM；1nM<B≤10nM；10nM<C≤50nM；50nM<D≤100nM。
体内药效实验部分:
研究受试药物在卵巢癌SK-OV-3动物模型,以及前列腺癌PC-3M动物模型是否具有体内药效。有关实验中对动物饲养，饲料成分，实验观察，实验指标，实验终止以及数据分析的描述如下：
■动物饲养：动物到达后在实验环境饲养3－7天后方能开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养(每笼5只)。所有笼具、垫料及饮水在使用前均需灭菌，灭菌消毒记录见附件。所有实验人员在动物房操作时应穿着防护服和乳胶手套。每笼动物信息卡应注明笼内动物数目，性别，品系，接收日期，给药方案，实验编号，组别以及实验开始日期。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下：
√温度：20～26℃
√湿度：40～70％
√光照周期：12小时光照，12小时无光照
■饲料成分：饲料符合实验动物食物鉴定标准。污染物最高含量在可控范围内并由生产厂家负责例检。饮水采用高压灭菌的饮用水。
■动物分组：给药前称重动物，测量瘤体积。根据瘤体积随机分组(随机区组设计)。
■观察：本实验方案的拟定及任何修改将在上海药明康德实验动物伦理委员会(IACUC)进行评估核准后方可实行。实验动物的使用及福利将遵照国际实验动物评估和认可委员会(AAALAC)的规则执行。每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动，摄食摄水量，体重变化(每周测量两次体重)，外观体征或其它不正常情况。基于各组动物数量记录组内动物死亡数和副作用，相关记录见附件。
■实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效(TGI)用T-C(天)和T/C(％)评价。T-C(天)反映肿瘤生长延迟指标，T表示用药组肿瘤达到预先设定体积 (如1,000mm3)所用的平均天数，C表示对照组肿瘤达到相同体积所用的平均天数。T/C(％)的百分比值反映肿瘤生长抑制率，T和C分别表示给药组和对照组在某一天的瘤重(瘤体积)。
肿瘤生长抑制率用下列公式计算:TGI(％)＝[1-(Ti-T0)/(Vi-V0)]×100,其中Ti为某一天某给药组的平均肿瘤体积，T0为此给药组在开始给药时的平均肿瘤体积；Vi为某一天(与Ti同一天)溶媒对照组的平均肿瘤体积，V0为溶媒对照组在给开始药时的平均肿瘤体积。在实验结束后将检测肿瘤重量，并计算T/C百分比，T和C分别表示给药组和溶媒对照组的瘤重。
■实验终止：若动物健康状况持续恶化，或瘤体积超过2,000mm3，或有严重疾病，或疼痛，须处以安乐死。有以下情况者，通知兽医并处以安乐死：
√明显消瘦，体重降低大于20％；
√不能自由取食和饮水；
√对照组瘤体积平均值达到2,000mm3，实验终止。
√动物出现以下临床表现且持续恶化：
o立毛
o弓背
o耳、鼻、眼或足色发白
o呼吸仓促
o抽搐
o连续腹泻
o脱水
o行动迟缓
o发声
■数据分析：三组或多组间比较用one-way ANOVA。如果F值有显著性差异，应在ANOVA分析之后再进行多重比较。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
受试药物对人卵巢癌SK-OV-3细胞皮下异种移植肿瘤模型体内药效实验：
实验设计
■细胞培养：人卵巢癌SK-OV-3细胞(ATCC,马纳萨斯,弗吉尼亚州,批号：HTB-77)体外单层培养，培养条件为McCoy’s 5A培养基中加10％胎牛血清，100U/ml青霉素和100μg/ml链霉素，37℃ 5％CO2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。
■动物：BALB/c裸小鼠，雌性，4周龄，体重12-14克。由上海西普尔-必凯实验动物有限公司提供。
■肿瘤接种：将0.2ml(1×107)SK-OV-3细胞(加基质胶，体积1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约100-200mm3时开始分组给药。
■体内药效结果：见图1。
研究受试药对人前列腺癌PC-3M细胞皮下异种移植肿瘤模型的体内药效学研究：
实验目的：研究受试药对人前列腺癌PC-3M细胞皮下异种移植肿瘤模型具有体内药效。
实验设计
■细胞培养：人前列腺癌PC-3M细胞，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/ml青霉素和100μg/ml链霉素，37℃ 5％CO2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。
■动物：BALB/c裸小鼠，雄性，4周龄，体重12-14克。由上海西普尔-必凯实验动物有限公司提供。
■肿瘤接种：将0.2ml(1×107)PC-3M细胞皮下接种于每只小鼠的右后背，肿瘤平均体积达到约150～200mm3时开始分组给药。实验分组和给药方案见下表。
■体内药效结果：见图2-1、图2-2、图2-3a和图2-3b。

Claims (10)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐
    Figure PCTCN2015081519-appb-100001
    其中，
    可将结构单元
    Figure PCTCN2015081519-appb-100002
    替换为
    Figure PCTCN2015081519-appb-100003
    E选自任选被12或3个R3取代的C1-6烷基、3～10元环烃基或杂环烃基；
    L和Q中，一个选自-C(R3)(R3)-、-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-，另一个选自单键或-C(R3)(R3)-；A、T分别独立地选自N或C(R3)；
    X、Y、Z中的0或1个选自N，其余选自C(R3)；
    B选自-C(R3)(R3)-、-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-；
    杂原子或杂原子团分别独立地选自-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-；
    m1分别独立地选自0、1、2或3；
    R1-3分别选自H、F、Cl、Br、I、CN、ORa、N(Rb)(Rc)、任选被Rd取代的C1-3烷基、
    Figure PCTCN2015081519-appb-100004
    Figure PCTCN2015081519-appb-100005
    D1选自单键、-C(Re)(Re)-、-C(＝O)N(Ra)-、-N(Ra)-、-C(＝NRa)-、-S(＝O)2N(Ra)-、-S(＝O)N(Ra)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(Ra)C(＝O)N(Ra)-；
    D2选自-C(Ra)(Ra)-；
    n选自1、2、3、4、5或6；
    Ra、Rb、Rc分别独立地选自H、任选Rd取代的C1-6烷基或C3-6环烷基；
    Re选自H、任选Rd取代的C1-6烷基或烷氧基、任选Rd取代的C3-6环烷基或环烷氧基；
    Rd选自F、Cl、Br、I、CN、OH、CHO、COOH、CH3、CF3、CH3O、CH3CH2O,Rd的数目选自0、1、 2或3；
    任选地，任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间共同连接到同一碳原子或氧原子上形成一个或两个3、4、5或6元碳环或氧杂环，其中氧原子的数目为1或2。
  2. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其中，E选自被R3取代的C1-6烷基或C3-6环烷基，R3的数目选自0、1、2或3，或者E选自
    Figure PCTCN2015081519-appb-100006
    Figure PCTCN2015081519-appb-100007
    其中，
    G1～5中的0、1、2或3个选自N，其余选自C(R3)；
    G6选自-C(R3)(R3)-、-C(＝O)N(R3)-、-N(R3)-、-C(＝NR3)-、-S(＝O)2N(R3)-、-S(＝O)N(R3)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R3)C(＝O)N(R3)-；
    G7～9中的0、1或2个选自N，其余选自C(R3)；
    G10～16中的0、1、2、3或4个选自N，其余选自C(R3)；
    G17选自N或者C(R3)；
    G18～22中的0、1、2或3个选自-C(＝O)N(R3)-、-N(R3)-、-C(＝NR3)-、-S(＝O)2N(R3)-、-S(＝O)N(R3)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R3)C(＝O)N(R3)-，其余选自-C(R3)(R3)-；
    其余变量如权利要求1所定义。
  3. 根据权利要求2所述的式(I)所示化合物或其药学上可接受的盐，其中，E选自任选被1、2或3个R3取代的甲基、乙基、丙基、
    Figure PCTCN2015081519-appb-100008
    Figure PCTCN2015081519-appb-100009
  4. 根据权利要求3所述的式(I)所示化合物或其药学上可接受的盐，其中，E选自任选被1、2、或3个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)、N(C1-3烷基)2、C1-3烷基、三氟甲基、三氟乙基、C(＝O)NH2、C1-3烷基C(＝O)、C1-3烷基C(＝O)NH、C1-3烷基S(＝O)、C1-3烷基S(＝O)NH、C1-3烷基S(＝O)2或C1-3烷基 S(＝O)2NH所取代的：
    Figure PCTCN2015081519-appb-100010
    Figure PCTCN2015081519-appb-100011
    C1-3烷基；
    任选地，E选自
    Figure PCTCN2015081519-appb-100012
    Figure PCTCN2015081519-appb-100013
    Figure PCTCN2015081519-appb-100014
  5. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其中，L和Q中，一个选自-S(＝O)2NH-、-S(＝O)2-、-NH-、-NHC(＝O)NH-，另一个选自单键、-CH2-。
  6. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其中，X、Y、Z中的0或1个选自N，其余选自CH、C(CH3)、C(CF3)、CCl、CF。
  7. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其中，A、T分别独立地选自N、CH、C(CH3)、C(CF3)、CCl、CF；或者，B选自NH、N(CH3)或N(CF3)。
  8. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其中，任意两个R1之间、同一个D2中的Ra与Ra之间、两个D2之间、或Ra与一个D2之间所成的环选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、1,3-二氧五环基。
  9. 根据权利要求1～8任意一项所述的式(I)所示化合物或其药学上可接受的盐，其中，R1-3选自H、F、Cl、Br、I、CN、OH、NH2、甲基、乙基、丙基、甲氧基、乙氧基、甲氨基、二甲氨基、卤代甲基、卤代乙基、卤代丙基、氨甲基、氨乙基、氨丙基、环丙基、
    Figure PCTCN2015081519-appb-100015
    Figure PCTCN2015081519-appb-100016
  10. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其选自：化合物1～化合物284。
PCT/CN2015/081519 2014-06-17 2015-06-16 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物 Ceased WO2015192761A1 (zh)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA2952992A CA2952992C (en) 2014-06-17 2015-06-16 Pyridino[1,2-a]pyrimidone analogue used as mtor/pi3k inhibitor
JP2017518398A JP6386177B2 (ja) 2014-06-17 2015-06-16 ｍＴＯＲ／ＰＩ３Ｋ阻害剤としてのピリド［１，２−ａ］ピリミジノン類似体
EP15810204.6A EP3159342B1 (en) 2014-06-17 2015-06-16 Pyridino[1,2-a]pyrimidone analogue used as mtor/pi3k inhibitor
RU2017100119A RU2658912C1 (ru) 2014-06-17 2015-06-16 АНАЛОГ ПИРИДИНО[1,2-А]ПИРИМИДОНА, ИСПОЛЬЗУЕМЫЙ В КАЧЕСТВЕ ИНГИБИТОРА mTOR/PI3K
BR112016029825-0A BR112016029825B1 (pt) 2014-06-17 2015-06-16 composto
US15/319,728 US9868737B2 (en) 2014-06-17 2015-06-16 Pyridino[1,2-A]pyrimidone analogue used as MTOR/P13K inhibitor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410271554.5A CN105461712B (zh) 2014-06-17 2014-06-17 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物
CN201410271554.5 2014-06-17
CN201510326169 2015-06-12
CN201510326169.0 2015-06-12

Publications (1)

Publication Number Publication Date
WO2015192761A1 true WO2015192761A1 (zh) 2015-12-23

Family

ID=54934873

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/081519 Ceased WO2015192761A1 (zh) 2014-06-17 2015-06-16 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物

Country Status (8)

Country Link
US (1) US9868737B2 (zh)
EP (1) EP3159342B1 (zh)
JP (1) JP6386177B2 (zh)
BR (1) BR112016029825B1 (zh)
CA (1) CA2952992C (zh)
RU (1) RU2658912C1 (zh)
TW (1) TWI600655B (zh)
WO (1) WO2015192761A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017101829A1 (zh) * 2015-12-16 2017-06-22 辰欣药业股份有限公司 吡啶并[1,2-a]嘧啶酮类似物的晶型及其制备方法和中间体
WO2022152296A1 (zh) * 2021-01-18 2022-07-21 广州嘉越医药科技有限公司 一种吡啶并[1,2-a]嘧啶酮类似物的应用
CN114788829A (zh) * 2021-01-25 2022-07-26 广州嘉越医药科技有限公司 一种吡啶并[1,2-a]嘧啶酮类似物的应用
CN115671289A (zh) * 2021-07-27 2023-02-03 广州嘉越医药科技有限公司 药物组合及其应用
US11725010B2 (en) 2019-12-02 2023-08-15 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102495840B1 (ko) * 2014-06-17 2023-02-03 치아타이 티안큉 파마수티컬 그룹 주식회사 PI3K 억제제로 사용되는 피리디노[1,2-a]피리미돈 유사체
KR102731762B1 (ko) * 2015-12-16 2024-11-18 치아타이 티안큉 파마수티컬 그룹 주식회사 피리도[1,2-a]피리미돈 유사체, 이의 결정형, 이의 중간체 및 이의 제조방법
CN110386932A (zh) 2018-04-20 2019-10-29 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
PH12022550015A1 (en) * 2019-07-30 2022-11-21 Xrad Therapeutics Inc Dual atm and dna-pk inhibitors for use in anti-tumor therapy
CN112480116B (zh) * 2019-09-11 2024-03-29 南京正大天晴制药有限公司 Pkb抑制剂
WO2021219101A1 (zh) * 2020-04-30 2021-11-04 广州嘉越医药科技有限公司 一种含杂环的化合物的应用
TWI843217B (zh) * 2021-09-30 2024-05-21 大陸商廣州嘉越醫藥科技有限公司 一種藥物組合及其應用
WO2025136936A1 (en) * 2023-12-19 2025-06-26 Merck Sharp & Dohme Llc Agonists of trem2 activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013071698A1 (zh) * 2011-11-17 2013-05-23 山东轩竹医药科技有限公司 三环类PI3K和/或mTOR抑制剂
CN103539777A (zh) * 2012-07-13 2014-01-29 广东东阳光药业有限公司 Pi3激酶调节剂及其使用方法和用途
WO2014022128A1 (en) * 2012-07-29 2014-02-06 Calitor Sciences, Llc Pi3 kinase modulators and methods of use

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004016607A1 (en) * 2002-08-16 2004-02-26 Kinacia Pty Ltd. Inhibition of phosphoinositide 3-kinase beta
DE602004008098T8 (de) * 2003-10-10 2008-04-17 Pfizer Products Inc., Groton Substituierte 2h-[1,2,4]triazolo[4,3-a]pyrazine als gsk-3-inhibitoren
CN101541783B (zh) * 2006-06-30 2014-10-01 苏尼西斯制药有限公司 吡啶酮基pdk1抑制剂
JO2985B1 (ar) * 2006-12-20 2016-09-05 Takeda Pharmaceuticals Co مثبطات كينازmapk/erk
MX2009008486A (es) 2007-02-20 2009-08-20 Novartis Ag Imidazoquinolinas como inhibidores dobles de cinasa de lipido y mtor.
PE20090717A1 (es) 2007-05-18 2009-07-18 Smithkline Beecham Corp Derivados de quinolina como inhibidores de la pi3 quinasa
JP2011500823A (ja) * 2007-10-22 2011-01-06 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー Ｐｉ３キナーゼ阻害物質としてのピリドスルホンアミド誘導体
EP2138493A1 (en) * 2008-06-26 2009-12-30 Sanofi-Aventis Substituted pyrimidone derivatives
PT2448938E (pt) * 2009-06-29 2014-07-31 Incyte Corp Pirimidinonas como inibidoras de pi3k
UA48943U (en) * 2009-10-27 2010-04-12 Институт Органической Химии Нан Украины Process for the preparation of 1,6-8-aryl-dioxo-1,3,4,6,7,8-hexahydro-2h-pyrazino[1,2-c]pyrimidine-9-carboxylates
TWI574962B (zh) * 2012-11-14 2017-03-21 加拓科學公司 作爲ｐｉ３激酶調節劑的芳雜環化合物及其使用方法和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013071698A1 (zh) * 2011-11-17 2013-05-23 山东轩竹医药科技有限公司 三环类PI3K和/或mTOR抑制剂
CN103539777A (zh) * 2012-07-13 2014-01-29 广东东阳光药业有限公司 Pi3激酶调节剂及其使用方法和用途
WO2014022128A1 (en) * 2012-07-29 2014-02-06 Calitor Sciences, Llc Pi3 kinase modulators and methods of use

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017101829A1 (zh) * 2015-12-16 2017-06-22 辰欣药业股份有限公司 吡啶并[1,2-a]嘧啶酮类似物的晶型及其制备方法和中间体
US11725010B2 (en) 2019-12-02 2023-08-15 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors
US12195458B2 (en) 2019-12-02 2025-01-14 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors
WO2022152296A1 (zh) * 2021-01-18 2022-07-21 广州嘉越医药科技有限公司 一种吡啶并[1,2-a]嘧啶酮类似物的应用
CN114796228A (zh) * 2021-01-18 2022-07-29 广州嘉越医药科技有限公司 一种吡啶并[1,2-a]嘧啶酮化合物的应用
CN114796228B (zh) * 2021-01-18 2024-01-09 广州嘉越医药科技有限公司 一种吡啶并[1,2-a]嘧啶酮化合物的应用
CN114788829A (zh) * 2021-01-25 2022-07-26 广州嘉越医药科技有限公司 一种吡啶并[1,2-a]嘧啶酮类似物的应用
CN115671289A (zh) * 2021-07-27 2023-02-03 广州嘉越医药科技有限公司 药物组合及其应用
CN115671289B (zh) * 2021-07-27 2024-04-26 广州嘉越医药科技有限公司 药物组合及其应用

Also Published As

Publication number Publication date
CA2952992C (en) 2019-05-07
US9868737B2 (en) 2018-01-16
TWI600655B (zh) 2017-10-01
BR112016029825A2 (pt) 2017-08-22
EP3159342B1 (en) 2020-08-05
BR112016029825B1 (pt) 2020-10-27
TW201602107A (zh) 2016-01-16
CA2952992A1 (en) 2015-12-23
US20170129888A1 (en) 2017-05-11
JP2017518382A (ja) 2017-07-06
EP3159342A4 (en) 2018-05-16
RU2658912C1 (ru) 2018-06-26
EP3159342A1 (en) 2017-04-26
JP6386177B2 (ja) 2018-09-05

Similar Documents

Publication Publication Date Title
TWI600655B (zh) 作為ｍＴＯＲ／ＰＩ３Ｋ抑制劑的吡啶并［１，２－ａ］嘧啶酮類似物
JP6577613B2 (ja) キナーゼ阻害剤としての縮合環式または三環式アリールピリミジン化合物
CN105461712B (zh) 作为mTOR/PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物
JP6680774B2 (ja) ＰＩ３Ｋ阻害剤としてのピリド［１，２−ａ］ピリミドン類似体
CN105461711B (zh) 作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物
ES2787449T3 (es) Compuesto de alfa y beta-amida insaturada derivado de benzotriazol usado como inhibidor de TGF-betaRI
WO2016192563A1 (zh) Janus激酶抑制剂
KR20140058431A (ko) 단백질 키나아제의 조절제로서 신규한 화합물
CN102399218A (zh) 一类并合三杂环及其作为pi3k抑制剂的用途
TW201639831A (zh) 作為抗癌藥物的取代的２－氫－吡唑衍生物
JP2013505965A (ja) Ｐｉ３ｋ（デルタ）選択的阻害剤
KR20100120680A (ko) Ｐｉ３ｋ 저해제로서의 피롤로피리미딘 유도체 및 그의 용도
KR20190104142A (ko) 신규 옥소이소퀴놀린 유도체
WO2014100540A1 (en) Pyrazole substituted imidazopyrazines as casein kinase 1 d/e inhibitors
JP6511692B2 (ja) ヒドロキシプリン類化合物及びその応用
WO2020119592A1 (zh) 一种新颖的三并环结构化合物及其制备方法和用途
WO2021027503A1 (zh) 三环类化合物、其制备方法、中间体及应用
HK1238629B (zh) 作为pi3k抑制剂的吡啶并[1，2-a]嘧啶酮类似物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15810204

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017518398

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2952992

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 15319728

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112016029825

Country of ref document: BR

REEP Request for entry into the european phase

Ref document number: 2015810204

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015810204

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017100119

Country of ref document: RU

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112016029825

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20161219