WO2017024968A1 - 作为fgfr和vegfr抑制剂的乙烯基化合物 - Google Patents

作为fgfr和vegfr抑制剂的乙烯基化合物 Download PDF

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WO2017024968A1
WO2017024968A1 PCT/CN2016/092989 CN2016092989W WO2017024968A1 WO 2017024968 A1 WO2017024968 A1 WO 2017024968A1 CN 2016092989 W CN2016092989 W CN 2016092989W WO 2017024968 A1 WO2017024968 A1 WO 2017024968A1
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group
crr
mmol
etoac
lcms
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PCT/CN2016/092989
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English (en)
French (fr)
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陈曙辉
陈正霞
戴美碧
谢程
李鹏
张杨
梁贵柏
王强
廖江鹏
孙飞
胡国平
黎健
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南京明德新药研发股份有限公司
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Priority to CN201680046188.0A priority Critical patent/CN107922349B/zh
Priority to EP16834592.4A priority patent/EP3333157B1/en
Priority to JP2018507641A priority patent/JP6898306B2/ja
Priority to US15/750,704 priority patent/US10519133B2/en
Publication of WO2017024968A1 publication Critical patent/WO2017024968A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a FGFR and a VEGFR inhibitor, and in particular to a compound of the formula (I), a pharmaceutically acceptable salt or a tautomer thereof as an FGFR and a VEGFR inhibitor.
  • Fibroblast growth factor has been recognized as an important mediator of many physiological processes such as developmental morphogenesis and angiogenesis.
  • the fibroblast growth factor receptor (FGFR) family is composed of four members (FGFR1-FGFR4), which are composed of extracellular immunoglobulin (Ig)-like domains, hydrophobic transmembrane regions, and regions including tyrosine kinases.
  • Ig immunoglobulin
  • the glycoprotein consisting of the cytoplasmic part.
  • FGF binding results in FGFR dimerization followed by activation of receptor autophosphorylation and downstream signaling pathways. Receptor activation is sufficient to regenerate and activate specific downstream signaling partners involved in the regulation of diverse processes such as cell growth, cell metabolism, and cell survival.
  • the FGF/FGFR signaling pathway has multiple effects in many biological processes critical for tumor cell proliferation, migration, invasion, and angiogenesis.
  • Vinyl carbazoles are known in the field of cancer treatment, see WO 0210137 and WO2003101968.
  • FGFR inhibitors are also known in the art, see WO 2002022598.
  • the present invention provides a compound of the formula (I) or (II), a pharmaceutically acceptable salt thereof or a tautomer thereof,
  • R 1 and R 2 is selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 and the other is selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH 2 ;
  • 0 to 2 of T 11-15 are selected from N, and the rest are selected from C(R);
  • 0 to 2 of T 16-18 are selected from N, and the rest are selected from C(R);
  • B 2 is selected from a 5- to 10-membered aryl or heteroaryl group optionally substituted by R;
  • B 4 is selected from a 5- to 6-membered aryl or heteroaryl group optionally substituted by R, a 5- to 6-membered cycloalkyl or heterocycloalkyl group;
  • T 31-34 are each independently selected from N or C(R);
  • n is 0 or 1, when n is 0, the defined structural unit thereof represents a single bond which only serves as a connection;
  • R, R', R", hetero atom or hetero atomic group is independently selected from 0, 1, 2 or 3, respectively;
  • the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, hydroxymethyl, hydroxyethyl, carboxypropyl, carboxymethyl, methoxy, ethoxy Base, propoxy, methyl, ethyl, propyl, isopropyl, monohalomethyl, dihalomethyl, trihalomethyl, methylamino, dimethylamino,
  • any two of the above D 41-45 or T 31-34 are joined together to the same atom or group of atoms to form a benzene ring.
  • the above B 2 is selected from the group consisting of:
  • the above B 4 is selected from the group consisting of:
  • the structural unit From:
  • the above compound is selected from the group consisting of
  • the invention also provides a preparation method of the compound of the above formula (I), comprising the following steps:
  • P is selected from the group consisting of halogen, OH, NH 2 and CN; P 1 is an amino protecting group, specifically THP; other variables are as defined above.
  • the method for preparing the compound of the above formula (I) comprises the following steps:
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound, a pharmaceutically acceptable salt or a tautomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention further provides the use of the above compound, a pharmaceutically acceptable salt or a tautomer thereof, or a pharmaceutical composition as described above for the preparation of a medicament for treating cancer.
  • C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ;
  • C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .
  • C 1-12 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 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 organic acid salts including, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, amber Acids, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, cit
  • 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, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, 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.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • 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. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present 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 diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and 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).
  • 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.
  • 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 cyclohexadiene.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • 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.
  • 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).
  • 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, p is 1 or 2).
  • 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, p is 1 or 2).
  • 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 , 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 hetero 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 invention adopts the following abbreviations: aq for water; HATU for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate; EDC representative 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 Representative of ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butylcarbony
  • Example 1A To a solution of Example 1A (90 g, 0.36 mol) in dichloromethane (1.2 L) was added NIS (88 g, 0.4 mol The reaction solution was stirred at 10 ° C for 2 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography eluting elut elut elut LCMS (ESI) m / z: 375 [M + 1] +.
  • Example 1B was dissolved in a mixed solvent of dichloromethane (1 liter) and tetrahydrofuran (0.4 liter), then methanesulfonic acid (6.0 g, 60 mmol) was added, and finally, 3,4-tetrahydrogen was added.
  • -2 Hydrogen-pyran (124.2 g, 0.92 mol) was added portionwise to the reaction mixture. After the addition was completed, the mixture was stirred at 12 ° C for 5 hours. The reaction mixture was diluted with dichloromethane (500 mL) andEtOAc. The organic layer was washed with brine and dried over anhydrous sodium The residue was purified by EtOAc EtOAcqqqq LCMS (ESI) m / z: 459 [M + 1] +.
  • Example 1D 35 g, 0.1 mol
  • Example 1F 33 g, 0.12 mol
  • yttrium carbonate 66 g, 0.2 mol
  • acetonitrile 1.5 L
  • Example 1H (7.2 g, 17.1 mmol), a mixture of diethyl phosphite (5.4 ml, 51.4 mmol) and hydrazine hydroxide octahydrate (2.7 g, 8.6 mmol) in tetrahydrofuran (130 ml) was heated to 50 °C and react for 5 hours. The reaction raw material disappeared by TLC and the reaction was completed. Filtration and EtOAc (EtOAc)EtOAc. LCMS (ESI) m / z: 558 [M + 1] +.
  • Example 1J Sodium hydrogen (60% content) (0.63 g, 3.0 mmol) was added portionwise to a solution of Example 1J (1.42 g, 2.5 mmol) in tetrahydrofurane (15 mL). After the addition was completed, the reaction solution was stirred at 10 ° C for 30 minutes. 6-(morpholinemethyl)-3-aldehyde pyridine (0.63 g, 3.0 mmol) was added to the stirred reaction solution, and then the reaction solution was heated to 80 ° C and reacted for 3 hours. The dot plate shows that the reaction is complete. After the reaction mixture was cooled to room temperature, water (2 mL) was evaporated. The combined organic layers were washed with brine brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc EtOAc LCMS (ESI) m/z: 612[M+1] +
  • Example 1L was used for SFC separation (SFC separation conditions were as follows: column: Chiralpak AD-3 50*4.6 mm ID, 3 um mobile phase: ethanol (0.05% DEA) - CO 2 from 5% to 40% rate: 4 mL/min Wavelength: 254 nm)
  • Example 2 Example 3, Example 4, Example 5, and Byproduct Example 6 were obtained.
  • Example 7A To a solution of Example 7A (20 g, 120 mmol) of trimethyl orthoformate (400 ml) was slowly added dropwise with formic acid (40 ml) at 0 ° C, stirring at this temperature for 30 minutes, then dripping Concentrated sulfuric acid (1.2 ml) was added, and the dropwise addition was completed. The mixture was heated to 50 ° C for 30 minutes, and then cooled to 25 ° C for 3 hours. After cooling to room temperature, it was added to water (100 ml), EtOAc (EtOAc (EtOAc) The title compound (25 g, 98.8% yield).
  • Example 7B To a solution of Example 7B (8 g, 38 mmol) in tetrahydrofuran (120 mL), EtOAc (EtOAc) Stir under 1 hour. Quenched with water (4 ml), EtOAc (EtOAc (EtOAc) step.
  • Example 7E A mixed solution of Example 7E (0.2 g, 0.34 mmol) and p-bromobenzenesulfonic acid monohydrate (12 mg, 0.068 mmol) in water (8 ml) and acetone (10 ml) was stirred under heating at 50 ° C for 3 hours.
  • the title compound (140 mg, 76% yield) eluted eluted eluted eluted Rate) is used directly in the next step.
  • Example 7F To a mixed solution of Example 7F (70 mg, 130 ⁇ mol) and (S)-2-aminopropan-1-ol (29 mg, 390 ⁇ mol) in 1,2-dichloroethane (1 mL) Acetic acid (9 mg, 147.77 mmol) was added dropwise, and the mixture was stirred at 20 ° C for 30 minutes after completion of dropwise addition. Sodium cyanoborohydride (24 mg, 390 ⁇ mol) was slowly added and stirring was continued at 20 ° C for 2 hours. The mixture was extracted with EtOAc (EtOAc) (EtOAc m. The title compound (3 mg, 3.32% yield) was obtained. LCMS (ESI) m/z: 600.1 [M+1] + .
  • Example 7F To a mixed solution of Example 7F (50 mg, 90 ⁇ mol) and 3-hydroxypyrrole (23 mg, 270 ⁇ mol) in 1,2-dichloroethane (1 ml), acetic acid (8.87 mg, 147.77 ⁇ mol), after completion of the dropwise addition, stirring was carried out at 20 ° C for 30 minutes. Sodium cyanoborohydride (17 mg, 270 micromoles) was added slowly and stirring was continued at 20 °C for 2 hours. The mixture was extracted with EtOAc (EtOAc m. Column purification gave the title compound (29 mg, 53%). LCMS (ESI) m / z: 612.5 [M + 1] +.
  • Example 13A (23 g, 205.4 mmol) was dissolved in acetic acid (100 ml), and liquid bromine (55.03 g, 348.5 mmol) was added dropwise to the above solution under vigorous stirring. The temperature during the dropwise addition did not exceed 40 ° C. After the dropwise addition was completed, the mixture was reacted at 80 ° C for half an hour. After cooling to room temperature, filtration, the filter cake was washed twice with methyl t-butyl ether to afford title compound (20 g, yield: EtOAc). LCMS (ESI) m / z: .
  • Example 13B A mixture of Example 13B (18 g, 163.44 mmol) and phosphorus bromide (93.8 g, 327.6 mmol) was stirred at 70 ° C overnight. The mixture was cooled to 40 ° C, EtOAc (EtOAc m. Filtration and evaporation gave the title compound 3-bromo-6-methylpyridazine (8 g, 31% yield).
  • Example 13C (8.0 g, 48.0 mmol) of NBS (9.44 g, 48.0 mmol) was dissolved in carbon tetrachloride (200 mL), and AIBN (1.58 g, 9.6 mmol) was added to the mixture at 80 ° C The reaction was allowed to react for 12 hours, the mixture was filtered and evaporated, mjjjjjj LCMS (ESI) m/z: 353 [M+] + &lt ; "&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
  • Example 1G (1 g, 1.93 mmol), Pd(PPh 3 ) 2 Cl 2 (136 mg, 0.19 mmol), trimethylsilylacetylene (227 mg, 2.32 mmol), cuprous iodide (368 mg) , 0.19 mmol) and triethylamine (586 mg, 5.79 mmol) were suspended in acetonitrile (14 mL). The reaction solution was stirred at 80 ° C for 18 hours.
  • Example 13G (1 g, 2.4 mmol), silver fluoride (762 mg, 6 mmol) and NBS (470 mg, 2.64 mmol) were added to a mixture of acetonitrile (10 mL) and water (1 mL) The solution is sealed in a tube. The reaction solution was stirred at 80-90 ° C for 18 hours. The progress of the reaction was monitored by TLC. After the reaction solution was cooled to room temperature, saturated brine (10 ml) was added to the reaction mixture, and the mixture was evaporated. The title compound (cis-mixture, colorless oily liquid, 200 mg, yield 16%) was obtained.
  • Example 13H (30 mg, 58 ⁇ mol), bispinacol borate (16 mg, 64 ⁇ mol), Pd(dppf)Cl 2 CH 2 Cl 2 (5 mg, 6 ⁇ mol) and potassium acetate (12 mg, 120 ⁇ mol) was suspended in dioxane (1.5 ml). After replacing nitrogen, the reaction mixture was stirred at 100 ° C for 18 hours. The progress of the reaction was monitored by TLC. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. Mg, yield 30%). LCMS (ESI) m / z: 562.1 [M + 1] +.
  • Example 13I (10 mg, 18 ⁇ mol), Example 13E (9 mg, 36 ⁇ mol), Pd(DTBPF)Cl 2 (2 mg, 3.6 ⁇ mol) and potassium carbonate (5 mg, 36 ⁇ mol) suspended
  • the reaction was carried out under microwave conditions at 105 ° C for 15 minutes in a mixed solvent of tetrahydrofuran (1 ml) and water (0.2 ml). After the reaction mixture was cooled to room temperature, the title compound (yield: EtOAc (EtOAc) LCMS (ESI) m / z: 613.2 [M + 1] +.
  • Example 13J (5 mg, 8 ⁇ mol) was dissolved in dry methanol (1 mL). The reaction solution was stirred at 40 ° C for 3 hours. After completion of the reaction, the solvent was evaporated, mjjjjd LCMS (ESI) m / z: 541.1 [M + 1] +.
  • Example 16A 1.6 g, 7 mmol
  • the reaction mixture was poured into EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the title compound (1 g, yield: 60%) was obtained.
  • Example 16D To a solution of Example 16D (300 mg, 1.45 mmol) and diethyl phosphinate (603 mg, 4.36 mmol) in tetrahydrofuran (5 mL) , 0.728 mmol), the reaction solution was heated to 45 ° C and stirred for 4 hours. After completion of the reaction, water (20 ml), EtOAc (EtOAc (EtOAc) Chromatography on silica gel column chromatography eluted elute LCMS (ESI) m / z: 345.1 [M + 1] +.
  • Example 16E 120 mg, 0.35 mmol
  • dichloromethane 5 mL
  • EtOAc EtOAc
  • the reaction solution was stirred at 0 ° C for 1 hour. After the reaction was completed, the ⁇ Rate: 50%), a colorless liquid.
  • Example 7E To a mixed solution of Example 7E (900 mg, 1.53 mmol) in acetone (4 mL), water (4 mL), EtOAc (EtOAc m. Stir at 50 ° C for 10 hours. After completion of the reaction, water (4 ml), EtOAc (EtOAc (EtOAc) , yield: 92%).
  • Example 17E 50 mg, 90 ⁇ mol
  • tetrahydro-2-hydro-pyran-4-amine 18 mg, EtOAc, EtOAc
  • acetic acid about 0.1 ml
  • Sodium cyanoborohydride (12 mg, 180 ⁇ mol) was added to the reaction mixture at room temperature, stirring was continued for 1 hour, water (5 ml) was added, and dichloromethane (20 ml x 3) was added for extraction. Wash with saline (20 ml), dry over sodium sulfate, filter and evaporate the residue by flash chromatography
  • the title compound (20 mg, yield: 34.7%) was obtained.
  • the sample was used for chiral column resolution to give Example 17F-R configuration (8 mg), Example 17F-S configuration (8 mg).
  • Example 24E To a mixed solution of Example 24E (12.00 g, 51.26 mmol) of tetrahydrofuran (50 ml) and methanol (50 ml) at 20 ° C, 1 M sodium hydroxide solution (51.26 ml, 51.26 mmol) was added dropwise at 20 After stirring at ° C for half an hour, the reaction was completed by TLC, diluted with water (30 ml), and ethyl acetate (100 ml x 3). The combined organic layers were washed w ⁇ LCMS (ESI) m / z: 191.8 [M + 1] +.
  • Example 25E 24 g, 46.3 mmol in DMF (500 ml) was added Pd (PPh 3) 2 Cl 2 (1.63 g, 2.32 mmol) and sodium formate (9.5 g, 139.0 mmol) .
  • the hydrogenation bottle is then replaced with carbon monoxide gas to fill the bottle with carbon monoxide gas.
  • the reaction solution was stirred at carbon monoxide (50 psi) and 80 ° C for 12 hours.
  • Filtration and EtOAc EtOAc
  • Example 24C To a mixed solution of Example 24C (703.99 mg, 2.52 mmol) and EXAMPLE 24J (1.00 g, 1.94 mmol) of tetrahydrofuran (9 mL) was added Pd(dppf)Cl 2 (141.95 mg, 194.00 Molar), then stirred at 80 ° C under reflux overnight. The title compound (1.0 g, 90% yield).
  • Example 24K A mixed solution of Example 24K (1.00 g, 1.70 mmol) and p-toluenesulfonic acid monohydrate (194. mg, 1.02 mmol) in water (8 ml) and acetone (10 ml) was stirred and stirred at 50 ° C for 12 hours. . The mixture was cooled with EtOAc EtOAc EtOAc m. Used in the next step. LCMS (ESI) m / z: 541.4 [M + 1] +.
  • Example 24L To a mixed solution of Example 24L (80 mg, 147.77 ⁇ mol) and 1-amino-2-methylpropan-2-hydroxy (54.78 mg, 443.31 ⁇ mol) of 1,2-dichloroethane (2 mL) Acetic acid (8.87 mg, 147.77 ⁇ mol) was added dropwise, and the mixture was stirred at 20 ° C for 30 minutes after completion of dropwise addition. Sodium cyanoborohydride (27.86 mg, 443.31 micromoles) was added slowly and stirring was continued at 20 °C for 2 hours. The mixture was extracted with EtOAc (EtOAc m. Column purification gave the title compound (30 mg, m. LCMS (ESI) m / z: 613.2 [M + 1] +.
  • Example 24L To a mixed solution of Example 24L (80 mg, 147.77 ⁇ mol) and 2-piperazine-1-ethanol (57.71 mg, 443.31 ⁇ mol) in 1,2-dichloroethane (2 ml), acetic acid was added dropwise. (8.87 mg, 147.77 ⁇ mol), and the mixture was stirred at 20 ° C for 30 minutes after completion of the dropwise addition. Sodium cyanoborohydride (27.86 mg, 443.31 micromoles) was added slowly and stirring was continued at 20 °C for 2 hours. The mixture was extracted with EtOAc (3 mL EtOAc) Purification gave the title compound (30 mg, 30.9%). LCMS (ESI) m / z: 655.2 [M + 1] +.
  • Example 29A (2.1 g, 7.7 mmol) was added to ethyl acetate (30 ml), and the mixture was stirred at room temperature for 16 hours. The dot plate shows that the reaction is complete. The reaction mixture was evaporated to dryness crystals crystals crystals
  • Example 29B A mixture of the solution of Example 29B (15 mg, 87 ⁇ mol) and EtOAc (EtOAc, m. Sodium cyanoborohydride (5.5 mg, 87 ⁇ mol) was added to the reaction mixture. Finally, the reaction solution was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was isolated by HPLC to afford the title compound (30 mg, LCMS (ESI) m / z: 698.6 [M + 1] +.
  • Example 29D To a mixed solvent of Example 29D (30 mg, 49 ⁇ mol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) ). The reaction solution was stirred at 21 ° C for 16 hours. LCMS showed the reaction was completed. The reaction solution was evaporated to dryness, then dissolved in methanol and filtered, and evaporated. The residue was purified by EtOAcqqqqqq LCMS (ESI) m/z: 585.2 [M+1] + .
  • Example 24J (720 mg, 1.40 mmol), Example 36A (311.72 mg, 1.40 mmol) of tetrahydrofuran (9 mL), and added potassium phosphate (1 mol/L, 3. Pd(dppf)Cl 2 (102 mg, 0.14 mmol) was stirred for 10 minutes and then heated to 80 ° C for 6 hours. After cooling to room temperature, ethyl acetate (40 mL EtOAc) was evaporated, evaporated, evaporated. The title compound (480 mg, yield: 64.52%). LCMS (ESI) m / z: .
  • Example 45A (30.00 mg, 50.65 mol), 4-amino - tetrahydropyran (6.15 mg, 60.78 mol), sodium tert-butoxide (14.60 mg, 151.95 [mu] mol) and ( ⁇ ) -2,2 ' - bis-(diphenylphosphino)-1,1'-binaphthyl (6.31 mg, 10.13 ⁇ mol) was added to toluene (2 ml), and the mixture was reacted under nitrogen at 110 ° C for 12 hours. The title compound (11.00 mg, 35.46%) was obtained eluted directly by HPLC. LCMS (ESI) m / z: 612.1 [M + 1] +.
  • Example 48A To a solution of Example 48A (80 mg, 0.15 mmol) in tetrahydrofuran (2.5 mL) and water (0.5 mL), 4-((5-bromopyridin-2-yl)methyl)morpholine (60 mg) , 0.23 mmol, Pd(dppf)Cl 2 (20 mg, 0.027 mmol) and sodium carbonate (80 mg, 0.75 mmol), and the mixture was stirred at a temperature of 90 ° C for 1.5 hours. After cooling to room temperature, it was poured into ice water (5 ml). The title compound (50 mg, 57% yield) was obtained.
  • Example 52B A solution of Example 52B (8.8 g, 79.9 mmol). The reaction mixture was poured into EtOAc (EtOAc m. 1 H NMR (400 MHz, DMSO-d 6 ) ppm 2.27 (s, 3H) 8.64 (s, 2H).
  • Example 61B (200 mg, 0.63 mmol) was dissolved in toluene (4 mL), and 4,4,5,5-tetramethyl-2-vinyl-1,3 was added to the solution under nitrogen.
  • 2-boronic acid pinacol ester 200 mg, 1.98 mmol
  • Pd(t-Bu 3 P) 2 48 mg, 0.09 mmol
  • Et 3 N 200 mg, 1.98 mmol
  • the mixture was stirred at 80 ° C for 1 hour.
  • the reaction mixture was poured into EtOAc EtOAc. (195 mg, 56% yield).
  • Example 61C (150 mg, 0.28 mmol) was dissolved in a mixture of tetrahydrofuran and water (5/1, 3 mL). Then, 1 G (170 mg, 0.28 mmol), Na 2 CO 3 (100 mg, 0.84 mmol) and Pd(dppf)Cl 2 (20 mg, 0.027 mmol) were added to the above solution under nitrogen atmosphere. The reaction solution was reacted at 80 ° C for 1 hour under microwave conditions in a nitrogen atmosphere. Water (5 ml) was added with EtOAc (EtOAc (EtOAc)EtOAc. Compound (220 mg, 96% yield). LCMS (ESI) m / z: 656.0 [M + 1] +.
  • Lithium tetrahydroaluminum (10.27 mg, 270.55 mmol) was slowly added to a solution of Example 66F (100 mg, 180.37 ⁇ mol) in tetrahydrofuran (1 ml) at 0 ° C, and then stirred at this temperature for 30 min.
  • the title compound (30 mg, 30.33) was obtained eluted eluted eluted eluted eluted eluted eluted eluted %).
  • Example 66H To a mixed solution of Example 66H (30 mg, 57.21 ⁇ mol) and morpholine (15 mg, 171.63 mol) of 1,2-dichloroethane (2 ml), acetic acid (3.44 mg, 57.2 Molar), after completion of the dropwise addition, the mixture was stirred at 28 ° C for 2 hours. Sodium cyanoborohydride (11 mg, 171.6 micromoles) was slowly added and stirring was continued at 28 ° C for 1 hour. The water was quenched and the aqueous layer was evaporated eluting eluting eluting eluting eluting eluting compound (25 mg, crude), LCMS (ESI) m / z: 594.2 [m + 1] +.
  • Example 66I (25 mg, 42 ⁇ mol) was dissolved in dry methanol (1 mL). The reaction solution was stirred at 40 ° C for 1 hour. Concentration in vacuo and EtOAc EtOAc m. LCMS (ESI) m / z: .
  • Example 1G 400 mg, 0.78 mmol in acetonitrile (6 mL) and water (2 mL), 5-(4,4,5,5-tetramethyl-1,3,2- 2-(2)pyridin-2-yl diborate (205 mg, 0.93 mmol), Pd(dppf)Cl 2 (57 mg, 0.078 mmol) and sodium carbonate (165 mg, 1.56 mmol).
  • the reaction was heated to 100 ° C by microwave under a nitrogen atmosphere and the reaction was stirred for 15 minutes. Water (10 ml) was added to EtOAc EtOAc m.
  • Example 70A To a solution of Example 70A (100 mg, 0.21 mmol, m. The reaction solution was stirred at 15 ° C for 18 hours. Water (10 ml) was added to EtOAc (3 mL, dry. Yield 63%). LCMS (ESI) m / z: 559.6 [M + 1] +.
  • Example 71A To Example 71A (1.0 g, 3.90 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxacyclopentane borane (0.66 g, at 30 ° C, 4.30 mmol) and triethylamine (0.79 g, 7.80 mmol) in toluene (10 ml) were added Pd(tBu 3 P) 2 (20 mg, 0.04 mmol), and the mixture was degassed for 10 min and then used Nitrogen protection. Heat to 80 ° C and stir for 16 hours. The mixture was cooled to 35 ° C. LCMS (ESI) m / z: 330.0 [M + 1] +.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • This example was prepared as described in Example 17.
  • Example 111B (50 mg, 0.08 mmol) was dissolved in MeOH (2 mL). The reaction solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound (18 mg, yield: 42%).
  • This embodiment was prepared as described in Example 111.
  • This embodiment was prepared as described in Example 111.
  • This embodiment was prepared as described in Example 111.
  • This embodiment was prepared as described in Example 111.
  • This embodiment was prepared as described in Example 111.
  • This embodiment was prepared as described in Example 111.
  • Example 24H (600 mg, 1.16 mmol), 3-methoxycarbonyl-phenylboronic acid (229.23 mg, 1.27 mmol), Pd (dppf) Cl 2 (84.73 mg, 115.79 ⁇ mol) and tris
  • Example 1A 600 mg, 1.14 mmol
  • methanol / tetrahydrofuran / water 6 / 6 / 4 ml
  • lithium hydroxide monohydrate 51.34 mg, 1.35 mmol
  • EtOAc EtOAc
  • Example 127A 80 mg, 156.13 ⁇ mol
  • HATU 89.05 mg, 234.20 ⁇ mol
  • DIPEA 80.72 mg, 624.54 ⁇ mol
  • the suspension was stirred at 30 ° C for 2 h.
  • Add water 50 ml
  • EtOAc EtOAc m.
  • LCMS ESI
  • Example 132B 70 mg, 133.99 ⁇ mol
  • tetrahydropyran-4-amino 40.66 mg, 401.97 ⁇ mol
  • 1,2-dichloroethane 1,2-dichloroethane
  • acetic acid was added dropwise. (0.80 mg, 13.4 ⁇ mol), stirred at 20 ° C for 30 minutes after completion of the dropwise addition.
  • Sodium cyanoborohydride 25.26 mg, 401.98 ⁇ mol
  • the mixture was extracted with EtOAc (EtOAc m.
  • EtOAc EtOAc m.
  • the title compound (yellow oily liquid, 30 mg, 49.38 micromoles, 36.85% yield).
  • Example 132C (30.00 mg, 49.38 ⁇ mol) was dissolved in anhydrous methanol (1 mL), then EtOAc (EtOAc) The reaction solution was heated to 40 ° C and stirred for 30 hours. After completion of the reaction, the solvent was evaporated, mjjjjjj LCMS (ESI) m/z [M+H] + :522.3

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Abstract

提供一种 FGFR 和 VEGFR 抑制剂，具体公开了作为 FGFR 和 VEGFR 抑制剂的式(I)或(Ⅱ)所示化合物、药学上可接受的盐或其互变异构体。

Description

作为FGFR和VEGFR抑制剂的乙烯基化合物 技术领域
本发明涉及一种FGFR和VEGFR抑制剂，具体涉及作为FGFR和VEGFR抑制剂的式(I)所示化合物、药学上可接受的盐或其互变异构体。
背景技术
成纤维细胞生长因子(FGF)已经被公认为如发育期形态发生和血管形成的许多生理学过程的重要媒介。成纤维细胞生长因子受体(FGFR)家族是由四个成员(FGFR1-FGFR4)组成，其为由细胞外免疫球蛋白(Ig)样结构域、疏水性跨膜区域和包括酪氨酸激酶区域的细胞质部分所组成的糖蛋白。FGF结合导致FGFR二聚化，随后为受体自体磷酸化和下游信号通路的激活。受体活化足以复元和活化参与如细胞生长、细胞新陈代谢和细胞存活的多元化过程调控的特定下游信号伙伴。因此，在对于肿瘤细胞增殖、迁移、入侵和血管形成关键性的许多生物过程中，该FGF/FGFR信号通路具有多效应作用。
乙烯基吲唑类在癌症治疗领域是已知的，参见WO 0210137和WO2003101968。FGFR抑制剂在此领域中也是已知的，参见WO 2002022598。
发明内容
本发明提供式(I)或(Ⅱ)所示化合物、其药学上可接受的盐或其互变异构体，
Figure PCTCN2016092989-appb-000001
其中，
R1和R2其中一个选自F、Cl、Br、I、CN、OH、NH2，另一个选自H、F、Cl、Br、I、CN、OH、NH2；
B1选自
Figure PCTCN2016092989-appb-000002
其中，
T11-15中的0～2个选自N，其余选自C(R)；
T16-18中的0～2个选自N，其余选自C(R)；
D11选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-；
T41选自N或C(R)；
D41选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-；
D42-45中的0～2个分别独立地选自单键、-[C(R)(R)]1-3-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-，其余选自-C(R)(R)-；任选地，D41-45中的任意两个共同连接到同一原子或原子团上形成一个3～6元环；
L1、L3分别独立地选自-(CRR)0-3-、-(CRR)0-3-C(＝O)N(R)-(CRR)0-3-、-(CRR)0-3-N(R)-(CRR)0-3-、-(CRR)0-3-C(＝NR)-(CRR)0-3-、-(CRR)0-3-S(＝O)2N(R)-(CRR)0-3-、-(CRR)0-3-S(＝O)N(R)-(CRR)0-3-、-(CRR)0-3-O-(CRR)0-3-、-(CRR)0-3-S-(CRR)0-3-、-(CRR)0-3-C(＝O)O-(CRR)0-3-、-(CRR)0-3-C(＝O)-(CRR)0-3-、-(CRR)0-3-C(＝S)-(CRR)0-3-、-(CRR)0- 3-S(＝O)-(CRR)0-3-、-(CRR)0-3-S(＝O)2-(CRR)0-3-或-(CRR)0-3-N(R)C(＝O)N(R)-(CRR)0-3-；
B2选自任选被R取代的5～10元芳基或杂芳基；
B4选自任选被R取代的5～6元芳基或杂芳基、5～6元环烷基或杂环烷基；
T31-34分别独立地选自N或C(R)；
任选地，T31-34中的任意两个共同连接到同一原子或原子团上形成一个3～6元环；
n为0或1，当n为0时，其限定的结构单元表示仅起连接作用的单键；
R选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2，或选自任选R’取代的C1-12烷基或杂烷基、C3-12环烃基或杂环烃基、被C3-12环烃基或杂环烃基取代的C1-12烷基或杂烷基；
R’选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、＝NH、＝O、＝S、或任选被R”取代的：NHC(＝O)CH3、C1-12烷基、C1-12烷氨基、N,N-二(C1-12烷基)氨基、C1-12烷氧基、C1-12烷酰基、C1-12烷氧羰基、C1-12烷基磺酰基、C1-12烷基亚磺酰基、3～12元环烷基、3～12元环烷氨基、3～12元杂环烷氨基、3～12元环烷氧基、3～12元环烷基酰基、3～12元环烷氧羰基、3～12元环烷基磺酰基、3～12环烷基亚磺酰基、5～12元芳基或杂芳基、5～12元芳烷基或杂芳烷基；
R”选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、＝NH、＝O、＝S、三卤代甲基、二卤代甲基、一卤代甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基；
“杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-和/或-N(R)C(＝O)N(R)-；
上述每种情况下，R、R’、R”、杂原子或杂原子团的数目分别独立地选自0、1、2或3；
且式(I)化合物不包括
Figure PCTCN2016092989-appb-000003
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH2、CN、羟甲基、羟乙基、羧丙基、羧甲基、甲氧基、乙氧基、丙氧基、甲基、乙基、丙基、异丙基、一卤代甲基、二卤代甲基、三卤代甲基、甲氨基、二甲氨基、
Figure PCTCN2016092989-appb-000004
Figure PCTCN2016092989-appb-000005
本发明的一些方案中，上述D41-45或T31-34中的任意两个共同连接到同一原子或原子团上形成一个苯环。
本发明的一些方案中，上述B1选自H、F、
Figure PCTCN2016092989-appb-000006
Figure PCTCN2016092989-appb-000007
Figure PCTCN2016092989-appb-000008
本发明的一些方案中，上述L1、L3分别独立地选自单键、NH、
Figure PCTCN2016092989-appb-000009
CH2、CH2CH2、
Figure PCTCN2016092989-appb-000010
O、C(＝O)、
Figure PCTCN2016092989-appb-000011
Figure PCTCN2016092989-appb-000012
本发明的一些方案中，上述B2选自：
Figure PCTCN2016092989-appb-000013
其中，
T选自N或C(R)；
D选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-。
本发明的一些方案中，上述B2选自：
Figure PCTCN2016092989-appb-000014
本发明的一些方案中，上述B4选自任选被1、2或3个R取代的苯基、吡啶基、咪唑基、呋喃基、噻唑基、哌啶基、哌嗪基或吗啉基。
本发明的一些方案中，上述B4选自：
Figure PCTCN2016092989-appb-000015
本发明的一些方案中，上述结构单元
Figure PCTCN2016092989-appb-000016
选自：
Figure PCTCN2016092989-appb-000017
Figure PCTCN2016092989-appb-000018
本发明的一些方案中，上述化合物选自：
Figure PCTCN2016092989-appb-000019
Figure PCTCN2016092989-appb-000020
Figure PCTCN2016092989-appb-000021
Figure PCTCN2016092989-appb-000022
Figure PCTCN2016092989-appb-000023
Figure PCTCN2016092989-appb-000024
Figure PCTCN2016092989-appb-000025
本发明还提供了上述式(Ⅰ)化合物的制备方法，包括如下步骤：
Figure PCTCN2016092989-appb-000026
其中，P选自卤素、OH、NH2和CN；P1为氨基保护基，具体为THP；其他变量如上述所定义。
本发明的一些方案中，上述式(Ⅰ)化合物的的制备方法，包括如下步骤：
Figure PCTCN2016092989-appb-000027
本发明进一步提供了一种药物组合物，其含有治疗有效量的上述化合物、药学上可接受的盐或其互变异构体和药学上可接受的载体。
本发明进一步提供了上述化合物、药学上可接受的盐或其互变异构体，或上述药物组合物在制备治疗癌症的药物中的应用。
定义和说明：
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。
C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。
C1-12烷基或杂烷基、C3-12环基或杂环烃基、被C3-12环烃基或杂环烃基取代的C1-12烷基或杂烷基包括但不限于：
C1-12烷基、C1-12烷氨基、N,N-二(C1-12烷基)氨基、C1-12烷氧基、C1-12烷酰基、C1-12烷氧羰基、C1-12烷基磺酰基、C1-12烷基亚磺酰基、C3-12环烷基、C3-12环烷氨基、C3-12杂环烷氨基、C3-12环烷氧基、C3-12环烷基酰基、C3-12环烷基氧羰基、C3-12环烷基磺酰基、C3-12环烷基亚磺酰基、5～12元芳基或杂芳基、5～12元芳烷基或杂芳烷基；
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；
Figure PCTCN2016092989-appb-000028
Figure PCTCN2016092989-appb-000029
Figure PCTCN2016092989-appb-000030
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；
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，所述有机酸包括如甲酸、乙酸、三氟乙酸、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 Pharmaceutical Science 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。除非另有说明，用
Figure PCTCN2016092989-appb-000031
表示一个立体中心的绝对构型，楔形键，波浪线
Figure PCTCN2016092989-appb-000032
表示相对构型。
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常规方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 of Pharmacy,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 PCTCN2016092989-appb-000033
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
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。
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，p是1或2)。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，p是1或2)。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、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、噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、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2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；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；THP代表四氢吡喃；Novozyme 435代表诺维信脂肪酶；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；dppf代表1,1'-双(二苯基膦)二茂铁；TBSCl代表叔丁基二甲基氯硅烷；NIS代表N-碘代丁二酰亚胺；TBAF代表四丁基氟化铵；MsCl代表甲磺酰氯；LDA代表二异丙基氨基锂；TEA代表三乙胺；DAST代表二乙胺基三氟化硫；SFC代表超临界液相色谱；NBS代表N-溴代丁二酰亚胺；TMSA代表三甲基硅基乙炔；DMAP代表4-二甲氨基吡啶；DCE代表1,2-二氯乙烷；MW代表微波反应；AIBN代表偶氮二异丁腈；POT代表三邻甲基三苯基膦；DTBPF代表1,1'-双(二叔丁基膦)二茂铁；mp代表熔点。
化合物经手工或者
Figure PCTCN2016092989-appb-000034
软件命名，市售化合物采用供应商目录名称。
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A
Figure PCTCN2016092989-appb-000035
实施例1
Figure PCTCN2016092989-appb-000036
实施例1A
Figure PCTCN2016092989-appb-000037
室温下，向1-氢-吲唑-5-羟基(54克，0.4摩尔)和咪唑(40克，0.6摩尔)的DMF(1升)溶液中分批加入TBSCl(90克，0.6摩尔)。加完后，反应在15℃下搅拌5个小时。最终反应液加入3升水稀释，用乙酸乙酯(0.8升x 3)萃取,合并的有机相用水(0.8升x 3)洗涤，有机层用无水硫酸钠干燥，过滤并蒸发。残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(90克，90％收率)。LCMS(ESI)m/z:249[M+1]+.
实施例1B
Figure PCTCN2016092989-appb-000038
10℃下，向实施例1A(90克，0.36摩尔)的二氯甲烷(1.2升)的溶液中分批加入NIS(88克，0.4摩尔)。反应液在10℃下搅拌2个小时。用10％的亚硫酸钠溶液(加体积)淬灭反应，有机层用饱和食盐水洗涤(300毫升x 2)，合并有机相然后用无水硫酸钠干燥，过滤并蒸发。残留物通过快速色谱法硅胶柱层析纯化得到标题化合物(125克，92％收率)。LCMS(ESI)m/z:375[M+1]+.
实施例1C
Figure PCTCN2016092989-appb-000039
先将实施例1B溶解到二氯甲烷(1升)和四氢呋喃(0.4升)的混合溶剂里面，然后把甲基磺酸(6.0克，60毫摩尔)加进去，最后将3,4-四氢化-2氢-吡喃(124.2克，0.92摩尔)分批加入反应液中。加完后，在12℃下搅拌5个小时。反应完的反应液用二氯甲烷(500毫升)稀释，用饱和的碳酸氢钠溶液(300毫升)洗涤。有机层用饱和食盐水再次洗涤并用无水硫酸钠干燥，过滤蒸干。残留物通过快速色谱法硅胶柱层析纯化得到标题化合物(132克，93.6％收率)。LCMS(ESI)m/z:459[M+1]+.
实施例1D
Figure PCTCN2016092989-appb-000040
10℃下，向实施例1C(132克，0.29摩尔)的四氢呋喃(1.4升)溶液中一次性加入四丁基氟化铵的四氢呋 喃溶液(0.35升，0.35摩尔，1摩尔/升)。混合溶液在10℃下搅拌2个小时。将反应液倒入1.5升的冰水中，充分搅拌20分钟。水相用乙酸乙酯(400毫升x 3)萃取，合并有机相用饱和食盐水(200毫升x 2)洗涤，并用无水硫酸钠干燥，过滤蒸发。残留物通过快速色谱法硅胶柱层析纯化得到标题化合物(64克，65％收率)。LCMS(ESI)m/z:345[M+1]+.
实例1E
Figure PCTCN2016092989-appb-000041
在-78℃氮气保护下，向3,5-二氯吡啶(58.8克，404毫摩尔)的四氢呋喃(600毫升)溶液中滴加LDA(242毫升，484毫摩尔，2.0摩尔/升)。滴加完后在-78℃氮气保护下搅拌一个小时。之后，无水乙醛(35.5克，808毫摩尔)分批加入到反应液中。滴加完后，将反应液升到室温20℃继续搅拌2个小时。加入饱和氯化铵(200毫升)淬灭反应，然后用乙酸乙酯(400毫升x 3)萃取，合并有机相用无水硫酸钠干燥，过滤滤液浓缩得到残留物，通过快速色谱法硅胶柱层析纯化得到标题化合物(51克，66％收率)。1H NMR(400MHz,METHANOL-d4)ppm:8.43(s,2H),5.53(t,J＝6Hz,1H),3.12(d,J＝6Hz,1H),1.64(d,J＝6.8Hz,3H).
实施例1F
Figure PCTCN2016092989-appb-000042
在0℃下，向混合物实施例1E(36克，0.91摩尔)和三乙胺(21克，0.21摩尔)的二氯甲烷(1升)溶液中分批加入MsCl(32克，0.28mol)。在0℃下反应液搅拌3个小时，然后在冰浴下加水(100毫升)淬灭并且充分搅拌1个小时。分层后，有机相用饱和碳酸氢钠溶液(200毫升x 3)和饱和食盐水(200毫升)洗涤，然后用无水硫酸钠干燥，过滤，滤液浓缩得到残留物，通过快速色谱法硅胶柱层析纯化得到标题化合物(浅黄色，50克，98％收率)。
实施例1G
Figure PCTCN2016092989-appb-000043
实施例1D(35克，0.1摩尔)，实例1F(33克，0.12摩尔)和碳酸铯(66克，0.2摩尔)的乙腈(1.5升)混合物在90℃反应12个小时。冷却到室温后，过滤，将滤液蒸干得到粗品化合物。残留物通过快速色谱法硅胶柱层析纯化得到标题化合物(35克，85％收率)。LCMS(ESI)m/z:518[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.44(s,2H),7.46(dd,J＝2.8,8.8Hz,1H),7.17(dd,J＝2.4,9.2Hz,1H),6.71(s,1H),6.08(d,J＝6.8Hz,1H),5.64～5.59(m,1H),4.01～3.97(m,1H),3.73～3.69(m,1H),2.48～2.47(m,1H),2.13～2.11(m,2H),1.83(d,J＝6.8Hz,3H),1.75～1.64(m,3H).
实施例1H
Figure PCTCN2016092989-appb-000044
室温氮气下，向实施例1G(10克，19.3毫摩尔)的DMF(300毫升)溶液中加入Pd(PPh3)2Cl2(1.36克,2毫摩尔)和甲酸钠(6克,58毫摩尔)。然后氢化瓶用一氧化碳气体置换，使瓶内充满一氧化碳气体。反应液在一氧化碳(50psi)及80℃下搅拌反应12个小时。过滤，滤液浓缩得到残留物，通过快速色谱法硅胶柱层析纯化得到标题化合物(7.2克，89％收率)。LCMS(ESI)m/z:420[M+1]+.
实施例1I
Figure PCTCN2016092989-appb-000045
实施例1H(7.2克，17.1毫摩尔)，亚磷酸二乙酯(5.4毫升，51.4毫摩尔)和八水合氢氧化钡(2.7克，8.6毫摩尔)的四氢呋喃溶液(130毫升)混合物加热到50℃并反应5个小时。TLC检测反应原料消失，反应结束。过滤,浓缩得到残留物，通过快速色谱法硅胶柱层析纯化得到标题化合物(无色油状液体，5.5克，58％收率)。LCMS(ESI)m/z:558[M+1]+.
实施例1J
Figure PCTCN2016092989-appb-000046
氮气保护下，冰浴下向实施例1I(5.5克，9.9毫摩尔)的二氯乙烷(100毫升)溶液缓慢滴加DAST(3.7毫升，29.7毫摩尔)。滴加完后，在0℃氮气保护下搅拌反应2个小时。TLC检测，原料全部消失并生成一个新的主点。反应液在冰浴条件下用水(10毫升)淬灭，然后充分搅拌10分钟。分液后，有机相用饱和碳酸氢钠(20毫升x 2)和食盐水(20毫升)依次洗涤，并用无水硫酸钠干燥，最后过滤蒸发。残留物通过快速色谱法硅胶柱层析纯化得到标题化合物(黄色油状物，2.7克，50％收率)。LCMS(ESI)m/z:560[M+1]+.
实施例1K
Figure PCTCN2016092989-appb-000047
10℃氮气保护下，向实施例1J(1.42克，2.5毫摩尔)的四氢呋喃(15毫升)溶液中分批加入钠氢(60％含量)(0.63克，3.0毫摩尔)。加完后，反应液在10℃下搅拌30分钟。6-(吗啡啉甲基)-3-醛基吡啶(0.63克，3.0毫摩尔)加到搅拌中的反应液中，然后将反应液加热到80℃并反应3个小时。点板显示反应完成。待反应液冷却到室温后，加水(2毫升)淬灭反应，冰水淬灭后在室温下搅拌十分钟，然后用乙酸乙酯(10毫升x 3)萃取。合并有机相并用饱和的食盐水洗涤，用无水硫酸钠干燥，过滤蒸干。残留物通过快速色谱法硅胶柱层析纯化得到标题化合物(黄色油状物，0.28克混合物1K(顺式1Ka和反式1Kb)，54％收率)。LCMS(ESI)m/z:612[M+1]+
实施例1L
Figure PCTCN2016092989-appb-000048
0℃下，向甲醇(12毫升)中缓慢滴加乙酰氯(3毫升)。然后反应液在室温下搅拌反应15分钟。将实施例1K(800毫克，1.3毫摩尔)加到搅拌着的反应液中。将反应液加热到40℃，并且搅拌反应3个小时。LCM S显示反应完成。反应液直接蒸干，得到化合物1L(消旋体)，LCMS(ESI)m/z:528.4[M+1]+
实施例2
Figure PCTCN2016092989-appb-000049
将实施例1L用于SFC分离(SFC分离条件如下：柱子:Chiralpak AD-3 50*4.6mm I.D.,3um流动相:乙醇(0.05％DEA)-CO2从5％到40％速率:4mL/min波长:254nm)得到实例2，实例3，实例4，实例5，副产物实例6。
实例2LCMS(ESI)m/z:528.4[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.81(s,1H),8.49(s,2H),8.10(d,1H),7.65-7.43(m,2H),7.17(d,J＝7.3Hz,1H),6.84(m,1H),6.77-6.63(m,1H),6.01(m,1H),4.54(s,2H),4.02-3.87(m,4H),3.31(m,4H),1.84(d,3H).
实施例3
Figure PCTCN2016092989-appb-000050
这个实施例如实施例2中描述的方法制备。LCMS(ESI)m/z:528.4[M+1]+.1H NMR(400MHz,DMSO-d6)ppm8.65(s,1H),8.55(s,2H),7.96(d,J＝8.0Hz,1H),7.56(d,J＝9.0Hz,1H),7.46(d,J＝8.3Hz,1H),7.14(dd,J＝2.3,9.0Hz,1H),6.84(s,1H),6.78(s,2H),5.94(q,J＝6.4Hz,1H),4.44(s,2H),3.83(m,4H),3.22(m,4H),1.71(d,J＝6.5Hz,3H).
实施例4
Figure PCTCN2016092989-appb-000051
这个实施例如实施例2中描述的方法制备。LCMS(ESI)m/z:528.4[M+1]+.
1H NMR(400MHz,DMSO-d6)ppm 8.94(s,1H),8.60(s,2H),8.21(d,J＝8.3Hz,1H),7.71-7.52(m,2H),7.23-7.12(m,2H),6.80-6.65(m,1H),6.14(q,J＝6.5Hz,1H),4.54(s,2H),3.88(m,4H),3.31(m,4H),1.77(d,J＝6.5Hz,3H).
实施例5
Figure PCTCN2016092989-appb-000052
这个实施例如实施例2中描述的方法制备。LCMS(ESI)m/z:528.4[M+1]+.
1H NMR(400MHz,METHANOL-d4)ppm 8.98(s,1H),8.52(s,2H),8.36(d,J＝7.5Hz,1H),7.78(d,J＝8.3Hz,1H),7.51(d,J＝8.8Hz,1H),7.26-7.14(m,2H),6.74-6.60(m,1H),6.18(q,J＝6.5Hz,1H),4.63(s,2H),3.99(m,4H),3.46(m,4H),1.83(d,J＝6.5Hz,3H).
实施例6
Figure PCTCN2016092989-appb-000053
这个实施例如实施例2中描述的方法制备。LCMS(ESI)m/z:526.4[M+1]+.
1H NMR(400MHz,METHANOL-d4)ppm 8.92(s,1H),8.49(s,2H),8.41(d,J＝7.3Hz,1H),8.11(d,J＝7.8Hz,1H),7.55(d,J＝9.0Hz,1H),7.43(d,J＝2.0Hz,1H),7.19(dd,J＝2.0,9.0Hz,1H),6.10(q,J＝6.5Hz,1H),4.74(d,J＝7.8Hz,4H),3.99(br.s.,4H),3.47(br.s.,4H),1.79(d,J＝6.8Hz,3H).
流程B
Figure PCTCN2016092989-appb-000054
实施例7(参考例)
Figure PCTCN2016092989-appb-000055
实施例7A
Figure PCTCN2016092989-appb-000056
0℃条件下，向6-甲酸甲酯-1-甲基吡啶(20克，0.13摩尔)的N,N-二甲基亚砜(200毫升)的溶液中加入碘单质(33.5克，0.13毫摩尔)和三氟乙酸(35.3毫升，0.4毫摩尔)，搅拌1小时，然后升温到140℃下搅拌2.5小时。冷却到0℃后，饱和硫代硫酸钠溶液(30毫升)淬灭，搅拌30分钟，水层用乙酸乙酯(150毫升×3)萃取，结合有机层饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过硅胶快速色谱法硅胶柱层析纯化纯化得到标题化合物(8克，37％产率)。1H NMR(400MHz,CHLOROFORM-d)ppm:10.14(s,1H),9.36(s,1H),8.47(dd,J＝1.3,8.0Hz,1H),8.03(d,J＝8.0Hz,1H),4.05-3.94(s,3H).
实施例7B
Figure PCTCN2016092989-appb-000057
0℃条件下，向实施例7A(20克，120毫摩尔)的原甲酸三甲酯(400毫升)的溶液中，慢慢滴加甲酸(40毫升)，该温度下搅拌30分钟，然后滴加浓硫酸(1.2毫升)，滴加完成，升温到50℃搅拌30分钟，然后再降温到25℃搅拌3小时。冷却到室温，加到水(100毫升)中，水层用乙酸乙酯(200毫升×3)萃取，合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩得到棕色油状标题化合物(25克，98.8％产率)，直接用于下一步。
实施例7C
Figure PCTCN2016092989-appb-000058
0℃氮气保护下，向实施例7B(8克，38毫摩尔)的四氢呋喃(120毫升)溶液中，分批加入四氢铝锂(4.4克，114毫摩尔)，加入完成之后，在该温度下搅拌1小时。用水(4.4毫升)，15％氢氧化钠(4.4毫升)然后再加水(13.2毫升)淬灭，搅拌30分钟过滤，真空浓缩得到黄色油状标题化合物(5克，71％收率)直接用于下一步。
实施例7D
Figure PCTCN2016092989-appb-000059
向实施例7C(5克，27毫摩尔)的二氯甲烷(120毫升)溶液中，加入二氧化锰(19克，216毫摩尔)，然后升温到40℃搅拌16小时。冷却到室温后，过滤，真空浓缩，残余物通过硅胶快速色谱法硅胶柱层析纯化得到黄色油状标题化合物(2.62克，52.4％产率)。1H NMR(400MHz,CHLOROFORM-d)ppm 10.1(s,1H),9.04-9.13(m,1H),8.22(dd,J＝2.01,8.03Hz,1H),7.75(d,J＝8.03Hz,1H),5.44(s,1H),3.43(s,6H).
实施例7E
Figure PCTCN2016092989-appb-000060
在5℃氮气保护下，向实施例7D(2.7克，5毫摩尔)的四氢呋喃(80毫升)溶液中分批加入钠氢(600毫克，60％，14.5毫摩尔)，完成之后，该温度下搅拌30分钟，加入实施例1J(2克，10.6毫摩尔)，然后加热到70℃搅拌16小时。冷却到室温后，倒入冰水(50毫升)中，水层用乙酸乙酯(40毫升×3)萃取，合 并有机相，用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过柱层析纯化得到无色油状标题化合物(1.35克，48％产率)。
此混合物通过手性HPLC拆分得到顺反异构体，手性柱:Chiralcel OD-3 150×4.6mm I.D.,3um，流动相:乙醇(0.05％DEA)-CO2，从5％到40％，流速:2.5mL/min,波长:220nm。
实施例7F
Figure PCTCN2016092989-appb-000061
实施例7E(0.2克,0.34毫摩尔)和一水合对苯甲磺酸(12毫克,0.068毫摩尔)的水(8毫升)和丙酮(10毫升)混合溶液在50℃下加热搅拌3小时。冷却，水层用二氯甲烷(4毫升×3)萃取，结合有机层饱和食盐水(4毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩得到标题化合物(140毫克，76％产率)直接用于下一步。LCMS(ESI)m/z:541.4[M+1]+.
实施例7G
Figure PCTCN2016092989-appb-000062
向实施例7F(70毫克，130微摩尔)和(S)-2-氨基丙烷-1-醇(29毫克,390微摩尔)的1,2-二氯乙烷(1毫升)的混合溶液中，滴加醋酸(9毫克,147.77毫摩尔)，滴加完成后20℃下搅拌30分钟。慢慢加入氰基硼氢化钠(24毫克,390微摩尔)，继续在20℃下搅拌2小时。加水(1毫升)淬灭，水层用二氯甲烷(5毫升×3)萃取，结合有机层饱和食盐水(3毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备HPLC(HCl)分离纯化得到标题化合物(3毫克，3.32％产率)。LCMS(ESI)m/z:600.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.94(s,1H),8.49(s,2H),8.36-8.30(m,1H),7.69(dd,J＝8.8,18.8Hz,2H),7.25-7.15(m,2H),6.78-6.64(m,1H),6.17(q,J＝6.5Hz,1H),5.86-5.76(m,1H),4.59-4.45(m,2H),4.03-3.88(m,2H),3.85-3.75(m,1H),3.69(dd,J＝6.0,12.0Hz,1H),3.56-3.47(m,1H),2.56-2.40(m,1H),2.18-2.08(m,1H),2.02(d,J＝13.3Hz,1H),1.83(d,J＝6.5Hz,3H),1.73-1.62(m,2H),1.42(d,J＝6.8Hz,3H).
实施例7H
Figure PCTCN2016092989-appb-000063
这个实施例如实施例1L中描述的方法制备。LCMS(ESI)m/z:516.1[M+1]+.1H NMR(400MHz,DMSO-d6)ppm8.89(br.s.,1H),8.58(s,2H),8.17(d,J＝8.53Hz,1H),7.51-7.66(m,2H),7.27(s,1H),7.01(s,1H),6.63-6.76(m,2H),6.13(d,J＝6.78Hz,1H),4.38(br.s.,2H),3.68(d,J＝15.81Hz,2H),2.66(br.s.,1H),1.76(d,J＝6.53Hz,3H),1.25(d,J＝6.53Hz,3H).
实施例9
Figure PCTCN2016092989-appb-000064
这个实施例如实施例7中描述的方法制备。LCMS(ESI)m/z:556.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.93(s,1H),8.49(s,2H),8.23(d,J＝6.27Hz,1H),7.45-7.66(m,2H),7.10-7.26(m,2H),6.53-6.70(m,1H),6.12-6.22(m,1H),4.50(br.s.,2H),3.49(br.s.,2H),3.17(br.s.,2H),2.03(d,J＝12.80Hz,2H),1.83(d,J＝6.53Hz,3H),1.59(br.s.,2H),1.29(s,2H).
实施例10
Figure PCTCN2016092989-appb-000065
这个实施例如实施例7中描述的方法制备。LCMS(ESI)m/z:542.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.91(s,1H),8.50(s,2H),8.23(d,J＝8.28Hz,1H),7.49-7.61(m,2H),7.17-7.27(m,2H),6.53-6.71(m,2H),6.14-6.26(m,2H),4.48(s,2H),4.05-4.13(m,2H),3.39-3.59(m,4H),2.15(d,J＝12.05Hz,3H),1.70-1.90(m,5H).
实施例11
Figure PCTCN2016092989-appb-000066
这个实施例如实施例7中描述的方法制备。LCMS(ESI)m/z:571.4[M+1]+.1H NMR(400MHz,METHANOL-d4) ppm 8.92(s,1H),8.50(s,2H),8.25(d,J＝8.28Hz,1H),7.47-7.67(m,3H),7.16-7.28(m,2H),6.56-6.69(m,1H),6.19(q,J＝6.61Hz,1H),4.57(s,2H),4.04(br.s.,4H),3.60-3.80(m,5H),3.49(br.s.,3H),1.85(d,J＝6.78Hz,3H).
实施例12
Figure PCTCN2016092989-appb-000067
实施例12A
Figure PCTCN2016092989-appb-000068
向实施例7F(50毫克，90微摩尔)和3-羟基吡咯(23毫克,270微摩尔)的1,2-二氯乙烷(1毫升)的混合溶液中，滴加醋酸(8.87毫克,147.77微摩尔)，滴加完成后20℃下搅拌30分钟。慢慢加入氰基硼氢化钠(17毫克,270微摩尔)，继续在20℃下搅拌2小时。水淬灭，水层用二氯甲烷(5毫升×3)萃取，结合有机层饱和食盐水(3毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速色谱法硅胶柱纯化得到标题化合物(29毫克，53％产率)。LCMS(ESI)m/z:612.5[M+1]+.
实施例12B
Figure PCTCN2016092989-appb-000069
这个实施例如实施例7中描述的方法制备。LCMS(ESI)m/z:528.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.95(br.s.,1H),8.52(br.s.,2H),8.33(br.s.,1H),7.73(d,J＝4.77Hz,1H),7.50(d,J＝9.03Hz,1H),7.13-7.24(m,2H),6.58-6.73(m,1H),6.18(d,J＝6.53Hz,1H),4.60-4.73(m,4H),3.35(s,2H),1.83(d,J＝6.27Hz,4H),1.28(s,1H).
流程C
Figure PCTCN2016092989-appb-000070
实施例13
Figure PCTCN2016092989-appb-000071
实施例13A
Figure PCTCN2016092989-appb-000072
乙酰丙酸乙酯(30克，208毫摩尔)溶解在乙醇(100毫升)中，向其中慢慢滴加水合肼(15.63克，312毫摩尔，85％)，混合物在80℃下搅拌回流2小时，反应液冷却至室温，析出即为目标化合物6-甲基-4,5-二-氢哒嗪-3(2-氢)-酮(23克，产率，98％)，化合物无需纯化直接进行下一步反应。
实施例13B
Figure PCTCN2016092989-appb-000073
实施例13A(23克，205.4毫摩尔)溶解在醋酸(100毫升)中，在强力搅拌下向上述溶液中滴入液溴(55.03克，348.5毫摩尔),滴加过程中温度不要超过40℃，滴加完毕后，混合物在80℃下反应半小时。冷却至室温，过滤，滤饼用甲基叔丁基醚冲洗两遍得到目标化合物(20克87％收率)可直接用于下一步骤而无需进一步纯化。LCMS(ESI)m/z:133[M+1]+.1HNMR(CHLOROFORM-d,Bruker Avance 400MHz):ppm 7.36-7.39(m,1H),6.69-6.89(m,1H),2.22(s,3H).
实施例13C
Figure PCTCN2016092989-appb-000074
实施例13B(18克，163.44毫摩尔)和三溴氧磷(93.8克，327.6毫摩尔)混合物在70℃下搅拌过夜。混合物冷却至40℃，将其倒入冰水中，用碳酸氢钠饱和溶液(20毫升)淬灭反应，再用二氯甲烷(100毫升x 3)萃取，合并有机层用无水硫酸钠干燥，过滤并蒸发，得到目标化合物3-溴-6-甲基哒嗪(8克，31％收率)为。LCMS(ESI)m/z:173[M+1]+.1H NMR(CHLOROFORM-d,Bruker Avance 400MHz):ppm 7.86-7.88(d,1H,J＝8Hz),7.52-7.54(d,1H,J＝8Hz),2.55(s,3H).
实施例13D
Figure PCTCN2016092989-appb-000075
实施例13C(8.0克，48.0毫摩尔)NBS(9.44克，48.0毫摩尔)溶解在四氯化碳(200毫升)中，溶液中加入AIBN(1.58克，9.6毫摩尔)，混合物在80℃下反应12小时，混合物过滤，浓缩，残余物通过快速色谱法硅胶柱纯化得到目标化合物3-溴-6-(溴甲基)哒嗪(2.2克，19％收率)。LCMS(ESI)m/z:332[M+1]+.1H NMR(400MHz,CHLOROFORM-d)ppm 7.69(d,J＝8.53Hz,1H),7.56(d,J＝9.04Hz,1H).
实施例13E
Figure PCTCN2016092989-appb-000076
实施例13D(2.0克，8.0毫摩尔)溶解在DMF(15毫升)中，吗啡啉(1.4克，16毫摩尔)和K2CO3(2.2克，16毫摩尔)加入到溶液中，混合物在20℃下反应12小时。向混合物中加入5毫升水，用二氯甲烷萃取，将有机相浓缩，残余物通过快速色谱法硅胶柱纯化得到目标化合物(1.46克，72％收率)。LCMS(ESI)m/z:258[M+1]+.1H NMR(400MHz,CHLOROFORM-d)ppm 8.19(d,J＝8.53Hz,1H),7.86(d,J＝8.53Hz,1H),4.00(s,2H),3.71-3.78(m,4H),2.53-2.60(m,4H).
实施例13F
Figure PCTCN2016092989-appb-000077
实施例1G(1克，1.93毫摩尔)、Pd(PPh3)2Cl2(136毫克，0.19毫摩尔)、三甲基硅乙炔(227毫克，2.32毫摩尔)、碘化亚铜(368毫克，0.19毫摩尔)和三乙胺(586毫克，5.79毫摩尔)悬浮在乙腈中(14毫升)。反应液在80℃下搅拌18小时。待反应液冷却至室温后过滤，减压浓缩溶剂，得到标题化合物(黄色液体，0.8克，粗品)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.42(s,1H),7.48(d,J＝9.03Hz,1H),7.12(dd,J＝2.51,9.03Hz,1H),6.91(d,J＝2.01Hz,1H),6.04(d,J＝6.53Hz,1H),5.58-5.68(m,1H),3.95(br.s.,1H),3.63-3.74(m,1H),2.47(d,J＝9.54Hz,1H),2.11(br.s.,1H),2.00(br.s.,1H),1.81(d,J＝6.53Hz,3H),1.58-1.75(m,3H),0.30(s,9H).
实施例13G
Figure PCTCN2016092989-appb-000078
将1摩尔/升的四丁基氟化胺四氢呋喃溶液(8.6毫升，8.6毫摩尔)滴加到实施例13F(2.8克，5.73毫摩尔)的四氢呋喃(30毫升)溶液中。反应液在15℃搅拌3小时。饱和食盐水(50毫升)加入到反应液中，乙酸乙酯萃取(40毫升x 3次)，分液，合并有机相，用无水硫酸钠干燥，过滤，减压旋干溶剂后经硅胶快速色谱法硅胶柱层析纯化分离(石油醚/乙酸乙酯＝20/1到10/1)得到标题化合物(无色油状液体，1克，产率42％)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.42(s,2H),7.50(dd,J＝3.01,9.03Hz,1H),7.13(dd,J＝2.26,9.29Hz,1H),7.01(d,J＝2.01Hz,1H),6.06(q,J＝6.69Hz,1H),5.64(ddd,J＝3.01,6.15,8.91Hz,1H),3.92-4.00(m,1H),3.64-3.74(m,1H),3.35(s,1H),2.49(dd,J＝1.76,8.78Hz,1H),1.97-2.20(m,2H),1.61-1.86(m,6H).
实施例13H
Figure PCTCN2016092989-appb-000079
实施例13G(1克，2.4毫摩尔)，氟化银(762毫克，6毫摩尔)和NBS(470毫克，2.64毫摩尔)加入到装有乙腈(10毫升)和水(1毫升)的混合溶液的封管中。反应液在80-90℃下搅拌18小时。反应进程由 TLC监测。待反应液冷却到室温后，饱和食盐水(10毫升)加入到反应液中，乙酸乙酯萃取(20毫升x 3)，有机相用无水硫酸钠干燥，过滤，真空旋干溶剂后经硅胶快速色谱法硅胶柱层析纯化分离(石油醚/乙酸乙酯＝20/1到10/1)得到标题化合物(顺反混合物，无色油状液体，200毫克，产率16％)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.45(s,2H),7.47-7.55(m,1H),7.12-7.20(m,1H),7.10(s,1H),6.30-6.46(m,1H),6.01-6.12(m,1H),5.60-5.70(m,1H),3.95-4.06(m,1H),3.66-3.79(m,1H),2.42-2.55(m,1H),2.09-2.21(m,1H),1.95-2.05(m,1H),1.83(d,J＝6.78Hz,3H),1.62-1.79(m,3H).
实施例13I
Figure PCTCN2016092989-appb-000080
实施例13H(30毫克，58微摩尔)、双联频哪醇硼酸酯(16毫克，64微摩尔)、Pd(dppf)Cl2CH2Cl2(5毫克，6微摩尔)和醋酸钾(12毫克，120微摩尔)悬浮在二氧六环(1.5毫升)中，置换氮气后反应液在100℃下搅拌18小时。反应进程由TLC监测。待反应液冷却到室温后，减压下除去溶剂，快速色谱法硅胶柱快速色谱法硅胶柱层析纯化分离(石油醚/乙酸乙酯＝10/1)得到标题化合物(无色油状液体，10毫克，产率30％)。LCMS(ESI)m/z:562.1[M+1]+.
实施例13J
Figure PCTCN2016092989-appb-000081
实施例13I(10毫克，18微摩尔)、实施例13E(9毫克，36微摩尔)、Pd(DTBPF)Cl2(2毫克，3.6微摩尔)和碳酸钾(5毫克，36微摩尔)悬浮在四氢呋喃(1毫升)和水(0.2毫升)的混合溶剂中，微波条件105℃反应15分钟。待反应液冷却到室温后，由制备板分离(石油醚/乙酸乙酯＝10/1)得到标题化合物(无色油状液体，5毫克，产率46％)。LCMS(ESI)m/z:613.2[M+1]+.
实施例13K
Figure PCTCN2016092989-appb-000082
将实施例13J(5毫克，8微摩尔)溶于无水甲醇(1毫升)中，然后将此溶液滴加到新鲜配制的乙酰氯(0.5 毫升)无水甲醇(2毫升)溶液中。反应液在40℃下搅拌3小时。反应完毕，旋去溶剂得到标题化合物(4毫克，产率91％)。LCMS(ESI)m/z:541.1[M+1]+.
流程D
Figure PCTCN2016092989-appb-000083
流程D
Figure PCTCN2016092989-appb-000084
实施例16
Figure PCTCN2016092989-appb-000085
实施例16A
Figure PCTCN2016092989-appb-000086
氮气保护，室温下向6-甲基-烟酸甲酯(5克,30毫摩尔)和溴代丁二酰亚胺(6.48克,30毫摩尔)的四氯化碳(40毫升)溶液中加入偶氮二异丁氰(1.08克,7毫摩尔)，反应液加热到80℃搅拌12个小时，趁热过滤。滤液蒸干，残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(1.6克，收率：21％)。1H NMR(400MHz,CHLOROFORM-d)ppm 9.16(d,J＝1.00Hz,1H),8.29(dd,J＝1.76,8.03Hz,1H),7.53(d,J＝8.03Hz,1H),4.58(s,2H),3.95(s,3H).
实施例16B
Figure PCTCN2016092989-appb-000087
氮气保护下，室温向实施例16A(1.6克,7毫摩尔)的DMF(12毫升)溶液中，一次性加入碳酸钾(1.16克,8.4毫摩尔)并搅拌过夜。将反应液倒入冰水(20毫升)，加入乙酸乙酯(40毫升x 3)萃取，合并有机相用饱和食盐水(50毫升)洗涤，硫酸钠干燥，过滤浓缩，残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(1克，收率：60％)。1H NMR(400MHz,CHLOROFORM-d)ppm 9.15(d,J＝1.51Hz,1H),8.26(dd,J＝2.01,8.03Hz,1H),7.53(d,J＝8.28Hz,1H),3.94(s,3H),3.68-3.78(m,6H),2.46-2.55(m,4H).
实施例16C
Figure PCTCN2016092989-appb-000088
氮气保护下，0℃向实施例16B(6.7克,28.4毫摩尔)的四氢呋喃(85毫升)溶液中，分批加入四氢铝锂(1.08克,28.4毫摩尔)，搅拌2个小时。缓慢向反应液中依次加入水(1毫升)，氢氧化钠(1毫升，15％)，水(3毫升)搅拌20分钟，过滤，减压下滤液浓度得到标题化合物(4.8克，收率：70％)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.45(s,1H),7.68(dd,J＝1.51,8.03Hz,1H),7.38(d,J＝8.03Hz,1H),4.67(s,2H),3.67-3.72(m,4H),3.61(s,2H),2.41-2.52(m,4H).
实施例16D
Figure PCTCN2016092989-appb-000089
室温，向实施例16C(4.06克,19.5毫摩尔)的二氯甲烷(70毫升)溶液中，分批加入活性二氧化锰(39克,449毫摩尔)，反应液加热回流16个小时。反应完毕，过滤，滤液蒸干，残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(1.2克，30％收率)。1H NMR(400MHz,CHLOROFORM-d)ppm 10.10(s,1H),9.02(d,J＝1.00Hz,1H),8.15(dd,J＝2.01,8.03Hz,1H),7.65(d,J＝8.03Hz,1H),3.73-3.79(m,6H),2.49-2.58(m,4H).
实施例16E
Figure PCTCN2016092989-appb-000090
室温下，向实施例16D(300毫克,1.45毫摩尔)和亚膦酸二乙酯(603毫克,4.36毫摩尔)的四氢呋喃(5毫升)溶液中，一次性加入八水合氢氧化钡(229毫克,0.728毫摩尔)，反应液加热至45℃搅拌4个小时。反应完毕，加入水(20毫升)，加入乙酸乙酯(40毫升x 3)萃取，合并有机相合并有机相用饱和食盐水(50毫升)洗涤，并用硫酸钠干燥，过滤浓缩，残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(120毫克，24％收率)，为黄色液体。LCMS(ESI)m/z:345.1[M+1]+.
实施例16F
Figure PCTCN2016092989-appb-000091
0℃下，向实施例16E(120毫克,0.35毫摩尔)的二氯甲烷(5毫升)溶液中，缓慢滴加二乙胺基三氟化硫(168毫克,1.04毫摩尔)，滴加完毕，反应液0℃搅拌1个小时。反应完毕，反应液用饱和碳酸氢钠(5毫升)饱和食盐水(5毫升)洗涤，并用硫酸钠干燥，过滤浓缩，残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(60毫克，收率：50％)，为无色液体。LCMS(ESI)m/z:347.1[M+1]+.
实施例16G
Figure PCTCN2016092989-appb-000092
氮气保护，室温向实施例16F(400毫克,1.15毫摩尔)的四氢呋喃(10毫升)溶液，分批加入钠氢(139毫克,60％矿物油中，3.46毫摩尔)并搅拌10分钟，5-(1-(3,5-二氯吡啶-4-)乙氧基)-1-(四氢化-2氢-吡喃-2-)-1氢-吲唑-3-甲醛(485毫克,1.15毫摩尔)1H加入到上述反应液中，搅拌10分钟。然后反应液加热到80℃搅拌3小时。反应完毕，冷却至室温，用水(10毫升)淬灭，加入乙酸乙酯(40毫升x 3)萃取，合并有机相合并有机相用饱和食盐水(50毫升)洗涤，并用硫酸钠干燥，过滤浓缩，残余物通过快速色谱法硅胶柱层析纯化，再经手性HPLC拆分得到标题化合物(Z式)(250毫克，收率：35％)，异构体(E式)(200毫 克，收率：28％)为黄色液体。LCMS(ESI)m/z:612[M+1]+.
实施例16H
Figure PCTCN2016092989-appb-000093
氮气保护，室温往实施例16G(80毫克,1.3毫摩尔)的甲醇(1毫升)溶液中，加入新鲜制备的乙酰氯(1毫升)，甲醇(3毫升)溶液。反应液在40℃搅拌3个小时。真空除去溶液即为标题化合物(33毫克，收率：52％)。LCMS(ESI)m/z:528.4[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 9.08(s,1H),8.52(br.s.,1H),8.26(d,J＝7.03Hz,1H),7.66(d,J＝8.03Hz,1H),7.48(d,J＝9.79Hz,1H),7.23(br.s.,2H),6.92-7.08(m,1H),6.12(d,J＝6.78Hz,1H),4.63(s,2H),4.00(br.s.,4H),3.47(br.s.,4H),1.83(d,J＝6.53Hz,3H).
流程E
Figure PCTCN2016092989-appb-000094
实施例17
Figure PCTCN2016092989-appb-000095
实施例17A
Figure PCTCN2016092989-appb-000096
室温下，向实施例7E(900毫克,1.53毫摩尔)的丙酮(4毫升),水(4毫升)混合溶液中，加入一水合对甲苯磺酸(291毫克，1.53毫摩尔)，反应液加热至50℃搅拌10小时。反应完毕，加入水(4毫升)，加入二氯甲烷(30毫升x 3)萃取，合并有机相，用饱和食盐水(20毫升)洗涤，并用硫酸钠干燥，过滤并蒸发得到标题化合物(850毫克，收率：92％)。LCMS(ESI)m/z:541[M+1]+.
实施例17B
Figure PCTCN2016092989-appb-000097
氮气保护下，室温向实施例17A(850毫克,1.57毫摩尔)的甲醇(8毫升)溶液中，分批加入硼氢化钠(119毫克,3.14毫摩尔)，搅拌1小时。加入水(30毫升)淬灭，加入乙酸乙酯(40毫升x 3)萃取，有机相合并用饱和食盐水(20毫升)洗涤，并用硫酸钠干燥，过滤并蒸发，得到标题化合物(900毫克，粗品)，为黄色液体。LCMS(ESI)m/z:543[M+1]+.
实施例17C
Figure PCTCN2016092989-appb-000098
室温氮气保护下，往实施例17B(900毫克,粗品)的甲醇(2毫升)溶液中，加入新鲜配制的乙酰氯(2毫 升)，甲醇(6毫升)溶液。反应液在40℃搅拌3个小时。真空除去溶液即为标题化合物(850毫克，粗品)。LCMS(ESI)m/z:459[M+1]+.
实施例17D
Figure PCTCN2016092989-appb-000099
室温氮气保护下，往实施例17C(748毫克,1.63毫摩尔)的二氯甲烷(12毫升)溶液中，加入三乙胺(495毫克,4.89毫摩尔),二碳酸二叔丁酯(356毫克,1.63毫摩尔)，DMAP(20毫克,0.16毫摩尔)，反应液在室温下搅拌30分钟。反应完毕，用1M盐酸调节pH至7左右，加入二氯甲烷(20毫升x 3)萃取，有机相合并用饱和食盐水(20毫升)洗涤，并用硫酸钠干燥，过滤并蒸发，残余物通过快速色谱法硅胶柱层析纯化纯化得到标题化合物(280毫克，收率：30.7％)。LCMS(ESI)m/z:559[M+1]+.
实施例17E
Figure PCTCN2016092989-appb-000100
室温下，往实施例17D(280毫克，0.5毫摩尔)的二氯甲烷(6毫升)溶液中，分批加入戴斯-马丁试剂(318.毫克，0.75毫摩尔)，反应液在室温搅拌2个小时，反应完，反应液用冰水浴冷却，过滤，滤液蒸干得标题化合物(230毫克，收率：82.4％)。LCMS(ESI)m/z:557[M+1]+.
实施例17F
Figure PCTCN2016092989-appb-000101
室温下，往实施例17E(50毫克，90微摩尔)，四氢化-2氢-吡喃-4胺(18毫克，180微摩尔)的1,2-二氯乙烷(2.5毫升)溶液中，加入醋酸(约0.1毫升)至pH为5左右，搅拌2个小时。氰基硼氢化钠(12毫克,180微摩尔)室温下加入到反应液中，继续搅拌1个小时，加入水(5毫升)，加入二氯甲烷(20毫升x3)萃取，有机相合并用饱和食盐水(20毫升)洗涤，并用硫酸钠干燥，过滤并蒸发，残余物通过快速色谱 法硅胶柱层析纯化得到标题化合物(20毫克，收率：34.7％)。样品用于手性柱拆分得到实施例17F-R构型(8毫克)，实施例17F-S构型(8毫克)。
LCMS(ESI)m/z:642[M+1]+.
手性柱方法：手性柱，Chiralcel OJ-H 250×4.6mm I.D.,5um；流动相，甲醇(0.05％DEA)-CO2从5％到40％；流速，2.35mL/min；波长，280nm。
实施例17G
Figure PCTCN2016092989-appb-000102
室温氮气保护下，往实施例17F-S构型(15毫克,23微摩尔)(按照实施例17F的制备方法，放大200毫克规模的反应，得到17F-S构型产物15毫克)的甲醇(1毫升)溶液中，加入新鲜配置的乙酰氯(1毫升)，甲醇(3毫升)溶液。反应液在40℃搅拌3个小时。真空除去溶液即为标题化合物(33毫克，收率：52％)。LCMS(ESI)m/z:542[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 9.04(s,1H),8.50(br.s.,2H),8.23(d,J＝7.03Hz,1H),7.64(d,J＝8.03Hz,1H),7.49(d,J＝8.53Hz,1H),7.18-7.26(m,2H),7.04(s,2H),6.12(q,J＝6.53Hz,1H),4.53(s,2H),4.08(dd,J＝4.02,11.54Hz,2H),3.56-3.66(m,7H),2.15(d,J＝11.04Hz,2H),1.83(d,J＝6.53Hz,4H),1.18(t,J＝7.03Hz,9H).
实施例18
Figure PCTCN2016092989-appb-000103
本实施例中如实施例17中描述的方法制备施例17F，放大200毫克规模的反应，得到17F-R构型产物15毫克)得到实施例18。LCMS(ESI)m/z:542[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.95-9.12(m,1H),8.44-8.59(m,1H),8.25(br.s.,1H),7.68(br.s.,1H),7.51(d,J＝8.78Hz,1H),7.25(d,J＝15.06Hz,2H),6.91-7.10(m,1H),6.13(d,J＝5.77Hz,1H),4.54(br.s.,2H),4.07(d,J＝10.54Hz,2H),3.42-3.57(m,3H),2.15(d,J＝10.79Hz,2H),1.83(m,5H).
实施例18b
Figure PCTCN2016092989-appb-000104
向实施例18(15毫克，27.68微摩尔)和无水乙醛(5毫克，110微摩尔)的1,2-二氯乙烷(2毫升)的混合溶液中，滴加醋酸(2.21毫克,38.87微摩尔)，滴加完成后20℃下搅拌1小时。慢慢加入氰基硼氢化钠(7毫克，110微摩尔)，继续在20℃下搅拌1小时。水淬灭，水层用二氯甲烷(3毫升×2)萃取，结合有机层饱和食盐水(5毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备柱层析纯化得到实施例18b(12毫克，76％收率)。
LCMS(ESI)m/z:571[M+1]+
1H NMR(400MHz,METHANOL-d4)9.09(s,1H),8.31(d,J＝8.03Hz,1H),7.72(d,J＝8.28Hz,1H),7.54(d,J＝9.03Hz,1H),7.24-7.33(m,2H),7.00-7.16(m,1H),6.17(q,J＝6.69Hz,1H),4.11(d,J＝8.53Hz,2H),3.79(t,J＝11.80Hz,1H),3.38-3.58(m,4H),3.26-3.32(m,2H),2.09(br.s.,2H),1.90-2.01(m,2H),1.85(d,J＝6.78Hz,3H),1.39(t,J＝7.15Hz,3H)
实施例21
Figure PCTCN2016092989-appb-000105
本实施例中如实施例17中描述的方法制备。LCMS(ESI)m/z:556.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 9.10(br.s.,1H),8.58(br.s.,1H),8.29(br.s.,1H),7.72(br.s.,1H),7.53(d,J＝8.53Hz,1H),7.21-7.33(m,3H),6.97-7.18(m,1H),6.14(d,J＝5.52Hz,1H),4.59(br.s.,2H),3.57-3.74(m,6H),3.50(br.s.,3H),3.19(br.s.,1H),2.03(d,J＝12.55Hz,3H),1.83(d,J＝5.52Hz,6H),1.66(br.s.,3H).
实施例22
Figure PCTCN2016092989-appb-000106
本实施例中如实施例17中描述的方法制备。LCMS(ESI)m/z:556.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 9.09(s,1H),8.54(br.s.,2H),8.27(d,J＝7.53Hz,1H),7.68(d,J＝8.03Hz,1H),7.51(d, J＝9.03Hz,1H),7.23-7.28(m,2H),7.09(s,1H),6.14(q,J＝6.53Hz,1H),4.57(br.s.,2H),3.66(d,J＝7.03Hz,2H),3.50(br.s.,2H),2.03(d,J＝13.55Hz,3H),1.83(d,J＝6.53Hz,4H),1.64(br.s.,2H),1.29(br.s.,3H).
实施例23
Figure PCTCN2016092989-appb-000107
本实施例中如实施例17中描述的方法制备。LCMS(ESI)m/z:528.1[M+1]+.
1H NMR(400MHz,DMSO-d6)ppm 9.08(s,1H),8.62(s,2H),8.29(d,J＝6.27Hz,1H),7.73(d,J＝7.78Hz,1H),7.50(d,J＝9.03Hz,1H),7.09-7.33(m,3H),6.04(q,J＝6.53Hz,1H),4.38-4.68(m,1H),2.68(br.s.,1H),2.33(br.s.,1H),1.69-1.82(m,3H).
流程F
Figure PCTCN2016092989-appb-000108
实施例24(参考例)
Figure PCTCN2016092989-appb-000109
实施例24A
Figure PCTCN2016092989-appb-000110
在-20℃氮气保护下，向5-溴-2-碘吡啶(61克,214.87毫摩尔)的四氢呋喃(700毫升)溶液中慢慢滴加异丙基氯化镁格式试剂(26.52克,257.84毫摩尔)的四氢呋喃溶液，然后该溶液在-20℃搅拌3小时，升温至0℃，N,N-二甲基甲酰胺(18.85克,257.84毫摩尔)在0℃下分批滴加，滴加完成后升温至20℃，继续搅拌6小时。薄层色谱板检测反应完成，加入饱和氯化铵(100毫升)淬灭，水层用乙酸乙酯(140毫升x 3)萃取，结合有机层饱和食盐水(100毫升x 2)洗涤，无水硫酸钠干燥，过滤，真空浓缩得到标题化合物(44克)可直接用于下一步骤而无需进一步纯化。1H NMR(400MHz,CHLOROFORM-d)ppm 10.04(s,1H),8.85(d,J＝1.8Hz,1H),8.03(dd,J＝1.8,8.3Hz,1H),7.86(d,J＝8.3Hz,1H).
实施例24B
Figure PCTCN2016092989-appb-000111
氮气保护下，20℃向实施例1A(40克，215.05毫摩尔)，原甲酸三甲酯(27.38克,258.06毫摩尔)的甲醇(400毫升)的混合溶液中分批加入一水合对甲苯磺酸(818.11毫克,4.30毫摩尔)。滴加完毕之后，20℃下搅拌10分钟，升温至70℃搅拌16小时。薄层色谱板检测反应完成，降温至20℃，部分真空浓缩，倒入冰水(150毫升)中搅拌20分钟，水层用乙酸乙酯(100毫升x 3)萃取，合并有机相，用饱和食盐水(100毫升x 2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速色谱法硅胶柱提纯得到黄色油状标题化合物(19克，38.07％产率)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.67(d,J＝2.0Hz,1H),7.86(dd,J＝2.3,8.3Hz,1H),7.46(d,J＝8.0Hz,1H),3.39(s,6H).
实施例24C
Figure PCTCN2016092989-appb-000112
氮气保护下，向实施例24B(2克，8.62毫摩尔)，双联频哪醇硼酸酯(2.85克，11.21毫摩尔)，醋酸钾(2.54克，25.86毫摩尔)的二氧六环(10毫升)混合溶液中加入Pd(dppf)Cl2(630.73毫克,862.00微摩尔)，然后110℃下反应2小时。LC-MS检测反应完成。冷却到室温后过滤，真空浓缩，残余物通过快速色谱法硅胶 柱提纯得到黑色油状标题化合物(2克，83.12％产率)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.94(s,1H),8.11(dd,J＝1.4,7.7Hz,1H),7.54(d,J＝7.8Hz,1H),5.40(s,1H),3.39(s,6H),1.35(s,12H).
实施例24D
Figure PCTCN2016092989-appb-000113
20℃下，向1E 1-(3,5-二氯吡啶-4-)乙醇(85.60克，445.74摩尔)，三乙胺(90.21克，891.47毫摩尔)的二氯甲烷(1.50升)溶液中，滴加乙酰氯(41.99克，534.88毫摩尔)，在20℃下搅拌1小时后，TLC检测反应完毕，减压蒸干溶剂，残余物通过柱色谱纯化得到标题化合物(无色油状物，57.10克，54.7％产率)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.44(s,2H),6.25(q,J＝6.8Hz,1H),2.09(s,3H),1.63(d,J＝7.2Hz,3H).
实施例24E
Figure PCTCN2016092989-appb-000114
20℃下，向实施例24D(31克,243毫摩尔)DMSO(78毫升)与1M NaH2PO4/Na2HPO4缓冲液(pH 7.5，775毫升)的混合溶液中加入诺维信脂肪酶435(31.78克，3.12×104PLU)。在51℃下搅拌129小时后，LCMS检测约50％原料完成转化。加水(1升)稀释，用乙酸乙酯(1升x 5)。合并的有机层用水(500毫升)，盐水(500毫升x 2)洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(无色油状物，12.00克，77％产率)。LCMS(ESI)m/z:233.9[M+1]+
实施例24F
Figure PCTCN2016092989-appb-000115
20℃下，向实施例24E(12.00克，51.26毫摩尔)的四氢呋喃(50毫升)和甲醇(50毫升)混合溶液中，滴加1M氢氧化钠溶液(51.26毫升，51.26毫摩尔)，在20℃下搅拌半小时后，TLC检测反应完毕，加水(30毫升)稀释，用乙酸乙酯(100毫升x 3)萃取。合并的有机层用盐水(20毫升x 2)洗涤后，经硫酸钠干燥减压蒸干溶剂得到标题化合物(无色油状物，7.99克，81.2％产率)。LCMS(ESI)m/z:191.8[M+1]+.
实施例24G
Figure PCTCN2016092989-appb-000116
0℃冰浴下，向实物25F(18克，94毫摩尔)和三乙胺(28.45克，281毫摩尔)的二氯甲烷(400毫升)混合溶液中缓慢加入甲烷磺酰氯(32.21克,281.2毫摩尔)。反应液在室温条件下搅拌4个小时。反应完成后，加水淬灭反应并用二氯甲烷(500毫升x 3)萃取。合并有机相，用无水硫酸钠干燥，蒸干得到残留物，通过柱层析得到实物24G(24克，88.9毫摩尔，94.8％收率)。
实施例24H
Figure PCTCN2016092989-appb-000117
氮气保护下，实物24G(24克，88.9毫摩尔)，实施例1D(35克，101.7毫摩尔)和碳酸铯(57.9克，177.7毫摩尔)的乙腈(1000毫升)溶液在油浴下加热到110℃并搅拌反应12个小时。反应完成后，过滤，取滤液蒸干得到残留物，通过柱层析得到实施例25E(26克，50.2毫摩尔，56.5％收率)微黄色物体。LCMS(ESI)m/z:518.0[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.44(s,2H),7.46(dd,J＝2.8,8.8Hz,1H),7.17(dd,J＝2.4,9.2Hz,1H),6.71(s,1H),6.08(d,J＝6.8Hz,1H),5.64～5.59(m,1H),4.01～3.97(m,1H),3.73～3.69(m,1H),2.48～2.47(m,1H),2.13～2.11(m,2H),1.83(d,J＝6.8Hz,3H),1.75～1.64(m,3H)
实施例24I
Figure PCTCN2016092989-appb-000118
室温氮气下，向实例25E(24克，46.3毫摩尔)的DMF(500毫升)溶液中加入Pd(PPh3)2Cl2(1.63克,2.32毫摩尔)和甲酸钠(9.5克,139.0毫摩尔)。然后氢化瓶用一氧化碳气体置换，使瓶内充满一氧化碳气体。反应液在一氧化碳(50psi)及80℃下搅拌反应12个小时。过滤，滤液浓缩干，残留物通过柱层析得到标题化合物(16克，64％收率)。LCMS(ESI)m/z:420.1[M+1]+.
实施例24J
Figure PCTCN2016092989-appb-000119
0℃条件下，向24F[1-(3,5-二氯-4-吡啶)乙氧基]-1-四氢吡喃-2-苯并吲唑-3-甲醛(10克，23.8毫摩尔)的乙醇(180毫升)溶液中加入水合肼(2.38克，47.6毫摩尔)，然后该混合物在20℃下搅拌3小时。加入乙二胺(2.86克，47.6毫摩尔)和氯化亚铜(2.35.6克，23.8毫摩尔)，10分钟之后，在0℃条件下，慢慢滴加三溴氟甲烷(16.1克，59.6毫摩尔)，滴加完毕之后，在20℃下搅拌16小时。薄层色谱板检测反应完成，滴加1摩尔柠檬酸淬灭反应，水层用乙酸乙酯(50毫升x 3)萃取，结合有机层饱和食盐水(50毫升x 2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速色谱法硅胶柱纯化得到黄色油状标题化合物(6克，48.97％产率)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.41(s,2H),7.46-7.43(m,1H),7.13-7.10(dd,J＝2.3,9.0Hz,1H),6.98(d,J＝2.5Hz,1H),6.33(d,J＝2.5Hz,1H),6.25(d,J＝20Hz 1H),6.02(q,J＝6.7Hz,1H),5.69-5.57(m,1H),4.04-3.92(m,1H),3.74-3.65(m,1H),2.54-2.40(m,1H),2.19-2.06(m,1H),2.04-1.93(m,1H),1.80(d,J＝6.5Hz,3H),1.76-1.60(m,3H).
实施例24K
Figure PCTCN2016092989-appb-000120
在氮气保护下，向实例24C(703.99毫克,2.52毫摩尔)和实施例24J(1.00克,1.94毫摩尔)的四氢呋喃(9毫升)混合溶液中加入Pd(dppf)Cl2(141.95毫克,194.00微摩尔)，然后80℃下搅拌回流过夜。冷却，过滤，真空浓缩，残余物通过快速色谱法硅胶柱纯化得到黄色油状标题化合物(1.0克，90％产率)。LCMS(ESI)m/z:587.1[M+1]+.1H NMR(400MHz,CHLOROFORM-d)ppm 8.98-8.93(m,1H),8.41(s,2H),7.98(d,J＝7.0Hz,1H),7.64(d,J＝8.5Hz,1H),7.48(dd,J＝3.8,9.3Hz,1H),7.24-7.13(m,2H),6.84-6.70(m,1H),6.05(q,J＝6.5Hz,1H),5.68-5.61(m,1H),5.44(s,1H),4.03(m,1H),3.72(m.,1H),3.49(d,J＝4.5Hz,1H),3.45(s,6H),2.57-2.42(m,1H),2.07-1.98(m,2H),1.81(d,J＝6.5Hz,3H),1.78-1.70(m,2H).
实施例24L
Figure PCTCN2016092989-appb-000121
实施例24K(1.00克,1.70毫摩尔)和一水合对苯甲磺酸(194.毫克,1.02毫摩尔)的水(8毫升)和丙酮(10毫升)混合溶液在50℃下加热搅拌12小时。冷却，水层用二氯甲烷(10毫升x 3)萃取，结合有机层饱和食盐水(10毫升x 2)洗涤，无水硫酸钠干燥，过滤，真空浓缩得到标题化合物(940毫克，粗品)直接用于下一步。LCMS(ESI)m/z:541.4[M+1]+.
实施例24M
Figure PCTCN2016092989-appb-000122
向实施例24L(80毫克，147.77微摩尔)和1-氨-2-甲基丙烷-2-羟基(54.78毫克,443.31微摩尔)的1,2-二氯乙烷(2毫升)的混合溶液中，滴加醋酸(8.87毫克,147.77微摩尔)，滴加完成后20℃下搅拌30分钟。慢慢加入氰基硼氢化钠(27.86毫克,443.31微摩尔)，继续在20℃下搅拌2小时。水淬灭，水层用二氯甲烷(5毫升x 3)萃取，结合有机层饱和食盐水(3毫升x 2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速色谱法硅胶柱纯化得到黄色油状标题化合物(30毫克，33％)。LCMS(ESI)m/z:613.2[M+1]+.
实施例24N
Figure PCTCN2016092989-appb-000123
本实施例中如实施例24中描述的方法制备。LCMS(ESI)m/z:529.4[M+1]+。1H NMR(400MHz,METHANOL-d4)ppm 9.09(s,1H),8.55(s,2H),8.32(d,J＝7.0Hz,1H),7.72(d,J＝8.0Hz,1H),7.56(d,J＝9.0Hz,1H),7.35-7.24(m,2H),7.16-7.00(m,1H),6.16(q,J＝6.5Hz,1H),4.57(s,2H),3.16(s,2H),1.84(d,J＝6.5Hz,3H),1.42-1.35(m,6H).
实施例26
Figure PCTCN2016092989-appb-000124
本实施例如实施例24中描述的方法制备。LCMS(ESI)m/z:529.4[M+1]+。1H NMR(400MHz,METHANOL-d4)ppm 9.04(s,1H),8.51(m,2H),8.23(d,J＝6.8Hz,1H),7.68-7.43(m,1H),7.26-7.17(m,2H),7.06-6.88(m,2H),6.12(d,J＝6.5Hz,1H),4.55(m,1H),4.40(s,2H),4.08-4.01(m,1H),2.61(d,J＝6.0Hz,2H),2.41(m,2H),1.84(d,J＝6.5Hz,3H).
实施例27
Figure PCTCN2016092989-appb-000125
实施例27A
Figure PCTCN2016092989-appb-000126
向实施例24L(80毫克，147.77微摩尔)和2-哌嗪-1-乙醇(57.71毫克,443.31微摩尔)的1,2-二氯乙烷(2毫升)的混合溶液中，滴加醋酸(8.87毫克,147.77微摩尔)，滴加完成后20℃下搅拌30分钟。慢慢加入氰基硼氢化钠(27.86毫克,443.31微摩尔)，继续在20℃下搅拌2小时。水淬灭，水层用二氯甲烷(5毫升x3)萃取，结合有机层饱和食盐水(3毫升x 2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速色谱法硅胶柱纯化得到标题化合物(30毫克，30.9％)。LCMS(ESI)m/z:655.2[M+1]+.
实施例27B
Figure PCTCN2016092989-appb-000127
向实施例27A(20毫克，30.51微摩尔)的甲醇(1毫升)的溶液中，加入甲醇(1毫升)/乙酰氯(0.25毫升)混合溶液，加热到40℃搅拌3小时。冷却真空浓缩得到标题化合物(11.50毫克,65.5％收率)。LCMS(ESI)m/z:571.4[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm:9.07(s,1H),8.58-8.49(m,3H),7.92(d,J＝8.5Hz,1H),7.50(d,J＝9.0Hz,1H),7.27-7.20(m,1H),7.18-7.06(m,2H),6.14(q,J＝6.5Hz,1H),4.32(s,2H),3.98-3.92(m,2H),3.67-3.45(m,4H),3.43-3.37(m,2H),3.28-3.13(m,4H),1.85(d,J＝7.0Hz,3H).
实施例29
Figure PCTCN2016092989-appb-000128
实例29A
Figure PCTCN2016092989-appb-000129
氮叔丁氧羰基哌啶(2克，10.7毫摩尔)，溴乙酸乙酯(1.79克，10.7毫摩尔)和碳酸钾(4.45克，32.2毫摩尔)的乙腈(30毫升)溶液混合物加热到90℃并且搅拌反应16个小时。点板显示反应原料消失。过滤，滤液蒸干，残留物通过快速色谱法硅胶柱纯化快速色谱法硅胶柱层析纯化得到标题化合物(无色油状物，2.1克，7.7毫摩尔)。LCMS(ESI)m/z:273.2[M+1]+.
实施例29B
Figure PCTCN2016092989-appb-000130
将实施例29A(2.1克，7.7毫摩尔)加到盐酸乙酸乙酯(30毫升)里面，然后反应液在室温条件下搅拌16个小时。点板显示反应完成。直接将反应液蒸干得到标题化合物(1.2克，90.4％收率)可直接用于下一步骤而无需进一步纯化。
实施例29C
Figure PCTCN2016092989-appb-000131
实施例29B(15毫克，87微摩尔)和实例24L(47毫克，87微摩尔)的1,2-二氯乙烷(4毫升)溶液混合物在室温条件下搅拌1个小时，冰浴下，将氰基硼氢化钠(5.5毫克，87微摩尔)加到反应液中。最后将反应液升到室温并搅拌3个小时。加水淬灭反应，用二氯甲烷萃取，有机相用无水硫酸钠干燥，蒸干。残留物通过HPLC制备分离得到标题化合物(30毫克，49.5％收率)。LCMS(ESI)m/z:698.6[M+1]+.
实施例29D
Figure PCTCN2016092989-appb-000132
0℃下，向甲醇(8毫升)中缓慢滴加乙酰氯(3毫升)。然后反应液在室温下搅拌反应15分钟。将实施例29C(35毫克，50微摩尔)加到搅拌着的反应液中。将反应液加热到40℃，并且搅拌反应3个小时。LCMS显示反应完成。将反应液直接蒸干得到标题化合物(深黄色油状物，30毫克，97.5％收率)可直接用于下一步骤无需进一步纯化。LCMS(ESI)m/z:614.5[M+1]+.
实施例29E
Figure PCTCN2016092989-appb-000133
室温下，向实施例29D(30毫克，49微摩尔)的四氢呋喃(1毫升)，甲醇(1毫升)和水(1毫升)的混合溶剂中一次性加入氢氧化钠(10毫克，245微摩尔)。反应液在21℃下搅拌16个小时。LCMS显示反应完成。将反应液直接蒸干，然后用甲醇溶解，过滤，得到滤液蒸发。残留物通过制备色谱分离得到标题化合物(绿色油状物，5毫克，17.5％收率)。LCMS(ESI)m/z:585.2[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm9.11(s,1H),8.87(d,J＝8Hz,1H),8.53(s,2H),8.00(d,J＝8.4Hz,1H),7.50(d,J＝9.2Hz,1H),7.24(m,2H),7.18(d,J＝33.6Hz,1H),6.14(t,J＝6.8Hz,1H),4.40(s,2H),4.21(s,2H),3.65(s,4H),3.3(m,2H),1.84(d,J＝6.8Hz,3H).
实施例30
Figure PCTCN2016092989-appb-000134
本实施例中如实施例24中描述的方法制备。LCMS(ESI)m/z:556.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 9.10(br.s.,1H),8.58(br.s.,1H),8.29(br.s.,1H),7.72(br.s.,1H),7.53(d,J＝8.53Hz,1H),7.21-7.33(m,3H),6.97-7.18(m,1H),6.14(d,J＝5.52Hz,1H),4.59(br.s.,2H),3.57-3.74(m,6H),3.50(br.s.,3H),3.19(br.s.,1H),2.03(d,J＝12.55Hz,3H),1.83(d,J＝5.52Hz,6H),1.66(br.s.,3H).
实施例31
Figure PCTCN2016092989-appb-000135
本实施例中如实施例24中描述的方法制备。LCMS(ESI)m/z:528.1[M+1]+.
1H NMR(400MHz,DMSO-d6)ppm 9.08(s,1H),8.62(s,2H),8.29(d,J＝6.27Hz,1H),7.73(d,J＝7.78Hz,1H),7.50(d,J＝9.03Hz,1H),7.09-7.33(m,3H),6.04(q,J＝6.53Hz,1H),4.38-4.68(m,1H),2.68(br.s.,1H),2.33(br.s.,1H),1.69-1.82(m,3H).
实施例32
Figure PCTCN2016092989-appb-000136
本实施例中如实施例24中描述的方法制备。LCMS(ESI)m/z:527.1[M+1]+.
1H NMR(400MHz,METHANOL-d4)ppm 9.07(s,1H),8.51(s,3H),7.89(d,J＝8.4Hz,1H),7.49(d,J＝8.8Hz,1H),7.23-7.21(m,2H),7.15(d,J＝43.2Hz,1H),6.13(q,J＝6.4Hz,1H),4.44(s,2H),3.56-3.53(m,4H),3.37(m,4H),1.84(d,J＝6.4Hz,3H).
实施例33
Figure PCTCN2016092989-appb-000137
本实施例中如实施例24中描述的方法制备。LCMS(ESI)m/z:541.1[M+1]+.
1H NMR(400MHz,METHANOL-d4)ppm 9.06(s,1H),8.59(d,J＝8.0Hz,1H),7.95(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.25-7.21(m,2H),7.14(d,J＝40Hz,1H),6.14(q,J＝8.0Hz,1H),4.20(s,2H),3.00(s,3H),1.85(d,J＝8.0Hz,3H).
实施例34
Figure PCTCN2016092989-appb-000138
本实施例中如实施例24中描述的方法制备。LCMS(ESI)m/z:542.4[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 9.04-9.14(m,1H),8.53(s,2H),8.26(dd,J＝2.01,8.28Hz,1H),7.65(d,J＝8.28Hz,1H),7.52(d,J＝9.03Hz,1H),7.21-7.32(m,2H),6.15(q,J＝6.53Hz,1H),4.72(s,2H),4.32-4.24(m.,1H),3.41(s,3H),1.85(d,J＝6.78Hz,3H).
流程G
Figure PCTCN2016092989-appb-000139
实施例36
Figure PCTCN2016092989-appb-000140
实施例36A
Figure PCTCN2016092989-appb-000141
氮气保护下，室温向5-溴-2氟-吡啶(10克,56.82毫摩尔)，双联频哪醇硼酸酯(21.64克,85.23毫摩尔)，醋酸钾(16.73克,170.46毫摩尔)的二氧六环(100毫升)溶液中，一次性加入Pd(dppf)Cl2(4.16克,5.68毫摩尔)，搅拌10分钟，加热回流6小时。反应完毕，直接蒸干除去溶剂，残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(10.5克，收率：82.85％)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.59(s,1H),8.15(dt,J＝1.76,8.41Hz,1H),6.91(dd,J＝2.26,8.28Hz,1H),1.35(s,12H).
实施例36B
Figure PCTCN2016092989-appb-000142
氮气保护下，室温向实施例24J(720毫克,1.40毫摩尔)，实施例36A(311.72毫克,1.40毫摩尔)的四氢呋喃(9毫升)，加入磷酸钾(1摩尔/升,3.毫升)和Pd(dppf)Cl2(102毫克,0.14毫摩尔)搅拌10分钟，然后加热到80℃搅拌6小时。冷却至室温，加入乙酸乙酯(40毫升x 3)萃取，有机相合并用饱和食盐水(20毫升)洗涤，并用硫酸钠干燥，过滤并蒸发，残余物通过快速色谱法硅胶柱层析法纯化得到标题化合物(480毫克，收率：64.52％)，为无色油状物。LCMS(ESI)m/z:531.0[M+1]+.1H NMR(400MHz,CHLOROFORM-d)ppm 8.56(s,1H),8.41(s,2H),8.04(t,J＝6.78Hz,1H),7.48(dd,J＝4.02,9.03Hz,1H),7.13-7.23(m,2H),7.04(dd,J＝2.76,8.78Hz,1H),6.59-6.75(m,1H),6.05(q,J＝6.53Hz,1H),5.59-5.69(m,1H),4.03(br.s.,1H),3.66-3.80(m,1H),2.43-2.56(m,1H),2.13(br.s.,1H),2.02(br.s.,1H),1.81(d,J＝6.53Hz,3H),1.62-1.78(m,3H).
实施例36C
Figure PCTCN2016092989-appb-000143
室温下，微波管中加入四氢吡喃-4-醇(35毫克,0.34毫摩尔)的四氢呋喃(2毫升)溶液，缓慢分批加入钠氢(10毫克,0.25毫摩尔)并搅拌10分钟，往其中加入实施例36B(45毫克，0.085毫摩尔)搅拌10分钟。微波仪上70℃反应10分钟后，监测发现仍有原料，90℃继续反应30分钟。冷却至室温用冰水(5毫升)小心淬灭，有机相分离后用食盐水洗，并用硫酸钠干燥，过滤并蒸发，残余物通过快速色谱法硅胶柱层析法纯化得到标题化合物(35毫克，收率：67％)，为无色油状物。LCMS(ESI)m/z:613.2[M+1]+.
实施例36D
Figure PCTCN2016092989-appb-000144
本实施例中如实施例24中描述的方法制备。LCMS(ESI)m/z:529.4[M+1]+1H NMR(400MHz,METHANOL-d4)ppm 8.70(s,1H),8.60-8.56(m,3H),7.60(d,J＝9.29Hz,1H),7.54(d,J＝6.78Hz,1H),7.39(d,J＝9.03Hz,1H),7.33(br.s.,1H),6.98-7.17(m,1H),6.21(q,J＝6.19Hz,1H),5.34(br.s.,1H),4.02(d,J＝11.54Hz,2H),3.64-3.75(m,2H),2.20(d,J＝11.54Hz,2H),1.81-1.96(m,5H).
实施例37
Figure PCTCN2016092989-appb-000145
本实施例中如实施例36中描述的方法制备。LCMS(ESI)m/z:516.1[M+1]+.1H NMR(400MHz,DMSO-d6)ppm8.89(s,1H),8.58(s,2H),8.16(d,J＝8.28Hz,1H),7.49-7.65(m,3H),7.32(s,3H),7.14(d,J＝9.03Hz,1H),7.06(s,2H),6.62-6.77(m,2H),6.13(d,J＝6.78Hz,1H),4.38(br.s.,2H),3.61-3.71(m,2H),2.62-2.70(m,2H),1.75(d,J＝6.53Hz,3H),1.26(d,J＝6.53Hz,3H).
实施例38
Figure PCTCN2016092989-appb-000146
本实施例中如实施例37中描述的方法制备。LCMS(ESI)m/z:516.1[M+1]+1H NMR(400MHz,DMSO-d6)ppm 8.89(s,1H),8.58(s,2H),8.16(d,J＝8.28Hz,1H),7.49-7.65(m,3H),7.32(s,3H),7.14(d,J＝9.03Hz,1H),7.06(s,2H),6.62-6.77(m,2H),6.13(d,J＝6.78Hz,1H),4.38(br.s.,2H),3.61-3.71(m,2H),2.62-2.70(m,2H),1.75(d,J＝6.53Hz,3H),1.26(d,J＝6.53Hz,3H).
实施例41
Figure PCTCN2016092989-appb-000147
实施例41A
Figure PCTCN2016092989-appb-000148
0℃氮气保护下，往四氢化-2氢-吡喃-4-羧酸甲酯(3克,21毫摩尔)的四氢呋喃(30毫升)溶液中，缓慢分批加入四氢铝锂(1.18克,31毫摩尔)。反应液在0℃搅拌1小时。小心用H2O(1.2毫升),NaOH(1.2毫升,15％),H2O(3.6毫升)依次淬灭并搅拌20分钟。过滤，滤液直接浓缩得标题化合物(2.1克，87％收率)为无色液体。1H NMR(400MHz,CHLOROFORM-d)ppm 4.00(dd,J＝4.02,11.04Hz,1H),3.51(t,J＝5.77Hz,1H),3.41(dt,J＝1.76,11.67Hz,1H),1.70-1.81(m,1H),1.66(d,J＝13.05Hz,2H),1.27-1.40(m,3H).
实施例41B
Figure PCTCN2016092989-appb-000149
本实施例中如实施例36中描述的方法制备。LCMS(ESI)m/z:529.4[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.43-8.68(m,1H),7.54(d,J＝9.29Hz,1H),7.40(d,J＝9.03Hz,1H),7.31(dd,J＝1.88,9.16Hz,1H),7.26(s,1H),6.90-7.06(m,1H),6.16(q,J＝6.53Hz,1H),4.36(d,J＝6.53Hz,2H),4.01(dd,J＝3.51,11.29Hz,2H),3.50(t,J＝10.92Hz,2H),2.20(br.s.,1H),1.74-1.87(m,6H),1.48-1.58(m,2H),0.99(d,J＝5.02Hz,2H)
实施例43
Figure PCTCN2016092989-appb-000150
实施例43A
Figure PCTCN2016092989-appb-000151
室温下，微波管中加入叔丁基氧羰基4-羟基哌啶(13.12毫克0.11微摩尔)的四氢呋喃(3毫升)溶液，缓慢分批加入钠氢(14毫克,0.34毫摩尔)并搅拌10分钟，而后往其中加入实施例36B(40毫克，0.075毫摩尔)搅拌10分钟。微波仪上80℃反应15分钟后，冷却至室温用冰水(5毫升)小心淬灭，加入乙酸乙酯(40毫升x 3)萃取，有机相分离合并后用食盐水洗，并用硫酸钠干燥，过滤并蒸发，残余物通过快速色谱法硅胶柱层析法纯化得到标题化合物(31毫克，收率：66％)，为无色油状物。LCMS(ESI)m/z:712.3[M+1]+.
实施例43B
Figure PCTCN2016092989-appb-000152
室温氮气保护下，往实施例43A(40毫克,56微摩尔)的甲醇(1毫升)溶液中，加入新鲜配置的乙酰氯(1毫升)，甲醇(3毫升)溶液。反应液在40℃搅拌3个小时。真空除去溶液即为标题化合物(35毫克，收率：98％)。LCMS(ESI)m/z:528.2[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.43-8.68(m,1H),7.54(d,J＝9.29Hz,1H),7.40(d,J＝9.03Hz,1H),7.31(dd,J＝1.88,9.16Hz,1H),7.26(s,1H),6.90-7.06(m,1H),6.16(q,J＝6.53Hz,1H),4.36(d,J＝6.53Hz,2H),4.01(dd,J＝3.51,11.29Hz,2H),3.50(t,J＝10.92Hz,2H),2.20(br.s.,1H),1.74-1.87(m,6H),1.48-1.58(m,2H),0.99(d,J＝5.02Hz,2H).
实施例44
Figure PCTCN2016092989-appb-000153
本实施例中如实施例36中描述的方法制备。LCMS(ESI)m/z:529.4[M+1]+1H NMR(400MHz,METHANOL-d4)ppm 8.46-8.58(m,3H),8.04-8.13(m,1H),7.46(d,J＝9.03Hz,1H),7.14-7.24(m,2H),7.03(d,J＝8.78Hz,1H),6.62-6.78(m,1H),6.11(q,J＝6.53Hz,1H),5.53(br.s.,1H),3.67(d,J＝12.80Hz,1H),3.38(s,3H),3.21-3.30(m,1H),2.95-3.00(m,3H),2.50-2.60(m,1H),2.40(d,J＝15.56Hz,1H),2.12-2.24(m,1H),1.84(d,J＝6.78Hz,3H).
流程H
Figure PCTCN2016092989-appb-000154
实施例45
Figure PCTCN2016092989-appb-000155
实施例45A
Figure PCTCN2016092989-appb-000156
(5-溴-2-吡啶)硼酸酯(70毫克，0.35毫摩尔)，24J(198.56毫克，385.40微摩尔)，Pd(dppf)Cl2(28.20毫克，38.54微摩尔)和磷酸钾(245.43毫克，1.16毫摩尔)溶解在四氢呋喃(4毫升)，水(2毫升)中，混合物在氮气保护下90℃反应12小时。反应混合物减压浓缩用薄层色谱法(石油醚：乙酸乙酯＝2/1)分离得到标题化合物(70.00毫克，118.19微摩尔，30.67％)。LCMS(ESI)m/z:593.1[M+1]+.
实施例45B
Figure PCTCN2016092989-appb-000157
实施例45A(30.00毫克，50.65微摩尔)，4-氨基-四氢吡喃(6.15毫克,60.78微摩尔)，叔丁醇钠(14.60毫克，151.95微摩尔)和(±)-2,2'-双-(二苯膦基)-1,1'-联萘(6.31毫克，10.13微摩尔)加入到甲苯(2毫升)中，混合物在氮气保护下110℃反应12小时反应混合物减压浓缩后，直接用用HPLC制备分离得到标题化合物(11.00毫克，35.46％)。LCMS(ESI)m/z:612.1[M+1]+.
实施例45C
Figure PCTCN2016092989-appb-000158
乙酰氯(0.5毫升)和甲醇(2毫升)在0℃下搅拌30分钟，滴加到实施例44B(11.00毫克，17.96微摩尔)的甲醇溶液中，反应混合物在40℃下搅拌2小时。反应混合物直接减压浓缩得到标题化合物(6.00毫克，11.36微摩尔，63.22％)。LCMS(ESI)m/z:528.0[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.59(br.s.,2H),8.30(br.s.,1H),8.13(br.s.,1H),7.57(d,J＝9.03Hz,1H),7.34(d,J＝9.03Hz,1H),7.19-7.28(m,2H),6.86-7.01(m,1H),6.17(d,J＝6.53Hz,1H),4.07(br.s.,1H),4.05(br.s.,2H),3.64(t,J＝11.29Hz,2H),2.09(d,J＝12.05Hz,2H),1.82-1.89(m,3H),1.74(d,J＝9.54Hz,2H).
实施例47
Figure PCTCN2016092989-appb-000159
本实施例中如实施例45中描述的方法制备。LCMS(ESI)m/z:527.1[M+1]+1H NMR(400MHz,METHANOL-d4)ppm 8.51(s,1H),8.28(d,J＝9.29Hz,1H),8.11(s,1H),7.51(d,J＝9.29Hz,1H),7.27(d,J＝9.54Hz,1H),7.21(dd,J＝2.01,9.29Hz,1H),7.14(s,1H),6.71-6.87(m,1H),6.04-6.16(m,1H),4.06-4.20(m,1H),3.59(d,J＝13.30Hz,2H),3.21-3.29(m,2H),2.38(d,J＝12.30Hz,2H).
流程I
Figure PCTCN2016092989-appb-000160
实施例48
Figure PCTCN2016092989-appb-000161
实施例48A
Figure PCTCN2016092989-appb-000162
氮气保护下，向1G(1.5克，2.89毫摩尔)的甲苯(10毫升)溶液中加入乙烯基频哪醇硼酸酯(890毫克，5.79毫摩尔)，Pd(t-Bu3P)2(130毫克，0.3毫摩尔)和三乙胺(900毫克，8.9毫摩尔)，该混合物在微波条件90℃下搅拌2小时。将反应液倒入到碳酸氢钠溶液(50毫升)中，水层用乙酸乙酯(50毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过柱层析纯化得到标题化合物(1.2克，76％产率)。LCMS(ESI)m/z:544.1[M+1]+.
实施例48B
Figure PCTCN2016092989-appb-000163
氮气保护下，向实施例48A(80毫克，0.15毫摩尔)的四氢呋喃(2.5毫升)和水(0.5毫升)中加入4-((5-溴吡啶-2基)甲基)吗啡啉(60毫克,0.23毫摩尔)，Pd(dppf)Cl2(20毫克,0.027毫摩尔)和碳酸钠(80毫克，0.75毫摩尔)，该混合物在微波90℃条件下，搅拌1.5小时。冷却到室温后，倒入到冰水(5毫升)中，水层用乙酸乙酯(10毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备薄层色谱板纯化得到标题化合物(50毫克，57％产率)。LCMS(ESI)m/z:594.1[M+1]+.
实施例48C
Figure PCTCN2016092989-appb-000164
向实施例48B(50毫克，0.08毫摩尔)的甲醇(8毫升)溶液中滴加盐酸水溶液(0.6毫升)，该混合物在28 ℃条件下，搅拌16小时。饱和碳酸氢钠溶液(15毫升)碱化，水层用乙酸乙酯(20毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备薄层色谱板纯化(二氯甲烷/甲醇＝30:1)得到标题化合物(20毫克，40％产率)。LCMS(ESI)m/z:594.1[M+1]+.1HNMR(400MHz,DMSO-d6)ppm 8.94(s,1H),8.60(s,2H),8.27(dd,J＝8.0&2.0Hz,1H),7.65-7.69(m,2H),7.49(d,J＝8.8Hz,1H),7.40(s,1H),7.29(d,J＝17.2Hz,1H),7.11(dd,J＝9.2&2.0Hz,1H),6.18(q,J＝6.8Hz,1H),4.53(s,2H),3.89(s,4H),3.31(s,4H),1.79(d,J＝7.2Hz,3H).
实施例49
Figure PCTCN2016092989-appb-000165
实施例49A
Figure PCTCN2016092989-appb-000166
向2-氯烟醛(2克,0.014摩尔)的四氢呋喃溶液(40毫升)中加入吗啡啉(1.48克,0.017摩尔)和冰醋酸(0.2mL)，在20℃下搅拌2小时。加入NaBH(OAc)3(6克,0.028摩尔)，搅拌1小时，加水(40毫升)，用乙酸乙酯(30毫升×3)萃取。合并的有机层用饱和食盐水洗涤后，经硫酸钠干燥，过滤后减压蒸干溶剂得到标题化合物(无色油状物，2克，67％产率)。1H NMR(CHLOROFORM-d,Bruker Avance 400MHz)ppm 8.30(d,J＝5.0Hz,1H),7.34(s,1H),7.21(d,J＝4.3Hz,1H),3.79-3.65(m,4H),3.48(s,2H),2.52-2.36(m,4H).
实施例49B
Figure PCTCN2016092989-appb-000167
这个实施例如实施例48中描述的方法制备。LCMS(ESI)m/z:510.0[M+1]+.
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 8.74(d,J＝4.8Hz,1H),8.62(s,2H),7.90(d,J＝16.6Hz,1H),7.73(s,1H),7.51(d,J＝9.0Hz,1H),7.43(d,J＝4.5Hz,1H),7.37-7.27(m,2H),7.12(dd,J＝2.1,8.9Hz,1H),6.17(q,J＝6.4Hz,1H),4.40(br.s.,2H),3.22(br.s.,8H),1.79(d,J＝6.5Hz,3H).
实施例50
Figure PCTCN2016092989-appb-000168
实施例50A
Figure PCTCN2016092989-appb-000169
向5-溴烟醛(2克,0.01摩尔)的四氢呋喃溶液(40毫升)中加入吗啡啉(1.1克,0.013摩尔)和冰醋酸(0.2mL)，在20℃下搅拌2小时。加入NaBH(OAc)3(4.3克,0.02摩尔)，搅拌1小时，加水(40毫升)，用乙酸乙酯(30毫升×3)萃取。合并的有机层用饱和食盐水洗涤后，经硫酸钠干燥，过滤后减压蒸干溶剂得到标题化合物(无色油状物，2克，71％产率)。
实施例50B
Figure PCTCN2016092989-appb-000170
这个实施例如实施例48中描述的方法制备。LCMS(ESI)m/z:510.0[M+1]+..
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 8.91(s,1H),8.60(s,2H),8.28(s,1H),7.62(d,J＝16.8Hz,1H),7.49(d,J＝9.0Hz,1H),7.40(s,1H),7.30(d,J＝16.8Hz,1H),7.11(dd,J＝2.1,9.2Hz,1H),6.22-6.13(m,1H),4.44(br.s.,2H),4.02-3.62(m,4H),3.27-3.13(m,4H),1.79(d,J＝6.8Hz,3H).
实施例51
Figure PCTCN2016092989-appb-000171
这个实施例如实施例48中描述的方法制备。LCMS(ESI)m/z:511.1[M+1]+.
1H NMR(DMSO-d6，Bruker Avance 400MHz)ppm 13.35(s,1H),9.24(s,2H),8.60(s,2H),7.83(d,J＝16.8Hz,1H),7.51-7.46(m,2H),7.29(d,J＝16.8,1H),7.11-7.09(m,1H),6.20-6.16(m,1H),4.72(s,2H),3.93(d,J＝19.8,4H),3.52(s,4H),1.79(s,3H).
实施例52
Figure PCTCN2016092989-appb-000172
实施例52A
Figure PCTCN2016092989-appb-000173
0℃下，慢慢滴加DMF(62毫升)到剧烈搅拌的氧氯化磷(64毫升)中，保持温度不超过30℃。升温到40℃，1,1-二乙氧基丙烷(53毫升，307.9毫摩尔)慢慢加入，反应液温度保持在60℃-70℃，然后深棕色反应液升温到70℃搅拌2小时。冷却到室温后，混合物倒入到冰水中过夜，无水碳酸钾调节pH为9，水层用二氯甲烷萃取，有机层干燥，真空浓缩得到液体标题化合物(15克，粗品混合物)。
实施例52B
Figure PCTCN2016092989-appb-000174
室温下，向无水乙醇(200毫升)中加入钠单质(12.2克，530.3毫摩尔)，搅拌至钠单质消失。然后加入(E)-3-乙氧基-2-甲基丙烯醛和(E)-3-(二甲基氨)-2-甲基丙烯醛(15克，134毫摩尔)的乙醇溶液(100毫升)和尿素(9.6克，159毫摩尔)，混合物回流搅拌2天。调节pH为9，继续回流过夜。真空浓缩，残余物通过柱层析纯化得到标题化合物(9克)。1H NMR(400MHz,DMSO-d6)ppm 7.92-8.14(m,2H),2.52(s,3H).
实施例52C
Figure PCTCN2016092989-appb-000175
实施例52B(8.8克，79.9毫摩尔)的氧氯化磷(50毫升)溶液90℃下搅拌过夜。反应液倒入冰水中，加入碳酸氢钠溶液，水层用二氯甲烷萃取，有机层浓缩得到标题化合物(2.8克)。1H NMR(400MHz,DMSO-d6)ppm 2.27(s,3H)8.64(s,2H).
实施例52D
Figure PCTCN2016092989-appb-000176
向实施例52C(0.2克，1.56毫摩尔)的四氯化碳(10毫升)溶液中加入NBS(0.28克，1.56毫摩尔)和AIBN(0.05克，0.31毫摩尔)，该混合物在80℃下搅拌12小时。加入水，水层用二氯甲烷萃取，有机层用制备薄层色谱板(乙酸乙酯)纯化得到标题化合物(40毫克)，LCMS(ESI)m/z:206[M+1]+.
实施例52E
Figure PCTCN2016092989-appb-000177
向5-(溴甲基)-2-氯嘧啶(0.5克，2.4毫摩尔)的DMF(5毫升)溶液中加入吗啡啉(0.25克，2.9毫摩尔)和碳酸钾(0.65克，4.8毫摩尔)，该混合物在室温下搅拌12小时。加入水，水层用二氯甲烷萃取，有机层用制备薄层色谱板纯化得到标题化合物(330毫克)，LCMS(ESI)m/z:214[M+1]+.1H NMR(400MHz,DMSO-d6)ppm 2.34-2.42(m,4H),3.50-3.54(m,2H),3.56(d,J＝4.52Hz,4H),8.71(s,2H).
实施例52F
Figure PCTCN2016092989-appb-000178
这个实施例如实施例24K中描述的方法制备。LCMS(ESI)m/z:511.1[M+1]+.
1H NMR(DMSO-d6,Bruker Avance 400MHz)ppm 1.85(d,J＝6.62Hz,3H)3.46-3.56(m,1H)3.81(t,J＝12.46Hz,1H)4.10(d,J＝12.13Hz,2H)4.50(s,2H)6.20(d,J＝6.62Hz,1H)7.21(dd,J＝9.04,1.98Hz,1H)7.27(s,1H)7.35(d,J＝16.32Hz,1H)7.50(d,J＝9.04Hz,1H)8.28(d,J＝16.32Hz,1H)8.50(s,2H)9.00(s,2H).
实施例53
Figure PCTCN2016092989-appb-000179
这个实施例如实施例52中描述的方法制备。LCMS(ESI)m/z:511.2[M+1]+.
1H NMR(DMSO-d6,Bruker Avance 400MHz)ppm 1.83(d,J＝6.39Hz,3H)3.33-3.46(m,2H)3.60(d,J＝9.26Hz,2H)3.90(br.s.,2H)4.09(d,J＝11.91Hz,2H)4.65(br.s.,2H)6.17(d,J＝6.39Hz,1H)7.17-7.26(m,2H)7.36(d,J＝16.10Hz,1H)7.50(d,J＝9.04Hz,1H)8.03(d,J＝16.32Hz,1H)8.52(br.s.,2H)8.75-8.87(m,2H).
实施例54
Figure PCTCN2016092989-appb-000180
这个实施例如实施例52中描述的方法制备。LCMS(ESI)m/z:511.1[M+1]+.
1H NMR(MeOD-d4,Bruker Avance 400MHz)ppm 8.49(s,2H),8.23(d,J＝8.4Hz,1H),8.07(d,J＝16.4Hz,1H),7.92(d,J＝8.8Hz,1H),7.51-7.49(m,2H),7.36(s,1H),7.22(d,J＝2.0Hz,1H),6.25-6.20(q,1H),4.79(s,2H),4.02(s,4H),3.54(s,4H),1.86(d,J＝6.4Hz,3H).
实施例55
Figure PCTCN2016092989-appb-000181
这个实施例如实施例51中描述的方法制备。LCMS(ESI)m/z:543.1[M+1]+.1H NMR(DMSO-d6,Bruker Avance 400MHz)ppm 1.77(d,J＝6.62Hz,3H)2.33(d,J＝1.76Hz,4H)3.49(s,2H)3.60(d,J＝4.19Hz,4H)5.97-6.26(m,1H)6.99-7.19(m,1H)7.26-7.38(m,2H)7.39-7.60(m,5H)7.89(d,J＝7.94Hz,1H)8.57(s,2H)13.21(s,1H).
实施例56
Figure PCTCN2016092989-appb-000182
这个实施例如实施例51中描述的方法制备。LCMS(ESI)m/z:559.1[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.45-8.33(m,4H),7.93(d,J＝9.2Hz,1H),7.81(d,J＝6.4Hz,4H),7.54(d,J＝8.8Hz,2H),7.32-7.28(m,2H),6.20(d,J＝6Hz,1H),4.96(s,2H)4.06(d,J＝12.4Hz 2H)3.85-3.80(m,2H)3.48(s,4H),1.84(d,J＝6.4Hz,3H).
实施例57
Figure PCTCN2016092989-appb-000183
这个实施例如实施例51中描述的方法制备。LCMS(ESI)m/z:577.1[M+1]+.1H NMR(CD3OD,400MHz):ppm8.47(s,2H),8.16(s,1H),8.04(d,J＝6.8Hz,1H),7.86(d,J＝8.4Hz,1H),7.58(d,J＝16.8Hz,1H),7.46(d,J＝9.2Hz,1H),7.30(d,J＝13.6Hz,2H),7.23(d,J＝31.2Hz,1H),6.23-6.18(m,1H),4.62(s,2H),4.08(br.s.,2H),3.80(br.s.,2H),3.46(d,J＝41.6Hz,4H),1.84(d,J＝6.8Hz,3H).
实施例58
Figure PCTCN2016092989-appb-000184
这个实施例如实施例51中描述的方法制备。LCMS(ESI)m/z:523.2[M+1]+.1H NMR(DMSO-d6,Bruker Avance400MHz)ppm 1.78(d,J＝6.62Hz,3H)2.43-2.46(m,3H)3.84-3.97(m,4H)4.35(br.s.,2H)6.17(q,J＝6.62Hz,1H)7.09(dd,J＝8.93,1.87Hz,1H)7.18(d,J＝16.76Hz,1H)7.33(s,1H)7.44-7.53(m,2H)7.57(s,2H)7.69(d,J＝8.38Hz,1H)8.61(s,2H).
实施例59
Figure PCTCN2016092989-appb-000185
这个实施例如实施例51中描述的方法制备。LCMS(ESI)m/z:577.1[M+1]+.
1H NMR(MeOD-d4,Bruker Avance 400MHz)ppm 8.49(s,2H),7.46-7.41(m,2H),7.26-7.19(m,5H),6.22-6.19(m,1H),4.58(s,2H),3.70(t,J＝4.4Hz,4H),2.58(s,4H),1.85(d,J＝6.8Hz,3H).
实施例60
Figure PCTCN2016092989-appb-000186
实施例60A
Figure PCTCN2016092989-appb-000187
2-溴-5-甲基苯腈(0.5克，2.53毫摩尔)和NBS(404.58毫克，2.27毫摩尔)溶解在四氯甲烷(20毫升)，AIBN(催化量)加入到上述溶液中。反应液在60℃到80℃范围内回流12小时，反应液倒入水(20毫升)中，分出有机层，有机相用饱和食盐水洗涤，然后，用无水硫酸钠干燥，减压浓缩，得到标题化合物(无色液体，0.5g，72％收率)。
实施例60B
Figure PCTCN2016092989-appb-000188
2-溴-5-(苄溴)苯腈溶解在甲醇(20毫升)中，向上述溶液中逐滴加入吗啡啉(661.3毫克，7.58毫摩尔)，反应在室温下搅拌16小时。将反应液的pH值调到2.0，有机相加水(10毫升x 3)洗涤，然后，把有机层的pH值调到11。最后有机相用二氯甲烷(20毫升)萃取三次，将有机相浓缩得到标题化合物(淡黄色油状，350毫克，收率：49.4％)。LCMS(ESI)m/z:281.6[M+1]+.
实施例60C
Figure PCTCN2016092989-appb-000189
这个实施例如实施例51中描述的方法制备。LCMS(ESI)m/z:534.1[M+1]+.
1H NMR(MeOD-d4,Bruker Avance 400MHz):ppm.77(d,J＝6.39Hz,3H)2.39(br.s.,4H)3.60(br.s.,6H)6.15(d, J＝6.62Hz,1H)7.12(d,J＝8.82Hz,1H)7.39-7.59(m,3H)7.63-7.73(m,2H)7.77(s,1H)8.06(d,J＝8.16Hz,1H)8.57(s,2H)13.33(br.s.,1H).
实施例61
Figure PCTCN2016092989-appb-000190
实施例61A
Figure PCTCN2016092989-appb-000191
1-溴-2-氟-4-甲基-5-硝基苯(2.0克,8.5毫摩尔)和NBS(1.53克,8.6毫摩尔)溶解在CCl4(15毫升)中，将AIBN(100毫克,0.61毫摩尔)加入到上述溶液中。反应液回流16小时。向溶液中加入水(20毫升)，分离得到有机层用饱和食盐水洗涤，再用无水硫酸钠干燥，减压浓缩得到标题化合物(棕色油状，2.7克，50％收率)。
实施例61B
Figure PCTCN2016092989-appb-000192
实施例61A(2.7克,4.3毫摩尔)溶解在甲醇中，在0℃下，缓慢滴加吗啡啉(750毫克，8.6毫摩尔)，反应液在0℃搅拌4小时。反应液加水(50毫升)稀释，用二氯甲烷(50毫升x 2)萃取，有机相有无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物用柱层析分离(乙酸乙酯/石油醚＝1/10～1/5)得到标题化合物(740毫克，54％收率)。LCMS(ESI)m/z:318.7[M+1]+.
实施例61C
Figure PCTCN2016092989-appb-000193
实施例61B(200毫克，0.63毫摩尔)溶解在甲苯(4毫升)中，在氮气保护下，向溶液中加入4,4,5,5-四甲基-2-乙烯基-1,3,2-硼酸频哪醇酯(200毫克，1.98毫摩尔)，Pd(t-Bu3P)2(48毫克,0.09毫摩尔)，Et3N(200毫克，1.98毫摩尔)，反应液在微波条件下80℃搅拌1小时。将反应液倒入碳酸氢钠溶液(10毫升)中，用乙酸乙酯(10毫升x 3)萃取，再用饱和食盐水洗涤，干燥，减压浓缩得到残余物用柱层色谱分离得到标题化合物(195毫克，56％收率)。LCMS(ESI)m/z:393[M+1]+.
实施例61D
Figure PCTCN2016092989-appb-000194
实施例61C(150毫克,0.28毫摩尔)溶解在四氢呋喃和水的混合液中(5/1，3毫升)。然后，1G(170毫克，0.28毫摩尔)，Na2CO3(100毫克，0.84毫摩尔)和Pd(dppf)Cl2(20毫克，0.027毫摩尔)在氮气保护下加入到上述溶液中。反应液在氮气氛围中微波条件下80℃反应1小时。加水(5毫升)用乙酸乙酯(10毫升x 3)，用饱和食盐水洗涤，干燥，减压浓缩得到的残余物通过薄层色谱分离(乙酸乙酯/石油醚＝1/2)得到标题化合物(220毫克，96％收率)。LCMS(ESI)m/z:656.0[M+1]+.
实施例61E
Figure PCTCN2016092989-appb-000195
实施例61D(80毫克,0.12毫摩尔)溶解在乙醇(10毫升)和水(5毫升)的混合液中，向反应液中加入还原铁粉(50毫克，0.89毫摩尔)，氯化铵(50毫克，0.94毫摩尔)，反应液回流6小时。用饱和碳酸氢钠溶液(10毫升)淬灭反应，再用二氯甲烷(10毫升x3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到残余物，用薄层色谱分离(二氯甲烷/甲醇＝20/1)得到标题化合物(浅黄色液体，80毫克，产率：73％)。LCMS(ESI)m/z:538.9[M+1]+.
实施例61F
Figure PCTCN2016092989-appb-000196
实施例61E(80毫克，0.09毫摩尔)溶解在甲醇(2毫升)中，然后向溶液中滴加浓盐酸(0.1毫升)。反应液在30℃下搅拌16小时，反应液中加入饱和碳酸氢钠(15毫升)，用乙酸乙酯(20毫升x 3)萃取，将有机相减压浓缩得残留物，残余物用薄层色谱分离(二氯甲烷/甲醇＝10/1)得到标题化合物(浅黄色液体，44毫克，63％收率)。LCMS(ESI)m/z:542.0[M+1]+.1H NMR(CDCl3,Bruker Avance 400MHz):ppm 8.44(s,2H),7.37(d,J＝8.8Hz,1H),7.34(s,2H),7.25(d,J＝2.0Hz,1H),7.16(dd,J1＝2.0Hz,J2＝8.8,1H),6.91(d,J＝6.4Hz,1H),6.83(d,J＝10.4Hz,1H),6.10(q,J＝6.4Hz,1H),4.35(d,J＝4.8Hz,2H),3.75(s,3H),3.56(s,1H),3.48(s,6H),1.82(d,J＝6.4Hz,3H).
实施例62
Figure PCTCN2016092989-appb-000197
实施例62A
Figure PCTCN2016092989-appb-000198
2-溴-4-氟-5-甲基苯腈(1克，4.67毫摩尔)和NBS(838毫克，4.7毫摩尔)溶解到四氯化碳(15毫升)中。然后AIBN(50毫克，0.30毫摩尔)加到溶液中。最后反应液回流16个小时。将反应液淬灭在水(20毫升)中，分出有机相，用饱和食盐水(40毫升)洗涤。有机相用无水硫酸钠干燥，蒸发得到粗品标题化合物(棕色油状物，1.2克(70％纯度)，)。
实施例62B
Figure PCTCN2016092989-appb-000199
0℃条件下，向实施例62A(1.2克，2.9毫摩尔)的甲醇(40毫升)溶液中滴加吗啡啉(500毫克，5.8毫摩尔)，并且反应4个小时.。反应液用水(50毫升)稀释，用二氯甲烷(50毫升x 2)萃取，收集有机相用无水硫酸钠干燥，过滤得到滤液，加压蒸干的到残留物，通过柱层析得到标题化合物(600毫克，69％收率)。LCMS(ESI)m/z:300.6[M+1]+.
实施例62C
Figure PCTCN2016092989-appb-000200
这个实施例如实施例51中描述的方法制备。LCMS(ESI)m/z:551.9[M+1]+.
1H NMR(MeOD-d4,Bruker Avance 400MHz):ppm 8.47(s,2H),8.14(d,J＝6.8Hz,1H),7.96(d,J＝11.2Hz,1H),7.60-7.8(m,2H),7.50(d,J＝9.6Hz,1H),7.42(d,J＝1.6Hz,1H),7.23(dd,J1＝8.8Hz,J2＝2.0Hz,1H),6.24(q,J＝7.2Hz,1H),4.52(s,2H),4.09(d,J＝12.4Hz,2H),3.83(t,J＝12.4Hz,2H),3.50(d,J＝12Hz,2H),3.35(t,J＝12.4Hz,2H),1.84(d,J＝6.4Hz,3H).
实施例63
Figure PCTCN2016092989-appb-000201
实施例63A
Figure PCTCN2016092989-appb-000202
向4-溴苯甲醛(1克，5.45毫摩尔)的甲苯溶液(10毫升)中加入乙烯基频哪醇硼酸酯(923毫克，6毫摩尔)，Pd(t-Bu3P)2(56毫克，0.11毫摩尔)和三乙胺(1.1克，10.9毫摩尔)，氮气保护下，80℃条件下，搅拌5小时。倒入碳酸氢钠溶液(10毫升)中，水层用乙酸乙酯(10毫升x 3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过柱层析纯化得到微黄色固状标题化合物(1克，71％收率)。1HNMR(CHLOROFORM-d,Bruker Avance 400MHz)ppm 10.01(s,1H),7.86(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),7.43(d,J＝18.6Hz,1H),6.33(d,J＝18.3Hz,1H),1.33(s,12H).
实施例63B
Figure PCTCN2016092989-appb-000203
向实施例63A(300毫克，1.2毫摩尔)的二氯甲烷溶液(5毫升)中加入吗啡啉(202毫克，2.4毫摩尔)，氰基硼氢化钠(93毫克，1.5毫摩尔)和冰醋酸(0.1毫升)，该混合物在30℃条件下，搅拌2小时。加入水(5毫升)，水层用二氯甲烷(10毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备薄层色谱板纯化(乙酸乙酯/石油醚＝1:10)得到微黄色油状标题化合物(240毫克，63％收率)，LCMS(ESI)m/z:330.1[M+1]+.
实施例63C
Figure PCTCN2016092989-appb-000204
氮气保护下，向1G(100毫克，0.19毫摩尔)的四氢呋喃(5毫升)和水(1.0毫升)中63B(96毫克，0.29毫摩尔)，Pd(dppf)Cl2(15毫克，0.02毫摩尔)和碳酸钠(40毫克，0.38毫摩尔)，该混合物在80℃条件下，搅拌18小时。冷却到室温后，倒入到冰水(5毫升)中，水层用乙酸乙酯(10毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备薄层色谱板纯化(乙酸乙酯/石油醚＝1:2)得到微黄色油状标题化合物(50毫克，43％收率)。LCMS(ESI)m/z:593.5[M+1]+.
实施例63D
Figure PCTCN2016092989-appb-000205
向实施例63C(50毫克，0.08毫摩尔)的甲醇(2毫升)溶液中滴加盐酸水溶液(0.1毫升)，该混合物在30℃条件下，搅拌4小时。真空浓缩，残渣用制备液相色谱纯化得到标题化合物(15毫克，35％产率)，LCMS(ESI)m/z:501.0[M+1]+.1H NMR(DMSO-d6,Bruker Avance 400MHz)ppm 11.35(br.s.,1H),8.62(s,2H),7.78-7.71(m,2H),7.67(d,J＝8.3Hz,2H),7.55-7.46(m,2H),7.35(d,J＝2.0Hz,1H),7.24(d,J＝16.6Hz,1H),7.14-7.08(m,1H),6.18(q,J＝6.8Hz,1H),4.35(d,J＝4.8Hz,2H),4.00-3.92(m,3H),3.26(d,J＝12.0Hz,2H),3.11(d,J＝12.0Hz,3H),1.79(d,J＝6.5Hz,3H).
实施例64
Figure PCTCN2016092989-appb-000206
这个实施例如实施例63中描述的方法制备。LCMS(ESI)m/z:577.1[M+1]+.
1H NMR(CDCl3,Bruker Avance 400MHz):ppm8.46(s,2H),7.84-7.80(m,2H),7.72(s,1H),7.44-7.37(m,2H),7.22-7.16(m,3H),6.12-6.06(m,1H),3.73(d,J＝28.0Hz,6H),2.53(s,4H),1.85(d,J＝6.8Hz,3H).
流程J
Figure PCTCN2016092989-appb-000207
实施例65
Figure PCTCN2016092989-appb-000208
实施例65A
Figure PCTCN2016092989-appb-000209
向6-氧-1,6-二氢哒嗪-3-羧酸(3克，0.02摩尔)加入HCl/MeOH溶液(4M，30毫升)，将混合物加热至80℃，搅拌2小时。减压蒸干溶剂得到标题化合物(2.8克，85％产率)。1H NMR(CHLOROFORM-d,Bruker Avance 400MHz)ppm 11.26(br.s.,1H),7.91(d,J＝10.0Hz,1H),7.02(d,J＝10.0Hz,1H),3.99(s,3H).
实施例65B
Figure PCTCN2016092989-appb-000210
室温下向实施例65A(2.8克，0.018摩尔)的甲苯溶液中加入POCl3(5.60克，0.036摩尔)，将混合物加热 至120℃，搅拌2小时。蒸干溶剂，加水(20毫升)，用乙酸乙酯(15毫升×3)萃取。合并的有机层用饱和食盐水洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(1.5克，50％产率)。1H NMR(CHLOROFORM-d,Bruker Avance 400MHz)ppm 8.17(d,J＝8.8Hz,1H),7.68(d,J＝8.8Hz,1H),4.09(s,3H).
实施例65C
Figure PCTCN2016092989-appb-000211
室温下向微波反应管中加入47A(1克，1.93毫摩尔)、实施例65B(400毫克，2.32毫摩尔)、Na2CO3(307毫克，2.9毫摩尔)、乙腈/水(9毫升/3毫升)混合溶剂和Pd(PPh3)2Cl2(135毫克，0.19毫摩尔)。氮气置换，于微波反应器中加热至130℃，反应30分钟。加水(10毫升)稀释，用乙酸乙酯(15毫升×3)萃取。合并的有机层用饱和食盐水洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(500毫克，50％收率)。LCMS(ESI)m/z:540.0[M+1]+.
实施例65D
Figure PCTCN2016092989-appb-000212
室温下向实施例65C(450毫克，0.83毫摩尔)的DMF溶液中加入碳酸钾(229毫克，1.66毫摩尔)，滴加碘甲烷(118毫克，0.83毫摩尔)。在20℃下搅拌2小时。加水(10毫升)，用乙酸乙酯(15毫升x 3)萃取。合并的有机层用饱和食盐水洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(160毫克，35％收率)。LCMS(ESI)m/z:554.0[M+1]+.
实施例65E
Figure PCTCN2016092989-appb-000213
0℃下向实施例65D(160毫克，0.29毫摩尔)的四氢呋喃(5毫升)溶液中加入LiAlD4(24毫克，0.58毫摩尔)。在0℃下搅拌2小时。加水(0.1毫升)淬灭反应，过滤，滤液减压蒸干溶剂得到标题化合物(158毫克，粗品)。LCMS(ESI)m/z:528.1[M+1]+.
实施例65F
Figure PCTCN2016092989-appb-000214
0℃下向实施例65E(158毫克，0.30毫摩尔)和三乙胺(61毫克，0.60毫摩尔)的二氯甲烷(5毫升)溶液中分批加入甲烷磺酰氯(38毫克，0.33毫摩尔)。在0℃下搅拌1小时。将反应液倒入冰水(10毫升)中，分液后，有机层依次用饱和碳酸氢钠溶液(10毫升)、饱和食盐水(20毫升)洗涤，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(84毫克，46％产率)。LCMS(ESI)m/z:606.0[M+1]+
实施例65G
Figure PCTCN2016092989-appb-000215
向实施例65F(84毫克，0.14毫摩尔)的二氯甲烷(5毫升)溶液中加入吗啡啉(14.5毫克，0.17毫摩尔)和三乙胺(21毫克，0.029毫摩尔)。在15℃下搅拌18小时。加水(10毫升)，用二氯甲烷(15毫升x 3)萃取。合并的有机层用饱和食盐水洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(40毫克，49％收率)。LCMS(ESI)m/z:597.1[M+1]+.
实施例65H
Figure PCTCN2016092989-appb-000216
向实施例65G(40毫克，0.07毫摩尔)的甲醇(2毫升)溶液中滴加浓盐酸(0.1毫升)。将混合物加热至50℃，搅拌4小时。过滤，滤液经制备级高效液相色谱分离得到标题化合物(26毫克，76％产率)。LCMS(ESI)m/z:513.1[M+1]+.1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 8.60(s,2H),8.21(d,J＝8.8Hz,1H),8.06(d,J＝16.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.55-7.44(m,2H),7.38(s,1H),7.14(dd,J＝2.3,9.0Hz,1H),6.22-6.15(m,1H),3.87(br.s.,4H),3.34(br.s.,4H),1.79(d,J＝6.5Hz,3H).
流程K
Figure PCTCN2016092989-appb-000217
实施例66
Figure PCTCN2016092989-appb-000218
实施例66A
Figure PCTCN2016092989-appb-000219
向2-羰基戊二酸(20克，136.89毫摩尔)的乙醇溶液(200毫升)中加入水合肼(6,85克，136.89毫摩尔)，该混合物在60℃下搅拌3小时。冷却，过滤得到部分标题化合物(12克，粗品)，滤液浓缩得到微黄色标题化合物(8克，粗品)。1H NMR(400MHz,DMSO-d6)ppm 11.17(s,1H),2.78-2.68(m,2H),2.45-2.36(m,2H).
实施例66B
Figure PCTCN2016092989-appb-000220
在25℃条件下，向实施例66A(20克，140.74毫摩尔)的冰醋酸溶液(200毫升)中慢慢滴加液溴(38.23克，239.25毫摩尔)，滴加完成之后升温到80℃搅拌3小时。薄层色谱板检测原料消耗完全，冷却，过滤得到标题化合物(20克，粗品)。1H NMR(400MHz,DMSO-d6)ppm 13.49(s,1H),7.80(d,J＝9.8Hz,1H),6.92(d,J＝9.8Hz,1H).
实施例66C
Figure PCTCN2016092989-appb-000221
向实施例66B(20克，142.76毫摩尔)的甲醇溶液(500毫升)中慢慢滴加浓硫酸(19.9克，202.9毫摩尔)，滴加完成之后，升温到70℃搅拌2小时。冷却，真空浓缩，加入冰水(300毫升)，过滤，滤饼水洗，得到标题化合物(17克，73.4％收率)。1H NMR(400MHz,DMSO-d6)ppm 13.62(s.,1H),7.83(d,J＝10.0Hz,1H),6.97(d,J＝9.8Hz,1H),3.85(s,3H).
实施例66D
Figure PCTCN2016092989-appb-000222
实施例66C(5克，32.44毫摩尔)的氧氯化磷溶液(60毫升)在110℃下搅拌3小时。冷却，真空浓缩，残余物慢慢加入到冰水(20毫升)中，沉淀过滤，水洗滤饼得到浅白色标题化合物(1.8克，32.15％收率)。1H NMR(400MHz,DMSO-d6)ppm 8.27(d,J＝9.0Hz,1H),8.13(d,J＝9.0Hz,1H),3.96(s,3H).
实施例66E
Figure PCTCN2016092989-appb-000223
氮气保护下，实施例65D(600毫克，3.48毫摩尔)，乙烯基频哪醇硼酸酯(803.2毫克，5.22毫摩尔)，碳酸钾(961.07毫克，6.95毫摩尔)和Pd(PPh3)4(602.66毫克，521.53毫摩尔)的DMF(8毫升)溶液在100℃下搅拌5小时。冷却，过滤，真空浓缩，残余物通过柱层析纯化得到标题化合物(500毫克，84.02％收率)。1H NMR(400MHz,CHLOROFORM-d)ppm 8.18(d,J＝8.8Hz,1H),7.72(d,J＝8.8Hz,1H),7.16(dd,J＝11.0,17.8Hz,1H),6.44(d,J＝17.8Hz,1H),5.85(d,J＝10.8Hz,1H),4.10(s,3H).
实施例66F
Figure PCTCN2016092989-appb-000224
氮气保护下，实施例66E(200毫克，1.22毫摩尔)，1G(694.43毫克，1.34毫摩尔)，POT(37.08毫克，121.83微摩尔)，醋酸钯(27.35毫克，121.83毫摩尔)和三乙胺(369.85毫摩尔，3.65毫摩尔)的DMF(4毫升)混悬液在110℃微波条件下搅拌30分钟。冷却，过滤，真空浓缩，残余物通过制备薄层色谱板纯化得到黄标题化合物(345毫克，50％收率)，LCMS(ESI)m/z:554.4[M+1]+。1H NMR(400MHz,DMSO-d6)ppm 8.60(s,2H),8.26(q,J＝9.0Hz,1H),8.13(d,J＝16.6Hz,1H),7.74(d,J＝9.0Hz,1H),7.59(d,J＝17.1Hz,1H),7.47(s,1H),7.20(d,J＝9.0Hz,1H),6.23(dd,J＝3.0,6.5Hz,1H),5.86(d,J＝9.5Hz,1H),4.00(s,3H),3.87(br.s.,1H),3.75(br.s.,1H),2.68(br.s.,1H),2.41-2.31(m,2H),2.00(br.s.,3H),1.81(d,J＝6.5Hz,3H).
实施例66G
Figure PCTCN2016092989-appb-000225
0℃条件下，实施例66F(100毫克，180.37微摩尔)的四氢呋喃溶液(1毫升)中慢慢加入四氢铝锂(10.27毫克，270.55毫摩尔)，然后在该温度下搅拌30分钟。淬灭用水(0.1毫升)，氢氧化钠水溶液(0.1毫升，15％)，水(0.3毫升)，过滤，真空浓缩，残余物通过制备薄层色谱板纯化得到黄色油状标题化合物(30毫克，30.33％)。LCMS(ESI)m/z:526.4[M+1].1H NMR(400MHz,METHANOL-d4)ppm 8.51(s,2H),8.08(d,J＝8.8Hz,1H),7.93-7.86(m,2H),7.65(d,J＝9.0Hz,1H),7.54(d,J＝16.8Hz,1H),7.36(s,1H),7.22(dd,J＝2.1,9.2Hz,1H),6.24(q,J＝6.7Hz,1H),5.79(d,J＝9.3Hz,1H),4.94(s,2H),3.99(br.s.,1H),3.81(t,J＝10.8Hz,1H),3.62-3.56(m,1H),2.58-2.44(m,1H),2.15(d,J＝13.3Hz,1H),2.05(br.s.,1H),1.87(d,J＝6.8Hz,3H),1.76-1.62(m,3H).
实施例66H
Figure PCTCN2016092989-appb-000226
0℃条件下，向实施例66G(30毫克，56.99毫摩尔)的二氯甲烷溶液(2毫升)中加入Dess-Martin氧化剂(36.26毫克，85.48毫摩尔)，该混悬液在25℃下搅拌12小时。过滤，真空浓缩，残余物通过制备薄层层析板纯化得到标题化合物(25毫克，81.98％收率)，LCMS(ESI)m/z:524.4[M+1]+.
1H NMR(400MHz,CHLOROFORM-d)ppm 10.44(s,1H),8.47(s,2H),8.14-8.00(m,2H),7.82(d,J＝8.8Hz,1H),7.70-7.51(m,2H),7.35(s,1H),7.19(dd,J＝2.1,9.2Hz,1H),6.16(q,J＝6.5Hz,1H),5.70(dd,J＝2.9,8.9Hz,1H),4.04(br.s.,1H),3.81-3.71(m,1H),2.54(d,J＝9.5Hz,1H),2.24-2.02(m,2H),1.87(d,J＝6.5Hz,3H),1.82-1.67(m,3H).
实施例66I
Figure PCTCN2016092989-appb-000227
向实施例66H(30毫克，57.21微摩尔)和吗啡啉(15毫克,171.63微摩尔)的1,2-二氯乙烷(2毫升)的混合溶液中，滴加醋酸(3.44毫克,57.2微摩尔)，滴加完成后28℃下搅拌2小时。慢慢加入氰基硼氢化钠(11毫克,171.6微摩尔)，继续在28℃下搅拌1小时。水淬灭，水层用二氯甲烷(3毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备薄层色谱板纯化得到黄色油状标题化合物(25毫克，粗品)，LCMS(ESI)m/z:594.2[M+1]+.
实施例66J
Figure PCTCN2016092989-appb-000228
将实施例66I(25毫克，42微摩尔)溶于无水甲醇(1毫升)中，然后将此溶液滴加到乙酰氯(0.2毫升)的无水甲醇(0.8毫升)中。反应液在40℃下搅拌1小时。真空浓缩，残余物通过制备液相色谱纯化得到黄色油状标题化合物(8毫克，37.26％收率)。LCMS(ESI)m/z:528.4[M+1]+.1H NMR(400MHz,METHANOL-d4)ppm 8.59(m,2H),8.20(d,J＝8.8Hz,1H),8.06(d,J＝16.8Hz,1H),7.88(d,J＝8.5Hz,1H),7.60-7.48(m,2H),7.36(s,1H),7.26-7.19(m,1H),6.28-6.20(m,1H),4.80(m,2H),4.03(m,4H),3.62-3.48(m,4H),1.91-1.83(d,3H).
实施例67
Figure PCTCN2016092989-appb-000229
这个实施例如实施例66中描述的方法制备。1H NMR(400MHz,DMSO-d6)ppm 8.59(s,2H),8.21(d,J＝8.8Hz,1H),8.09-7.97(m,2H),7.55-7.43(m,2H),7.38(d,J＝1.8Hz,1H),7.12(dd,J＝2.3,9.0Hz,1H),6.17(q,J＝6.5Hz,1H),4.72(s,2H),3.90(m,4H),3.35(m,4H),1.78(d,J＝6.5Hz,3H)
实施例68
Figure PCTCN2016092989-appb-000230
这个实施例如实施例66中描述的方法制备。1H NMR(400MHz,DMSO-d6)ppm 9.50(m,1H),8.59(s,2H),8.20(d,J＝8.8Hz,1H),8.01(d,J＝16.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.52(d,J＝9.0Hz,1H),7.46(d,J＝16.8Hz,1H),7.36(s,1H),7.15-7.10(m,1H),6.17(d,J＝6.8Hz,1H),4.58(m,2H),3.95(d,J＝7.3Hz,1H),2.66(m,2H),2.32(m,2H),2.06(d,J＝11.5Hz,2H),1.78(d,J＝6.5Hz,3H),1.70(d,J＝11.8Hz,2H)
实施例69
Figure PCTCN2016092989-appb-000231
这个实施例如实施例66中描述的方法制备。1H NMR(400MHz,METHANOL-d4)ppm 8.63(d,J＝9.0Hz,1H),8.51(s,2H),8.30(d,J＝16.6Hz,1H),8.20(d,J＝9.0Hz,1H),7.65(d,J＝16.6Hz,1H),7.55(d,J＝9.0Hz,1H),7.49(d,J＝1.8Hz,1H),7.23(dd,J＝2.0,9.0Hz,1H),6.27(q,J＝6.8Hz,1H),5.04-4.94(m,2H),4.67(br.s.,1H),4.09-3.72(m,3H),2.33-2.11(m,2H),1.88(d,J＝6.5Hz,3H).
流程L
Figure PCTCN2016092989-appb-000232
实施例70
Figure PCTCN2016092989-appb-000233
实施例70A
Figure PCTCN2016092989-appb-000234
向实施例1G(400毫克，0.78毫摩尔)的乙腈(6毫升)和水(2毫升)的混合溶液中加入5-(4,4,5,5-四甲基-1,3,2-二硼酸-2-位)吡啶-2-氨基(205毫克，0.93毫摩尔)，Pd(dppf)Cl2(57毫克,0.078毫摩尔)和碳酸钠(165毫克，1.56毫摩尔)。反应在氮气保护下通过微波加热到100℃并且搅拌反应15分钟。水(10毫升)加到反应液中并用乙酸乙酯(15毫升x 3)，饱和食盐水洗涤，干燥浓缩得到残留物，通过柱层析得到标题化合物(340毫克，91％收率)。LCMS(ESI)m/z:483.9[M+1]+.
实施例70B
Figure PCTCN2016092989-appb-000235
向实施例70A(100毫克，0.21毫摩尔)的二氯甲烷(5毫升)溶液中加入二氯乙酰氯(35毫克，0.31毫摩尔)和三乙胺(31毫克，0.31毫摩尔)。反应液在15℃下搅拌18个小时。水(10毫升)加到反应液中，用二氯甲烷(15毫升x 3)萃取，用饱和食盐水洗涤，干燥蒸发得到残留物，通过柱层析得到标题化合物(棕色油状物，73毫克，收率63％)。LCMS(ESI)m/z:559.6[M+1]+.
实施例70C
Figure PCTCN2016092989-appb-000236
实施例70B(73毫克，0.13毫摩尔)的二氯甲烷(5毫升)溶液中加入吗啡啉(14毫克，0.16毫摩尔)和三乙胺(20毫克，0.20毫摩尔)。反应液在15℃下搅拌18个小时。水(10毫升)加到反应液中，用二氯甲烷(15毫升x 3)萃取，用饱和食盐水洗涤，干燥蒸发得到残留物，通过薄层析制备分离得到标题化合物(棕色油状物，75毫克，74％收率)。LCMS(ESI)m/z:611.1[M+1]+.
实施例70D
Figure PCTCN2016092989-appb-000237
向实施例70C(75毫克，0.12毫摩尔)的甲醇(2毫升)溶液中滴加浓盐酸(0.1毫升)。反应液在50℃下搅拌反应4小时。过滤得到滤液，通过液相色谱柱分离得到标题化合物(23毫克，34％收率)。LCMS(ESI)m/z:510.0[M+1]+.1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 10.18(s,1H),8.76(s,1H),8.58(s,2H),8.27-8.18(m,2H),7.51(d,J＝8.8Hz,1H),7.25(s,1H),7.12(dd,J＝2.0,9.0Hz,1H),6.16(q,J＝6.6Hz,1H),3.73-3.60(m,4H),3.25(s,2H),2.57(br.s.,4H),1.76(d,J＝6.5Hz,3H).
流程M
Figure PCTCN2016092989-appb-000238
实施例71
Figure PCTCN2016092989-appb-000239
实施例71A
Figure PCTCN2016092989-appb-000240
在30℃下向5-溴-2-氟吡啶(5.0克，28.4毫摩尔)的DMF溶液(50毫升)中加入N-甲基哌嗪(2.8克,28.4毫摩尔)和碳酸钾(7.8克，56.8毫摩尔).，将混合物加热至80-90℃，搅拌16小时。冷却至33℃，加水(50毫升)，用乙酸乙酯(50毫升×3)萃取。合并的有机层用水(20毫升x 3)洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物(5.3克，73％收率)。1H NMR(CDCl3,Bruker Avance 400MHz):ppm 8.21(d,J＝2.3Hz,1H),7.54(dd,J＝9.0Hz,2.5Hz,1H),6.56(d,J＝9.0Hz,1H),3.57-3.52(m,4H),2.55-2.50(m,4H),2.36(s,3H).
实施例71B
Figure PCTCN2016092989-appb-000241
在30℃下向实施例71A(1.0克,3.90毫摩尔)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧环戊硼烷(0.66克,4.30毫摩尔)和三乙胺(0.79克,7.80毫摩尔)的甲苯溶液(10毫升)中加入Pd(tBu3P)2(20毫克,0.04毫摩尔)，将混合物脱气10分钟，再用氮气保护。加热至80℃，搅拌16小时。冷却至35℃，减压蒸去溶剂，残余物通过柱色谱纯化得到标题化合物(黄色油状物，370毫克，粗品)。LCMS(ESI)m/z:330.0[M+1]+.
实施例71C
Figure PCTCN2016092989-appb-000242
在37℃下向实施例71B(50毫克,0.15毫摩尔)的四氢呋喃/水(v/v＝5/1,5毫升)混合溶液中加入5-(1-(3,5-二氯吡啶-4-位)乙氧基)-3-碘-1-(四氢-2H-吡喃-2-位)-1H-吲唑(79毫克,0.15毫摩尔)、碳酸钾(32毫克,0.30毫摩尔)和Pd(dppf)Cl2(11毫克,0.015毫摩尔)。.将混合物脱气10分钟，再用氮气保护。加热至75℃，搅拌16小时。冷却至30℃，加水(10毫升)，用乙酸乙酯(20毫升)萃取。有机层经硫酸钠干燥，过滤并蒸发，残余物通过制备薄层色谱纯化得到标题化合物(黄色油状物，50毫克，粗品)。LCMS(ESI)m/z:606.2[M+1]+.
实施例71D
Figure PCTCN2016092989-appb-000243
在0℃下向实施例70C(50毫克,0.08毫摩尔)的甲醇(4毫升)溶液中滴加浓盐酸(0.2毫升)。将混合物加热至38℃，搅拌16小时。反应液经制备级高效液相色谱分离，再在乙腈中重结晶得到标题化合物(5.0毫克，10％产率)。1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 8.61(s,2H),8.36(d,J＝1.8Hz,1H),8.23(d,J＝8.8Hz,1H),7.47-7.36(m,3H),7.26-7.16(m,2H),7.08(dd,J1＝9.0Hz,J2＝2.0Hz,1H),6.17(q,J＝6.6Hz,1H),4.52(d,J＝13.6Hz,2H),3.45-3.36(m,4H),3.24-2.95(m,4H),2.81(d,J＝2.5Hz,3H),1.78(d,J＝6.5Hz,3H).
流程N
Figure PCTCN2016092989-appb-000244
实施例72
Figure PCTCN2016092989-appb-000245
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:523.2[M+1]+.
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 10.83-10.65(m,1H),8.61(s,2H),7.77-7.62(m,4H),7.56-7.45(m,2H),7.33(s,1H),7.24(d,J＝16.8Hz,1H),7.15-7.07(m,1H),6.22-6.11(m,1H),4.28(dd,J＝13.3,4.5Hz,2H),3.32(d,J＝11.5Hz,2H),3.18-3.12(m,2H),2.99-2.90(m,1H),2.07-1.90(m,2H),1.84-1.69(m,5H).
实施例73
Figure PCTCN2016092989-appb-000246
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:536.3[M+1]+.
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 12.09-11.52(m,1H),8.63-8.57(m,2H),7.72(s,4H),7.54-7.46(m,2H),7.34(d,J＝1.5Hz,1H),7.24(d,J＝16.8Hz,1H),7.10(dd,J＝9.0,2.0Hz,1H),6.16(q,J＝7.0Hz,1H),4.58-4.40(m,3H),3.46(brs,4H),2.81(brs,6H),2.42-2.28(m,1H),1.77(d,J＝6.5Hz,3H).
实施例74
Figure PCTCN2016092989-appb-000247
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:537.2[M+1]+.
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 10.48(brs,1H),8.61(s,2H),7.73(d,J＝8.0Hz,2H),7.65(d,J＝8.0Hz,2H),7.54-7.46(m,2H),7.34(d,J＝1.8Hz,1H),7.24(d,J＝16.8Hz,1H),7.11(dd,J＝8.9,1.9Hz,1H), 6.17(q,J＝6.5Hz,1H),4.27(d,J＝4.8Hz,2H),3.38-3.26(m,4H),2.91(q,J＝10.5Hz,2H),1.87-1.77(m,5H),1.69-1.44(m,3H).
实施例76
Figure PCTCN2016092989-appb-000248
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:536.1[M+1]+.
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 10.80(brs,1H),9.74(brs,1H),8.61(s,2H),7.75-7.64(m,4H),7.53-7.46(m,2H),7.35(s,1H),7.24(d,J＝16.6Hz,1H),7.10(dd,J＝9.0,2.0Hz,1H),6.18(q,J＝6.5Hz,1H),4.24-4.17(m,2H),3.51(d,J＝11.5Hz,2H),3.31-3.25(m,1H),3.02(q,J＝11.1Hz,2H),2.71(d,J＝4.3Hz,3H),2.40-2.33(m,2H),2.16-2.02(m,2H),1.78(d,J＝6.5Hz,3H).
实施例77(参考例)
Figure PCTCN2016092989-appb-000249
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:497.1[M+1]+
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 9.23(brs,1H),9.02(brs,1H),8.61(s,2H),7.74-7.69(m,2H),7.67-7.61(m,2H),7.53-7.46(m,2H),7.34(s,1H),7.23(d,J＝16.8Hz,1H),7.10(dd,J＝8.9,1.9Hz,1H),6.18(q,J＝6.5Hz,1H),4.21(t,J＝5.3Hz,2H),3.63-3.57(m,2H),3.21-3.15(m,1H),1.78(d,J＝6.5Hz,3H),1.28(d,J＝6.5Hz,3H).
实施例78
Figure PCTCN2016092989-appb-000250
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:523.1[M+1]+
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 9.53(brs,2H),8.61(s,2H),7.75-7.70(m,2H),7.68-7.64(m,2H),7.53-7.46(m,2H),7.34(d,J＝1.5Hz,1H),7.24(d,J＝16.8Hz,1H),7.10(dd,J＝9.0,2.0Hz,1H),6.18(q,J＝6.5Hz,1H),4.17(d,J＝5.5Hz,4H),3.35-3.27(m,3H),2.11-2.04(m,2H),1.80-1.71(m,5H).
实施例80
Figure PCTCN2016092989-appb-000251
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:555.1[M+1]+
实施例81
Figure PCTCN2016092989-appb-000252
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:507.1[M+1]+
1H NMR(400MHz,METHANOL-d4):ppm 8.60-8.47(m,2H),7.83-7.76(m,2H),7.68-7.63(m,2H),7.61-7.55(m,1H),7.52-7.43(m,2H),7.41-7.34(m,1H),7.33-7.30(m,1H),6.29-6.21(m,1H),4.37(s,2H),3.56-3.47(m,2H),3.10-2.98(m,2H),2.04-1.93(m,2H),1.88(d,m,6H),1.63-1.51(m,1H).
实施例82
Figure PCTCN2016092989-appb-000253
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:583.1[M+1]+
1H NMR(400MHz,METHANOL-d4):ppm 8.58-8.44(m,2H),7.87-7.73(m,2H),7.68-7.60(m,2H),7.54-7.42(m,2H),7.38-7.21(m,8H),6.27-6.17(m,1H),4.43(s,2H),3.72-3.62(m,2H),3.28-3.18(m,2H),3.00-2.88(m,1H),2.22-1.96(m,4H),1.90-1.83(m,3H).
实施例83
Figure PCTCN2016092989-appb-000254
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:584.1[M+1]+
实施例86
Figure PCTCN2016092989-appb-000255
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:600.2[M+1]+
实施例87
Figure PCTCN2016092989-appb-000256
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:529.1[M+1]+
实施例88
Figure PCTCN2016092989-appb-000257
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:539.1[M+1]+
1H NMR(400MHz,DMSO-d6):ppm 11.5(brs,1H),8.60(s,2H),7.75-7.66(m,4H),7.54-7.47(m,2H),7.34(s,1H),7.26-7.22(m,1H),7.10(dd,J＝8.0,1.6Hz,1H),6.20-6.15(m,1H),4.37(brs,2H),4.01–3.99(m,2H),3.41–3.48(m,3H),3.38–3.28(m,2H),3.06–2.91(m,2H),1.78(d,J＝6.4Hz,3H).
实施例89
Figure PCTCN2016092989-appb-000258
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:552.1[M+1]+
1H NMR(400MHz,DMSO-d6):ppm 11.4(brs,1H),9.85(brs,2H),8.61(s,2H),7.73-7.66(m,4H),7.53-7.47(m,2H),7.35(s,1H),7.26-7.22(m,1H),7.11(dd,J＝8.0,1.6Hz,1H),6.20-6.15(m,1H),4.23(brs,2H),4.00(brs, 2H),3.56(brs,3H),3.17(brs,2H),1.76(d,J＝6.4Hz,3H).
实施例90
Figure PCTCN2016092989-appb-000259
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:597.1[M+1]+
实施例91
Figure PCTCN2016092989-appb-000260
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:557.1[M+1]+
实施例93
Figure PCTCN2016092989-appb-000261
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:522.1[M+1]+
实施例94
Figure PCTCN2016092989-appb-000262
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:543.1[M+1]+
实施例95
Figure PCTCN2016092989-appb-000263
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:558.1[M+1]+
实施例97
Figure PCTCN2016092989-appb-000264
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:522.1[M+1]+
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 10.34–10.21(m,1H),10.14(brs,1H),8.65-8.59(m,2H),7.77-7.69(m,4H),7.55-7.46(m,2H),7.35(d,J＝2.0Hz,1H),7.24(d,J＝16.8Hz,1H),7.10(dd,J＝9.0,2.0Hz,1H),6.18(q,J＝7.0Hz,1H),4.41(brs,2H),3.86-3.76(m,1H),3.62-3.46(m,4H),3.34-3.26(m,1H),3.15(t,J＝12.3Hz,1H),1.78(d,J＝6.5Hz,3H),1.32(d,J＝6.3Hz,3H).
实施例99
Figure PCTCN2016092989-appb-000265
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:514.9[M+1]+
实施例100
Figure PCTCN2016092989-appb-000266
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:523.1[M+1]+
实施例101
Figure PCTCN2016092989-appb-000267
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:537.1[M+1]+
实施例102
Figure PCTCN2016092989-appb-000268
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:550.1[M+1]+
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 11.64(br.s.,1H),8.61(s,2H),7.79-7.73(m,2H),7.71-7.65(m,2H),7.55-7.45(m,2H),7.35(d,J＝1.5Hz,1H),7.24(d,J＝16.8Hz,1H),7.10(dd,J＝2.0,9.0Hz,1H),6.18(q,J＝6.5Hz,1H),4.42(br.s.,2H),3.69-3.45(m,9H),1.78(d,J＝6.5Hz,3H),1.28(d,J＝6.0Hz,6H).
实施例103
Figure PCTCN2016092989-appb-000269
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z564.1[M+1]+
实施例104
Figure PCTCN2016092989-appb-000270
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:549.2[M+1]+
实施例106
Figure PCTCN2016092989-appb-000271
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:509.0[M+1]+
1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 11.56–11.41(m,0.5H),11.08–10.94(m,0.5H),8.61(s,2H),7.76–7.64(m,4H),7.54–7.45(m,2H),7.35(s,1H),7.24(d,J＝16.8Hz,1H),7.10(dd,J＝9.0,1.8Hz,1H),6.18(q,J＝6.4Hz,1H),4.47–4.32(m,3H),3.55–3.39(m,1.5H),3.32–3.12(m,2H),3.01–2.96(m,0.5H),2.34–2.26(m,0.5H),2.08–1.86(m,1.5H),1.78(d,J＝6.8Hz,3H).
实施例107
Figure PCTCN2016092989-appb-000272
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:524.9[M+1]+
实施例108
Figure PCTCN2016092989-appb-000273
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:537.1[M+1]+
实施例109
Figure PCTCN2016092989-appb-000274
这个实施例如实施例17中描述的方法制备。
LCMS(ESI)m/z:550.1[M+1]+
流程O
Figure PCTCN2016092989-appb-000275
实施例111(参考例)
Figure PCTCN2016092989-appb-000276
实施例111A
Figure PCTCN2016092989-appb-000277
氮气保护，室温下向化合物1G(200毫克,0.39毫摩尔)的四氢呋喃(5毫升)水(1毫升)混合溶液中加入4-羧基苯硼酸酯(84毫克,0.50毫摩尔)，Pd(dppf)Cl2(29毫克,0.04毫摩尔)，碳酸钠(83毫克,0.78毫摩尔)，反应液加热到80℃搅拌18个小时。反应液冷却至室温加入水(5毫升)，乙酸乙酯(10毫升x3)萃取，合并有机相，食盐水洗涤，干燥，滤液蒸干，残余物通过快速色谱法硅胶柱层析纯化得到标题化合物(85毫克，收率：43％)。LCMS(ESI)m/z:512.0[M+1]+1
实施例111B
Figure PCTCN2016092989-appb-000278
室温下实施例111A(40毫克,0.08毫摩尔)，HATU(46毫克,0.12毫摩尔)三乙胺(24毫克，0.24毫摩尔)的DMF(2毫升)溶液中加入(R)-1-氨基异丙醇(7毫克,0.09毫摩尔)。反应液30℃下搅拌1个小时。反应液加入水(5毫升)，乙酸乙酯(10毫升x3)萃取，合并有机相，食盐水洗涤，干燥，滤液蒸干得到 标题化合物(50毫克，粗品)。LCMS(ESI)m/z:569.1[M+1]+1
实施例111C
Figure PCTCN2016092989-appb-000279
实施例111B(50毫克,0.08毫摩尔)溶解在甲醇(2毫升)，慢慢滴加浓HCl(0.1毫升)。反应液室温下搅拌4个小时。反应液浓缩，制备HPLC纯化得到目标化合物(18毫克,收率:42％)。
LCMS(ESI)m/z:485[M+1]+1 1H NMR(DMSO-d6,Bruker Avance 400MHz):ppm 8.63(s,2H),8.53(t,J＝5.3Hz,1H),8.01(d,J＝8.3Hz,2H),7.84(d,J＝8.3Hz,2H),7.52(d,J＝9.0Hz,1H),7.20(d,J＝1.8Hz,1H),7.13(dd,J＝2.1,8.9Hz,1H),6.13(q,J＝6.5Hz,1H),3.84(td,J＝6.2,12.4Hz,2H),3.32-3.18(m,2H),1.77(d,J＝6.5Hz,3H),1.10(d,J＝6.3Hz,3H).
实施例112
Figure PCTCN2016092989-appb-000280
这个实施例如实施例111中描述的方法制备。
LCMS(ESI)m/z:510.1[M+1]+
1H NMR(400MHz,DMSO-d6):ppm 9.64(d,J＝10.4Hz,1H),9.16(s,2H),8.63(d,J＝4.4Hz,2H),7.82(t,J＝3.6Hz,2H),7.59(d,J＝7.6Hz,2H),7.52(d,J＝4.4Hz,1H),7.16-7.11(m,2H),6.12-6.07(m,1H),4.51(m,1H),4.06(m,1H),3.21(m,3H),3.05(m,2H),1.76(d,J＝6.8Hz,3H),1.39(d,J＝5.6Hz,3H).
实施例113
Figure PCTCN2016092989-appb-000281
这个实施例如实施例111中描述的方法制备。
LCMS(ESI)m/z:497.0[M+1]+
实施例114
Figure PCTCN2016092989-appb-000282
这个实施例如实施例111中描述的方法制备。
LCMS(ESI)m/z:511.1[M+1]+
1H NMR(DMSO-d6,varian 400MHz):ppm 8.60(s,2H),7.77(d,J＝8.0Hz,3H)7.50(s,1H)7.49(d,J＝8.0Hz,2H),7.13(d,J＝2Hz,2H),7.11-7.08(m,2H),6.07(dd,J＝6.8Hz,J＝13.6Hz,1H),4.02(s,1H),3.75(m,1H),3.20(s,2H),1.75-1.73(m,5H),1.39(s,2H).
实施例115
Figure PCTCN2016092989-appb-000283
这个实施例如实施例111中描述的方法制备。
LCMS(ESI)m/z:540.2[M+1]+
实施例116
Figure PCTCN2016092989-appb-000284
这个实施例如实施例111中描述的方法制备。LCMS(ESI)m/z:509.9[M+1]+
实施例117
Figure PCTCN2016092989-appb-000285
这个实施例如实施例111中描述的方法制备。LCMS(ESI)m/z:538.3[M+1]+
实施例119
Figure PCTCN2016092989-appb-000286
这个实施例如实施例111中描述的方法制备。LCMS(ESI)m/z:497.3[M+1]+
1H NMR(400MHz,DMSO-d6):ppm 8.63(d,2H),7.80(d,J＝8,2H),7.65(dd,J＝3.2,J＝7.6,2H),7.51(d,J＝9.2,1H),7.16(s,1H),7.13(d,J＝8.8,1H),6.10(t,J＝2.8,1H),4.28(s,2H),3.45-3.66(m,3H),1.98-1.92(m,2H),1.76(d,J＝6.4,3H).
实施例120
Figure PCTCN2016092989-appb-000287
这个实施例如实施例111中描述的方法制备。LCMS(ESI)m/z:552.3[M+1]+
实施例121
Figure PCTCN2016092989-appb-000288
这个实施例如实施例111中描述的方法制备。LCMS(ESI)m/z:524.2[M+1]+
1H NMR(400MHz,DMSO-d6):ppm 11.42(s,1H),8.64(s,2H),7.82(d,J＝7.60Hz,2H),7.69(d,J＝6.80Hz,2H),7.52(d,J＝9.20Hz,1H),7.13(t,2H),6.07(d,J＝6.40Hz,1H),3.89(m,5H),2.80(s,6H),2.29(m,3H),1.74(d,J＝6.80Hz,3H).
实施例125
Figure PCTCN2016092989-appb-000289
这个实施例如实施例111中描述的方法制备。
LCMS(ESI)m/z:540.2[M+1]+
实施例126
Figure PCTCN2016092989-appb-000290
这个实施例如实施例111中描述的方法制备。
LCMS(ESI)m/z:532.1[M+23]+
1H NMR(400MHz,DMSO-d6):ppm 13.26(s,1H),8.62(s,2H),8.18(s,1H),7.81(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),7.51(d,J＝9.2Hz,1H),7.17(s,1H),7.12(dd,J1＝2Hz,J2＝9.2Hz 1H),6.12-6.06(m,1H),4.41-4.39(m,2H),3.12-2.85(m,5H),1.76(d,J＝6.4Hz,3H),1.12-1.10(m,3H).
流程P
Figure PCTCN2016092989-appb-000291
实施例127
Figure PCTCN2016092989-appb-000292
实施例127A
Figure PCTCN2016092989-appb-000293
氮气保护下，实施例24H(600毫克，1.16毫摩尔)，3-甲氧羰基-苯硼酸(229.23毫克，1.27毫摩尔)，Pd(dppf)Cl2(84.73毫克，115.79微摩尔)和三水磷酸钾(925.10毫克，3.47毫摩尔)和三乙胺(555.53毫摩尔，5.49毫摩尔)的THF/H2O(4/2毫升)混悬液在100℃条件下搅拌2小时。加水(50毫升)，用乙酸乙酯(50毫升*3)萃取，无水硫酸钠干燥，真空浓缩，残余物通过柱层析纯化得到标题化合物(600毫克，93.35％收率)，LCMS(ESI)m/z:526.2[M+1]+.1H NMR(CHLOROFORM-d,400MHz)ppm 8.51(d,J＝1.00Hz,1H),8.40(d,J＝2.51Hz,2H),7.95-8.07(m,2H),7.47-7.58(m,2H),7.24(d,J＝1.51Hz,1H),7.15(dd,J＝2.01,9.03Hz,1H),6.08(q,J＝6.53Hz,1H),5.69(ddd,J＝3.01,6.02,9.03Hz,1H),4.00-4.07(m,1H),3.97(s,3H),3.73(t,J＝10.29Hz,1H),2.59(dd,J＝3.26,7.78Hz,1H),2.06-2.23(m,2H),1.71-1.84(m,5H).
实施例127B
Figure PCTCN2016092989-appb-000294
30℃条件下，向实施例1A(600毫克，1.14毫摩尔)的甲醇/四氢呋喃/水溶液(6/6/4毫升)中一次性加入一水氢氧化锂(51.34毫克，1.35毫摩尔)，然后在该温度下搅拌5小时。真空浓缩，加水(50毫升)，用2M稀盐酸调pH至6，用乙酸乙酯(50毫升*3)萃取，无水硫酸钠干燥，合并真空浓缩得到标题化合物(520毫克，85.26％收率)。1H NMR(CHLOROFORM-d,400MHz)ppm 8.44-8.56(m,1H),8.03-8.19(m,1H),7.48-7.62(m,1H),7.12-7.23(m,1H),6.08(q,J＝6.53Hz,1H),5.66-5.75(m,1H),4.03(d,J＝6.53Hz,1H),3.74(br.s.,1H),2.53-2.67(m,1H),2.06-2.23(m,2H),1.59-1.86(m,6H).
实施例127C
Figure PCTCN2016092989-appb-000295
30℃条件下，向实施例127A(80毫克，156.13微摩尔)，HATU(89.05毫克，234.20微摩尔)和DIPEA(80.72毫克，624.54微摩尔)的DMF溶液(5毫升)中加入4-氨基四氢吡喃盐酸盐(23.63毫克，1.42毫摩尔)，该混悬液在30℃下搅拌2小时。加水(50毫升)，用乙酸乙酯(50毫升*3)萃取，无水硫酸钠干燥，真空浓缩，残余物通过制备薄层层析板纯化得到黄色油状标题化合物(90毫克，89.05％收率)，LCMS(ESI)m/z:595.1[M+1]+.
实施例127D
Figure PCTCN2016092989-appb-000296
0℃条件下，向甲醇(4毫升)滴加乙酰氯(1毫升)，搅拌15分钟后，向溶液中加入实施例127C(90毫克，151.13微摩尔)，滴加完成后40℃下搅拌2小时。真空浓缩，残余物通过HPLC(盐酸体系)制备得到标题化合物(20毫克，24.16％收率).
LCMS(ESI)m/z:511.2[M+1]+.1H NMR(METHANOL-d4,400MHz)ppm 8.49(s,2H),8.22(s,1H),7.88(d,J＝7.28Hz,2H),7.59-7.67(m,1H),7.54(d,J＝9.29Hz,1H),7.27(dd,J＝2.01,9.03Hz,1H),7.16(d,J＝1.76Hz,1H),6.15(q,J＝6.78Hz,1H),4.11-4.27(m,1H),4.02(d,J＝9.29Hz,2H),3.56(t,J＝11.67Hz,2H),1.97(d,J＝11.29Hz,2H),1.66-1.84(m,5H).
实施例129
Figure PCTCN2016092989-appb-000297
这个实施例如实施例127中描述的方法制备。LCMS(ESI)m/z[M+H]+:497.1[M+1]+.
实施例130
Figure PCTCN2016092989-appb-000298
这个实施例如实施例127中描述的方法制备。LCMS(ESI)m/z[M+H]+:525.3[M+1]+.
流程Q
Figure PCTCN2016092989-appb-000299
实施例132
Figure PCTCN2016092989-appb-000300
实施例132A
Figure PCTCN2016092989-appb-000301
3-溴苯甲醛(1克，5.40毫摩尔)，4,4,5,5-四甲基-2-乙烯基-1,3,2-硼酸频哪醇酯(1.2克，8.10微摩尔)，Pd(OAc)2(121.24毫克，0.54毫摩尔)和PPh3(283.27毫克，1.08毫摩尔)，Na2CO3(1.14毫克，10.80毫摩尔)溶解在水(3毫升)和DMF(9毫升)的混合液中，混合物在氮气保护下80℃反应12小时。薄层色谱显示(石油醚：乙酸乙酯＝2/1)原料反应完全。反应混合物减压浓缩用硅胶柱层析分离(石油醚/乙酸乙酯＝40/1-30/1)得到标题化合物(黄色油状液体，540.00毫克，3.40微摩尔，收率63.05％)。1H NMR(400MHz,METHANOL-d4)9.99-10.05(m,1H),7.98(s,1H),7.71-7.86(m,2H),7.48-7.60(m,1H),6.78-6.90(m,1H),5.93(d,J＝17.57Hz,1H),5.38(d,J＝11.04Hz,1H)
实施例132B
Figure PCTCN2016092989-appb-000302
实施例24H(300.00毫克，0.58毫摩尔)，132A(76.52毫克，578.96微摩尔)，Et3N(175.75毫克，1.74毫摩尔)和PPh3(283.27毫克，1.08毫摩尔)，Pd(OAc)2(13.00毫克，57.90毫摩尔)，三邻甲苯基膦(17.62毫克，57.90毫摩尔)溶解在DMF(4毫升)中，混合物在氮气保护下100℃反应12小时。薄层色谱显示(石油醚：乙酸乙酯＝2/1)原料反应完全。反应液加5毫升冰水淬灭，搅拌5分钟，然后用乙酸乙酯萃取10毫升X3次，分液。有机相用饱和食盐水洗涤，无水硫酸钠脱水，过滤，蒸干溶剂后由硅胶柱层析分离(石油醚/乙酸乙酯＝15/1)得到标题化合物(220.00毫克，421.12微摩尔，收率72.74％)。LCMS(ESI)m/z[M+H]+:552.1.
实施例132C
Figure PCTCN2016092989-appb-000303
向实施例132B(70毫克，133.99微摩尔)和四氢吡喃-4-氨基(40.66毫克,401.97微摩尔)的1,2-二氯乙烷(1毫升)的混合溶液中，滴加醋酸(0.80毫克,13.4微摩尔)，滴加完成后20℃下搅拌30分钟。慢慢加入氰基硼氢化钠(25.26毫克,401.98微摩尔)，继续在20℃下搅拌2小时。水淬灭，水层用二氯甲烷(10毫升×3)萃取，结合有机层饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过薄层色谱(石油醚/乙酸乙酯＝1/1)纯化得到标题化合物(黄色油状液体，30毫克，49.38微摩尔，36.85％产率)。LCMS(ESI)m/z[M+H]+:607.4
实施例132D
Figure PCTCN2016092989-appb-000304
将实施例132C(30.00毫克，49.38微摩尔)溶于无水甲醇(1毫升)中，然后在0℃下将此溶液滴加到乙酰 氯(1毫升)的无水甲醇(4毫升)中。反应液升温至40℃下搅拌30小时。反应完毕后旋去溶剂得到标题化合物(22毫克，42.03微摩尔，产率85.11％)。LCMS(ESI)m/z[M+H]+:522.3
实施例134
Figure PCTCN2016092989-appb-000305
这个实施例如实施例132中描述的方法制备。LCMS(ESI)m/z[M+H]+:509.1
实施例135
Figure PCTCN2016092989-appb-000306
这个实施例如实施例132中描述的方法制备。LCMS(ESI)m/z[M+H]+:537.5
流程R
Figure PCTCN2016092989-appb-000307
实施例137
Figure PCTCN2016092989-appb-000308
实施例137A
Figure PCTCN2016092989-appb-000309
氮气保护下，双频哪醇硼酸酯(995.45毫克，6.46毫摩尔)，5-溴-2-(二甲氧基甲基)吡啶(1克，4.31毫摩尔)，Pd(dppf)Cl2(315.29毫克，0.43毫摩尔)和碳酸钾(1.79克，12.93毫摩尔)的二氧六环(15毫升)混悬液在100℃下加热16小时。冷却，加入水(10毫升)，乙酸乙酯(3x 10毫升)萃取，饱和食盐水洗涤，干燥，过滤，真空浓缩，残余物通过柱层析纯化得到黄色油状标题化合物(700毫克，87％收率)。1H NMR(400MHz,CHLOROFORM-d)＝8.63(d,J＝1.8Hz,1H),7.80(dd,J＝2.1,8.2Hz,1H),7.53(d,J＝8.3Hz,1H),6.74(dd,J＝11.0,17.6Hz,1H),5.86(d,J＝17.8Hz,1H),5.45-5.37(m,2H),3.43(s,6H)
实施例137B
Figure PCTCN2016092989-appb-000310
氮气保护下，实施例137A(850毫克，4.74毫摩尔)，24H(2.46克，4.74毫摩尔)，POT(144.27毫克，474微摩尔)，醋酸钯(106.42毫克，474毫摩尔)和DIEA(1.84克，14.2毫摩尔)的DMF(30毫升)混悬液在100℃条件下搅拌16小时。冷却，过滤，真空浓缩，残余物通过制备柱层析纯化得到黄色油状标题化合物(1.4克，52％收率)。LCMS(ESI)m/z[M+H]+:569.4.1H NMR(400MHz,CHLOROFORM-d)ppm 8.82-8.77(m,1H),8.46(s,2H),8.40-8.36(m,1H),7.95(dd,J＝2.0,8.3Hz,1H),7.60(d,J＝8.0Hz,1H),7.45(d,J＝16.8Hz,1H),7.28-7.22(m,1H),7.21-7.15(m,2H),6.18-6.07(m,1H),5.65(ddd,J＝2.5,5.8,9.0Hz,1H),5.47-5.43(m,1H),4.05(t,J＝8.9Hz,1H),3.86-3.69(m,2H),3.50-3.42(m,6H),2.61-2.49(m,1H),2.22-2.11(m,1H),2.09-1.99(m,3H),1.85(d,J＝6.5Hz,3H),1.80-1.73(m,2H)
实施例137C
Figure PCTCN2016092989-appb-000311
实施例137B(1.4克,2.46毫摩尔)和一水合对苯甲磺酸(234毫克,1.23毫摩尔)的水(5毫升)和丙酮(15毫升)混合溶液在50℃下加热搅拌3小时。冷却，水层用二氯甲烷(10毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩得到标题化合物(1.2克，76％产率)，直接用于下一步。LCMS(ESI)m/z:541.4(M+1).
实施例137D
Figure PCTCN2016092989-appb-000312
向实施例137C(100毫克，191微摩尔)和吗啡啉(50毫克,573.15微摩尔)，的1,2-二氯乙烷(2毫升)的混合溶液中，滴加醋酸(100微升)到pH为5，滴加完成后29℃下搅拌2小时。慢慢加入氰基硼氢化钠(36毫克,573.15微摩尔)，继续在29℃下搅拌3小时。水淬灭，水层用二氯甲烷(5毫升×3)萃取，结合有机层饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩，得到黑色油状标题化合物(100毫克，粗品)，LCMS(ESI)m/z:594.2[M+1]+.
实施例137E
Figure PCTCN2016092989-appb-000313
向实施例137D(100毫克，148微摩尔)的甲醇(1毫升)的溶液中，加入甲醇(1毫升)/乙酰氯(0.25毫升)混合溶液，加热到40℃搅拌3小时。冷却真空浓缩得到标题化合物(20.00毫克,46％收率)。LCMS(ESI)m/z 510.4(M+1).1H NMR(400MHz,METHANOL-d4)ppm 8.95(d,J＝1.8Hz,1H),8.51(s,2H),8.26(dd,J＝2.0,8.3Hz,1H),7.67(d,J＝8.0Hz,1H),7.60(d,J＝16.8Hz,1H),7.51(d,J＝9.3Hz,1H),7.37(s,2H),7.25(dd,J＝2.1,9.2Hz,1H),6.24(q,J＝6.7Hz,1H),4.61(s,2H),4.04-3.98(m,4H),3.47(t,J＝4.5Hz,4H),1.87(d,J＝6.5Hz,3H).
实施例138
Figure PCTCN2016092989-appb-000314
1H NMR(400MHz,METHANOL-d4)ppm 9.06(s,1H),8.60-8.49(m,3H),7.98(d,J＝8.0Hz,1H),7.71(d,J＝16.6Hz,1H),7.57(d,J＝9.0Hz,1H),7.46(d,J＝16.8Hz,1H),7.39-7.28(m,2H),6.25(q,J＝6.5Hz,1H),4.84(s,2H),4.66(br.s.,1H),3.70(br.s.,4H),2.39(br.s.,1H),2.18(br.s.,1H),1.86(d,J＝6.5Hz,3H).
实施例140
Figure PCTCN2016092989-appb-000315
这个实施例如实施例137中描述的方法制备。LCMS(ESI)m/z:538.4(M+1).
实施例142
Figure PCTCN2016092989-appb-000316
流程S
Figure PCTCN2016092989-appb-000317
实
施例142A
Figure PCTCN2016092989-appb-000318
-20℃条件下，向DIPCl(3.09克，9.65毫摩尔)的四氢呋喃(5毫升)溶液中滴加1-(3-氯-4-吡啶)乙酮(1克，6.43毫摩尔)四氢呋喃(5毫升)溶液，在该温度下搅拌1.5小时，升到0℃搅拌半个小时。甲醇(3毫升)淬灭，浓缩。残余物加入水(15毫升)，乙酸乙酯(3x 10毫升)萃取，饱和食盐水(10毫升)洗涤，干燥，过滤，真空浓缩，残余物通过柱层析纯化得到黄色油状标题化合物(650毫克，61％收率)。
LCMS(ESI)m/z:158.5[M+1]+
实施例142B
Figure PCTCN2016092989-appb-000319
0℃条件下，向实施例142A(650毫克，4.12毫摩尔)的二氯甲烷(6毫升)溶液在加入MsCl(1.42克,12.37毫摩尔)和三乙胺(1.25克，12.37毫摩尔)，该温度下搅拌1小时。水(1毫升)，碳酸氢钠水溶液碱化pH 7～8,加入水(10毫升)，二氯甲烷(2x 8毫升)萃取，饱和食盐水(5毫升)洗涤，干燥，过滤，真空浓缩，残余物通过柱层析纯化得到黄色油状标题化合物。
LCMS(ESI)m/z:236.7[M+1]+
实施例142
Figure PCTCN2016092989-appb-000320
从化合物3到实施例142，是按照实施例24中相同的方法合成的，得到实施例142(11.00毫克,20％收率)。LCMS(ESI)m/z:508.1[M+1]+
1H NMR(400MHz,METHANOL-d4)Shift 9.05-9.18(m,1H),8.78(d,J＝5.52Hz,1H),8.24-8.32(m,2H),7.66(d,J＝8.03Hz,1H),7.57(d,J＝9.54Hz,1H),7.41(s,1H),7.32(d,J＝9.03Hz,1H),7.03-7.18(m,1H),6.05(q,J＝6.02Hz,1H),4.54(s,2H),4.09(dd,J＝4.02,11.54Hz,2H),3.45-3.65(m,3H),2.16(d,J＝10.54Hz,2H),1.74-1.89(m,5H)
实施例143
Figure PCTCN2016092989-appb-000321
流程T
Figure PCTCN2016092989-appb-000322
实施例143A
Figure PCTCN2016092989-appb-000323
2-氯-4-氟苯甲酸(10.00克，57.29毫摩尔)，1-甲氧基-1-甲胺盐酸盐(10.00克，57.29毫摩尔)，1-羟基苯并三唑(11.61克，85.94毫摩尔)，1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(16.47克，85.94毫摩尔)，三乙胺(14.49克，143.23毫摩尔)的DCM(200.00毫升)溶液在15℃条件下搅拌3小时。加水(300毫升)，用DCM(200毫升*3)萃取，盐水(500毫升*2)洗，有机相合并，无水硫酸钠干燥，过滤，真空浓缩，残余物通过柱层析纯化得到无色油状实施例143A(12.30克，98.66％收率)。
1H NMR(400MHz,CHLOROFORM-d)7.35(dd,J＝6.02,8.53Hz,1H),7.17(dd,J＝2.51,8.53Hz,1H),7.04(dt,J＝2.26,8.28Hz,1H),3.27-3.58(m,6H).
实施例143B
Figure PCTCN2016092989-appb-000324
-78℃条件下30分钟内向实施例144A(12.30克，56.52毫摩尔)的四氢呋喃(100.00毫升)溶液中滴加甲基溴化镁(13.48克，113.04毫摩尔)，在0℃条件下搅拌5小时。加饱和氯化铵水溶液(100毫升)，加水(50毫升)稀释，用乙酸乙酯(200毫升*3)萃取，盐水(400毫升*2)洗，有机相合并，无水硫酸钠干燥，过滤，真空浓缩，残余物通过柱层析纯化得到无色油状实施例143B(9.60克，98.42％收率)。
1H NMR(400MHz,CHLOROFORM-d)7.64(dd，J＝6.02，8.53Hz，1H)，7.17(dd，J＝2.38，8.41Hz，1H)，7.01-7.07(m,1H),2.61-2.67(m,3H).
实施例143C
Figure PCTCN2016092989-appb-000325
0℃条件下向实施例144B(9.60克，55.63毫摩尔)的MeOH(80.00毫升)溶液中加入硼氢化钠(5.26克，139.08毫摩尔)，15℃条件下搅拌3小时。0℃下加水(100毫升)，用DCM(100毫升*2)萃取，盐水(200毫升*3)洗，有机相合并，无水硫酸钠干燥，过滤，真空浓缩，残余物通过柱层析纯化得到无色油状实施例143C(9.50克，97.81％收率)。
实施例143
Figure PCTCN2016092989-appb-000326
从化合物4到实施例143，是按照实施例24中相同的方法合成的，得到实施例143(350.00毫克，33.84％收率)。
LCMS(ESI)m/z[M+H]+:525.1[M+1]+
1H NMR(400MHz,METHANOL-d4)9.04(d，J＝1.76Hz，1H)，8.23(dd，J＝2.26，8.28Hz，1H)，7.52-7.65(m,2H),7.48(d,J＝9.03Hz,1H),7.16-7.28(m,3H),6.90-7.10(m,2H),5.79(q,J＝6.36Hz,1H),4.52(s,2H),4.08(dd,J＝4.52,11.80Hz,2H),3.39-3.58(m,3H),2.14(dd,J＝2.38,12.42Hz,2H),1.79(dq,J＝4.64,12.26Hz,2H),1.60-1.69(m,3H).
实施例144
Figure PCTCN2016092989-appb-000327
这个实施例如实施例144中描述的方法制备。LCMS(ESI)m/z:509.1[M+1]+
实施例145
Figure PCTCN2016092989-appb-000328
这个实施例如实施例144中描述的方法制备。LCMS(ESI)m/z:525.1[M+1]+
1H NMR(400MHz,METHANOL-d4)9.07(s,1H),8.25(d,J＝8.03Hz,1H),7.63(d,J＝8.28Hz,1H),7.44(d,J＝9.03Hz,1H),7.37(br.s.,1H),7.22-7.31(m,2H),7.17(d,J＝9.03Hz,1H),6.90-7.09(m,2H),6.01(d,J＝6.53Hz,1H),4.53(s,2H),4.10(d,J＝8.28Hz,2H),3.43-3.58(m,3H),2.16(d,J＝12.30Hz,2H),1.81(d,J＝6.53Hz,5H).
实施例146
Figure PCTCN2016092989-appb-000329
这个实施例如实施例144中描述的方法制备。LCMS(ESI)m/z:510.4[M+1]+
1H NMR(400MHz,METHANOL-d4)9.09-9.38(m,1H),8.42-8.82(m,3H),7.85-8.06(m,1H),7.55-7.76(m,2H),7.31-7.54(m,2H),5.92-6.30(m,1H),4.65(br.s.,2H),4.07(d,J＝7.78Hz,2H),3.41-3.67(m,3H),2.20(d,J＝9.79Hz,2H),1.88(br.s.,5H)
实施例147
Figure PCTCN2016092989-appb-000330
这个实施例如实施例144中描述的方法制备。
LCMS(ESI)m/z:509.5[M+1]+.
1H NMR(400MHz,METHANOL-d4)9.09(d,J＝1.25Hz,1H),8.28(d,J＝6.78Hz,1H),7.66(d,J＝8.03Hz,1H),7.43-7.55(m,2H),7.26-7.35(m,1H),7.22(dd,J＝2.01,9.03Hz,1H),7.00-7.16(m,1H),6.94(t,J＝8.53Hz,2H),5.89(q,J＝6.53Hz,1H),4.54(s,2H),4.08(dd,J＝4.27,11.54Hz,2H),3.42-3.59(m,3H),2.16(d,J＝11.04Hz,2H),1.67-1.89(m,5H).
实施例148
Figure PCTCN2016092989-appb-000331
这个实施例如实施例137中描述的方法制备。LCMS(ESI)m/z:475.3[M+1]+.
1H NMR(400MHz,METHANOL-d4)7.79-7.84(m,2H),7.54-7.63(m,4H),7.52(d,J＝7.53Hz,2H),7.40-7.49(m,1H),7.15(d,J＝9.03Hz,1H),4.49(t,J＝5.77Hz,1H),4.41(s,2H),4.03-4.15(m,2H),3.73-3.85(m,2H),3.67(br.s.,2H),3.38-3.50(m,3H),3.17-3.27(m,5H),2.93-3.06(m,1H),2.05-2.37(m,1H),1.40(br.s.,3H),1.38(br.s.,3H),1.35-1.37(m,2H)
实施例149
Figure PCTCN2016092989-appb-000332
这个实施例如实施例137中描述的方法制备。LCMS(ESI)m/z:461.3[M+1]+.
1H NMR(400MHz,METHANOL-d4)7.79-7.84(m,2H),7.56-7.61(m,3H),7.51-7.56(m,2H),7.50(d,J＝9.29Hz,1H),7.13-7.19(m,1H),4.45-4.53(m,2H),4.41(s,2H),4.09(d,J＝13.30Hz,2H),3.78(t,J＝12.80Hz,2H),3.35-3.48(m,4H),3.20-3.30(m,4H),3.07(t,J＝13.05Hz,1H),2.90(s,3H),1.97(s,3H),1.36-1.40(m,3H),1.31(br.s.,2H)
实施例150(参考例)
Figure PCTCN2016092989-appb-000333
这个实施例如实施例137中描述的方法制备。
1H NMR(400MHz,METHANOL-d4)δ＝8.95(d,J＝1.5Hz,1H),8.52(s,2H),8.33(dd,J＝2.0,8.3Hz,1H),7.72(d,J＝8.3Hz,1H),7.62(d,J＝16.8Hz,1H),7.53(d,J＝9.0Hz,1H),7.38(d,J＝16.8Hz,1H),7.33(d,J＝1.8Hz,1H),7.27(dd,J＝2.0,9.0Hz,1H),6.25(q,J＝6.5Hz,1H),4.55(s,2H),4.10(dd,J＝4.3,11.5Hz,2H),3.61-3.42(m,4H),2.22-2.12(m,2H),1.91-1.76(m,5H)
实验例1：本发明化合物的体外酶活性测试
实验目的：
通过Z′-LYTETM Detection Kinase Assay检测酶活性,以化合物的IC50值为指标，来评价化合物对FGFR1的抑制作用。
实验材料:
FGFR1(Invitrogen#PV4105)
Tyr4(Invitrogen-PR5053U)
ATP(Sigma-A7699)
DMSO(Sigma cat#34869-100ML)
反应缓冲液：50mM Hepes(pH 7.5),10mM MgCl2,1mM EGTA,0.01％Brij-35,1mM DTT,2mM MnCl2
384反应板(Corning Costar 3573)
384化合物板(Greiner#781280)
Development reagent B(Invitrogen#PR5193D)
Development Buffer(Invitrogen#PR4876B)
离心机(Eppendorf#5810R)
电子加样枪(Eppendorf)
Multidrop液体工作站(ThermoScientific)
Bravo自动液体工作站(Agilent)
Envision(Perkin Elmer)
实验步骤和方法：
A.准备酶/底物混和液
0.6nM FGFR1,2uM Tyr4peptide及10uM ATP于反应缓冲液(50mM Hepes，pH7.5,10mM MgCl2,0.01％BRIJ-35,1mM EGTA,4mM MnCl2,2mM DTT)。
B.化合物加样:
a.用DMSO将化合物稀释成10mM，3倍稀释，11个梯度，双复孔.
b.在Bravo自动液体工作站转移化合物1:25稀释到中间板中。然后再转移2.5ul至反应板中，保证DMSO终浓度为1％。
c.转移酶/底物缓冲液5ul于每孔中
d.使用Multidrop液体工作站依次加入ATP溶液到每孔中
e.1000rpm离心1分钟
f.将反应板放置于23℃恒温箱中反应60min。
C.显色反应实验：
a.配制1:128配制Development regent B与Development Buffer的混和液
b.于每孔加入5ul，1000rpm离心1分钟
c.离心后将反应板置于恒温箱(23℃)90分钟，取出后在Envision(Perkin Elmer)读板仪中读数
D.分析数据:使用XLFIT(IDBS)分析数据，计算化合物的IC50值。
实验结果见表1：
表1 Z′-LYTETM检测IC50测试结果
Figure PCTCN2016092989-appb-000334
Figure PCTCN2016092989-appb-000335
Figure PCTCN2016092989-appb-000336
注：50nM＜A≤1uM,10nM＜AA≤50nM,AAA≤10nM,N/A表示未测。
结论：本发明化合物对FGFR1的抑制作用显著。
实验例2：本发明化合物的体外体外细胞学抑制活性
实验目的：
通过
Figure PCTCN2016092989-appb-000337
Luminescent Cell Viability Assay检测细胞内ATP变化,以化合物的IC50值为指标，来评价化合物对体外细胞SNU-16的抑制作用。
实验材料:
细胞系：SNU-16细胞株
SNU-1细胞培养基:RPMI 1640(Invitrogen#22400105),10％血清(Invitrogen#10099141),
Penicillin-Streptomycin(Invitrogen Gibco#15140-122)
胰酶(Invitrogen,#25200-072)
DPBS(Hyclone,#SH30028.01B)
384细胞板(Greiner#781090)
384化合物板(Greiner#781280)
CO2培养箱(Thermo#371)
离心机(Eppendorf#5810R)
Vi-cell细胞计数仪(Beckman Coulter)
Bravo自动液体工作站(Agilent)
Envision(Perkin Elmer)
实验步骤和方法：
E.细胞接种(SNU-16细胞)
a.37℃水浴预热培养基、胰酶、DPBS。吸掉细胞培养的培养基，用10mL DPBS清洗；
b.加入预热过的胰酶到培养瓶中，旋转培养瓶使胰酶均匀覆盖培养瓶,放到37℃、5％CO2培养箱中消化1-2分钟；
c.每个T150用10-15mL培养基垂悬细胞，800rpm离心5分钟，用10mL培养基重悬细胞，吸取1mL细胞重悬液，用Vi-cell计数；
d.用培养基稀释SNU-16用排枪将稀释好的细胞加入到384板(Greiner.781090)(50μL/孔,SNU-16细胞750cells/孔，)。将细胞板放置于37℃、5％CO2培养箱过夜。
F.化合物加样:
g.用DMSO将化合物稀释成10mM，3倍稀释，10个梯度，双复孔.
h.在Bravo自动液体工作站转移化合物2.4ul至已加47.6ul细胞培养液的中间板中。然后再转移5ul到55ul细胞培养板中，保证DMSO终浓度为0.4％。
i.将细胞板放置于37℃、5％CO2培养箱继续培养3天。
G.CTG实验：
d.将Cell Titer Glo试剂平衡至室温
e.以1:2的比例取30ul Cell Titer Glo试剂到每一个样品孔，轻轻混合2分钟
f.将细胞培养板置于恒温箱(23℃)10分钟，取出后1000rpm离心1分钟
g.在Envision(Perkin Elmer)读板仪中读数
H.分析数据:使用XLFIT(IDBS)分析数据，计算化合物的IC50值。
实验结果见表2：
表2
Figure PCTCN2016092989-appb-000338
检测IC50测试结果
Figure PCTCN2016092989-appb-000339
Figure PCTCN2016092989-appb-000340
注：10nM＜+≤1uM,++≤10nM。
结论：本发明化合物对SNU-16的抑制作用显著。
实验例3：肿瘤生长抑制(TGI)分析
肿瘤的演化生长势通过肿瘤体积与时间的关系来进行评价的。皮下肿瘤的长轴(L)和短轴(W)通过测径器每周测定两次，肿瘤的体积(TV)通过公式((LxW2)/2)进行计算。TGI由溶剂组小鼠肿瘤体积的中值和药物组组小鼠肿瘤体积中值得差值来进行计算，以溶剂对照组肿瘤体积中值得百分比来表示，
通过下述公式进行计算：
％TGI＝((中间肿瘤体积(对照)-中间肿瘤体积(给药组))/中间肿瘤体积(对照组))x100
原始统计分析是通过重复方差测定分析来完成。接下来通过Scheffe psot hoc实验方法进行多重比较。单独溶剂(0.5％甲基纤维素+0.2％吐温水溶液)为阴性对照。
实验结果见表3：
  FGFR1/2高表达的人源肿瘤肝癌移植模型 TGI％(末次给药)
实施例16 15mg/kg,BID 84.5
实施例18 5mg/kg,BID 85
实施例54 10mg/kg,BID 85.4
实施例63 15mg/kg,BID 86
本发明化合物优异的体外FGFR1激酶抑制活性和SNU-16细胞抑制活性，可以作为小分子的络氨酸激酶抑制剂；具有抑制细胞增殖及血管生成，具有优良的抗肿瘤活性，对用于治疗各种哺乳动物(包括人类)有优良的效果。
实验例4：分子中引入氟烯代替烯能够明显提高化合物体内的代谢稳定性，增加化合物的生物利用度，如WX_018和WX_150比较
实验过程：将1mg/ml 20％DMSO/60％PEG400/20％water试验化合物的澄清溶液经尾静脉注射到雌性Balb/c nude小鼠体内(过夜禁食，7-9周龄)，给药剂量为1mg/kg。将1mg/ml悬浮在0.5％Methocel/0.2％Tween80的试验化合物灌胃给予到雌性Balb/c nude小鼠(过夜禁食，7-9周龄)，给药剂量为10mg/kg。两组动物均 于给药后0.0833、0.25、0.5、1.0、2.0、4.0、8.0和24h从颈静脉或尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlinTM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验数据分析：雌性Balb/c nude小鼠单次静脉注射给药1.0mg/kg WX_018后，其血浆清除率(CL)为53.0±1.69mL/min/kg，稳态表观分布容积(Vdss)为5.45±0.491L/kg，消除半衰期(T1/2)和0点到最后一个可定量时间点血浆浓度曲线下面积(AUC0-last)的值分别为1.57±0.0286h和567±19.4nM·h。
雌性Balb/c nude小鼠单次灌胃给予10mg/kg WX_018后，其生物利用度为30.1％,AUC0-last为1649±40.1nM·h，达峰浓度(Cmax)为479±62.9nM，达峰时间出现在给药后2.00h。雌性Balb/c nude小鼠单次静脉注射给药1.0mg/kg WX_150后，其血浆清除率(CL)为83.5±18.5mL/min/kg，稳态表观分布容积(Vdss)为5.31±0.268L/kg，消除半衰期(T1/2)和0点到最后一个可定量时间点血浆浓度曲线下面积(AUC0-last)的值分别为0.971±0.461h和386±88.3nM·h。
雌性Balb/c nude小鼠单次灌胃给予10mg/kg WX_150后，其生物利用度为11.4％,AUC0-last为439±202nM·h，达峰浓度(Cmax)为134±68.3nM，达峰时间出现在给药后1.50±0.866h。
另外，在烯键上引入一个氟还有很多优点，比如：1)氟烯的结构本身就是一个新颖的设计，合成上需要有很大的技巧；2)能够显著地改善化合物物化性质，提高在生物膜上的溶解性，改变化合物的酸碱性，改善化合物与有机组织的亲和作用，促进生物体内吸收的传递速度；3)同时增加化合物的稳定性，提高化合物体内代谢稳定性，增加暴露量，潜在地能够提高体内药效，同等药效下，能够降低给药量。
实验例5：式(I)化合物B1为环比其为链能够明显提高化合物体内的代谢稳定性，增加化合物的生物利用度，如WX_077和WX_063比较
实验过程：将0.4mg/ml 20％DMSO/60％PEG400/20％water试验化合物的澄清溶液灌胃给予到雌性Balb/c nude小鼠(过夜禁食，7-9周龄)，给药剂量为2mg/kg。两组动物均于给药后0.25、0.5、1.0、2.0、4.0、8.0和24h从颈静脉或尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlinTM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验数据分析：雌性Balb/c nude小鼠单次灌胃给予2mg/kg WX_077后，AUC0-last为72.1±19.8nM·h，达峰浓度(Cmax)为41.7±6.45nM，达峰时间出现在给药后0.25h。
雌性Balb/c nude小鼠单次灌胃给予2mg/kg WX_063后，AUC0-last为221±71.3nM·h，达峰浓度(Cmax)为214±39.7nM，达峰时间出现在给药后0.25h。

Claims (14)

  1. 式(I)或(Ⅱ)所示化合物、其药学上可接受的盐或其互变异构体，
    Figure PCTCN2016092989-appb-100001
    其中，
    R1和R2其中一个选自F、Cl、Br、I、CN、OH、NH2，另一个选自H、F、Cl、Br、I、CN、OH、NH2；B1选自
    Figure PCTCN2016092989-appb-100002
    其中，
    T11-15中的0～2个选自N，其余选自C(R)；
    T16-18中的0～2个选自N，其余选自C(R)；
    D11选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-；
    T41选自N或C(R)；
    D41选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-；
    D42-45中的0～2个分别独立地选自单键、-[C(R)(R)]1-3-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-，其余选自-C(R)(R)-；
    任选地，D41-45中的任意两个共同连接到同一原子或原子团上形成一个3～6元环；
    L1、L3分别独立地选自-(CRR)0-3-、-(CRR)0-3-C(＝O)N(R)-(CRR)0-3-、-(CRR)0-3-N(R)-(CRR)0-3-、-(CRR)0- 3-C(＝NR)-(CRR)0-3-、-(CRR)0-3-S(＝O)2N(R)-(CRR)0-3-、-(CRR)0-3-S(＝O)N(R)-(CRR)0-3-、-(CRR)0-3-O-(CRR)0-3-、-(CRR)0-3-S-(CRR)0-3-、-(CRR)0-3-C(＝O)O-(CRR)0-3-、-(CRR)0-3-C(＝O)-(CRR)0-3-、-(CRR)0-3-C(＝S)-(CRR)0-3-、-(CRR)0-3-S(＝O)-(CRR)0-3-、-(CRR)0-3-S(＝O)2-(CRR)0-3-或-(CRR)0-3-N(R)C(＝O)N(R)-(CRR)0-3-；
    B2选自任选被R取代的5～10元芳基或杂芳基；
    B4选自任选被R取代的5～6元芳基或杂芳基、5～6元环烷基或杂环烷基；
    T31-34分别独立地选自N或C(R)；
    任选地，T31-34中的任意两个共同连接到同一原子或原子团上形成一个3～6元环；
    n为0或1，当n为0时，其限定的结构单元表示仅起连接作用的单键；
    R选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2，或选自任选R’取代的C1-12烷基或杂烷基、C3-12环烃基或杂环烃基、被C3-12环烃基或杂环烃基取代的C1-12烷基或杂烷基；
    R’选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、＝NH、＝O、＝S、或任选被R”取代的：NHC(＝O)CH3、C1-12烷基、C1-12烷氨基、N,N-二(C1-12烷基)氨基、C1-12烷氧基、C1-12烷酰基、C1-12烷氧羰基、C1-12烷基磺酰基、C1-12烷基亚磺酰基、3～12元环烷基、3～12元环烷氨基、3～12元杂环烷氨基、3～12元环烷氧基、3～12元环烷基酰基、3～12元环烷氧羰基、3～12元环烷基磺酰基、3～12环烷基亚磺酰基、5～12元芳基或杂芳基、5～12元芳烷基或杂芳烷基；
    R”选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、＝NH、＝O、＝S、三卤代甲基、二卤代甲基、一卤代甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基；
    “杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-和/或-N(R)C(＝O)N(R)-；
    上述每种情况下，R、R’、R”、杂原子或杂原子团的数目分别独立地选自0、1、2或3；
    且式(I)化合物不包括
    Figure PCTCN2016092989-appb-100003
  2. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中所述R选自H、F、Cl、Br、I、OH、NH2、CN、羟甲基、羟乙基、羧丙基、羧甲基、甲氧基、乙氧基、丙氧基、甲基、乙基、丙基、异丙基、一卤代甲基、二卤代甲基、三卤代甲基、甲氨基、二甲氨基、
    Figure PCTCN2016092989-appb-100004
    Figure PCTCN2016092989-appb-100005
    Figure PCTCN2016092989-appb-100006
  3. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其互变异构体，其中所述D41-45或T31-34中的任意两个共同连接到同一原子或原子团上形成一个苯环。
  4. 根据权利要求3所述的化合物、其药学上可接受的盐或其互变异构体，其中所述B1选自
    Figure PCTCN2016092989-appb-100007
    Figure PCTCN2016092989-appb-100008
  5. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其互变异构体，其中所述L1、L3分别独 立地选自单键、NH、
    Figure PCTCN2016092989-appb-100009
    CH2、CH2CH2、
    Figure PCTCN2016092989-appb-100010
    Figure PCTCN2016092989-appb-100011
  6. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其互变异构体，其中所述B2选自：
    Figure PCTCN2016092989-appb-100012
    其中，
    T选自N或C(R)；
    D选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-。
  7. 根据权利要求6所述的化合物、其药学上可接受的盐或其互变异构体，其中所述B2选自：
    Figure PCTCN2016092989-appb-100013
  8. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其互变异构体，其中所述B4选自任选被 1、2或3个R取代的苯基、吡啶基、咪唑基、呋喃基、噻唑基、哌啶基、哌嗪基或吗啉基；
    任选地，B4选自：
    Figure PCTCN2016092989-appb-100014
  9. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其互变异构体，其中结构单元
    Figure PCTCN2016092989-appb-100015
    选自：
    Figure PCTCN2016092989-appb-100016
    Figure PCTCN2016092989-appb-100017
  10. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其选自：
    Figure PCTCN2016092989-appb-100018
    Figure PCTCN2016092989-appb-100019
    Figure PCTCN2016092989-appb-100020
    Figure PCTCN2016092989-appb-100021
    Figure PCTCN2016092989-appb-100022
    Figure PCTCN2016092989-appb-100023
    Figure PCTCN2016092989-appb-100024
  11. 根据权利要求1所述式(Ⅰ)化合物的制备方法，包括如下步骤：
    Figure PCTCN2016092989-appb-100025
    其中，P选自卤素、OH、NH2和CN；P1为氨基保护基，具体为THP；其他变量如权利要求1所定义。
  12. 根据权利要求11所述式(Ⅰ)化合物的的制备方法，包括如下步骤：
    Figure PCTCN2016092989-appb-100026
  13. 一种药物组合物，其含有治疗有效量的根据权利要求1～10任意一项所述的化合物、其药学上可接受的盐或其互变异构体和药学上可接受的载体。
  14. 根据权利要求1～10任意一项所述的化合物、其药学上可接受的盐或其互变异构体，或根据权利要 求13所述的药物组合物在制备治疗癌症的药物中的应用。
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KR102668124B1 (ko) 2019-02-02 2024-05-23 노바온코 제이에스 테라퓨틱스 컴퍼니 리미티드 Pd-l1 면역조절제인 비닐 피리딘 카르복사미드 화합물
WO2020249096A1 (zh) * 2019-06-14 2020-12-17 南京明德新药研发有限公司 作为fgfr和vegfr双重抑制剂的并环类化合物
CN114072387A (zh) * 2019-11-06 2022-02-18 暨南大学 吲唑类化合物及其药用组合物和应用
CN114072387B (zh) * 2019-11-06 2024-03-08 暨南大学 吲唑类化合物及其药用组合物和应用
WO2022033472A1 (zh) * 2020-08-11 2022-02-17 河南迈英诺医药科技有限公司 Fgfr抑制剂化合物及其用途

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JP2018531218A (ja) 2018-10-25
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US20180222886A1 (en) 2018-08-09
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