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WO2018090973A1 - Fgfr4抑制剂及其制备方法和应用 - Google Patents

Fgfr4抑制剂及其制备方法和应用 Download PDF

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Publication number
WO2018090973A1
WO2018090973A1 PCT/CN2017/111634 CN2017111634W WO2018090973A1 WO 2018090973 A1 WO2018090973 A1 WO 2018090973A1 CN 2017111634 W CN2017111634 W CN 2017111634W WO 2018090973 A1 WO2018090973 A1 WO 2018090973A1
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Prior art keywords
etoac
mmol
group
reaction
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/CN2017/111634
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English (en)
French (fr)
Inventor
陈正霞
龙超峰
张杨
陈小新
王一恺
戴美碧
刘星
赵海霞
刘卓伟
胡国平
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Guangdong Zhongsheng Pharmaceutical Co Ltd
Original Assignee
Medshine Discovery Inc
Guangdong Zhongsheng Pharmaceutical Co Ltd
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Publication date
Priority to JP2019526465A priority Critical patent/JP7063899B2/ja
Priority to KR1020197016780A priority patent/KR102249632B1/ko
Priority to US16/461,373 priority patent/US11008292B2/en
Priority to AU2017359819A priority patent/AU2017359819B2/en
Priority to CA3043948A priority patent/CA3043948C/en
Priority to EP17871196.6A priority patent/EP3543227B1/en
Priority to MX2019005723A priority patent/MX389403B/es
Priority to NZ754218A priority patent/NZ754218A/en
Application filed by Medshine Discovery Inc, Guangdong Zhongsheng Pharmaceutical Co Ltd filed Critical Medshine Discovery Inc
Priority to CN201780070537.7A priority patent/CN109952290B/zh
Publication of WO2018090973A1 publication Critical patent/WO2018090973A1/zh
Priority to IL266659A priority patent/IL266659B/en
Anticipated expiration legal-status Critical
Priority to ZA2019/03845A priority patent/ZA201903845B/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a class of compounds which are FGFR4 inhibitors and their use in the manufacture of a medicament for the treatment of FGFR4-related disorders. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • Fibroblast growth factor receptor 4 is a human protein compiled from the FGFR4 gene. This protein is a member of the fibroblast growth factor receptor family, and the amino acid sequence homology between FGFR1-4 members is highly homologous. A glycoprotein consisting of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane domain, and a cytoplasmic fraction comprising a tyrosine kinase domain. Binding of the extracellular domain to FGF results in the dimerization of FGFR, autophosphorylation of the receptor, activation of downstream signaling pathways, ultimately affecting cell division and variation.
  • Ig immunoglobulin
  • FGFR4 is distinct from FGFR1-3, which has a specific structure of cysteine 552 (CYS552), thus enabling selective inhibition of FGFR4 without inhibiting the development of FGFR1-3 inhibitors.
  • CYS552 cysteine 552
  • FGFR4 inhibitors will not only be limited to the treatment of liver cancer with high expression of FGFR4, but also in other solid tumors with abnormal FGFR4 signaling pathway, and there is also the possibility of being combined with other therapies. Therefore, the development of FGFR4 inhibitors has a wider market space and application prospects.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • X, Y, Z are each independently selected from C(R) or N;
  • R 1 and R 2 are selected from F and the other is selected from H or CH 3 ;
  • Ring A is selected from the group consisting of: phenyl, 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl;
  • R' is selected from the group consisting of CH 3 and CH 2 CH 3 ;
  • hetero of the 5-6 membered heterocycloalkyl group is independently selected from: -NH-, -O-, N;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R 1 is selected from F
  • R 2 is selected from H or CH 3
  • other variables are as defined herein.
  • R 1 above is selected from H or CH 3
  • R 2 is selected from F
  • other variables are as defined herein.
  • R is selected from H or is selected from the group consisting of: 1, 3 or 3 R's substituted: CH 3 , CH 2 CH 3 , Other variables are as defined by the present invention.
  • the above R is selected from the group consisting of: H, CH 3 , CH 2 CH 3 , Other variables are as defined by the present invention.
  • the A ring is selected from the group consisting of phenyl, cyclohexane, cyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, and other variables are as defined herein.
  • the A ring is selected from the group consisting of: Other variables are as defined by the present invention.
  • R 3 , R 4 , R 5 are each independently selected from H, F, Cl, or selected from: CH 3 optionally substituted by 1, 2 or 3 R, Other variables are as defined by the present invention.
  • R 3 , R 4 , and R 5 are each independently selected from the group consisting of: H, F, Cl, CH 3 , Other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of: H, F, Cl, CH 3 , and other variables are as defined herein.
  • R 4 is selected from the group consisting of: H, F, Cl, Other variables are as defined by the present invention.
  • R 5 is selected from the group consisting of: H, F, Cl, Other variables are as defined by the present invention.
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 1 , R 2 , R 3 , R 4 , R 5 , Z, X, Y are as defined in the present invention.
  • the invention further provides a compound of the formula, a pharmaceutically acceptable salt thereof, and tautomers thereof, selected from the group consisting of:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a FGFR4-related disorder.
  • the invention also provides the use of a composition as described above for the manufacture of a medicament for the treatment of a FGFR4-related disorder.
  • the above application is characterized in that the medicament is a medicament for treating liver cancer or gastric cancer.
  • the acrylamide and fluoroolefin bond core structure of the compound of the present invention can obtain a series of high-selection compounds of FGFR4, and have excellent inhibitory activity against FGFR4 kinase, but no activity on subtype FGFR1 kinase, and the selectivity is at least ten or more than 100 times.
  • dichloro chloride can greatly enhance the inhibitory activity of FGFR4; as in Example 1, the activity is increased by 70 times as compared with the control example 1; the olefin bond introduces a fluorine atom, and the fluorine atom is adjacent to the second Chloroaniline can increase the target activity of FGFR4, as in Example 15, the activity is improved by nearly 9-fold compared with Comparative Example 2, and the activity of Example 19 is improved by nearly 9-fold compared with Comparative Example 3.
  • the fluorine of the compound of the present invention can greatly improve the stability of drug metabolism compared with the benzyl ether structure, and also greatly improve the oral absorption bioavailability of the drug; and the compound of the present invention has excellent antitumor activity and is useful for treating various mammals.
  • Tumorous diseases including humans, such as liver cancer and gastric cancer, have excellent effects.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, 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, phen
  • 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.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a 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).
  • 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, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • 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.
  • 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.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. 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. When the recited 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 or It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • 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, phenyl, pyridine, 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.
  • one or more atoms ie C, O, N or S
  • 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, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , 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 is selected from C 1
  • 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.
  • hydrocarbyl means a straight or branched chain radical 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 hydrocarbon 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 isomers body.
  • 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 hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • 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.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • 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.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include 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.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), 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.
  • 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, 5-
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • 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 solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; 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 acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Nitric acid 13.39 g, 146.61 mmol was slowly added dropwise to a solution of Comparative Example 2A (29.56 g, 146.61 mmol) in sulfuric acid (150 ml) at 0 ° C. After completion of the dropwise addition, stirring at this temperature 30 After the reaction was completed, the reaction solution was slowly poured into ice water which was continuously stirred, and a large amount of light purple solid was precipitated immediately, and the filter cake was washed with water several times to obtain a light purple control example 2G (34 g) without further purification, directly Used in the next step.
  • Aqueous sodium hydroxide solution (4 mol, 229.19 ml) was added to a solution of the mixture of 2 g (34 g, 137.86 mmol) in tetrahydrofuran (5 ml), and the mixture was heated to 95 ° C for 2 hours; the reaction was completed, cooled, and Ethyl acetate (50 ml) and water (50 ml), and ethyl acetate (100 ml) Dry over anhydrous sodium sulfate, EtOAc (EtOAc m.)
  • N,N-diisopropylethylamine (7.13) was added dropwise to a solution of EtOAc (2 mL) Mg, 55.20 micromoles) and acryloyl chloride (2.50 mg, 27.60 micromoles). The reaction was stirred at 0 ° C for 15 minutes. After the reaction was completed by LCMS, 10 ml of ethyl acetate and 15 ml of water were added to the mixture. After the mixture was uniformly mixed, the layers were separated, and the aqueous phase was extracted three times with 10 ml of ethyl acetate. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:
  • Comparative Example 4A 400 mg, 0.99 mmol was dissolved in a single-necked flask (50 mL) containing dioxane (3 mL), and then bis-sodium succinate (305 mg, 1.2 mM).
  • Pd 2 (dba) 3 90.84 mg, 0.1 mmol
  • KOAc 196 mg, 2.0 mmol
  • tricyclohexylphosphine 55.64 mg, 0.2 mmol
  • Comparative Example 4C (170 mg, 0.5 mmol) was dissolved in a single-necked flask (50 mL) containing acetonitrile (5 mL) and then (2,6-difluoro-3,5-dimethoxyphenyl)methyl Methanesulfonic acid (183 mg, 0.65 mmol), Cs 2 CO 3 (325.5 mg, 1.0 mmol) was placed at 80-90 ° C for 2 hours. The reaction mixture was filtered, and the filtrate was evaporated to ethylamine.
  • Comparative Example 7 and Comparative Example 8 were prepared as described below in Reference Example 4.
  • Methanesulfonyl chloride (195 mg, 1.70 mmol) was slowly added dropwise to a solution of the compound 6B (290.00 mg, 1.42 mmol) and triethylamine (287 mg, 2.84 mmol) The reaction solution (N 2 protection) was further reacted at 0 ° C for 1.5 hours. The reaction was quenched with water (5 mL)EtOAc. The combined organic phases were washed with EtOAc EtOAc m. This crude product was used in the next reaction without purification.
  • Example 1A A solution of Example 1A (18.86 g, 72.24 mmol) in anhydrous tetrahydrofuran (360 mL) was cooled to -20. Then, sulfuryl chloride (24.38 g, 180.6 mmol, 18.1 ml) was slowly added dropwise, and after the dropwise addition was completed, the reaction mixture was further reacted at -20 ° C for 1 hour. The reaction was quenched with water (20 mL) and EtOAc EtOAc EtOAc It was then extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with EtOAc EtOAc m.
  • Example 1B 600 mg, 1.82 mmol), 3,5-dimethoxyphenylboronic acid (435 mg, 1.82 mmol), Pd(dppf)Cl 2 (133 mg, 182 ⁇ mol) and potassium phosphate ( 966 mg, 4.55 mmol) was placed in a 50 ml sealed tube, and tetrahydrofuran (9.0 ml) and water (3.0 ml) were added separately, and after replacing three times with nitrogen, the reaction liquid was heated to 80 ° C in an oil bath and reacted 2 hour. After the reaction was cooled to room temperature, diluted with water (5 mL) The combined organic layers were washed with EtOAc EtOAc m.
  • the crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut M+1] + .
  • Example 1C 300 mg, 827 ⁇ mol), 2-methyl-6-nitroaniline (189 mg, 1.24 mmol), Pd 2 (dba) 3 76 mg, micromoles, Xphos (79 mg) , 165 ⁇ mol) and N,N-dimethylacetamide (6.0 ml) were placed in a 50 ml single-necked flask equipped with a reflux condenser, and after three times with nitrogen, the reaction mixture was heated in an oil bath. The reaction was carried out at 110 ° C for 2 hours. After the reaction was cooled to room temperature, the ⁇ The combined organic layers were washed with EtOAc EtOAc m. The crude product was purified by flash column eluting with EtOAc EtOAc
  • Example 1E (41 mg, 89 ⁇ mol), N,N-diisopropylethylamine (23 mg, 178 ⁇ mol) and dichloromethane (2.0 mL) were placed in a 50 mL round bottom flask and The solution was cooled to 0 ° C with an ice water bath. The acryloyl chloride (7.3 mg, 80 ⁇ mol) was added dropwise, and the reaction mixture was reacted at 0 ° C for 30 minutes, and the reaction was completed by LCMS. Dilute with 5.0 ml of dichloromethane. It was extracted with dichloromethane (2 x 5.0 mL). The combined dichloromethane solution was washed with saturated brine (5 mL) andEtOAc The crude product is then subjected to preparative high performance liquid chromatography (trifluoroacetic acid system) to obtain the target compound.
  • preparative high performance liquid chromatography trifluoroacetic acid system
  • Example 1A (2.00 g, 6.06 mmol), bis-pinacol borate (3.08 g, 12.12 mmol) and potassium acetate (1.78 g, 18.2 mmol) in dioxane (30 mL) Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (495 mg, 606 ⁇ mol) was added, and the reaction solution was replaced with nitrogen three times, and then stirred at 90 ° C for 16 hours under nitrogen atmosphere. The reaction was completed by TLC. After the reaction mixture was cooled to room temperature, then the mixture was diluted with ethyl acetate. The crude product was separated on a flash silica gel column (EtOAc (EtOAc:EtOAc)
  • Example 2C (640 mg, 2.07 mmol) in ethanol (10 ml) was added iron powder (578 mg, 10.4 mmol), ammonium chloride (554 mg, 10.4 mmol), and stirred at 90 ° C for 2 hours. . Filtration, concentrating in vacuo, EtOAc (EtOAc:EtOAc)
  • Example 2D (373 mg, 1.34 mmol), Example 2A (606 mg, 1.34 mmol), Pd 2 (dba) 3 (122 mg, 133 ⁇ mol), Xphos (127 mg, 267 ⁇ mol), phosphoric acid
  • a mixture of potassium (567 mg, 2.67 mmol) in acetonitrile (3.0 ml) and water (1.0 ml) was replaced with nitrogen three times and then stirred at 100 ° C for 2 hours under nitrogen atmosphere. The mixture was stirred with EtOAc EtOAc (EtOAc m. Purification (petroleum ether / ethyl acetate ratio: 3 / 1) was purified to afford compound (yield:
  • Example 7A To a solution of Example 7A (4.00 g, 15.6 mmol) in EtOAc (30 mL) The conversion of the starting material was completed by TLC. Then, ethylenediamine (2.80 g, 46.65 mmol) and cuprous chloride (154 mg, 1.55 mmol) were added to the reaction solution, and the mixture was stirred at 20 ° C for 30 minutes. The reaction solution was cooled to 0 ° C with an ice bath, then tribromofluoromethane (10.52 g, 38.9 mmol) was added dropwise and stirred at 20 ° C for 16 hours. It was diluted with water (100 ml) and extracted with ethyl acetate (50 ml ⁇ 3). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by EtOAc EtOAcjjjjjjjjjj
  • Example 9A Activated manganese dioxide (41.8 g, 481 mmol) was added to a solution of Example 9A (5.48 g, 30.1 mmol) in tetrahydrofuran (100 mL) at room temperature (20 ° C). The reaction was placed in an oil bath and heated to reflux for 2 hr. and the product formed in Example 9A was obtained by TLC and LCMS. Filtration, the solid was washed with EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut
  • Example 10B A solution of hydrazine monohydrate (4.17 g, 83.2 mmol, 4.05 ml) was added dropwise to a solution of Example 10B (5.00 g, 27.8 mmol) of ethanol (50 ml) at room temperature (25 ° C). After stirring at 28 ° C for 16 hours, the reaction of 3,5-dimethoxyacetophenone by TLC was completely added to the reaction flask to add ethylenediamine (5.51 g, 83.2 mmol) and cuprous chloride (275 mg). , 2.78 mmol).
  • Example 10G 260 mg, 528 ⁇ mol
  • EtOAc 500 mg, 5..
  • the mixture was replaced several times with hydrogen and then stirred at 20 ° C for 4 hours (15 psi).
  • the disappearance of the reactants was detected by LCMS. Filtration and concentration under reduced pressure afforded EtOAc (EtOAc m.
  • Example 10H (235 mg, 508 ⁇ mol), N,N-diisopropylethylamine (131 mg, 1.02 ⁇ mol) and dichloromethane (5.0 mL) were placed in a 50 mL round bottom flask and The solution was cooled to 0 ° C with an ice water bath. Acryloyl chloride (46 mg, 508 ⁇ mol) was added dropwise. After the reaction mixture was stirred at 0 ° C for 30 min, the reaction was completed by LCMS. EtOAc (EtOAc) It was extracted with dichloromethane (2 x 5 mL). The combined dichloromethane solution was washed with EtOAc EtOAc m. The crude product was subjected to preparative HPLC (trifluoroacetic acid system) to give the objective compound Example 10 (45 mg, yield: 17.0%). LCMS (ESI) m/z: 516.1, 518.1 [M+1] +
  • Example 26A 500.00 mg, 2.17 mmol
  • NBS 424.84 mg, 2.39 mmol
  • the reaction mixture was stirred at a temperature of 30 ° C for 16 hours.
  • the reaction mixture was concentrated with EtOAc EtOAc (EtOAc:EtOAc:
  • Example 16D (2.00 g, 6.47 mmol), Example 26B (3.66 g, 9.71 mmol), potassium phosphate (2.75 g, 12.94 mmol), Pd (dppf) Cl 2 (473.41 mg, 647.00 micromoles)
  • dioxane 30.00 ml
  • water 10.00 ml
  • nitrogen gas was replaced three times, and then the reaction liquid was stirred under a nitrogen atmosphere at a temperature of 100 ° C for 16 hours.
  • the reaction mixture was poured into EtOAc EtOAc (EtOAc m. (Petroleum ether / ethyl acetate ratio: 3 / 1) was purified to afford a yellow solid, m.p.
  • Example 26D (200.00 mg, 358.31 ⁇ mol), 1-acetyl-piperazine (91.85 mg, 716.62 ⁇ mol), Pd 2 (dba) 3 (32.81 mg, 35.83 ⁇ mol), XPhos (34.16 mg, 71.66 ⁇ m) Mole) and Cs 2 CO 3 (233.49 mg, 716.62 ⁇ mol) were added to DMA (5.00 mL), and nitrogen gas was replaced three times, and then the reaction solution was stirred under a nitrogen atmosphere at a temperature of 120 ° C for 2 hours. The reaction mixture was poured into 10 ml of ice water, EtOAc (EtOAc (EtOAc) The residue was purified by EtOAc EtOAcjjjjjjjjjj
  • Example 26E Add Raney-Ni (11.32 mg, 132.13 micromoles) to Example 26E (80.00 mg, 132.13 micromoles) in ethanol (1.00 mL), replace 3 hydrogens, then hydrogen (15 psi), 30 ° C Stir at a temperature for 0.5 hours. The reaction mixture was filtered and evaporated.
  • Example 13A The synthesis method of Example 13A is as in Comparative Example 2H.
  • Example 13A 400 mg, 2.35 mmol), 2-chloropyrimidine (269 mg, 2.35 mmol), Pd2 (dba) 3 (107 mg, 0.12 mmol), Xphos (112 mg, 0.24 mmol), K 2 CO 3 (974 mg, 7.05 mmol) was added to a toluene solution (4 mL), and N 2 was replaced by three times, and then heated to 110 ° C and stirred for 12 hours. The dot plate shows that the raw material is consumed. 20 mL of water was added to the reaction mixture, and ethyl acetate (20 ml, EtOAc) was evaporated.
  • Example 13B (530 mg, 2.14 mmol) was dissolved in chloroform (7 mL). The dot plate shows that the raw material is consumed. The reaction mixture was concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
  • Example 13C (1.15 g, 3.52 mmol) in EtOAc (10 mL). The reaction mixture was poured into EtOAc EtOAc (EtOAc (EtOAc) The title compound was obtained as a yellow oil (yield: EtOAc, m.
  • Example 13D embodiment 350 mg, 830.786 mol
  • Example 16D embodiment (313.24 mg, 830.78 [mu] mol)
  • Pd (dppf) Cl 2 60.79 mg, 83.08 [mu] mol
  • potassium phosphate 352.70 mg, 1.66 mmol
  • Example 13E 200 mg, 338.15 micromoles in ethanol (10 mL) / tetrahydrofuran (10 mL) mixture was added to Raney nickel (28.97 mg, 338.15 micromoles) under a nitrogen atmosphere, under hydrogen balloon conditions (15 psi) Stir at 20 ° C for 0.5 hours. Filtration, EtOAc (EtOAc)EtOAc.
  • Example 13F 200 mg, 356.20 ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; Further, sodium hydroxide (56.99 mg, 1.42 mmol) was added, and the mixture was stirred at 65 ° C for 5 hours. The mixture was extracted with EtOAc (EtOAc)EtOAc. Purification
  • Example 16A To a solution of Example 16A (20.00 g, 62.11 mmol, 1.00 eq.) in toluene (600 mL) was added tetrabutylammonium fluoride trihydrate (195.96 g, 621.10 mmol, 10.00 eq.) at 110 ° C Reaction for 16 hours. Thin layer chromatography was used to detect the completion of the reaction. The reaction mixture was diluted with EtOAc EtOAc (EtOAc m. Liquid Example 16B (12.84 g, yield: 79.18%).
  • Example 16B To a solution of Example 16B (24.80 g, 94.99 mmol, 1.00 eq.) in THF (500.00 mL), THF (32.05 g, 237.48 mmol, 23.74 mL, 2.50 eq.) of tetrahydrofuran was added dropwise at -5 °C. (15 ml) solution, the reaction solution was reacted at -5 ° C to 5 ° C for 3 hours. A solution of sulfonyl chloride (1 ml) in tetrahydrofuran (10 ml) was added and the reaction was continued at -5 ° C to 5 ° C for 1 hour.
  • Example 16C To a solution of Example 16C (20.00 g, 60.61 mmol, 1.00 eq.) and bis-pinacol borate (30.78 g, 121.22 mmol, 2.00 eq.) in dioxane (300 mL) Benzylacetone)dipalladium (5.55 g, 6.06 mmol, 0.10 eq.), tricyclohexylphosphine (6.80 g, 24.24 mmol, 0.40 eq.), potassium acetate (23.79 g, 242.44 mmol, 4.00 eq. The reaction was carried out at 90 ° C for 16 hours under a nitrogen atmosphere. The reaction was completed by EtOAc (EtOAc) (EtOAc:EtOAc.
  • Example 16E 795.00 mg, 2.90 mmol, 1.00 eq.
  • Example 16D (1.44 g, 3.83 mmol, 1.32 eq) of dioxane (12.00 mL) and water (4.00 mL) 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (254.64 mg, 348.00 micromoles, 0.12 equivalents), potassium phosphate (1.54 g, 7.25 mmol, 2.50 equiv) under N2
  • the reaction was carried out at 100 ° C for 1.5 hours.
  • the reaction was carried out by thin-layer chromatography and liquid chromatography.
  • Example 16F To Example 16F (513.00 mg, 1.15 mmol, 1.00 eq.), phthalimide (203.04 mg, 1.38 mmol, 1.20 eq.) and triphenylphosphine (44.28 mg, 168.81 micromoles, 1.50 equivalents) To a solution of tetrahydrofuran (6.00 ml) was added diisopropyl azodicarboxylate (348.81 mg, 1.73 mmol, 335.40 ⁇ l, 1.50 eq.) and allowed to react at 20 ° C for half an hour. The reaction was completed by TLC and LC/MS. The reaction mixture was filtered and evaporated in vacuo. Mg, yield 100.00%)
  • Example 16G To a solution of Example 16G (659.00 mg, 1.15 mmol, 1.00 eq.) in ethanol (10.00 mL) was added hydrazine monohydrate (230.13 mg, 4.60 mmol, 223.43 dl, 4.00 eq.) and reacted at 80 ° C. hour. The reaction was completed by thin-layer chromatography. The reaction mixture was filtered and evaporated. mjjjjjjjjjjjjj )
  • Example 16H To a solution of Example 16H (246.00 mg, 554.93 ⁇ mol, 1.00 eq.) and N,N-diisopropylethylamine (222.33 mg, 1.72 mmol, 300.45 dl, 3.10 eq.) in dichloromethane (20.00 mL) Among them, acryloyl chloride (44.40 mg, 490.55 ⁇ mol, 40.00 ⁇ l, 0.88 equivalent) was added at 0 ° C, and the mixture was reacted at 0 ° C for 1 hour. The liquid was tested by a liquid-liquid instrument. The reaction mixture was quenched with EtOAc (EtOAc (EtOAc) Purification by high performance liquid chromatography (trifluoroacetic acid system) gave Example 16 (150.00 mg, yield 54.35%).
  • EtOAc EtOAc
  • Example 19A 24.00 g, 278.78 mmol
  • aqueous ammonia (218.40 g, 1.74 mol, 240.00 ml) were added to the reaction flask, and the reaction was carried out at 100 ° C for 14 hours. The reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated to give a crude brown oil.
  • Example 19B the yield was 82.4%.
  • Example 19B (23.70 g, 229.83 mmol) was dissolved in MeOH (MeOH) (MeOH) (EtOAc) (EtOAc (EtOAc: EtOAc) ), react at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was completed, solvent was evaporated, then 100 ml of methyl tert-butyl ether was added and stirred for 15 minutes. The filtered cake was the product, which was obtained without further purification to give 38.78 g of pale yellow solid. 19C, the yield was 83.0%.
  • Example 19C (38.78 g, 190.82 mmol), phthalimide (33.69 g, 228.98 mmol) and triphenylphosphine (60.06 g, 228.98 mmol) dissolved in 500 mL of tetrahydrofuran, azo Diisopropyl diformate (46.30 g, 228.98 mmol, 44.52 ml) was reacted at room temperature for 14 hours. The reaction was monitored by TLC. After the reaction mixture was evaporated, mjjjjjjjjj
  • Example 19D (85.50 g, 257.26 mmol) was dissolved in 850 ml of dry ethanol, and hydrazine hydrate (75.76 g, 2572.6 mmol, 73.55 ml) was added and reacted at 80 ° C for 1 hour. The reaction was monitored by TLC. After the reaction was completed, the obtained white solid was filtered, and the solvent was evaporated to dryness. Then, 200 ml of dichloromethane was added, and the insoluble solid was filtered off, and the solvent was evaporated to give 49.6 g. Yellow solid crude product Example 19E.
  • Example 19F (15.62 g, 43.47 mmol), Example 16D (14.90 g, 39.52 mmol) was dissolved in 150 mL of 1,4-dioxane and 75 ml of water, and Pd(dppf)Cl 2 (2.89 g) was added. , 3.95 mmol) and anhydrous potassium phosphate (16.78 g, 79.04 mmol) were reacted at 95 ° C for 14 hours under a nitrogen atmosphere. The reaction was monitored by TLC.
  • Example 19G (4.60 g, 8.69 mmol) was dissolved in 30 mL of DCM eluting with trifluoroacetic acid (15.40 g, 135.04 mmol, 10.00 mL). The reaction was monitored by LC-MS. EtOAc was evaporated.
  • Example 19H (7.20 g, 13.25 mmol) was dissolved in 40 mL DCM, DIEA (6.85 g, 53.00 mmol) was added, the reaction mixture was cooled to 0 ° C, and acryloyl chloride (599.63 mg, 6.63 mmol) was added to room temperature. Reaction for 20 min. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched with water (30 ml), and then extracted with dichloromethane (15 ml*3). Filter and spin dry.
  • Example 19 (2.7 g, 5.59 mmol) was subjected to SFC (column: OD (250 mm * 30 mm, 5 ⁇ m); mobile phase: [0.1% NH3H2O EtOH]; B%: 40% - 40%, 10 min) to obtain 830 mg of Example 20 (purity: 98.43%) retention time 5.204, 610 mg of Example 21 (purity: 99.22%) retention time 7.294.
  • Example 34A An aqueous solution of Example 34A (9.0 g, 48.59 mmol) in 90 ml of ammonia was heated to 90 ° C and stirred for 4 hours. The reaction solution turned reddish brown. The reaction mixture was evaporated to dryness. EtOAc m.
  • Triethylamine (0.41 ml, 2.98 mmol) was added to a solution of EtOAc (m.) The reaction solution was stirred at 10-20 ° C for 1 hour. The dot plate detects the consumption of raw materials. The reaction mixture was extracted with EtOAc (EtOAc) (EtOAc (EtOAc. 670 mg, crude).
  • Example 34E 00 mg, 35 mL of ethyl acetate
  • MeOH &lt
  • RTI ID 0.0>> Stir for 16 hours.
  • the dot plate detects the consumption of raw materials.
  • Counter The solution turned green and was filtered to dryness to abr.
  • Example 34F 166 mg, 0.83 mmol
  • DIEA 106.63 mg, 0.083 mmol
  • 2-chloro-5-[(Z)-2-(2,6- Dichloro-3,5-dimethoxy-benzene)-2-fluoro-vinyl]pyridine 100 mg, 0.28 mmol
  • the product was formed by LCMS and the reaction of the starting material was completed.
  • Example 34H (30 mg, 51.51 micromol) was added HCl / EA (4 mL, 4 mol / liter), N2 and EtOAc. LCMS showed product production and the starting material was consumed. The reaction mixture was directly concentrated to give the product m. LCMS (ESI) m / z: 482.1 (M + 1) +
  • test compounds were subjected to a 3-fold concentration gradient dilution at a final concentration of 10 ⁇ M to 0.5 nM 10 concentrations of two replicate wells per concentration; DMSO was 1% in the assay reaction.
  • test plate was Bar-coded Corning, low volume NBS, black 384-well plate, reacted at room temperature for 60 minutes, and the reaction system was 10 ⁇ L.
  • test plate was a Black Proxiplate 384-Plus plate (PerkinElmer), and reacted at room temperature for 60 minutes, and the reaction system was 10 ⁇ L.
  • the reaction was stopped by adding 5 ⁇ L of Development reagent B (1:64) to the kinase reaction solution and incubated at 23 ° C for 60 minutes, and the plate was read by Envision instrument.
  • the unit is nM, N/A, indicating no test.
  • the acrylamide and fluoroolefin bond nucleus structure of the present invention can obtain a series of high-selection compounds of FGFR4, and have excellent inhibitory activity against FGFR4 kinase, but no activity on subtype FGFR1 kinase, and the selectivity is at least ten or more than 100 times.
  • dichloro chloride can greatly enhance the inhibitory activity of FGFR4; as in the case of Example 1, the activity is increased by 70 times as compared with the control example 1; the olefin bond introduces a fluorine atom, and the fluorine atom is adjacent to the second Chloroaniline was able to increase the target activity of FGFR4, and as in Example 15, the activity was improved by nearly 9-fold compared with Comparative Example 2, and the activity of Example 19 was improved by nearly 9-fold compared with Comparative Example 3.
  • Both groups of animals collected blood from the jugular vein or tail vein at a dose of 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h after administration, and placed about 30 ⁇ L in an anticoagulant tube supplemented with EDTA-K2, and centrifuged plasma. . Determination of plasma concentration, using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) software pharmacokinetics, trapezoidal method to calculate the number of linearly related noncompartmental pharmacokinetic parameters using LC-MS / MS method. The use of solvent and corresponding doses are shown in Table 2.
  • Example 16 having a fluoroolefin structure, compared with Comparative Example 4 of the benzyl ether structure the plasma clearance (CL) was 23.9 mL/min/kg, the stability was improved by 3 times, and the drug was orally administered.
  • the absorption increased from 0% to 40% or more;
  • Example 24 having a fluoroolefin structure, compared with Comparative Example 5 of the benzyl ether structure and Comparative Example 6 the plasma clearance (CL) was 50 mL/min/kg, and the stability was respectively Increased by 2 to 3 times, while oral absorption of drugs increased from 0% to 14.8%.
  • the bioavailability of Example 21 over Comparative Example 7 and Comparative Example 8 also showed a substantial increase.
  • the fluoroolefin structure of the compound of the present invention can greatly improve the stability of drug metabolism compared with the benzyl ether structure, and at the same time greatly improve the oral absorption bioavailability of the drug.
  • the evolutionary growth potential of tumors was evaluated by the relationship between tumor volume and time.
  • the long axis (L) and the short axis (W) of the subcutaneous tumor were measured twice a week by a caliper, and the volume of the tumor (TV) was calculated by the formula ((LxW 2 )/2).
  • TGI was calculated from the median value of the tumor volume of the solvent group mice and the difference in the tumor volume of the drug group mice, expressed as a percentage of the tumor volume in the solvent control group.
  • %TGI ((intermediate tumor volume (control)-intermediate tumor volume (administered group))/intermediate tumor volume (control group)) ⁇ 100%
  • the compound of the present invention has excellent FGFR4 enzyme inhibitory activity in vitro, and can be used as a small molecule tyrosine kinase inhibitor, and has excellent antitumor activity, and is useful for treating tumor diseases of various mammals including humans, such as Liver cancer, stomach cancer, etc. have excellent effects.

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Abstract

提供一类作为FGFR4抑制剂的式（I）所示化合物及其药学上可接受的盐，其制备方法及其在制备治疗FGFR4相关病症的药物上的应用。

Description

FGFR4抑制剂及其制备方法和应用
相关申请的交叉引用
本申请主张2016.11.17提交的中国专利申请CN201611012431.5的优先权，其内容在此并入本申请。
技术领域
本发明涉及了一类作为FGFR4抑制剂的化合物，及其在制备治疗FGFR4相关病症的药物上的应用。具体涉及式(Ⅰ)所示化合物及其药学上可接受的盐。
背景技术
成纤维细胞生长因子受体4(FGFR4)是由FGFR4基因编译的一种人蛋白。此蛋白是成纤维细胞生长因子受体家族中的一员，FGFR1-4成员之间的氨基酸序列同源性很高，高度相似。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。膜外区域与FGF结合导致FGFR二聚，受体发生自体磷酸化，激活下游信号通路，最终影响细胞的分裂和变异。
在基因结构方面，FGFR4与FGFR1-3有明显的区别，其具有半胱氨酸552(CYS552)特异结构，因此能够实现选择性地抑制FGFR4,而不抑制FGFR1-3抑制剂的开发，能够减少FGFR1-3抑制带来的潜在毒性；据近些年研究表明，FGFR4-FGF19信号轴与肝癌，肾癌，结肠癌，乳腺癌等紧密相关，使得FGFR4成为治疗肝癌，肾癌，结肠癌，乳腺癌等非常有潜力的靶标之一。
FGFR4抑制剂在临床上将不只局限于治疗FGFR4高表达的肝癌，在FGFR4信号通路异常的其他实体瘤中也可以应用，同时还存在和其他疗法联合使用的可能。因此，开发FGFR4抑制剂具有较为广泛的市场空间和应用前景。
发明内容
本发明提供了式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体，
Figure PCTCN2017111634-appb-000001
其中，
X、Y、Z分别独立地选自C(R)或N；
R1、R2中一个选自F，另一个选自H或CH3；
A环选自：苯基、5-6元环烷基、5-6元杂环烷基；
R3、R4、R5分别独立地选自H、F、Cl，或者选自任选被1、2或3个R取代的：C1-3烷基、C1-3烷氧基、C1-3烷基-C(＝O)-、5-6元杂环烷基；
R选自H，或者选自任选被1、2或3个R’取代的：C1-3烷基、C1-3烷基-C(＝O)-、5-6元杂环烷基；
R’选自：CH3、CH2CH3；
所述5-6元杂环烷基之“杂”分别独立选自：-NH-、-O-、N；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R1选自F，R2选自H或CH3，其他变量如本发明所定义。
本发明的一些方案中，上述R1选自H或CH3，R2选自F，其他变量如本发明所定义。
本发明的一些方案中，上述R选自H，或者选自任选被1、2或3个R’取代的：CH3、CH2CH3、
Figure PCTCN2017111634-appb-000002
Figure PCTCN2017111634-appb-000003
其他变量如本发明所定义。
本发明的一些方案中，上述R选自：H、CH3、CH2CH3、
Figure PCTCN2017111634-appb-000004
其他变量如本发明所定义。
本发明的一些方案中，上述A环选自：苯基、环己烷基、环戊烷基、四氢吡喃基、四氢呋喃基、吡咯烷基，其他变量如本发明所定义。
本发明的一些方案中，上述A环选自：
Figure PCTCN2017111634-appb-000005
Figure PCTCN2017111634-appb-000006
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017111634-appb-000007
选自：
Figure PCTCN2017111634-appb-000008
Figure PCTCN2017111634-appb-000009
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017111634-appb-000010
选自：
Figure PCTCN2017111634-appb-000011
Figure PCTCN2017111634-appb-000012
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017111634-appb-000013
选自：
Figure PCTCN2017111634-appb-000014
Figure PCTCN2017111634-appb-000015
Figure PCTCN2017111634-appb-000016
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017111634-appb-000017
选自：
Figure PCTCN2017111634-appb-000018
其他变量如本发明所定义。
本发明的一些方案中，上述R3、R4、R5分别独立地选自H、F、Cl，或者选自任选被1、2或3个R取代的：甲基、乙基、C1-3烷氧基、C1-3烷基-C(＝O)-、哌嗪基，其他变量如本发明所定义。
本发明的一些方案中，上述R3、R4、R5分别独立地选自H、F、Cl，或者选自任选被1、2或3个R取代的：CH3、
Figure PCTCN2017111634-appb-000019
其他变量如本发明所定义。
本发明的一些方案中，上述R3、R4、R5分别独立地选自：H、F、Cl、CH3、
Figure PCTCN2017111634-appb-000020
Figure PCTCN2017111634-appb-000021
其他变量如本发明所定义。
本发明的一些方案中，上述R3选自：H、F、Cl、CH3，其他变量如本发明所定义。
本发明的一些方案中，上述R4选自：H、F、Cl、
Figure PCTCN2017111634-appb-000022
其他变量如本发明所定义。
本发明的一些方案中，上述R5选自：H、F、Cl、
Figure PCTCN2017111634-appb-000023
其他变量如本发明所定义。
本发明还有一些方案是由上述变量任意组合而来。
本发明的一些方案中，上述化合物、其药学上可接受的盐及其互变异构体，其选自：
Figure PCTCN2017111634-appb-000024
Figure PCTCN2017111634-appb-000025
其中，R1、R2、R3、R4、R5、Z、X、Y的定义如本发明所定义。
本发明的一些方案中，上述式(Ⅰ)中所示化合物的结构单元
Figure PCTCN2017111634-appb-000026
选自：
Figure PCTCN2017111634-appb-000027
Figure PCTCN2017111634-appb-000028
其他变量如本发明所定义。
本发明还有提供了下式化合物、其药学上可接受的盐及其互变异构体，选自：
Figure PCTCN2017111634-appb-000029
Figure PCTCN2017111634-appb-000030
Figure PCTCN2017111634-appb-000031
本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述的化合物或其药学上可接受的盐在制备治疗FGFR4相关病症的药物上的应用。
本发明还提供了上述的组合物在制备治疗FGFR4相关病症的药物上的应用。
本发明的一些方案中，上述应用的特征在于，所述药物是治疗肝癌或胃癌的药物。
技术效果
本发明化合物丙烯酰胺和氟烯键母核结构能得到一系列FGFR4高选择的化合物，对FGFR4激酶有优异的抑制活性，而对亚型FGFR1激酶没有活性，选择性至少十或百倍以上。另外发现，双甲氧基二氯苯环的结构中，双氯能够大大提高FGFR4的抑制活性；如实施例1与对照例1相比活性提高70倍；烯键引入氟原子，氟原子靠近二氯苯胺，能够提高FGFR4的靶点活性，如实施例15与对照例2相比，活性提高了近9倍，实施例19与对照例3相比，活性提高近9倍；本发明化合物的氟烯结构，与苄醚结构相比，能够大大提高药物代谢的稳定性，同时也大大提高药物的口服吸收生物利用度；并且本发明化合物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)的肿瘤性疾病，如肝癌，胃癌等有优良的效果。
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。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of 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。
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。
除非另有说明，用楔形键和虚线键
Figure PCTCN2017111634-appb-000032
表示一个立体中心的绝对构型，用
Figure PCTCN2017111634-appb-000033
表示一个立体中心的相对构型。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)。
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。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
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，可以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。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。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 PCTCN2017111634-appb-000034
或
Figure PCTCN2017111634-appb-000035
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。
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、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)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(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C12表示1至12个碳，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。)。“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“烃基”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。不饱和烃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。杂原子或杂原子团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，但术语“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。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。
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。环烃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“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
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。除非另有规定，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，除非另有规定，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。除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，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。
除非另有规定，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。
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。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；ATP代表腺嘌呤核苷三磷酸；HEPES代表4-羟乙基哌嗪乙磺酸；MgCl2代表氯化镁；MnCl2代表二氯化锰；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；DTT代表二硫苏糖醇；DIEA代表N,N-二异丙 基乙胺；NaBH4代表硼氢化钠；NBS代表N-溴代琥珀酰亚胺；XPhos代表2-二-叔丁膦基-2',4',6'-三异丙基联苯。
化合物经手工或者
Figure PCTCN2017111634-appb-000036
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
流程A
Figure PCTCN2017111634-appb-000037
对照例1
Figure PCTCN2017111634-appb-000038
对照例1A
Figure PCTCN2017111634-appb-000039
在室温条件下(28℃)，将水合肼(18.1克，361毫摩尔)滴入3,5-二甲氧基苯甲醛(20克，120毫摩尔)。在室温条件下，搅拌2小时后，经TLC检测3,5-二甲氧基苯甲醛没有反应完全，延长反应时间。继续反应16小时后，向反应瓶中加入乙二胺(21.70克，361毫摩尔)和氯化亚铜(1.19克，12.04毫摩尔)。搅拌30分后，反应液置于冰浴冷却至0℃后，将三溴氟甲烷(81.46克，301毫摩尔)的乙醇(30毫升)溶液经恒压滴液漏斗滴加到反应液中(在滴加过程中有少量气体放出)。滴加完毕后，该反应在0℃下搅拌1小时后，缓慢升至室温(28℃)然后再继续反应1小时。待中间体E-3,5 -二甲氧基苯腙完全反应后，过滤，固体用乙酸乙酯洗涤，滤液经减压浓缩蒸除大部分溶剂。用乙酸乙酯(200毫升)稀释，并用柠檬酸(1M，50毫升)水溶液洗涤，分液，水相然后用乙酸乙酯萃取(3×100毫升)。合并的有机相用饱和的食盐水(150毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱分离(流动相：0～15％乙酸乙酯/石油醚)后得到浅黄色液体对照例1A(18.86克，收率：60％)。
1H NMR(400MHz,CHLOROFORM-d)δ6.56(d,J＝2.4Hz,2H),6.43-6.39(m,1H),5.92(d,J＝32.4Hz,1H),3.80(s,6H).
对照例1B
Figure PCTCN2017111634-appb-000040
该对照例1B采用实施例1C的相同的方法合成，分析数据如下；
LCMS(ESI)m/z:294.1[M+1]+
对照例1C
Figure PCTCN2017111634-appb-000041
向对照例1B(190毫克，647微摩尔)和2-甲基-3-硝基苯胺(148毫克，971微摩尔)的N,N-甲基乙酰胺溶液中加入三(二亚苄基丙酮)二钯(59毫克，64.69微摩尔)，2-二环己基磷-2,4,6-三异丙基联苯(62毫克，129微摩尔)，碳酸铯(421毫克，1.29毫摩尔)，该混合物在氮气保护的条件下于110℃搅拌2小时。混合物加乙酸乙酯(20毫升)，用水(250毫升)洗涤，乙酸乙酯萃取3遍，有机相用无水硫酸钠干燥，过滤，旋干溶液，拌样过柱，得到暗红色对照例1C(197毫克)。
LCMS(ESI)m/z:410.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ(ppm)＝8.46(d,J＝2.0Hz,1H),8.08(br.s.,1H),7.93(d,J＝8.0Hz,1H),7.74(dd,J＝2.4,8.4Hz,1H),7.54(d,J＝7.6Hz,1H),7.26(s,1H),6.78(d,J＝2.0Hz,2H),6.57(d,J＝9.2Hz,1H),6.41(t,J＝2.0Hz,1H),6.01-6.17(m,1H),3.82(s,6H),2.26(s,3H).
对照例1D
Figure PCTCN2017111634-appb-000042
向化对照例1C(197毫克，481微摩尔)的90％乙醇溶液(6.0毫升)中加入铁粉(134毫克，2.41毫摩尔)，氯化铵(129毫克，2.41毫摩尔)。该混合物在100℃的条件下搅拌2小时。该混合物用乙酸乙酯(10毫升)稀释，水洗，乙酸乙酯萃取3遍，无水硫酸钠干燥，旋干溶剂，得到对照例1D(189毫克，粗品)。
LCMS(ESI)m/z:380.1[M+1]+
对照例1
Figure PCTCN2017111634-appb-000043
在0℃的条件下，向粗品对照例1D(152毫克，401微摩尔)的二氯甲烷(7.0毫升)溶液中依次加入N,N-二异丙基乙胺(104毫克，801微摩尔)和丙烯酰氯(29毫克，320微摩尔)的二氯甲烷(1.0毫升)溶液并搅拌半个小时。该混合物用水(5.0毫升)淬灭，水洗涤，二氯甲烷萃取3遍，后处理得到最终化合物对照例1(20毫克)。
LCMS(ESI)m/z:434.3[M+1]
1H NMR(400MHz,CHLOROFORM-d)δ11.27(br.s.,1H),8.25(br.s.,1H),8.15(s,1H),8.02(d,J＝8.0Hz,1H),7.91(d,J＝9.2Hz,1H),7.34(dd,J＝8.0,8.0Hz,1H),7.13(d,J＝7.6Hz,1H),6.75(d,J＝1.6Hz,2H),6.50(d,J＝9.6Hz,1H),6.45(s,1H),6.35-6.42(m,1H),6.22-6.31(m,1H),6.12(d,J＝38.4Hz,1H),5.74(d,J＝10.4Hz,1H),3.83(s,6H)
流程B
Figure PCTCN2017111634-appb-000044
Figure PCTCN2017111634-appb-000045
对照例2
Figure PCTCN2017111634-appb-000046
对照例2A
Figure PCTCN2017111634-appb-000047
将水合肼(27.11克，541.62毫摩尔)加入到3,5-二甲氧基苯甲醛(30.00克，180.54毫摩尔)的乙醇(300.00毫升)溶液中，80-90℃搅拌2小时。薄层层析板显示反应完成后，低压浓缩除去溶剂得无色油状对照例2A(33.10克)。
1H NMR(400MHz,CHLOROFORM-d)δ3.80(s,6H)5.54(br.s.,2H)6.42(t,J＝2.26Hz,1H)6.71(d,J＝2.01Hz,2H)7.66(s,1H).
对照例2B
Figure PCTCN2017111634-appb-000048
将氨水(54.67克，389.97毫摩尔)和氯化亚铜(1.79克，18.05毫摩尔)加入到对照例2A(32.53克，180.54毫摩尔)的二甲基亚砜(300.00毫升)溶液中。室温搅拌下，将氯仿(136.88克，541.62毫摩尔)缓慢滴加(反应放热明显)到反应液中。完成后，反应置于30-40℃油浴中搅拌26小时。反应完成后冷却至室温，向其中加入1200毫升水，500毫升乙酸乙酯，混合均匀后分层。水相用1200毫升(600毫升*2)乙酸乙酯萃取。有机相经无水硫酸钠干燥后过滤，低压浓缩得到粗品。粗品经快速硅胶柱(石油醚：乙酸乙酯＝20:1)纯化得到淡黄色对照例2B(14.13克，58.12毫摩尔,32.19％产率)。
1H NMR(400MHz,CHLOROFORM-d)δ6.99-7.06(m,1H)6.86(d,J＝2.01Hz,2H)6.39-6.50(m,2H)3.81(s,6H).
对照例2C
Figure PCTCN2017111634-appb-000049
在-60到-50℃下，将磺酰氯(19.61克，145.20毫摩尔)缓慢滴加到对照例2B(14.12克，58.08毫摩尔)的四氢呋喃(140.00毫升)溶液中，搅拌5分钟后，薄层层析板监测反应完成。向反应液中加入200毫升水以淬灭反应，再向其中加入100毫升乙酸乙酯，混合均匀后分液。水相用150毫升乙酸乙酯萃取2次。有机相用无水硫酸钠干燥后过滤，低压浓缩得到淡黄色固体对照例2C(19.53克粗品)。
1HNMR(400MHz,CHLOROFORM-d)δ3.87-3.93(m,6H)6.49-6.55(m,1H)6.85-6.93(m,1H)7.10-7.19(m,1H).
对照例2D
Figure PCTCN2017111634-appb-000050
将对照例2C(19.53克，62.60毫摩尔)、双联嚬吶醇醇硼酸酯(16.06克,63.23毫尔)、Pd(dppf)Cl2(4.58克，6.26毫摩尔)和乙酸钾(19.29克,125.20毫摩尔)溶于二氧六环(200毫升)溶液中，氮气置换三次后，反应液在80-90℃搅拌18小时。反应完成后，将反应液冷却至室温后过滤。低压浓缩得到粗品。粗品经快速硅胶柱(石油醚：乙酸乙酯＝10:1)纯化得到白色固体对照例2D(13.15克，36.62毫摩尔,58.51％产率)。
1HNMR(400MHz,CHLOROFORM-d)δ7.31-7.39(m,1H)6.51(s,1H)6.15(d,J＝18.82Hz,1H)3.92(s, 6H)1.32(s,12H).
对照例2E
Figure PCTCN2017111634-appb-000051
往2氯-5溴嘧啶(10克，51.70毫摩尔)，对照例2D(20.42g,56.87mmol),Pd(dppf)Cl2(3.78g,5.17mmol)，K3PO4(21.95g,103.40mmol)的混合物中加入二氧六环(100.00mL)，水(20.00mL)。反应液在100℃搅拌21个小时。点板显示原料反应完毕，加水(100毫升)，用乙酸乙酯(100毫升X3)萃取3次，合并有机相，无水硫酸钠干燥，过滤旋干，残余物通过快速硅胶柱纯化得到黄色固体对照例2E(7.56g,17.50mmol,33.85％收率,80％纯度)。
对照例2F
Figure PCTCN2017111634-appb-000052
10℃条件下，将氯乙酰氯(18.23克，161.42毫摩尔)的乙酸乙酯(30.00mL)溶液滴加到4-氟-2-甲基苯胺(20.00克，159.82毫摩尔)的乙酸乙酯(160.00mL)和碳酸钠(16.94克，159.82毫摩尔)混悬液中，滴加完成后，该温度下搅拌30分钟；反应完成，加水，乙酸乙酯(30毫升X3)萃取，结合有机层依次用水(20毫升X2)和饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，得到对照例2F未进行纯化，直接用于下一步。
1HNMR(400MHz,CHLOROFORM-d)δ8.14(br.s.,1H),7.74(dd,J＝5.5,9.5Hz,1H),7.01-6.89(m,2H),4.32-4.20(m,2H),2.35-2.25(m,3H).
对照例2G
Figure PCTCN2017111634-appb-000053
0℃条件下，将硝酸(13.39克,146.61毫摩尔)慢慢滴加到对照例2A(29.56克,146.61毫摩尔)的硫酸(150毫升)溶液中，滴加完成后，该温度下搅拌30分钟；反应完成，反应液慢慢倒入到不停搅拌的冰水中，马上析出大量浅紫色固体，过滤，滤饼用水多次冲洗，得到浅紫色对照例2G(34克)未进一步纯化，直接用于下一步。
1HNMR(400MHz,CHLOROFORM-d)δ8.99(br.s.,1H),8.67(d,J＝7.0Hz,1H),8.29(br.s.,1H),7.61(dd,J＝2.5,7.0Hz,1H),7.30(dd,J＝2.5,8.0Hz,1H),7.17(d,J＝11.5Hz,1H),4.76(br.s.,1H),4.27(s,2H),4.22(s,1H),2.40(s,3H),2.35(s,2H)
对照例2H
Figure PCTCN2017111634-appb-000054
将氢氧化钠水溶液(4摩尔，229.19毫升)加入到对照例2G(34克,137.86毫摩尔)的四氢呋喃(5毫升)溶液中，反应液加热到95℃搅拌2小时；反应完成，冷却，向反应液中加入乙酸乙酯(50毫升)和水(50毫升)，乙酸乙酯(100毫升X 5)萃取，结合有机层依次用水(20毫升X 2)和饱和食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱纯化得到黄色固体对照例2H(4.91克,28.86毫摩尔)。
1HNMR(400MHz,DMSO-d6)δ7.65(dd,J＝2.3,9.3Hz,1H),7.39(d,J＝8.0Hz,1H),7.25-7.05(m,1H),2.23(s,3H).
对照例2I
Figure PCTCN2017111634-appb-000055
将Pd(dba)2(169.05毫克，294.00微摩尔)，XPhos(280.31毫克，588.00微摩尔)和碳酸钾(1.22克,8.82毫摩尔)加入到对照例2H(500.00毫克，2.94毫摩尔)和对照例2E(1.32克，3.82毫摩尔)的叔丁醇(5.00毫升)溶液中，该混悬液在氮气保护下，加热到110℃，搅拌4小时；反应完成，冷却，过滤，滤液真空浓缩，残余物通过快速硅胶柱纯化得到浅黄色固体产物(2.90克，6.05毫摩尔)。
1HNMR(400MHz,CHLOROFORM-d)δ8.55(s,2H),7.75(s,1H),7.62(dd,J＝2.9,7.9Hz,1H),7.31(dd,J＝2.8,8.3Hz,1H),7.09-6.87m,2H),6.54(s,1H),3.95(s,6H),2.36(s,3H).
LCMS(ESI)m/z:479.0[M+1]+
对照例2J
Figure PCTCN2017111634-appb-000056
将N-甲基哌嗪(714.75毫克，6.26毫摩尔)加入到对照例2I(300毫克,625.93微摩尔)的二甲基亚砜(3毫升)溶液中，135℃搅拌18小时。反应完成后冷却至室温，向反应液中加入30毫升乙酸乙酯和35毫升水，混合均匀后分液。水相用15毫升乙酸乙酯萃取2次，有机相用无水硫酸钠干燥，过滤低压浓缩得到粗品。粗品经快速硅胶柱分离(二氯甲烷：甲醇＝15:1-10:1)，并经薄层层析制备板(二氯甲烷：甲醇＝10:1)再次纯化得到黄色固体标题对照例2J(20毫克，34.88毫摩尔，5.57％产率)。
LCMS(ESI)m/z:573.3[M+1]+
对照例2K
Figure PCTCN2017111634-appb-000057
15Psi氢气压下，将Raney-Ni(400毫克,4.67毫摩尔)加入到对照例2J(20毫克，34.88微摩尔)的乙醇(2毫升)和四氢呋喃(2毫升)混合溶液中，反应液在5-10℃搅拌10分钟。LCMS显示反应完成后，将反应液过滤，低压浓缩即得黄色固体对照例2K(15.00毫克粗品)。
LCMS(ESI)m/z:543.1[M+1]+
对照例2
Figure PCTCN2017111634-appb-000058
冰浴下，向对照例2K(15毫克粗品)的二氯甲烷(2毫升)溶液中依次滴加N,N-二异丙基乙胺(7.13 毫克，55.20微摩尔)和丙烯酰氯(2.50毫克，27.60微摩尔)。反应液在0℃搅拌15分钟。LCMS监测反应完成后，向反应液中加入10毫升乙酸乙酯和15毫升水。混合均匀后静置分层，将水相用10毫升乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后过滤，低压浓缩得粗品。粗品经液相高效色谱分离(三氟乙酸-乙腈)并冻干即可得到黄色固体对照例2(3.00毫克，5.02微摩尔，18.19％产率)。
LCMS(ESI)m/z:597.1[M+1]+
1H NMR(400MHz,METHANOL-d4)δ1.44(t,J＝7.40Hz,3H)2.27(s,3H)3.12-3.31(m,6H)3.68-3.78(m,2H)3.94-4.00(m,8H)5.78(dd,J＝10.04,1.76Hz,1H)6.30-6.37(m,1H)6.42-6.51(m,1H)6.83(s,1H)6.93-7.02(m,2H)7.25(d,J＝16.81Hz,1H)7.34-7.42(m,1H)8.65-8.88(m,2H).
流程C
Figure PCTCN2017111634-appb-000059
对照例3
Figure PCTCN2017111634-appb-000060
对照例3A
Figure PCTCN2017111634-appb-000061
向对照例2E(300.00毫克,868.03微摩尔,1.00当量)和实施例20E(300.00毫克,1.14毫摩尔,1.31当量)的N-甲基吡咯烷酮(6毫升)溶液中加入碳酸氢钠(150.22毫克,1.79毫摩尔,2.06当量)，于100℃反应18个小时。薄层色谱法和液质连用仪检测反应完全，反应液用20毫升水稀释，乙酸乙酯(15毫升每次)萃取2遍，饱和食盐水(10毫升每次)洗涤两遍。有机相用无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱纯化(石油醚/乙酸乙酯＝1/0到4/1)得到黄色固体对照例3A(178.00毫克,收率：40.10％)
LCMS(ESI)m/z:511.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.49(s,3H),6.95-7.02(m,2H),6.85-6.92(m,2H),6.52(s,2H),5.61(br s,1H),5.21(br s,1H),4.98(br s,1H),4.75(quin,J＝6.52Hz,1H),4.46(br s,1H),4.18(dd,J＝6.52,9.02Hz,1H),4.07-4.15(m,4H),3.94(s,9H),3.65-3.73(m,2H),2.04(s,4H),1.39(s,8H).
对照例3B
Figure PCTCN2017111634-appb-000062
向对照例3A((40.00毫克,78.22微摩尔,1.00当量)中加入盐酸乙酸乙酯溶液(4摩尔,5毫升,255.69当量)，于30℃下反应1小时。液质连用仪检测原料有剩余，反应液继续于100℃下反应16小时。液质连用仪检测反应完全，反应经过滤，真空浓缩，得到黄色固物对照例3B(30.00毫克)直接用于下一步。
LCMS(ESI)m/z:411.0[M+1]+
对照例3
Figure PCTCN2017111634-appb-000063
在0℃，向对照例3B(30.00毫克,72.94微摩尔,1.00当量)和N,N-二异丙基乙胺(19.70毫克,152.45毫摩尔,26.63微升,2.09当量)的二氯甲烷(4毫升)溶液中加入丙烯酰氯(0.25摩尔每升，150.00微升,0.51当量)，并在0℃下反应0.5小时。液质连用仪检测原料有剩余，继续于0℃下反应1小时。液质连用仪检测反应完全，反应液用水(15毫升)淬灭，用二氯甲烷(10毫升每次)萃取3遍，有机相用无水硫酸钠干燥，过滤，真空浓缩，高效液相色谱法纯化(三氟乙酸体系:柱子:Boston Green ODS150*30 5u；流动相:[水(0.1％三氟乙酸)-乙腈]；B％:36％-46％,8min)，冷冻干燥，得到白色固体对照例3(6.00毫克,收率：17.68％.)
LCMS(ESI)m/z:465.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.51(br s,2H),6.99-7.05(m,1H),6.85-6.92(m,1H),6.54(s,1H),6.41(br s,1H),6.22-6.28(m,1H),6.03-6.11(m,1H),5.64(d,J＝9.03Hz,1H),4.78-4.88(m,2H),4.19(td,J＝6.43,9.47Hz,2H),3.91-3.96(m,6H),3.74-3.86(m,3H).
流程X
Figure PCTCN2017111634-appb-000064
对照例4
Figure PCTCN2017111634-appb-000065
对照例4A
Figure PCTCN2017111634-appb-000066
(3R,4R)-3-[(5-溴嘧啶-2-基)胺]四氢-2H-吡喃-4-醇(600.00mg,2.19mmol,)溶于干燥四氢呋喃中(10mL)中，一次性加入三苯基膦(861.19毫克，3.29毫摩尔)，再慢慢加入DIAD(663.93毫克，3.29毫摩尔)。反应液在20℃反应3个小时。反应液浓缩干得到粗品，粗品经快速硅胶柱(石油醚:乙酸乙酯＝3/1-1/1)纯化，得到粗品对照例4A(黄色固体，1.3克)。
LCMS(ESI)m/z:402.8,404.8[M+1]+
对照例4B
Figure PCTCN2017111634-appb-000067
将对照例4A(400毫克，0.99毫摩尔)，溶于含二氧六环(3mL)的单口瓶(50mL)中，再加入双联频钠醇硼酸酯(305毫克，1.2毫摩尔)，Pd2(dba)3(90.84毫克,0.1毫摩尔)，KOAc(196毫克，2.0毫摩尔)，三环己基膦(55.64毫克,0.2毫摩尔)，置换3次氮气，然后将反应液在氮气的保护下，90℃的温度下搅拌12小时。将反应液过滤，滤液减压旋干得对照例4B粗品(600毫克)直接用于下一步。
LCMS(ESI)m/z:369.1[M+1]+
对照例4C
Figure PCTCN2017111634-appb-000068
对照例4B（550毫克，粗品）溶于四氢呋喃（10mL）中，然后加入双氧水（0.22mL，30%），在室温（15-20℃）下，搅拌2小时。加水10毫升水淬灭，用乙酸乙酯（20毫升×2）萃取，合并有机层，再用饱和食盐水（30毫升）洗涤，无水硫酸钠干燥，过滤，真空浓缩得粗品。粗品经制备板（石油醚：乙酸乙酯=1/1）分离纯化，得对照例4C（白色固体，200毫克，39%收率）。LCMS(ESI)m/z:341.1[M+1]+
对照例4D
Figure PCTCN2017111634-appb-000069
将对照例4C（170毫克，0.5毫摩尔）溶于含乙腈（5mL）的单口瓶（50mL）中，再加入(2,6-二氟-3,5-二甲氧基苯基)甲基甲烷磺酸（183毫克，0.65毫摩尔），Cs2CO3（325.5毫克，1.0毫摩尔），置于80-90℃下，反应2小时。反应液过滤，滤液浓缩得粗品，粗品经制备板（洗脱剂PE:EA=1/1）分离纯化，得对照例4D（白色固体，140毫克，43.65%收率）。
LCMS(ESI)m/z:527.1[M+1]+
对照例4E
Figure PCTCN2017111634-appb-000070
将对照例4D（100毫克，0.19毫摩尔）溶于乙醇（4.00mL）中，然后水合肼(0.1毫升)，将反应液在80-90℃的温度下搅拌2小时。反应液直接真空浓缩，得到粗品，往其中加入二氯甲烷（5毫升）并搅拌5分钟，过滤得到的滤液再浓缩得到粗品。粗品经制备板（洗脱剂DCM/MeOH=10/1）分离纯化，得对照例4E（无色油状物，45毫克，59.77%收率）
LCMS(ESI)m/z:397.1[M+1]+
对照例4
Figure PCTCN2017111634-appb-000071
将对照例4E（35毫克，88微摩尔）溶于含二氯甲烷（3mL）的单口瓶（50毫升）中，再加入DIEA（23毫克，176微摩尔），将丙酰氯用二氯甲烷稀释(0.42毫升，0.25摩尔/升)并滴加，10-15℃下搅拌30分钟。加水10毫升水淬灭，用二氯甲烷（20毫升）萃取，合并有机层，再用饱和食盐水（10毫升）洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备板分离（DCM:MeOH=10:1）纯化得到对照例8（白色固体，18毫克，41.53%收率）。
LCMS(ESI)m/z:451.2[M+1]+
1H NMR(400MHz,METHANOL-d4)δ8.03(s,2H),6.81(t,J=8.3Hz,1H),6.13-5.88(m,2H),5.49(dd,J=2.6,9.4Hz,1H),5.00(t,J=1.5Hz,2H),4.31(br s,1H),4.14(td,J=4.1,11.4Hz,1H),3.87(td,J=3.6,11.5Hz,1H),3.77(s,6H),3.75-3.71(m,1H),3.58(dd,J=2.0,11.8Hz,1H),3.47(dt,J=2.8,11.4Hz,1H),1.39-1.27(m,2H)
如下对照例7和对照例8参考对照例4中描述的方法制备。
Figure PCTCN2017111634-appb-000072
流程Y
Figure PCTCN2017111634-appb-000073
对照例5
Figure PCTCN2017111634-appb-000074
对照例5A
Figure PCTCN2017111634-appb-000075
在0℃条件下，向2,6-二氯-3,5-二甲氧基苯甲醛(1.00克，4.25毫摩尔)的乙醇(15.00毫升)溶液中分批加入NaBH4(321.56毫克,8.50毫摩尔)。在0℃条件下反应1小时，接着在15℃条件下反应16h。反应结束后于反应液中加入饱和NH4Cl溶液(1毫升)，然后用乙酸乙酯萃取(2×10毫升)，饱和食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品对照例5A(1.00克,收率99.25％)。
1H NMR(400MHz,CHLOROFORM-d)δ6.56(s,1H),5.00(d,J＝7.2Hz,2H),3.93(s,6H),2.16(t,J＝7.2Hz,1H).
对照例5B
Figure PCTCN2017111634-appb-000076
在0℃条件下，向对照例5A(1.00克,4.22毫摩尔)和三乙胺(640.53毫克,6.33毫摩尔)的二氯甲烷(20.00毫升)溶液中逐滴滴加甲烷磺酰氯(580.0毫克，5.06毫摩尔)。反应液于0℃下搅拌反应1小时。反应结束后加入水(10毫升)淬灭反应。然后使用二氯甲烷(2×10毫升)萃取水相。合并有机相，有机相用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到对照例5B(1克,收率：96.9％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝6.64(s,1H),5.56(s,2H),3.94(s,6H),3.09(s,3H).
对照例5C
Figure PCTCN2017111634-appb-000077
将对照例5B(447.2毫克，3.43毫摩尔)，4-氯,5-羟基嘧啶(447.2毫克，3.43毫摩尔)和碳酸铯(2.23克，6.85毫摩尔)，加入乙腈(15.00毫升)中。然后将反应用油浴加热到回流。搅拌1.0h后，经LCMS检测反应完成。加水(10毫升)稀释，调节pH反应液pH为9。有机相用水洗涤至中性，然后使用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到对照例5C(1.02克，收率85.1％)。
1H NMR(400MHz,CHLOROFORM-d)δ8.40(s,2H),6.64(s,1H),5.43(s,2H),3.95(s,6H).
对照例5D
Figure PCTCN2017111634-appb-000078
将对照例5C(300.00毫克，0.86毫摩尔)，2-甲基-6-硝基苯胺(195.85毫克，1.29毫摩尔)，Pd2(dba)3(39.29毫克，42.91微摩尔)，XPhos(81.82毫克，171.62微摩尔)，碳酸铯(559.19毫克，1.72毫摩尔)和DMA(6.00毫升)。依次置于100毫升的装有回流冷凝管的单口烧瓶中，用氮气置换三次后，将该反应混合物用油浴加热到110℃并反应3小时。反应冷却到室温后，过滤反应液，并向反应液中加入水(10毫升)。然后用乙酸乙酯萃取(10毫升×2)，合并的有机相依次用水(10毫升)，饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～25％ 乙酸乙酯/石油醚)纯化得到白色固体对照例5D(220毫克,，收率：55.1％)。
LCMS(ESI):m/z＝465.0,467.0[M+1]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.13(s,2H),7.90(s,1H),7.80(d,J＝8.0Hz,1H),7.44(d,J＝7.6Hz,1H),7.14(t,J＝7.6Hz,1H),6.54(s,1H),5.24(s,2H),3.86(s,6H),2.23(s,3H).
对照例5E
Figure PCTCN2017111634-appb-000079
在20℃条件下，将对照例5D(220.00毫克，472.82微摩尔),还原铁粉(132.03毫克，2.36mmol)和氯化铵(126.46毫克,2.36毫摩尔)加入乙醇(8.00毫升)和水(1.60毫升)的混合溶液中，然后将反应用油浴加热到回流，搅拌2小时后，过滤反应液。使用乙酸乙酯萃取反应液(10毫升×2)。合并的有机相用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到对照例5E(205.82毫克)
LCMS(ESI):m/z＝435.1,437.1[M+1]+.
对照例5
Figure PCTCN2017111634-appb-000080
将对照例5E(195.00毫克,447.97μmol)，DIEA(173.69毫克,1.34mmol,234.72μL)和DCM(6.00毫升)加入50毫升圆底烧瓶中，并将该溶液用冰水浴冷却至0℃。滴加丙烯酰氯(38.52毫克,425.57μmol,34.70μL)该反应液在0℃反应30min后，经LCMS检测反应完成，加冰水(0.5毫升)萃灭反应并用二氯甲烷萃取(2×10毫升)。合并的二氯甲烷溶液用饱和的食盐水(5毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到残留物。将该粗品采用中性prep-HPLC分离，最终得到目标化合物对照例5(5毫克，收率2.3％)
LCMS(ESI)m/z＝489.0,491.0[M+1]+.
1H NMR(400MHz,CHLOROFORM-d)δ＝8.25-8.17(m,3H),8.07(br.s.,1H),7.25-7.20(m,1H),7.07(d,J＝7.6Hz,1H),6.62(s,1H),6.37-6.29(m,2H),6.23-6.11(m,1H),5.70(d,J＝10.4Hz,1H),5.33(s,2H),5.30(s,1H),3.95(s,6H),2.25(s,3H),2.19(s,1H).
流程Z
Figure PCTCN2017111634-appb-000081
对照例6
Figure PCTCN2017111634-appb-000082
对照例6A
Figure PCTCN2017111634-appb-000083
用冰浴将3,5-二甲氧基苯甲醛(1.00g，6.02mmol)的CH3CN(15毫升)溶液冷却至0℃，然后向其中分批加入[2.2.2]辛烷二(四氟硼酸)盐(3.20g，9.03mmol)，该反应液在0℃反应1小时后，体系温度缓慢升至15℃，然后继续搅拌16小时。TLC显示原料消失，而且有主要的新点生成。反应液经减压浓缩，得到油状残留物。该残留物用水(10毫升)稀释，然后用饱和的NaHCO3(5％)调节pH＝7，经乙酸乙酯萃取(3×10毫升)。合并的乙酸乙酯溶液用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到残留物。该粗品再经过快速硅胶柱(流动相：0～30％乙酸乙酯/石油醚)纯化得到浅黄色化合物对照例6A(310毫克，收率：25.5％)。
LCMS(ESI)m/z:202.8[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ10.36(s,1H),6.89(t,J＝8.2Hz,1H),3.92(s,6H).
对照例6B
Figure PCTCN2017111634-appb-000084
在0℃下，向对照例6A(310毫克，1.53mmol)的乙醇(6.0毫升)溶液中加入硼氢化钠(116毫克，3.06mmol)。该反应液在0℃继续搅拌60分钟(直至没有气体放出)。加入饱和的氯化铵水溶液(5毫升)萃灭反应，减压浓缩除掉大部分乙醇后，用水稀释(20毫升)，然后经乙酸乙酯萃取(2×10毫升)。合并的乙酸乙酯溶液用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到白色固体对照例6B(290毫克，收率：92.8％)。
对照例6C
Figure PCTCN2017111634-appb-000085
在0℃下，向对照例6B(290.00毫克，1.42mmol)和三乙胺(287毫克，2.84mmol)的二氯甲烷(6.0毫升)溶液中缓慢滴加甲烷磺酰氯(195毫克，1.70mmol)，该反应液(N2保护)继续在0℃反应1.5小时。加水(5毫升)萃灭反应，分液，水相再经二氯甲烷(2×5毫升)萃取。合并的有机相经饱和的食盐水(5毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到对照例6C(440毫克，粗品)。该粗品不经纯化直接用于下一步反应。
对照例6D
Figure PCTCN2017111634-appb-000086
将粗品对照例6C(440毫克，1.56mmol)和2-氯-5-羟基吡啶(203.48毫克，1.56mmol)的CH3CN(8.00毫升)溶液中加入Cs2CO3(762.42毫克，2.34mmol)固体，然后将反应液加热至回流搅拌2小时。经LCMS原料转化完全，有产物生成。待反应液冷却至室温后，加(5毫升)萃灭反应，分液，水相再经乙酸乙酯(2×10毫升)萃取。合并的有机相经饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经快速硅胶柱(流动相：0～20％乙酸乙酯/石油醚)得到白色固体化合物对照例6D(188.00毫克，收率：33.87％)。
LCMS(ESI)m/z:316.9,318.9[M+1]+
对照例6E
Figure PCTCN2017111634-appb-000087
将对照例6D(188毫克，594μmol,)，2-甲基-6-硝基苯胺(135毫克，890μmol)，Pd(dba)2(34毫克，59μmol)，XPhos(56毫克,118μmol)，Cs2CO3(386.84毫克，1.19mmol)和DMA(4.0毫升)依次置于20毫升的密闭管中，用氮气置换三次后，将该反应混合物加热到110℃并反应3小时。反应经TLC检测原料完全转化，待反应冷却到室温后，用水稀释(10毫升)，然后用乙酸乙酯萃取(3×10毫升)。合并的有机相用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～40％乙酸乙酯/石油醚)纯化得到黄色固体化合物对照例6E(202毫克,，收率：78.70％)。
LCMS(ESI)m/z:433.0[M+1]+
对照例6F
Figure PCTCN2017111634-appb-000088
在室温条件下，将还原铁粉(129毫克,2.31mmol)和NH4Cl(124毫克,2.31mmol)加入到化合物对照例6E(200毫克,463μmol)的EtOH(5.0毫升)和H2O(1.0毫升)的混合溶液中，然后将反应用油浴加热到回流，搅拌1.0小时。过滤，滤液经减压浓缩得到粗品。该固体用乙酸乙酯(20毫升)稀释，然后用饱和的碳酸氢钠水溶液调剂pH＝8，分液，水相用乙酸乙酯(10毫升×2)萃取。合并的乙酸乙酯相经饱和食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到浅黄色固体对照例6F(180.00毫克，收率：96.71％)。
LCMS(ESI)m/z:403.0[M+1]+
对照例6
Figure PCTCN2017111634-appb-000089
在0℃下，将丙烯酰氯(40毫克，448μmol)加入对照例6F(180毫克，447μmol)和N-乙基二 异丙基胺(116毫克，895μmol)的二氯甲烷(5.0毫升)溶液中，该反应在0℃搅拌30分钟。经LCMS显示反应完成。加冰水(2毫升)萃灭反应，然后经乙酸乙酯萃取(2×5毫升)。合并的有机溶剂用饱和的食盐水(5毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到残留物。该残留物经过快速硅胶柱分离(流动相：0～50％乙酸乙酯/石油醚)得到浅黄色化合物对照例6(155毫克，收率：74.4％)。LCMS(ESI)m/z:457.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.22(br.s.,1H),8.16(s,2H),8.04(d,J＝6.0Hz,1H),7.22(t,J＝8.0Hz,1H),7.06(d,J＝7.6Hz,1H),6.67(t,J＝8.0Hz,1H),6.45(br.s.,1H),6.36-6.28(m,1H),6.20-6.11(m,1H),5.68(d,J＝11.2Hz,1H),5.12(s,2H),3.88(s,6H),2.22(s,3H).
流程D
Figure PCTCN2017111634-appb-000090
实施例1
Figure PCTCN2017111634-appb-000091
实施例1A
Figure PCTCN2017111634-appb-000092
在室温条件下(28℃)，将水合肼(18.1克，361毫摩尔)滴入3,5-二甲氧基苯甲醛(20克，120毫摩尔)。在室温条件下，搅拌2小时后，经TLC检测3,5-二甲氧基苯甲醛没有反应完全，延长反应时间。继续反应16小时后，向反应瓶中加入乙二胺(21.70克，361毫摩尔)和氯化亚铜(1.19克，12.04毫摩尔)。搅拌30分后，反应液置于冰浴冷却至0℃后，将三溴氟甲烷(81.46克，301毫摩尔) 的乙醇(30毫升)溶液经恒压滴液漏斗滴加到反应液中(在滴加过程中有少量气体放出)。滴加完毕后，该反应在0℃下搅拌1小时后，缓慢升至室温(28℃)然后再继续反应1小时。待中间体E-3,5-二甲氧基苯腙完全反应后，过滤，固体用乙酸乙酯洗涤，滤液经减压浓缩蒸除大部分溶剂。用乙酸乙酯(200毫升)稀释，并用柠檬酸(1M，50毫升)水溶液洗涤，分液，水相然后用乙酸乙酯萃取(3×100毫升)。合并的有机相用饱和的食盐水(150毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～15％乙酸乙酯/石油醚)纯化得到浅黄色液体实施例1A(18.86克，收率：60％)。
1H NMR(400MHz,CHLOROFORM-d)δ6.56(d,J＝2.4Hz,2H),6.43-6.39(m,1H),5.92(d,J＝32.4Hz,1H),3.80(s,6H).
实施例1B
Figure PCTCN2017111634-appb-000093
将实施例1A(18.86克，72.24毫摩尔)的无水四氢呋喃(360毫升)溶液冷却到-20℃。然后缓慢滴加磺酰氯(24.38克，180.6毫摩尔,18.1毫升)，滴加完毕后，该反应液在-20℃继续反应1小时。加水(20毫升)萃灭反应，用5％碳酸氢钠水溶液中和到pH＝7。然后用乙酸乙酯萃取(3×100毫升)。合并的有机相经饱和的食盐水(150毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到淡黄色固体实施例1B(21.64克，收率：91％)。
1H NMR(400MHz,CHLOROFORM-d)δ6.56(s,1H),6.11-5.99(d,J＝31.6Hz,1H),3.93(s,6H)
实施1C
Figure PCTCN2017111634-appb-000094
将实施例1B(600毫克，1.82毫摩尔)，3,5-二甲氧基苯硼酸(435毫克，1.82毫摩尔)，Pd(dppf)Cl2(133毫克，182微摩尔)和磷酸钾(966毫克，4.55毫摩尔)置于50毫升的密封管中，并分别加入四氢呋喃(9.0毫升)和水(3.0毫升)，用氮气置换三次后，将反应液用油浴加热到80℃后反应2小时。反应冷却到室温后，用水稀释(5毫升)，然后用乙酸乙酯萃取(2×10毫升)。合并的有机相用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～16％乙酸乙酯/石油醚)纯化得到白色固体实施例1C(302毫克，收率：42.6％)LCMS(ESI)m/z:363.8,361.8[M+1]+.
实施例1D
Figure PCTCN2017111634-appb-000095
分别将实施例1C(300毫克，827微摩尔)，2-甲基-6-硝基苯胺(189毫克，1.24毫摩尔)，Pd2(dba)376毫克，微摩尔)，Xphos(79毫克，165微摩尔)和N,N-二甲基乙酰胺(6.0毫升)依次置于50毫升的装有回流冷凝管的单口烧瓶中，用氮气置换三次后，将该反应混合物用油浴加热到110℃并反应2小时。反应冷却到室温后，将反应物倒入水中(20毫升)，然后用乙酸乙酯萃取(3×10毫升)。合并的有机相依次用水(3×15毫升)，饱和的食盐水(15毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～25％乙酸乙酯/石油醚)纯化得到实施例1D(243毫克，收率：71％)。
LCMS(ESI)m/z:363.8,361.8[M+1]+.
实施例1E
Figure PCTCN2017111634-appb-000096
在室温条件下，将还原铁粉(142毫克，2.54毫摩尔)加到实施例1D(243毫克，508微摩尔)和氯化铵(136毫克，2.54毫摩尔)的乙醇(95％，6.0毫升)溶液中，然后将反应用油浴加热到回流。搅1.5小时后，反应液趁热过滤，固体用乙醇冲洗，滤液经减压浓缩得到棕色固体。将固体分配到加乙酸乙酯(20毫升)和水(10毫升)中，在加饱和碳酸氢钠调节到pH＝9。水相然后用乙酸乙酯萃取(2×5.0毫升)。合并的有机相用饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～40％乙酸乙酯/石油醚)纯化得到粗品实施例1E(41毫克)。LCMS(ESI)m/z:448.0,450.0[M+1]+.
实施例1
Figure PCTCN2017111634-appb-000097
将实施例1E(41毫克，89微摩尔)，N,N-二异丙基乙基胺(23毫克，178微摩尔)和二氯甲烷(2.0毫升)加入50毫升圆底烧瓶中，并将该溶液用冰水浴冷却至0℃。滴加丙烯酰氯(7.3毫克，80微摩尔)，该反应液在0℃反应30分钟后，经LCMS检测反应完成，加冰水(2.0毫升)萃灭反应，加入 5.0毫升二氯甲烷稀释。并用二氯甲烷萃取（2×5.0毫升）。合并的二氯甲烷溶液用饱和的食盐水（5.0毫升）洗涤，后处理得到粗品。该粗品再经过制备高效液相色谱（三氟乙酸体系）分离得到目标化合物
实施例1（5.0毫克，收率：11%）。
LCMS(ESI)m/z:502.1,504.1[M+1]+.
1H NMR(400MHz,CHLOROFORM-d)δ11.30(br.s.,1H),8.31(br.s.,1H),8.21(d,J=1.6Hz,1H),8.00(dd,J=8.8,8.8Hz,2H),7.34(dd,J=8.0,8.0Hz,1H),7.13(d,J=7.6Hz,1H),6.61-6.57(m,1H),6.53(d,J=9.6Hz,1H),6.42-6.36(m,1H),6.32-6.20(m,2H),5.75(d,J=10.0Hz,1H),3.98-3.93(m,6H),2.24(s,3H)
如下实施例如实施例1中描述的方法制备。
Figure PCTCN2017111634-appb-000098
流程E
Figure PCTCN2017111634-appb-000099
实施例2
Figure PCTCN2017111634-appb-000100
实施例2A
Figure PCTCN2017111634-appb-000101
实施例1A(2.00克，6.06毫摩尔)、双联频那醇硼酸酯(3.08克，12.12毫摩尔)和乙酸钾(1.78克，18.2毫摩尔)的二氧六环(30毫升)的混合物中加入Pd(dppf)Cl2·CH2Cl2(495毫克，606微摩尔)，该反应液用氮气置换3次，然后在氮气保护下于90℃搅拌16小时。经TLC检测反应完成，待反应物冷却至室温之后，然后用该混合物用乙酸乙酯稀释，过滤，滤液经减压浓缩得到粗品。该粗品经快速硅胶柱分离(石油醚:乙酸乙酯＝0％-20％)，得到白色固体化合物实施例2A(2.25克，收率：98.5％)。
1H NMR(400MHz,CHLOROFORM-d)δ6.57-6.41(m,2H),3.92(s,6H),1.36(s,12H).
实施例2B
Figure PCTCN2017111634-appb-000102
2-氯嘧啶(3.00克，26.19毫摩尔)，2-甲基-6-硝基苯胺(3.98克，26.2毫摩尔)，Pd2(dba)3(1.20 克，1.31毫摩尔)，Xphos(1.25克，2.62毫摩尔)，碳酸铯(17.07克，52.4毫摩尔)的N,N-二甲基乙酰胺(100毫升)混合液经氮气置换3次后，氮气保护下在100℃下搅拌3小时。加水100毫升水淬灭，用乙酸乙酯(100毫升×3)萃取，合并有机层再用饱和食盐水(150毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例：5/1)纯化得到黄色固体标题化合物实施例2B(4.50克，收率：74.6％)。
LCMS(ESI)m/z:231.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.37(d,J＝4.8Hz,1H),7.92(br.s.,1H),7.86(d,J＝8.4Hz,1H),7.53(d,J＝7.2Hz,1H),7.26-7.30(m,1H),6.74(m,1H),2.33(s,3H).
实施例2C
Figure PCTCN2017111634-appb-000103
向实施例2B(500毫克，2.17毫摩尔)的氯仿(5毫升)溶液中，加NBS(425毫克，2.39毫摩尔)，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯比例：5/1)纯化得到棕色固体标题化合物实施例2C(640毫克，收率：95.4％)。
LCMS(ESI)m/z:310.9,312.9[M+1]+
实施例2D
Figure PCTCN2017111634-appb-000104
实施例2C(640毫克，2.07毫摩尔)的乙醇(10毫升)溶液中加入铁粉(578毫克，10.4毫摩尔)，氯化铵(554毫克，10.4毫摩尔)，在90℃下搅拌2小时。过滤，真空浓缩，残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例：3/1)纯化得到黄色固体化合物实施例2D(423毫克，收率：73.4％)。
1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.37(br.s.,2H),6.85(dd,J＝7.6,7.6Hz,1H),6.56(d,J＝7.6Hz,1H),6.42(d,J＝7.2Hz,1H),4.71(s,2H),1.96-2.05(m,3H).
实施例2F
Figure PCTCN2017111634-appb-000105
实施例2D(373毫克，1.34毫摩尔)，实施例2A(606毫克，1.34毫摩尔)，Pd2(dba)3(122毫克，133微摩尔)，Xphos(127毫克,267微摩尔)，磷酸钾(567毫克，2.67毫摩尔)的乙腈(3.0毫升)和 水(1.0毫升)的混合液经氮气置换3次后，氮气保护下在100℃下搅拌2小时。加水10毫升水淬灭，用乙酸乙酯(10毫升×3)萃取，合并有机层再用饱和食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例：3/1)纯化得到黄色油状化合物实施例2F(250毫克，收率：41.5％)。
LCMS(ESI)m/z:449.2,451.2[M+1]+
1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.51-8.80(m,2H),6.92(s,1H),6.88(dd,J＝7.6,7.6Hz,1H),6.49-6.64(m,2H),6.45(d,J＝7.2Hz,1H),4.74(br.s.,2H),3.82-3.99(m,6H),2.00-2.07(m,3H)
实施例2
Figure PCTCN2017111634-appb-000106
向实施例2F(250毫克，556微摩尔)的二氯甲烷(5.0毫升)溶液中，0℃加N,N-二异丙基乙基胺(180毫克，1.39毫摩尔)和丙烯酰氯(50毫克，556微摩尔)，在0℃下搅拌30分钟。加水10毫升水淬灭，用二氯甲烷(10毫升×2)萃取，合并有机层，真空浓缩，残余物通过制备HPLC(三氟乙酸体系)纯化得到化合物实施例2(66毫克，收率：23.1％)。
LCMS(ESI)m/z:503.1,505.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.86(s,1H),8.70(br.s.,1H),7.72(d,J＝7.6Hz,1H),7.15-7.25(m,1H),7.09(d,J＝7.6Hz,1H),6.88-6.96(m,1H),6.64(s,1H),6.47-6.59(m,1H),6.22(d,J＝17.2Hz,1H),5.71(d,J＝10.4Hz,1H),3.93(s,6H),2.13(s,3H).
如下实施例如实施例2中描述的方法制备。
Figure PCTCN2017111634-appb-000107
流程F
Figure PCTCN2017111634-appb-000108
实施例7
Figure PCTCN2017111634-appb-000109
实施例7A
Figure PCTCN2017111634-appb-000110
2-氯-5-吡啶甲醛(4.50克，31.8毫摩尔)，2-甲基-6-硝基-苯胺(4.84克，31.8毫摩尔)，Pd2(dba)3(2.91克，3.18毫摩尔)，Xphos(3.03克，6.36毫摩尔)和碳酸铯(20.7克，63.6毫摩尔)的N,N-二甲基甲酰胺(90毫升)混合液经氮气置换3次后，氮气保护下在110℃下搅拌2小时。待反应冷却至室温后，加水(200毫升)水稀释，然后用乙酸乙酯(50毫升×3)萃取。合并有机层依次用水(50毫升×3)，饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩。残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例：3/1)纯化得到黄色油状化合物实施例7A(4.00克，收率：48.9％)。
LCMS(ESI)m/z:257.9[M+1]+
实施例7B
Figure PCTCN2017111634-appb-000111
在20℃下，向实施例7A(4.00克，15.6毫摩尔)的乙醇(30毫升)溶液中加入水合肼(2.34克，46.6毫摩尔)，该反应在20℃搅拌2小时。经TLC检测原料转化完全。然后向反应溶液中加入乙二胺(2.80克，46.65毫摩尔)和氯化亚铜(154毫克，1.55毫摩尔)，在20℃搅拌30分钟。将反应液用冰浴冷却至0℃，然后滴加三溴氟甲烷(10.52克，38.9毫摩尔)，在20℃搅拌16小时。加水(100毫升)水稀释，然后用乙酸乙酯(50毫升×3)萃取。合并有机层用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩。残余物通过快速硅胶柱(石油醚/乙酸乙酯比例：10/1)纯化得到黄色固体化合物实施例7B(1.56克，收率：28.5％)。
LCMS(ESI)m/z:352.0,354.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.11(d,J＝2.4Hz,1H),7.98-8.08(m,1H),7.90(d,J＝8.0Hz,2H),7.66(dd,J＝2.4,8.8Hz,1H),7.51(d,J＝7.2Hz,2H),7.22(dd,J＝8.0,8.0Hz,2H),6.49-6.58(m,2H),5.86(d,J＝33.2Hz,1H),2.23(s,3H).
实施例7C
Figure PCTCN2017111634-appb-000112
实施例实施例7B(1.56克，4.43毫摩尔)，3,5-二甲氧基苯硼酸(802毫克，4.43毫摩尔)，Pd2(dba)3(406毫克，443微摩尔)，Sphos(3641毫克，886微摩尔)和磷酸钾(2.35克，11.1毫摩尔)的乙腈(3.0毫升)/水(1.0毫升)混合液经氮气置换3次后，氮气保护下在90℃下搅拌3小时。加水(30毫升)稀释，用乙酸乙酯(30毫升×3)萃取。合并有机层用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩。残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例：3/1)纯化得到棕色油状化合物实施例7C(1.4克，收率：67.2％)。
LCMS(ESI)m/z:410.1[M+1]+
实施例7D
Figure PCTCN2017111634-appb-000113
在-78℃下，向实施例7C(700毫克，1.71毫摩尔)的四氢呋喃(7.0毫升)溶液中，滴加磺酰氯(577毫克，4.28毫摩尔)，在-78℃下搅拌1小时。将-20℃加水20毫升水淬灭，用乙酸乙酯(30毫升×3)萃取，合并有机层，再用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物未进一步纯化得到黄色油状粗品实施例7D(750毫克，粗品)。
LCMS(ESI)m/z:478.2,480.2[M+1]+
实施例7E
Figure PCTCN2017111634-appb-000114
向实施例7D(750毫克，1.57毫摩尔)的乙酸乙酯(10毫升)溶液中加入二水合二氯化锡(1.77克，7.85微摩尔)，在80℃下搅拌1小时。反应液经饱和碳酸氢钠调节pH至8，用乙酸乙酯(50毫升×3)萃取，合并有机层再用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物未进一步纯化得到黄色固体粗品实施例7E(500毫克，粗品)。
LCMS(ESI)m/z:448.1,450.1[M+1]+
实施例7
Figure PCTCN2017111634-appb-000115
在0℃下,向实施例7E(500毫克，1.12毫摩尔)的二氯甲烷(5.0毫升)溶液中依次加N,N-二异丙基乙基胺(362毫克，2.80毫摩尔)和丙烯酰氯(101毫克，1.12毫摩尔)，该反应在0℃搅拌2小时。加水20毫升水淬灭，用二氯甲烷(20毫升×3)萃取，合并有机层，再用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备HPLC(TFA条件)纯化，再经过制备薄层分离纯化(石油醚/乙酸乙酯＝1/1)得到标题化合物实施例7(24毫克，收率：3.97％)
LCMS(ESI)m/z:502.0,504.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.16-8.33(m,3H),7.83(dd,J＝8.8,2.0Hz,1H),7.23-7.29(m,1H),7.06(d,J＝7.6Hz,1H),6.60-6.65(m,1H),6.28-6.37(m,2H),6.10-6.24(m,2H),5.64-5.81(m,2H),3.94(s,6H),2.21(s,3H)
如下实施例如实施例7中描述的方法制备。
Figure PCTCN2017111634-appb-000116
Figure PCTCN2017111634-appb-000117
流程G
Figure PCTCN2017111634-appb-000118
实施例10
Figure PCTCN2017111634-appb-000119
实施例10A
Figure PCTCN2017111634-appb-000120
在氮气保护下，将3,5-二甲氧基-苯甲醛(5.00克，30.1毫摩尔)的四氢呋喃(75毫升)溶液至于250毫升的三口烧瓶中，将该溶液用干冰盐浴冷却至-10℃。缓慢滴加MeMgBr(3.0M，15.0毫升)的乙醚溶液，在滴加过程中保持反应液的温度不超过0℃。滴加完毕后将该反应在0℃下搅拌1小时经LCMS检测原料反应完毕，搅拌1小时后，向反应液中加入饱和的氯化铵溶液，然后加入用乙酸乙酯萃取(2×30毫升)。合并的有机相饱和的食盐水(30毫升)萃取，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物实施例10A，为浅粉色固体(5.48克，收率：63.6％)。该化合物不经纯化直接用于下一步。
LCMS(ESI)m/z:164.9[M-17]+
1H NMR(400MHz,CHLOROFORM-d)δ6.54(d,J＝2.0Hz,2H),6.40-6.35(m,1H),4.84(q,J＝6.4Hz,1H),3.83-3.76(m,6H),1.48(d,J＝6.4Hz,3H)
实施例10B
Figure PCTCN2017111634-appb-000121
在室温条件下(20℃)，将活性二氧化锰(41.8克，481毫摩尔)加入到实施例9A(5.48克，30.1毫摩尔)的四氢呋喃(100毫升)溶液中。将该反应置于油浴中加热回流2小时，经TLC和LCMS检测，实施例9A反应完毕产物生成。过滤，固体经四氢呋喃(2×30毫升)洗涤，合并滤液，经减压浓缩得到粗品。该粗品经快速硅胶柱(石油醚:乙酸乙酯＝30:1–15:1)纯化得到淡黄色油状物实施例10B(4.55克，收率：84.0％)。
LCMS(ESI)m/z:181.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ7.09(d,J＝2.4Hz,2H),6.65(t,J＝2.4Hz,1H),3.84(s,6H),2.58 (s,3H).
实施例10C
Figure PCTCN2017111634-appb-000122
在室温条件下(25℃)，将一水合肼(4.17克，83.2毫摩尔，4.05毫升)滴入实施例10B(5.00克，27.8毫摩尔)乙醇(50毫升)溶液中。在28℃下，搅拌16小时后，经TLC检测3,5-二甲氧基苯乙酮反应完全向反应瓶中加入乙二胺(5.51克，83.2毫摩尔)和氯化亚铜(275毫克，2.78毫摩尔)。30分钟后，用冰浴冷却至0℃后，将三溴氟甲烷(18.8克，69.4毫摩尔)的乙醇(50毫升)溶液经恒压滴液漏斗滴加到反应液中(在滴加过程中有少量气体放出)。滴加完毕后，该反应在0℃下搅拌1小时后，升至25℃后再反应72小时。待中间体完全反应后，过滤，固体用乙酸乙酯洗涤，滤液经减压浓缩蒸除大部分溶剂。用乙酸乙酯(200毫升)稀释，并用柠檬酸(1M，50毫升)水溶液洗涤，分液，水相然后用乙酸乙酯萃取(3×100毫升)。合并的有机相用饱和的食盐水(150毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～30％乙酸乙酯/石油醚)纯化得到淡黄色油状物实施例10C(1.27克，收率：16.6％)。
LCMS(ESI)m/z:275.0,277.0[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ6.51(s,1H),6.46-6.41(m,1H),3.82(s,6H),2.10-2.06(m,3H)
实施例10D
Figure PCTCN2017111634-appb-000123
在氮气保护下，将5-溴-2-氨基-苯胺(10.0克，57.8毫摩尔)的四氢呋喃(200毫升)溶液至于500毫升的三口烧瓶中，将该溶液用干冰浴冷却至0℃。将钠氢(3.47克，86.7毫摩尔，纯度：60％)分批加入到反应液中。搅拌半个小时后，将2-氟-3-甲基硝基苯胺(13.5克，86.7毫摩尔)的四氢呋喃(5.0毫升)溶液缓慢滴加到该反应液中，滴加完毕后，将该反应升至25℃搅拌16小时。LCMS检测大部分原料反应完毕，向反应液中加入水(40毫升)萃灭反应，然后加入用乙酸乙酯萃取(2×50毫升)。合并的有机相饱和的食盐水(100毫升)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～15％乙酸乙酯/石油醚)纯化得到黄色固体实施例10D(10.0克，收率：56.3％)。
LCMS(ESI)m/z:307.8,309.8[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.21(d,J＝2.4Hz,1H),7.98(br.s.,1H),7.92(d,J＝8.0Hz,1H),7.60(dd,J＝8.8,2.4Hz,1H),7.52(d,J＝7.6Hz,1H),7.23(t,J＝8.0Hz,1H),6.48(d,J＝8.4Hz,1H),2.27- 2.20(m,3H).
实施例10E
Figure PCTCN2017111634-appb-000124
将实施例10D(1.00克，3.25毫摩尔)，双联频那醇硼酸酯(990毫克，3.90毫摩尔)，Pd(dppf)Cl2(265毫克，325微摩尔)和醋酸钾(638毫克，6.50毫摩尔)置于50毫升的圆底烧瓶中，并分别加入二氧六环(10.0毫升)，用氮气置换三次后，将反应液用油浴加热到90℃并反应16小时(氮气保护)。经TLC(石油醚:乙酸乙酯＝5:1)，检测反应物消失。反应冷却到室温后乙酸乙酯稀释(30毫升)。过滤，滤液经减压浓缩后得到粗品。该粗品经过快速硅胶柱(流动相：0～30％乙酸乙酯/石油醚)纯化得到黄色固体化合物实施例10E(1.52克，收率：92.2％，纯度：70％)。
实施例10F
Figure PCTCN2017111634-appb-000125
向化合物实施例10C(580毫克，2.11毫摩尔)和实施例10E(899毫克，2.53毫摩尔)的二氧六环溶液(6.0毫升)和水(1.8毫升)的混合溶液中加入Pd(dppf)Cl2(71毫克，106微摩尔)和碳酸钾(583毫克，4.22微摩尔)，在氮气保护条件下，混合物在100℃下反应16个小时。经TLC和LCMS检测，反应完全。待反应冷却后，加入水(20毫升)和乙酸乙酯(20毫升)稀释，分液后水相用乙酸乙酯(3×10毫升)萃取3遍。合并的有机相用无水硫酸钠干燥，过滤，滤液经减压浓缩得到油状残留物。该残留物经快速硅胶柱(石油醚:乙酸乙酯＝7:3)纯化得到黄色固体化合物10F(262毫克，收率：29.3％)。
1H NMR(400MHz,CHLOROFORM-d)δ8.36(s,1H),8.07(br.s.,1H),7.92(d,J＝8.0Hz,1H),7.68(dd,J＝8.4,2.0Hz,1H),7.54(d,J＝7.6Hz,1H),7.22-7.28(m,1H),6.56-6.66(m,3H),6.42(t,J＝2.0Hz,1H),4.13(q,J＝7.2Hz,1H),3.82(s,6H),2.28(s,3H).
实施例10G
Figure PCTCN2017111634-appb-000126
将实施例10F(240毫克，567微摩尔)的无水四氢呋喃(6.0毫升)溶液冷却到-20℃。然后缓慢滴加磺酰氯(191毫克，1.42毫摩尔)，滴加完毕后，该反应液在-20℃反应1h。经TLC(石油醚：乙酸乙酯＝5:1)，LCMS检测原料完全转化为产物实施例26D。加水(2.0毫升)萃灭反应，用5％碳酸氢钠水溶液中和到pH＝7。然后用乙酸乙酯萃取(3×10毫升)。合并的有机相经饱和的食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到淡黄色固体实施例10G(280毫克)。该化合物直接用于下一步。
LCMS(ESI)m/z:491.1,493.9[M+1]+
实施例10H
Figure PCTCN2017111634-appb-000127
在室温条件下(20℃)向实施例10G(260毫克，528微摩尔)的乙醇(15.0毫升)溶液中加入雷尼镍(500毫克，5.84毫摩尔)(氮气保护)。该混合物用氢气置换几次后在20℃下搅拌4小时(15psi)。LCMS检测反应物消失。过滤，减压浓缩，得浅黄色固体化合物实施例10H(220毫克，收率：90.1％)，该化合物直接用于下一步。
LCMS(ESI)m/z:462.0,464.0[M+1]+
实施例10
Figure PCTCN2017111634-appb-000128
将实施例10H(235毫克，508微摩尔)，N,N-二异丙基乙基胺(131毫克，1.02微摩尔)和二氯甲烷(5.0毫升)加入50毫升圆底烧瓶中，并将该溶液用冰水浴冷却至0℃。滴加丙烯酰氯(46毫克，508微摩尔)，该反应液在0℃反应30分钟后，经LCMS检测反应完成，加冰水(2毫升)萃灭 反应，加入5毫升二氯甲烷稀释。并用二氯甲烷萃取（2×5毫升）。合并的二氯甲烷溶液用饱和的食盐水（5毫升）洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到残留物。该粗品再经过制备HPLC(三氟乙酸体系)得到目标化合物实施例10（45毫克，收率：17.0%）。LCMS(ESI)m/z:516.1,518.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ11.18(br.s.,1H),8.49(br.s.,1H),8.15(br.s.,1H),7.99-7.87(m,2H),7.31(t,J=8.0Hz,1H),7.13(d,J=7.6Hz,1H),6.56(s,2H),6.45-6.35(m,1H),6.34-6.23(m,1H),5.75(d,J=10.8Hz,1H),3.94(s,6H),2.23(s,3H),2.04(d,J=2.8Hz,3H).
流程H
Figure PCTCN2017111634-appb-000129
实施例26
Figure PCTCN2017111634-appb-000130
实施例26A
Figure PCTCN2017111634-appb-000131
2-甲基-6-硝基苯胺(13.28克，87.31毫摩尔)，2-氯嘧啶(10.00克，87.31毫摩尔)，Pd2(dba)3(4.00克，4.37毫摩尔)，XPhos(4.16克，8.73毫摩尔)和Cs2CO3(56.90克，174.62毫摩尔)加入到DMA(250.00mL)中，置换3次氮气，然后将反应液在氮气的保护下，100℃的温度下搅拌3小时。反应液倒入250毫升冰水，用EtOAc(200毫升×3)萃取，合并有机层再用水(50毫升×3)洗涤，饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯：5/1)纯化得到棕色固体标题化合物实施例26A(11.00克，54.72％收率)。
LCMS(ESI)m/z:230.9[M+1]+
实施例26B
Figure PCTCN2017111634-appb-000132
实施例26A(500.00毫克，2.17毫摩尔)，NBS(424.84毫克，2.39毫摩尔)加入到氯仿(5.00mL)中，然后将反应液在30℃的温度下搅拌16小时。反应液直接真空浓缩，残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例：5/1)纯化得到黄色固体实施例26B(540.00毫克，80.50％收率)。
LCMS(ESI)m/z:310.8[M+3]+
1H NMR(400MHz,CHLOROFORM-d)δ8.37(s,2H),7.89(br s,1H),7.83-7.88(m,1H),7.54(d,J＝7.53Hz,1H),7.28(t,J＝8.03Hz,1H),2.32(s,3H).
实施例26C
Figure PCTCN2017111634-appb-000133
实施例16D(2.00克，6.47毫摩尔)，实施例26B(3.66克，9.71毫摩尔)，磷酸钾(2.75克，12.94毫摩尔)，Pd(dppf)Cl2(473.41毫克，647.00微摩尔)加入到二氧六环(30.00毫升)和水(10.00毫升)的混合溶液中，置换3次氮气，然后将反应液在氮气的保护下，100℃的温度下搅拌16小时。反应液倒入50毫升冰水，用EtOAc(30毫升×3)萃取，合并有机层用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱分离(石油醚/乙酸乙酯比例：3/1)纯化得到黄色固体实施例26C(2.40克，77.39％收率)。
LCMS(ESI)m/z:479.1[M+1]+
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),8.02(s,1H),7.88(d,J＝7.53Hz,1H),7.55(d,J＝7.53Hz,1H),7.27-7.31(m,1H),6.65(s,1H),5.61-5.79(m,1H),3.95(s,6H),2.35-2.37(m,3H).
实施例26D
Figure PCTCN2017111634-appb-000134
实施例26C(1.10克，2.30毫摩尔)，NBS(1.23克，6.90毫摩尔)，加入到醋酸(10.00mL)中，在60℃的温度下搅拌16小时。反应液用碳酸钠水溶液调pH＝7，倒入30毫升冰水，用EtOAc(20毫升×3)萃取，合并有机层再用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯比例：3/1)纯化得到标题化合物实施例26D(370.00毫克，28.82％收率)。
LCMS(ESI)m/z:558.9[M+3]
实施例26E
Figure PCTCN2017111634-appb-000135
实施例26D(200.00毫克，358.31微摩尔)，1-乙酰基-哌嗪(91.85毫克，716.62微摩尔)，Pd2(dba)3(32.81毫克，35.83微摩尔)，XPhos(34.16毫克，71.66微摩尔)和Cs2CO3(233.49毫克，716.62微摩尔)加入到DMA(5.00mL)中，置换3次氮气，然后将反应液在氮气的保护下，120℃的温度下搅拌2小时。反应液倒入10毫升冰水，用EtOAc(10毫升×3)萃取，合并有机层再用水(5毫升×3)洗涤，饱和食盐水(5毫升)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯比例：1/1)纯化得到乳白色固体标题化合物实施例26E(70.00毫克，32.27％收率)。
LCMS(ESI)m/z:605.1[M+1]
实施例26F
Figure PCTCN2017111634-appb-000136
向实施例26E(80.00毫克，132.13微摩尔)的乙醇(1.00毫升)中加入Raney-Ni(11.32毫克，132.13微摩尔)，置换3次氢气，然后在氢气(15psi)的条件下，30℃的温度下搅拌0.5小时。反应液经过滤，真空浓缩，残余物未进一步纯化得到固体粗品实施例26F(68.00毫克，粗品)。
LCMS(ESI)m/z:575.0[M+1]
实施例26
Figure PCTCN2017111634-appb-000137
向实施例26F(68.00毫克，118.17微摩尔)的二氯甲烷(2毫升)溶液中，0℃加DIEA(30.54毫克，236.33微摩尔)和丙烯酰氯(10.70毫克,118.17微摩尔)，在0℃下搅拌20分钟。加水10毫升水淬灭，用二氯甲烷(10毫升×3)萃取，合并有机层，再用饱和食盐水(5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(碱性条件)纯化得到标题化合物实施例26(18毫克，24.20％收率)。
LCMS(ESI)m/z:629.3[M+1]
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),8.04(br s,1H),7.84(br s,1H),6.65(s,1H),6.62(d,J＝2.51Hz,1H),6.47(s,1H),6.38(d,J＝1.25Hz,1H),6.12-6.21(m,1H),5.72-5.75(m,1H),5.64-5.71(m,1H),3.95(s,6H),3.72-3.78(m,2H),3.57-3.63(m,2H),3.23(td,J＝5.11,15.87Hz,4H),2.20(s,3H),2.14(s,3H)
如下实施例如实施例26中描述的方法制备。
Figure PCTCN2017111634-appb-000138
Figure PCTCN2017111634-appb-000139
流程I
Figure PCTCN2017111634-appb-000140
实施例13
Figure PCTCN2017111634-appb-000141
实施例13A
Figure PCTCN2017111634-appb-000142
实施例13A的合成方法如对照例2H
实施例13B
Figure PCTCN2017111634-appb-000143
实施例13A(400毫克，2.35毫摩尔)，2-氯嘧啶(269毫克，2.35毫摩尔)，Pd2(dba)3(107毫克，0.12毫摩尔)，Xphos(112毫克，0.24毫摩尔)，K2CO3(974毫克，7.05毫摩尔)在甲苯溶液中(4mL)，N2置换3次后，加热到110℃搅拌12小时。点板显示原料消耗完毕。反应液中加入20mL水，乙酸乙酯萃取(20毫升X3)3次，合并有机相，旋干得粗品，经柱层析纯化得到实施例13B(470毫克，80.58％收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.40(d,J＝5.0Hz,2H),8.30(br s,1H),7.97(dd,J＝5.6,9.2Hz,1H),7.12-7.00(m,1H),6.80(t,J＝4.9Hz,1H).
实施例13C
Figure PCTCN2017111634-appb-000144
实施例13B(530毫克，2.14毫摩尔)溶解在氯仿溶液中(7mL)，加入NBS(419毫克，2.35毫摩尔)室温下搅拌16小时。点板显示原料消耗完毕。反应液浓缩得粗品，经快速硅胶柱(石油醚：乙酸乙酯＝5:1)纯化得到黄色固体实施例13C(460毫克，65.71％收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.40(s,2H),8.25(br s,1H),7.98(dd,J＝5.5,9.3Hz,1H),7.11-6.98(m,1H).
实施例13D
Figure PCTCN2017111634-appb-000145
实施例13C(1.15克，3.52毫摩尔)的DMSO(10毫升)加入分批乙基哌嗪(4.02克，35.20毫摩尔)，在130℃下搅拌16小时。反应液倒入200毫升水，用乙酸乙酯(200毫升×3)萃取，合并有机层再用饱和食盐水(300毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱(二氯甲烷/甲醇：10/1)纯化得到黄色油状标题化合物实施例13D(1.30克，87.66％收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.38(s,2H),8.36(s,1H),7.96(d,J＝9.04Hz,1H),6.89(d,J＝9.04Hz,1H),3.12(t,J＝4.64Hz,4H),2.63(br s,4H),2.50(q,J＝7.28Hz,2H),2.18(s,3H),1.13(t,J＝7.16Hz,3H).
实施例13E
Figure PCTCN2017111634-appb-000146
实施例13D(350毫克，830.786微摩尔)，实施例16D(313.24毫克，830.78微摩尔)，Pd(dppf)Cl2(60.79毫克，83.08微摩尔)和磷酸钾(352.70毫克，1.66毫摩尔)的二氧六环(9毫升)/水(3毫升)混合液经氮气置换3次后，氮气保护下在100℃下搅拌1小时。加水20毫升水淬灭，用乙酸乙酯(20毫升×3)萃取，合并有机层再用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱(二氯甲烷/甲醇：10/1)纯化得到黄色油状标题化合物实施例13E(400毫克，81.40％收率)。
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),8.50(s,1H),7.97(d,J＝9.04Hz,1H),6.89(d,J＝9.04Hz,1H),6.64(s,1H),5.60-5.77(m,1H),3.94(s,6H),3.09-3.18(m,4H),2.65(br s,4H),2.51(q,J＝7.20Hz,2H),2.21(s,3H),1.10-1.17(m,3H).
实施例13F
Figure PCTCN2017111634-appb-000147
实施例13E(200毫克，338.15微摩尔)的乙醇(10毫升)/四氢呋喃(10毫升)混合液在氮气保护下加入雷尼镍(28.97毫克，338.15微摩尔)，在氢气球条件下(15psi)，于20℃搅拌0.5小时。过滤，真空浓缩，残余物未进一步纯化得到黄色固体标题化合物实施例13F(200毫克，粗品)。
LCMS(ESI)m/z:561.0(M+1)
实施例13
Figure PCTCN2017111634-appb-000148
0℃下向实施例13F(200毫克，356.20微摩尔)的四氢呋喃(5毫升)/水(0.5毫升)溶液中加入氯丙酰氯(47.49毫克,374.01微摩尔)，在25℃下搅拌1小时。再加入氢氧化钠(56.99毫克,1.42毫摩尔)，在65℃下搅拌5小时。加水20毫升水淬灭，用乙酸乙酯(20毫升×3)萃取，合并有机层，再用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过制备HPLC纯化得到标题化合物实施例13(30毫克，11.90％收率)。
LCMS(ESI)m/z:615.1(M+1)
1H NMR(400MHz,CHLOROFORM-d)δ8.63(s,2H),7.99(br s,1H),7.81(br d,J＝8.54Hz,1H),7.08(d,J＝8.78Hz,1H),6.80(s,1H),6.64(s,1H),6.28-6.39(m,1H),6.08-6.22(m,1H),5.61-5.76(m,2H),3.95(s,6H),2.96(t,J＝4.64Hz,4H),2.62(br s,3H),2.50(q,J＝7.28Hz,2H),2.22(s,3H),1.14(t,J＝7.28Hz,3H).
如下1个实施例如实施例13中描述的方法制备。
Figure PCTCN2017111634-appb-000149
Figure PCTCN2017111634-appb-000150
流程J
Figure PCTCN2017111634-appb-000151
实施例16
Figure PCTCN2017111634-appb-000152
实施例16A
Figure PCTCN2017111634-appb-000153
在0℃，氮气保护的条件下，向三苯基膦(126.28克,481.43毫摩尔,4.00当量)的二氯甲烷(400.00毫升)溶液中加入四溴化碳(79.83克,240.72毫摩尔,2.00当量)，并在0℃条件下继续反应5分钟，向反应液中加入3,5-二甲氧基苯甲醛(20.00克,120.36毫摩尔,1.00当量)，并在0℃下搅拌4个小时。薄层色谱法检测原料反应完全，有一个极性较大的新点。合并两批反应液，过滤，真空浓缩，用600毫升乙酸乙酯洗涤，过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯＝20/1)纯化得白色固体实施例16A(39.92克,收率：84.20％)。
1H NMR(400MHz,CHLOROFORM-d)δ7.42(s,1H),6.69(d,J＝2.26Hz,2H),6.46(t,J＝2.26Hz,1H),3.80(s,6H).
实施例16B
Figure PCTCN2017111634-appb-000154
向实施例16A(20.00克,62.11毫摩尔,1.00当量)的甲苯(600毫升)溶液中加入四丁基氟化铵三水合物(195.96克,621.10毫摩尔,10.00当量)，在110℃条件下反应16个小时。薄层色谱法检测原料反应完全。反应液用1200毫升水稀释，900毫升乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯＝20/1)纯化得到黄色液体实施例16B(12.84克,收率：79.18％)。
1H NMR(400MHz,CHLOROFORM-d)δ6.65(d,J＝2.26Hz,1H),6.62(d,J＝2.26Hz,2H),6.07-6.16(m,1H),3.80(s,6H).
实施例16C
Figure PCTCN2017111634-appb-000155
向实施例16B(24.80克,94.99毫摩尔,1.00当量)的四氢呋喃(500.00毫升)溶液中在-5℃下逐滴滴加磺酰氯(32.05克,237.48毫摩尔,23.74毫升,2.50当量)的四氢呋喃(15毫升)溶液，反应液在-5℃下到5℃之间反应3个小时。补加磺酰氯(1毫升)的四氢呋喃(10毫升)溶液，继续在-5℃下到5℃之间反应1个小时。薄层色谱法检测反应完全，反应液用饱和碳酸氢钠(150毫升)水溶液淬灭，乙酸乙酯(70毫升每次)萃取三遍，有机相用无水硫酸钠干燥，过滤，干燥浓缩，残余物通过快速硅胶柱 (石油醚/乙酸乙酯＝9/1)得到黄色固体实施例16C(27.75克,收率：88.53％)
1H NMR(400MHz,CHLOROFORM-d)δ6.57(s,1H),5.78-5.87(m,1H),3.94(s,6H)
实施例16D
Figure PCTCN2017111634-appb-000156
向实施例16C(20.00克,60.61毫摩尔，1.00当量)和双联频哪醇硼酸酯(30.78克,121.22毫摩尔，2.00当量)的二氧六环(300毫升)溶液中加入三(二亚苄基丙酮)二钯(5.55克，6.06毫摩尔，0.10当量)，三环己基膦(6.80克，24.24毫摩尔，0.40当量)，乙酸钾(23.79克，242.44毫摩尔，4.00当量)，在氮气保护下，于90℃下反应16个小时。薄层色谱法检测反应完全，反应液经过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯＝4/1)纯化得到黄色固体实施例16D(16.82克,收率73.60％)
1H NMR(400MHz,CHLOROFORM-d)δ6.59(s,1H),4.82-4.97(m,1H),3.92(s,6H),1.25-1.28(m,12H),1.17-1.19(m,1H).
实施例16E
Figure PCTCN2017111634-appb-000157
向(3R，4R)-3-氨基-四氢-2H-吡喃-4-醇(2.02克,17.25毫摩尔,1.51当量)和2-氯-5-溴嘧啶(2.21克，11.43毫摩尔，1.00当量)的二氧六环(40.00毫升)溶液中加入N,N-二异丙基乙胺(4.45克，34.43毫摩尔，6.01毫升，3.01当量)，于105℃下反应16个小时。薄层色谱法检测反应完全，反应液用30毫升水稀释，乙酸乙酯(50毫升每次)萃取3遍，有机相用无水硫酸钠干燥，过滤，真空浓缩，以石油醚/乙酸乙酯＝1/1的比例，再换为二氯甲烷/甲醇＝10/1的比例过柱纯化，得到黄色油状物实施例16E(2.60克,收率83.06％)
1H NMR(400MHz,CHLOROFORM-d)δ8.28(s,2H),5.47(br d,J＝7.28Hz,1H),4.05-4.18(m,1H),3.95(td,J＝4.48,11.60Hz,1H),3.84(dq,J＝4.14,7.82Hz,1H),3.70-3.79(m,1H),3.42-3.55(m,4H),3.25(dd,J＝8.02,11.28Hz,1H),2.08(ddd,J＝2.26,4.58,6.71Hz,1H),2.02-2.11(m,1H),1.70(dtd,J＝4.26,9.24,13.64Hz,1H).
实施例16F
Figure PCTCN2017111634-appb-000158
向实施例16E(795.00毫克，2.90毫摩尔，1.00当量)和实施例16D(1.44克，3.83毫摩尔，1.32当量)的二氧六环(12.00毫升)和水(4.00毫升)的混合溶液中加入1,1-双(二苯基膦)二茂铁二氯化钯(254.64毫克，348.00微摩尔，0.12当量)，磷酸钾(1.54克，7.25毫摩尔，2.50当量)，在氮气保护下，于100℃反应1.5个小时。薄层色谱法和液质连用仪检测反应完全，反应液经过滤，用30毫升水稀释，乙酸乙酯(15毫升每次)萃取3遍，有机相用无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯＝2/3)纯化得到黄色固体实施例16F(513.00毫克,收率：39.82％)
LCMS(ESI):444.2[M+H]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.56(s,2H),6.64(s,1H),5.60-5.73(m,1H),5.33(br d,J＝7.02Hz,1H),4.14-4.17(m,1H),3.94-3.97(m,6H),3.77(dt,J＝4.38,8.72Hz,1H),3.44-3.54(m,1H),3.27(dd,J＝8.78,11.04Hz,1H),2.06-2.12(m,1H),1.65-1.79(m,2H).
实施例16G
Figure PCTCN2017111634-appb-000159
向实施例16F(513.00毫克，1.15毫摩尔，1.00当量)，邻苯二甲酰亚胺(203.04毫克，1.38毫摩尔l，1.20当量)和三苯基膦(44.28毫克，168.81微摩尔，1.50当量)的四氢呋喃(6.00毫升)溶液中加入偶氮二甲酸二异丙酯(348.81毫克，1.73毫摩尔，335.40微升,1.50当量)，在20℃下反应半个小时。薄层色谱法和液质连用仪检测反应完全，反应液经过滤，真空浓缩，残余物通过快速硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到黄色胶状物实施例16G(659.00毫克,收率100.00％)
LCMS(ESI):573.4[M+H]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.74(s,1H),7.72-7.76(m,2H),7.51-7.58(m,6H),6.62(s,1H),5.34-5.47(m,1H),5.34-5.47(m,1H),4.16-4.25(m,1H),4.07-4.15(m,2H),3.93-3.96(m,6H),3.77(dd,J＝1.76,12.04Hz,1H),3.39-3.67(m,2H),1.77-1.82(m,1H),1.77-1.82(m,1H).
实施例16H
Figure PCTCN2017111634-appb-000160
向实施例16G(659.00毫克,1.15毫摩尔,1.00当量)的乙醇(10.00毫升)溶液中加入一水合肼(230.13毫克,4.60毫摩尔,223.43微升,4.00当量)，于80℃下反应1个小时。薄层色谱法检测反应完全，反应液经过滤，真空浓缩，残余物通过快速硅胶柱(二氯甲烷/甲醇＝9/1)纯化得到黄色胶状物实施例16H(312.00毫克,收率61.20％)
1H NMR(400MHz,CHLOROFORM-d)δ8.47(s,2H),6.57(s,1H),5.52-5.64(m,1H),4.22-4.32(m,1H),4.05(q,J＝7.02Hz,1H),3.93(br s,1H),3.87-3.91(m,6H),3.82(dd,J＝3.64,11.66Hz,1H),3.55(dd,J＝2.12,11.66Hz,1H),3.44(dt,J＝2.88,11.10Hz,1H),3.10(td,J＝4.10,10.34Hz,1H),1.66-1.75(m,1H),1.54-1.63(m,1H).
实施例16
Figure PCTCN2017111634-appb-000161
向实施例16H(246.00毫克，554.93微摩尔，1.00当量)和N,N-二异丙基乙胺(222.33毫克，1.72毫摩尔，300.45微升，3.10当量)的二氯甲烷(20.00毫升)溶液中，于0℃下，加入丙烯酰氯(44.40毫克,490.55微摩尔,40.00微升,0.88当量)，于0℃下反应1个小时。液质连用仪检测反应完全，反应液用20毫升饱和碳酸氢钠水溶液淬灭，乙酸乙酯(10毫升每次)萃取3遍，有机相用无水硫酸钠干燥，过滤，真空浓缩，粗品经高效液相色谱法(三氟乙酸体系)纯化得到实施例16(150.00毫克,收率54.35％)。
LCMS(ESI):497.4[M+H]+.
1H NMR(400MHz,CHLOROFORM-d)δ8.72(br s,1H),8.54(br s,1H),6.80(br d,J＝7.52Hz,1H),6.59(s,1H),6.18(dd,J＝1.00,17.06Hz,1H),5.94-6.03(m,1H),5.58-5.70(m,1H),5.54-5.58(m,1H),4.27-4.40(m,2H),4.06-4.14(m,1H),3.97(br d,J＝10.04Hz,1H),3.89(s,6H),3.46-3.60(m,2H),1.93-2.06(m,1H),1.82(br d,J＝10.54Hz,1H).
流程K
Figure PCTCN2017111634-appb-000162
实施例19
Figure PCTCN2017111634-appb-000163
实施例19A
Figure PCTCN2017111634-appb-000164
2，5-二氢呋喃(80.00克,1.14摩尔,86.02毫升)溶于1000毫升二氯甲烷中，然后分批加入间氯过氧苯甲酸(277.74克,1.37摩尔)，室温反应14h。反应由TLC监测，反应完后，滤去固体，滤液用饱和亚硫酸钠溶液洗，至使淀粉-KI试纸不变蓝，然后用饱和碳酸氢钠溶液洗涤，至溶液PH＝7～8。有机相用无水硫酸钠干燥，过滤并旋干溶剂后，不需进一步纯化，得到48.50克黄色产物实施例19A，产率为49.4％。
1HNMR(400MHz,CHLOROFORM-d)δ3.99(d,J＝10.29Hz,2H),3.77(s,2H),3.63(d,J＝10.54Hz,2H).
实施例19B
Figure PCTCN2017111634-appb-000165
向反应瓶中加入实施例19A(24.00克,278.78毫摩尔)和氨水(218.40克,1.74摩尔,240.00毫升)，在100℃下，反应14小时。反应由TLC监测，反应完后，旋干溶剂，得到23.70克棕色油状粗 品实施例19B，产率为82.4％。
1HNMR(400MHz,CHLOROFORM-d)δ4.00-4.16(m,3H),3.63-3.81(m,1H),3.48-3.59(m,1H),3.34-3.45(m,1H).
实施例19C
Figure PCTCN2017111634-appb-000166
实施例19B(23.70克,229.83毫摩尔)溶于200毫升甲醇中，加入三乙胺(4.65克,45.97毫摩尔,6.37毫升)，然后滴加Boc-酸酐(65.21克,298.78毫摩尔,68.64毫升)，室温下反应3小时。反应由TLC监测，反应完后，旋干溶剂，然后加入100毫升甲基叔丁基醚，搅拌15分钟，过滤后的滤饼即为产物，不需进一步纯化，得到38.78克淡黄色固体实施例19C，产率为83.0％。
1HNMR(400MHz,CHLOROFORM-d)δ4.78(br s,1H),4.24-4.31(m,1H),3.98-4.13(m,2H),3.94(br s,1H),3.66-3.73(m,1H),3.62(dd,J＝2.76,9.29Hz,1H),1.44(s,9H).
实施例19D
Figure PCTCN2017111634-appb-000167
实施例19C(38.78克,190.82毫摩尔)，邻苯二甲酰亚胺(33.69克,228.98毫摩尔)和三苯基膦(60.06克,228.98毫摩尔)溶于500毫升四氢呋喃中，加入偶氮二甲酸二异丙酯(46.30克,228.98毫摩尔,44.52毫升)，室温下反应14小时。反应由TLC监测，反应完后，旋干溶剂，用快速硅胶柱(石油醚/乙酸乙酯＝3/1)纯化得到85.50克白色固体产物实施例19D。
1HNMR(400MHz,CHLOROFORM-d)δ7.85-7.88(m,2H),7.74-7.76(m,2H),4.88(br d,J＝9.54Hz,1H),4.44-4.55(m,1H),4.37(br t,J＝8.16Hz,1H),4.12-4.21(m,2H),3.78-3.90(m,1H),1.10(s,9H).
实施例19E
Figure PCTCN2017111634-appb-000168
实施例19D(85.50克，257.26毫摩尔)溶于850毫升无水乙醇中，加入水合肼(75.76克，2572.6毫摩尔,73.55毫升)，80℃下反应1小时。反应由TLC监测，反应完后，滤去产生的白色固体，旋干溶剂后，再加入200毫升二氯甲烷，过滤掉不溶解的固体，旋干溶剂后，不需进一步纯化，得到49.6克微黄色固体粗产物实施例19E。
1HNMR(400MHz,CHLOROFORM-d)δ5.32(br s,1H),4.06-4.17(m,1H),3.94-4.05(m,2H),3.52-3.62(m,2H),3.47(dd,J＝5.02,9.03Hz,1H),1.36-1.50(m,9H).
实施例19F
Figure PCTCN2017111634-appb-000169
实施例19E(14.00克,69.22毫摩尔)和2-氯-5-溴嘧啶(11.38克,58.84毫摩尔)溶于100毫升NMP，加入碳酸氢钠(17.45克,207.66毫摩尔)，110℃下反应14小时。反应由TLC监测，反应完后，加入300毫升乙酸乙酯，然后用饱和食盐水溶液(200毫升*3)洗，有机相用无水硫酸钠干燥，过滤并旋干溶剂，再用快速硅胶柱(石油醚/乙酸乙酯＝3/1)进行纯化，得到15.66克黄色固体实施例19F，产率为62.97％。
1HNMR(400MHz,CHLOROFORM-d)δ8.30(s,2H),5.71(br s,1H),4.58-4.70(m,1H),4.44(br s,1H),4.03-4.11(m,2H),3.63-3.73(m,2H),2.04(s,4H),1.38(s,9H).
实施例19G
Figure PCTCN2017111634-appb-000170
实施例19F(15.62克,43.47毫摩尔)，实施例16D(14.90克,39.52毫摩尔)溶于150毫升1,4-二氧六环和75毫升水中，加入Pd(dppf)Cl2(2.89克,3.95毫摩尔)和无水磷酸钾(16.78克,79.04毫摩尔)，在氮气保护下，95℃反应14小时。反应由TLC监测，反应完后，加入300mL乙酸乙酯，然后用饱和食盐水溶液(200毫升*3)洗，有机相用无水硫酸钠干燥，过滤并旋干溶剂，残余物用快速硅胶柱(石油醚/乙酸乙酯＝1/1)进行纯化，得到4.6克黄色固体实施例19G，产率为21.99％。
1HNMR(400MHz,CHLOROFORM-d)δ8.57(s,2H),6.64(s,1H),5.79(br d,J＝6.53Hz,1H),5.58-5.72(m,1H),5.09(br s,1H),4.70-4.80(m,1H),4.47(br s,1H),4.12-4.23(m,2H),3.72(br d,J＝6.78Hz,2H),1.39(s,9H).
实施例19H
Figure PCTCN2017111634-appb-000171
实施例19G(4.60克,8.69毫摩尔)溶于30毫升DCM中，滴加三氟乙酸(15.40克,135.04毫摩尔,10.00毫升)，室温反应30min。反应由LC-MS监测，反应完后，旋干溶剂，不需进一步纯化，得到7.20克棕黄色固体粗产物实施例19H。
LCMS(ESI):429(M+1)+
实施例19
Figure PCTCN2017111634-appb-000172
实施例19H(7.20克,13.25毫摩尔)溶于40mL DCM，加入DIEA(6.85克,53.00毫摩尔)，反应液冷却至0℃，加入丙烯酰氯(599.63毫克,6.63毫摩尔μL),升至室温反应20min。反应由LC-MS监测，反应完后，加入30毫升水淬灭反应，然后用二氯甲烷(15毫升*3)萃取，合并有机相，再用40mL饱和食盐水洗，无水硫酸钠干燥后，过滤并旋干。用快速硅胶柱(先石油醚/乙酸乙酯＝1/1，然后二氯甲烷/甲醇＝10/1)纯化，得到的2.7克实施例19(两步收率，64.3％)
实施例20,21
Figure PCTCN2017111634-appb-000173
将实施例19(2.7g，5.59mmol)进行SFC(column:OD(250mm*30mm,5μm)；mobile phase:[0.1％NH3H2O EtOH]；B％:40％-40％,10min)拆分，得到830毫克实施例20(纯度：98.43％)保留时间5.204，610毫克实施例21(纯度：99.22％)保留时间7.294。
实施例20：1H NMR(400MHz,CHLOROFORM-d)δ8.57(s,2H),6.65(s,1H),6.38(br d,J＝6.53Hz,1H),6.25(dd,J＝1.13,16.94Hz,1H),5.98-6.11(m,1H),5.59-5.78(m,3H),4.70-4.85(m,2H),4.20(ddd,J＝6.02,9.47,12.36Hz,2H),3.92-3.98(m,6H),3.70-3.83(m,2H).
实施例21：1H NMR(400MHz,CHLOROFORM-d)δ8.58(s,2H),6.65(s,1H),6.35(br d,J＝6.27Hz, 1H),6.21-6.29(m,1H),5.99-6.10(m,1H),5.59-5.74(m,3H),4.69-4.82(m,2H),4.20(ddd,J=6.02,9.47,13.11Hz,2H),3.95(s,6H),3.77(ddd,J=4.52,9.54,16.56Hz,2H).
如下3个实施例如实施例19中描述的方法制备。
Figure PCTCN2017111634-appb-000174
流程L
Figure PCTCN2017111634-appb-000175
实施例34
Figure PCTCN2017111634-appb-000176
实施例34A
Figure PCTCN2017111634-appb-000177
向N-Boc-2,5-二氢吡咯(25克,147.74毫摩尔)的200毫升二氯甲烷溶液中分批加入间氯过氧苯甲酸(38.24克,221.61毫摩尔),反应液在25℃条件下搅拌16个小时。点板(磷钼酸)显示有个主要新点生产。反应液中用亚硫酸钠饱和溶液(500毫升)萃灭，二氯甲烷(150毫升X2)萃取2次，有机相分层，用碳酸钠水溶液(300毫升X2)洗2次，食盐水(300毫升X2)洗两次，无水硫酸钠干燥，过滤，浓缩得到浅黄色油状产品实施例34A(22.5克，82.22％收率)，直接用于下一步。
1H NMR(400MHz,CHLOROFORM-d)δ＝3.78(d,J＝6.4Hz,1H),3.71(d,J＝6.4Hz,1H),3.65-3.63(m,2H),3.31-3.26(m,2H),1.41(s,9H).
实施例34B
Figure PCTCN2017111634-appb-000178
实施例34A(9.0克,48.59毫摩尔)的90毫升氨水溶液加热到90℃搅拌4个小时。反应液变成红棕色。反应液旋干，往里面加入二氯甲烷200毫升，甲醇20毫升，无水硫酸钠干燥，过滤，滤液浓缩得到红棕色油状产品实施例34B(8克)直接用于下一步。
实施例34C
Figure PCTCN2017111634-appb-000179
向实施例34B(2克,9.89毫摩尔)的20毫升甲苯与10毫升水的混合溶液中加入碳酸钠(5.24克，49.45毫摩尔)，氯甲酸苄酯(2.53克，14.84毫摩尔)慢慢滴入，反应液控制温度在10-20℃搅拌4小时。 点板检测原料消耗完毕。反应液加入水30毫升，乙酸乙酯萃取(30毫升X2)2次，合并有机相，食盐水洗涤(40毫升)，无水硫酸钠干燥，滤液浓缩得到粗品，经过快速硅胶柱(二氯甲烷：甲醇＝10:1)纯化得到黄色油状产品实施例34C(1.45克，43.59％收率)。
1HNMR(400MHz,CHLOROFORM-d)δ＝7.45-7.30(m,5H),5.19-4.87(m,3H),4.27(br s,1H),4.00(br s,1H),3.88-3.75(m,1H),3.72-3.65(m,1H),3.37-3.07(m,2H),1.47(s,9H).
实施例34D
Figure PCTCN2017111634-appb-000180
实施例34C(500毫克，1.49毫摩尔)的10毫升二氯甲烷溶液中加入三乙胺(0.41毫升，2.98毫摩尔),再往反应液中滴加甲烷磺酰氯(256毫克，2.24毫摩尔)，反应液在10-20℃搅拌1小时。点板检测原料消耗完毕。反应液加10毫升水萃灭，二氯甲烷萃取(20毫升X 2)2次，合并有机相，食盐水洗(20毫升)，无水硫酸钠干燥，过滤减压浓缩得黄色固体实施例34D(670毫克，粗品)。
1H NMR(400MHz,METHANOL-d4)δ＝7.31-7.13(m,5H),5.06-4.87(m,3H),4.15(br s,1H),3.63-3.51(m,2H),3.50-3.42(m,1H),3.28-3.25(br d,J＝11.8Hz,1H),3.07(s,3H),1.42(s,9H)
实施例34E
Figure PCTCN2017111634-appb-000181
向含有实施例34D(600毫克，1.45毫摩尔)醋酸钠(237.89毫克，2.90毫摩尔)的5毫升DMF溶液中加入叠氮钠(282.79毫克，4.35毫摩尔)，反应液100℃搅拌3小时。点板检测原料消耗完毕。反应液加入20毫升水，乙酸乙酯(20毫升X2)萃取2次。合并有机相，食盐水洗涤(30毫升)，无水硫酸钠干燥，得到约35毫升实施例34E乙酸乙酯溶液直接用于下一步。
实施例34F
Figure PCTCN2017111634-appb-000182
向实施例34E(00毫克,35毫升的乙酸乙酯溶液)的30毫升甲醇溶液中，N2保护下加入Pd/C(200毫克，干)，反应液氢气置换3次，最后在H2(40psi)下搅拌16个小时。点板检测原料消耗完毕。反 应液变绿色，过滤旋干得450毫克浅绿色油状物实施例34F(粗品)。
1HNMR(400MHz,METHANOL-d4)δ＝3.60-3.49(m,2H),3.42-3.35(m,2H),3.23-3.14(m,2H),1.47(s,9H).
实施例34G
Figure PCTCN2017111634-appb-000183
向实施例34F(166毫克，0.83毫摩尔)的3毫升二氧六环溶液，加入DIEA(106.63毫克，0.083毫摩尔)，2-氯-5-[(Z)-2-(2,6-二氯-3,5-二甲氧基-苯)-2-氟-乙烯]吡啶(100毫克，0.28毫摩尔)，反应液在N2保护下，90-100℃反应8个小时。LCMS检测发现产物生成，原料反应完毕。反应液加入20毫升水，乙酸乙酯萃取(20毫升X2)2次，合并有机相，食盐水洗涤(20毫升)，无水硫酸钠干燥，过滤，滤液旋干得到粗品，经过薄层层析板纯化(石油醚：乙酸乙酯＝1:1)得到无色油状产品实施例34G(45毫克，30.96％收率)。
LCMS(ESI)m/z:528.0(M+1)+
实施例34H
Figure PCTCN2017111634-appb-000184
向实施例34G(30毫克，56.78微摩尔)的无水二氯甲烷(2毫升)溶液中加入DIEA(14.68毫克，113.56微摩尔)，再加入丙烯酰氯(0.23毫升，0.25摩尔/升的二氯甲烷溶液)，0-10℃下搅拌30分钟。LCMS显示产物生产，原料消耗完毕。反应液用水(5毫升)萃灭过滤，二氯甲烷(20毫升)萃取，无水硫酸钠干燥后，浓缩得到粗品黄色油状产物实施例34H(30毫克，粗品)。
LCMS(ESI)m/z:582.1(M+1)+
实施例34I
Figure PCTCN2017111634-appb-000185
向实施例34H(30毫克，51.51微摩尔)中加入HCl/EA(4毫升，4摩尔/升)，N2保护，25-32℃下搅拌1小时。LCMS显示产物生产，原料消耗完毕。反应液直接浓缩得到无色油状产品实施例34I。LCMS(ESI)m/z:482.1(M+1)+
实施例34
Figure PCTCN2017111634-appb-000186
向实施例34I(20毫克，41.47微摩尔)的无水二氯甲烷(2毫升)溶液中加入DIEA(16.08毫克，124.41微摩尔)，再加入乙酰氯(0.13毫升，0.25摩尔/升的二氯甲烷溶液)，0-10℃下搅拌30分钟。LCMS显示产物生产，原料消耗完毕。反应液用水(10毫升)萃灭过滤，二氯甲烷(20毫升)萃取，无水硫酸钠干燥后，浓缩得到粗品黄色油状产物，经过层析板纯化(石油醚：乙酸乙酯＝1:1)得到产品实施例34(2毫克，8.35％收率)。LCMS(ESI)m/z:524.1(M+1)+
实验例1：本发明化合物的体外酶活性测试
实验目的
通过
Figure PCTCN2017111634-appb-000187
检测酶活性,以化合物的IC50值为指标，来评价化合物对FGFR4激酶的抑制作用。该活性测试在Life technology完成。
实验方法
将测试化合物进行3倍浓度梯度稀释，终浓度为10μM到0.5nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
FGFR4酶反应：
1.94至84ng FGFR1蛋白激酶,2μM Tyr4底物,150μM ATP,50mM HEPES(pH 7.5),0.01％BRIJ-35,10mM MgCl2,2mM MnCl2,1mM EGTA,1mM DTT。检测板为Bar-coded Corning,low volume NBS,black 384-well plate，室温反应60分钟，反应体系为10μμL。
FGFR1酶反应：
1nM FGFR1蛋白激酶,2μM Tyr4peptide,25μM ATP,50mM HEPES(pH 7.5),10mM MgCl2,1mM EGTA,0.01％BRIJ-35,2mM MnCl2,1mM DTT。检测板为Black Proxiplate 384-Plus plate(PerkinElmer)，室温反应60分钟，反应体系为10μμL。
反应检测：
激酶反应液中添加5μL Development reagent B(1:64)终止反应并于23℃孵育60分钟，Envision仪器读板。
数据分析
将数据转化为磷酸化率和抑制率，使用Model 205in XLFIT(iDBS)进行曲线拟合，得到化合物IC50数据。若曲线底部不在-20％到20％范围内，将其设为0％；若曲线顶部不在70％到130％范围内，将其设为100％。
表1.Z′-LYTETM检测IC50测试结果
Figure PCTCN2017111634-appb-000188
Figure PCTCN2017111634-appb-000189
注：单位为nM,N/A,表示未测。
结论：本发明化合物丙烯酰胺和氟烯键母核结构能得到一系列FGFR4高选择的化合物，对FGFR4激酶有优异的抑制活性，而对亚型FGFR1激酶没有活性，选择性至少十或百倍以上。另外发现，双甲氧基二氯苯环的结构中，双氯能够大大提高FGFR4的抑制活性；如实施例子1与对照例1相比活性提高70倍；烯键引入氟原子，氟原子靠近二氯苯胺，能够提高FGFR4的靶点活性，如实施例15与对照例2相比，活性提高了近9倍，实施例19与对照例3相比，活性提高近9倍。
实验例2：本发明化合物的药代动力学评价
实验过程：将1mg/ml在某种溶媒中(见表格2)的试验化合物的澄清溶液经尾静脉注射到雌性Balb/c nude小鼠(上海灵畅生物科技有限公司)体内(过夜禁食，7-9周龄)，给药剂量为2mg/kg。将1mg/ml悬浮在对应溶媒中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、6.0、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。使用溶媒和对应给药剂量见表2.
表2.各化合物小鼠药代动力学实验条件
Figure PCTCN2017111634-appb-000190
实验数据结果如表3所示：
表3.各化合物小鼠药代动力学实验结果
Figure PCTCN2017111634-appb-000191
注：
血浆清除率(CL)mL/min/kg，稳态表观分布容积(Vdss)L/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)
生物利用度F％,达峰浓度(Cmax)nM，达峰时间Tmax(h)
ND:未检测到数据。
实验结论：
从实验结果来看，具有氟烯结构的实施例16与苄醚结构的对照例4相比，其血浆清除率(CL)为23.9mL/min/kg，稳定性提高了3倍，同时药物口服吸收从0％增加到40％以上；具有氟烯结构的实施例24与苄醚结构的对照例5和对照例6相比，其血浆清除率(CL)为50mL/min/kg，稳定性分别提高了2到3倍以上，同时药物口服吸收从0％增加到14.8％。实施例21比对照例7和对照例8生物利用度也展示了大幅提高。综上，本发明化合物的氟烯结构，与苄醚结构相比，能够大大提高药物代谢的稳定性，同时也大大提高药物的口服吸收生物利用度。
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))×100％
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+1％吐温水溶液)为阴性对照。实验结果见表4：
表4 小鼠体内抗肿瘤活性试验结果
  Hep3B移植模型 TGI％(末次第21天给药)
实施例7 30mg/kg BID 108％
实施例16 100mg/kg,BID 89％
实施例21 100mg/kg,BID 106％
注：BID:一天两次.
结论：本发明化合物优异的体外FGFR4酶抑制活性,可以作为小分子的络氨酸激酶抑制剂，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)的肿瘤性疾病，如肝癌，胃癌等有优良的效果。

Claims (22)

  1. 式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体，
    Figure PCTCN2017111634-appb-100001
    其中，
    X、Y、Z分别独立地选自C(R)或N；
    R1、R2中一个选自F，另一个选自H或CH3；
    A环选自：苯基、5-6元环烷基、5-6元杂环烷基；
    R3、R4、R5分别独立地选自H、F、Cl，或者选自任选被1、2或3个R取代的：C1-3烷基、C1-3烷氧基、C1-3烷基-C(＝O)-、5-6元杂环烷基；
    R选自H，或者选自任选被1、2或3个R’取代的：C1-3烷基、C1-3烷基-C(＝O)-、5-6元杂环烷基；
    R’选自：CH3、-CH2CH3；
    所述5-6元杂环烷基之“杂”分别独立选自：-NH-、-O-、N；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物、其药学上可接受的盐及其互变异构体，其中，R选自H，或者选自任选被1、2或3个R’取代的：CH3、-CH2CH3、
    Figure PCTCN2017111634-appb-100002
  3. 根据权利要求2所述化合物、其药学上可接受的盐及其互变异构体，其中，R选自：H、CH3、-CH2CH3、
    Figure PCTCN2017111634-appb-100003
  4. 根据权利要求1～3任意一项所述化合物、其药学上可接受的盐及其互变异构体，其中，A环选自：苯基、环己烷基、环戊烷基、四氢吡喃基、四氢呋喃基、吡咯烷基。
  5. 根据权利要求4所述化合物、其药学上可接受的盐及其互变异构体，其中，A环选自：
    Figure PCTCN2017111634-appb-100004
    Figure PCTCN2017111634-appb-100005
  6. 根据权利要求1～3或5任意一项所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2017111634-appb-100006
    选自：
    Figure PCTCN2017111634-appb-100007
    Figure PCTCN2017111634-appb-100008
  7. 根据权利要求6所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2017111634-appb-100009
    选自：
    Figure PCTCN2017111634-appb-100010
  8. 根据权利要求7所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2017111634-appb-100011
    选自：
    Figure PCTCN2017111634-appb-100012
    Figure PCTCN2017111634-appb-100013
  9. 根据权利要求1～3任意一项所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2017111634-appb-100014
    选自：
    Figure PCTCN2017111634-appb-100015
  10. 根据权利要求1～3任意一项所述化合物、其药学上可接受的盐及其互变异构体，其中，R3、R4、R5 分别独立地选自H、F、Cl，或者选自任选被1、2或3个R取代的：甲基、乙基、C1-3烷氧基、C1-3烷基-C(＝O)-、哌嗪基。
  11. 根据权利要求10所述化合物、其药学上可接受的盐及其互变异构体，其中，R3、R4、R5分别独立地选自H、F、Cl，或者选自任选被1、2或3个R取代的：CH3、
    Figure PCTCN2017111634-appb-100016
  12. 根据权利要求11所述化合物、其药学上可接受的盐及其互变异构体，其中，R3、R4、R5分别独立地选自：H、F、Cl、CH3、
    Figure PCTCN2017111634-appb-100017
  13. 根据权利要求12所述化合物、其药学上可接受的盐及其互变异构体，其中，R3选自：H、F、Cl、CH3。
  14. 根据权利要求12所述化合物、其药学上可接受的盐及其互变异构体，其中，R4选自：H、F、Cl、
    Figure PCTCN2017111634-appb-100018
    Figure PCTCN2017111634-appb-100019
  15. 根据权利要求12所述化合物、其药学上可接受的盐及其互变异构体，其中，R5选自：H、F、Cl、
    Figure PCTCN2017111634-appb-100020
    Figure PCTCN2017111634-appb-100021
  16. 根据权利要求1～8任意一项所述化合物、其药学上可接受的盐及其互变异构体，其选自：
    Figure PCTCN2017111634-appb-100022
    其中，R1、R2、R3、R4、R5、Z、X、Y的定义如权利要求1～8所定义。
  17. 下式化合物、其药学上可接受的盐及其互变异构体，其选自：
    Figure PCTCN2017111634-appb-100023
    Figure PCTCN2017111634-appb-100024
    Figure PCTCN2017111634-appb-100025
  18. 一种药物组合物，包括治疗有效量的根据权利要求1～17任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  19. 根据权利要求1～17任意一项所述的化合物或其药学上可接受的盐在制备治疗FGFR4相关病症的药物上的应用。
  20. 根据权利要求18所述的组合物在制备治疗FGFR4相关病症的药物上的应用。
  21. 根据权利19所述的应用，其特征在于，所述药物是治疗肝癌或胃癌的药物。
  22. 根据权利20所述的应用，其特征在于，所述药物是治疗肝癌或胃癌的药物。
PCT/CN2017/111634 2016-11-17 2017-11-17 Fgfr4抑制剂及其制备方法和应用 Ceased WO2018090973A1 (zh)

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