WO2018133866A1 - 作为ask1抑制剂的吡啶衍生物及其制备方法和应用 - Google Patents

作为ask1抑制剂的吡啶衍生物及其制备方法和应用 Download PDF

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Publication number
WO2018133866A1
WO2018133866A1 PCT/CN2018/073640 CN2018073640W WO2018133866A1 WO 2018133866 A1 WO2018133866 A1 WO 2018133866A1 CN 2018073640 W CN2018073640 W CN 2018073640W WO 2018133866 A1 WO2018133866 A1 WO 2018133866A1
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Prior art keywords
compound
mmol
group
added
reaction
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PCT/CN2018/073640
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English (en)
French (fr)
Inventor
吴成德
于涛
李宁
陈曙辉
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福建广生堂药业股份有限公司
南京明德新药研发股份有限公司
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Priority to AU2018209574A priority Critical patent/AU2018209574B2/en
Priority to KR1020197022629A priority patent/KR102089234B1/ko
Priority to SG11201906579UA priority patent/SG11201906579UA/en
Priority to ES18741136T priority patent/ES2870524T3/es
Priority to PL18741136T priority patent/PL3572412T3/pl
Priority to JP2019539988A priority patent/JP6650552B2/ja
Priority to BR112019014756-0A priority patent/BR112019014756B1/pt
Priority to MX2019008698A priority patent/MX2019008698A/es
Application filed by 福建广生堂药业股份有限公司, 南京明德新药研发股份有限公司 filed Critical 福建广生堂药业股份有限公司
Priority to EP18741136.8A priority patent/EP3572412B1/en
Priority to US16/478,132 priority patent/US11040968B2/en
Priority to EA201991693A priority patent/EA037005B1/ru
Priority to CN201880001401.5A priority patent/CN109071538B/zh
Priority to CA3050346A priority patent/CA3050346C/en
Priority to DK18741136.8T priority patent/DK3572412T3/da
Publication of WO2018133866A1 publication Critical patent/WO2018133866A1/zh
Priority to ZA2019/04737A priority patent/ZA201904737B/en
Priority to PH12019501688A priority patent/PH12019501688A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound of the formula (II), a tautomer thereof or a pharmaceutically acceptable salt thereof, and to its use in the preparation of a medicament for treating an ASK1-related disease.
  • Apoptosis signal-regulating kinase 1 is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family.
  • ASK1 can be activated by a range of stimuli such as oxidative stress, reactive oxygen species (ROS), LPS, TNF-a, FasL, endoplasmic reticulum stress, and increased intracellular calcium concentration.
  • ROS reactive oxygen species
  • LPS reactive oxygen species
  • TNF-a TNF-a
  • FasL endoplasmic reticulum stress
  • ASK1 responds to this series of stimuli by activating JNK (c-Jun N-terminal kinase) and p38 MAPK (p38mitogen-activated protein kinases) and induces a variety of apoptosis through signals involving the mitochondrial cell death pathway.
  • ASK1 Activation and signaling of ASK1 play an important role in many diseases, including neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, autoimmune diseases, and metabolic disorders. Therefore, when a patient suffers from a neurodegenerative disease, a cardiovascular disease, an inflammation, an autoimmune disease, and a metabolic disease, the use of an ASK1 inhibitor as a therapeutic drug can improve the life of the patient.
  • the present invention provides a compound of the formula (II), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • At least one of X 1 , X 2 , and X 3 is N, and the rest is CH;
  • n is selected from 0 or 1;
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 or is selected from C 1-4 alkyl, C 1-4 heteroalkyl, 3 to 6-membered heterocyclic ring optionally substituted by R An alkyl group, a 5- to 6-membered heteroaryl group;
  • R 2 is selected from the group consisting of H, F, Cl, Br, I;
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 ;
  • R is selected from F, Cl, Br, I, OH, NH 2 or is selected from the group consisting of 1, 2 or 3 R's substituted: C 1-3 alkyl, C 1-3 alkoxy and 3 to 6-membered heterocycloalkyl;
  • R' is selected from the group consisting of F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl;
  • hetero of the C 1-4 heteroalkyl group, the 5- to 6-membered heteroaryl group, and the 3 to 6-membered heterocycloalkyl group are each independently selected from: -NH-, N, -O-, -S-, ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • said R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 or selected from the group consisting of: 1, 2 or 3 R's: Me,
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , Me,
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 or is selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R, C 1-3 alkoxy, C 1-3 alkylamino, morpholinyl, pyridyl, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 or is selected from the group consisting of: 1, 2 or 3 R: Me, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, 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:
  • X 1 , X 2 , X 3 , R 1 , R 2 and R 3 are as defined in the present invention.
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 1 , R 2 and R 3 are as defined in the present invention.
  • the invention also provides a compound of formula (I), a pharmaceutically acceptable salt thereof, and tautomers thereof:
  • At least one of X 1 , X 2 , and X 3 is N, and the rest is CH;
  • n is selected from 0 or 1;
  • the structural unit From:
  • the structural unit From:
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • X 1 , X 2 and X 3 are as defined above.
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • n is as defined above.
  • the invention also provides a compound of the formula, a pharmaceutically acceptable salt thereof, and tautomers thereof:
  • 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 an ASK1-related disorder.
  • the invention also provides the use of the above composition for the manufacture of a medicament for the treatment of an ASK1-related disorder.
  • the compounds of the present invention have a significant inhibitory effect on ASK1.
  • the compound of the present invention has good drug-forming properties because of its good solubility, permeability, and the like, strong targeting, and stable metabolism.
  • 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.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • Wedge and dashed keys unless otherwise stated Represents the absolute configuration of a stereocenter, using wavy lines Indicates a wedge or dashed key use Indicates the relative configuration of the stereocenter.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms 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).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, 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.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a 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.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • 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.
  • the "5-7 membered ring” includes, for example, phenyl, pyridine and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term “ring” also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, 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.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl 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.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • 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, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • 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.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the 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
  • WXBB-1-1 (50.00 g, 127.48 mmol, 1.00 eq) was dissolved in acetonitrile (500.00 mL) followed by WXBB-1-2 (12.87 g, 152.98 mmol, 15.14 mL, 1.20 eq. The reaction was carried out at 70 ° C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the mixture was spun-dried at 40 ° C, then dissolved in dichloromethane (150 mL), washed with water (75 mL*2), and then concentrated to about 90 75 mL*3 (removing residual dichloromethane) to the organic phase to give a white solid.
  • WXBB-1-4a (20.00 g, 98.02 mmol, 1.00 eq) was dissolved in N-methylpyrrolidone (100.00 mL), and copper cyanide (17.56 g, 196.04 mmol, 42.83 mL, 2.00 eq) was added at 180 ° C. 3 hours.
  • reaction solution was cooled to room temperature, and water (300 mL) and aqueous ammonia (300 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, ethyl acetate (200 mL*3), and the organic phase was washed with brine (200 mL) Dry over anhydrous sodium sulfate, and then dry with suction and dryness to give a crude brown solid.
  • WXBB-1-3 (6.00 g, 39.96 mmol, 1.00 eq)
  • WXBB-1-4 was added to a vial, followed by diisopropylethylamine (10.85 g, 83.92 mmol, 14.66 mL, 2.10 eq).
  • the reaction was carried out at 100 ° C for 18 hours under a nitrogen atmosphere.
  • the reaction solution was cooled to room temperature, 50 mL of water was added, and after separation, the organic phase was sequentially subjected to 50 mL of ammonium chloride solution (27%), 50 mL of sodium hydrogen carbonate solution (9%), and saturated brine 45 mL.
  • WXBB-1-5 (1.25 g, 5.38 mmol, 1.00 eq) was placed in a 100 mL single-necked flask containing acetic acid (20.00 mL) and solid potassium thiocyanide (1.05 g, 10.76 mmol, 1.05 mL, 2.00 eq) It was added to the reaction liquid, replaced with nitrogen three times, and reacted at 110 ° C for 5 hours under nitrogen atmosphere.
  • reaction solution was cooled to room temperature, and the oil pump was spun dry at 60 ° C, dissolved in 10 mL of dichloromethane, and the organic phase was washed with water (5 mL*2), and the aqueous phase was extracted with 10 mL*2 dichloromethane. Dry over anhydrous sodium sulfate and spin dry to give a brown solid, which was dissolved with ethyl acetate (5 mL), 15 mL of n-hexane, and the mixture was layered. The upper layer was brown, and the magnets were stirred, and no solids were precipitated. The mixture was dried to give a brown oil.
  • reaction solution was cooled to room temperature, and 4 mL of a 20% sodium sulfite solution was added thereto, and the mixture was stirred at room temperature for 0.5 hr. 4 mL of water was added to the white solid, and the pH was adjusted to about 10 with 4N aqueous ammonia. The aqueous phase was extracted with methylene chloride (6 mL*3). EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • a reaction solution of WXBB-1-7 (200.00 mg, 828.98 ⁇ mol, 1.00 eq) and hydrochloric acid (6.00 mL, 38% purity) was added to a dried 100 mL vial for 18 hours at 100 °C. After the reaction was completed, the reaction mixture was cooled to room temperature, and then evaporated to dryness.
  • Phosphorus pentasulfide (52.24g, 235.02mmol, 24.99mL, 2.00eq) was dissolved in tetrahydrofuran (300.00mL), sodium carbonate (12.45g, 117.51mmol, 1.00eq) was slowly added, and the system was stirred at 20 ° C for 1 hour, the compound WXBB -2-1 was added to the system, and the system was warmed to 60 ° C and stirred for 48 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The crude product was purified by column (0-60% EA/PE).
  • the compound WXBB-4-1 (20.00 g, 131.45 mmol, 1.00 eq) was dissolved in methanol (200.00 mL) to give a pale yellow solution, hydrazine hydrate (19.74 g, 394.35 mmol, 19.17 mL, 3.00 eq) was slowly added. Stir at 75 ° C for 1.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (50mL*2), and the filter cake was evaporated to dryness.
  • WXBB-1 (100.00 mg, 337.02 ⁇ mol, 1.00 eq, HCl) and WXBB-2 (80.00 mg, 369.73 ⁇ mol, 1.10 eq) (93% purity) were dissolved in pyridine (5.00 mL), and phosphorus oxychloride was slowly added. 50.00 mg, 326.09 ⁇ mol, 30.30 uL, 0.97 eq). The system was stirred at 50 ° C for 1 hour. The reaction mixture was quenched with water, concentrated under reduced pressure to give the crude product, the crude product was purified by prep-HPLC separation and purification (obtained in neutral WX001 1 HNMR:.
  • WXBB-1 (100.00 mg, 337.02 ⁇ mol, 1.21 eq, HCl) was dissolved in dichloromethane (5.00 mL) and oxalyl chloride (70.76 mg, 557.49 ⁇ mol, 48.80 ⁇ L, 2.00 eq) and N, N were added under nitrogen.
  • - dimethylformamide (20.37 mg, 278.75 ⁇ mol, 21.45 ⁇ L, 1.00 eq)
  • the reaction solution was dried under reduced pressure and dichloromethane ( 5.00 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc, EtOAc hour.
  • WX003-1 (1.50 g, 9.99 mmol, 1.00 eq) was dissolved in acetonitrile (60.00 mL) and cooled to 0 ° C, and isoamyl nitrite (1.76 g, 14.99 mmol, 2.02 mL, 1.50 eq) was added, followed by TMSN 3 (1.73g, 14.99mmol, 1.96mL, 1.50eq) was added dropwise to the reaction solution. After 25 minutes, the ice bath was removed, and the temperature was raised to 25 ° C for 2 hours. Then WX003-2 (1.98 g, 29.97 mmol, 2.48) was added.
  • WX003-4 (300.00 mg, 1.15 mmol, 1.00 eq) was dissolved in anhydrous dichloromethane (10.00 mL). After replacing nitrogen, oxalyl chloride (248.15 mg, 1.95 mmol, 171.14 ⁇ L, 1.70 eq) was added to become turbid. After the addition of anhydrous N,N-dimethylformamide (8.41 mg, 115.00 ⁇ mol, 8.85 ⁇ L, 0.10 eq), the mixture was reacted at 25 ° C for 2 hours under nitrogen atmosphere.
  • the material WX004-2 (27.00 g, 115.86 mmol, 1.00 eq) was dissolved in methanol (200.00 mL), and concentrated sulfuric acid (11.36 g, 115.86 mmol, 6.18 mL, 1.00 eq) was added and reacted at 90 ° C for 18 hours.
  • WX004-6 800.00 mg, 7.26 mmol, 1.00 eq
  • WX004-5 (1.54 g, 7.26 mmol, 1.00 eq)
  • Cu 2 O 51.98 mg, 363.00 ⁇ mol, 37.13 ⁇ L, 0.05 eq
  • the reaction solution was cooled to room temperature, diluted with dichloromethane (40 mL), and washed with 1M hydrochloric acid aq 60 mL and saturated brine (60 mL), and then dried over anhydrous sodium sulfate.
  • WX004-7 (500.00 mg, 1.81 mmol, 1.00 eq) was dissolved in tetrahydrofuran (5.00 mL) and water (5.00 mL). LiOH (130.04 mg, 5.43 mmol, 3.00 eq) was added and the reaction was reacted at 25 ° C 2 After an hourly extraction with 10 mL of methyl tert-butyl ether, an aqueous phase was obtained, and the mixture was adjusted to pH 2 with 2N hydrochloric acid, and extracted with ethyl acetate 20 mL*3.
  • WX004-8 (150.00 mg, 572.00 ⁇ mol, 1.00 eq) was placed in a thumb bottle containing anhydrous dichloromethane (7.00 mL). After replacing the nitrogen three times, oxalyl chloride (123.43 mg, 972.40 ⁇ mol, 85.12 ⁇ L, 1.70) was added. After eq), it became an emulsion, and then N,N-dimethylformamide (4.18 mg, 57.20 ⁇ mol, 4.40 ⁇ L, 0.10 eq) was added, and the reaction was carried out at 25 ° C for 1 hour under nitrogen atmosphere.
  • WX004-9 (130.40 mg, 464.58 ⁇ mol, 1.00 eq) was dissolved in anhydrous dichloromethane (3.00 mL) in a thumb bottle, and WXBB-3 (100.00 mg, 464.58 ⁇ mol, 1.00 eq) and diisopropyl B were added.
  • the amine 60.04 mg, 464.58 ⁇ mol, 81.14 ⁇ L, 1.00 eq was reacted at 25 ° C for 18 hours under nitrogen atmosphere. The reaction mixture was washed with brine (1 mL), dried over anhydrous sodium sulfate and evaporated.
  • WX005-3a (2.28 g, 33.91 mmol, 2.50 mL, 1.00 eq) was added to a pre-dried 100 mL three-necked flask, and three times of nitrogen was added, followed by 10 mL of hydrochloric acid (4.87 N in dioxane), followed by nitrogen protection.
  • Anhydrous ethanol (1.56 g, 33.91 mmol, 1.98 mL, 1.00 eq) was added dropwise to the reaction mixture. After the addition was completed, the mixture was reacted at 25 ° C for 3 hours. The reaction solution was filtered and dried to give WX005-3.
  • WX005-1 (1.72 g, 11.46 mmol, 1.00 eq) was dissolved in hydrochloric acid (63.00 mL), cooled to 0 ° C, and sodium nitrite (948.49 mg, 13.75 mmol, 746.84 ⁇ L, 1.20 eq) was added dropwise to the solution.
  • the solution of water (6.00 mL) was added to the reaction solution at 0-5 ° C for 0.5 hour.
  • WX005-2 (3.00 g, 14.88 mmol, 1.00 eq) and WX005-3 (2.23 g, 14.88 mmol, 1.00 eq) were added to a pre-dried 40 mL vial, followed by absolute ethanol (45.00 mL), followed by Triethylamine (3.01 g, 29.76 mmol, 4.12 mL, 2.00 eq) was added and allowed to react at 20 ° C for half an hour. The solvent was spun off by rotary distillation.
  • WX005-5 (500.00 mg, 2.06 mmol, 1.00 eq) was added to a pre-dried 100 ml flask and dissolved in hydrochloric acid (10.20 g, 279.76 mmol, 10.00 mL, 135.81 eq). The reaction was stirred at 100 ° C for 16 hours. The reaction system was cooled to room temperature, and a large amount of solid was precipitated after cooling. The filter cake was collected by filtration using a five-hole funnel to obtain WX005-6.
  • the reaction system was diluted with 10 ml of water / 10 ml of dichloromethane, and the organic phase was collected, and the aqueous phase was extracted with dichloromethane (5 ml x 3). The combined organic layers were washed with EtOAc EtOAc m. The crude product was separated by Prep-HPLC (neutral) and purified to give the product pure product WX005.
  • WX006-1 (100.00 g, 455.48 mmol, 1.00 eq) and EtOH (700.00 mL) were added to a pre-dried 250 mL three-necked flask, and H 2 SO 4 (223.37 g, 2.28 mol, 121.40 mL, was added dropwise to the reaction mixture. 5.00 eq) reflux at 80 ° C for 5 hours.
  • the reaction system was cooled to room temperature, diluted with 200 mL of EA, the organic phase was separated, and the aqueous phase was extracted with EA (2*100 ml). The combined organic layers were washed with EtOAc EtOAc EtOAc. Get WX006-2.
  • Acetic acid 53.19 mL
  • water 10.00 mL
  • hydrogen peroxide 4.49 g, 39.61 mmol, 3.81 mL, 30% purity, 3.00 eq
  • WX006-5 4.5 g, 13.20 mmol, 1.00 eq
  • WX006-9 (0.3 g, 627.72 ⁇ mol, 1.00 eq), 3-pyridineboronic acid (154.32 mg, 1.26 mmol, 2.00 eq), palladium acetate (14.09 mg, 62.77 ⁇ mol, 0.10 eq) was added to a pre-dried 10 mL thumb bottle.
  • n-butylbis(1-adamantyl)phosphine 22.51 mg, 62.77 ⁇ mol, 0.10 eq
  • potassium carbonate 260.27 mg, 1.88 mmol, 3.00 eq
  • reaction vessel was placed in an oil bath at 90 ° C under a nitrogen atmosphere, and stirred for 2 hours. After the reaction mixture was directly dried, it was quickly passed through a short silica gel column (100-200 mesh purification to afford WX006.
  • 1 H NMR 400MHz, CHLOROFORM- d
  • WX007-3 (12.64g, 47.86mmol, 1.00eq)
  • WXBB-10 13.39g, 52.65mmol, 1.10eq
  • toluene 120mL
  • the reaction was increased to 100 °C and then added to two.
  • m/z 346.1, 348.1 [M + 1].
  • the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • WX007-6 (7.1 g, 19.99 mmol, 1.00 eq) and triethylamine (4.05 g, 39.98 mmol, 5.56 mL, 2.00 eq) were added to a 250 mL hydrogenated bottle, followed by methanol (100 mL) and Pd(dppf)Cl. 2 (2.19 g, 3.00 mmol, 0.15 eq), was purged three times with carbon monoxide and pressurized to 50 psi.
  • the reaction vessel was placed in an oil bath (external temperature) at 70 ° C for 10 hours.
  • WX007-8 (574.83 mg, 1.79 mmol, 1.00 eq) was added to a pre-dried 100 mL round bottom flask, three times of nitrogen was added, and then dichloromethane (20 mL) was added, followed by dropwise addition of oxalyl chloride (455.57 mg, 3.59 mmol, 314.19 ⁇ L, 2.00 eq) and N,N-dimethylformamide (13.12 mg, 179.46 ⁇ mol, 13.81 ⁇ L, 0.10 eq) were reacted at 25 ° C for 1 hour after completion of the dropwise addition. After the reaction is completed, the reaction solution is directly steamed in a water pump.
  • the WX008-2 (26.5g, 81.26mmol, 1eq) was dissolved in MeOH (500mL), was added portionwise NiCl 2 .6H 2 O (69.53g, 292.53 mmol, 3.6eq), added in batches at 0 °C NaBH 4 ( 15.37 g, 406.26 mmol, 5 eq) was stirred and stirred at 25 ° C for 0.5 h.
  • EtOAc EtOAc EtOAc
  • WX008-4 (15g, 35.58mmol, 1 eq) (purity: 89.71%) was added to AcOH (120 mL), KSCN (6.91 g, 71.15 mmol, 6.91 mL, 2 eq) was added, and the mixture was stirred under nitrogen at 110 ° C. hour. The reaction solution was cooled to room temperature, poured into water (300 mL), and stirred for 15 min, and the solid was precipitated, filtered, and the filter cake was evaporated to dryness to give WX008-5.
  • WX015-1 (24 g, 101.70 mmol, 1 eq) was dissolved in anhydrous dichloromethane (200 mL), EtOAc (EtOAc, EtOAc, EtOAc, 35.43 mL, 2 eq), the system was cooled to 0 ° C, and Tf 2 O (43.04 g, 152.55 mmol, 25.17 mL, 1.5 eq) was slowly added at 0 ° C, then the system was gradually warmed to 20 ° C and stirred for 2 hours. Water (200 mL) was added to the reaction mixture under stirring, and the organic phase was evaporated to dryness.
  • EtOAc EtOAc, EtOAc, 35.43 mL, 2 eq
  • WX015-3 (8 g, 26.22 mmol, 1 eq) was dissolved in glacial acetic acid (80 mL), and iron powder (5.86 g, 104.88 mmol, 4 eq) was slowly added portionwise with stirring, and the system was stirred at 20 ° C for 1 hour.
  • reaction solution was dried under reduced pressure to dryness crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss
  • WXBB-1-3 (6.98 g, 27.47 mmol, 3 eq) was dissolved in anhydrous toluene (30 mL).
  • WX015-4 (3 g, 9.16 mmol, 1 eq) (purity: 83.959%), diisopropylethylamine (2.49) g, 19.27 mmol, 3.36 mL, 2.1 eq).
  • the system was heated to 140 ° C under microwave conditions for 1 hour.
  • the reaction solution was cooled to room temperature, water (50 mL) was evaporated and evaporated.
  • the crude product was purified by column chromatography from 0 to 12% ethyl acetate / petroleum ether to afford product WX015-5.
  • WX015-5 (1.2 g, 2.71 mmol, 1 eq) (purity 80.641%) was dissolved in glacial acetic acid (20 mL), potassium thiocyanate (0.36 g, 3.70 mmol, 360.00 ⁇ L, 1.37 eq) was added and the system was stirred at 110 ° C. 3 hours.
  • reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (50 mL*3), and the organic phase was combined, and the saturated organic sodium hydrogen carbonate solution (200 mL) was added to the organic phase, stirred for 5 min, and the pH test paper was tested for organic
  • the phase was 7-8, the organic phase was separated, and the organic phase was washed with water (200 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was evaporated to dryness to afford product WX015-6.
  • WX015-6 (1.2g, 2.62mmol, 1eq) (purity 87.114) was dissolved in a mixed solution of glacial acetic acid (12mL) and water (2.5mL), hydrogen peroxide (0.9g, 7.94mmol, 762.71 ⁇ L) was added with stirring , 30% purity, 3.02 eq), the system was stirred at 45 ° C for 0.5 h.
  • the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (50 mL*3).
  • the organic phase was combined, and the saturated sodium sulfite solution (50 mL) was added to the organic phase, stirred for 5 min, and the starch potassium iodide test paper was detected.
  • WX015-9 (0.1 g, 301.80 ⁇ mol, 1 eq) was dissolved in anhydrous dichloromethane (2 mL), and N,N-dimethylformamide (5 mg, 68.41 ⁇ mol, 5.26 uL, 2.27e-1 eq) was added. Under the conditions of N2, oxalyl chloride (0.08 g, 630.29 ⁇ mol, 55.17 uL, 2.09 eq) was added, and the system was stirred at 20 ° C for 0.5 hour, and the reaction mixture was stirred under reduced pressure until viscous, and anhydrous dichloromethane (2 mL) was added again.
  • WX016-1 (20 g, 201.75 mmol, 1 eq) was added to CHCl 3 (200 mL) in a pre-dried 100 mL round bottom flask. After the reaction system was lowered to 0 ° C, PCl 5 (84.03 g, 403.51 mmol) was added in portions. 2 eq), the system was reacted at 0 ° C for 30 min, after which ZnCl 2 (1.37 g, 10.09 mmol, 472.48 ⁇ L, 0.05 eq) and Br 2 (64.48 g, 403.51 mmol, 20.80 mL, 2 eq) were added to the system. The reaction was continued for 5 hours at 0-25 °C.
  • the material WX016-2 (10 g, 38.92 mmol, 1 eq) was added to a pre-dried 250 ml round bottom flask, and a mixture of H 2 O (5 mL) and MeOH (45 mL) was added, and at a temperature of 40 ° C, PPh 3 (10.21 g, 38.92 mmol, 1 eq) was slowly added to the system and stirring was continued for 3 hours.
  • the solvent of the reaction system was concentrated to about half in vacuo, and water was added slowly until no solids were precipitated.
  • WX016-3 (7.2 g, 28.31 mmol, 1 eq) was added to a dry round bottom flask, ACN (20 mL) was added, and then KOAc (11.11 g, 113.24 mmol, 4 eq) and 18-crown-6 (2.24 g, 8.49 mmol, 0.3 eq), stirring was continued, and the mixture was heated to reflux at 85 ° C for 1 hour. The reaction system was cooled to room temperature, and then the mixture was adjusted to pH 3-4 with 1M hydrochloric acid and extracted with dichloromethane (3 ⁇ 20 ml).
  • reaction solution was cooled to room temperature, then water (250 mL) was added, and pH was adjusted to 4 to 5 with 1M hydrochloric acid, and then the aqueous phase was washed with ethyl acetate (200 mL*3), and the obtained aqueous phase was adjusted with 1 M sodium hydroxide.
  • the mixture was extracted with methylene chloride (250 mL*3).
  • EtOAc EtOAc m.
  • the crude product was isolated and purified by prep-HPLC (water (0.04% NH3.H2O + 10 mM NH 4 HCO 3 )-CAN) to give compound WX016-7.
  • reaction solution was clarified, and the reaction mixture was concentrated to 15 mL, anhydrous dichloromethane (20 mL), and then concentrated to 15 Then, anhydrous dichloromethane (20 mL) was added, and the air in the system was replaced with a nitrogen balloon. The operation was repeated twice, and the compound WX016-7 (3.50 g, 12.03 mmol, 0.9 eq) and N, N-di were added under a nitrogen atmosphere. Isopropylethylamine (2.4 mL, 13.78 mmol, 1 eq) was stirred at room temperature (20 ° C) for 1 hour.
  • the compound WX016 was separated by SFC (column: YMC CHIRAL Amylose-C (250 mm*30 mm, 10 ⁇ m): mobile phase: [0.1% NH 3 .H 2 O EtOH]: B: 55%-55%, min) to obtain retention The times were 0.921 min and 1.459 min for WX017 and WX018, respectively.
  • Base Reaction Buffer 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO
  • test compound was formulated into a 10 mM stock solution in DMSO, diluted 10 times in 3 folds, and placed in a 384-well plate (Cyclic Olefin Copolymer LDV). ).
  • Type recombinant human full-length protein, GST-tagged
  • Substrate Myelin basic protein, MBP (Active Motif, Carlsbad, CA)
  • Kinase activity data is expressed as the ratio of the remaining kinase activity in the test sample to the kinase activity in the vehicle (DMSO),
  • the compounds of the present invention have a significant inhibitory effect on ASK1.
  • mice were used to quantitatively determine the concentration of the drug in the plasma of mice at different time points by intravenous or oral administration of the test compound by LC/MS/MS method. Pharmacokinetic characteristics in mice.
  • test compound was injected into C57BL/6 mice via the tail vein (fasting overnight, 7-10 weeks old), and the test compound was intragastrically administered to C57BL/6 mice (overnight fast, 7-10 weeks) age).
  • Animals were collected from the jugular vein or tail vein at a dose of 0.0833, 0.25, 0.5, 1, 2 , 4, 6, 8 and 24 hours after administration.
  • Approximately 30 ⁇ L was placed in an anticoagulant tube supplemented with EDTA-K 2 at 4 ° C. Plasma was taken by centrifugation at 3000 g for 15 min.
  • the compounds of the present invention have high exposure and bioavailability in mice.

Abstract

本发明公开了式(Ⅱ)所述的化合物、其互变异构体或其药学上可接受的盐，并公开了其在制备治疗ASK1相关疾病药物中的应用。

Description

作为ASK1抑制剂的吡啶衍生物及其制备方法和应用
相关申请的交叉引用
本申请主张2017年1月22日提交的中国专利申请CN201710054224.4的优先权，其内容在此并入本申请。
技术领域
本发明涉及式(Ⅱ)所示化合物、其互变异构体或其药学上可接受的盐，并涉及其在制备治疗ASK1相关疾病药物中的应用。
背景技术
细胞凋亡信号调节激酶1(apotosis signal-regulating kinase 1,ASK1)是细胞丝裂原活化蛋白激酶激酶激酶(mitogen-activated protein kinase kinase kinase,MAP3K)家族成员之一。ASK1可以被一系列的刺激激活，比如氧化应激、活性氧簇(ROS)、LPS、TNF-a、FasL、内质网应激及细胞内钙离子浓度的增加等。ASK1通过活化JNK(c-Jun N-terminal kinase)和p38MAPK(p38mitogen-activated protein kinases)以应对这一系列的刺激，并通过涉及线粒体细胞死亡途径的信号而诱导多种细胞凋亡。ASK1的活化和信号传导在很多疾病中扮演着重要的角色，这些疾病包括神经退行性疾病、心血管疾病、炎症性疾病、自身免疫性疾病及代谢障碍性疾病。因此，当患者患有神经退行性疾病，心血管疾病，炎症，自身免疫疾病和代谢疾病时，用ASK1抑制剂作为治疗药物能改善患者生活。
发明内容
本发明提供了式(Ⅱ)所示化合物、其药学上可接受的盐及其互变异构体，
Figure PCTCN2018073640-appb-000001
X 1、X 2、X 3至少一个为N，其余为CH；
n选自0或1；
R 1选自H、F、Cl、Br、I、OH、NH 2，或者选自任选被R取代的：C 1-4烷基、C 1-4杂烷基、3～6元杂环烷基、5～6元杂芳基；
R 2选自H、F、Cl、Br、I；
R 3选自H、F、Cl、Br、I、OH、NH 2；
R选自F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基和3～6 元杂环烷基；
R’选自F、Cl、Br、I、OH、NH 2和C 1-3烷基；
所述C 1-4杂烷基、5～6元杂芳基、3～6元杂环烷基之“杂”分别独立地选自：-NH-、N、-O-、-S-、；
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R选自F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R’取代的：Me、
Figure PCTCN2018073640-appb-000002
本发明的一些方案中，上述R选自F、Cl、Br、I、OH、NH 2、Me、
Figure PCTCN2018073640-appb-000003
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、吗啉基、吡啶基，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R取代的：Me、
Figure PCTCN2018073640-appb-000004
其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、Me、
Figure PCTCN2018073640-appb-000005
Figure PCTCN2018073640-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 PCTCN2018073640-appb-000007
选自：
Figure PCTCN2018073640-appb-000008
Figure PCTCN2018073640-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 PCTCN2018073640-appb-000010
选自：
Figure PCTCN2018073640-appb-000011
其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明的一些方案中，上述的化合物、其药学上可接受的盐及其互变异构体，其选自：
Figure PCTCN2018073640-appb-000012
其中，X 1、X 2、X 3、R 1、R 2和R 3如本发明所定义。
本发明的一些方案中，上述的化合物、其药学上可接受的盐及其互变异构体，其选自：
Figure PCTCN2018073640-appb-000013
其中，
R 1、R 2和R 3如本发明所定义。
本发明还提供了式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体：
Figure PCTCN2018073640-appb-000014
X 1、X 2、X 3至少一个为N，其余为CH；
n选自0或1；
本发明的一些方案中，上述结构单元
Figure PCTCN2018073640-appb-000015
选自：
Figure PCTCN2018073640-appb-000016
Figure PCTCN2018073640-appb-000017
本发明的一些方案中，上述结构单元
Figure PCTCN2018073640-appb-000018
选自：
Figure PCTCN2018073640-appb-000019
本发明的一些方案中，上述结构单元
Figure PCTCN2018073640-appb-000020
选自：
Figure PCTCN2018073640-appb-000021
Figure PCTCN2018073640-appb-000022
其他变量如上述定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018073640-appb-000023
选自：
Figure PCTCN2018073640-appb-000024
其他变量如上述定义。
本发明还有一些方案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 PCTCN2018073640-appb-000025
其中，X 1、X 2、X 3上述所定义。
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 PCTCN2018073640-appb-000026
其中，n如上述定义。
本发明还提供了下式化合物、其药学上可接受的盐及其互变异构体：
Figure PCTCN2018073640-appb-000027
Figure PCTCN2018073640-appb-000028
本发明还提供了一种药物组合物，包括治疗有效量的上述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ASK1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ASK1相关病症的药物上的应用。
技术效果
作为一种新型的ASK1抑制剂，本发明化合物对ASK1的抑制作用显著。同时，因其溶解性、渗透性等良好，靶向性强，代谢稳定，本发明化合物具有良好的成药性。
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。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2018073640-appb-000029
表示一个立体中心的绝对构型，用波浪线
Figure PCTCN2018073640-appb-000030
表示楔形键或虚线键
Figure PCTCN2018073640-appb-000031
用
Figure PCTCN2018073640-appb-000032
表示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)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“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。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018073640-appb-000033
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018073640-appb-000034
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018073640-appb-000035
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018073640-appb-000036
所述连接基团、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。
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C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“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-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
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-CH 2F)或多取代 的(如-CF 3)，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，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
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，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
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(C 1-C 4)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，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6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、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、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。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。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；NaCNBH 3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；Boc 2O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；SOCl 2代表氯化亚砜；CS 2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-Bu 4NF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；DMP代表邻苯二甲酸二甲酯；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Xant-Phos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；DIEA代表N,N-二异丙基乙胺；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；AIBN代表偶氮二异丁腈；Pd2(dba)3代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；BnBr代表苄基溴；DMAP代表4-二甲氨基吡啶；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；TMSN 3代表叠氮基三甲基硅烷；(Bpin) 2代表双联嚬哪醇硼酸酯；BnBr代表苄化溴；Tf 2O代表三氟甲磺酸酐；三氟甲磺酸酐；Hepes代表4-羟乙基哌嗪乙磺酸；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸。
化合物经手工或者
Figure PCTCN2018073640-appb-000037
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。
片段WXBB-1
Figure PCTCN2018073640-appb-000038
合成路线：
Figure PCTCN2018073640-appb-000039
步骤1.化合物WXBB-1-3的合成
将WXBB-1-1(50.00g,127.48mmol,1.00eq)溶于乙腈(500.00mL)中，随后加入WXBB-1-2(12.87g,152.98mmol,15.14mL,1.20eq)，氮气保护下于70℃反应2小时。反应完全后，将反应液降到室温后，40℃水泵旋干，随后用二氯甲烷(150mL)溶解，用水(75mL*2)洗涤后，将有机相浓缩到约90mL剩余后，加入正己烷75mL*3(除去残留的二氯甲烷)到有机相旋出白色固体。将白色固体过滤，并用正己烷180mL洗滤饼，将滤饼旋干。得到白色固体状的WXBB-1-3(27.00g,106.17mmol,83.29％产率)。 1H NMR(400MHz,DMSO-d 6)δppm 0.79-0.86(m,2H)0.88-0.97(m,2H)1.99-2.10(m,1H)2.42(s,3H)4.98(s,2H)7.49(d,J＝8.16Hz,2H)7.82(d,J＝8.28Hz,2H)，m/z＝255.1(M+1)
步骤2.化合物WXBB-1-4的合成
将WXBB-1-4a(20.00g,98.02mmol,1.00eq)溶于N-甲基吡咯烷酮(100.00mL)，加入氰化亚铜(17.56g,196.04mmol,42.83mL,2.00eq)，180℃反应3小时。反应液冷却至室温，向反应液中加入水(300mL)及氨水(300mL)，室温搅拌30min，乙酸乙酯萃取(200mL*3)，有机相用饱和食盐水洗(200mL)，水洗(200mL)，无水硫酸钠干燥，抽滤旋干得粗品，粗品为棕黑色固体。粗品经硅胶柱层析分离(PE:EA＝20:1-3:1)得到WXBB-1-4(12.00g,79.92mmol,81.53％产率)为黄色固体。 1H NMR(400MHz,CHLOROFORM-d)δppm 2.21(s,3H)3.68(br s,2H)6.80(d,J＝5.40Hz,1H)6.91(d,J＝9.29Hz,1H)
步骤3.化合物WXBB-1-5的合成
将WXBB-1-3(6.00g,39.96mmol,1.00eq)，WXBB-1-4加入单口瓶中，随后加入二异丙基乙基胺(10.85g,83.92mmol,14.66mL,2.10eq)，氮气保护下100℃反应18小时。反应完全后，将反应液降到室温，加入50mL水，分液后，将有机相依次用50mL的氯化铵溶液(27％)，50mL的碳酸氢钠溶液(9％)，饱和食盐水45mL洗涤，无水硫酸钠干燥后，45℃水泵旋干～30mL甲苯剩余，有机相中加入正己烷60mL后有固体析出，过滤，用异丙醇(冰浴放置10min)60mL洗滤饼，40℃水泵旋干滤饼(白色固体)，粗品用层析柱(SiO 2,100-200目，PE:EA＝10:1-3:1)纯化，得到黄色固体状的WXBB-1-5(1.80g,7.75mmol,19.39％产率)。 1H NMR(400MHz,DMSO-d 6)δppm 0.81-0.86(m,2H)0.87-0.90(m,2H)2.42(s,3H)4.98(s,2H)5.20-5.28(m,1H)5.23(s,1H)6.67(d,J＝5.52Hz,2H)6.87(d,J＝5.77Hz,1H)
步骤4.化合物WXBB-1-6的合成
将WXBB-1-5(1.25g,5.38mmol,1.00eq)放入装有乙酸(20.00mL)的100mL单口瓶中，将固体硫氰化钾(1.05g,10.76mmol,1.05mL,2.00eq)加入到反应液中，置换氮气三次，氮气保护下于110℃反应5小时。反应完全后，将反应液降到室温，油泵60℃旋干后，用二氯甲烷10mL溶解，用水5mL*2洗有机相，在用10mL*2二氯甲烷萃取水相，将有机相合并，无水硫酸钠干燥后旋干得棕色固体，用5mL乙酸乙酯溶解，加入15mL正己烷，溶液分层，上层为褐色，加入磁子搅拌，未有固体析出，将混合液旋干得到棕色油状物，粗品用层析柱(SiO 2,100-200目，PE:EA＝10:1-3:1)纯化，得到黄色 固体状WXBB-1-6(390.00mg,756.23umol,14.06％产率,53％纯度)。m/z＝274.0(M+1)
步骤5.化合物WXBB-1-7的合成
在预先干燥的100mL三口瓶中，加入乙酸(8.00mL)，水(1.60mL)和双氧水(487.96mg,4.30mmol,413.53μL,30％纯度,3.01eq)，将混合液在氮气保护下加热到45℃(內温)，将WXBB-1-6(390.00mg,1.43mmol,1.00eq)以固体形式加入(內温保持在55℃以下)后，反应液在45℃下反应30min。反应完全后，将反应液降到室温，加入20％的亚硫酸钠溶液4mL后，室温搅拌0.5小时，用油泵旋干得白色固体。向白色固体中加入4mL水，再用4N的氨水调pH约为10。水相用二氯甲烷(6mL*3)萃取，有机相用无水硫酸钠干燥后旋干，得到黄色固体状的WXBB-1-7(200.00mg,828.98μmol,57.97％产率)。m/z＝242.2(M+1)
步骤6.化合物WXBB-1的合成
在干燥的100mL单口瓶中加入WXBB-1-7(200.00mg,828.98μmol,1.00eq)和盐酸(6.00mL，38％纯度)反应液在100℃下反应18小时。反应完全后，将反应液降到室温，旋干，再将5mL*2甲苯的加入旋干得到棕色固体状的WXBB-1(200.00mg,768.46μmol,92.70％产率)。1H NMR(400MHz,DMSO-d6)δppm0.81-0.89(m,2H)0.98-1.06(m,2H)1.96-2.05(m,1H)2.24(s,3H)7.54(d,J＝11.29Hz,1H)7.74(s,1H)8.00(d,J＝6.78Hz,1H)9.28(s,1H)，m/z＝261.1(M+1)
片段WXBB-2
Figure PCTCN2018073640-appb-000040
合成路线：
Figure PCTCN2018073640-appb-000041
步骤1：化合物WXBB-2-2的合成
将五硫化二磷(52.24g,235.02mmol,24.99mL,2.00eq)溶于四氢呋喃(300.00mL)，缓慢加入碳酸钠(12.45g,117.51mmol,1.00eq),体系在20℃下搅拌1小时，将化合物WXBB-2-1加入到体系中，将体系升温至60℃并搅拌48小时。将反应液冷却至室温，过滤，将滤液减压旋干得到粗品。粗品经过(0～60％EA/PE)过柱纯化。得到化合物WXBB-2-2(6.20g,61.28mmol,52.15％产率)为白色固体， 1H NMR(400MHz,CHLOROFORM-d)δppm 2.166-2.249(m,2H)2.896-2.936(m,2H)3.664-3.699(m,2H)8.676(s,1 H)。
步骤2：化合物WXBB-2的合成
将化合物WXBB-2-2(200.00mg,1.98mmol,1.00eq)和化合物WXBB-4(360.00mg,2.37mmol,1.19eq)溶于环己醇(4.00mL)，体系在氮气保护下于170℃搅拌24小时。将反应液冷却至室温，加水(80mL)稀释，用乙酸乙酯(30mL*6)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经过(0～10％MeOH/DCM)过柱纯化。得到化合物WXBB-2(180.00mg,831.88umol,42.01％产率,93％纯度)为黄色固体， 1H NMR(400MHz,DMSO-d6)δppm 2.71-2.64(m,2H)2.86(d,J＝7.2Hz,2H)4.32(t,J＝7.2Hz,2H)6.13(br.s,2H)6.48(d,J＝8.4Hz,1H)7.22(d,J＝7.2Hz,1H)7.52-7.47(m,1H)。m/z＝202.0[M+H]+.
片段WXBB-3
Figure PCTCN2018073640-appb-000042
合成路线：
Figure PCTCN2018073640-appb-000043
步骤1:化合物WXBB-3-2的合成
将五硫化二磷(56.06g,252.19mmol,26.82mL,1.00eq)加入到乙腈(500.00mL)中形成悬浮液，缓慢加入三乙胺(25.52g,252.19mmol,34.96mL,1.00eq)，体系在室温下搅拌1小时，加入WXBB-3-1(25.00g,252.19mmol,1.00eq)，体系在60℃下搅拌19小时。将反应液倒入次氯酸钠(200mL)，减压浓缩除去乙腈，用二氯甲烷(200mL*3)萃取，合并有机相，依次用水(400mL)和饱和食盐水(400mL)洗涤,用无水硫酸镁干燥，过滤，将滤液减压旋干得到粗品。粗品经过(0～10％MeOH/DCM)过柱纯化。得到化合物WXBB-3-2(10.00g,86.81mmol,34.42％产率)为黄色固体， 1H NMR(400MHz,DMSO-d6)δppm 1.53-1.71(m,4H)2.57-2.67(m,2H)3.13(br s,1H)3.18(td,J＝5.77,2.51Hz,1H)。
步骤2:化合物WXBB-3的合成
将化合物WXBB-3-2(6.00g,52.08mmol,1.00eq)和化合物WXBB-4(8.72g,57.29mmol,1.10eq)溶于环己醇(100.00mL)，体系在氮气保护下于170℃搅拌6小时将反应液冷却至室温，加水(200mL)稀释，用盐酸(2N，100mL)调节pH至5，用乙酸乙酯(200mL)萃取，水相用氢氧化钠(2N，100mL)调节pH至 9，用乙酸乙酯(200mL*2)萃取，有机相依次用水(200mL)和饱和食盐水(200mL)洗涤，用无水硫酸镁干燥，过滤，滤液减压浓缩得到粗品。粗品经过(0～10％DCM/MeOH)过柱纯化。得到化合物WXBB-3(5.00g,17.50mmol,33.60％产率,75.32％纯度)为棕色固体。m/z＝216.0[M+H]+.
片段WXBB-4
Figure PCTCN2018073640-appb-000044
合成路线：
Figure PCTCN2018073640-appb-000045
步骤1:化合物WXBB-4的合成
将化合物WXBB-4-1(20.00g,131.45mmol,1.00eq)溶于甲醇(200.00mL)得到淡黄色溶液，缓慢加入水合肼(19.74g,394.35mmol,19.17mL,3.00eq)，反应体系在75℃下搅拌1.5小时。反应完全后，将反应液冷却至室温，过滤，用乙酸乙酯(50mL*2)洗涤滤饼，将滤饼减压旋干。得到化合物WXBB-4(20.00g,131.45mmol,100.00％产率)为白色固体， 1H NMR(400MHz,DMSO-d6)δppm 4.48(br s,2H)6.09(s,2H)6.60(d,J＝8.28Hz,1H)7.11(d,J＝7.03Hz,1H)7.51(t,J＝7.78Hz,1H)9.19(br s,1H)。
实施例001：WX001
Figure PCTCN2018073640-appb-000046
合成路线：
Figure PCTCN2018073640-appb-000047
步骤1.化合物WX001的合成
将WXBB-1(100.00mg,337.02μmol,1.00eq,HCl)和WXBB-2(80.00mg,369.73μmol,1.10eq)(93％纯 度)溶于吡啶(5.00mL)，缓慢加入三氯氧磷(50.00mg,326.09μmol,30.30uL,0.97eq)。体系在50℃搅拌1小时。将反应液用水淬灭，减压浓缩得到粗品，粗品经prep-HPLC(中性体系分离纯化得到WX001。 1HNMR:0.63-0.71(m,2H)0.74-0.83(m,2H)1.76-1.89(m,1H)2.23(s,3H)2.67(quin,J＝7.34Hz,2H)2.81-2.92(m,2H)4.38(t,J＝7.03Hz,2H)7.17(d,J＝0.75Hz,1H)7.47(d,J＝10.79Hz,1H)7.56-7.64(m,1H)7.68(d,J＝1.00Hz,1H)7.85(d,J＝7.53Hz,1H)7.98(t,J＝7.91Hz,1H)8.15(d,J＝8.28Hz,1H)10.90(s,1H)，m/z＝444.2(M+1)。
实施例002：WX002
Figure PCTCN2018073640-appb-000048
合成路线：
Figure PCTCN2018073640-appb-000049
步骤1.化合物WX002的合成
将WXBB-1(100.00mg,337.02μmol,1.21eq,HCl)溶于二氯甲烷(5.00mL)，在氮气条件下加入草酰氯(70.76mg,557.49μmol,48.80μL,2.00eq)和N,N-二甲基甲酰胺(20.37mg,278.75μmol,21.45μL,1.00eq)，体系在0℃下搅拌1小时。将反应液减压旋干，依次加入二氯甲烷(5.00mL)，WXBB-3(60.00mg,278.75μmol,1.00eq)和DMAP(136.22mg,1.12mmol,4.00eq).体系在0℃搅拌3小时。将反应液减压旋蒸得到粗品，粗品经prep-TLC(DCM:MeOH＝20:1)板分离得到WX002。 1H NMR(400MHz,METHANOL-d4)ppm 9.17(s,1H),8.47(d,J＝8.3Hz,1H),8.16-8.08(m,1H),8.06-7.96(m,2H),7.63(s,1H),7.50(d,J＝10.8Hz,1H),4.82(br.s.,2H),3.27(t,J＝6.0Hz,2H),2.36(s,3H),2.20(br.s.,2H),2.15-2.04(m,3H),1.22-1.12(m,2H),0.98-0.89(m,2H)
实施例003：WX003
Figure PCTCN2018073640-appb-000050
合成路线：
Figure PCTCN2018073640-appb-000051
步骤1.化合物WX003-3的合成
将WX003-1(1.50g,9.99mmol,1.00eq)在乙腈(60.00mL)中溶解降温到0℃，加入亚硝酸异戊酯(1.76g,14.99mmol,2.02mL,1.50eq)，随后将TMSN 3(1.73g,14.99mmol,1.96mL,1.50eq)滴加到反应液中，25min后撤去冰浴，升到室温25℃，反应2小时,再将WX003-2(1.98g,29.97mmol,2.48mL，3.00eq)和Cu 2O(142.95mg,999.00μmol,102.11μL,0.10eq)加入反应液中，氮气保护50℃反应18小时。反应完成后，将反应液降到室温旋干，用二氯甲烷50mL稀释，依次用饱和氯化铵30mL和饱和食盐水30mL洗涤，无水硫酸钠干燥旋干。用层析柱(SiO 2,PE:EA＝10:1到4:1)纯化粗品。得到WX003-3，m/z＝242.9[M+1]。
步骤2.化合物WX003-4的合成
将WX003-3(380.00mg,1.57mmol,1.00eq)放入到38％的盐酸(15.00mL)中，100℃回流18小时。向反应液中加碳酸钠固体调pH～9，用乙酸乙酯10mL*3萃取，保留水相，水相用2N HCl调pH～2，用乙酸乙酯30mL*3萃取，保留有机相，无水硫酸钠干燥后，过滤，将滤液旋干，得到WX003-4，m/z＝261.9[M+1]。
步骤3.化合物WX003-5的合成
将WX003-4(300.00mg,1.15mmol,1.00eq)溶于无水二氯甲烷(10.00mL)，置换氮气后加入草酰氯(248.15mg,1.95mmol,171.14μL,1.70eq)后变为乳浊液,随后加入无水N,N-二甲基甲酰胺(8.41mg,115.00μmol,8.85μL,0.10eq)，氮气保护下25℃反应2小时。反应液中加入5mL无水二氯甲烷，35℃减压浓缩～5mL无水二氯甲烷剩余，按此方法重复四次，得到的产品在无水DCM中直接用于下一步反应。得到WX003-5溶解在5mL二氯甲烷中。m/z＝276.1[甲酯MS]。
步骤4.化合物WX003的合成
在WX003-5(285.29mg,1.02mmol,1.00eq)的无水二氯甲烷(6.00mL)溶液中在氮气保护下加入二异丙基乙基胺(131.82mg,1.02mmol,178.14uL,1.00eq)，随后加入WXBB-3(220.00mg,1.02mmol,1.00eq)，氮气保护下于25℃反应18小时。反应完成后，向反应液中加入5mL饱和食盐水，分液后有机相旋干(40℃水泵旋干)得粗品，粗品经prep-HPLC(柱子：water Xbridge 150*25 5u；流动相:[水(10mM NH 4HCO 3)-ACN]；B％:12％-52％,10.5min)纯化，得到化合物WX003， 1H NMR(400MHz,CHLOROFORM-d)δppm 0.95-1.00(m,2H)1.03-1.10(m,2H)1.95-2.02(m,2H)2.04-2.12(m,3H)2.35(s,3H)3.10(t,J＝6.34Hz,2H)4.51(t,J＝6.09Hz,2H)7.23(s,1H)7.50(s,1H)7.90(t,J＝8.03Hz,1H)8.12(dd,J＝15.37,7.34Hz,2H)8.36(d,J＝8.28Hz,1H)9.02(br d,J＝14.30Hz,1H).
实施例004：WX004
Figure PCTCN2018073640-appb-000052
合成路线：
Figure PCTCN2018073640-appb-000053
步骤1.化合物WX004-2的合成
将N-溴代丁二酰亚胺(22.97g,129.75mmol,1.00eq)加入到WX004-1(20.00g,129.75mmol,1.00eq)和浓硫酸(200.00mL)的混合液中，20℃下搅拌20min。将反应液倒入搅拌状态的冰水(1000mL)中，有白色固体生成。过滤之后要滤饼，用二氯甲烷500mL将其溶解，硫酸镁干燥，过滤后旋干。得到WX004-2。 1H NMR(400MHz,CHLOROFORM-d)δppm 2.45(s,3H)7.07(d,J＝11.17Hz,1H)8.16(d,J＝6.90Hz,1H)
步骤2.化合物WX004-3的合成
将原料WX004-2(27.00g,115.86mmol,1.00eq)溶于甲醇(200.00mL)，加入浓硫酸(11.36g,115.86mmol,6.18mL,1.00eq)后在90℃反应18小时。将反应液旋干，用250mL二氯甲烷溶解后，加入碳酸氢钠的饱和溶液150mL，萃取旋干得到WX004-3, 1H NMR(400MHz,CHLOROFORM-d)δppm2.42(s,3H)3.92(s,3H)7.04(d,J＝11.04Hz,1H)8.09(d,J＝6.90Hz,1H)
步骤3.化合物WX004-4的合成
将WX004-3(5.00g,20.24mmol,1.00eq)溶于二氧六环(60.00mL)中，随后将(Bpin) 2(7.71g,30.36mmol,1.50eq)，乙酸钾(5.96g,60.72mmol,3.00eq)和Pd(dppf)Cl 2(2.96g,4.05mmol,0.20eq)加入其中，置换氮气并在氮气保护下于90℃反应18小时。反应完成后，用硅藻土过滤，将滤液旋干。粗品用层析柱(SiO 2,PE:EA＝20:1-7:1)纯化。得到WX004-4， 1H NMR(400MHz,CHLOROFORM-d)δppm1.31-1.37(m,12H)2.53-2.58(m,3H)3.90(s,3H)6.92(d,J＝12.17Hz,1H)8.32(d,J＝8.53Hz,1H)
步骤4.化合物WX004-5的合成
将WX004-4溶于四氢呋喃(35.00mL)，加入高碘酸钠(5.09g,23.80mmol,1.32mL,2.00eq)和1N的盐酸溶液(10.00mL)，反应液在25℃下反应18小时。反应完成后，将反应液旋干，加入乙酸乙酯60mL稀释，分别用水40mL，饱和食盐40mL洗有机相，有机相用无水硫酸钠干燥，旋干得粗品。柱层析(SiO 2,PE:EA＝5:1到EA)纯化得到WX004-5。
步骤5.化合物WX004-6的合成
将叠氮钠(9.69g,149.05mmol,2.50eq)和三丁基氯化锡(48.52g,149.05mmol,40.10mL,2.50eq)加入到WX004-6a(4.00g,59.62mmol,4.40mL,1.00eq)的邻二甲苯(50.00mL)溶液中，氮气保护下160℃反应6小时。(反应用具用次氯酸钠淬灭)。反应液冷却到室温后，用20％的氢氧化钠调pH～9，室温搅拌1h后分液。用2N盐酸调节水相的pH＝2,用乙酸乙酯100mL*3萃取，无水硫酸钠干燥，放置挡板旋干后得到WX004-6。 1H NMR(400MHz,METHANOL-d 4)δppm 1.01-1.09(m,2H)1.19-1.25(m,2H)2.17-2.25(m,1H)
步骤6.化合物WX004-7的合成
将WX004-6(800.00mg,7.26mmol,1.00eq)，WX004-5(1.54g,7.26mmol,1.00eq)和Cu 2O(51.98mg,363.00μmol,37.13μL,0.05eq)依次放入二甲亚枫(24.00mL)中，溶液在O 2保护下于110℃反应18小时。反应完成后，将反应液冷却到室温，用二氯甲烷80mL稀释，分别用1M盐酸aq 60mL和饱和食盐水60mL洗，分液后用无水硫酸钠干燥，将有机相旋干。粗品用层析柱(SiO2,石油醚：乙酸乙酯＝1:0到50:1到20:1)纯化。得到WX004-7， 1H NMR(400MHz,CHLOROFORM-d)δppm 1.1(m,2H)1.2(m,2H)2.2(m,1H)2.42(s,3H)3.94(m,3H)7.19(d,J＝10.67Hz,1H)8.19(d,J＝6.65Hz,1H)
步骤7.化合物WX004-8的合成
将WX004-7(500.00mg,1.81mmol,1.00eq)溶于四氢呋喃(5.00mL)和水(5.00mL)中，加入LiOH(130.04mg,5.43mmol,3.00eq)，反应液于25℃下反应2小时用甲基叔丁基醚10mL萃取后要水相，用2N盐酸调pH～2，用乙酸乙酯20mL*3萃取，有机相用无水硫酸钠干燥后旋干。得到WX004-8， 1H NMR(400MHz,CHLOROFORM-d)δppm 1.18(d,J＝6.78Hz,4H)2.26-2.36(m,1H)2.45(s,3H)7.23(d, J＝10.79Hz,1H)8.27(d,J＝6.65Hz,1H)
步骤8.化合物WX004-9的合成
将WX004-8(150.00mg,572.00μmol,1.00eq)放入装有无水二氯甲烷(7.00mL)的拇指瓶中，置换氮气三次后加入草酰氯(123.43mg,972.40μmol,85.12μL,1.70eq)后变为乳浊液，随后加入N,N-二甲基甲酰胺(4.18mg,57.20μmol,4.40μL,0.10eq)，氮气保护下25℃反应1小时。反应液中加入5mL无水二氯甲烷,室温旋～2mL无水二氯甲烷剩余，按此方法重复四次，得到WX004-9溶解在2mL无水二氯甲烷中。m/z＝277.1(M+1)(甲酯MS)
步骤9.化合物WX004的合成
在拇指瓶中将WX004-9(130.40mg,464.58μmol,1.00eq)溶于无水二氯甲烷(3.00mL)，加入WXBB-3(100.00mg,464.58μmol,1.00eq)和二异丙基乙基胺(60.04mg,464.58μmol,81.14μL,1.00eq)，氮气保护下25℃反应18小时。反应液用饱和食盐水10mL洗涤，无水硫酸钠干燥后旋蒸后得到粗品。用prep-HPLC(柱:Waters Xbridge 150*25mm 5μm；流动相:[水(10mM NH 4HCO 3)-ACN]；B％:25％-60％,10.5min)纯化粗品，得到WX004，m/z＝460.2[M+1]。 1H NMR(400MHz,CHLOROFORM-d)δppm1.19(d,J＝6.65Hz,4H)1.94-2.13(m,4H)2.32(t,J＝6.53Hz,1H)2.49(s,3H)3.11(t,J＝6.15Hz,2H)4.52(t,J＝5.96Hz,2H)7.26(br s,1H)7.91(t,J＝8.03Hz,1H)8.11(d,J＝7.28Hz,1H)8.35-8.40(m,1H)8.45(d,J＝7.28Hz,1H)9.01(br d,J＝15.06Hz,1H)
实施例005：WX005
Figure PCTCN2018073640-appb-000054
合成路线：
Figure PCTCN2018073640-appb-000055
步骤1.化合物WX005-3的合成
在预先干燥过的100mL三口烧瓶中加入WX005-3a(2.28g,33.91mmol,2.50mL,1.00eq)，氮气置换三次后加入10mL的盐酸(4.87N在二噁烷中)，随后在氮气的保护下向反应体系中滴加无水乙醇(1.56g,33.91mmol,1.98mL,1.00eq)，加料完毕后，混合物在25℃下反应3小时。反应液过滤旋干得到WX005-3。 1H NMR(400MHz,CHLOROFORM-d)δppm 1.12-1.23(m,4H)1.36(t,J＝7.03Hz,3H)2.30-2.41(m,1H)4.54(q,J＝7.03Hz,2H)11.15(br s,1H)12.24(br s,1H).
步骤2.化合物WX005-2的合成
将WX005-1(1.72g,11.46mmol,1.00eq)溶解在盐酸(63.00mL)中，冷却至0℃，向该溶液中滴加亚硝酸钠(948.49mg,13.75mmol,746.84μL,1.20eq)的水(6.00mL)溶液，滴加完成后在0-5℃反应0.5小时向该反应液中滴加二水合氯化锡(7.76g,34.38mmol,2.86mL,3.00eq)的盐酸(4mL,37％)溶液，反应在25℃下进行3小时，生成大量灰色沉淀。反应完成后，将反应液过滤，滤饼中加入甲醇(20mL)。用饱和碳酸氢钠水溶液调节滤液pH值至8，用乙酸乙酯(3×100mL)萃取。有机相合并后用饱和食盐水(2×100mL)洗涤，无水硫酸钠干燥，减压浓缩得到深黄色固体。深黄色固体通过快速柱层析分离(硅胶目数：100-200目；DCM:MeOH:20:1)，得到产物WX005-2。m/z＝166.3[M+1].
步骤3.化合物WX005-5的合成
在预先干燥的40mL投库瓶中加入WX005-2(3.00g,14.88mmol,1.00eq)和WX005-3(2.23g,14.88mmol,1.00eq)，随后加入无水乙醇(45.00mL)，紧接着加入三乙胺(3.01g,29.76mmol,4.12mL,2.00eq)，在20℃下反应半小时。用旋蒸旋出溶剂。然后向粗产品中分别加入WX005-4(15.79g,148.80mmol,16.28mL,10.00eq)和氨甲酸(1.88g,29.76mmol,2.00eq)温度升到℃后反应15.5小时。将反应体系冷却至室温，加入饱和碳酸氢钠50毫升和50毫升乙酸乙酯稀释，分液后收集有机相，水相用乙酸乙酯萃取(20毫升x3)。合并有机相，用饱和食盐水洗涤(50毫升)，无水硫酸钠干燥，减压浓缩得到残余物黄色固体。粗产品通过乙酸乙酯/石油醚＝1/5(30毫升)重结晶，得到产物WX005-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.01(s,1H),7.54(d,J＝5.9Hz,1H),7.23-7.13(m,1H),2.31-2.21(m,3H),2.05(quin,J＝6.6Hz,1H),0.97(d,J＝6.7Hz,4H)
步骤4.化合物WX005-6的合成
在预先干燥过的100毫升烧瓶中加入WX005-5(500.00mg,2.06mmol,1.00eq)，溶于盐酸(10.20g,279.76mmol,10.00mL,135.81eq)。反应在100℃并搅拌16小时。将反应体系冷却至室温，冷却后有大量固体析出，用五孔漏斗过滤收集滤饼，得到WX005-6。 1H NMR(400MHz,METHANOL-d4)δ＝9.67(s,1H),8.06(d,J＝6.6Hz,1H),7.36(d,J＝11.0Hz,1H),2.32(s,3H),2.26-2.11(m,1H),1.27-1.18(m,2H),1.15-1.05(m,2H)
步骤5.化合物WX005-7的合成
在预先干燥的40mL投库瓶瓶中加入WX005-6(300.00mg,1.15mmol,1.00eq)，加入无水二氯甲烷(5.00mL)置换氮气后在0℃下缓慢滴加草酰氯(291.51mg,2.30mmol,201.04μL,2.00eq)和无水N,N-二甲基甲酰胺(8.39mg,114.83μmol,8.83μL,0.10eq)，滴加完毕后在20℃下反应1小时。将反应体系减压浓缩并用无水二氯甲烷反复溶解再旋干3次，得到WX005-7。
步骤6.化合物WX005的合成
在预先干燥过的40毫升投库瓶中加入原料WX005-7(300.00mg,1.07mmol,1.00eq)，接着加入二氯甲烷(3mL)。用氮气置换后在冰水浴中冷却至0℃，随后加入原料WXBB-3(230.32mg,1.07mmol,1.00eq)，在0℃将二异丙基乙基胺(138.29mg,1.07mmol,186.88uL,1.00eq)的二氯甲烷(2mL)溶液缓慢加入。自然升温至室温，反应在20℃并搅拌16小时。向反应体系中加入10毫升水/10毫升二氯甲烷稀释，分液后收集有机相，水相用二氯甲烷萃取(5毫升x3)。合并有机相，用饱和食盐水洗涤(20毫升)，无水硫酸钠干燥，减压浓缩得到残余物。粗产品通过Prep-HPLC分离(中性)，纯化得到产物纯品WX005。 1H NMR(400MHz,CHLOROFORM-d)δ＝9.02(br d,J＝14.8Hz,1H),8.36(d,J＝7.7Hz,1H), 8.16-8.08(m,2H),7.90(t,J＝7.9Hz,1H),7.22(d,J＝12.3Hz,1H),4.51(t,J＝6.1Hz,2H),3.10(t,J＝6.5Hz,2H),2.37(s,3H),2.22-2.11(m,1H),2.11-2.03(m,2H),2.02-1.92(m,2H),1.10-1.00(m,4H)
实施例006：WX006
Figure PCTCN2018073640-appb-000056
合成路线：
Figure PCTCN2018073640-appb-000057
步骤1.化合物WX006-2的合成
在预先干燥的250mL的三口烧瓶中加入WX006-1(100.00g,455.48mmol,1.00eq)和EtOH(700.00mL)，向反应液中滴加H 2SO 4(223.37g,2.28mol,121.40mL,5.00eq)80℃下回流5小时。将反应体系冷却至室温，加入200mL EA稀释，分液后收集有机相，水相用EA萃取(2*100毫升)。合并有机相，依次用饱和碳酸氢钠水溶液(2*100毫升)，水(2*100毫升)、饱和食盐水洗涤(2*100毫升)，无水硫酸钠 干燥，减压浓缩得到残余物。得到WX006-2。
步骤2.化合物WX006-3的合成
在预先干燥的2L的圆底烧瓶中加入WX006-2(117.00g,472.52mmol,1.00eq)，Fe(65.98g,1.18mol,2.50eq)NH 4Cl(27.80g,519.77mmol,18.17mL,1.10eq)溶剂H 2O(345.00mL)和EtOH(1.10L)，该反应液在80℃下回流6小时。将反应液冷却至室温，通过铺有硅藻土的布氏漏斗，滤饼用二氯甲烷(300mL)洗涤，滤液用二氯甲烷(2×400mL)萃取。合并有机相，用饱和食盐水(2×300mL)洗涤，经无水硫酸钠干燥，减压浓缩得到残余物。得到WX006-3。
步骤3.化合物WX006-4的合成
在预先干燥过的500mL圆底烧瓶中加入WX006-3(37.00g,,170.02mmol,1.00eq)，WXBB-1-3(47.56g,187.02mmol,1.10eq)和DIEA(65.92g,510.06mmol,89.08mL,3.00eq)，随后加入二甲苯(300.00mL)，并在140℃下继续搅拌10小时。将反应体系冷却至室温，加入150mL水稀释，分液后收集有机相，水相用EA萃取(2*150毫升)。合并有机相，依次用饱和氯化铵(2*150毫升)，饱和食盐水洗涤(2*100毫升)洗涤，无水硫酸钠干燥，减压浓缩得到WX006-4。
步骤4.化合物WX006-5的合成
在预先干燥过的500mL烧瓶中加入WX006-4(47.80g,159.48mmol,1.00eq)和AcOH(250.00mL),随后加入硫氰酸钾(31.00g,318.96mmol,31.00mL,2.00eq)，在110℃下继续搅拌4小时。反应完全后，反应液直接减压旋干，旋干后的残余物重新溶于DCM(150mL)中，加入水(150mL)，水相用DCM(2×100mL)萃取。合并有机相，无水硫酸钠干燥后，抽滤减压旋干。残余物通过EA(15毫升)重结晶，得到WX006-5。
步骤5.化合物WX006-6的合成
在预先干燥过的250毫升三口烧瓶中加入醋酸(53.19mL)，水(10.00mL)和双氧水(4.49g,39.61mmol,3.81mL,30％纯度,3.00eq)，加入内温度计使反应温度控制在45℃，紧接着分批加入WX006-5(4.5g,13.20mmol,1.00eq)使温度控制在55℃以下，在此温度下反应30min。反应30min后冷却至室温，加入饱和的亚硫酸钠溶液20mL，并用淀粉碘化钾试纸检测无变蓝，减压旋蒸后溶于100mL水中，氨水调制pH值为10，然后用二氯甲烷萃取(2×150mL)，合并有机相用无水硫酸钠干燥后减压旋蒸。粗品经硅胶柱(EA:PE＝1:10-1:2),得到WX006-6。
步骤6.化合物WX006-7的合成
在预先干燥过的250ml圆底烧瓶中加入WX006-6(3.85g,12.47mmol,1.00eq)，氢氧化锂(895.97mg,37.41mmol,3.00eq)和四氢呋喃(38.00mL)，水(38.00mL)，该澄清溶液在25℃下搅拌2小时。用2N的盐酸调至pH值为4-5后，用氯仿：异丙醇(3:1，5×50mL)萃取，合并有机相，无水硫酸钠干燥后，抽滤减压旋蒸得到WX006-7。m/z＝281.1[M+1].
步骤7.化合物WX006-8的合成
在预先干燥的100mL圆底烧瓶中加入WX006-7(2.06g,7.34mmol,1.00eq)，氮气置换三次后加入二氯甲烷(54.00mL)，随后在氮气保护下缓慢滴加草酰氯(1.86g,14.68mmol,1.29mL,2.00eq)和N,N-二甲基甲酰胺(53.65mg,734.00μmol,56.47μL,0.10eq)，滴加完毕后在25℃下反应1小时。直接在水泵旋蒸，当溶液体积大约降至三分之一时，再加10mL无水二氯甲烷，连续三次，得到WX006-8在二氯甲烷中的溶液直接用于下一步反应。m/z＝295.1[M+14].
步骤8.化合物WX006-9的合成
氮气抽换气三次装有WX006-8(1.08g,3.61mmol,1.00eq)的100mL圆底烧瓶，之后加入二氯甲烷(30mL)和二异丙基乙基胺(699.93mg,5.42mmol,943.30μL,1.5eq)，在氮气保护下加入WXBB-3(816.03mg,3.79mmol,1.05eq)，该澄清溶液在25℃下反应0.5小时。用二氯甲烷(20mL)重新溶解产物，用pH＝2的水(3×30mL)萃取，后将水相调制pH＝10后，用二氯甲烷(3×50mL)萃取。合并有机相，无水硫酸钠干燥，抽滤旋干后得到WX006-9。m/z＝478.2[M+1]
步骤9.化合物WX006的合成
在预先干燥过的10mL拇指瓶中加入WX006-9(0.3g,627.72μmol,1.00eq)，3-吡啶硼酸(154.32mg,1.26mmol,2.00eq)，醋酸钯(14.09mg,62.77μmol,0.10eq)，正丁基二(1-金刚烷基)膦(22.51mg,62.77μmol,0.10eq)和碳酸钾(260.27mg,1.88mmol,3.00eq)，氮气抽换气三次之后加入水(0.5mL)和二氧六环(5mL)，在氮气保护下将反应容器置于90℃的油浴中，搅拌2小时。反应液直接旋干后，快速通过短硅胶柱(100-200目纯化得到WX006。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.59-0.67(m,2H)0.73-0.83(m,2H)1.73(ddd,J＝13.34,8.38,4.96Hz,1H)1.86-2.07(m,4H)3.03(br t,J＝6.28Hz,2H)4.44(br t,J＝5.95Hz,2H)6.53(s,1H)7.16(s,1H)7.21-7.26(m,1H)7.32(d,J＝11.91Hz,1H)7.85(t,J＝8.05Hz,1H)8.05(d,J＝7.72Hz,1H)8.17(d,J＝7.06Hz,1H)8.31(d,J＝8.38Hz,1H)8.46(d,J＝1.76Hz,1H)8.57(dd,J＝4.52,1.65Hz,1H)8.99(br d,J＝13.89Hz,1H)
实施例007：WX007
Figure PCTCN2018073640-appb-000058
合成路线：
Figure PCTCN2018073640-appb-000059
步骤1.化合物WX007-2的合成
在预先干燥的250mL圆底烧瓶中加入2-溴-1-甲氧基乙烷(20g,84.75mmol,1eq)和N,N-二甲基甲酰胺(150mL)，然后加入WX007-1(14.13g,101.70mmol,9.55mL,1.2eq)和碳酸钾(23.43g,169.49mmol,2eq)，体系在50℃下反应20小时。将反应液旋干后重新溶解于乙酸乙酯(100mL)和水(100mL)中，分离有机相和水相后用乙酸乙酯(3×50mL)萃取水相，合并有机相，用饱和食盐水(2×150mL)洗涤有机相，无水硫酸钠干燥，抽滤后得到粗品。粗品通过快速硅胶柱(EA:PE＝1:10-1:4)纯化WX007-2。 1H NMR(400MHz,CHLOROFORM-d)δppm 3.41(s,3H)3.73-3.82(m,2H)4.14-4.28(m,1H)4.14-4.28(m,1H)6.93(d,J＝9.92Hz,1H)8.10(d,J＝7.28Hz,1H)
步骤2.化合物WX007-3的合成
在预先干燥的1000mL的茄形瓶中加入WX007-2(22.3g,75.83mmol,1.00eq)，铁粉(12.71g,227.49mmol,3eq)，氯化铵(4.46g,83.41mmol,2.92mL,1.10eq),水(130mL)和乙醇(400mL)。该反应液在80℃下回流6小时。反应液通过硅藻土后，旋干。溶于二氯甲烷(100mL)和水(80mL)，用二氯甲烷 (2×50mL)萃取水相，合并有机相，用饱和食盐水(2×100mL)洗涤有机相，干燥，过滤浓缩得到粗品。通过快速硅胶柱(乙酸乙酯：石油醚＝1:8-1:1)得到WX007-3。 1H NMR(400MHz,CHLOROFORM-d)δppm 3.41(s,3H)3.71-3.77(m,4H)4.06-4.10(m,2H)6.62(d,J＝9.92Hz,1H)6.80(d,J＝6.84Hz,1H)。
步骤3.化合物WX007-4的合成
在预先干燥的500mL反应瓶中加入WX007-3(12.64g,47.86mmol,1.00eq)，WXBB-10(13.39g,52.65mmol,1.10eq)和甲苯(120mL)，反应升至100℃后加入二异丙基乙基胺(12.37g,95.72mmol,16.67mL,2.00eq)，并在100℃下反应10小时。旋干后层析柱纯化(乙酸乙酯：石油醚＝0-1:10),得到WX007-4。m/z＝346.1,348.1[M+1].
步骤4.化合物WX007-5的合成
在预先干燥的500mL圆底烧瓶中加入WX007-4(14.85g,42.90mmol,1.00eq)和冰乙酸(200mL)，随后加入硫氰酸钾(8.34g,85.79mmol,8.34mL,2.00eq)，反应升至110℃反应3小时。反应完全后，反应液直接减压旋干，旋干后的残余物重新溶于二氯甲烷(60mL)中，加入水(60mL)，水相用二氯甲烷(2×40mL)萃取。合并有机相，有机相用饱和食盐水(2×50mL)洗涤，无水硫酸钠干燥后，抽滤减压旋干。层析柱纯化(乙酸乙酯：石油醚＝1:10-1:1)，得到WX007-5。m/z＝387.1,389.1[M+1].
步骤5.化合物WX007-6的合成
在预先干燥过的250毫升三口烧瓶中加入冰乙酸(100mL)，水(18mL)和过氧化氢(9.39g,82.80mmol,7.95mL,30％纯度,3.00eq)，加入内温度计使反应温度控制在45℃，紧接着分批加入WX007-5(10.69g,27.60mmol,1.00eq)使温度控制在55℃以下，在此温度下反应30min。反应冷却至室温，加入饱和的亚硫酸钠溶液20mL，并用淀粉碘化钾试纸检测无变蓝，减压旋蒸后溶于100mL水中，氨水调制pH值为10，然后用二氯甲烷萃取(2×150mL)，合并有机相用无水硫酸钠干燥后减压旋蒸得到WX007-6。m/z＝355.1,357.1[M+1].
步骤6.化合物WX007-7的合成
在250毫升氢化瓶中加入WX007-6(7.1g,19.99mmol,1.00eq)和三乙胺(4.05g,39.98mmol,5.56mL,2.00eq)，随后加入甲醇(100mL)和Pd(dppf)Cl 2(2.19g,3.00mmol,0.15eq),用一氧化碳抽换气三次并加压到50psi。反应容器置于70℃的油浴(外温)搅拌10小时。反应液旋干后经层析柱(乙酸乙酯：石油醚＝1:10-1:1)分离，得到WX007-7， 1H NMR(400MHz,CHLOROFORM-d)δppm 0.70-0.78(m,2H)0.81-0.89(m,2H)1.81-1.91(m,1H)3.36(s,3H)3.66-3.73(m,2H)3.88(s,3H)4.14-4.21(m,2H)6.78(d,J＝11.69Hz,1H)6.90(s,1H)7.66(s,1H)7.84(d,J＝7.50Hz,1H)
步骤7.化合物WX007-8的合成
在预先干燥过的100mL烧瓶中加入WX007-7(0.6g,1.79mmol,1.00eq)，氢氧化锂(128.94mg,5.38mmol, 3.00eq)，四氢呋喃(12mL)和水(12mL)，该澄清溶液在25℃下搅拌1小时。反应完全后，将反应液直接在水泵旋干后加入甲苯(2×10mL)带走未旋去的水分，得到WX007-8，m/z＝321.2[M+1]
步骤8.化合物WX007-9的合成
在预先干燥的100mL圆底烧瓶中加入WX007-8(574.83mg,1.79mmol,1.00eq)，氮气置换三次后加入二氯甲烷(20mL)，随后在氮气保护下缓慢滴加草酰氯(455.57mg,3.59mmol,314.19μL,2.00eq)和N,N-二甲基甲酰胺(13.12mg,179.46μmol,13.81μL,0.10eq)，滴加完毕后在25℃下反应1小时。反应完全后，将反应液直接在水泵旋蒸，当溶液体积大约降至三分之一时，再加20mL无水二氯甲烷，连续三次，得到WX007-9在二氯甲烷中的溶液直接用于下一步反应。m/z＝335.2[M+14]
步骤9.化合物WX007的合成
氮气抽换气三次装有WX007-9(721.80mg,2.13mmol,1.05eq)的100mL圆底烧瓶，之后加入二氯甲烷(30mL)和二异丙基乙基胺(393.39mg,3.04mmol,530.17μL,1.5eq)，在氮气保护下加入WXBB-3(687.43mg,2.03mmol,1.00eq)，该澄清溶液在25℃下反应10小时。用pH＝2的水(3×30mL)萃取，后将水相调制pH＝10后，用二氯甲烷(3×50mL)萃取。合并有机相，无水硫酸钠干燥，抽滤旋干后得到粗品。经快速制备分离得到WX007(42.7mg,82.50μmol,4.07％产率)。 1H NMR(400MHz,METHANOL-d4)δppm0.78-0.91(m,2H)1.02-1.10(m,2H)1.98-2.13(m,5H)3.05(t,J＝6.40Hz,2H)3.41(s,3H)3.77(dd,J＝5.14,3.39Hz,2H)4.34-4.42(m,2H)4.59(t,J＝5.96Hz,2H)7.32(d,J＝12.42Hz,1H)7.46(s,1H)7.91(d,J＝7.15Hz,1H)7.99-8.06(m,2H)8.34(d,J＝7.78Hz,1H)8.66(s,1H)
实施例008：WX008
Figure PCTCN2018073640-appb-000060
合成路线：
Figure PCTCN2018073640-appb-000061
步骤1：化合物WX008-2的合成
将WX008-1(28g,118.65mmol,1eq)溶解于无水DMF(200mL)中，加入K 2CO 3(32.80g,237.29mmol,2eq)和BnBr(24.35g,142.38mmol,16.91mL,1.2eq)，混合物在20℃下搅拌16小时。将反应液倒入水(600mL)中，用EA(300mL*2)萃取，有机相用水(300mL)和饱和食盐水(300mL)洗，无水硫酸钠干燥，过滤，滤液减压旋干。粗品用PE/EA＝5/1(120mL)在20℃打浆0.5小时，过滤，滤饼减压抽干。得到WX008-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.20(d,J＝7.3Hz,1H),7.50-7.38(m,5H),6.94(d,J＝9.8Hz,1H),5.25(s,2H)
步骤2：化合物WX008-3的合成
将WX008-2(26.5g,81.26mmol,1eq)溶于MeOH(500mL)，分批加入NiCl 2.6H 2O(69.53g,292.53 mmol,3.6eq)，0℃下分批次加入NaBH 4(15.37g,406.26mmol,5eq)混合在25℃下搅拌0.5小时。向反应液中加入饱和氯化铵溶液(500mL)，旋掉甲醇，加入EA(500mL)，搅拌10分钟，过滤掉不溶的固体，滤液分液得到有机相，水相再用EA(250mL)萃取，合并有机相，饱和食盐水(250mL)洗，无水硫酸钠干燥，过滤，滤液减压旋干得到WX008-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.43(br s,5H),6.87(br d,J＝5.0Hz,1H),6.70(br d,J＝9.5Hz,1H),5.07(br s,2H),3.75(br s,2H)
步骤3：化合物WX008-4的合成
将WX008-3(22g,63.81mmol,1eq)(纯度：85.59％)加入到无水甲苯(200mL)中，加入WXBB-1-3(17.04g,67.00mmol,1.05eq)和DIEA(16.49g,127.62mmol,22.23mL,2eq)，混合物在100℃下搅拌16小时。将反应液旋干，加入水(200mL)，EA(200mL*2)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。向粗品中加入PE/EA＝5/1(60mL)，20℃下打浆0.5小时，过滤，滤饼减压旋干得到WX008-4。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.38-7.23(m,5H),6.58(d,J＝9.8Hz,1H),6.48(d,J＝6.8Hz,1H),5.02(br d,J＝4.8Hz,1H),5.00(s,2H),4.06(d,J＝5.0Hz,2H),1.98-1.88(m,1H),1.08(quin,J＝3.8Hz,2H),0.96-0.87(m,2H)
步骤4：化合物WX008-5的合成
将WX008-4(15g,35.58mmol,1eq)(纯度：89.71％)加入到AcOH(120mL)中，加入KSCN(6.91g,71.15mmol,6.91mL,2eq)，混合物在110℃氮气保护下搅拌4小时。反应液冷却至室温，倒入水(300mL)中，搅拌15分钟，固体析出，过滤，滤饼减压旋干得到WX008-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝11.56(br s,1H),7.60(d,J＝7.3Hz,1H),7.30-7.21(m,5H),6.79(d,J＝9.8Hz,1H),6.31(s,1H),5.02(s,2H),1.67-1.58(m,1H),0.84-0.77(m,2H),0.61-0.53(m,2H)
步骤5：化合物WX008-6的合成
将WX008-5溶于AcOH(150mL)和H 2O(15mL)的混合溶液，滴加H 2O 2(12.97g,114.42mmol,10.99mL,30％纯度,3.22eq)，体系在45℃下搅拌0.5小时。冷却至室温，将反应液慢慢加到亚硫酸钠(30g)的水溶液(300mL)中，用EA(300mL*2)萃取，有机相饱和碳酸氢钠(300mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。粗品经过柱纯化(EA/PE＝0～10％～20％)得到WX008-6。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.64(d,J＝1.0Hz,1H),7.48(d,J＝7.0Hz,1H),7.42-7.34(m,3H),7.33-7.29(m,2H),6.94-6.88(m,2H),5.11(s,2H),1.95-1.86(m,1H),0.92-0.86(m,2H),0.83-0.77(m,2H)
步骤6：化合物WX008-7的合成
将WX008-6(6g,14.56mmol,1eq)(纯度93.95％)溶于无水MeOH(100mL)，加入Pd(dppf)Cl 2(1.07g,1.46mmol,0.1eq)，Et 3N(2.95g,29.11mmol,4.05mL,2eq)，体系在CO(50psi)条件下于80℃搅拌4小时。反应液过滤，滤液减压旋干。粗品经过柱纯化(EA/PE＝0～10％～20％～40％)得到WX008-7。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.92(d,J＝7.5Hz,1H),7.67(d,J＝0.8Hz,1H),7.44-7.31(m,5H), 6.93(d,J＝0.8Hz,1H),6.87(d,J＝11.8Hz,1H),5.19(s,2H),3.94(s,3H),1.96-1.86(m,1H),0.93-0.86(m,2H),0.84-0.78(m,2H)
步骤7：化合物WX008-8的合成
将WX008-7(2.7g,7.37mmol,1eq)溶于无水THF(20mL)，加入LiOH(530mg,22.13mmol,3eq)溶于H 2O(10mL)中的溶液，混合物在20℃搅拌1小时。把反应液直接拉干得到粗品。粗品用(DCM：MeOH＝10:1，44mL)在20℃打浆0.5小时，过滤，滤液减压旋干得到WX008-8。 1H NMR(400MHz,DMSO-d 6)δppm 0.59-0.65(m,2H)0.69-0.78(m,2H)1.73-1.83(m,1H)5.15(s,2H)6.99(d,J＝11.80Hz,1H)7.08(s,1H)7.33(br dd,J＝7.78,4.77Hz,1H)7.36(d,J＝1.51Hz,2H)7.37(br s,2H)7.57(d,J＝7.78Hz,1H)7.64(s,1H)
步骤8：化合物WX008-9的合成
在预先干燥的50mL圆底烧瓶中加入化合物WX008-8(690mg,1.96mmol,1eq),氮气置换三次后加入二氯甲烷(50mL)，随后于氮气保护下在25℃缓慢滴加草酰氯(497.12mg,3.92mmol,342.84μL,2eq)和N,N-二甲基甲酰胺(14.31mg,195.82μmol,15.07μL,0.1eq)，滴加完毕后在25℃下反应1小时。反应液直接在水泵旋蒸，当溶液体积大约降至三分之一时，再加50mL无水二氯甲烷，连续三次，后直接用于下一步反应。得到WX008-9(0.726g)的二氯甲烷溶液。MS:m/z＝367[甲酯M+1].
步骤9：化合物WX008-10的合成
向装有化合物WX008-9(0.726g,1.96mmol,1eq)的圆底烧瓶中加入二氯甲烷(30mL)，随后将化合物WXBB-3(442.52mg,2.06mmol,1.05eq)的二氯甲烷(20mL)溶液快速滴入反应瓶中，最后在氮气保护下加入二异丙基乙胺(278.34mg,2.15mmol,375.13μL,1.1eq),该澄清溶液在25℃下反应1小时。将反应液浓缩后，用二氯甲烷(100mL)重新溶解产物，加入1M盐酸水溶液调到pH＝2-3充分搅拌后静置分层后分液，要水相并将水相用碳酸氢钠调制pH＝8-9后析出固体，过滤得到固体用二氯溶解后用无水硫酸钠干燥，过滤，滤液浓缩后得到WX008-10(0.8g,1.30mmol,66.17％产率,89％纯度)。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.89(br d,J＝14.8Hz,1H),8.28(d,J＝8.2Hz,1H),8.07(d,J＝8.2Hz,1H),8.00(d,J＝7.5Hz,1H),7.82(t,J＝7.9Hz,1H),7.65(d,J＝0.9Hz,1H),7.36-7.30(m,2H),7.30-7.25(m,2H),6.90(s,1H),6.84(d,J＝13.5Hz,1H),5.15(s,2H),4.41(t,J＝6.0Hz,2H),3.02(t,J＝6.4Hz,2H),2.04-1.95(m,2H),1.94-1.88(m,2H),1.83(br dd,J＝4.1,9.2Hz,1H),0.87-0.79(m,2H),0.76-0.69(m,2H)。
步骤10：化合物WX008的合成
将化合物WX008-9(0.8g,1.46mmol,1eq)溶于甲醇(50mL)，加入钯碳(0.8g,50％纯度)，混合物在氢气(50Psi)条件下于25℃搅拌2小时。将反应液用硅藻土过滤，滤饼依次用甲醇(500mL),二氯甲烷(500mL),四氢呋喃(500mL)和甲醇(500mL)洗涤。滤液减压浓缩得到粗品，粗品用甲醇(10mL)打浆，过滤，滤液浓缩后得到WX008(0.15g,319.93μmol,21.98％产率,98％纯度)。 1H NMR(400MHz,DMSO- d6)δ＝10.66(s,1H),8.16(d,J＝7.9Hz,1H),7.98(t,J＝7.9Hz,1H),7.85(d,J＝7.5Hz,1H),7.80(s,1H),7.69(d,J＝7.5Hz,1H),7.23(d,J＝0.9Hz,1H),6.90(d,J＝11.9Hz,1H),4.47(t,J＝5.8Hz,2H),2.91(t,J＝6.3Hz,2H),1.92(br d,J＝4.6Hz,2H),1.88-1.79(m,3H),0.82-0.75(m,2H),0.71-0.64(m,2H)。
实施例009：WX009
Figure PCTCN2018073640-appb-000062
合成路线：
Figure PCTCN2018073640-appb-000063
步骤1：化合物WX009的合成
往预先干燥的40mL投库小瓶中依次加入化合物WX008(200mg,435.28μmol,1eq)，碳酸钾(120.32mg,870.56μmol,2eq)，丙酮(50mL)和2-溴乙醇(81.59mg,652.92μmol,46.36μL,1.5eq)。反应溶液在75℃搅拌16小时。反应溶液用油泵减压浓缩得到固体粗品。固体粗品用N,N-二甲基甲酰胺(8mL)溶解后经快速制备分离(水(10mM NH 4HCO 3)-CAN)，纯化得到化合物WX009。 1H NMR(400MHz,METHANOL-d4)δ＝8.32(d,J＝8.2Hz,1H),8.02-7.88(m,4H),7.23(m,2H),4.57(t,J＝5.8Hz,2H),4.30-4.22(m,2H),3.90(t,J＝4.4Hz,2H),3.07-2.99(m,2H),2.06(br d,J＝4.2Hz,2H),2.00(br s,2H),1.89(br s,1H),0.87(br d,J＝6.0Hz,2H),0.75(br s,2H)。
实施例010：WX010
Figure PCTCN2018073640-appb-000064
合成路线：
Figure PCTCN2018073640-appb-000065
步骤1：化合物WX010-2的合成
在预先干燥的40mL反应瓶中加入化合物WX010-1(200mg,1.96mmol,194.17μL,1eq)和二氯甲烷(5mL)，然后依次加入三乙胺(297.24mg,2.94mmol,408.85μL,1.5eq)，二甲氨基吡啶(23.92mg,195.83μmol,0.1eq)和对甲苯磺酰氯(448.01mg,2.35mmol,1.2eq)。反应液在25℃搅拌3小时。向反应液中加入饱和氯化铵水溶液(10mL)，用二氯甲烷萃取(10mLx3)，合并有机相，无水硫酸钠干燥，减压浓缩得粗品。粗产品通过薄层层析硅胶板(石油醚:乙酸乙酯＝3:1)纯化得到WX010-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.82(d,J＝8.2Hz,2H),7.37(d,J＝7.9Hz,2H),4.44-4.30(m,4H),4.12(s,2H),2.47(s,3H),1.32(s,3H)。
步骤2：化合物WX010的合成
往预先干燥的40mL反应瓶中依次加入化合物WX008(100mg,217.64μmol,1eq),碳酸钾(45.12mg,326.46μmol,1.5eq),N,N-二甲基甲酰胺(4mL)和化合物WX010-2(66.94mg,261.17μmol,1.2eq)。反应溶液在80℃搅拌16小时。反应液经快速制备分离(水(10mM NH 4HCO 3)-ACN)纯化后得到WX010。1H NMR(400MHz,CHLOROFORM-d)δ＝8.99(d,J＝14.8Hz,1H),8.37(d,J＝8.2Hz,1H),8.17(d,J＝8.2Hz,1H),8.09(d,J＝7.7Hz,1H),7.91(t,J＝8.0Hz,1H),7.63(d,J＝1.3Hz,1H),6.98-6.89(m,2H),4.54-4.49(m,2H),4.48(s,4H),4.23(s,2H),3.11(t,J＝6.4Hz,2H),2.09-2.08(m,2H),2.06–2.00(m,2H),1.99-1.91(m,1H),1.39(s,3H),0.90-0.88(m,2H),0.82-0.79(m,2H)。
实施例011：WX011
Figure PCTCN2018073640-appb-000066
合成路线：
Figure PCTCN2018073640-appb-000067
步骤1：化合物WX011-2的合成
在预先干燥的40mL反应瓶中加入化合物WX011-1(200mg,2.27mmol,1eq)和二氯甲烷(5mL)，然后依次加入三乙胺(344.56mg,3.41mmol,473.94μL,1.5eq)，二甲氨基吡啶(27.73mg,227.00μmol,0.1eq)和对甲苯磺酰氯l(519.34mg,2.72mmol,1.2eq)。反应液在25℃搅拌16小时。向反应液中加入饱和氯化铵水溶液(20mL)，用二氯萃取(20mLx3)，合并有机相，无水硫酸钠干燥，减压浓缩得粗品。粗产品通过薄层层析硅胶板(石油醚:乙酸乙酯＝3:1)纯化得到WX011-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.78(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),4.70(dd,J＝7.6,6.4Hz,2H),4.30(t,J＝6.4Hz,2H),4.23(d,J＝76.8Hz,2H),3.29-3.22(m,1H),2.43(s,3H)
步骤2：化合物WX011的合成
往预先干燥的40mL反应瓶中加入化合物WX008(100mg,217.64μmol,1eq)和N,N-二甲基甲酰胺(4mL)然后依次加入碳酸钾(45.12mg,326.46μmol,1.5eq)，碘化钾(18.06mg,108.82μmol,0.5eq)和化合物WX011-2(63.28mg,261.17μmol,2.32μL,1.2eq)。反应溶液在80℃搅拌16小时。反应液过滤后经快速制备分离纯化。反应液经快速制备分离纯化得到WX011。1H NMR(400MHz,DMSO-d6)δ＝10.83(s,1H),8.17(d,J＝7.7Hz,1H),8.00(t,J＝8.0Hz,1H),7.87(dd,J＝0.8,7.6Hz,1H),7.80-7.74(m,2H),7.40(d,J＝12.1Hz,1H),7.24(d,J＝1.3Hz,1H),4.68(dd,J＝6.2,7.9Hz,2H),4.47(br t,J＝5.7Hz,2H),4.43-4.37(m,4H),3.44-3.36(m,1H),2.92(t,J＝6.3Hz,2H),1.97-1.89(m,2H),1.84(br dd,J＝5.2,8.5Hz,3H),0.81-0.75(m,2H),0.68-0.63(m,2H)
实施例012：WX012
Figure PCTCN2018073640-appb-000068
合成路线：
Figure PCTCN2018073640-appb-000069
步骤1：化合物WX012的合成
往预先干燥的40mL反应瓶中依次加入化合物WX008(150mg,221.99μmol,1eq)，碳酸钾(61.36mg,443.99μmol,2eq)，N,N-二甲基甲酰胺(4mL)和1-溴-2-氟-乙烷(56.37mg,443.99μmol,30.91μL,2eq)。反应溶液在100℃搅拌5小时。将反应溶液用滤头过滤得到澄清的溶液，经快速制备分离纯化得到WX012。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.98(br d,J＝14.8Hz,1H),8.39-8.33(m,1H),8.16(d,J＝8.2Hz,1H),8.08(dd,J＝0.9,7.7Hz,1H),7.95-7.86(m,1H),7.73(d,J＝1.1Hz,1H),6.99(d,J＝1.1Hz,1H),6.89(d,J＝13.2Hz,1H),4.86-4.81(m,1H),4.75-4.68(m,1H),4.50(t,J＝6.1Hz,2H),4.41-4.37(m,1H),4.36-4.31(m,1H),3.10(t,J＝6.4Hz,2H),2.11-2.03(m,2H),2.02-1.95(m,2H),1.95-1.88(m,1H),0.94-0.87(m,2H),0.87-0.81(m,2H).
实施例013：WX013
Figure PCTCN2018073640-appb-000070
合成路线：
Figure PCTCN2018073640-appb-000071
步骤1：化合物WX013的合成
往预先干燥的40mL反应瓶中依次加入化合物WX008(100mg,148.00μmol,1eq)，碳酸钾(40.91mg,295.99μmol,2eq)，N,N-二甲基甲酰胺(1mL)和1-溴-3-氟-丙烷(41.73mg,295.99μmol,30.91μL,2eq)。反应溶液在90℃搅拌2小时。将反应溶液用滤头过滤得到澄清的溶液。该澄清溶液经快速制备分离纯化得到WX013。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.99(br d,J＝15.2Hz,1H),8.37(d,J＝8.2Hz,1H),8.15(d,J＝8.2Hz,1H),8.08(d,J＝7.7Hz,1H),7.90(t,J＝8.0Hz,1H),7.67(d,J＝0.9Hz,1H),6.96-6.86(m,2H),4.64(t,J＝5.5Hz,1H),4.56-4.47(m,3H),4.25(t,J＝6.1Hz,2H),3.10(t,J＝6.4Hz,2H),2.24(t,J＝5.7 Hz,1H),2.18(t,J＝5.7Hz,1H),2.11-2.03(m,2H),2.02-1.95(m,2H),1.94-1.87(m,1H),0.94-0.86(m,2H),0.85-0.79(m,2H)
实施例014：WX014
Figure PCTCN2018073640-appb-000072
合成路线：
Figure PCTCN2018073640-appb-000073
步骤1：化合物WX014-2的合成
将化合物WX014-1(24g,101.70mmol,1eq)溶于无水二氯甲烷(200mL)，加入二甲氨基吡啶(0.65g,5.32mmol,0.05eq)，二异丙基乙胺(26.29g,203.39mmol,35.43mL,2eq)，将体系降温至0℃，在0℃下缓慢加入三氟甲磺酸酐(43.04g,152.55mmol,25.17mL,1.5eq)，然后升温至20℃搅拌2小时。在搅拌下向反应液中加入水(200mL)，将有机相减压旋干得到粗品。粗品经过过柱(乙酸乙酯/石油醚＝0～5％)纯化得到化合物WX014-2。 1H NMR(400MHz,CHLOROFORM-d)δppm 7.29(d,J＝7.53Hz,1H)8.51(d,J＝6.52Hz,1H)。
步骤2：化合物WX014-3的合成
将化合物WX014-2(24g,65.21mmol,1eq)溶于无水甲苯(200mL)，用氮气置换3次，加入二甲胺(4.80g,58.86mmol,5.39mL,0.9eq,HCl)，叔丁醇钠(9.36g,97.39mmol,1.49eq)和Pd 2(dba) 3(4.80g,5.24mmol,0.08eq)，混合物在氮气环境下于105℃搅拌12小时。反应液冷却至室温，加入水(400mL)，用乙酸乙酯200mL*3)萃取，合并有机相，用饱和氯化钠(300mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。粗品经过过柱(乙酸乙酯/石油醚＝0～5％)纯化得到化合物WX014-3。 1H NMR(400MHz,CHLOROFORM-d)δppm 2.91(s,6H)6.75(d,J＝11.04Hz,1H)8.02-8.07(m,1H)。
步骤3：化合物WX014-4的合成
将化合物WX014-3(9g,28.59mmol,1eq)(纯度83.568％)溶于醋酸(80mL)，分批加入铁粉(6.39g,114.36mmol,4eq)，混合物于20℃搅拌16小时。反应液滴加到饱和NaOH(100mL)中，用乙酸乙酯(50mL*3)萃取，有机层用氯化钠(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。粗品经过过柱(乙酸乙酯/石油醚＝0～25％)纯化得到化合物WX014-4。 1H NMR(400MHz,CHLOROFORM-d)δppm 2.65(s,6H)6.80(d,J＝10.29Hz,1H)6.86(d,J＝6.78Hz,1H)。
步骤4：化合物WX014-5的合成
将化合物WX014-4(1.1g,3.42mmol,1eq)(纯度72.474％)溶于无水甲苯(10mL)，加入化合物WXBB-1-3(3g,11.80mmol,3.45eq),二异丙基乙胺(928.29mg,7.18mmol,1.25mL,2.1eq)，混合物于140℃在微波环境下反应0.5小时。反应液冷却至室温，加入水(50mL)，用乙酸乙酯(50mL*3)萃取，合并有机相，用氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。粗品经过过柱(乙酸乙酯/石油醚＝0～10％)纯化得到化合物WX014-5。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.93(dq,J＝7.47,3.70Hz,2H)1.09(quin,J＝3.83Hz,2H)1.90-1.99(m,1H)2.56(s,6H)4.07(d,J＝3.51Hz,2H)6.49(d,J＝6.53Hz,1H)6.73(d,J＝10.04Hz,1H)。
步骤5：化合物WX014-6的合成
将化合物WX014-5(750mg,2.38mmol,1eq)溶于醋酸(8mL)，用氮气置换三次，加入硫氰酸钾(463mg,4.76mmol,463.00μL,2eq)，混合物在氮气环境下于110℃搅拌4小时。反应液冷却至室温，减压浓缩，加入饱和碳酸氢钠(20mL)调节PH＝8，用二氯甲烷(20mL*3)萃取，有机层用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。产品直接用于下一步反应不需要纯化得到化合物WX014-6。 1H NMR(400MHz,DMSO-d6)δppm 0.64-0.71(m,2H)0.78-0.89(m,2H)1.67-1.76(m,1H)2.57(s,6H)6.75(d,J＝1.51Hz,1H)7.00(d,J＝11.80Hz,1H)7.40(d,J＝7.53Hz,1H)12.28(br s,1H)。
步骤6：化合物WX014-7的合成
将化合物WX014-6(500mg,1.40mmol,1eq)溶于醋酸(5mL)，加入水(1mL)和过氧化氢(477mg,4.21mmol,404.24μL,30％纯度,3eq)，混合物在45℃下搅拌1小时。反应液冷却至室温，加入饱和亚硫酸 钠直到淀粉碘化钾试纸不变蓝，旋掉部分溶剂，用淀粉碘化钾试纸检测无过氧化氢剩余，用饱和碳酸氢钠(20mL)调节PH＝8，用二氯甲烷(20mL*3)萃取，有机层用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。产品直接用于下一步反应不需要纯化得到化合物WX014-7。 1H NMR(400MHz,DMSO-d6)δppm 0.62-0.71(m,2H)0.77-0.82(m,2H)2.32-2.34(m,1H)2.43(s,6H)7.08(d,J＝11.29Hz,1H)7.14(s,1H)7.56(d,J＝7.53Hz,1H)7.69(s,1H)。
步骤7：化合物WX014-8的合成
将化合物WX014-7(400mg,1.09mmol,1eq)(纯度88.522％)溶于甲醇(4mL)，加入Pd(dppf)Cl 2(120mg,164.00μmol,0.15eq)，三乙胺(221mg,2.18mmol,303.99μL,2eq),通入一氧化碳(50Psi)，混合物在70℃下搅拌16小时。直接拉干反应液。粗品经过过柱(乙酸乙酯/石油醚＝0～30％)纯化。产品继续用prep-TLC(乙酸乙酯)纯化得到化合物WX014-8。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.77-0.83(m,2H)0.85-0.92(m,2H)1.86-1.95(m,1H)2.61(s,6H)3.89(s,3H)6.63(d,J＝13.30Hz,1H)6.86(d,J＝1.00Hz,1H)7.54(d,J＝1.00Hz,1H)7.73(d,J＝7.78Hz,1H)。
步骤8：化合物WX014-9的合成
将化合物WX014-8(200mg,566.13μmol,1eq)(纯度85.863％)溶于四氢呋喃(1mL)和水(1mL)的混合液中(体积比1:1)，加入氢氧化锂(41mg,1.71mmol,3.02eq)，混合物在20℃搅拌1小时。直接拉干反应液。得到化合物WX014-9。 1H NMR(400MHz,DMSO-d6)δppm 0.65-0.71(m,2H)0.75-0.81(m,2H)1.79-1.88(m,1H)2.41(s,6H)6.67(d,J＝12.30Hz,1H)7.06(s,1H)7.44(d,J＝8.03Hz,1H)7.61(s,1H)。
步骤9：化合物WX014的合成
将化合物WX014-9(160mg,553.05μmol,1eq)溶于二氯甲烷(2mL)，加入N,N-二甲基甲酰胺(4mg,54.72μmol,4.21μL,0.1eq)，草酰氯(120mg,945.43μmol,82.76μL,1.71eq)，混合物在20℃下搅拌2小时。减压旋掉溶剂至混合物粘稠，然后加入5mL无水二氯甲烷，重复三次。加入化合物WXBB-3(119mg,552.84μmol,1eq)，二异丙基乙胺(72mg,557.09μmol,97.04μL,1.01eq)，混合物在20℃搅拌1小时。向反应液中加入水(50mL)，用二氯甲烷(20mL*3)萃取，有机层用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。旋干的粗品经过prep-TLC(二氯甲烷/甲醇＝10/1)纯化后快速制备分离得到WX014。 1H NMR(400MHz,DMSO-d6)δppm 0.69(br s,2H)0.79(br d,J＝8.03Hz,2H)1.24(br s,1H)1.80-2.00(m,6H)2.53(br s,6H)4.43-4.51(m,2H)6.97(br d,J＝13.05Hz,1H)7.15(s,1H)7.55(br d,J＝7.28Hz,1H)7.71(s,1H)7.85(d,J＝7.53Hz,1H)7.98(t,J＝7.91Hz,1H)8.15(d,J＝8.03Hz,1H)10.61(s,1H)。
实施例015：WX015
Figure PCTCN2018073640-appb-000074
合成路线：
Figure PCTCN2018073640-appb-000075
步骤1.化合物WX015-2的合成
将WX015-1(24g,101.70mmol,1eq)溶于无水二氯甲烷(200mL)，加入DMAP(0.65g,5.32mmol,0.05eq)，二异丙基乙基胺(26.29g,203.39mmol,35.43mL,2eq)，将体系降温至0℃，在0℃下缓慢加入Tf 2O(43.04g,152.55mmol,25.17mL,1.5eq)，然后将体系逐渐升温至20℃并搅拌2小时。在搅拌下向反应液中加入水(200mL)，将有机相减压旋干得到粗品。粗品经0～5％乙酸乙酯/石油醚过柱纯化得到产品WX015-2， 1H NMR(400MHz,CHLOROFORM-d)δppm 7.20(d,J＝7.28Hz,1H)8.41(d,J＝6.53Hz,1H)
步骤2.化合物WX015-3的合成
将WX015-2(13g,35.32mmol,1eq)溶于无水甲苯(130mL)，加入叔丁醇钠(5.20g,54.11mmol,1.53eq)，Pd 2(dba) 3(2.60g,2.84mmol,0.08eq)体系在氮气条件下于105℃下搅拌20小时。将反应液冷却至室温，加入到水(200mL)中，用二氯甲烷(200mL*2)萃取将有机相依次用水(300mL)和饱和食盐水(300mL)洗涤，经无水硫酸钠干燥，过滤，将滤液减压旋干得到粗品。粗品经0～20％乙酸乙酯/石油醚过柱纯化得到产品WX015-3， 1H NMR(400MHz,CHLOROFORM-d)δppm 3.04-3.09(m,4H)3.84-3.87(m,4H)6.86(d,J＝10.04Hz,1H)8.12(d,J＝7.03Hz,1H)
步骤3.化合物WX015-4的合成
将WX015-3(8g,26.22mmol,1eq)溶于冰乙酸(80mL)，在搅拌下缓慢分批加入铁粉(5.86g,104.88mmol,4eq)，体系在20℃下搅拌1小时。将反应液减压旋干得到粗品，加入水(200mL)稀释，加入饱和碳酸氢钠溶液(200mL)至溶液pH为8～9，用二氯甲烷(100mL*2)萃取，将有机相用水(200mL)洗涤，经无水硫酸钠干燥，过滤，将滤液减压旋干得到产品WX015-4。
步骤4.化合物WX015-5的合成
将WXBB-1-3(6.98g,27.47mmol,3eq)溶于无水甲苯(30mL)加入WX015-4(3g,9.16mmol,1eq)(纯度83.959％)，二异丙基乙基胺(2.49g,19.27mmol,3.36mL,2.1eq)，体系在微波条件下加热至140℃搅拌1小时。将反应液冷却至室温，加入水(50mL)，用二氯甲烷(50mL*2)萃取，有机相经无水硫酸钠干燥，过滤，将滤液减压旋干得到粗品。粗品经0～12％乙酸乙酯/石油醚过柱纯化得到产品WX015-5。
步骤5.化合物WX015-6的合成
将WX015-5(1.2g,2.71mmol,1eq)(纯度80.641％)溶于冰乙酸(20mL)加入硫氰酸钾(0.36g,3.70mmol,360.00μL,1.37eq)，体系在110℃下搅拌3小时。将反应液冷却至室温，加入水(100mL)稀释，用二氯甲烷(50mL*3)萃取，合并有机相，向有机相中加入饱和碳酸氢钠溶液(200mL)，搅拌5min，pH试纸检测有机相pH为7～8，分离有机相，用水(200mL)洗涤有机相，经无水硫酸镁干燥，过滤，将滤液减压旋干得到产品WX015-6。
步骤6.化合物WX015-7的合成
将WX015-6(1.2g,2.62mmol,1eq)(纯度87.114)溶于冰乙酸(12mL)和水(2.5mL)的混合溶液，在搅拌下加入过氧化氢(0.9g,7.94mmol,762.71μL,30％纯度,3.02eq)，体系在45℃下搅拌0.5小时。将反应液冷却至室温，加入水(100mL)稀释，用二氯甲烷(50mL*3)萃取，合并有机相，向有机相中加入饱和亚硫酸钠溶液(50mL)，搅拌5min，淀粉碘化钾试纸检测不变蓝，然后加入饱和Na 2CO 3溶液(200mL)，搅拌5min，pH试纸检测有机相pH为7～8，分离有机相，用水(200mL)洗涤有机相，经无水硫酸镁干燥，过滤，将滤液减压旋干得到产品WX015-7。
步骤7.化合物WX015-8的合成
将WX015-7(1g,1.78mmol,1eq)(纯度65.303％)溶于甲醇(10mL)，加入Pd(dppf)Cl 2(0.04g,54.67μmol,0.15eq)，三乙胺(400.00mg,3.95mmol,550.21μL,2.22eq)，体系在CO(50psi)条件下于70℃搅拌16小时。将反应液减压旋干得到粗品。经0～40％乙酸乙酯/石油醚过柱纯化得到产品WX015-8。
步骤8.化合物WX015-9的合成
将WX015-8(0.6g,1.55mmol,1eq)(纯度89.457％)溶于无水四氢呋喃(5mL)，加入氢氧化锂(0.112g,4.68mmol,3.01eq)在水(5mL)中的溶液，体系在20℃下搅拌1小时。将反应液减压旋干得到粗品。向粗品中加入二氯甲烷/甲醇＝10/1的混合溶液(15mL)，搅拌15min，静置，过滤，将滤液减压旋干得到产品WX015-9。 1H NMR(400MHz,DMSO-d 6)δppm 0.66(br d,J＝3.01Hz,2H)0.72-0.84(m,2H)1.77-1.91(m,1H)2.58(br s,4H)3.55(br s,4H)6.74(d,J＝11.80Hz,1H)7.16(s,1H)7.50(d,J＝7.78Hz,1H)7.72(s,1H)
步骤9.化合物WX015的合成
将WX015-9(0.1g,301.80μmol,1eq)溶于无水二氯甲烷(2mL)，加入N,N-二甲基甲酰胺(5mg,68.41μmol,5.26uL,2.27e-1eq)，在N2条件下加入草酰氯(0.08g,630.29μmol,55.17uL,2.09eq)，体系在20℃下搅拌0.5小时，将反应液减压旋至粘稠，加入无水二氯甲烷(2mL)，再次旋至粘稠，重复三次，依次加入无水二氯甲烷(2mL)，WXBB-3(0.065g,301.97μmol,1.00eq)，二异丙基乙基胺(0.08g,618.99μmol,107.82μL,2.05eq)，体系在20℃下搅拌1小时。向反应液中加入水(20mL)稀释，用二氯甲烷(20mL*2)萃取，将有机相用水(30mL)洗涤，经无水硫酸钠干燥，过滤，将滤液减压旋干得到粗品。粗品经快速制备分离纯化得到WX015。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.80(br d,J＝3.26Hz,2H)0.91(br d,J＝8.03Hz,2H)1.87-1.94(m,1H)1.96-2.09(m,4H)2.79(br d,J＝4.02Hz,4H)3.10(br t,J＝6.27Hz,2H)3.73(br s,4H)4.50(br t,J＝6.02Hz,2H)6.81(d,J＝13.80Hz,1H)6.99(s,1H)7.71(s,1H)7.84-7.96(m,1H)8.05(dd,J＝15.69,7.91Hz,2H)8.36(d,J＝8.28Hz,1H)9.00(br d,J＝15.56Hz,1H)
实施例016：WX016
Figure PCTCN2018073640-appb-000076
合成路线：
Figure PCTCN2018073640-appb-000077
步骤1.化合物WX016-2的合成
在预先干燥的100mL圆底烧瓶中加入WX016-1(20g,201.75mmol,1eq)溶于CHCl 3(200mL)中，反应体系降至0℃后分批次加入PCl 5(84.03g,403.51mmol,2eq)，体系在0℃下反应30min，之后向体系中加入ZnCl 2(1.37g,10.09mmol,472.48μL,0.05eq)和Br 2(64.48g,403.51mmol,20.80mL,2eq)，之后反应升至0-25℃继续反应5小时。将反应混合液搅拌下缓慢加入饱和亚硫酸钠溶液，至pH＝8-9，分液后收集有机相，水相用二氯甲烷萃取(3*100毫升)，合并有机相，用饱和食盐水(1*200毫升)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩得WX016-2。
步骤2：化合物WX016-3的合成
在预先干燥的250ml圆底烧瓶中加入原料WX016-2(10g,38.92mmol,1eq)，加入H 2O(5mL)和MeOH(45mL)的混合物，在40℃下，将PPh 3(10.21g,38.92mmol,1eq)慢慢加入到体系中，继续搅拌3小时。将反应体系的溶剂真空浓缩到大约一半，缓慢加水至没有固体析出为止，将固体过滤掉，滤液用二氯甲烷萃取(3*30毫升)，有机相用饱和食盐水洗涤(2*40毫升)，有机相用无水硫酸钠干燥，过滤，减压浓缩得WX016-3。 1H NMR(400MHz,CHLOROFORM-d)δppm 1.73-1.87(m,2H)2.13-2.23(m,2H)2.23-2.31(m,3H)3.37-3.49(m,2H)4.51(t,J＝4.39Hz,1H)，m/z＝178.09[M+1].
步骤3：化合物WX016-4的合成
在干燥的圆底烧瓶中加入WX016-3(7.2g,28.31mmol,1eq)，加入ACN(20mL)，再加入KOAc(11.11g,113.24mmol,4eq)和18-冠醚-6(2.24g,8.49mmol,0.3eq)，继续搅拌，在85℃下加热回流1小时。将反 应体系冷却至室温，先用1M盐酸将反应液调节至pH＝3-4，用二氯甲烷萃取(3×20毫升)。合并有机相，用饱和碳酸氢钠溶解调节pH＝8-9，用二氯甲烷萃取(3×30毫升)，有机相用饱和食盐水洗涤(2×40毫升)，无水硫酸钠干燥，减压浓缩。残余物经柱层析(DCM：MeOH＝100:0～40:1～20:1)进行纯化得到WX016。 1H NMR(400MHz,CHLOROFORM-d)δppm 1.79-1.96(m,4H)2.01-2.08(m,1H)2.22-2.32(m,2H)3.25-3.37(m,3H)5.17-5.25(m,1H)，m/z＝158.1[M+1]
步骤4.化合物WX016-6的合成
将化合物WX016-4(20.00g,127.25mmol,1eq)和化合物WX016-5(14.52g,38.18mmol,0.3eq)加入到干燥的圆底烧瓶中，往反应瓶中加入乙腈(250mL)，将反应体系升温至60℃搅拌4小时。将反应液冷却至室温，然后旋干，往反应瓶中加入水(250mL)和二氯甲烷(250mL)，有机相和水相分液后，用二氯甲烷(200mL*2)萃取水相，合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压减压旋干得到WX016-6。 1HNMR(1H NMR(400MHz,CHLOROFORM-d)δppm 1.86-1.93(m,2H)1.96-2.07(m,2H)2.11(s,3H)3.28-3.35(m,2H)5.41-5.47(m,1H)。
步骤5:化合物WX016-7的合成
将化合物WX016-6(12.00g,67.29mmol,1eq)加入到干燥的圆底烧瓶中，往反应瓶中依次加入化合物WXBB-4(10.54g,69.27mmol,1eq)和环己醇(200mL)，用氮气球置换体系内空气，重复操作两遍，将反应体系升温至135℃搅拌12小时。将反应液冷却至室温，然后加入水(250mL)，用1M的盐酸调节PH＝4～5，之后用乙酸乙酯(200mL*3)洗涤水相，得到的水相用1M的氢氧化钠调节PH＝9，用二氯甲烷(250mL*3)萃取，合并有机相，用饱和食盐水(250mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干(水泵，50℃)，得到粗品，粗品经过prep-HPLC(水(0.04％NH3.H2O+10mMNH 4HCO 3)-CAN)分离纯化，得到化合物WX016-7。 1H NMR(400MHz,CHLOROFORM-d)δppm 1.99-2.09(m,2H)2.11(s,3H)2.14-2.26(m,2H)4.21-4.37(m,1H)4.56(br s,2H)4.75(dt,J＝13.93,4.83Hz,1H)6.24(t,J＝4.02Hz,1H)6.51-6.58(m,1H)7.51-7.57(m,1H)7.60-7.65(m,1H)。MS m/z:274[M+H]+。
步骤6:化合物WX016-8的合成
将化合物WXBB-1(3.50g,13.39mmol,1eq)加入到干燥的圆底烧瓶中，往反应瓶中加入二氯甲烷(35mL)，用氮气球置换体系内空气，重复操作两遍，在氮气环境下，加入N,N-二甲基甲酰胺(0.1mL，1.3mmol,0.1eq)和草酰氯(2mL,22.85mmol，1.7eq)，将反应体系在室温(20℃)下搅拌3小时至反应液澄清，将反应液浓缩至15mL，加入无水二氯甲烷(20mL)，再次浓缩至15mL，重复操作3遍。然后加入无水二氯甲烷(20mL)，用氮气球置换体系内空气，重复操作两遍，在氮气环境下，加入化合物WX016-7(3.50g，12.03mmol,0.9eq)和N,N-二异丙基乙胺(2.4mL,13.78mmol，1eq)，将反应体系在室温(20℃)下搅拌1小时。然后向反应液中加入水(50mL)，然后用碳酸钾固体调节PH＝9，用二氯甲烷(50mL*3)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干得到WX016-8。 1H NMR (400MHz,DMSO-d6)δppm 0.68-0.73(m,2H)0.78-0.83(m,2H)1.81-1.89(m,1H)1.99-2.08(m,4H)2.09(s,3H)2.25(s,3H)4.28-4.36(m,1H)4.71-4.81(m,1H)6.19(s,1H)7.19(d,J＝1.25Hz,1H)7.49(d,J＝11.04Hz,1H)7.64(d,J＝6.53Hz,1H)7.70(d,J＝1.25Hz,1H)7.93(d,J＝7.03Hz,1H)8.04(t,J＝7.91Hz,1H)8.22(d,J＝8.03Hz,1H)11.03(s,1H)。MS m/z:516.4[M+H]+。
步骤7:化合物WX016的合成
将化合物WX016-8(3.00g，4.23mmol，1eq)(纯度72.65％)加入到干燥的圆底烧瓶中，往反应瓶中加入四氢呋喃(15mL)和水(5mL)的混合液，然后往反应瓶中加入一水合氢氧化锂(532mg，12.68mmol，3eq)，将反应体系在室温(24℃)下搅拌2小时。往反应液中加入水(50mL)，然后用二氯甲烷(50mL*3)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干得到WX016， 1HNMR(400MHz,DMSO-d6)δppm 0.68-0.73(m,2H)0.78-0.83(m,2H)1.81-1.89(m,1H)1.99-2.08(m,4H)2.09(s,3H)2.25(s,3H)4.28-4.36(m,1H)4.71-4.81(m,1H)6.19(s,1H)7.19(d,J＝1.25Hz,1H)7.49(d,J＝11.04Hz,1H)7.64(d,J＝6.53Hz,1H)7.70(d,J＝1.25Hz,1H)7.93(d,J＝7.03Hz,1H)8.04(t,J＝7.91Hz,1H)8.22(d,J＝8.03Hz,1H)11.03(s,1H)。MS m/z:474.2[M+H]+。
实施例017：WX017WX018
Figure PCTCN2018073640-appb-000078
步骤1：化合物WX017，WX018的合成
将化合物WX016经SFC(柱:YMC CHIRAL Amylose-C(250mm*30mm,10μm):流动相:[0.1％NH 3.H 2O EtOH]：B:55％-55％,min)分离，得到保留时间分别为0.921min和1.459min的WX017和WX018。
WX017，保留时间为0.921min， 1H NMR(400MHz,DMSO-d6)δppm 0.67-0.73(m,2H)0.77-0.84(m,2H)1.82-1.97(m,4H)2.14(br dd,J＝9.16,5.65Hz,1H)2.25(s,3H)4.20-4.30(m,1H)4.68(br d,J＝13.80Hz,1H)4.90(br d,J＝4.77Hz,1H)5.81(d,J＝5.27Hz,1H)7.19(d,J＝1.25Hz,1H)7.49(d,J＝10.79Hz,1H)7.63(d,J＝6.53Hz,1H)7.70(d,J＝1.25Hz,1H)7.91(d,J＝7.53Hz,1H)8.02(t,J＝7.91Hz,1H)8.20(d,J＝8.28Hz,1H)10.99(s,1H)。MS m/z:474.5[M+H]+。
WX018，保留时间为1.459min。 1H NMR(400MHz,DMSO-d6)δppm 0.68-0.73(m,2H)0.77-0.84(m,2H)1.81-1.98(m,4H)2.14(br dd,J＝8.91,5.40Hz,1H)2.25(s,3H)4.21-4.29(m,1H)4.68(br d,J＝14.31Hz,1H)4.87-4.93(m,1H)5.82(d,J＝5.02Hz,1H)7.19(d,J＝1.00Hz,1H)7.49(d,J＝10.79Hz,1H)7.63(d,J＝6.53Hz,1H)7.70(d,J＝1.00Hz,1H)7.91(d,J＝7.28Hz,1H)8.02(t,J＝7.91Hz,1H)8.20(d,J＝8.03 Hz,1H)11.00(s,1H)。MS m/z:474.2[M+H]+。
生物活性测试：
实验例1：酶活性
试剂：
基础反应缓冲液：20mM Hepes(pH 7.5)，10mM MgCl 2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na 3VO 4,2mM DTT,1％DMSO
化合物处理:
将待测化合物用DMSO配制成10mM的储备液，3倍递减稀释10个浓度，并将之置于384孔板中(Cyclic Olefin Copolymer LDV
Figure PCTCN2018073640-appb-000079
)。
激酶名称:ASK1/MAP3K5(Invitrogen,Carlsbad,CA)
类型:重组人全长蛋白,GST-tagged
酶最终反应浓度:20nM
底物:髓磷脂碱性蛋白,MBP(Active Motif,Carlsbad,CA)
基质最终反应浓度:20μM
实验操作:
1.将底物溶于新制备的基础反应缓冲液中，
2.向上述底物溶液中加入所需的辅酶因子，
3.向底物溶液中加入激酶并缓慢混匀，
4.向激酶反应液中加入待测化合物的DMSO溶液，室温下孵育20分钟，
5.将 33P-ATP(比活10μCi/μl)加入反应液中以启动反应，
6.室温下孵育2小时，
7.将小部分反应物点到P-81离子交换滤纸上，
8.将滤纸用0.75％磷酸缓冲液洗涤三次以洗去未结合的磷酸盐，然后将滤纸干燥，
9.测定滤纸上残留的放射性，
10.激酶活性数据用测试样品中剩余激酶活性与溶媒(DMSO)中激酶活性的比值表示，
11.通过Prism(GraphPad软件)获得IC50值和曲线拟合。实验结果如表1、表2所示：
表1.本发明化合物体外筛选试验结果
序号 化合物 IC 50(nM)
1 实施例001：WX001 1.82
2 实施例002：WX002 5.6
3 实施例003：WX003 943
4 实施例004：WX004 >1000
5 实施例005：WX005 35.3
6 实施例006：WX006 19.20
7 实施例007：WX007 16.60
8 实施例008：WX008 5.44
9 实施例010：WX010 7.20
10 实施例011：WX011 7.61
11 实施例012：WX012 7.04
12 实施例013：WX013 7.93
13 实施例014：WX014 10.70
14 实施例015：WX015 10.10
15 实施例016：WX016 4.12
16 实施例017：WX017 12.50
17 实施例017：WX018 6.57
表2.本发明化合物体外筛选试验结果
序号 化合物 IC50值
1 实施例001 A
2 实施例002 A
3 实施例003 B
4 实施例004 B
5 实施例005 A
注：A≤100nM；B>100nM。
结论：本发明化合物对ASK1的抑制作用显著。
实验例2：药代动力学性质研究
实验方法：
本研究选用C57BL/6雄性小鼠受试动物，应用LC/MS/MS法定量测定了小鼠分别静脉注射或口服给予测试化合物不同时间点的血浆中的药物浓度，以评价受试药物在小鼠体内的药代动力学特征。
将试验化合物的澄清溶液经尾静脉注射到C57BL/6小鼠体内(过夜禁食，7-10周龄)，将试验化合物灌胃给予到C57BL/6小鼠(过夜禁食，7-10周龄)。动物均于给药后0.0833,0.25,0.5,1,2,4,6,8和24小时从颈静脉或尾静脉采血约30μL置于添加了EDTA-K 2的抗凝管中，4℃，3000g离心15min取血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。实验结果如表3所示：
表3.药代动力学测试结果
化合物 暴露量(nM·h) 生物利用度
WX002 408566 156％
WX017 59396 165％
WX018 53367 102％
实验结论：本发明化合物在小鼠体内具有较高的暴露量和生物利用度。

Claims (14)

  1. 式(Ⅱ)所示化合物、其药学上可接受的盐及其互变异构体，
    Figure PCTCN2018073640-appb-100001
    X 1、X 2、X 3至少一个为N，其余为CH；
    n选自0或1；
    R 1选自H、F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R取代的：C 1-4烷基、C 1-4杂烷基、3～6元杂环烷基、5～6元杂芳基；
    R 2选自H、F、Cl、Br、I；
    R 3选自H、F、Cl、Br、I、OH、NH 2；
    R选自F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基和3～6元杂环烷基；
    R’选自F、Cl、Br、I、OH、NH 2和C 1-3烷基；
    所述C 1-4杂烷基、5～6元杂芳基、3～6元杂环烷基之“杂”分别独立地选自：-NH-、N、-O-、-S-、；
    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所述的化合物、其药学上可接受的盐及其互变异构体，其中，R选自F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R’取代的：Me、
    Figure PCTCN2018073640-appb-100002
  3. 根据权利要求2所述的化合物、其药学上可接受的盐及其互变异构体，其中，R选自F、Cl、Br、I、OH、NH 2、Me、
    Figure PCTCN2018073640-appb-100003
  4. 根据权利要求1～3任意一项所述的化合物、其药学上可接受的盐及其互变异构体，其中，R 1选自H、F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、吗啉基、吡啶基。
  5. 根据权利要求4所述的化合物、其药学上可接受的盐及其互变异构体，其中，R 1选自H、F、Cl、Br、I、OH、NH 2，或者选自任选被1、2或3个R取代的：Me、
    Figure PCTCN2018073640-appb-100004
    Figure PCTCN2018073640-appb-100005
  6. 根据权利要求5所述的化合物、其药学上可接受的盐及其互变异构体，其中，R 1选自H、F、Cl、Br、 I、OH、NH 2、Me、
    Figure PCTCN2018073640-appb-100006
    Figure PCTCN2018073640-appb-100007
  7. 根据权利要求1～3任意一项所述的化合物、其药学上可接受的盐及其互变异构体，其中结构单元
    Figure PCTCN2018073640-appb-100008
    选自：
    Figure PCTCN2018073640-appb-100009
  8. 根据权利要求1～3任意一项所述的化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2018073640-appb-100010
    选自：
    Figure PCTCN2018073640-appb-100011
  9. 根据权利要求1～6任意一项所述的化合物、其药学上可接受的盐及其互变异构体，其选自：
    Figure PCTCN2018073640-appb-100012
    其中，
    X 1、X 2、X 3、R 2和R 3如权利要求1所定义；
    R 1如权利要求1、4～6任意一项所定义。
  10. 根据权利要求9所述的化合物、其药学上可接受的盐及其互变异构体，其选自：
    Figure PCTCN2018073640-appb-100013
    其中，
    R 2和R 3如权利要求1所定义；
    R 1如权利要求1、4～6任意一项所定义。
  11. 下式化合物、其药学上可接受的盐及其互变异构体，
    Figure PCTCN2018073640-appb-100014
  12. 一种药物组合物，包括治疗有效量的根据权利要求1～11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。
  13. 根据权利要求1～11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ASK1相关病症的药物上的应用。
  14. 根据权利要求12所述的组合物在制备治疗ASK1相关病症的药物上的应用。
PCT/CN2018/073640 2017-01-22 2018-01-22 作为ask1抑制剂的吡啶衍生物及其制备方法和应用 WO2018133866A1 (zh)

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