WO2017202376A1 - 磺酰胺衍生物 - Google Patents

磺酰胺衍生物 Download PDF

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Publication number
WO2017202376A1
WO2017202376A1 PCT/CN2017/086040 CN2017086040W WO2017202376A1 WO 2017202376 A1 WO2017202376 A1 WO 2017202376A1 CN 2017086040 W CN2017086040 W CN 2017086040W WO 2017202376 A1 WO2017202376 A1 WO 2017202376A1
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compound
group
mmol
reaction
preparation
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PCT/CN2017/086040
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French (fr)
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张杨
伍文韬
李志详
陈曙辉
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南京明德新药研发股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a series of sulfonamide compounds and their use in the preparation of therapeutic pain, in particular to compounds of formula (I), tautomers thereof or pharmaceutically acceptable salts thereof
  • the sulfonamide derivatives of the present invention are sodium channel modulators and have a variety of therapeutic applications, particularly for the treatment of pain.
  • the voltage-gated sodium channel can be found in all excitable cells, including muscle cells of the muscles and neurons of the central and peripheral nervous systems. In neuronal cells, the sodium channel is mainly responsible for the rapid overshoot of the action potential. In this manner, sodium channels are necessary for the induction and development of electronic signals in the nervous system. The correct and appropriate action of the sodium channel is therefore necessary for the normal functioning of neurons. Therefore, it is generally believed that abnormal sodium channel effects can highlight a variety of medical diseases (for a general review of hereditary ion channel diseases, see HubnerCA, Jentsch TJ, Hum. Mol. Genet., 11(20): 2435-45 (2002)). Contains epilepsy (Yogeeswariet al., Curr.
  • WO 2010079443 discloses compound PF-05089771.
  • the present invention provides a compound of the formula (I) and formula (II), a tautomer or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of: 1, 2 or 3, R: 5 to 12 membered aryl, 5 to 12 membered heteroaryl;
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, or selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl, C 1- alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, N, N- two (C 1-3 alkyl) amino;
  • L is selected from -(CRR) 1-4 -;
  • D is selected from: NR 3 , C(R 3 ) 2 or N(R 3 )C(R 3 ) 2 ;
  • Ring B is selected from the group consisting of 1, 2 or 3 R: 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 5- to 6-membered non-aromatic heteroalkenyl;
  • n is selected from 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • R is selected from H, F, Cl, Br, I, OH, CN, NO 2 , NH 2 or selected from C 1-3 alkylamino, N, optionally substituted by 1, 2 or 3 R'. N-di(C 1-3 alkyl)amino, C 1-3 alkyl, C 1-3 alkyloxy, C 1-3 alkylthio;
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me, Et, CH 2 F, CHF 2 , CF 3 , CH 3 O, CH 3 S, NH(CH 3 ), N (CH 3 ) 2 ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me, Et, CF 3 , NH(CH 3 ), N (CH3) ) 2 .
  • R 1 is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, 1,3,4-thiadiazole Base, 1,2,4-thiadiazolyl, 2H-tetrazolyl, isoxazolyl, benzo[d]thiazole.
  • R 1 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • R 1 is selected from the group consisting of
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, CF 3 , Me.
  • the L is selected from the group consisting of CH 2 , CH 2 CH 2 , and CH(CH 3 ).
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , NO 2 , COOH, CN, Me, or selected from the group consisting of 1, 2 or 3 R :Me, Et,
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , NO 2 , COOH, CN, Me, Et,
  • the above D is selected from the group consisting of:
  • the structural unit From:
  • the above ring B is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, pyrazolyl, imidazolyl, thienyl , oxazolyl, 3,6-dihydro-2H-pyranyl.
  • the above ring B is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • the ring B is selected from the group consisting of:
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me, Et, CF 3 , NH(CH 3 ), N (CH3) 2 )
  • Other variables are as defined above.
  • R 1 is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, 1,3,4-thiadiazole Base, 1,2,4-thiadiazolyl, 2H-tetrazolyl, isoxazolyl, benzo[d]thiazole, other variables are as defined above.
  • R 1 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • R 1 is selected from the group consisting of Other variables are as defined above.
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, CF 3 , Me, and other variables are as defined above.
  • the above L is selected from the group consisting of CH 2 , CH 2 CH 2 , CH(CH 3 ), and other variables are as defined above.
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , NO 2 , COOH, CN, Me, or selected from the group consisting of 1, 2 or 3 R :Me, Et, Other variables are as defined above.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , NO 2 , COOH, CN, Me, Et, Other variables are as defined above.
  • the above D is selected from the group consisting of: Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the above ring B is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, pyrazolyl, imidazolyl, thienyl , oxazolyl, 3,6-dihydro-2H-pyranyl, other variables are as defined above.
  • the above ring B is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: Other variables are as defined above.
  • the ring B is selected from the group consisting of: Other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • n 0, 1, 2 or 3;
  • R, R 1 , R 2 , R 3 , L, X, n are as defined above.
  • 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, ethanol Acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, Oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • 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 preparations are in the field of cosmetics or local It is well known to those skilled in the 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.
  • substituents When a 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. 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.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • 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, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes aryl as defined above Base and heteroaryl ring.
  • 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
  • the compound of the present invention has a significant improvement in the drug-forming properties, such as a decrease in plasma binding rate and an increase in solubility.
  • 2-iodobenzoic acid (53.5 g, 191.0 mmol) was slowly added to a solution of LA 1-4 (44.0 g, 127.3 mmol) in dimethyl sulfoxide (500 mL) at 25 °C. After stirring for 2 hours, the reaction solution was poured into water (500 mL), and a large yellow solid was precipitated and filtered to give a yellow solid. The yellow solid was added to aq. EtOAc (EtOAc) (EtOAc). -5 (25.5 g, yield: 58.3%).
  • LA1-5 (320 mg, 931.51 ⁇ mol) and N-phenylbis(trifluoromethanesulfonyl)imide (666 mg, 1.86 mmol) were dissolved in tetrahydrofuran (12 mL). After the reaction system was replaced with nitrogen three times, it was cooled to -78 ° C, and sodium hexamethyldisilazide (1 M, 1.21 mL) was slowly added dropwise. After the addition was completed, the reaction was carried out at -78 ° C for 3 hours, and then the temperature was raised to 15 ° C to continue the reaction for 16 hours. The reaction was quenched by the addition of 5 mL aqueous sodium hydrogen carbonate and 15 mL water.
  • LA 1-1 (500 mg, 1.63 mmol) was dissolved in dimethyl sulfoxide (10 mL) at 25 ° C, then 2-iodobenzoic acid (913 mg, 3.26 mmol). After stirring for 12 hours, the reaction was quenched by the addition of 20 mL of water. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The crude product was purified by chromatography (jjjjjjjjjjjj MS m/z: 205.9 [M-100+1] + .
  • Methyltriphenylphosphonium bromide (702 mg, 1.97 mmol) was dissolved in tetrahydrofuran (4 mL) under nitrogen. After cooling to -40 ° C, n-butyl lithium n-hexane solution (2.5 M, 786.01 ⁇ L) was added. After stirring at this temperature for 30 minutes, a solution of LA27-1 (300 mg, 982.51 ⁇ mol) in tetrahydrofuran (2 mL) was added. After the temperature was raised to 25 ° C and the reaction was stirred for 2.5 hours, the reaction was quenched by the addition of 15 mL of water. The aqueous phase was extracted with ethyl acetate (20 mL x 3).
  • LA27-2 (200 mg, 659.26 ⁇ mol) was dissolved in tetrahydrofuran (4 mL), cooled to 0 ° C, and a solution of 9- boron bicyclo(3,3,1)-decanetetrahydrofuran (0.5 M, 3.96 mL) was added under nitrogen. . After stirring for 2 hours, a solution of 9-borobicyclo(3,3,1)-decane tetrahydrofuran (0.5 M, 3.96 mL) was again added. After reacting at 0 ° C for 1 hour, the temperature was raised to 25 ° C, and the reaction was continued for 5 hours.
  • reaction solution was cooled to -15 ° C, and hydrogen peroxide (1.50 g, 13.19 mmol, 1.27 mL) and sodium hydroxide (1M, 1. After heating to 25 ° C for 12 hours, the reaction was quenched by the addition of 20 mL of water. The aqueous phase was extracted with ethyl acetate (15 mL EtOAc).
  • LA28-1 (30 g, 158.55 mmol) was dissolved in tetrahydrofuran (450 mL) with nitrodiazole and then carbonyldiimidazole (35.99 g, 221.97 mmol). After stirring at 20 ° C for 1 hour, pre-mixed potassium monomethyl malonate (49.52 g, 317.10 mmol) and magnesium chloride (15.10 g, 158.55 mmol) were added, and the reaction was continued for 16 hours. Filtration and concentration of the filtrate in vacuo were diluted with 300 mL of water. The aqueous phase was extracted with ethyl acetate (150 mL ⁇ 3). The filtrate was washed with aq.
  • LA28-4 (3 g, 12.33 mmol) was dissolved in tetrahydrofuran (30 mL) and then lithium borohydride (806 mg, 36.99 mmol). The mixture was warmed to 60 ° C and stirred for 16 hours, then cooled, quenched by the addition of 50 mL of water, and then diluted with 20 mL of saturated sodium bicarbonate. The aqueous phase was extracted with a mixture of dichloromethane and methanol (10:1, 30 mL x 3).
  • LA28-5 (1.83 g, 8.42 mmol) was dissolved in dichloromethane (30 mL) then triethylamine (1.70 g, 16.84 mmol). After cooling to 0 ° C, tert-butyldimethylsilyl chloride (2.54 g, 16.84 mmol) and 4-dimethylaminopyridine (103 mg, 842.00 ⁇ mol) were sequentially added. After the reaction was stirred at 20 ° C for 16 hours, the reaction was quenched by the addition of 60 mL of water. The aqueous phase was extracted with dichloromethane (30 mL ⁇ 3).
  • LA28-6 (2.04 g, 6.15 mmol) was dissolved in dimethyl sulfoxide (40 mL) then 2-iodobenzoic acid (3.44 g, 12.30 mmol). After stirring the reaction at 20 ° C for 16 hours, the reaction was quenched by the addition of 60 mL of water. The aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with 50 mL of brine, dried over anhydrous sodium sulfate.
  • LA28-8 (1.20g, 2.60mmol) was dissolved in a mixed solution of toluene (24mL) and ethanol (8mL), then p-toluic acid (437mg, 3.12mmol), sodium carbonate (551mg, 5.20mmol), palladium acetate (29 mg, 130.00 ⁇ mol) and triphenylphosphine (68 mg, 260.00 ⁇ mol).
  • the reaction system was replaced with nitrogen three times, and then the temperature was raised to 80 ° C and the reaction was stirred for 3 hours. After cooling, the reaction mixture was filtered through EtOAc EtOAc.
  • reaction solution was filtered through Celite, and poured into 50 mL of water, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with EtOAc EtOAc m.
  • LB21-2 (8.00g) and chlorine [2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl] under nitrogen protection [2-(2-Aminoethyl)phenyl)]palladium (CAS: 1447763-75-8, 45 mg, 57 ⁇ mol) was added to tetrahydrofuran (10 mL). After stirring well, LB1-3 (945 mg, 2.84 mmol) was added, and the mixture was heated to reflux for 16 hours. After cooling, the reaction was quenched by pouring into 100 mL of water. The aqueous phase was extracted with ethyl acetate (100 mL x 3).
  • LB 21-3 (180.0 mg, 517 ⁇ mol) was dissolved in tetrahydrofuran (10 mL) at 0 ° C, then lithium aluminum hydride (40 mg, 1.03 mmol) was slowly added. The reaction solution was slowly warmed to 15 ° C and the reaction was continued for 2 hours. After cooling to 0 ° C, 0.04 mL of water, 0.04 mL of a sodium hydroxide (15%) aqueous solution, 0.12 mL of water and 3 g of anhydrous magnesium sulfate were slowly added to the stirred reaction solution. After stirring for 10 minutes, the reaction solution was filtered, and the cake was washed with ethyl acetate. The filtrate was concentrated under vacuum to give a yellow crude product.
  • Triphenylphosphine (979.3 mg, 3.73 mmol) was added to a solution of phthalimide (274.7 mg, 1.87 mmol) in tetrahydrofuran (4 mL) at 25 °C. Under the protection of nitrogen, (-)-LB2 (400.0 mg, 1.24 mmol) and diethyl azodicarboxylate (433.5 mg, 2.49 mmol) were sequentially added to the reaction mixture. After stirring at 25 ° C for 2 hours, the reaction was concentrated under vacuum to give a crude material. The crude product was purified by chromatography (jjjjjjjjj .
  • Diisopropyl azodicarboxylate (756.27 mg, 3.74 mmol) was added to a solution of triphenylphosphine (980.9 mg, 3.74 mmol) in tetrahydrofuran (12 mL). After stirring for 10 minutes, a solution of (-)-LB2 (600.0 mg, 1.87 mmol) in THF (2 mL). After stirring for 15 minutes, thioacetic acid (284.7 mg, 3.74 mmol) was added. After the reaction solution was slowly warmed to 25 ° C, stirring was continued for 1 hour.
  • the starting material R8-1 (35.0 g, 349.5 mmol) and 2,4-dimethoxybenzaldehyde (101.6 g, 611.6 mmol) were added to toluene (600 mL) at 20 ° C, then piperidine (3.0 g, 34.9 mmol). The mixture was heated to reflux for 16 hours, and water was separated by a water separator. After cooling, the reaction mixture was evaporated mjjjjjjj MS m/z: 280.9 [M+32] + . The crude product was used in the next step without purification.
  • reaction solution was poured into 60 mL of water to quench the reaction, and the aqueous layer was extracted with ethyl acetate (80mL ⁇ 3). The combined organic layers were washed with EtOAc EtOAc EtOAc m.
  • R23-1 (45 g, 339.57 mmol) was dissolved in ethanol (500 mL) and triethylamine (41 g, 407.48 mmol) and 2,4-dimethoxybenzylamine (62 g, 373. After warming to 60 ° C, the reaction was stirred for 48 hours. After cooling, it was concentrated directly under vacuum. The residue was triturated with ethyl acetate (50 mL) and petroleum ether (200 mL) and filtered. The obtained solid was dispersed in 500 mL of water and extracted with ethyl acetate (500 mL ⁇ 2). The combined organic phases were washed with 100 mL of brine, dried over anhydrous sodium sulfate.
  • R23-2 (10 g, 37.98 mmol) was dissolved in tetrahydrofuran (100 mL).
  • 5-chloro-2,4-difluorobenzenesulfonyl chloride (11 g, 45.58 mmol) was added. After slowly rising to 25 ° C, stirring was continued for 6 hours. The reaction was quenched by pouring into 100 mL of water, and the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 3).
  • R27-1 (10.00 g, 40.94 mmol) was dissolved in tetrahydrofuran (120 mL) under ice-water bath, and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2-.
  • R27-3 hydrochloride 200 mg, 1.29 mmol was dissolved in N,N-dimethylformamide (2 mL) and triethylamine (130.91 mg, 1.29 mmol). After stirring at 25 ° C for 10 min, the mixture was cooled to 0 ° C, and then 2-(trimethylsilyl)ethoxymethyl chloride (219.37 mg, 1.32 mmol). After slowly raising the temperature to 25 ° C, stirring was continued for 1 hour. The reaction solution was filtered to give aq. MS m/z: 248.9 [M + 1] + .
  • R28-2 (700 mg, 2.38 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) under ice-water bath, EtOAc (2.33 g, 7.14 mmol) and p-methoxybenzyl chloride ( 559.10 mg, 3.57 mmol). After slowly raising the temperature to 20 ° C, the reaction was stirred for 16 hours. The reaction was quenched by the addition of 10 mL EtOAc. The combined organic solvents were washed with 10 mL of water and brine, dried over anhydrous sodium sulfate.
  • LA37-1 (126 mg, 176.9 ⁇ mol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.54 g, 13.5 mmol). After the reaction was stirred at 25 ° C for 1.5 hours, the reaction mixture was directly concentrated to give a crude material. The crude product was purified by high-performance liquid chromatography column (HCl system) to give a colorless oil. After separation of SFC, (-)-A37 (5.5 mg, yield: 6.9%) was obtained.
  • the compound (-)-B11 (60 mg, 121.46 ⁇ mol) was dissolved in methanol (6 mL), and then acetaldehyde (41 mg, 364 ⁇ mol), sodium cyanoborohydride (31 mg, 486 ⁇ mol), acetic acid (210 mg, 3.50 mmol). After the reaction mixture was stirred at 10 ° C for 1.5 hours, the reaction was quenched with 15 mL of water, and the aqueous phase was extracted with ethyl acetate (15 mL x 3).
  • Step 1 Preparation of Compounds (-)-B55 and (+)-B55
  • N,N-dimethylformamide dimethyl acetal 23 mg, 195.3 ⁇ mol
  • formyl hydrazide 12 mg, 195.3 ⁇ mol
  • B2 50 mg, 97.7 ⁇ mol
  • acetic acid 210 mg, 3.5 mmol
  • E1-1 and E2-1 (545 mg, 780.58 ⁇ mol) were dissolved in dichloromethane (5 mL) then trifluoroacetic acid (2 g, 17.54 mmol). After reacting at 15 ° C for 2 hours, the reaction mixture was concentrated in vacuo to give a crude oil. The crude product was purified by high-purity preparative column (NH 4 OH system) to give two products E1 (70 mg, yield: 18.0%) and E2 (16 mg, yield: 4.1%).
  • the cells used in the experiments were CHO cell lines stably expressing the hNav1.7 ion channel, which was derived from Genious.
  • the composition of the extracellular fluid is (mM): N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) 5, NaCl 140, KCl 3, CaCl 2 1, MgCl 2 1, CdCl 2 1, TEA-Cl 20, adjust the pH to 7.4 with sodium hydroxide; adjust the osmotic pressure to 300-320 mOsm; store at 4 ° C after filtration.
  • HEPES N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid
  • composition of the electrode liquid is (mM): CsF 140, CsOH 5, Ethylene glycol-bis ( ⁇ -aminoethyl ether)-N, N, N', N'-tetraacetic acid (EGTA) 1, HEPES 10, NaCl 10 Adjust the pH to 7.3 with cesium hydroxide; adjust the osmotic pressure to 300-320 mOsm; and store at -20 °C after filtration.
  • test compound or the positive control compound was weighed, and the compound was dissolved in a solvent, and a 10 mM stock solution was prepared according to its solubility.
  • the above stock solution was diluted 10 times with DMSO before the experiment, and then further diluted with the extracellular fluid to the desired concentration.
  • the working concentration solution should be checked for precipitation before use. If a precipitate is precipitated, the stock solution will be diluted to increase the final concentration of DMSO in the extracellular fluid, but the final concentration of DMSO in the extracellular fluid does not exceed 0.3%.
  • the method of continuous perfusion from low concentration to high concentration was used in the experiment.
  • thermodynamic solubility of the compound was determined by the sputum method and HPLC.
  • solubility of a compound is an important property that affects drug screening of compounds and the absorption of compounds in animals and humans.
  • Buffer 50 mM phosphate buffer, pH 7.4.
  • Preparation of standard solution 50% acetonitrile solution and 50% buffer solution were mixed to obtain a diluted solution.
  • a 10 mM (10 ⁇ L/compound) stock solution was added to the dilution (490 ⁇ L/compound) and mixed into a 200 ⁇ M UV detection standard.
  • the 200 ⁇ M UV detection standard was diluted with a 10-fold or 100-fold dilution to obtain a 20 ⁇ M, 2 ⁇ M UV standard solution. 2, 20 and 200 ⁇ M UV standard solutions were used as standard samples for thermodynamic solubility tests.
  • Sample preparation method A sample powder of not less than 2 mg was weighed into a vial of Whatman miniuniprep. 450 ⁇ L of buffer (pH 7.4) was added to each Whatman miniuniprep vial. After the addition of the buffer, the Whatman miniuniprep filter cap is mounted and pressed above the liquid level so that the filter is in contact with the buffer solution during shaking. The solubility sample was vortexed for 2 minutes. And record the phenomenon of the solution. Shake at room temperature (about 22 to 25 ° C) for 24 hours at a speed of 550 rpm. Press the Whatman Miniunipreps filter cap to the bottom to obtain the filtrate of the sample solubility solution. All sample vials should be insoluble and leaky before and after filtration. The buffer was diluted 50 times to obtain a sample dilution.
  • thermodynamic solubility was determined by filtration and HPLC: 3 UV standards were injected from low to high concentrations into HPLC, and then the dilutions and supernatants of the test compounds were injected. The sample to be tested is injected twice. Integrate the UV peaks. The standard curve was simulated and the thermodynamic solubility of the sample was calculated.
  • thermodynamic solubility (TS) test results are as follows:
  • the purpose of this experiment is to determine the protein binding rate of the test article in plasma.
  • HTDialysis's 96-well equilibrium dialysis device was used to perform a protein binding study by plasma dialysis at a concentration of 2 ⁇ M for the test sample and the control compound at 37 ° C for 4-hr.
  • the plasma is stored in a -80 ° C freezer. See the table below for details.
  • the HTD balanced dialysis unit is assembled and ready according to the instructions.
  • Plasma sample preparation process of the test sample and the compound Transfer a certain volume of the test compound working solution or the warfarin working solution to the blank plasma so that the final concentration of the test compound or warfarin in the plasma sample is 2 ⁇ M. Mix the samples thoroughly. The final concentration of organic phase DMSO is ⁇ 1%.
  • T0 samples for recovery and stability determination Pipette 50 ⁇ L of test compound and warfarin plasma sample into the sample receiving plate (three parallels) and immediately add the corresponding volume of corresponding blank plasma or buffer. A volume of stop solution was then added to these T0 samples and stored at 2-8 ° C, awaiting subsequent processing with other dialyzed samples.
  • Dialysis procedure of plasma samples 150 ⁇ L of test compound and warfarin plasma sample were added to the drug delivery end of each dialysis well, and 150 ⁇ L of blank dialysis buffer was added to the corresponding receiving end of the dialysis well. The plate was then placed in a humidified, 5% CO 2 incubator and incubated for 4 hr at 37 ° C with shaking.
  • sample receiving plate 50 ⁇ L of the dialyzed buffer sample and the dialyzed plasma sample were pipetted into a new 96-well plate (sample receiving plate). A corresponding volume of corresponding blank plasma or buffer is added to the sample. All samples were subjected to protein precipitation and subjected to LC/MS/MS analysis. The concentration of the sample is expressed as the ratio of the peak area of the compound to the internal standard (semi-quantitative).
  • [F] is the concentration of the compound in the sample on the buffer side of the dialysis apparatus
  • [T] is the concentration of the compound in the plasma side sample in the dialysis apparatus
  • [T 0 ] is the concentration of the compound in the plasma sample at time zero.
  • the plasma protein binding rate (PPB) test results are as follows:
  • test results indicate that the plasma protein binding rate of the compound of the present invention is improved relative to the clinical compound PF-05089771.

Abstract

一类磺酰胺化合物及在制备治疗疼痛中的应用，具体涉及式(Ⅰ)和式(Ⅱ)所示化合物、其互变异构体或其药学上可接受的盐。

Description

磺酰胺衍生物 技术领域
本发明涉及一系列磺酰胺类化合物及在制备治疗疼痛中的应用，具体涉及式(I)所示化合物、其互变异构体或其药学上可接受的盐
背景技术
本发明的磺酰胺衍生物是钠通道调控剂，具有多种治疗应用，特别是用于治疗疼痛。
电压闸控型钠通道可见于所有的可兴奋细胞，包含肌肉的肌细胞及中枢和末稍神经***的神经元。于神经元细胞中，钠通道主要是负责动作电势快速上冲的产生。于此方式中，钠通道对神经***中的电子信号的诱发和发展是必要的。钠通道的正确和适当作用因而对神经元的正常作用是必须的。所以，一般认为异常钠通道作用会突显多种医学疾病(遗传性离子通道疾病的一般综述请参见HubnerCA，Jentsch TJ，Hum.Mol.Genet.，11(20)：2435-45(2002))，包含癫痫(Yogeeswariet al.，Curr.DrugTargets，5(7)：589-602(2004))、心律不整(NobleD.，Proc.Natl.Acad.Sci.USA，99(9)：5755-6(2002))、肌强直病(Cannon，SC，KidneyInt.57(3)：772-9(2000))、和疼痛(Wood，JNetal.，J.Neurobiol.，61(1)：55-71(2004))。
WO 2010079443公开了化合物PF-05089771。
Figure PCTCN2017086040-appb-000001
发明内容
本发明提供了式(Ⅰ)和式(Ⅱ)所示化合物、其互变异构体或药学上可接受的盐，
Figure PCTCN2017086040-appb-000002
其中，
R1选自任选被1、2或3个R取代的：5～12元芳基、5～12元杂芳基；
R2选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的：C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、N,N-二(C1-3烷基)氨基；
X选自：O、S、S(＝O)、S(＝O)2、NR；
L选自-(CRR)1-4-；
D选自：NR3、C(R3)2或N(R3)C(R3)2；
R3选自H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN，或选自任选被1、2或3个R取代的：C1-6烷基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基、N,N-二(C1-6烷基)氨基、C3-6环烷基氨基、3～6元环烷基 氨基、5～6元芳基、5～6元杂芳基、C2-4烷烯基-C(＝O)NH-、C2-4烯烷基-C(＝O)NH-；
环B选自任选被1、2或3个R取代的：5～6元芳基、5～6元杂芳基、5～6元非芳杂烯基；
n选自0、1、2或3；
m选自0、1或2；
R选自H、F、Cl、Br、I、OH、CN、NO2、NH2，或选自任选被1、2或3个R’取代的：C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基、C1-3烷基硫基；
R’选自：F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CH2F、CHF2、CF3、CH3O、CH3S、NH(CH3)、N(CH3)2；
所述“杂”代表杂原子或杂原子团，选自：-C(＝O)NH-、N、-NH-、-C(＝NH)-、-S(＝O)2NH-、-S(＝O)NH-、-O-、-S-、N、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、和-NHC(＝O)NH-；
上述任何一种情况下，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：H、F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CF3、NH(CH3)、N(CH3)2。
本发明的一些方案中，上述R1选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、噻唑基、1,3,4-噻二唑基、1,2,4-噻二唑基、2H-四唑基、异噁唑基、苯并[d]噻唑。
本发明的一些方案中，上述R1选自任选被1、2或3个R取代的：
Figure PCTCN2017086040-appb-000003
Figure PCTCN2017086040-appb-000004
本发明的一些方案中，上述R1选自：
Figure PCTCN2017086040-appb-000005
Figure PCTCN2017086040-appb-000006
本发明的一些方案中，上述R2选自：F、Cl、Br、I、OH、NH2、NO2、CN、COOH、CF3、Me。
本发明的一些方案中，上述L选自：CH2、CH2CH2、CH(CH3)。
本发明的一些方案中，上述X选自：O、S、S(＝O)、S(＝O)2、NH、N(CH3)。
本发明的一些方案中，上述R3选H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me，或选自任选被1、2或3个R取代的：C1-3烷基、C1-3烷基氨基、N,N-二(C1-3烷基)氨基、4～6元杂环烷基、4～6元杂环烷基氨基、5～6元芳基、5～6元杂芳基、C2-4烷烯基-C(＝O)NH-、C2-4烯烷基-C(＝O)NH-。
本发明的一些方案中，上述R3选自H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me，或选 自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2017086040-appb-000007
Figure PCTCN2017086040-appb-000008
本发明的一些方案中，上述R3选自：H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me、Et、
Figure PCTCN2017086040-appb-000009
本发明的一些方案中，上述D选自：
Figure PCTCN2017086040-appb-000010
Figure PCTCN2017086040-appb-000011
本发明的一些方案中，上述结构单元
Figure PCTCN2017086040-appb-000012
选自：
Figure PCTCN2017086040-appb-000013
Figure PCTCN2017086040-appb-000014
Figure PCTCN2017086040-appb-000015
本发明的一些方案中，上述结构单元
Figure PCTCN2017086040-appb-000016
选自
Figure PCTCN2017086040-appb-000017
本发明的一些方案中，上述环B选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、呋喃基、吡唑基、咪唑基、噻吩基、噁唑基、3,6-二氢-2H-吡喃基。
本发明的一些方案中，上述环B选自任选被1、2或3个R取代的：
Figure PCTCN2017086040-appb-000018
Figure PCTCN2017086040-appb-000019
本发明的一些方案中，上述环B选自：
Figure PCTCN2017086040-appb-000020
Figure PCTCN2017086040-appb-000021
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CF3、NH(CH3)、N(CH3)2，其他变量如上述所定义。
本发明的一些方案中，上述R1选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、噻唑基、1,3,4-噻二唑基、1,2,4-噻二唑基、2H-四唑基、异噁唑基、苯并[d]噻唑，其他变量如上述所定义。
本发明的一些方案中，上述R1选自任选被1、2或3个R取代的：
Figure PCTCN2017086040-appb-000022
Figure PCTCN2017086040-appb-000023
其他变量如上述所定义。
本发明的一些方案中，上述R1选自：
Figure PCTCN2017086040-appb-000024
Figure PCTCN2017086040-appb-000025
Figure PCTCN2017086040-appb-000026
其他变量如上述所定义。
本发明的一些方案中，上述R2选自：F、Cl、Br、I、OH、NH2、NO2、CN、COOH、CF3、Me，其他变量如上述所定义。
本发明的一些方案中，上述L选自：CH2、CH2CH2、CH(CH3)，其他变量如上述所定义。
本发明的一些方案中，上述X选自：O、S、S(＝O)、S(＝O)2、NH、N(CH3)，其他变量如上述所定义。
本发明的一些方案中，上述R3选H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me，或选自任选被1、2或3个R取代的：C1-3烷基、C1-3烷基氨基、N,N-二(C1-3烷基)氨基、4～6元杂环烷基、4～6元杂环烷基氨基、5～6元芳基、5～6元杂芳基、C2-4烷烯基-C(＝O)NH-、C2-4烯烷基-C(＝O)NH-，其他变量如上述所定义。
本发明的一些方案中，上述R3选自H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me，或选自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2017086040-appb-000027
Figure PCTCN2017086040-appb-000028
其他变量如上述所定义。
本发明的一些方案中，上述R3选自：H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me、Et、
Figure PCTCN2017086040-appb-000029
Figure PCTCN2017086040-appb-000030
其他变量如上述所 定义。
本发明的一些方案中，上述D选自：
Figure PCTCN2017086040-appb-000031
Figure PCTCN2017086040-appb-000032
Figure PCTCN2017086040-appb-000033
其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017086040-appb-000034
选自：
Figure PCTCN2017086040-appb-000035
Figure PCTCN2017086040-appb-000036
Figure PCTCN2017086040-appb-000037
其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017086040-appb-000038
选自
Figure PCTCN2017086040-appb-000039
其他变量如上述所定义。
本发明的一些方案中，上述环B选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、呋喃基、吡唑基、咪唑基、噻吩基、噁唑基、3,6-二氢-2H-吡喃基，其他变量如上述所定义。
本发明的一些方案中，上述环B选自任选被1、2或3个R取代的：
Figure PCTCN2017086040-appb-000040
Figure PCTCN2017086040-appb-000041
其他变量如上述所定义。
本发明的一些方案中，上述环B选自：
Figure PCTCN2017086040-appb-000042
Figure PCTCN2017086040-appb-000043
Figure PCTCN2017086040-appb-000044
其他变量如上述所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2017086040-appb-000045
其中，
m选自0、1、2或3；
R、R1、R2、R3、L、X、n如上述定义。
本发明还有一些方案是由上述变量任意组合而来。
下式所示化合物，其选自：
Figure PCTCN2017086040-appb-000046
Figure PCTCN2017086040-appb-000047
Figure PCTCN2017086040-appb-000048
Figure PCTCN2017086040-appb-000049
Figure PCTCN2017086040-appb-000050
Figure PCTCN2017086040-appb-000051
Figure PCTCN2017086040-appb-000052
Figure PCTCN2017086040-appb-000053
Figure PCTCN2017086040-appb-000054
Figure PCTCN2017086040-appb-000055
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。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部 药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，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 PCTCN2017086040-appb-000056
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 PCTCN2017086040-appb-000057
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 PCTCN2017086040-appb-000058
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 PCTCN2017086040-appb-000059
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***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-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C12表示1至12个碳，C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“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(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳 基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
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***-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2017086040-appb-000060
软件命名，市售化合物采用供应商目录名称。
技术效果：
相对于临床化合物PF-05089771，本专利化合物在成药性上有较明显改善，如：血浆结合率下降和溶解度提高等。
具体实施方式
参考例1:合成中间体LA1
Figure PCTCN2017086040-appb-000061
步骤1：化合物LA1-2的制备
将LA1-1(100.0g,618.9mmol)和叔丁基二甲基氯硅烷(111.9g,742.6mmol)加入到N,N-二甲基甲酰胺(1.5L)中,搅拌下向反应液中缓慢加入咪唑(126.4g,1.9mol)。将反应温度升至60℃后，继续搅拌16小时。降温至室温，缓慢倒入水中(2000mL)淬灭反应，析出大量固体。过滤后得固体为粗品，经乙酸乙酯(100mL)重结晶后得到白色固体LA1-2(57.0g,产率：38.5％)。1H NMR(400MHz,CHLOROFORM-d):δ8.64(br.s.,1H),8.04(dd,J＝1.6,4.4Hz,1H),7.19-7.13(m,1H),7.13-7.07(m,1H),5.09(s,2H),0.95(s,9H),0.80(s,6H).
步骤2：化合物LA1-3的制备
20℃下,将LA1-2(57.0g,238.1mmol)和二氧化铂(5.4g,23.8mmol)在乙醇(2.0L)/水(1L)的混合物加入到高压釜中。在2Mpa氢气压力下，加热至50℃搅拌反应48小时。冷却到室温后，过滤除去催化剂,滤饼用乙醇(500mL)冲洗。滤液在真空下浓缩得到淡黄色油状粗品LA1-3(62.0g)，粗产品未经纯化直接用于下一步。1H NMR(400MHz,CHLOROFORM-d):δ4.93(br.s.,1H),3.92-3.85(m,1H),3.77-3.64(m,1H),3.11-2.95(m,1H),2.73-2.58(m,2H),1.94-1.78(m,2H),1.77-1.56(m,2H),1.49-1.38(m,1H),0.98-0.91(m,9H),0.15-0.08(m,6H).
步骤3：化合物LA1-4的制备
将二碳酸二叔丁酯(53.4g,244.5mmol)加入到LA1-3(60.0g,244.5mmol)的乙醇(500mL)溶液中，再加入三乙胺(49.4g,489.0mmol)20℃下搅拌16小时。真空下浓缩反应液，剩余物溶于乙酸乙酯(200mL)中，依次用20％柠檬酸水溶液(200mL)、饱和碳酸钠水溶液(200mL)和饱和食盐水(200mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到淡黄色粗品LA1-4(44.0g)，粗产品未经纯化直接用于下一步。1H NMR(400MHz,CHLOROFORM-d):δ4.51-4.41(m,1H),4.16-4.10(m,1H)4.00-3.55(m,4H),2.66(t,J＝12.8Hz,1H),1.99-1.87(m,1H),1.75-1.47(m,2H),1.46(s,9H),0.91(s,9H),0.11(d,J＝4.4Hz,6H).
步骤4：化合物LA1-5的制备
25℃下，将2-碘酰基苯甲酸(53.5g,191.0mmol)缓慢加入到LA1-4(44.0g,127.3mmol)的二甲基亚砜(500mL)溶液中。搅拌2小时后，将反应液缓慢倒入水(500mL)中，有大量黄色固体析出，过滤得黄色固体。将黄色固体加入500mL乙酸乙酯中，搅拌、过滤、真空下浓缩得到粗品，粗品用硅胶柱层析分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1)得到无色油状物LA1-5(25.5g,产率：58.3％)。1H NMR(400MHz,CHLOROFORM-d):δ4.52-4.29(m,1H),4.13-3.97(m,1H),3.96-3.79(m,2H),3.57 -3.29(m,1H),2.62-2.34(m,2H),2.04-2.00(m,1H),1.99-1.86(m,1H),1.47(s,9H),0.84(s,9H),0.04(s,6H).
步骤5：化合物LA1-6的制备
将LA1-5(320mg,931.51μmol)和N-苯基双(三氟甲烷磺酰)亚胺(666mg,1.86mmol)溶于四氢呋喃(12mL)中。反应体系用氮气置换三次后，冷却至-78℃，缓慢滴加六甲基二硅基胺基钠(1M,1.21mL)。加完后，-78℃反应3小时，然后升温至15℃继续反应16小时。加入5mL碳酸氢钠水溶液和15mL水淬灭反应，水相用乙酸乙酯(20mL×3)萃取。合并后的有机相用10mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到黄色粗产品。粗产品经硅胶柱柱层析分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1)得到无色油状液体LA1-6(500mg)。1H NMR(400MHz,CHLOROFORM-d):δ6.04(d,J＝6.0Hz,1H),4.63(s,1H),4.54(s,0.53H),4.28-4.13(m,0.56H),4.09-3.97(m,0.41H),3.95-3.80(m,2H),3.39-3.25(m,0.41H),3.24-3.10(m,0.56H),2.45-2.35(m,0.45H),2.21-2.09(m,1H),1.49(s,9H),0.87(s,9H),0.04(s,6H).
步骤6：化合物LA1-7的制备
将化合物LA1-6(500mg,1.1mmol)、三苯基磷(28mg,105.1μmol)、碳酸钠(223mg,2.1mmol)和醋酸钯(12mg,52.6μmol)加入到乙醇(1mL)和甲苯(3mL)的混合溶剂中，最后加入对氟苯硼酸(177mg,1.3mmol)。反应体系用氮气置换三次，升温至70℃反应16小时。冷却到室温后，反应液倒入30mL水中，水相用有乙酸乙酯(30mL×3)萃取。合并后的有机相用20mL水和20mL饱和食盐水各洗涤1次、无水硫酸钠干燥、过滤、真空下浓缩得到黄色粗产品。粗产品经薄层层析板分离纯化(展开液：石油醚/乙酸乙酯＝8/1)得到无色油状产物LA1-7(300mg,产率：67.8％)。1H NMR(400MHz,CHLOROFORM-d):δ7.39-7.34(m,2H),7.12-7.04(m,2H),6.08-6.01(m,1H),5.16-5.04(m,2H),4.05-4.15(m,1H),3.58–3.50(m,2H),3.30-3.15(m,1H),2.37-2.28(m,1H),2.24-2.14(m,1H),1.51(s,9H),0.82(s,9H),-0.04(s,6H).
以下化合物使用与化合物LA1-7类似的方法合成得到：
Figure PCTCN2017086040-appb-000062
Figure PCTCN2017086040-appb-000063
Figure PCTCN2017086040-appb-000064
Figure PCTCN2017086040-appb-000065
步骤7：中间体LA1的制备
将原料LA1-7(300mg,711.54μmol)溶于四氢呋喃(10mL)中，然后加入四丁基氟化铵四氢呋喃溶液(1M,1.07mL)。15℃反应16小时后，反应液倒入20mL水中淬灭反应。水相用乙酸乙酯(15mL×3)萃取。合并后的有机相用10mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到黄色粗产品。粗产品经薄层层析板分离纯化(展开液：石油醚/乙酸乙酯＝3/1)得到无色粘稠液体LA1(160mg,产率：73.1％)。1H NMR(400MHz,CHLOROFORM-d):δ7.32(d,J＝7.0Hz,2H),7.12-6.98(m,2H),6.06(br.s.,1H),3.62(br.s.,2H),2.17(d,J＝18.3Hz,1H),1.58-1.48(m,11H),1.46-1.33(m,1H)。以下化合物使用与化合物LA1类似的方法合成得到：
Figure PCTCN2017086040-appb-000066
Figure PCTCN2017086040-appb-000067
Figure PCTCN2017086040-appb-000068
参考例27:合成手性中间体(-)-LA1
Figure PCTCN2017086040-appb-000069
步骤1：化合物(-)-LA1-1的制备
将化合物LA1(1.80g,5.86mmol)溶于二异丙基醚(180mL)和乙烯乙酸酯(10.08g,117.20mmol)中。搅拌下，依次加入粉末状4A分子筛(900.0mg)和Lipase acrylic resin from Candida antarctica(SIGMA-L4777,1.80g)。25℃下搅拌16小时后，将反应液过滤、真空下浓缩得到淡黄色粗品。粗产品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至2/1)得到白色固体(-)-LA1-1(1.00g,产率：55.5％)。MS m/z:372.2[M+23]+.
步骤2：化合物(-)-LA1的制备
将(-)-LA1-1(700mg,2.0mmol)溶于甲醇(20mL)中，然后加入碳酸钾(1.11g,8.0mmol)。25℃下搅拌2小时后，将反应液过滤、真空下浓缩得到白色粘稠固体粗产品。粗产品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至3/1)得到白色固体(-)-LA1(400mg,产率：65％)。MS m/z:208.0[M-100+1]+，[α]＝-248(C＝1,EtOAc)。
参考例28:合成中间体LA27
Figure PCTCN2017086040-appb-000070
步骤1：化合物LA27-1的制备
25℃下，将LA1-1(500mg,1.63mmol)溶于二甲基亚砜(10mL)中，然后加入2-碘酰基苯甲酸(913mg,3.26mmol)。搅拌12小时后，加入20mL水淬灭反应。水相用乙酸乙酯(20mL x 3)萃取。合并后的有机相用50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝50/1至10/1)，得无色油状粗产物LA27-1(310mg)。MS m/z:205.9[M-100+1]+.
步骤2：化合物LA27-2的制备
氮气保护下，将甲基三苯基溴化磷(702mg,1.97mmol)溶于四氢呋喃(4mL)中。降温至-40℃后，加入正丁基锂正己烷溶液(2.5M,786.01μL)。在此温度下搅拌30分钟后，再加入LA27-1(300mg,982.51μmol)的四氢呋喃溶液(2mL)。升温至25℃搅拌反应2.5小时后，加入15mL水淬灭反应。水相用乙酸乙酯(20mL x 3)萃取。合并后的有机相用30mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝50/1至10/1)，得 无色油状物LA27-2(200mg,收率：67.10％)。1H NMR(400MHz，CHLOROFORM-d):δ7.32(m.,2H),7.01(t,J＝8.4Hz,2H),6.07(s.,1H),5.72(m,1H),5.09(d,J＝10.0Hz,1H),5.01(d,J＝17.2Hz,1H),4.19-3.97(m,2H),3.05-2.85(m,1H),2.43(m,1H),2.16(m,1H),1.51(s,9H).MS m/z:248.0[M-56+1]+.
步骤3：化合物LA27的制备
将LA27-2(200mg,659.26μmol)溶于四氢呋喃(4mL)中，冷却至0℃，氮气保护下加入9-硼双环(3,3,1)-壬烷四氢呋喃溶液(0.5M,3.96mL)。搅拌2小时后，再次加入9-硼双环(3,3,1)-壬烷四氢呋喃溶液(0.5M,3.96mL)。0℃下反应1小时后，升温至25℃，继续反应5小时。反应液冷却至-15℃，加入双氧水(1.50g,13.19mmol,1.27mL)和氢氧化钠(1M,1.32mL)。升温至25℃搅拌12小时后，加入20mL水淬灭反应。水相用乙酸乙酯(15mL x 3)萃取，合并后的有机相用30mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1至5/1)得无色油状物LA27(132mg,收率：62.3％)。1H NMR(400MHz,CHLOROFORM-d):δ7.36-7.28(m,2H),7.02(t,J＝8.4Hz,2H),5.95(d,J＝4.4Hz,1H),5.19(d,J＝11.6Hz,1H),4.16-4.01(m,2H),3.59-3.44(m,2H),2.90(dt,J＝3.6,12.8Hz,1H),2.48-2.35(m,1H),2.13(td,J＝4.8,17.6Hz,1H),1.77-1.73(m,1H),1.51(s,9H).MS m/z:344.1[M+23]+.
参考例29:合成中间体LA28
Figure PCTCN2017086040-appb-000071
步骤1：化合物LA28-2的制备
氮气保护下，将LA28-1(30g,158.55mmol)溶于四氢呋喃(450mL)中，再加入羰基二咪唑(35.99g,221.97mmol)。20℃搅拌1小时后，加入预先混合好的丙二酸单甲酯钾盐(49.52g,317.10mmol)和氯化镁(15.10g,158.55mmol)，然后继续反应16小时。过滤，滤液真空浓缩，加入300mL水稀释。水相用乙酸乙酯萃取(150mL x 3)，静置后有机相析出大量固体，过滤。滤液再用200mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色油状粗产物LA28-2(6.92g)。1H NMR(400MHz,CHLOROFORM-d):δ4.97(br.s.,1H),3.74(s,3H),3.46(s,2H),3.40-3.32(m,2H),2.78(t,J＝5.6Hz,2H),1.42(s,9H).
步骤2：化合物LA28-3的制备
将LA28-2(6.92g,28.21mmol)溶于乙腈(95mL)中，氮气保护下依次加入对甲苯磺酰叠氮(6.12g,31.03mmol)和三乙胺(8.56g,84.63mmol)。15℃搅拌反应1小时后，反应液在真空下浓缩。剩余物溶于200mL乙酸乙酯，依次用饱和碳酸氢钠溶液(100mL)、饱和氯化铵溶液(100mL)和饱和食盐水(100mL)洗涤。有机相用无水硫酸钠干燥、过滤、真空下浓缩得黄色固体粗产物LA28-3(12.97g)。1H NMR(400MHz,CHLOROFORM-d):δ5.01(br.s.,1H),3.83(s,3H),3.44(q,J＝5.6Hz,2H),3.04(t,J＝5.6Hz,2H),1.42(s,9H).
步骤3：化合物LA28-4的制备
将LA28-3(12.97g,47.81mmol)溶于甲苯(425mL)中，氮气保护下加入二聚醋酸铑(65mg,146.78μmol)。加热到90℃搅拌反应1小时后，反应液真空下浓缩得到粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至3/1)，得无色油状物LA28-4(5.86g,收率：50.4％)。1H NMR(400MHz,CHLOROFORM-d):δ4.64-4.49(m,1H),3.95-3.77(m,5H),2.72(t,J＝7.6Hz,2H),1.46(s,9H)。
步骤4：化合物LA28-5的制备
将LA28-4(3g,12.33mmol)溶于四氢呋喃(30mL)中，再加入硼氢化锂(806mg,36.99mmol)。升温至60℃搅拌反应16小时后，冷却，加入50mL水淬灭反应，再加入20mL饱和碳酸氢钠溶液稀释。水相用二氯甲烷和甲醇的混合液(10:1,30mL x 3)萃取。合并后的有机相用无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝2/1至1/1)得无色油状物LA28-5(1.62g,收率：60.5％)。1H NMR(400MHz,CHLOROFORM-d):δ4.51(br.s.,1H),4.01-3.82(m,3H),3.51-3.42(m,2H),2.54(br.s.,1H),2.13-1.90(m,2H),1.46(m,9H)。
步骤5：化合物LA28-6的制备
将LA28-5(1.83g,8.42mmol)溶于二氯甲烷(30mL)中，然后加入三乙胺(1.70g,16.84mmol)。冷却至0℃后，依次加入叔丁基二甲基氯硅烷(2.54g,16.84mmol)和4-二甲胺基吡啶(103mg,842.00μmol)。升温至20℃搅拌反应16小时后，加入60mL水淬灭反应。水相用二氯甲烷(30mL x 3)萃取，合并后的有机相用无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至5/1)，得无色油状物LA28-6(2.04g,收率：73.1％)。1H NMR(400MHz,CHLOROFORM-d):δ4.46(br.s.,1H),4.17-3.97(m,2H),3.79(d,J＝19.2Hz,1H),3.45-3.33(m,2H),2.12-2.01(m,1H),1.97-1.86(m,1H),1.46(s,9H),0.89(s,9H),0.08(d,J＝4.8Hz,6H)。
步骤6：化合物LA28-7的制备
将LA28-6(2.04g,6.15mmol)溶于二甲基亚砜(40mL)中，然后加入2-碘酰基苯甲酸(3.44g,12.30mmol)。20℃搅拌反应16小时后，加入60mL水淬灭反应。水相用乙酸乙酯(30mL x 3)萃取。合并后的有机相用50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝30/1至10/1)得无色油状物LA28-7(1.82g,收率：89.8％)。1H NMR(400MHz,CHLOROFORM-d):δ4.04-3.73(m,4H),3.69-3.58(m,1H),2.61-2.41(m,2H),1.49(s,9H),0.85(s,9H),0.02(d,J＝3.6Hz,6H).
步骤7：化合物LA28-8的制备
将LA28-7(1.82g,5.52mmol)和N-苯基双(三氟甲烷磺酰)亚胺(3.16g,8.83mmol)溶于四氢呋喃(50mL)中。反应体系用氮气置换三次，冷却至-78℃后，缓慢加入六甲基二硅基胺基钠的四氢呋 喃溶液(1M,11.04mL)。反应液维持在此温度下继续搅拌反应3小时后，加入100mL水淬灭反应。水相用乙酸乙酯(30mL x 3)萃取，合并后的有机相用50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝50/1)得无色油状物LA28-8(2.35g,收率：92.23％)。1H NMR(400MHz,CHLOROFORM-d):δ5.86-5.71(m,1H),4.59-4.42(m,1H),4.31-3.97(m,3H),3.82-3.68(m,1H),1.50(d,J＝5.2Hz,9H),0.88(s,9H),0.04(t,J＝5.2Hz,6H).
步骤8：化合物LA28-9的制备
将LA28-8(1.20g,2.60mmol)溶于甲苯(24mL)和乙醇(8mL)的混合溶液中，然后加入对甲苯硼酸(437mg,3.12mmol)、碳酸钠(551mg,5.20mmol)、醋酸钯(29mg,130.00μmol)和三苯基磷(68mg,260.00μmol)。反应体系用氮气置换三次，然后升温至80℃搅拌反应3小时。冷却后，反应液经硅藻土过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1)得无色油状物LA28-9(939.0mg,2.30mmol,收率：88.6％)。1H NMR(400MHz,CHLOROFORM-d):δ7.37-7.30(m,2H),7.03(t,J＝8.8Hz,2H),6.05-5.92(m,1H),5.01-4.87(m,1H),4.38-4.25(m,1H),4.17-4.06(m,2H),3.70-3.60(m,1H),1.53-1.49(m,9H),0.77(d,J＝2.4Hz,9H),-0.12(d,J＝9.6Hz,3H),-0.19(d,J＝3.6Hz,3H).MS m/z:430.2[M+23]+。
步骤9：化合物LA28的制备
将LA28-9(939mg,2.30mmol)溶于四氢呋喃(15mL)中，加入四丁基氟化铵的四氢呋喃溶液(1M,4.60mL)。20℃搅拌反应1.5小时后，反应液直接浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝5/1)得无色油状物LA28(597.0mg,收率：88.49％)。1H NMR(400MHz,CHLOROFORM-d):δ7.38(dd,J＝5.2,8.4Hz,2H),7.06(t,J＝8.4Hz,2H),6.00(s,1H),4.46(d,J＝9.2Hz,1H),4.39-4.30(m,1H),4.26-4.16(m,1H),3.94-3.85(m,1H),3.60(dd,J＝7.2,11.2Hz,1H),1.54-1.48(m,9H).MS m/z:316.0[M+23]+。
参考例30:合成中间体LA29
Figure PCTCN2017086040-appb-000072
步骤1：化合物LA29-1的制备
将LA1(444mg,1.44mmol)溶于二甲基亚砜(10mL)中，再加入2-碘酰基苯甲酸(806mg,2.88mmol)。15℃搅拌反应16小时后，加入20mL水淬灭反应，水相用乙酸乙酯(20mL x 3)萃取。合并后的有机相用20mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶柱层析分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1)，得无色油状物LA29-1(164mg,收率：37.30％)。1H NMR(400MHz,CHLOROFORM-d):δ9.48-9.28(m,1H),7.42(d,J＝5.2Hz,2H),7.09(t,J＝8.4Hz,2H),6.29-6.14(m,1H),5.67(br.s.,0.6H),5.34(br.s.,0.4H),4.04(br.s.,1H),3.14(d,J＝11.6Hz,1H),2.45(br.s.,1H),2.33-2.14(m,1H),1.59-1.48(m,9H).MS m/z:205.9[M-100+1]+.
步骤2：化合物LA29的制备
将LA29-1(154mg,504.36μmol)溶于四氢呋喃(3mL)中，降温至0℃，再加入甲基溴化镁乙 醚溶液(3M,420.30μL)。升温至15℃搅拌反应1小时后，加入10mL水淬灭反应，水相用乙酸乙酯(10mL x 3)萃取。合并后的有机相用20mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经制备层析板分离纯化(洗脱液：石油醚/乙酸乙酯＝3/1)，得无色油状物LA29(86.4mg)。MS m/z:344.0[M+23]+
参考例31:合成中间体LB1
Figure PCTCN2017086040-appb-000073
步骤1：化合物LB1-2的制备
将化合物LB1-1(100g,1.19mol)溶于丙酮(1.50L)中，然后加入硝酸银(202.2g,1.19mol)。25℃下搅拌10分钟后，再加入N-溴代丁二酰亚胺(243.6g,1.37mol)，并继续搅拌2小时。将反应液过滤，用500mL二氯甲烷冲洗滤饼后，真空下浓缩有机相得到粗品。粗品减压蒸馏(30mmHg，收集85-90℃馏分)得到浅黄色油状化合物LB1-2(210.0g,产率：72.3％)。1H NMR(400MHz,CHLOROFORM-d):δ3.80(s,3H)。
步骤2：化合物LB1-3的制备
将化合物LB1-2(100g,613.61mmol)溶于N-叔丁氧羰基-吡咯(410.4g,2.45mol)中。反应体系有氮气置换3次后，升温至90℃下搅拌16小时。冷却后，反应液直接用硅胶层析柱(洗脱液：石油醚/乙酸乙酯＝100/1至20/1)分离纯化得到黄色油状化合物LB1-3(65.0g,产率：32.1％)。1H NMR(400MHz,CHLOROFORM-d):δ7.20-7.02(m,2H),5.57-5.45(m,1H),5.23-5.08(m,1H),3.82(s,3H),1.44(s,9H)。
以下化合物使用与化合物LB1-3类似的方法合成得到：
Figure PCTCN2017086040-appb-000074
步骤3：化合物LB1-4的制备
将化合物LB1-3(65g,196.87mmol)溶于环已烷(1.50L)中，加入Pd/C(5g)。反应体系用氢气置换3次后，在氢氛下(～15psi)25℃搅拌16小时。反应结束后过旋，滤液在真空下浓缩得到黄色油状化合物LB1-4(64.8g,产率：99.1％)。1H NMR(400MHz,CHLOROFORM-d):δ5.05-4.94(m,1H),4.80-4.64(m,1H),3.81(s,3H),2.09-1.89(m,2H),1.44(s,9H),1.42-1.36(m,2H)。
以下化合物使用与化合物LB1-4类似的方法合成得到：
Figure PCTCN2017086040-appb-000075
步骤4：化合物LB1-5的制备
将化合物LB1-4(333mg,1.00mmol)溶于乙醇(3mL)和甲苯(9mL)的混合溶液中，依次加入对氯苯硼酸(188mg,1.20mmol)、三苯基磷(26mg,100.00μmol)、碳酸钠(212mg,2.00mmol)和醋酸钯(11mg,50.00μmol)。反应体系用氮气置换三次，然后升温至70℃搅拌3小时。冷却后，反应液经硅藻土过滤后倒入50mL水中，水相用乙酸乙酯(20mL x 3)萃取。合并后的有机相用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析柱(冼脱液：石油醚/乙酸乙酯＝30/1至10/1)分离纯化得到无色油状物LB1-5(360.0mg,产率：99.0％)。1H NMR(400MHz,CHLOROFORM-d):δ7.56(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),5.06(br.s.,1H),4.97(br.s.,1H),3.74(s,3H),2.15-2.06(m,2H),1.52-1.45(m,2H),1.43(s,9H).
以下化合物使用与化合物LB1-5类似的方法合成得到：
Figure PCTCN2017086040-appb-000076
Figure PCTCN2017086040-appb-000077
Figure PCTCN2017086040-appb-000078
步骤5：中间体LB1的制备
将化合物LB1-5(360mg,989.47μmol)溶于四氢呋喃(5mL)中，0℃下加入氢化铝锂(75mg,1.98mmol)，氮气保下升温至15℃搅拌反应3小时。加入1g十水硫酸钠淬灭反应后，过滤反应液，滤液在真空下浓缩得粗品。粗品经硅胶层析柱(石油醚：乙酸乙酯＝5:1-3:1)分离纯化得到淡黄色固体化合物LB1(215.0mg，产率：64.32％)。1H NMR(400MHz,CHLOROFORM-d):δ7.39(d,J＝8.8Hz,2H),7.22(d,J＝8.8Hz,2H),5.99(s.,1H),4.71(d,J＝6.8Hz,1H),4.13(d,J＝6.8Hz,1H),3.62(d,J＝10.4Hz,1H),3.49(dd,J＝5.6,11.6Hz,1H),2.67(br.s.,1H),2.29(br.s.,2H),1.76(qd,J＝6.8Hz,13.2Hz,1H),1.51-1.43(m,9H).
以下中间体使用与化合物LB1类似的方法合成得到：
Figure PCTCN2017086040-appb-000079
Figure PCTCN2017086040-appb-000080
Figure PCTCN2017086040-appb-000081
参考例49:合成手性中间体(-)-LB1
Figure PCTCN2017086040-appb-000082
步骤1：化合物(-)-LB1-1的制备
将化合物LB1(23g,68.08mmol)溶于二异丙基醚(1.5L)中，依次加入乙烯乙酸酯(117.2g,1.36mol)，4A分子筛(11.5g)和Lipase acrylic resin from Candida antarctica(SIGMA-L4777,23g)。在20℃下搅拌反应5小时后，反应液经硅藻土过滤。滤液在真空下浓缩得到粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝5/1至2/1)得到无色油状物(-)-LB1-1(943.0mg，产率：57.5％)和(+)-LB1(679.0mg,产率：48.54％)。
(-)-LB1-1:1H NMR(400MHz,CHLOROFORM-d):δ7.32-7.28(m,4H),6.09(br.s.,1H),4.77-4.75(d,J＝6.8Hz,1H),4.06-4.02(m,1H),3.90-3.85(m,1H),3.01-3.99(m,1H),2.30-2.29(m,2H),2.02-2.01(m,3H),1.85-1.83(m,2H),1.50-1.47(m,9H).
(+)-LB1:1H NMR(400MHz,CHLOROFORM-d):δ7.31-7.29(m,2H),7.25-7.22(m,2H),6.01(br.s.,1H),4.76-4.74(d,J＝8.8Hz,1H),3.64-3.61(dd,J＝3.2,11.2Hz,1H),3.51-1.45(dd,J＝6.0,12.0Hz,1H),2.69 (br.s.,1H),2.30-2.30(m 2H),1.93-1.92(m,1H),1.80-1.74(m,1H),1.48(s,9H).MS m/z:360.0[M+23]+。[α]＝+85.2(C＝1,MeOH)。
以下手性化合物使用与化合物(-)-LB1-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000083
步骤2：化合物(-)-LB1的制备
将(-)-LB1-1(943mg,2.48mmol)溶于甲醇(10mL)中，再加入碳酸钾(1.37g,9.92mmol)，然后在20℃下搅拌12小时。反应结束后经硅藻土过滤，滤液在真空下浓缩得到粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝5/1至3/1)得到无色油状物(-)-LB1(750.0mg,产率：89.5％)。1H NMR(400MHz,CHLOROFORM-d):δ7.28(d,J＝8.4Hz,2H),7.21(d,J＝8.4Hz,2H),5.99(s,1H),4.72(d,J＝7.6Hz,1H),3.63-3.56(m,1H),3.47(dd,J＝6.0Hz,11.6Hz,1H),2.67(br.s.,1H),2.29(br.s.,2H),1.91(m,1H),1.78-1.73(m,1H),1.46(s,9H).MS(m/z):238.0[M-100+1]+。[α]＝-80.1(C＝1,MeOH)。
以下手性中间体使用与化合物(-)-LB1类似的方法合成得到：
Figure PCTCN2017086040-appb-000084
参考例52和53:合成手性中间体(-)-LB19和(-)-LB20
Figure PCTCN2017086040-appb-000085
步骤1：化合物(-)-LB19-1的制备
将(-)-LB2(1g,3.11mmol)溶于二甲基亚砜(10mL)中，加入2-碘酰基苯甲酸(1.74g,6.22mmol)。 在25℃下搅拌反应12小时后，加入30mL水淬灭反应。水相用乙酸乙酯(20mL x 3)萃取，合并后的有机相用30mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至5/1)得到得无色油状物(-)-LB19-1(628mg，收率：63.2％)。1H NMR(400MHz,CHLOROFORM-d):δ9.43(d,J＝2.4Hz,1H),7.30-7.27(m,2H),7.02(t,J＝8.4Hz,2H),6.23(t,J＝3.2Hz,1H),4.74(br.s.,1H),4.38(br.s.,1H),3.61(br.s.,1H),2.35(br.s.,2H),1.85-1.71(m,2H),1.46(s,9H).
步骤2：化合物(-)-LB19和(-)-LB20的制备
将(-)-LB19-1(617mg,1.93mmol)溶于四氢呋喃(10mL)中，冷却至-40℃，缓慢加入甲基溴化镁***溶液(3M,965μL)。缓慢升温至25℃后继续搅拌反应5小时。加入20mL水淬灭反应，水相用乙酸乙酯(20mL x 3)萃取，合并后的有机相用30mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至2/1)得到两个无色油状非对映异构体(-)-LB19(90mg,收率：13.9％)和(-)-LB20(81mg,收率：12.5％)。
(-)-LB19：MS m/z:358.1[M+23]+.
(-)-LB20：MS m/z:358.1[M+23]+.
参考例54:合成中间体LB21
Figure PCTCN2017086040-appb-000086
步骤1：化合物LB21-2的制备
在0℃氮气保护下，将LB21-1(5.28g,30.0mmol)的四氢呋喃(20mL)溶液缓慢加入到搅拌的异丙基氯化镁四氢呋喃溶液(2M,16.5mL)中。反应液升温至15℃后，继续搅拌16小时。再冷却至0℃后，缓慢加入二氯化锌四氢呋喃溶液(1M,36mL)。升温至15℃后，继续搅拌2小时。缓慢加入二氧六环(6.08g,69.00mmol)。反应液搅拌10分钟后，将反应液直接真空浓缩得到棕黄色固体粗产物LB21-2(16g)。粗产品保存于氮气气氛下，未经纯化直接用于下一步反应。
步骤2：化合物LB21-3的制备
在氮气保护下，将LB21-2(8.00g)和氯[2-(二叔丁基膦基)-2',4',6'-三异丙基-1,1'-联苯基][2-(2-氨基乙基)苯基)]钯(CAS:1447963-75-8,45mg,57μmol)加入到四氢呋喃(10mL)中。搅拌均匀后，加入LB1-3(945mg,2.84mmol)，加热至回流反应16小时。冷却后，倒入100mL水中淬灭反应。水相用乙酸乙酯萃取(100mL x 3)。合并后的有机相用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝16/1)得到黄色油状产物产物LB21-3(348mg，产率：35.1％)。1H NMR(400MHz,CHLOROFORM-d):δ8.49(d,J＝3.2Hz,1H),8.40(dd,J＝4.4,8.8Hz,1H),7.43(dt,J＝3.2,8.4Hz,1H),5.36(d,J＝3.2Hz,1H),5.11(br.s.,1H),3.81(s,3H),2.24-2.07(m,2H),1.56(d,J＝10.4Hz,2H),1.43(s,9H)。MS m/z:348.9[M+1]+.
步骤3：化合物LB21的制备
在0℃下，将LB21-3(180.0mg,517μmol)溶于四氢呋喃(10mL)中，然后缓慢加入氢化铝锂(40mg,1.03mmol)。反应液缓慢升温至15℃后继续反应2小时。冷却至0℃后，向搅拌的反应液中依次缓慢加入0.04mL水，0.04mL氢氧化钠(15％)水溶液，0.12mL水和3克无水硫酸镁。继续搅拌10分钟后，将反应液过滤、用乙酸乙酯洗涤滤饼。滤液在真空下浓缩得黄色粗产品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝3/1)得到淡黄色油状液体LB21(70mg，产率：42.0％)。1H NMR(400MHz,CHLOROFORM-d):δ8.34(d,J＝2.4Hz,1H),7.55-7.31(m,2H),6.39(t,J＝3.6Hz,1H),4.85-4.76(m,1H),4.13(br.s.,1H),3.67-3.61(m,2H),3.01-2.90(m,1H),2.39-2.31(m,2H),1.87-1.75(m,2H),1.48-1.34(m,9H).m/z:322.9[M+1]+
参考例55:合成中间体(-)-LC1
Figure PCTCN2017086040-appb-000087
步骤1：化合物(-)-LC1-1的制备
在25℃下，将三苯基磷(979.3mg,3.73mmol)加入到邻苯二甲酰亚胺(274.7mg,1.87mmol)的四氢呋喃(4mL)溶液中。氮气保护下，依次将(-)-LB2(400.0mg,1.24mmol)和偶氮二甲酸二乙酯(433.5mg,2.49mmol)加入到反应液中。在25℃下，搅拌2小时后，将反应液在真空下浓缩得到粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝50/1至5/1)得到得无色油状物(-)-LC1-1(500.0mg,产率：89.5％)。1H NMR(400MHz,CHLOROFORM-d):δ7.75-7.73(m,2H),7.69-7.66(m,2H),7.34-7.33(m,2H),6.91-6.86(t,J＝8.8Hz,2H),6.08(s,1H),4.76-4.74(m,1H),3.96(m,1H),3.67-3.64(m,2H),3.31-3.27(m,1H),2.34-2.30(m,2H),2.04-2.00(m,1H),1.92-1.90(m,1H),1.41(s,9H)
以下手性中间体使用与化合物(-)-LC1-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000088
Figure PCTCN2017086040-appb-000089
步骤2：化合物(-)-LC1的制备
将一水合肼（277.80mg,5.55mmol）加入到(-)-LC1-1（500.0mg,1.11mmol）的乙醇（2mL）溶液中，然后加热至50℃搅拌2小时，此时有大量白色固体生成。冷却到室温后过滤，滤液真空下浓缩得到白色固体化合物(-)-LC1（350mg,产率：98.4%）。1H NMR(400MHz,CHLOROFORM-d):δ7.25-7.21(m,2H),7.01-6.96(m,2H),5.93-5.91(m,1H),4.81-4.75(m,1H),4.10-4.00(m.,1H),2.55-2.53(m,3H),2.24-2.21(m,2H),1.84-1.1.80(m,1H),1.75-1.71(m,1H),1.44(s,9H).MS m/z:321.1[M+1]+
以下手性中间体使用与化合物(-)-LC1类似的方法合成得到：
Figure PCTCN2017086040-appb-000090
参考例61:合成中间体(-)-LC7
Figure PCTCN2017086040-appb-000091
步骤1：化合物(-)-LC7-1的制备
室温下，将2-碘酰基苯甲酸(261.4mg,933.5μmol)加入到(-)-LB2(200.0mg,622.3μmol)的二甲基亚砜(2mL)溶液中。搅拌16小时后，倒入水(5mL)中淬灭反应，有白色固体析出，过滤得粗产物。粗产物经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝50/1至3/1)得无色油状物(-)-LC7-1(100mg,产率：50.3％)。MS m/z:342.1[M+23]+
步骤2：化合物(-)-LC7的制备
室温下，将甲胺盐酸盐(42.3mg,626.2μmol)和乙酸(1.9mg,31.3μmol)加入到(-)-LC7-1(100.0mg,313.1μmol)的甲醇(2mL)溶液中。室温下搅拌1小时后，加入氰基硼氢化钠(39.4mg,626.2μmol)，继续搅拌15小时。将反应液倒入水(5mL)中淬灭反应，水相用乙酸乙酯(2mL x 3)萃取。合并后的有机相用饱和食盐水洗涤、无水硫酸钠干燥、真空下浓缩得粗品(-)-LC7(100mg，产率：95.5％)。粗产物未经纯化直接用于下一步反应。MS m/z:335.2[M+1]+
参考例62:合成中间体(-)-LD1
Figure PCTCN2017086040-appb-000092
步骤1：化合物(-)-LD1-1的制备
0℃下，将偶氮二甲酸二异丙酯(756.27mg,3.74mmol)加入到三苯基磷(980.9mg,3.74mmol)的四氢呋喃(12mL)溶液中。搅拌10分钟后，加入(-)-LB2(600.0mg,1.87mmol)的四氢呋喃(2mL)溶液。搅拌15分钟后，加入硫代乙酸(284.7mg,3.74mmol)。反应液缓慢升至25℃后，继续搅拌1小时。倒入40mL水中淬灭反应，水相用乙酸乙酯(30mL x 3)萃取。合并后的有机相依次用20mL水、20mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1至10/1)得到无色液体(-)-LD1-1(313mg,1.32mmol,产率：70.6％)。1H NMR(400MHz,CHLOROFORM-d):δ7.34-7.27(m,2H),7.03(t,J＝8.8Hz,2H),5.98(br.s.,1H),4.73(br.s.,1H),4.05(br.s.,1H),3.04(d,J＝13.2Hz,1H),2.80(br.s.,1H),2.76-2.66(m,1H),2.34-2.19(m,5H),1.90-1.72(m,2H),1.46(s,9H).MS m/z:402.1[M+23]+.
步骤2：化合物(-)-LD1的制备
将(-)-LD1-1(200.0mg,527.02μmol)溶于甲醇(3mL)中，然后加入碳酸钾(291.4mg,2.11mmol)。25℃搅拌1小时后，倒入20mL水中淬灭反应，水相用乙酸乙酯(20mL x 3)萃取。合并后的有机相用10mL水,10mL饱和食盐水各洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层 析分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1至10/1)得到(-)-LD1(90.0mg,266.71μmol,产率50.6％)，1H NMR(400MHz,CHLOROFORM-d):δ7.23(d,J＝5.6Hz,1H),7.01(t,J＝8.8Hz,2H),5.96(t,J＝3.2Hz,1H),4.67(d,J＝7.2Hz,1H),4.26(br.s.，1H),2.77(br.s.,1H),2.65(ddd,J＝3.2,8.8,13.6Hz,1H),2.40(td,J＝8.0,14.0Hz,1H),2.27(d,J＝4.4Hz,2H),1.91-1.69(m,2H),1.47(s,9H)。
参考例63:合成中间体LE1和LE2
Figure PCTCN2017086040-appb-000093
步骤1：化合物LE1-2的制备
在氮气保护下，将原料LE1-1(20g，77.74mmol)和硼氢化钠(7.38g，195.13mmol)的四氢呋喃(300mL)混合溶液加热至回流。然后将甲醇(60mL)缓慢滴加至上述溶液中(滴加4小时)，继续反回流应3时。反应液真空浓缩后，加入300mL水稀释，并用乙酸乙酯(300mL x 3)萃取。合并后的有机相依次用100mL水、100mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到黄色粗产品。粗品经硅胶层析分离纯化(洗脱液：二氯甲烷/甲醇＝10/1)得到黄色油状产物(-)-LE1-2(10g，产率：55.6)。MS m/z:254.0[M+23]+.
步骤2：化合物LE1-3的制备
将LE1-2(8g，34.59mmol)，叔丁基二甲基氯硅烷(6.52g，43.24mmol)加入到二氯甲烷(150mL)中，然后依次加入三乙胺(5.25g，51.89mmol)和DMAP(1.06g，8.65mmol)。20℃下反应16小时后，反应液倒入100mL冰水中。冰浴下，用稀盐酸(1M)调pH至5-6。然后用乙酸乙酯(150mL×3)萃取。合并后的有机相依次用50mL饱和碳酸氢钠、50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色粗产品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1)得到亮黄色液体LE1-3(5g，产率：41.8％).1H NMR(400MHz,CHLOROFORM-d):δ4.25-4.20(m,1H),3.98-3.70(m,4H),3.38-3.25(m,2H),1.81-1.70(m,2H),1.68-1.62(m,1H),1.48(s,9H),0.92(s,9H),0.10(d,J＝2.4Hz,6H).
步骤3：化合物LE1-4的制备
将原料LE1-3(5g，14.47mmol)加入到二甲基亚砜(100mL)中，然后加入2-碘酰基苯甲酸(8.10g，28.9mmol)，反应液颜色由无色变为黄色。25℃下反应16小时后，倒入150mL水萃灭反应，然后加入100mL乙酸乙酯稀释。将析出的固体滤除，滤液用乙酸乙酯(100mL×3)萃取。合并后的有 机相依次用50mL饱和碳酸氢钠、50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色粗产品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1)得到无色油状液体LE1-4(4.0g，产率：80.57％)。1H NMR(400MHz,CHLOROFORM-d):δ4.36(ddd,J＝1.6,6.0,13.6Hz,1H),4.25-4.05(m,1H),3.94(br.s.,1H),3.72(br.s.,1H),3.46-3.01(m,2H),2.73-2.34(m,3H),1.51(s,9H),0.90(s,9H),0.07(s,6H).
步骤4：化合物LE1-5和LE2-1的制备
将原料LE1-4(4.37g,12.22mmol)溶于四氢呋喃(100mL)中，反应体系用氮气置换三次，然后冷却至-78℃。将六甲基二硅基胺基钠(1M，11.35mL)缓慢加入，-78℃下继续反应3h。升温至15℃后继续反应16小时。依次加入25mL碳酸氢钠水溶液和100mL水萃灭反应。水相用乙酸乙酯(100mL x 3)萃取。合并后的有机相用50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色粗产品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝50/1至30/1)得到无色油状LE1-5和LE2-1的混合物(3.3g，产率：79.5％)。
步骤5：化合物LE1-6和LE2-2的制备
在氮气气氛下，将LE1-5和LE2-1的混合物(2g，4.21mmol)、三苯基磷(110.42mg，421.00μmol)、碳酸钠(892.44mg，8.42mmol)、醋酸钯(47.26mg，210.50μmol)和对氟苯硼酸(706.88mg，5.05mmol)加入到乙醇(10mL)和甲苯(30mL)的混合溶剂中。反应体系用氮气置换三次后，升温至70℃反应16小时。冷却后，反应液倒入至100mL水中，水相用乙酸乙酯(100mL x 3)萃取。合并后的有机相用50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色粗产品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1)得到无色油状LE1-6和LE2-2的混合物(1.7g，产率：95.8％)。MS m/z:444.2[M+23]+
步骤6：化合物LE1和LE2的制备
将LE1-6和LE2-2的混合物(1.7g，4.03mmol)溶入到四氢呋喃(10mL)中，然后加入四丁基氟化铵(1M，6.05mL)，反应液颜色由无色变为黄色。15℃下反应3小时后，反应液倒入40mL水中萃灭。水相用乙酸乙酯(40mL×3)萃取。合并后的有机相用12mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色粗产品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至5/1)得到无色粘稠液体LE1和LE2的混合物(1.20g，产率：96.7％)。1H NMR(400MHz,CHLOROFORM-d):δ7.33(dd,J＝5.8,8.3Hz,2H),7.02(t,J＝8.8Hz,2H),5.89(s,1.25H),4.65-4.28(m,2.3H),3.85-3.80(m,1.24H),3.59-2.74(m,5.3H),1.50(s,9H).MS m/z:308.8[M+1]+.
参考例64:合成中间体LE3
Figure PCTCN2017086040-appb-000094
步骤1：化合物LE3-2的制备
将LE3-1(8g,29.49mmol)溶于N,N-二甲基甲酰胺(200mL)中，在0℃下缓慢加入氢化钠(1.77g,44.23mmol,60％纯度)。搅拌10分钟后，再缓慢滴入N-苯基双(三氟甲烷磺酰)亚胺(13.69g,38.33 mmol)的N,N-二甲基甲酰胺(20mL)溶液。升温至25℃后继续搅拌16小时。将反应液倒入200mL水中淬灭稀释，水相用乙酸乙酯300mL(100mL x 3)萃.，合并后的有机相用饱和食盐水(100mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1)得到无色油状LE3-2(7.20g,产率：60.5％)。1H NMR(400MHz,CHLOROFORM-d):δ4.43-4.21(m,4H),3.64(s,2H),2.60-2.45(m,2H),1.50(s,9H),1.40-1.32(m,3H)。
步骤2：化合物LE3-3的制备
将LE3-2(1g,2.48mmol)、对氯苯硼酸(465.36mg,2.98mmol)、和碳酸钠(525.71mg,4.96mmol)和Pd(PPh3)4(286.58mg,248.00μmol)加入乙醇(5mL)和甲苯(15mL)的混合溶剂中。反应体系用氮气置换3次后，在80℃下搅拌16小时。冷却后过滤，并用乙酸乙酯30mL冲洗滤饼。滤液在真空下浓缩得到粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1)得到无色油状LE3-3(490.00mg,产率：54.0％)。1H NMR(400MHz,CHLOROFORM-d):δ7.32(s,2H),7.12-7.06(m,2H),4.27(br.s.,2H),4.06-3.90(m,2H),3.73-3.52(m,2H),2.55-2.39(m,2H),1.52(s,9H),1.07-0.93(m,3H)。
步骤2：化合物LE3的制备
将LE3-3(490mg,1.34mmol)溶于四氢呋喃(8mL)中，0℃下缓慢加入氢化铝锂(203mg,5.36mmol)。反应体系用氮气置换3次后，升温至25℃搅拌2小时。将十水硫酸钠缓慢加入到反应液中，直至无气泡产生。搅拌10分钟后，过滤，用乙酸乙酯(20mL)冲洗滤饼。旋干滤液得到粗品。滤液在真空下浓缩得到粗品。粗品经硅胶层析分离纯化(洗脱液：石油醚/乙酸乙酯＝5/1)得到无色油状LE3(200mg,产率：46.1％)。1H NMR(400MHz,CHLOROFORM-d):δ7.39-7.30(m,2H),7.20-7.14(m,2H),4.13-3.98(m,4H),3.66-3.53(m,2H),2.49-2.34(m,2H),1.58(s,9H)。
参考例65:合成中间体R1
Figure PCTCN2017086040-appb-000095
步骤1：化合物R1-2的制备
将化合物R1-1(20g,154.9mmol)溶于叔丁醇(800mL)中，然后加入三乙胺(17.4g,171.7mmol)和叠氮磷酸二苯酯(46.7g,169.8mmol)。90℃下搅拌12小时后，冷却，缓慢倒入200mL冰水中淬灭反应，水相用乙酸乙酯(100mL x 3)萃取。合并后的有机相用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析柱(冼脱液：石油醚/乙酸乙酯＝20/1至10/1)分离纯化得到白色固体R1-2(17.2g,产率：55.5％)。1H NMR(400MHz,DMSO-d6):δ10.23(br.s.,1H),8.90(d,J＝2.0Hz,1H),7.24(br.s.,1H),1.48(s,9H).MS m/z:201.0[M+1]+。
步骤2：中间体R1的制备
将化合物R1-2(3.0g,15.0mmol)溶于N,N-二甲基甲酰胺(50mL)中，0℃下加入氢化钠(898.8mg,22.5mmol)。0℃下反应10分钟后，加入5-氯-2,4-二氟苯磺酰氯(4.1g,16.5mmol)。反应液缓慢 升温至30℃后，搅拌反应4小时。反应液倒入30mL水中淬灭反应，水相用乙酸乙酯(50mL x 3)萃取。合并后的有机相用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经氧化铝层析柱(冼脱液：石油醚/乙酸乙酯＝10/1至5/1)分离纯化得到亮黄色固体化合物R1(3.0g，产率：49.07％)。1H NMR(400MHz,DMSO-d6):δ9.12(d,J＝2.0Hz,1H),8.24(t,J＝7.6Hz,1H),8.02-7.96(m,2H),1.27(s,9H).
以下中间体使用与化合物R1类似的方法合成得到：
Figure PCTCN2017086040-appb-000096
参考例72:合成中间体R8
Figure PCTCN2017086040-appb-000097
步骤1：化合物R8-2的制备
20℃下，将原料R8-1(35.0g,349.5mmol)和2,4-二甲氧基苯甲醛(101.6g,611.6mmol)加入到甲苯(600mL)中，然后加入哌啶(3.0g,34.9mmol)。加热回流16小时，用分水器分出水分。冷却后，反应液在真空下浓缩得到黑色油状物R8-2(100.0g)。MS m/z:280.9[M+32]+。粗产品未经纯化，直接用于下一步。
步骤2：化合物R8-3的制备
冰水浴条件下，将粗产物R8-2(86.8g,349.50mmol)溶于甲醇(500mL)中，分批加入硼氢化钠(13.2g,349.50mmol)。缓慢升温至25℃后，搅拌反应3小时，有大量固体析出。过滤，滤饼用甲醇(2x 30mL)洗涤，得到白色固体R8-3(76.0g,产率：86.87％)。1H NMR(400MHz,CHLOROFORM-d):δ7.23(d,J＝8.0Hz,1H),7.10(d,J＝2.8Hz,1H),6.49-6.42(m,3H),5.67(br.s.,1H),4.38(s,2H),3.84(s,3H),3.79(s,3H).MS m/z:251.0[M+1]+.
以下化合物使用与化合物R8-3类似的方法合成得到：
Figure PCTCN2017086040-appb-000098
步骤3：化合物R8的制备
将R8-3(2g,7.99mmol)溶于四氢呋喃(20mL)中。-78℃下，滴加六甲基二硅基胺基锂四氢呋喃溶液(1M,9.60mL,9.59mmol)。搅拌30分钟后，加入5-氯-2,4-二氟苯磺酰氯(2.37g,9.59mmol)的四氢呋喃(2mL)溶液。缓慢升温至20℃后，继续搅拌2小时。反应液倒入60mL水中淬灭反应，水相用乙酸乙酯(80mL×3)萃取。合并后的有机相用20mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗产品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1)得到白色固体R8(2.4g,收率：65.2％)。1H NMR(400MHz,CHLOROFORM-d):δ7.92(t,J＝7.2Hz,1H),7.43(d,J＝3.6Hz,1H),7.19(d,J＝8.0Hz,1H),7.04-6.98(m,2H),6.38-6.35(m,2H),5.18(s,2H),3.76(s,3H),3.73(s,3H).MS m/z:483.0[M+23]+.
以下化合物使用与化合物R8类似的方法合成得到：
Figure PCTCN2017086040-appb-000099
Figure PCTCN2017086040-appb-000100
参考例87:合成中间体R23
Figure PCTCN2017086040-appb-000101
步骤1：化合物R23-2的制备
将R23-1(45g,339.57mmol)溶于乙醇(500mL)中，搅拌下依次加入三乙胺(41g,407.48mmol)和2,4-二甲氧基苄胺(62g,373.53mmol)。升温至60℃后，搅拌反应48小时。冷却后，真空下直接浓缩。剩余物用乙酸乙酯(50mL)和石油醚(200mL)打浆，过滤。所得固体分散到500mL水中，用乙酸乙酯(500mL×2)萃取。合并后的有机相用100mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗产品。粗产品用50mL乙酸乙酯和200mL石油醚打浆，过滤，得到浅黄色固体R23-2(61.0g,收率：68.2％)。1H NMR(400MHz,CHLOROFORM-d):δ8.17(s,2H),7.24(d,J＝8.4Hz,1H),6.55-6.36(m,2H),5.63(br.s.,1H),4.52(d,J＝6.0Hz,2H),3.84(s,3H),3.79(s,3H).MS m/z:264.0[M+1]+。
以下化合物使用与化合物R23-2类似的方法合成得到：
Figure PCTCN2017086040-appb-000102
步骤2：化合物R23的制备
将R23-2(10g,37.98mmol)溶于四氢呋喃(100mL)中。-78℃下，滴加六甲基二硅基胺基锂四氢呋喃溶液(1M,49.37mL,49.37mmol)。搅拌30分钟后，加入5-氯-2,4-二氟苯磺酰氯(11g,45.58mmol)。缓慢升至25℃后，继续搅拌6小时。倒入100mL水中淬灭反应，水相用乙酸乙酯(100mL×3)萃取。合并后的有机相用50mL水和50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品，所得粗产品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1至5/1)得到浅黄色固体R23(6.0g,收率：33.3％)。1H NMR(400MHz,CHLOROFORM-d):δ8.32-8.31(m,2H),8.15-8.11(m,1H),7.19(d,J＝8.0Hz,1H),6.98(t,J＝8.8Hz,1H),6.45-6.41(m,2H),5.39(s,2H),3.78(s,6H).MS m/z:496.1[M+23]+.
以下化合物使用与化合物R23类似的方法合成得到：
Figure PCTCN2017086040-appb-000103
Figure PCTCN2017086040-appb-000104
参考例91:合成中间体R27
Figure PCTCN2017086040-appb-000105
步骤1：化合物R27-2的制备
冰水浴条件下，将R27-1(10.00g,40.94mmol)溶于四氢呋喃(120mL)中，搅拌下依次加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(23.21g,65.50mmol)和三水合磷酸钾(30.53g,114.63mmol)的水(40mL)溶液。缓慢升温至25℃后，搅拌反应2小时。过滤，滤液用乙酸乙酯萃取(50mL×3)。合并后的有机相用饱和食盐水(50mL×2)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1)得到白色固体R27-2(4.1g,收率：45.9％)。1H NMR(400MHz,DMSO-d6):δ11.48(br.s,1H),7.17(d,J＝2.4Hz,1H),1.48(s,9H).
步骤2：化合物R27-3的制备
将R27-2(1.00g,4.58mmol)溶于甲醇(2mL)中，然后加入盐酸甲醇溶液(4M,5mL)。25℃下反应16小时后，反应液在真空浓缩得到淡黄色粉末R27-3的盐酸盐(700mg，收率：98.9％)。1H NMR(400MHz,METHANOL-d4):δ7.20(s,1H).MS m/z:118.9[M+1]+.
步骤3：化合物R27-4的制备
将R27-3盐酸盐(200mg,1.29mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入三乙胺(130.91mg,1.29mmol)。25℃下搅拌10min后，降温至0℃，加入2-(三甲基硅)乙氧基甲基氯(219.37mg,1.32mmol)。 缓慢升温至25℃后，继续搅拌1小时。反应液过滤得到R27-4的N,N-二甲基甲酰胺溶液，未经纯化直接用于下一步。MS m/z:248.9[M+1]+。
步骤4：化合物R27的制备
将5-氯-2,4-二氟苯磺酰氯(318.70mg,1.29mmol)溶于四氢呋喃(8mL)中。0℃下，依次加入步骤3中得的R27-4N,N-二甲基甲酰胺溶液和1-甲基咪唑(317.73mg,3.87mmol)。缓慢升温至25℃后，继续搅拌2小时。倒入30mL水中淬灭反应，水相用乙酸乙酯(30mL x 3)萃取。合并后的有机相用10mL水和10mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗产品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1至10/1)得到黄色油状液体R27(248mg,收率：41.9％)。1H NMR(400MHz,CHLOROFORM-d):δ8.08(t,J＝7.2Hz,1H),6.99(t,J＝8.8Hz,1H),6.73(s,1H),5.28(s,2H),3.53(t,J＝8.4Hz,2H),0.89(t,J＝8.4Hz,2H),-0.04(s,9H).MS m/z:482.1[M+23]+.
参考例92:合成中间体R28
Figure PCTCN2017086040-appb-000106
步骤1：化合物R28-2的制备
冰水浴条件下，将R28-1(200mg,2.38mmol)溶于吡啶(5mL)中，加入5-氯-2,4-二氟苯磺酰氯(646.78mg,2.62mmol)。缓慢升温至20℃后，搅拌反应2小时。加入10mL水淬灭反应，水相用乙酸乙酯(20mLx3)萃取。合并后的有机相用5mL水和5mL饱和食盐水洗涤、干燥、过滤、真空下浓缩得到红棕色油状粗产物R28-2(700mg)，粗产物不经纯化直接用于下一步反应。1H NMR(400MHz,CHLOROFORM-d):δ8.25(d,J＝1.2Hz,1H),8.00(m,1H),7.05(m,1H),6.53(d,J＝1.2Hz,1H).
以下化合物使用与化合物R28-2类似的方法合成得到：
Figure PCTCN2017086040-appb-000107
步骤2：化合物R28的制备
冰水浴条件下，R28-2(700mg,2.38mmol)溶于无水N,N-二甲基甲酰胺(10mL)中，加入碳酸铯(2.33g,7.14mmol)和对甲氧基苄氯(559.10mg,3.57mmol)。缓慢升温至20℃后，搅拌反应16小时。加入10mL水淬灭反应，水相用乙酸乙酯(20mLx3)萃取。合并后的有机溶剂分别用10mL水和饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗产物。粗产物经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝4/1)得到无色油状产物R28(210mg,收率：21.3％)。1H NMR(400MHz,CHLOROFORM-d):δ8.23(d,J＝1.2Hz,1H),7.84-7.80(m,1H),7.35(d,J＝8.4Hz,2H),6.97(m,1H),6.79 (d,J＝8.4Hz,2H),6.61(d,J＝1.6Hz,1H),5.06(s,2H),3.78(s,3H).
以下化合物使用与化合物R28类似的方法合成得到：
Figure PCTCN2017086040-appb-000108
实施例1:化合物A1的制备
Figure PCTCN2017086040-appb-000109
步骤1：化合物A1-1的制备
0℃下，将LA1(80mg,260μmol)溶于N,N-二甲基甲酰胺(2mL)中，然后依次加入氢化钠(14mg,338μmol)和R1(128mg,312μmol)。缓慢升至15℃后，继续搅拌2小时。加入10mL水淬灭反应后，用乙酸乙酯(15mL×3)萃取。合并后的有机相用饱和食盐水(5mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗产品经硅胶制备板分离纯化(展开液：石油醚/乙酸乙酯＝3/1)得到黄色粘稠液体A1-1(80mg，产率：44.0％)。MS m/z:719.9[M+23]+.
以下化合物使用与化合物A1-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000110
Figure PCTCN2017086040-appb-000111
Figure PCTCN2017086040-appb-000112
Figure PCTCN2017086040-appb-000113
Figure PCTCN2017086040-appb-000114
步骤2：化合物A1的制备
将化合物A1-1(80mg,115μmol)溶于二氯甲烷(10mL)中，然后加入三氟乙酸(1g,8.77mmol)。 15℃下反应2小时后，反应液真空浓缩得到黄色油状粗品。粗品经高效液相制备分离得到化合物A1的盐酸盐(42mg，产率：68.6％)。1H NMR(400MHz,METHANOL-d4):δ8.74(d,J＝2.0Hz,1H),7.86(d,J＝7.2Hz,1H),7.40(dd,J＝5.6,8.4Hz,2H),7.15-7.03(m,3H),6.97(d,J＝11.6Hz,1H),6.31(br.s.,1H),5.00(br.s.,1H),4.43-4.25(m,2H),3.81-3.61(m,1H),3.57-3.43(m,1H),2.78-2.50(m,2H)。MS m/z:497.9[M+1]+
以下化合物使用与化合物A1类似的方法合成得到：
Figure PCTCN2017086040-appb-000115
Figure PCTCN2017086040-appb-000117
Figure PCTCN2017086040-appb-000118
Figure PCTCN2017086040-appb-000119
实施例37:化合物A36的制备
Figure PCTCN2017086040-appb-000120
步骤1：化合物A36的制备
将化合物A1三氟乙酸盐(30mg,49μmol)、HCHO(12mg,147μmol)和乙酸(40mg)依次加入到溶剂甲醇(1.50mL)中。搅拌10分钟后，再加入氰基硼氢化钠(9mg,147μmol)。15℃下搅拌2小时后，倒入5mL水中淬灭反应，水相用乙酸乙酯萃取(10mL x 3)。合并后的有机相用饱和食盐水 洗涤、无水硫酸钠干燥、过滤浓缩得到粗品。粗品经高效液相柱分离纯化后得到产物A36盐酸盐(14.5mg，产率：57.8％)。1H NMR(400MHz,METHANOL-d4):δ8.74(d,J＝1.6Hz,1H),7.86(d,J＝7.2Hz,1H),7.42(br.s.,2H),7.19-6.95(m,4H),6.33(br.s.,1H),5.13-4.94(m,1H),4.54(d,J＝12.0Hz,1H),4.31(d,J＝12.4Hz,1H),3.98-3.73(m,1H),3.63-3.40(m,1H),3.23-3.11(m,3H),2.70(t,J＝19.2Hz,2H)。MS m/z:512.1[M+1]+
实施例38:化合物(-)-A37的制备
Figure PCTCN2017086040-appb-000121
步骤1：化合物A37-1的制备
将LA28(120mg,373.4μmol)溶于N,N-二甲基甲酰胺(5mL)中，降温至0℃，加入氢化钠(23mg,560.1μmol,纯度：60％)。搅拌20分钟后，再加入R1(169mg,410.7μmol)。升温至25℃后继续搅拌1.5小时。加入20mL水淬灭反应，水相用乙酸乙酯(20mL x 3)萃取。合并后的有机相用50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1至2/1)得无色油状物A37-1(126mg,收率：47.4％)。MS m/z:634.0[M-100+23]+.
步骤2：化合物(-)-A37制备
将LA37-1(126mg,176.9μmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(1.54g,13.5mmol)。25℃下搅拌反应1.5小时后，反应液直接浓缩得粗品。粗品经高效液相制备柱分离纯化(HCl体系)得无色油状物。SFC分离后得到(-)-A37(5.5mg,收率：6.9％)。1H NMR(400MHz,METHANOL-d4):δ8.73(d,J＝2.4Hz,1H),7.90(d,J＝7.2Hz,1H),7.43(dd,J＝5.2,8.8Hz,2H),7.09-7.01(m,3H),6.94(d,J＝11.2Hz,1H),6.19(t,J＝3.6Hz,1H),4.77(br.s.,1H),4.62(br.s.,2H),4.26(br.s.,1H),4.06(br.s.,1H),2.66-2.53(m,2H),2.27(d,J＝14.8Hz,2H).MS m/z:512.2[M+1]+.
实施例39:化合物B1的制备
Figure PCTCN2017086040-appb-000122
步骤1：化合物B1-1的制备
0℃下，将LB1(29.0mg,85.7μmol)溶于N,N-二甲基甲酰胺(1mL)中，然后加入氢化钠(4.7mg,116.8μmol)。反应体系用氮气置换2次后，在25℃下搅拌30分钟。再加入R1(32.0mg,77.9μmol)，反应2小时。加入10mL水淬灭反应后，用乙酸乙酯(10mL×3)萃取。合并后的有机相用饱和食盐水(5mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到黄色油状粗品B1-1(40.00mg)，粗产物未经分离纯化直接用于下一步反应。MS m/z:750.1[M+23]+.
以下化合物使用与化合物B1-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000123
Figure PCTCN2017086040-appb-000124
Figure PCTCN2017086040-appb-000125
Figure PCTCN2017086040-appb-000126
Figure PCTCN2017086040-appb-000127
Figure PCTCN2017086040-appb-000128
Figure PCTCN2017086040-appb-000129
Figure PCTCN2017086040-appb-000130
Figure PCTCN2017086040-appb-000131
步骤2：化合物B1的制备
将B1-1(40.0mg,54.9μmol)溶于二氯甲烷(1mL)中，然后加入三氟乙酸(18.8mg,164.9μmol)。25℃搅拌1小时后，反应液真空下直接浓缩得到黄色油状粗品。粗品经高效液相制备分离得到化合物B1的盐酸盐(10.0mg，产率：34.5％)。1H NMR(400MHz,METHANOL-d4):δ8.72(d,J＝2.0Hz,1H),7.83(d,J＝7.2Hz,1H),7.35(s,4H),7.03(d,J＝2.0Hz,1H),6.89(d,J＝11.6Hz,1H),6.24(br.s.,1H),4.18-3.92(m,3H),3.37(br.s.,1H),2.53-2.20(m,3H),2.07-1.88(m,1H).MS m/z:528.1[M+1]+.
以下化合物使用与化合物B1类似的方法合成得到：
Figure PCTCN2017086040-appb-000132
Figure PCTCN2017086040-appb-000133
Figure PCTCN2017086040-appb-000134
Figure PCTCN2017086040-appb-000135
Figure PCTCN2017086040-appb-000136
Figure PCTCN2017086040-appb-000137
Figure PCTCN2017086040-appb-000138
Figure PCTCN2017086040-appb-000139
Figure PCTCN2017086040-appb-000140
实施例98:化合物B53的制备
Figure PCTCN2017086040-appb-000141
步骤1：化合物B53的制备
25℃下，将化合物B2(100.0mg,195.3μmol)溶于甲醇(3mL)中，加入无水乙醛(43.0mg,390.6μmol)和乙酸(105.00mg,1.75mmol)。搅拌10分钟后，加入氰基硼氢化钠(36.8mg,586.0μmol)，继续搅拌1小时。加入15mL水淬灭反应，并用乙酸乙酯(15mL x 3)萃取。合并后的有机相依次用饱和食盐水(30mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品用高效液相制备柱分离纯化(盐酸体系)得到B53的盐酸盐(45.3mg,产率：43％)。1H NMR(400MHz,METHANOL-d4):δ8.78-8.66(m,1H),7.90-7.74(m,1H),7.52-7.38(m,2H),7.10(s,2H),7.05-7.02(m,1H),6.95-6.86(m,1H),6.28-6.21(m,1H),4.18-4.01(m,2H),3.99-3.89(m,1H),3.58-3.41(m,1H),3.36-3.30(m,2H),2.53-2.21(m,3H),2.17-2.00(m,1H),1.45(t,J＝7.2Hz,3H).MS m/z:540.1[M+1]+
以下化合物使用与化合物B53类似的方法合成得到：
Figure PCTCN2017086040-appb-000142
Figure PCTCN2017086040-appb-000143
Figure PCTCN2017086040-appb-000144
Figure PCTCN2017086040-appb-000145
Figure PCTCN2017086040-appb-000146
Figure PCTCN2017086040-appb-000147
实施例131:化合物(-)-B84的制备
Figure PCTCN2017086040-appb-000148
步骤1：化合物(-)-B11的制备
化合物B11盐酸盐(125mg,235.6μmol)经SFC分离(AD柱)后得到(-)-B11(66mg)。1H NMR(400MHz,METHANOL-d4):δ8.72(d,J＝2.0Hz,1H),7.83(d,J＝7.2Hz,1H),7.40-7.24(m,5H),7.04(d,J＝2.0Hz,1H),6.85(d,J＝11.6Hz,1H),6.21(br.s.,1H),4.17-4.11(m,1H),4.09-4.02(m,1H),3.98(br.s.,1H),3.41(br.s.,1H),2.53-2.34(m,2H),2.31-2.20(m,1H),2.02-1.93(m,1H).
以下化合物使用与化合物(-)-B11类似的SFC分离方法得到：
Figure PCTCN2017086040-appb-000149
Figure PCTCN2017086040-appb-000150
步骤2：化合物(-)-B84的制备
将化合物(-)-B11(60mg,121.46μmol)溶于甲醇(6mL)中，依次加入乙醛(41mg,364μmol)，氰基硼氢化钠(31mg,486μmol)，乙酸(210mg,3.50mmol)。反应液于10℃搅拌反应1.5小时后，加入15mL水淬灭反应，水相用乙酸乙酯(15mL x 3)萃取。合并后的有机相用20mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经高效液相制备柱分离纯化(HCl体系)得到(-)-B84盐酸盐(20mg，收率：29.5％)。1H NMR(400MHz,METHANOL-d4):δ8.75(d,J＝1.6Hz,1H),7.82(d,J＝7.6Hz,1H),7.45-7.27(m,5H),7.04(d,J＝1.6Hz,1H),6.88(d,J＝11.6Hz,1H),6.27(br.s.,1H),4.17-3.91(m,3H),3.55(br.s.,1H),3.32-3.27(m,2H),2.51-2.22(m,3H),2.13(d,J＝12.0Hz,1H),1.45(t,J＝6.8Hz,3H).MS m/z:522.1[M+1]+
以下化合物使用与化合物(-)-B84类似的方法合成得到：
Figure PCTCN2017086040-appb-000151
Figure PCTCN2017086040-appb-000152
实施例137:化合物B90的制备
Figure PCTCN2017086040-appb-000153
步骤1：化合物B90-1的制备
将B4-1(44mg,58.7μmol)溶于N,N-二甲基甲酰胺(2mL)中，降温至0℃后，加入氢化钠(5mg,117.3μmol)。搅拌10分钟后，再加入碘甲烷(17mg,117.3μmol)。反应液缓慢升温至15℃后继续搅拌16小时。加入10mL水淬灭反应，水相用乙酸乙酯(10mL x 3)萃取，合并后的有机相用饱和食盐水(20mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析制备板分离纯化(展开剂：石油醚/乙酸乙酯＝1/1)得无色油状物B90-1(10mg，收率：22.4％)。MS m/z:782.4[M+23]+
以下化合物使用与化合物B90-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000154
步骤2：化合物B90的制备
将B90-1(10mg,13.1μmol)溶于二氯甲烷(2mL)中，边搅拌边加入三氟乙酸(612mg,5.4mmol)。反应液于15℃搅拌反应12小时后，加入0.1mL氨水淬灭反应。过滤浓缩后得到粗品，粗品经高效液相制备柱分离纯化(HCl体系)得到B90的盐酸盐(5.6mg,收率：71.6％)。1H NMR(400MHz,METHANOL-d4):δ8.72(d,J＝2.4Hz,1H),7.84(d,J＝7.2Hz,1H),7.46(t,J＝8.4Hz,1H),7.36(dd,J＝2.0,10.8Hz,1H),7.24(d,J＝8.4Hz,1H),7.04(d,J＝2.4Hz,1H),6.96(d,J＝11.2Hz,1H),6.36(br.s.,1H),4.18-4.12(m,1H),4.10-4.03(m,1H),3.86(br.s.,1H),3.50(br.s.,1H),2.91(s,3H),2.55-2.44(m,1H),2.40-2.25(m,2H),2.14(d,J＝12.4Hz,1H).MS m/z:560.2[M+1]+
以下化合物使用与化合物B90类似的方法合成得到：
Figure PCTCN2017086040-appb-000155
Figure PCTCN2017086040-appb-000156
实施例143:化合物(-)-B95的制备
Figure PCTCN2017086040-appb-000157
步骤1：化合物(-)-B95-1的制备
0℃下，将(-)-LB2(50mg,155.6μmol)溶于N,N-二甲基甲酰胺(2mL)中，依次加入氢化钠(9mg,233.4μmol,60％纯度)和R14(79mg,155.6μmol)。0℃下搅拌反应2小时后，加入10mL水淬灭反应，水相用乙酸乙酯(10mL×3)萃取。合并后的有机相用饱和食盐水(5mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到黄色油状粗品。粗品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝10/1-3/1)得无色油状物(-)-B95-1(60mg,收率：47.5％)。1H NMR(400MHz,CHLOROFORM-d):δ7.94(d,J＝7.2Hz,1H),7.71(dd,J＝8.0Hz,11.6Hz,2H),7.39-7.32(m,1H),7.29(s,1H),7.26-7.19(m,3H),6.97(t,J＝8.4Hz,2H),6.42-6.32(m,3H),6.04(br.s.,1H),5.36(s,2H),4.79(br.s.,1H),4.27-4.19(m,1H),4.00-3.91(m,1H),3.75(d,J＝12.4Hz,6H),3.10(br.s.,1H),2.30(br.s.,2H),1.96(br.s.,1H),1.86-1.66(m,1H),1.43(br.s.,9H).MS m/z:834.2[M+23]+.
步骤2：化合物(-)-B95-2的制备
将(-)-B95-1(60mg,73.9μmol)溶于二氯甲烷(5mL)中，然后加入三氟乙酸(1mL,13.5mmol)。反应液于25℃搅拌反应2.5小时后，加入0.5mL氨水调至pH＝10。加入无水硫酸钠干燥、过滤、滤饼用二氯甲烷洗涤。滤液在真空下浓缩得淡黄色油状粗产物(-)-B95-2(50mg)。MS m/z:562.1[M+1]+.
步骤3：化合物(-)-B95的制备
25℃下，将(-)-B95-2(50mg,89.0μmol)溶于甲醇(6mL)中，依次加入乙醛(20mg,177.92μmol,24.80μL)，乙酸(200μL,3.50mmol)和氰基硼氢化钠(22mg,355.84μmol)。搅拌反应1.5小时后，加入20mL水淬灭反应，水相用乙酸乙酯(15mL x 3)萃取。合并后的有机相用30mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经高效液相制备柱分离纯化(HCl体系)得到(-)-B95盐酸盐(5mg,产率：9.0％)。1H NMR(400MHz,METHANOL-d4):δ7.92(d,J＝7.2Hz,1H),7.69(d,J＝7.6Hz,1H),7.48-7.40(m,3H),7.38-7.34(m,1H),7.33-7.27(m,1H),7.09(t,J＝8.8Hz,2H),6.92(d,J＝11.2Hz,1H),6.25(br.s.,1H),4.17-4.10(m,1H),4.08-4.00(m,1H),3.97(br.s.,1H),3.50(br.s.,1H),3.36-3.30(m,2H),2.49-2.25(m,3H),2.12(d,J＝12.4Hz,1H),1.45(t,J＝7.2Hz,3H).MS m/z:590.1[M+1]+
实施例144和145:化合物(-)-B55和(+)-B55的制备
Figure PCTCN2017086040-appb-000158
步骤1：化合物(-)-B55和(+)-B55的制备
化合物B55(106mg,190.5μmol)经SFC(AD柱)分离后得到两个对映构体(-)-B55和(+)-B55的粗品。二者再经高效液相制备柱分离纯化(HCl体系)得到纯的(-)-B55(24.0mg,收率：21.3％)和(+)-B55(19.1mg,收率：16.9％)。
(-)-B55:1H NMR(400MHz,METHANOL-d4):δ8.77(br.s.,1H),7.81(d,J＝7.2Hz,1H),7.46-7.39(m,2H),7.38-7.33(m,2H),7.04(d,J＝2.0Hz,1H),6.92(d,J＝11.6Hz,1H),6.30(br.s.,1H),4.14(d,J＝8.4Hz,1H),4.08-4.01(m,1H),3.95(br.s.,1H),3.54(br.s.,1H),3.33(br.s.,2H),2.52-2.22(m,3H),2.13(d,J＝12.4Hz,1H),1.50-1.39(m,3H).MS m/z:556.1[M+1]+
(+)-B55:1H NMR(400MHz,METHANOL-d4):δ8.74(s,1H),7.81(d,J＝7.2Hz,1H),7.46-7.39(m,2H),7.38-7.31(m,2H),7.03(s,1H),6.91(d,J＝11.2Hz,1H),6.30(br.s.,1H),4.20-3.92(m,3H),3.53(br.s.,1H),3.33(br.s.,2H),2.53-2.21(m,3H),2.14(br.s.,1H),1.45(br.s.,3H).MS m/z:556.1[M+1]+
以下化合物使用与化合物(-)-B55和(+)-B55类似的SFC分离方法得到：
Figure PCTCN2017086040-appb-000159
实施例150:化合物B96的制备
Figure PCTCN2017086040-appb-000160
步骤1：化合物B96的制备
将化合物B2(10mg,20μmol)、***水溶液(7mg)和乙酸(33mg,547μmol)的甲醇(2mL)溶液搅拌20分钟后，加入氰基硼氢化钠(5mg,79μmol)。升温至15℃后，继续反应2小时。加入10mL水淬灭反应后，水相用二氯甲烷(15mL x 3)萃取。合并后的有机相用5mL饱和食盐水洗涤、 无水硫酸钠干燥、过滤、真空下浓缩得黄色粗产品。粗产品经高效液相制备柱分离分离纯化(HCl体系)得到B96(5mg，产率：46.9％)。1H NMR(400MHz,METHANOL-d4):δ8.72(d,J＝2.0Hz,1H),7.84(d,J＝7.2Hz,1H),7.46(dd,J＝5.2,8.4Hz,2H),7.16-7.01(m,3H),6.90(d,J＝11.2Hz,1H),6.26(br.s.,1H),4.17(d,J＝10.0Hz,1H),4.09-3.97(m,1H),3.88(br.s.,1H),3.68(br.s.,1H),3.18-2.99(m,6H),2.54-2.17(m,4H)。MS m/z:540.0[M+1]+.
以下化合物使用与化合物B96类似的合成方法得到：
Figure PCTCN2017086040-appb-000161
Figure PCTCN2017086040-appb-000162
实施例158:化合物B103的制备
Figure PCTCN2017086040-appb-000163
步骤1：化合物B103的制备
0℃下，将化合物B2盐酸盐(15mg,27μmol)和二异丙基乙基胺(11mg,82μmol)加入到二氯甲烷(5mL)中，然后加入乙酰氯(3mg,33μmol)。升温至15℃后，继续反应2小时。加入氨水(0.5mL)淬灭反应后，再加入10mL水稀释。水相用二氯甲烷(10mL x 3)萃取。合并后的有机相用10mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到黄色粗产品。粗产品经高效液相制备柱分离纯化(HCl体系)得到B103盐酸盐(5mg，产率：33.0％)。1H NMR(400MHz,METHANOL-d4):δ8.72(s,1H),7.78(d,J＝7.2Hz,1H),7.36-7.19(m,2H),7.07-6.92(m,3H),6.77(d,J＝11.6Hz,1H),6.04(br.s.,1H),4.44(br.s.,1H),4.13-3.85(m,2H),3.09(br.s.,1H),2.34(br.s.,2H),1.99(s,4H),1.87-1.69(m,1H).MS m/z:577.0[M+23]+.
实施例159化合物B104的制备
Figure PCTCN2017086040-appb-000164
步骤1：化合物B104的制备
将化合物B2盐酸盐(60mg,110μmol)溶于二氯甲烷(10mL)中，然后依次加入三乙胺(33mg,328μmol)、EDCI(32mg,164μmol)、HOBt(22mg,164μmol)和3-溴丙酸(27mg,175μmol)。15℃下搅拌16小时后，加入8mL水淬灭反应，水相用乙酸乙酯(15mL x 3)萃取。合并后的有机相用饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经高效液相柱分离纯化(HCl体系)后得到产物B104(11.8mg，产率：14.3％)。1H NMR(400MHz,DMSO-d6):δ11.32(s,1H),8.89(d, J＝2.4Hz,1H),8.14(d,J＝7.6Hz,1H),7.74(d,J＝7.2Hz,1H),7.33(dd,J＝5.6,8.8Hz,2H),7.15-7.02(m,4H),6.33(dd,J＝10.4,17.2Hz,1H),6.15-6.02(m,2H),5.65-5.54(m,1H),4.36(br.s.,1H),4.07-3.93(m,2H),3.12(br.s.,1H),2.32-2.11(m,2H),1.95-1.64(m,2H)。MS m/z:566.0[M+1]+
实施例160化合物B105的制备
Figure PCTCN2017086040-appb-000165
步骤1：化合物B105-1的制备
将中间体LB2(240mg,747μmol)溶于二氯甲烷(10mL)中，然后加入三氟乙酸(850mg)，反应液颜色由淡黄色变为棕色。15℃下搅拌2小时后，反应液直接真空下浓缩，得棕色油状液体粗产品B105-1(250mg)。粗产品未经纯化，直接用于下一步反应。1H NMR(400MHz,METHANOL-d4):δ7.40-7.31(m,2H),7.12-7.05(m,2H),6.07(t,J＝3.6Hz,1H),4.43-4.22(m,1H),3.88-3.70(m,1H),3.61(dd,J＝3.6,11.2Hz,1H),3.04-2.90(m,1H),2.37-2.30(m,2H),2.21-2.05(m,1H),2.03-1.79(m,1H)。MS m/z:221.9[M+1]+。
步骤2：化合物B105-2的制备
15℃下，将B105-1(160mg,723μmol)溶于乙腈(10mL)中，然后依次加入1,3-二溴丙烷(292mg,1.5mmol)和三乙胺(256mg,2.5mmol)。升温至50℃后，继续搅拌反应16小时后。加入20mL水淬灭反应，水相用乙酸乙酯(25mL x 3)萃取。合并后的有机相用饱和食盐水(10mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色油状粗产物。粗产品经高效液相制备柱分离纯化得到白色固体B105-2(48mg，产率：25.4％)。1H NMR(400MHz,METHANOL-d4):δ7.35(dd,J＝5.2,8.8Hz,2H),7.05(t,J＝8.8Hz,2H),6.01(br.s.,1H),3.44-3.34(m,5H),3.29-3.21(m,1H),2.89(br.s.,1H),2.66(d,J＝9.2Hz,1H),2.29-1.99(m,4H),1.80-1.58(m,2H)。MS m/z:262.1[M+1]+。
步骤3：化合物B105-3的制备
0℃下，将B105-2(48mg,184μmol)溶于N,N-二甲基甲酰胺(2mL)中，然后依次将氢化钠(9mg,220μmol)和R1(83mg,202μmol)加入。升温至15℃后继续反应2小时后。加入15mL水淬灭反应，水相用乙酸乙酯(15mL x 3)萃取。合并后的有机相用饱和食盐水(5mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得黄色油状粗产物B105-3(130mg)。粗产品未经纯化，直接用于下一步。MS m/z:651.9[M+1]+。
步骤4：化合物B105的制备
15℃下，将B105-3(126.49mg,193.95μmol溶于二氯甲烷(5mL)中，然后将加入三氟乙酸(670mg)。搅拌2小时后，反应液直接真空下浓缩，得到黄色油状液体粗品。粗品经高效液相柱分离纯化(HCl体系)后得到产物B105的盐酸盐(33.7mg，产率：29.5％)。1H NMR(400MHz,METHANOL-d4):δ8.92(d,J＝1.6Hz,1H),7.81(d,J＝7.6Hz,1H),7.43(dd,J＝5.6,8.4Hz,2H),7.14-7.03(m,3H),6.93(d,J＝11.2Hz,1H),6.23(br.s.,1H),4.55-4.33(m,3H),4.25(br.s.,1H),4.16-3.92(m,3H),3.28(br.s.,1H),2.82-2.63(m,1H),2.53-2.15(m,4H),2.14-2.01(m,1H).MS m/z:551.9[M+1]+
实施例161化合物B106的制备
Figure PCTCN2017086040-appb-000166
步骤1：化合物B106的制备
将化合物B2(50mg,98μmol)，3-氧杂环丁酮(21mg,293μmol)和乙酸(70mg)的甲醇(2mL)溶液搅拌5分钟后，再加入氰基硼氢化钠(18.4mg,293.0μmol)。升温至40℃后反应48小时。冷却至15℃后，依次加入***水溶液(39mg)、乙酸(29mg)和氰基硼氢化钠(24mg,387μmol)。15℃下反应1小时后，倒入10mL水淬灭反应，水相用二氯甲烷(15mL x 3)萃取。合并后的有机相用饱和食盐水(5mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经高效液相柱分离纯化后得到B106的盐酸盐(5.8mg，产率：10.3％)。1H NMR(400MHz,METHANOL-d4):δ8.73(s,1H),7.91-7.80(m,1H),7.60-7.34(m,2H),7.16-7.01(m,3H),6.90(d,J＝11.2Hz,1H),6.28(d,J＝14.0Hz,1H),5.06-4.95(m.,2H),4.91-4.74(m,2H),4.40-3.54(m,5H),3.21-2.88(m,3H),2.60-2.06(m,4H)。MS m/z:582.1[M+1]+.
实施例162化合物B107的制备
Figure PCTCN2017086040-appb-000167
步骤1：化合物B107的制备
将乙二醛(6mg,107.4μmol)和多聚甲醛(10mg,107.43μmol)溶于乙酸(3mL)中，加热至70℃后。再将B2(50mg,97.7μmol)和乙酸铵(8mg,97.7μmol)的乙酸(3mL)和水(500μL)的混合溶液缓慢滴加到反应液中。滴加完后，继续搅拌反应16小时。冷却至室温后，反应液直接浓缩得粗品。粗品经高效液相制备柱(三氟乙酸体系)分离纯化得到B107的三氟乙酸盐(4.5mg,收率:6.81％)。1H NMR(400MHz,METHANOL-d4):δ9.09(s,1H),8.72(d,J＝2.4Hz,1H),7.86(s,1H),7.82(d,J＝7.2Hz,1H),7.65(s,1H),7.36(dd,J＝5.6,8.4Hz,2H),7.09-6.98(m,3H),6.74(d,J＝11.6Hz,1H),6.17(br.s.,1H),5.09(br.s.,1H),4.04(dd,J＝5.2,10.4Hz,1H),3.98-3.91(m,1H),3.76(br.s.,1H),2.51(br.s.,1H),2.44-2.31(m,3H).MS m/z:563.1[M+1]+.
实施例163化合物B108的制备
Figure PCTCN2017086040-appb-000168
步骤1：化合物B108的制备
将N,N-二甲基甲酰胺二甲基缩醛(23mg,195.3μmol)和甲酰肼(12mg,195.3μmol)溶于乙腈(2mL)中，加热至60℃搅拌反应1小时后，再加入B2(50mg,97.7μmol)和乙酸(210mg,3.5mmol)。反应液升温至120℃后，继续搅拌反应16小时。冷却至室温后，反应液直接浓缩得粗品。粗品经高效液相制备柱(三氟乙酸体系)分离纯化得到B108的三氟乙酸盐(5.90mg,收率:8.91％)。1H NMR(400MHz,METHANOL-d4):δ9.02(s,2H),8.73(d,J＝2.0Hz,1H),7.81(d,J＝7.2Hz,1H),7.35(dd,J＝5.6,8.8Hz,2H),7.08-6.99(m,3H),6.75(d,J＝11.6Hz,1H),6.17(br.s.,1H),5.12-5.04(m,1H),4.07-4.00(m,1H),3.98-3.91(m,1H),3.71(br.s.,1H),2.55-2.47(m,1H),2.39-2.24(m,3H).MS m/z:564.1[M+1]+.
实施例164:化合物(-)-C1的制备
Figure PCTCN2017086040-appb-000169
步骤1：化合物(-)-C1-1的制备
在25℃下，将碳酸钾(172.6mg,1.25mmol)和R1(307.8mg,749.1μmol)加入到(-)-LC1(200.0mg,624.2μmol)的N,N-二甲基甲酰胺(2mL)溶液中，加热至80℃反应16小时。将反应液倒入饱和氯化铵水溶液(10mL)中淬灭反应，有固体析出，过滤得粗产物。粗产物用硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝50/1至2/1)得无色油状物(-)-C1-1(100mg,产率：22.5％)。MS m/z:733.3[M+23]+
以下化合物使用与化合物(-)-C1-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000170
Figure PCTCN2017086040-appb-000171
Figure PCTCN2017086040-appb-000172
步骤2：化合物(-)-C1的制备
在25℃下，将HCl/乙酸乙酯(4M,2mL)加入到(-)-C1-1(100.0mg,140.6μmol)的乙酸乙酯(2mL)溶液中。搅拌2小时后，反应液真空下浓缩得到(-)-C1盐酸盐(76.00mg,产率：98.7％)。1H NMR(400MHz,METHANOL-d4):δ8.74(d,J＝2.4Hz,1H),7.63(d,J＝7.2Hz,1H),7.37(dd,J＝5.2,8.4Hz,2H),7.11(t,J＝8.4Hz,2H),7.00(d,J＝2.0Hz,1H),6.15-6.03(m,2H),3.78(br.s.,1H),3.28-3.18(m,2H),3.05(br.s.,1H),2.52-2.31(m,2H),2.26-2.14(m,1H),1.99-1.85(m,1H).MS m/z:533.1[M+23]+
以下化合物使用与化合物(-)-C1类似的方法合成得到：
Figure PCTCN2017086040-appb-000173
Figure PCTCN2017086040-appb-000174
Figure PCTCN2017086040-appb-000175
实施例180:化合物(-)-C17的制备
Figure PCTCN2017086040-appb-000176
步骤1：化合物(-)-C17的制备
在30℃下，将乙醛(3.9mg,88.1μmol)加入到(-)-C1(30.0mg,58.7μmol)的甲醇(3mL)溶液中.然后加入氰基硼氢化钠(7.38mg,117.41μmol)和乙酸(1.8mg,29.35μmol)。搅拌2小时后，将反应液倒入水(10ml)中淬灭反应，水相用乙酸乙酯萃取(3mL x 3)。合并后的有机相用饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品用高效液相色谱柱(HCl体系)分离得(-)-C17盐酸盐(20.0mg,产率：59.2％)。1H NMR(400MHz,METHANOL-d4):δ8.74(d,J＝2.4Hz,1H),7.62(d,J＝7.2Hz,1H),7.39(dd,J＝5.2,8.4Hz,2H),7.15-7.06(m,2H),7.00(d,J＝2.4Hz,1H),6.16(d,J＝12.8Hz,1H),6.13-6.08(m,1H),3.77-3.68(m,1H),3.31-3.26(m,1H),3.25-3.09(m,4H),2.42(br.s.,1H),2.37-2.25(m,1H),2.15(br.s.,2H),1.35(t,J＝7.2Hz,3H).MS m/z:539.2[M+1]+
以下化合物使用与化合物(-)-C17类似的方法合成得到：
Figure PCTCN2017086040-appb-000177
实施例185:化合物(-)-D1的制备
Figure PCTCN2017086040-appb-000178
步骤1：化合物(-)-D1-1的制备
将R8(114.7mg,248.9μmol)溶于N,N-二甲基甲酰胺(4mL)中。0℃搅拌下，依次加入氢化钠(10mg,248.93μmol,60％纯度)和(-)-LD1(70.0mg,207.4μmol)。缓慢升温25℃后，继续搅拌2小时。倒入20mL冰水淬灭反应，水相用乙酸乙酯(20mL x 3)萃取。合并后的有机相用10mL水和10mL饱和食盐水各洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗产品经硅胶层析柱分离纯化(洗脱液：石油醚/乙酸乙酯＝20/1至3/1)得到(-)-D1-1(100.0mg,产率：61.9％)。MS m/z:800.2[M+23]+
以下化合物使用与化合物(-)-D1-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000179
Figure PCTCN2017086040-appb-000180
步骤2：化合物(-)-D1的制备
将(-)-D1-1(100mg,128.5μmol)溶于二氯甲烷(2mL)中，然后加入三氟乙酸(1.25g,10.96mmol)。25℃下反应1小时后，将反应液真空浓缩得到粗产品。粗产品经高效液相制备柱分离纯化得到白色粉末(-)-D1盐酸盐(50mg,产率：68.9％)。1H NMR(400MHz,METHANOL-d4):δ7.82(d,J＝6.2Hz,1H),7.33(dd,J＝5.6,8.4Hz,2H),7.19(d,J＝4.4Hz,1H),7.09(t,J＝8.4Hz,2H),6.89-6.77(m,2H),6.09(t,J＝3.6Hz,1H),3.98(br.s.,1H),3.24-2.96(m,3H),2.55-1.91(m,4H).MS m/z:528.1[M+1]+.
以下化合物使用与化合物(-)-D1类似的方法合成得到：
Figure PCTCN2017086040-appb-000181
实施例188:化合物(-)-D4的制备
Figure PCTCN2017086040-appb-000182
步骤1：化合物(-)-D4的制备
将(-)-D2三氟乙酸盐(153mg,238.3μmol)和乙醛(52.5mg,1.2mmol)溶于甲醇(3mL)中，然后加入乙酸(100.0mg,1.67mmol)和氰基硼氢化钠(104.8mg,1.67mmol)。25℃下反应2小时后，加入30mL水中淬灭反应，水相用乙酸乙酯(30mL x 3)萃取。合并后的有机相用15mL饱和食盐水洗 涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗产品经高效液相制备柱分离纯化(HCl体系)得到(-)-D4盐酸盐(25.0mg,产率：17.7％)。1H NMR(400MHz,METHANOL-d4):δ8.76(d,J＝1.6Hz,1H),7.81(d,J＝6.4Hz,1H),7.36(dd,J＝5.2,8.4Hz,2H),7.19-7.06(m,3H),6.86(d,J＝10.4Hz,1H),6.13(br.s.,1H),3.91(br.s.,1H),3.29-2.98(m,5H),2.16(br.s.,4H),1.39(t,J＝7.2Hz,3H).MS m/z:556.1[M+1]+.
以下化合物使用与化合物(-)-D4类似的方法合成得到：
Figure PCTCN2017086040-appb-000183
实施例191:化合物(-)-D7的制备
Figure PCTCN2017086040-appb-000184
步骤1：化合物(-)-D7的制备
将化合物(-)-D1盐酸盐(30mg,53.1μmol)和双氧水(18mg,159.4μmol,30％纯度)加入到乙酸(1mL)中，升温至65℃搅拌反应1.5小时。冷却后，加入5mL水淬灭反应，再加入饱和碳酸氢钠溶液调pH至8左右，水相用乙酸乙酯(10mL x 3)萃取。合并后的有机相用20mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗品。粗品经高效液相柱制备分离纯化(HCl体系)得到(-)-D7盐酸盐(5.7mg,收率：18.5％)。1H NMR(400MHz,METHANOL-d4):δ7.94(d,J＝5.6Hz,1H),7.68(d,J＝8.4Hz,1H),7.51-7.39(m,1H),7.25-7.08(m,2H),6.94(d,J＝7.2Hz,2H),6.85(dd,J＝4.4,14.4Hz,1H),6.18-6.02(m,1H),4.06-3.86(m,1H),3.65-3.51(m,1H),3.18-3.05(m,1H),3.02-2.83(m,1H),2.40(br.s.,2H),2.07(br.s.,1H),1.97(br.s.,1H).MS m/z:544.1[M+1]+
实施例192和193:化合物E1和E2的制备
Figure PCTCN2017086040-appb-000185
步骤1：化合物E1-1和E2-1的制备
0℃下，将LE1-1和LE1-2的混和物(240mg，780.84μmol)溶于N,N-二甲基甲酰胺(4mL)中，然后依次加入氢化钠(40.6mg，1.02mmol,60％纯度)和R1(378.5mg，921.4μmol)。0℃下反应3小时后，倒入15mL水中淬灭反应，水相用乙酸乙酯(15mL x 3)萃取。合并后的有机相用10mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到黄色粗产物E1-1和E2-1的混合物(600mg)，粗产品未经纯化直接用于下一步反应。MS m/z:720.2[M+23]+.
以下化合物使用与化合物E1-1和E2-1类似的方法合成得到：
Figure PCTCN2017086040-appb-000186
步骤2：化合物E1和E2的制备
将E1-1和E2-1(545mg，780.58μmol)溶于二氯甲烷(5mL)中，然后加入三氟乙酸(2g，17.54mmol)。15℃下反应2小时后，反应液直接真空下浓缩得到黄色油状粗产物。粗产物经高效液相制备柱分离纯化(NH4OH体系)得到两个产物E1(70mg，产率：18.0％)和E2(16mg，产率：4.1％)。
E1:1H NMR(400MHz,DMSO-d6):δ8.70(d,J＝2.0Hz,1H),7.69(d,J＝7.2Hz,1H),7.45(dd,J＝5.6,8.4Hz,2H),7.15(t,J＝8.8Hz,2H),6.96(d,J＝11.6Hz,1H),6.55(d,J＝1.6Hz,1H),6.14(br.s.,1H),4.15(t,J＝9.6Hz,1H),3.91(dd,J＝3.2,9.6Hz,1H),3.57(br.s.,2H),3.44-3.25(m,2H),3.08(dd,J＝3.6,12.4Hz,1H).MS m/z:498.1[M+1]+.
E2：1H NMR(400MHz,DMSO-d6):δ8.68(d,J＝2.0Hz,1H),7.71(d,J＝7.6Hz,1H),7.33-7.12(m,4H),6.95(d,J＝11.6Hz,1H),6.38(br.s.,1H),4.49(s,2H),3.67(br.s.,2H),3.17(t,J＝5.6Hz,2H),2.55-2.51(m,2H).MS m/z:498.1[M+1]+.
以下化合物使用与化合物E1和E2类似的方法合成得到：
Figure PCTCN2017086040-appb-000187
Figure PCTCN2017086040-appb-000188
hNav1.7体外膜片钳实验:
细胞：实验所用的细胞是稳定表达hNav1.7离子通道的CHO细胞株，此细胞株来自于Genious。
全自动膜片钳实验：在室温下采用全细胞膜片钳技术进行实验。细胞外液的组成成分有(mM)：N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid(HEPES)5、NaCl 140、KCl 3、CaCl2 1、MgCl2 1、CdCl2 1、TEA-Cl 20，用氢氧化钠调节pH至7.4；渗透压调至300-320mOsm；过滤后4℃保存。电极内液的组成成分有(mM)：CsF 140、CsOH 5、Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid(EGTA)1、HEPES 10、NaCl 10，用氢氧化铯调节pH至7.3；渗透压调至300-320mOsm；过滤后-20℃分装保存。
称取一定量的受试化合物或阳性对照化合物，将化合物溶于溶剂中，根据其溶解性配置成10mM的储备溶液。实验前用DMSO将上述储备溶液按照10倍逐级稀释，然后进一步用细胞外液稀释到所需浓度。工作浓度溶液使用前应检查有无沉淀析出，如果有沉淀析出，将稀释储备液，提高细胞外液中DMSO终浓度，但细胞外液中DMSO最终浓度不超过0.3％。实验中采用从低浓度到高浓度连续灌流的方式。
当hNav1.7细胞成长到培养皿的50％-80％的时候，用DPBS冲洗，然后用胰酶分离细胞。分离后的细胞用细胞外液混合。在离心之后，弃去上清液，并再次加入细胞外液让细胞处于悬浮状态，便可以直接用于全自动膜片钳试验。在全自动膜片钳软件(5.2版本，Sophion Bioscience)上建立所有的形成全细胞膜片钳和电压脉冲刺激的实验方案。化合物测试数据如下：
Figure PCTCN2017086040-appb-000189
Figure PCTCN2017086040-appb-000190
注：A≤0.01uM；0.01uM<B≤0.1uM；0.1uM<C≤1uM；1uM<B≤10uM；
体外活性测试证明：本发明化合物对Nav 1.7具有明显的抑制作用。
热力学溶解度(TS)测试实验:
检测原理：采用揺瓶法和HPLC测定化合物的热力学溶解度。化合物的溶解度是影响化合物药物筛选以及化合物在动物和人体内药物吸收的一个重要属性。
缓冲液(pH 7.4)：50mM磷酸盐缓冲液，pH值7.4。
标准溶液的制备：将50％的乙腈溶液和50％的缓冲溶液混合，得到的稀释液。10mM(10μL/化合物)储备液加入至稀释液(490μL/化合物)中，混合为200μM的的紫外检测标准液。以10倍或100倍量的稀释液稀释200μM的紫外检测标准液，以获取20μM，2μM的紫外标准溶液。2，20和200μM的紫外标准溶液作为热力学溶解性试验的标准样品。
样品制备方法：称量不少于2mg的样品粉末于Whatman miniuniprep的小瓶中。分别添加450μL缓冲液(pH值7.4)到每个Whatman miniuniprep小瓶中。加入缓冲液后，将Whatman miniuniprep带过滤的活塞盖装上并压至液面上方，使在震摇过程中过滤网与缓冲溶液液接触。涡旋摇动溶解度样品2分钟。并记录溶液现象。以550转每分钟的速度室温(约22～25℃)震摇24小时。按压Whatman Miniunipreps过滤瓶盖至底部，获得样品溶解度溶液的滤液。所有样品小瓶都应进行过滤前后不溶物质及其渗漏现象。 缓冲液稀释50倍得到样品稀释液。
通过过滤和HPLC测定热力学溶解度：从低浓度到高浓度注入3个紫外标准液至HPLC中，然后注入待测化合物的稀释液和上清。待测样品进样两次。对紫外色谱峰进行积分。模拟标准曲线并计算样品的热力学学溶解度。
HPLC条件：
Figure PCTCN2017086040-appb-000191
热力学溶解度(TS)测试结果如下:
化合物 TS(μmol) 化合物 TS(μmol)
PF-05089771 <2.0 (-)-B88 35.7
A1 66.2 (-)-C1 134.9
(-)-B53 26.5 (-)-C5 13.4
B60 5.5 (-)-C7 19.1
B82 68.8 (-)-C16 5.3
热力学溶解度测试结果证明：本发明化合物具有良好的溶解度性质。
血浆蛋白结合率(PPB)测试实验:
目的
1.本实验的目的是测定供试品在血浆中的蛋白结合率。
2.测试体系
本研究采用HTDialysis公司的96孔平衡透析装置，将浓度为2μM供试品和对照化合物的血浆样品在37℃平衡透析4-hr，来进行蛋白结合的研究。血浆存放在-80℃冰箱中，详细信息见下表。
Figure PCTCN2017086040-appb-000192
采用warfarin作为实验的对照化合物
3.实验步骤
2.1.样品制备
■HTD平衡透析装置按说明书进行组装备用。
■用DMSO将10mM储存液稀释到中间浓度400μM。供试品及照化合物的血浆样品配制过程：移取一定体积的供试化合物工作溶液或warfarin工作溶液到空白血浆中，使血浆样品中供试化合物或warfarin的终浓度为2μM。将样品充分混合。有机相DMSO的终浓度<1％。
■用于回收率及稳定性测定的T0样品的配制过程：移取50μL供试化合物和warfarin血浆样品到样品接收板中(三个平行)，立即加入相应体积的对应空白血浆或缓冲液。然后向这些T0样品中加入一定体积终止液，并存储于2-8℃，等待与其它透析完的样品一起进行后续处理。
■血浆样品的透析过程：将150μL供试化合物和warfarin血浆样品加入到每个透析孔的给药端，在透析孔对应的接收端中加入150μL空白透析缓冲液。然后将透析板置于湿润的、5％CO2的培养箱中，在37℃下振荡孵育4-hr。
■透析结束后，移取50μL透析后的缓冲液样品和透析后的血浆样品到新的96孔板中(样品接收板)。在样品中加入相应体积的对应空白血浆或缓冲液。所有样品经过蛋白沉淀后进行LC/MS/MS分析。样品的浓度用化合物与内标的峰面积比值表示(半定量)。
4.数据分析
化合物的％未结合率(％Unbound)、％结合率(％Bound)和回收率(％Recovery)的计算公式如下：
Figure PCTCN2017086040-appb-000193
％Bound＝100-％Unbound
Figure PCTCN2017086040-appb-000194
其中[F]是透析装置中缓冲液一侧样品中化合物的浓度；[T]是透析装置中血浆一侧样品中化合物的浓度；[T0]是零时刻血浆样品中化合物的浓度。
血浆蛋白结合率(PPB)测试结果如下:
Figure PCTCN2017086040-appb-000195
测试结果表明本发明化合物的血浆蛋白结合率相对于临床化合物PF-05089771有所改善。

Claims (19)

  1. 式(Ⅰ)和式(Ⅱ)所示化合物、其互变异构体或药学上可接受的盐，
    Figure PCTCN2017086040-appb-100001
    其中，
    R1选自任选被1、2或3个R取代的：5～12元芳基、5～12元杂芳基；
    R2选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的：C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氨基、N,N-二(C1-3烷基)氨基；
    X选自：O、S、S(＝O)、S(＝O)2、NR；
    L选自-(CRR)1-4-；
    D选自：NR3、C(R3)2或N(R3)C(R3)2；
    R3选自H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN，或选自任选被1、2或3个R取代的：C1-6烷基、C1-6烷氨基、C1-6烷氧基、C1-6烷硫基、N,N-二(C1-6烷基)氨基、C3-6环烷基氨基、3～6元环烷基氨基、5～6元芳基、5～6元杂芳基、C2-4烷烯基-C(＝O)NH-、C2-4烯烷基-C(＝O)NH-；
    环B选自任选被1、2或3个R取代的：5～6元芳基、5～6元杂芳基、5～6元非芳杂烯基；
    n选自0、1、2或3；
    m选自0、1或2；
    R选自H、F、Cl、Br、I、OH、CN、NO2、NH2，或选自任选被1、2或3个R’取代的：C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基、C1-3烷基硫基；
    R’选自：F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CH2F、CHF2、CF3、CH3O、CH3S、NH(CH3)、N(CH3)2；
    所述“杂”代表杂原子或杂原子团，选自：-C(＝O)NH-、N、-NH-,-C(＝NH)-、-S(＝O)2NH-、-S(＝O)NH-、-O-、-S-、N、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、和-NHC(＝O)NH-；
    上述任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R选自：H、F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CF3、NH(CH3)、N(CH3)2。
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R1选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、噻唑基、1,3,4-噻二唑基、1,2,4-噻二唑基、2H-四唑基、异噁唑基、苯并[d]噻唑。
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R1选自任选被1、2或3个R取代的：
    Figure PCTCN2017086040-appb-100002
    Figure PCTCN2017086040-appb-100003
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R1选自
    Figure PCTCN2017086040-appb-100004
    Figure PCTCN2017086040-appb-100005
  6. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R2选自：F、Cl、Br、I、OH、NH2、NO2、CN、COOH、CF3、Me。
  7. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，L选自：CH2、CH2CH2、CH(CH3)。
  8. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，X选自：O、S、S(＝O)、S(＝O)2、NH、N(CH3)。
  9. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R3选:H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me，或选自任选被1、2或3个R取代的：C1-3烷基、C1-3烷基氨基、N,N-二(C1-3烷基)氨基、4～6元杂环烷基、4～6元杂环烷基氨基、5～6元芳基、5～6元杂芳基、C2-4烷烯基-C(＝O)NH-、C2-4烯烷基-C(＝O)NH-。
  10. 根据权利要求9所述化合物或其药学上可接受的盐，其中，R3选自H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me，或选自任选被1、2或3个R取代的Me、Et、
    Figure PCTCN2017086040-appb-100006
    Figure PCTCN2017086040-appb-100007
  11. 根据权利要求10所述化合物或其药学上可接受的盐，其中，R3选自H、F、Cl、Br、I、OH、NH2、NO2、COOH、CN、Me、Et、
    Figure PCTCN2017086040-appb-100008
    Figure PCTCN2017086040-appb-100009
  12. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，D选自：
    Figure PCTCN2017086040-appb-100010
    Figure PCTCN2017086040-appb-100011
  13. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2017086040-appb-100012
    选自：
    Figure PCTCN2017086040-appb-100013
    Figure PCTCN2017086040-appb-100014
  14. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2017086040-appb-100015
    选自
    Figure PCTCN2017086040-appb-100016
  15. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，环B选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、呋喃基、吡唑基、咪唑基、噻吩基、噁唑基、3,6-二氢-2H-吡喃基。
  16. 根据权利要求15所述化合物或其药学上可接受的盐，其中，环B选自任选被1、2或3个R取代的：
    Figure PCTCN2017086040-appb-100017
  17. 根据权利要求16所述化合物或其药学上可接受的盐，其中，环B选自：
    Figure PCTCN2017086040-appb-100018
    Figure PCTCN2017086040-appb-100019
  18. 根据权利要求1～17任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017086040-appb-100020
    其中，
    m选自0、1、2或3；
    R、R1、R2、R3、L、X、n如权利要求1～17所定义。
  19. 下式所示化合物，其选自：
    Figure PCTCN2017086040-appb-100021
    Figure PCTCN2017086040-appb-100022
    Figure PCTCN2017086040-appb-100023
    Figure PCTCN2017086040-appb-100024
    Figure PCTCN2017086040-appb-100025
    Figure PCTCN2017086040-appb-100026
    Figure PCTCN2017086040-appb-100027
    Figure PCTCN2017086040-appb-100028
    Figure PCTCN2017086040-appb-100029
    Figure PCTCN2017086040-appb-100030
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