WO2018103757A1 - 作为ccr2/ccr5受体拮抗剂的联苯化合物 - Google Patents

作为ccr2/ccr5受体拮抗剂的联苯化合物 Download PDF

Info

Publication number
WO2018103757A1
WO2018103757A1 PCT/CN2017/115453 CN2017115453W WO2018103757A1 WO 2018103757 A1 WO2018103757 A1 WO 2018103757A1 CN 2017115453 W CN2017115453 W CN 2017115453W WO 2018103757 A1 WO2018103757 A1 WO 2018103757A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
pharmaceutically acceptable
mmol
acceptable salt
Prior art date
Application number
PCT/CN2017/115453
Other languages
English (en)
French (fr)
Inventor
罗云富
龙超峰
巴庾勇
陈小新
陈曙辉
Original Assignee
广东众生药业股份有限公司
南京明德新药研发股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东众生药业股份有限公司, 南京明德新药研发股份有限公司 filed Critical 广东众生药业股份有限公司
Priority to CN201780074929.0A priority Critical patent/CN110023286B/zh
Priority to US16/468,127 priority patent/US11155523B2/en
Priority to ES17877947T priority patent/ES2906992T3/es
Priority to JP2019530756A priority patent/JP7086075B2/ja
Priority to EP17877947.6A priority patent/EP3567028B1/en
Publication of WO2018103757A1 publication Critical patent/WO2018103757A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to a class of CCR2/CCR5 receptor antagonists and their use in the manufacture of a medicament for the treatment of a disease associated with CCR2/CCR5. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • Chemokines are a small family of pro-inflammatory cytokines that act as a leukocyte chemoattractant. They promote the transport of leukocytes from the vascular bed to surrounding tissues that respond to inflammatory signals. Chemotaxis begins with chemokine-receptor binding (GPCR) by initiating an increase in calcium flux, inhibition of cyclic adenosine production, cytoskeletal rearrangement, integrin activation, and signalling of cellular processes The pathway of conduction and increased expression of adhesion proteins.
  • GPCR chemokine-receptor binding
  • Cytokines are relatively small proteins (8-10 kD) that stimulate cell migration.
  • the chemokine family is divided into four subfamilies based on the number of amino acid residues between the first and second highly conserved cysteines.
  • Monocyte chemoattractant protein-1 MCP-1
  • MCP-1 is a member of the CC chemokine subfamily (where CC represents a subfamily with adjacent first and second cysteines) and binds to cell surface chemokines Receptor 2 (CCR2).
  • MCP-1 is a potent chemokine that mediates the migration (ie, chemotaxis) of monocytes and lymphocytes to sites of inflammation after binding to CCR2.
  • MCP-1 is also expressed by cardiomyocytes, vascular endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, mesangial cells, alveolar cells, T lymphocytes, esophageal cancer, and the like. After entering the inflammatory tissue, monocytes differentiate into CCR5-expressing macrophages, providing secondary sources of several pro-inflammatory regulators, including tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 (IL-1).
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-1 interleukin-1
  • IL-8CXC chemokine subfamily wherein CXC represents an amino acid residue between the first and second cysteines
  • IL-12 the IL-8CXC chemokine subfamily, wherein CXC represents an amino acid residue between the first and second cysteines
  • IL-12 the IL-8CXC chemokine subfamily, wherein CXC represents an amino acid residue between the first and second cysteines
  • IL-12 the IL-8CXC chemokine subfamily, wherein CXC represents an amino acid residue between the first and second cysteines
  • IL-12 IL-12
  • arachidonic acid metabolites eg, PGE 2 and LTB 4
  • oxygen-derived free radicals oxygen-derived free radicals
  • matrix metalloproteinases complement components.
  • CCR2 (also known as CKR-2, MCP-1RA or MCIRB) is primarily expressed on monocytes and macrophages and is essential for macrophage-dependent inflammation.
  • CCR2 is a G-protein coupled receptor (GPCR) that binds to several members of the chemokine MCP family (CCL2, CCL7, CCL8, etc.) with high affinity, triggering chemotaxis signals, leading to migration of directional receptor-carrying cells.
  • GPCR G-protein coupled receptor
  • CCR5 is a G-protein coupled receptor that binds to a variety of CC chemokine ligands, including CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL11 and CCL13.
  • the in vivo function of CCR5 is less clear than CCR2.
  • CCR5 is mainly expressed in activated Th1 cells and tissue macrophages differentiated from blood monocytes, which are accompanied by subsurface modulation of CCR2 expression.
  • CCR5 It contributes to the survival of macrophages during inflammation and infection, and also acts to retain macrophages in inflamed tissues.
  • CCR5 mediates the recruitment and activation of Th1 cells in inflammation.
  • CCR5 is also expressed on osteoclasts and is important for osteoclast formation, suggesting a contributing role of CCR5 in the pathology of rheumatoid arthritis. Activation of vascular smooth cells by CCL4/CCR5 may also contribute to atherosclerosis and pathology of AIH (accelerated intimal hyperplasia).
  • CCR2 and CCR5 The complementary cell distribution and differential cellular function of CCR2 and CCR5 provides a theoretical basis for dual targeting of two receptors that may have greater efficacy than targeting individual receptors.
  • CCR2 plays an important role in mediating migration from bone marrow to blood and from blood to tissue monocytes, where CCR5 primarily regulates the activation of macrophages in inflamed tissues. Survival and possible retention.
  • CCR5 blockade can improve the therapeutic potential of dual antagonists by inhibiting T cell responses in addition to effects on monocytes/macrophages. Based on the advantages of CCR2 and CCR5 dual targets, CCR2/5 dual antagonists have also been intensively studied.
  • the CCR2/5 dual antagonist has a good drug potential, and here we patent the biphenyl compound of the CCR2/5 dual antagonist.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1 1-6 alkoxy, 5- to 6-membered heterocycloalkyl optionally substituted by 1, 2 or 3 R;
  • R 5 and R 6 are each independently selected from H or independently selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
  • Ring A is selected from:
  • R 7 is selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R;
  • R 8 is selected from H or is selected from: C 1-6 alkyl optionally substituted by 1, 2 or 3 R;
  • R is selected from halogen, OH, or selected from C 1 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R';
  • R' is selected from the group consisting of F, Cl, Br, I, OH, CH 2 F, CHF 2 , CF 3 ;
  • hetero of the 5- to 6-membered heterocycloalkyl group is independently selected from: -NH-, -O-, N;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, or selected from C 1 -3 alkyl, C 1-4 alkane, optionally substituted by 1, 2 or 3 R' Oxyl, C 3-6 cycloalkyl.
  • said R is selected from the group consisting of F, Cl, Br, I, OH, or selected from the group consisting of: 1, 2 or 3 R's: Me,
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, CH 3 , CH 2 F, CHF 2 , CF 3 ,
  • R 1 above is selected from C 1 1-4 alkoxy, pyrrolidinyl optionally substituted by 1, 2 or 3 R.
  • 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 , R 3 , and R 4 are each independently selected from H, F, Cl, Br, I, OH, CN, or are independently selected from 1, 2, or 3, respectively.
  • R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, Me,
  • R 2 is selected from the group consisting of: H, F, Cl, OH, CN, Me,
  • R 3 is selected from the group consisting of: H, F, Cl, Me,
  • R 4 is selected from the group consisting of H, Cl.
  • R 5 and R 6 are each independently selected from H or Me.
  • R 7 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: Me,
  • R 7 is selected from the group consisting of Me,
  • R 8 is selected from H or is selected from the group consisting of: 1, 2 or 3, R: Me,
  • R 8 is selected from the group consisting of H, Me,
  • the ring A is selected from the group consisting of:
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition for the preparation of a medicament for treating a disease associated with CCR2 and/or CCR5.
  • the invention also provides the use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of inflammatory and autoimmune disorders and cancer.
  • R 1 above is selected from C 1 1-4 alkoxy, pyrrolidinyl optionally substituted by 1, 2 or 3 R, and other variables are as defined above.
  • R 1 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: Other variables are as defined above.
  • R 1 is selected from the group consisting of Other variables are as defined above.
  • R 2 , R 3 , and R 4 are each independently selected from H, F, Cl, Br, I, OH, CN, or are independently selected from 1, 2, or 3, respectively.
  • R Me
  • Other variables are as defined above.
  • R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, Me, Other variables are as defined above.
  • R 2 is selected from the group consisting of: H, F, Cl, OH, CN, Me, Other variables are as defined above.
  • R 3 is selected from the group consisting of: H, F, Cl, Me, Other variables are as defined above.
  • R 4 is selected from the group consisting of: H, Cl, and other variables are as defined above.
  • R 5 and R 6 are each independently selected from H or Me , and other variables are as defined above.
  • R 7 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: Me, Other variables are as defined above.
  • R 7 is selected from the group consisting of Me, Other variables are as defined above.
  • R 8 is selected from H or is selected from the group consisting of: 1, 2 or 3, R: Me, Other variables are as defined above.
  • R 8 is selected from the group consisting of H, Me, Other variables are as defined above.
  • the ring A is selected from the group consisting of: Other variables are as defined above.
  • the compounds of the present invention have significant CCR2 and CCR5 antagonism, plasma clearance rate is lower than that of oral administration, oral bioavailability is high, oral plasma system exposure is superior, and pharmacokinetic properties are excellent.
  • 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, carbonic acid Hydrogen radical, 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, horse Acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesul
  • inorganic acid salts including, for example, hydrochlor
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • 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, and Minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
  • 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.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent.
  • X When X is vacant in AX, the structure is actually A.
  • the substituent When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • the substituent 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. or It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example, 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 a ring system containing at least one ring, wherein each "ring” is independently Combined with 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 groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Step 1 Synthesis of Compound BB-1A-2
  • Step 2 Synthesis of the compound BB-1A.
  • Step 1 Synthesis of Compound BB-1B.
  • Step 1 Synthesis of Compound BB-2A
  • Step 1 Synthesis of Compound BB-2B
  • Step 1 Synthesis of Compound BB-2I
  • Step 1 Synthesis of Compound BB-2J
  • Step 1 Synthesis of compound BB-3A-2.
  • Step 2 Synthesis of compound BB-3A-3.
  • BB-3A-2 (210.00 g, 1.22 mol, 1.00 eq) was suspended in n-butanol (2.00 L) at 20 ° C, and hydrogen peroxide (207.32 g, was added dropwise to the suspension at 0 ° C, 1.83 mol, 175.69 mL, 1.50 eq. purity 30%), naturally warmed to 20 ° C, stirred for 16 hours.
  • the reaction solution was quenched with 100 mL of saturated sodium sulphate and then concentrated to dryness.
  • Step 3 Synthesis of compound BB-3A-4.
  • BB-3A-3 (40.00 g, 285.35 mmol, 1.00 eq) was dissolved in dichloromethane (150 mL), and chlorosulfoxide (82.15 g, 690.55 mmol, 50.09 mL, 2.42 eq) was added dropwise to the solution at room temperature. Heat to 40 ° C and stir for 30 minutes. The reaction solution was filtered, and the filtrate was evaporated. 300 mL of ethyl acetate was added to the crude product and the mixture was filtered, and then filtered to give compound BB-3A-4 (33.00 g, 169.15 mmol, hydrochloride, yield: 59.3%).
  • Step 4 Synthesis of compound BB-3A-5.
  • Step 5 Synthesis of compound BB-3A-6.
  • BB-3A-5 (10.00 g, 40.43 mmol, 1.00 eq) was dissolved in methyl isobutyl ketone (600 mL) and toluene (1.2 L), and p-dimethylbenzoyl-D- was added to the solution at room temperature. Tartrate (15.62 g, 40.43 mmol, 1.00 eq), the mixture was stirred at room temperature for 10 h, cooled to 0 ° C and H 2 O 2 (13.75 g, 121.29 mmol, 11.65 mL, 30%purity, 3.00 eq) was added dropwise. The mixture was stirred at room temperature for 96 hours. The mixture was quenched with aq.
  • Step 6 Synthesis of compound BB-3A.
  • Step 1 Synthesis of compound BB-3B-4-2.
  • BB-3B-4-1 (4.50 g, 43.23 mmol) was added dropwise to a solution of the compound hydrazine hydrate (2.80 g, 47.55 mmol) in ethanol (20.00 mL) at 0 °C. After the reaction mixture was stirred at room temperature for 15 hours, 1-propyl isocyanate (4.37 g, 43.18 mmol) was added dropwise to the reaction system. The temperature was raised to 40 ° C for 15 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to give crude compound BB-3B-4-2 (9.5 g, yield: 82.69%).
  • Step 1 Synthesis of Compound BB-3C
  • Step 1 Synthesis of Compound BB-3A'
  • Compound BB-3A'-1 was subjected to supercritical fluid chromatography (separation condition: Column: Chiralpak AS-3 150 ⁇ 4.6 mm I.D., 3 ⁇ m
  • Step 1 Synthesis of Compound BB-3G
  • Step 1 Synthesis of compound BB-3K, BB-3K'
  • Compound BB-3I was subjected to supercritical fluid chromatography (separation condition: Column: ChiralPaK AD-3 150*4.6 mm ID, 3 ⁇ m mobile phase: A: CO2B: Ethanol (0.05% DEA), gradient: 5% to 40% B, 5.5 Min, kept at 40% for 3 min, then kept at 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 40 ° C, wavelength: 220 nm), to obtain isomer BB-3K (retention time 5.828 minutes) and BB- 3K' (retention time 6.163 minutes).
  • Step 1 Synthesis of compound BB-3J, BB-3J'
  • Compound BB-3H was subjected to supercritical fluid chromatography (separation condition: Column: ChiralPaK AD-3 150*4.6 mm ID 3 ⁇ m; mobile phase: A: CO2B: Ethanol (0.05% DEA), gradient: 5%-40% B, 5.5 Min; kept at 40% B for 3 min, then maintained at 5% B 1.5 min, flow rate: 2.5 mL/min, column temperature: 40 C, wavelength; 220 nm) separated to give the isomer BB-3J (retention time 4.775 min) and isomer Body BB-3J' (retention time 4.521 minutes).
  • Step 1 Synthesis of Compound BB-4A-2
  • Step 1 Synthesis of Compound BB-4D-2
  • Step 1 Synthesis of Compound BB-5A
  • Step 1 Synthesis of Compound BB-5B
  • Step 1 Synthesis of Compound BB-5C-2
  • reaction mixture was cooled to room temperature, and nitrogen was added to the mixture to remove excess methyl iodide, and then the mixture was evaporated to ethyl acetate (5 mL x 3). The organic layer was combined, washed with brine (20 mL)
  • Triethylphosphorylacetate (25.02 g, 111.60 mmol) was dissolved in tetrahydrofuran under nitrogen atmosphere, and 60% pure sodium hydride (4.46 g, 111.60 mmol) was added portionwise at 0 °C. After stirring at 0-5 ° C for half an hour, a solution of compound BB-2A (16.00 g, 74.40 mmol) in tetrahydrofuran (20.00 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours under nitrogen. After the reaction is completed,
  • reaction solution was slowly poured into 50 ml of a saturated aqueous solution of ammonium chloride.
  • the oil and water phases were separated and the aqueous phase was extracted with ethyl acetate (40 mL*3).
  • the organic phase was combined, washed with brine brine (lizlili).
  • Compound WX086-1 was subjected to supercritical fluid chromatography (separation condition: Column: ChiralPaK AD-3 50*4.6 mm ID, 3 um mobile phase: A: CO2B: 40% Ethanol (0.05% DEA), flow rate: 4 mL/min, column temperature :40 ° C, wavelength: 220 nm) separation, the isomer WX086 ' (retention time 2.247 minutes) and WX086 (retention time 3.248 minutes).
  • Compound WX087-1 was subjected to supercritical fluid chromatography (separation condition: Column: ChiralPaK AD-3 50*4.6 mm ID, 3 um mobile phase: A: CO2B: 40% Ethanol (0.05% DEA), flow rate: 4 mL/min, column temperature :40 ° C, wavelength: 220 nm) separation, the isomer WX087' (retention time 2.409 minutes) and WX087 (retention time 3.392 minutes).
  • the inhibitory effect of the compound on CCR2 and CCR5 receptors was evaluated by measuring the intracellular calcium signal changes by FLIPR and using the IC50 value of the compounds as indicators.
  • Cell line Inoculate cells and incubate overnight at 37 ° C in a 5% CO 2 incubator
  • the compound was dissolved in DMSO to prepare a 10 mM solution, and the compound solution was placed in a nitrogen box.
  • MCP-1 was diluted 10 points in FLIPR assay buffer 1:2 starting at 0.5 uM (final 100 nM).
  • RANTES was diluted 10 points in FLIPR assay buffer 1:3 starting at 0.5 uM (final 100 nM).
  • 20 uL of serially diluted compound buffer was added to each well of the DRC plate according to the compound plate map.
  • Antagonist Compound Preparation Antagonist Reference Compound The standard compound was diluted 11 points in DMSO 1:3 starting at 1 mM. Test compounds were diluted 11 points in DMSO 1:3 starting at 2 mM. Transfer 250nL compound solution to cell plate using Echo (Greiner#781946)
  • WX037 62.2 44.2 WX084 51.2 4.6 WX038 42.5 12.5 WX085 5.2 5.6 WX039 70.1 760.0 WX086 13.0 1.8 WX040 11.3 10.5 WX087 66.0 2.1 WX041 22.5 21.4 WX088 3.5 4.3 WX042 52.8 4.0 WX089 15.0 ND WX043 249.6 9.1 WX090 5.5 6.9 WX044 293.2 16.1 WX091 4.7 4.4 WX045 77.6 14.8 WX092 3.9 10.1 WX046 1.1 2.8
  • the compounds of the present invention have significant antagonism to CCR2 and CCR5 receptors.
  • test compound was injected into SD rats via the tail vein (fasting overnight, 7-10 weeks old), and the test compound was orally administered to SD rats (overnight fast, 7-10 weeks old).
  • Animals were collected from the jugular vein or tail vein at a dose of 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
  • Approximately 200 ⁇ L was placed in an anticoagulant tube supplemented with EDTA-K2 at 4 ° C, 3000 g. The plasma was taken by centrifugation for 15 min.
  • Table 2 shows the pharmacokinetic parameters of the test compounds WX017, WX047, WX079 and the reference compound in rats.
  • test compound was injected into the cynomolgus monkey via the cephalic or saphenous vein (fasting overnight, 2.5-7 kg), and the test compound was intragastrically administered to the cynomolgus monkey.
  • Animals were transferred from peripheral venous blood collection of approximately 400 ⁇ L at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after administration to a commercialized centrifuge containing 0.85-1.15 mg of K2 EDTA*2H2O anticoagulant. In the tube, plasma was taken by centrifugation at 3000 g for 10 min at 4 °C.
  • Table 3 shows the pharmacokinetic parameters of the test compound WX047 and the reference compound in cynomolgus monkeys.
  • a total of 5 specific probe substrates for CYP's five isozymes, Phenacetin (CYP1A2), Diclofenac (CYP2C9), (S)-Mexantine (S)-Mephenytoin, CYP2C19), Dextromethorphan (CYP2D6), Midazolam (CYP3A4) were incubated with human liver microsomes and test compounds, respectively, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • LC-MS/MS liquid chromatography tandem mass spectrometry
  • the reference compound has a weak inhibitory effect on CYP3A4, while WX047 and WX079 do not inhibit the five isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450. The risk is better than the reference compound.

Landscapes

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

Abstract

提供了一类CCR2/CCR5受体拮抗剂，及其在制备治疗与CCR2/CCR5相关疾病的药物中的应用。具体公开了式(Ⅰ)所示化合物及其药学上可接受的盐。

Description

作为CCR2/CCR5受体拮抗剂的联苯化合物
相关申请的引用
本申请要求于2016年12月9日向中华人民共和国国家知识产权局提交的第CN201611137560.7号和2017年1月17日向中华人民共和国国家知识产权局提交的第CN201710037028.6号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本发涉及一类CCR2/CCR5受体拮抗剂，及其在制备治疗与CCR2/CCR5相关疾病的药物中的应用。具体涉及了式(Ⅰ)所示化合物及其药学上可接受的盐。
背景技术
趋化因子是一种小的，分泌促炎细胞因子的家族，起到白细胞化学引诱物的作用。它们促进白细胞从血管床到响应炎症信号的周围组织的运输。趋化性起始于趋化因子与受体结合(GPCR)，通过启动涉及增加的钙流量，环磷酸腺苷产生的抑制，细胞骨架的重排，整联蛋白的活化和细胞运动过程的信号传导途径以及增加粘附蛋白的表达。
化学诱导剂细胞因子(即趋化因子)是相对小的蛋白质(8-10kD)，其刺激细胞的迁移。基于第一和第二高度保守的半胱氨酸之间的氨基酸残基的数目，将趋化因子家族分成四个亚家族。单核细胞趋化蛋白-1(MCP-1)是CC趋化因子亚家族(其中CC代表具有相邻的第一和第二半胱氨酸的亚家族)的成员并且结合细胞表面趋化因子受体2(CCR2)。MCP-1是有效的趋化因子，其在结合CCR2后介导单核细胞和淋巴细胞向炎症位点的迁移(即趋化性)。MCP-1也由心肌细胞，血管内皮细胞，成纤维细胞，软骨细胞，平滑肌细胞，肾小球系膜细胞，肺泡细胞，T淋巴细胞，食管癌等表达。单核细胞进入炎症组织后，分化成表达CCR5的巨噬细胞，提供几种促炎调节剂的次级来源，包括肿瘤坏死因子-α(TNF-α)，白细胞介素-1(IL-1)，IL-8CXC趋化因子亚家族，其中CXC代表第一和第二半胱氨酸之间的一个氨基酸残基)，IL-12，花生四烯酸代谢物(例如PGE 2和LTB 4)，氧衍生的自由基，基质金属蛋白酶和补体成分。
CCR2(也称为CKR-2，MCP-1RA或MCIRB)主要在单核细胞和巨噬细胞上表达，并且对于巨噬细胞依赖性炎症是必需的。CCR2是以高亲和力结合趋化因子MCP家族(CCL2，CCL7，CCL8等)的几个成员的G蛋白偶联受体(GPCR)，引发趋化信号，导致定向受体携带细胞的迁移。慢性炎性疾病的动物模型研究已经证明，拮抗剂抑制MCP-1和CCR2之间的结合抑制炎症反应。
CCR5是结合多种CC趋化因子配体的G蛋白偶联受体，包括CCL3，CCL3L1，CCL4，CCL5，CCL7，CCL11和CCL13。相对于CCR2，CCR5的体内功能较不明确。与CCR2相比，CCR5主要表达在活化的Th1细胞和从血液单核细胞分化的组织巨噬细胞，其伴随地下调CCR2表达。已经显示CCR5 在炎症和感染过程中有助于巨噬细胞的存活，并且还可以起到在发炎组织内保留巨噬细胞的作用。此外，CCR5介导Th1细胞在炎症中的募集和激活。CCR5也在破骨细胞上表达，并且对于破骨细胞形成是重要的，这表明CCR5在类风湿性关节炎病理学中的贡献作用。通过CCL4/CCR5参与的血管平滑细胞的活化也可以促成动脉粥样硬化和AIH的病理学(加速的内膜增生)。
CCR2和CCR5的互补细胞分布和差异细胞功能提供了两个受体的双重靶向可能比靶向单独受体具有更大功效的理论基础。在单核细胞/巨噬细胞生物学中，CCR2在介导从骨髓到血液和从血液到组织的单核细胞的迁移中起重要作用，其中CCR5主要调节巨噬细胞在发炎组织中的活化，存活和可能的保留。此外，CCR5阻断可以通过除了对单核细胞/巨噬细胞的影响之外抑制T细胞应答来改善双重拮抗剂的治疗潜力。基于CCR2和CCR5双重靶点的优势，CCR2/5双重拮抗剂也开始被深入研究，进入临床的有4个药物，分别为Tobira公司的Cenicriviroc，百时美施贵宝公司的BMS-813160和辉瑞的PF-04634817。因此，CCR2/5双重拮抗剂具有较好的成药潜力，在这我们对CCR2/5双重拮抗剂的联苯化合物进行专利保护。
J.Med.Chem.2006,49,2037-2048报道了化合物Cenicriviroc，其结构如下所示。
Figure PCTCN2017115453-appb-000001
发明内容
本发明提供了式(Ⅰ)所示化合物或其药学上可接受的盐，
Figure PCTCN2017115453-appb-000002
其中，
R1选自任选被1、2或3个R取代的：C1-6烷氧基、5～6元杂环烷基；
R2、R3、R4分别独立地选自H、卤素、OH、CN，或分别独立地选自任选被1、2或3个R取代的：C1- 6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基-S(＝O)-、C1-6烷基-S(＝O)2-、C3-6环烷基；
R5、R6分别独立地选自H，或分别独立地选自任选被1、2或3个R取代的C1-3烷基；
环A选自：
Figure PCTCN2017115453-appb-000003
R7选自任选被1、2或3个R取代的：C1-6烷基；
R8选自H，或选自任选被1、2或3个R取代的：C1-6烷基；
L选自：-S(＝O)-或-S(＝O)2-
R选自卤素、OH，或选自任选被1、2或3个R’取代的：C1-6烷基、C1-6杂烷基、C3-6环烷基；
R’选自F、Cl、Br、I、OH、CH2F、CHF2、CF3；
所述5～6元杂环烷基之“杂”分别独立选自：-NH-、-O-、N；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自F、Cl、Br、I、OH，或选自任选被1、2或3个R’取代的：C1- 3烷基、C1-4烷氧基、C3-6环烷基。
本发明的一些方案中，上述R选自F、Cl、Br、I、OH，或选自任选被1、2或3个R’取代的：Me、
Figure PCTCN2017115453-appb-000004
本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CH3、CH2F、CHF2、CF3、
Figure PCTCN2017115453-appb-000005
Figure PCTCN2017115453-appb-000006
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：C1-4烷氧基、吡咯烷基。
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 PCTCN2017115453-appb-000007
Figure PCTCN2017115453-appb-000008
本发明的一些方案中，上述R1选自：
Figure PCTCN2017115453-appb-000009
Figure PCTCN2017115453-appb-000010
本发明的一些方案中，上述R2、R3、R4分别独立地选自H、卤素、OH、CN，或分别独立地选自任选被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烷基-S(＝O)-、C1-3烷基-S(＝O)2-、C4-5环烷基。
本发明的一些方案中，上述R2、R3、R4分别独立地选自H、F、Cl、Br、I、OH、CN，或分别独立 地选自任选被1、2或3个R取代的：Me、
Figure PCTCN2017115453-appb-000011
Figure PCTCN2017115453-appb-000012
本发明的一些方案中，上述R2、R3、R4分别独立地选自H、F、Cl、Br、I、OH、CN、Me、
Figure PCTCN2017115453-appb-000013
Figure PCTCN2017115453-appb-000014
本发明的一些方案中，上述R2选自：H、F、Cl、OH、CN、Me、
Figure PCTCN2017115453-appb-000015
Figure PCTCN2017115453-appb-000016
本发明的一些方案中，上述R3选自：H、F、Cl、Me、
Figure PCTCN2017115453-appb-000017
本发明的一些方案中，上述R4选自：H、Cl。
本发明的一些方案中，上述R5、R6分别独立地选自H或Me。
本发明的一些方案中，上述R7选自任选被1、2或3个R取代的：Me、
Figure PCTCN2017115453-appb-000018
Figure PCTCN2017115453-appb-000019
本发明的一些方案中，上述R7选自：Me、
Figure PCTCN2017115453-appb-000020
本发明的一些方案中，上述R8选自H，或选自任选被1、2或3个R取代的：Me、
Figure PCTCN2017115453-appb-000021
本发明的一些方案中，上述R8选自H、Me、
Figure PCTCN2017115453-appb-000022
本发明的一些方案中，上述环A选自：
Figure PCTCN2017115453-appb-000023
Figure PCTCN2017115453-appb-000024
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 PCTCN2017115453-appb-000025
其中，
R1、R2、R3、R4、R5、R6、R7和R8如上述所定义。
本发明还提供了下式所示化合物或其药学上可接受的盐，其选自：
Figure PCTCN2017115453-appb-000026
Figure PCTCN2017115453-appb-000027
Figure PCTCN2017115453-appb-000028
Figure PCTCN2017115453-appb-000029
Figure PCTCN2017115453-appb-000030
Figure PCTCN2017115453-appb-000031
Figure PCTCN2017115453-appb-000032
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 PCTCN2017115453-appb-000033
Figure PCTCN2017115453-appb-000034
Figure PCTCN2017115453-appb-000035
Figure PCTCN2017115453-appb-000036
Figure PCTCN2017115453-appb-000037
Figure PCTCN2017115453-appb-000038
Figure PCTCN2017115453-appb-000039
Figure PCTCN2017115453-appb-000040
Figure PCTCN2017115453-appb-000041
Figure PCTCN2017115453-appb-000042
Figure PCTCN2017115453-appb-000043
Figure PCTCN2017115453-appb-000044
Figure PCTCN2017115453-appb-000045
本发明还提供了一种药物组合物，其含有治疗有效量的上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供了上述的化合物或其药学上可接受的盐或上述的药物组合物在制备治疗与CCR2和/或CCR5相关疾病药物中的应用。
本发明还提供了上述的化合物或其药学上可接受的盐或上述的药物组合物在制备治疗炎症和自身免疫病症和癌症药物中的应用。
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：C1-4烷氧基、吡咯烷基，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 PCTCN2017115453-appb-000046
Figure PCTCN2017115453-appb-000047
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 PCTCN2017115453-appb-000048
Figure PCTCN2017115453-appb-000049
其他变量如上述所定义。
本发明的一些方案中，上述R2、R3、R4分别独立地选自H、卤素、OH、CN，或分别独立地选自任选被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烷基-S(＝O)-、C1-3烷基-S(＝O)2-、C4-5环烷基，其他变量如上述所定义。
本发明的一些方案中，上述R2、R3、R4分别独立地选自H、F、Cl、Br、I、OH、CN，或分别独立地选自任选被1、2或3个R取代的：Me、
Figure PCTCN2017115453-appb-000050
Figure PCTCN2017115453-appb-000051
其他变量如上述所定义。
本发明的一些方案中，上述R2、R3、R4分别独立地选自H、F、Cl、Br、I、OH、CN、Me、
Figure PCTCN2017115453-appb-000052
Figure PCTCN2017115453-appb-000053
Figure PCTCN2017115453-appb-000054
其他变量如上述所定义。
本发明的一些方案中，上述R2选自：H、F、Cl、OH、CN、Me、
Figure PCTCN2017115453-appb-000055
Figure PCTCN2017115453-appb-000056
Figure PCTCN2017115453-appb-000057
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、Me、
Figure PCTCN2017115453-appb-000058
其他变量如上述所定义。
本发明的一些方案中，上述R4选自：H、Cl，其他变量如上述所定义。
本发明的一些方案中，上述R5、R6分别独立地选自H或Me，其他变量如上述所定义。
本发明的一些方案中，上述R7选自任选被1、2或3个R取代的：Me、
Figure PCTCN2017115453-appb-000059
Figure PCTCN2017115453-appb-000060
其他变量如上述所定义。
本发明的一些方案中，上述R7选自：Me、
Figure PCTCN2017115453-appb-000061
其他变量如上述所定义。
本发明的一些方案中，上述R8选自H，或选自任选被1、2或3个R取代的：Me、
Figure PCTCN2017115453-appb-000062
其他变量如上述所定义。
本发明的一些方案中，上述R8选自H、Me、
Figure PCTCN2017115453-appb-000063
其他变量如上述所定义。
本发明的一些方案中，上述环A选自：
Figure PCTCN2017115453-appb-000064
Figure PCTCN2017115453-appb-000065
其他变量如上述所定义。
本发明还有一些方案是由上述各变量任意组合而来。
技术效果
本发明化合物具有显著的CCR2和CCR5拮抗作用，血浆清除率比参低，口服生物利用度高，口服血浆系统暴露量优势明显且药代动力学性质非常优异。
相关定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸 氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2017115453-appb-000066
表示一个立体中心的绝对构型，用
Figure PCTCN2017115453-appb-000067
表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
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。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代， 除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当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 PCTCN2017115453-appb-000068
或
Figure PCTCN2017115453-appb-000069
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 PCTCN2017115453-appb-000070
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 PCTCN2017115453-appb-000071
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 PCTCN2017115453-appb-000072
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符 合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另 一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如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-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2017115453-appb-000073
软件命名，市售化合物采用供应商目录名称。
具体实施方式
参考例1：片段BB-1A
Figure PCTCN2017115453-appb-000074
合成路线：
Figure PCTCN2017115453-appb-000075
步骤1：化合物BB-1A-2的合成
将化合物BB-1A-1(100g,0.846mol),对甲苯黄酰氯(146.67g,769.31mmol)，三乙胺(233.54g,2.31mol)溶于二氯甲烷中(0.5L)，在室温下，搅拌12小时。冷却至室温，减压除去溶剂，加入水(400mL)溶解残留物，水相用乙酸乙酯萃取三次(1.5L)，合并后有机相用饱和食盐水洗涤两次(400mL)，无水硫酸钠干燥。滤去干燥剂后减压去除溶剂得到褐色油状物BB-1A-2(170.10g,624.54mmol,收率81.18％)。1H NMR(400MHz,CDCl3)δppm 0.81(t,J＝7.40Hz,3H)1.16-1.27(m,3H)1.35-1.44(m,2H)2.37(s,3H)3.30(t,J＝6.53Hz,2H)3.50-3.55(m,2H)4.05-4.10(m,2H)7.27(d,J＝8.03Hz,2H)7.73(d,J＝8.28Hz,2H).MS m/z:273.9[M+H]+
步骤2：合物BB-1A的合成。
将化合物BB-1A-2(170.10g,624.54mmol)，对羟基苯硼酸酯(137.44g,624.54mmol)溶于乙腈(1.6L)中，在室温下加入碳酸钾(86.32g,624.54mmol)和碘化钾(10.37g,62.45mmol)。所得溶液在60℃氮气保护下加热回流并搅拌反应12小时。冷却至室温后，减压去除溶剂，加入水(500mL)溶解残留物，水相用乙酸乙酯萃取三次(2L)，合并后减压除去溶剂，通过柱层析法除去其他杂质得到黄色油状物化合物BB-1A(99.30g,310.09mmol,49.65％收率)1H NMR(400MHz,CDCl3-d)δppm 0.93(t,J＝7.40Hz,4H)1.28-1.36(m,13H)1.39(dd,J＝15.18,7.40Hz,1H)1.51-1.65(m,3H)3.54(t,J＝6.65Hz,2H)3.75-3.88(m,2H)4.06-4.25(m,2H)6.92(d,J＝8.53Hz,2H)7.75(d,J＝8.53Hz,2H).
参照参考例1中步骤1～2的合成方法，合成下表中各参考例。
Figure PCTCN2017115453-appb-000076
Figure PCTCN2017115453-appb-000077
参考例5：片段BB-1B
Figure PCTCN2017115453-appb-000078
合成路线：
Figure PCTCN2017115453-appb-000079
步骤1：化合物BB-1B的合成。
将化合物BB-1A-1(6g,27.26mmol)，正溴丁烷(5.6g，40.89mmol)溶于乙腈(50mL)中，在室温下加入碳酸钾(11.3g，81.78mmol)。所得溶液在80℃氮气保护下加热回流并搅拌反应6小时。冷却至室温后，减压去除溶剂，加入水(30mL)溶解残留物，水相用乙酸乙酯萃取三次(600mL)，合并后减压除去溶剂，红色油状物化合物BB-1B(7.05g,25.53mmol,收率93.64％)
1H NMR(400MHz,CDCl3-d)δ＝7.76(d,J＝8.5Hz,2H),7.11-6.70(m,2H),4.00(t,J＝6.5Hz,2H),1.82-1.74(m,2H),1.56-1.47(m,2H),1.38-1.32(m,11H),0.99(t,J＝7.4Hz,3H)
MS m/z：279.1[M+H]+
参照参考例5中步骤1的合成方法，合成下表中各参考例。
Figure PCTCN2017115453-appb-000080
参考例9：片段BB-2A
Figure PCTCN2017115453-appb-000081
步骤1：化合物BB-2A的合成
Figure PCTCN2017115453-appb-000082
室温下将化合物BB-2A-1(10.00g,49.75mmol)溶于N,N-二甲基甲酰胺(30.00mL)中，加入碳酸钾(20.63g,149.25mmol)和碘甲烷(25.80g,181.77mmol)。反应混合物在室温下搅拌15小时。反应完毕后向反应液中加入100毫升冰水，并用乙酸乙酯(100mL*3)萃取。合并有机相，用饱和食盐水(300mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，得到产物BB-2A(10.50g,收率98.15％)。
1H NMR(400MHz,CDCl3)δ＝10.38(s,1H),7.91(d,J＝2.8Hz,1H),7.63(dd,J＝2.6,8.9Hz,1H),6.89(d,J＝8.8Hz,1H),3.92(s,3H)
参照参考例9中步骤1的合成方法，合成下表中各参考例。
Figure PCTCN2017115453-appb-000083
Figure PCTCN2017115453-appb-000084
参考例15：片段BB-2B
Figure PCTCN2017115453-appb-000085
步骤1：化合物BB-2B的合成
Figure PCTCN2017115453-appb-000086
0℃，在氮气氛下，向乙腈(10.00mL)和水(1.00mL)的混合液中依次加入化合物1(1.51g,7.49mmol)、溴氟甲基磷酸二乙酯(3.00g,11.24mmo)和碳酸钾(2.07g,14.99mmol)，混合物在氮气保护下0℃搅拌0.5小时。反应完毕后，向混合物中加入水(50mL)，用乙酸乙酯(50mL x 3)萃取。有机相用饱和食盐水(50mL x 2)洗涤，经无水硫酸钠干燥，过滤，减压浓缩，得到目标化合物BB-2B(2.11g).
1H NMR(400MHz,CDCl3)δ：10.26(s,1H),7.97(d,J＝2.5Hz,1H),7.65(dd,J＝9.0,2.5Hz,1H),7.09(d,J＝8.53Hz,1H),7.09(d,J＝8.53Hz,1H),6.77-6.40(t,J＝72.4Hz,1H).
参考例16：片段BB-2H
Figure PCTCN2017115453-appb-000087
合成路线：
Figure PCTCN2017115453-appb-000088
步骤1：化合物BB-2H-2的合成
Figure PCTCN2017115453-appb-000089
室温下将化合物BB-2H-1(11.50g，58.66mmol)溶于四氯化碳(150mL)中，随后加入N-溴代丁儿酰亚胺(31.32g,175.98mmol)和过氧化苯甲酰(1.42g,5.87mmol)。加料完毕后将反应混合物加热至于85℃，搅拌10小时。反应完毕后将混合物冷却至室温，过滤，滤饼用乙酸乙酯(50mL)洗涤。合并滤液，减压浓缩。所得残留物溶于乙酸乙酯(50mL)中，用饱和食盐水(100mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩得到目标化合物BB-2H-2(浅黄色固体，20.00g)，粗产品不经纯化即可直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ：8.18(d,J＝1.8Hz,1H),7.60(dd,J＝1.8,8.3Hz,1H),7.48(d,J＝8.3Hz,1H),6.92(s,1H)
步骤2：化合物BB-2H的合成
Figure PCTCN2017115453-appb-000090
室温下将化合物BB-2H-2(5.00g，14.13mmol)溶于乙腈(20mL)中，随后加入由硝酸银(6.72g,39.56mmol)和水(10mL)配制而成的溶液。加料完毕后，将反应混合物加热至80℃并搅拌6小时。反应完毕后冷却至室温，过滤除去黄色溴化银沉淀。滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/20–1/5)纯化得到目标化合物BB-2H(1.20g，收率：40.44％)。
1H NMR(400MHz,CDCl3)δ：10.31(s,1H),8.19(d,J＝2.0Hz,1H),7.90(dd,J＝1.9,8.2Hz,1H),7.71(d,J＝8.3Hz,1H).
参考例42：片段BB-2I
Figure PCTCN2017115453-appb-000091
步骤1：化合物BB-2I的合成
Figure PCTCN2017115453-appb-000092
室温下将化合物BB-2I-1(20.00g，98.52mmol)和异丙基硫醇(11.25g,147.78mmol,13.72mL)溶于N,N-二甲基甲酰胺(200mL)中，随后加入碳酸钾(40.85g,295.56mmol)。加料完毕后，将反应混合物加热至60℃并搅拌12小时。反应完毕后冷却至室温，向反应液中加入1000mL饱和碳酸钠溶液，并用乙酸乙酯(800mL)萃取。合并有机相，用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，得到产物BB-2I(10.50g,收率98.15％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝10.47(s,1H),7.99(d,J＝1.5Hz,1H),7.70-7.58(m,1H),7.39(d,J＝8.3Hz,1H),4.11(q,J＝7.0Hz,1H),3.44-3.26(m,1H),3.47-3.22(m,1H),1.32(d,J＝6.8Hz,7H),1.28-1.23(m,1H)
MS m/z：260.9[M+H]+
参考例43：片段BB-2J
Figure PCTCN2017115453-appb-000093
步骤1：化合物BB-2J的合成
Figure PCTCN2017115453-appb-000094
将化合物BB-2I(5.00g,19.29mmol)溶于二氯甲烷(30.00mL)中，0℃下滴加碳酸氢钾(5.79g,57.87mmol)和水(10.00mL)配成的溶液。搅拌10分钟后，0℃下将液溴(4.62g,28.93mmol,1.49mL)滴加到反应液中。室温下反应50分钟。反应用饱和亚硫酸钠溶液(40mL)淬灭。向反应液中另外加入100mL水，并用二氯甲烷(00mL)萃取。合并有机相，用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，硅胶层析柱纯化(洗脱剂：石油醚/乙酸乙酯＝50/1,5/1)得到产物BB-2J(2.00g,收率37.68％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝10.00(s,1H),8.07(d,J＝2.0Hz,1H),8.05(s,1H),8.06-8.04(m,1H),7.98-7.94(m,1H),3.02(quin,J＝7.0Hz,1H),1.54(d,J＝7.0Hz,3H),0.93(d,J＝6.8Hz,3H)
MS m/z：276.7[M+H]+
参考例17：片段BB-3A
Figure PCTCN2017115453-appb-000095
合成路线：
Figure PCTCN2017115453-appb-000096
步骤1：化合物BB-3A-2的合成。
将化合物BB-3A-1(150g,1.57mol)，1,3-二羟基丙酮(110.28g,1.22mol)，硫氰酸钾(178.46g,1.84mol)溶于正丁醇(2L)中，在室温下加入乙酸(133.74mL，2.34mol)，室温搅拌16小时。向反应液中加入60mL水，室温搅拌30分钟后过滤，滤饼用水洗涤后烘干得到白色粉末状化合物BB-3A-2(210g,收率77.7％)
MS m/z:173.0[M+H]+
步骤2：化合物BB-3A-3的合成。
在20度下，将BB-3A-2(210.00g,1.22mol,1.00eq)悬浮于正丁醇(2.00L)中，0℃下向该悬浊液中滴加过氧化氢(207.32g,1.83mol,175.69mL,1.50eq.纯度30％)，自然升温至20℃，搅拌16小时。反应液用100mL饱和亚硫酸钠淬灭，溶液直接浓缩干得到粗品。粗品经柱层析(二氯甲烷：甲醇＝40：1～20：1)纯化得到化合物BB-3A-3(70.00g,收率40.93％)。
MS m/z:141.0[M+H]+
步骤3：化合物BB-3A-4的合成。
将BB-3A-3(40.00g,285.35mmol,1.00eq)溶于二氯甲烷(150mL)，室温下向该溶液中滴加二氯亚砜(82.15g,690.55mmol,50.09mL,2.42eq)，加热至40℃，搅拌30分钟。反应液过滤，滤液减压浓缩得到粗品。向粗品中加入300mL乙酸乙酯并过滤，收集滤饼得到化合物BB-3A-4(33.00g,169.15mmol,盐酸盐，收率59.3％)。
1H NMR(400MHz,DMSO-d6)δ:9.31(d,J＝1.5Hz,1H),7.82(d,J＝1.5Hz,1H),5.03(s,2H),4.29-4.12 (m,2H),1.93-1.82(m,2H),0.90(t,J＝7.4Hz,3H)
步骤4：化合物BB-3A-5的合成。
将4-胺基苯硫酚(52.94g,422.88mmol,2.5eq)和三乙胺(51.35g,507.45mmol,70.34mL,3.00eq)溶于异丙醇(1.00L)，室温下向该溶液中滴加BB-3A-4(33.00g,169.15mmol,1.00eq,盐酸盐)的水(100mL)溶液，室温搅拌16小时。该混合物用水(100mL)稀释，乙酸乙酯(200mL)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经柱层析(石油醚：乙酸乙酯＝50：1～10：1)得到BB-3A-5(15.00g,60.64mmol,收率35.85％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.41(s,1H),7.10-7.03(m,2H),6.62(s,1H),6.57-6.52(m,2H),3.91-3.83(m,4H),1.80(sxt,J＝7.4Hz,2H),0.93(t,J＝7.4Hz,3H)。
步骤5：化合物BB-3A-6的合成。
将BB-3A-5(10.00g,40.43mmol,1.00eq)溶于甲基异丁酮(600mL)和甲苯(1.2L)，室温下向该溶液中加入对二甲基苯甲酰基-D-酒石酸(15.62g,40.43mmol,1.00eq)，混合液室温搅拌10小时，冷却至0℃并逐滴加入H2O2(13.75g,121.29mmol,11.65mL,30％purity,3.00eq)，该混合物室温搅拌96小时。混合液用饱和亚硫酸钠水溶液淬灭，加入水(200mL)、氢氧化钠(3.08g,76.96mmol,1.00eq)和乙酸乙酯(500mL)，室温搅拌30分钟。有机相分液，无水硫酸钠干燥，过滤，浓缩得到粗品，将该粗品溶于水(100mL)和乙二醇二甲醚(100mL)，室温搅拌14小时后浓缩。粗品用乙腈：水＝1：1(80mL)洗涤并过滤得到BB-3A-6(8.00g,12.31mmol,收率40.53％)。
步骤6：化合物BB-3A的合成。
将BB-3A-6(8.00g,12.31mmol,1.00eq)分散于水(100mL)和乙酸乙酯(100mL)中，用1N盐酸调节pH＝3，该混合物室温搅拌30分钟。取水相，用饱和碳酸钠水溶液调节pH＝10，混合液用二氯甲烷：异丙醇＝10：1(3*200mL)萃取，有机相减压浓缩得到BB-3A(2.80g,10.63mmol,收率86.37％)。
1H NMR(400MHz,METHANOL-d4)δ＝7.66(s,1H),7.22-7.17(m,2H),6.77-6.70(m,3H),4.24(s,2H),3.75(dt,J＝1.5,7.3Hz,2H),1.72(sxt,J＝7.3Hz,2H),0.90(t,J＝7.5Hz,3H)
参照参考例17中步骤1～4的合成方法，合成下表中各参考例。
Figure PCTCN2017115453-appb-000097
Figure PCTCN2017115453-appb-000098
参考例22：片段BB-3B-4
Figure PCTCN2017115453-appb-000099
合成路线：
Figure PCTCN2017115453-appb-000100
步骤1：化合物BB-3B-4-2的合成。
0℃下将BB-3B-4-1(4.50g,43.23mmol)滴加到化合物水合肼(2.80g,47.55mmol)的乙醇(20.00mL)溶液中。反应混合物于室温中搅拌15小时后将1-丙基异氰酸酯(4.37g,43.18mmol)滴加到反应体系中。升温至40℃反应15小时。反应完毕后冷却至室温，减压浓缩得到粗品化合物BB-3B-4-2(9.5g,收率82.69％)。1H NMR(400MHz,DMSO-d6)δ＝9.63(s,1H),9.08(br s,1H),7.77(br s,1H),5.27(br s,1H),3.93(d,J＝5.8Hz,2H),3.42-3.36(m,2H),1.54-1.45(m,2H),0.88-0.78(m,3H)
步骤2：化合物BB-3B-4-3的合成
将化合物BB-3B-4-2(9.50g,35.76mmol)溶于正丁醇(40.00mL)中，反应物加热到80℃搅拌15小时。反应完毕后降温到25℃，产物BB-3B-4-3保存在正丁醇中直接用于下一步反应。
MS-ESI(m/z):173.8(M+H)+
步骤3：化合物BB-3B-4的合成
将化合物BB-3B-4-3(35.70mmol)的正丁醇(30.00mL)溶液在0℃滴加30％浓度双氧水(12.14g,107.10mmol)。反应液在室温下搅拌15小时。反应完毕后用亚硫酸钠饱和溶液(15mL)淬灭反应。分液后将水相用二氯甲烷(20mL x 5)萃取。合并有机相，用饱和食盐水(10mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，不经纯化得到目标化合物BB-3B-4(3g,粗品)。
参考例23：片段BB-3H-3
Figure PCTCN2017115453-appb-000101
合成路线：
Figure PCTCN2017115453-appb-000102
步骤1：化合物BB-3H-2的合成
0℃，在氮气氛下，将三苯基膦(47.64g,181.64mmol)和偶氮二甲酸二异丙酯(36.73g,181.64mmol)溶于四氢呋喃(120.00mL)中，随后依次加入化合物1(10.00g,90.82mmol)和正丙醇(10.91g,181.64mmol)。在氮气气氛下，混合物升温至25℃并搅拌12小时。反应完毕后，向混合液中加入稀盐酸(1M)调节至pH＝1，用乙酸乙酯(50mL x 3)萃取。随后用氢氧化钠(1M)将水相pH调节至13,用乙酸乙酯(50mL x 4)萃取。合并有机相，用饱和食盐水(50mL*2)洗涤，经无水硫酸钠干燥，过滤，减压浓缩。所得残留物经柱层析(石油醚：乙酸乙酯＝20:1-5:1)纯化得到目标化合物BB-3H-2((12.00g,浅黄色油状液体，收率：27.60％)。
1H NMR(400MHz,CDCl3)δ：9.81(s,1H),7.50(s,1H),4.19(t,J＝7.1Hz,2H),2.49(s,3H),1.98-1.74(m,2H),0.89(t,J＝7.5Hz,3H).
步骤2：化合物BB-3H-3的合成
0℃，在氮气氛下,向化合物2(11.00g,72.28mmol)的乙醇(30.00mL)溶液中加入硼氢化钠(3.28g,86.74mmol)，随后在氮气保护下，将反应混合物升温至25℃，并搅拌2小时。反应完毕后，向混合物中加入浓盐酸(12.5mL)淬灭，后加入氢氧化钠固体调节pH至12-13。向混合物中加入二氯甲烷(20mL)，过滤，减压浓缩。所得残余物经HPLC纯化得目标化合物BB-3H-3(7.50g,收率：67.22％)。
MS–ESI m/z:155[M+H]+
1H NMR(400MHz,CDCl3)δ：7.26(s,1H),4.54(s,2H),3.91-3.87(m,2H),2.06(s,3H),1.81-1.76(m,2H), 0.92(t,J＝7.4Hz,3H).
参照参考例23中步骤1～2的合成方法，合成下表中参考例。
Figure PCTCN2017115453-appb-000103
参照参考例17中步骤2～4的合成方法，合成下表中参考例。
Figure PCTCN2017115453-appb-000104
参考例27：BB-3C
Figure PCTCN2017115453-appb-000105
合成路线：
Figure PCTCN2017115453-appb-000106
步骤1：化合物BB-3C的合成
将化合物BB-3C-1(450.00mg,1.93mmol)溶于4-甲基2-戊酮(5.00mL)中，室温下滴加30％浓度的双氧水(555.86uL，5.79mmol)。室温下将反应混合物搅拌20小时。反应完毕后，降温至0-5℃，加入 2毫升饱和亚硫酸钠溶液淬灭反应。减压浓缩除去溶剂，所得粗品用硅胶板(展开剂：二氯甲烷/甲醇＝10/1)分离得到化合物BB-3C(150.00mg,收率28.15％yield)。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.48(s,1H),7.20-7.14(m,2H),6.73-6.67(m,2H),6.61(s,1H),4.09-3.97(m,4H),3.89-3.78(m,2H),1.38(t,J＝7.4Hz,3H)
MS-ESI(m/z):250.0(M+H)+
参照参考例27中步骤1的合成方法，合成下表中参考例。
Figure PCTCN2017115453-appb-000107
Figure PCTCN2017115453-appb-000108
参考例57:BB-3A’
Figure PCTCN2017115453-appb-000109
合成路线：
Figure PCTCN2017115453-appb-000110
步骤1：化合物BB-3A’的合成
将化合物BB-3A’-1经过超临界流体色谱(分离条件Column:Chiralpak AS-3 150×4.6mm I.D.,3μm
流动相:A:CO2B:Ethanol(0.05％DEA)，梯度：5％～40％B，5min，保持40％2.5min,然后保持5％B 2.5min，流速:2.5mL/min，柱温:35℃，波长:220nm)分离，得到异构体BB-3A’(保留时间4.238分钟)和BB-3A(保留时间4.602分钟).
MS-ESI(m/z):264.0(M+H)+
参考例35：BB-3G
Figure PCTCN2017115453-appb-000111
合成路线：
Figure PCTCN2017115453-appb-000112
步骤1：化合物BB-3G的合成
将化合物BB-3G-1(200.00mg,808.54umol)溶于4-甲基2-戊酮(5.00mL)中，室温下滴加30％浓度的双氧水(776.79Ul,8.09mmol)。室温下将反应混合物搅拌96小时。反应完毕后，降温至0-5℃，加入2毫升饱和亚硫酸钠溶液淬灭反应。减压浓缩除去溶剂，所得粗品用硅胶板(展开剂：二氯甲烷/甲醇＝10/1)分离得到化合物BB-3G(30.00mg,收率13.28％yield)。
MS–ESI m/z:279.9(M+H)+
参考例36：BB-3K,BB-3K’
Figure PCTCN2017115453-appb-000113
合成路线：
Figure PCTCN2017115453-appb-000114
步骤1：化合物BB-3K,BB-3K’的合成
将化合物BB-3I经过超临界流体色谱(分离条件Column:ChiralPaK AD-3 150*4.6mm I.D.,3μm流动相:A:CO2B:Ethanol(0.05％DEA)，梯度：5％～40％B，5.5min，保持40％3min,然后保持5％B 1.5min，流速:2.5mL/min，柱温:40℃，波长:220nm)分离，得到异构体BB-3K(保留时间5.828分钟)和BB-3K’(保留时间6.163分钟).
MS–ESI m/z:264.0(M+H)+
1H NMR(400MHz,CDCl3)δ:7.43(s,1H),7.15-7.10(m,2H),6.71-6.66(m,2H),4.07-3.95(m,4H),3.85(dq,J＝1.9,7.3Hz,2H),1.70(s,3H),1.39(t,J＝7.3Hz,3H)
参考例45：BB-3J,3J’
Figure PCTCN2017115453-appb-000115
合成路线：
Figure PCTCN2017115453-appb-000116
步骤1：化合物BB-3J,BB-3J’的合成
将化合物BB-3H经过超临界流体色谱(分离条件Column:ChiralPaK AD-3 150*4.6mm I.D.3μm；流动相:A:CO2B:Ethanol(0.05％DEA)，梯度:5％-40％B，5.5min；保持40％B 3min,然后保持5％B1.5min，流速:2.5mL/min，柱温:40C，波长；220nm)分离，得到异构体BB-3J(保留时间4.775分钟)和异构体BB-3J’(保留时间4.521分钟).
MS–ESI m/z:277.9(M+H)+
1H NMR(400MHz,CDCl3)δ:0.56(br s,3H)1.27-1.37(m,8H)1.39(br d,J＝7.03Hz,3H)3.41(br s,2H)3.59-3.76(m,5H)6.35(br d,J＝6.53Hz,4H)6.70-6.80(m,4H)7.05(s,2H)
参考例46：BB-3L
Figure PCTCN2017115453-appb-000117
合成路线：
Figure PCTCN2017115453-appb-000118
步骤1：化合物BB-3L-2的合成
将化合物BB-3L-1(5.00g,31.74mmol)和N,N-二甲基甲酰胺(1.07g,14.60mmol,1.12mL)溶于二 氯甲烷(50ml)中，室温下滴加草酰氯(10.07g,79.35mmol,6.94mL)。N2气氛围下，将反应液在室温下搅拌3小时后，加入甲醇(10mL)。反应液浓缩得化合物BB-3L-2(5.40g,收率99.16％)。
1H NMR(400MHz,CDCl3)δ:9.32(s,1H),9.09(d,J＝6.0Hz,1H),8.07(d,J＝6.0Hz,1H),4.05(s,3H).
步骤2：化合物BB-3L-3的合成
将化合物BB-3L-2(5.00g,29.14mmol)和乙烯基氟硼酸钾(3.90g,29.14mmol)溶于二氧六环(45mL)和水(15mL)中，室温下加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(213.22mg,291.40u mol)、碳酸钾(8.06g,58.28mmol)。在氮气保护下将反应混合物加热至100℃并搅拌12小时。反应完毕后冷却至室温，向混合物中加入水(10mL)，用二氯甲烷(10mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经快速硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/10)纯化得到目标化合物BB-3L-3(2.50g,收率52.58％yield)。
1H NMR(400MHz,CDCl3)δ:9.00(s,1H),8.57(d,J＝5.5Hz,1H),7.48-7.39(m,1H),7.37(d,J＝5.3Hz,1H),5.79(d,J＝17.6Hz,1H),5.50-5.44(m,1H),3.85(s,3H)
步骤3：化合物BB-3L-4的合成
将化合物BB-3L-3(1.00g,6.13mmol)溶于四氢呋喃(10.00mL)中，室温下加入向其中加入湿钯碳催化剂(1.8g，钯含量10％，水含量50％)。置换氩气3次后，向其中置换氢气3次。反应混合物在氢气氛围(15psi)中室温搅拌3小时。过滤除去催化剂，滤液减压浓缩得到目标化合物BB-3L-4(880.00mg,收率86.95％)。
1H NMR(400MHz,CDCl3)δ:8.94(s,1H),8.50(d,J＝5.0Hz,1H),7.12(d,J＝5.0Hz,1H),3.83(s,3H),2.91(q,J＝7.5Hz,2H),1.15(t,J＝7.5Hz,3H)
步骤4：化合物BB-3L-5的合成
将化合物BB-3L-4(880.00mg,5.33mmol)溶于四氢呋喃(10.00mL)中，室温下缓慢加入四氢铝锂(303.25mg,7.99mmol)。室温下将反应混合物搅拌1小时。反应用十水硫酸钠(10g)淬灭。加入水(10mL)，用二氯甲烷(10mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩滤液减压浓缩得到目标化合物BB-3L-5(470.00mg,收率64.39％yield)。
1H NMR(400MHz,CDCl3)δ:8.36(s,1H),8.32(d,J＝5.0Hz,1H),7.06(d,J＝5.0Hz,1H),4.66(s,2H),2.67(q,J＝7.5Hz,2H),2.26-2.14(m,1H),1.18(t,J＝7.5Hz,3H)
步骤5：化合物BB-3L-6的合成
将化合物BB-3L-5(470.00mg,3.43mmol)溶于二氯甲烷(5.00mL)中，室温下加入氯化亚砜(2.04g,17.13mmol,1.24mL,5.00eq)。氮气保护下，混合物在室温搅拌2小时。反应液减压浓缩得到化合物BB-3L-6的盐酸盐(670.00mg,盐酸盐，收率96.81％)。
MS–ESI m/z:156.0(M+H)+
步骤6：化合物BB-3L-7的合成
将化合物BB-3L-6(670.00mg,3.49mmol，盐酸盐)和对氨基苯硫酚(1.31g,10.47mmol)溶于二氯甲烷(5.00mL)中，室温下加入三乙胺(1.06g,10.47mmol,1.45mL)。氮气氛围中，混合物在室温下搅拌4小时。减压除去溶剂，粗品用硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/4-1/0)纯化得到目标化合物BB-3L-7(630.00mg,收率48.54％)。
MS–ESI m/z:245.0(M+H)+
步骤7：化合物BB-3L的合成
将化合物BB-3L-7(630.00mg,2.58mmol)溶于二氯甲烷(10.00mL)中，室温下滴加双氧水(2.92g,25.78mmol,2.48mL,30％purity)。氮气保护下，将反应液加热到40℃，并搅拌18小时。冷却到室温，向反应液中加入亚硫酸钠(10g)，并搅拌半小时。过滤，滤液减压浓缩，所得粗品用硅胶板纯化得到化合物BB-3L(320.00mg,收率47.64％yield)。
MS–ESI m/z:261.1(M+H)+
参照参考例46中步2～7的合成方法，合成下表中参考例。
Figure PCTCN2017115453-appb-000119
参照参考例46中步5～7的合成方法，合成下表中参考例。
Figure PCTCN2017115453-appb-000120
参考例37：BB-4A
Figure PCTCN2017115453-appb-000121
合成路线：
Figure PCTCN2017115453-appb-000122
步骤1：化合物BB-4A-2的合成
氮气氛围下将化合物BB-4A-1(1.00g,4.65mmol)和N,N-二甲基甲酰胺(33.99mg,465.00μmol)溶于二氯甲烷(10.00mL)中，在0℃下滴加草酰氯(1.48g,11.63mmol)。在氮气保护下将反应混合物于室温中搅拌1小时。将甲醇(1.49g,46.50mmol)滴加到反应液中。反应液减压浓缩除去溶剂得到粗品化合物BB-4A-2(1.00g,收率93.88％)。
步骤2：化合物BB-4A-3的合成
氮气氛围下将化合物BB-4A-2(1.00g,4.37mmol)，化合物BB-1A(1.40g,4.37mmol),碳酸钾(1.81g,13.10mmol)溶于1,4-二氧六环(10mL)和水(3mL)中，随后加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(356.50mg,436.55μmol)。在氮气保护下将反应混合物在90℃下搅拌10小时。反应完毕后，将反应液冷却至室温并减压浓缩。加入水(10mL)，并用乙酸乙酯(10mL x 3)萃取。合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经柱层析(洗脱剂：石油醚/乙酸乙酯＝100/1,9/1)纯化得到目标化合物BB-4A-3(黄色固体，1.00g,收率59.74％)。
1H NMR(400MHz,CDCl3)δ：8.03(d,J＝2.0Hz,1H),7.51(dd,J＝1.9,7.9Hz,1H),7.45(d,J＝8.8Hz,2H),7.21-7.17(m,1H),6.93(d,J＝8.8Hz,2H),4.11-4.08(m,2H),3.84(s,3H),3.74(t,J＝4.9Hz,2H),3.48(t,J＝6.7Hz,2H),2.55(s,3H),1.55-1.50(m,2H),1.36-1.28(m,2H),0.86(t,J＝7.4Hz,3H)
步骤3：化合物BB-4A的合成
氮气氛围下将化合物BB-4A-3溶于四氢呋喃(10mL)中，在0-5℃将四氢铝锂(299.23mg,7.89mmol)分批加入反应液。在氮气保护下将反应混合物在室温下搅拌15小时。反应完毕后，加入0.5毫升水和0.5毫升饱和碳酸钠溶液淬灭。过滤，所得滤液加入10毫升水，并用乙酸乙酯萃取(20mL*3)。合并有机相，用60毫升饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品用硅胶柱分离(洗脱剂：石油醚/乙酸乙酯＝50/1,10/1),得到化合物BB-4A(695.00mg,收率79.84％)。
1H NMR(400MHz,DMSO-d6)δ＝7.58(br s,1H),7.54(br d,J＝8.5Hz,2H),7.37(br d,J＝7.5Hz,1H),7.16(br d,J＝7.8Hz,1H),7.00(br d,J＝8.5Hz,2H),5.10(br t,J＝5.3Hz,1H),4.52(br d,J＝4.8Hz,2H),4.13-4.06(m,2H),3.74-3.65(m,2H),3.44(br t,J＝6.5Hz,2H),2.24(s,3H),1.53-1.45(m,2H),1.31(qd,J＝7.3,14.7Hz,2H),0.87(br t,J＝7.3Hz,3H)
参照参考例37中步骤1～3的合成方法，合成下表中参考例。
Figure PCTCN2017115453-appb-000123
Figure PCTCN2017115453-appb-000124
参考例40：BB-4D
Figure PCTCN2017115453-appb-000125
合成路线：
Figure PCTCN2017115453-appb-000126
步骤1：化合物BB-4D-2的合成
氮气氛围中，室温下将化合物BB-4D-1(10.00g，35.35mmol)和吡咯烷(2.77g，38.89mmol)溶于N,N-二甲基甲酰胺(100mL)中，随后加入碘化亚铜(673.24mg，3.54mmol)，L-脯氨酸(813.97mg，7.07mmol)和碳酸铯(13.82g，42.42mmol)。加料完毕后将反应混合物加热至于120℃，于氮气氛围中搅拌10小时。反应完毕后将混合物冷却至室温，加入饱和食盐水(200mL)淬灭反应，用乙酸乙酯(50mL x 3)萃取。合并有机相，用水(200mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物， 所得残留物经硅胶柱层析(洗脱剂：石油醚)纯化得到目标化合物BB-4D-2(白色固体，4.01g，收率：50.17％)。1H NMR(400MHz,CDCl3)δ：7.29(d,J＝9.0Hz,2H),6.43(d,J＝9.0Hz,2H),3.25(t,J＝6.7Hz,4H),2.01(td,J＝3.4,6.6Hz,4H)
步骤2：化合物BB-4D的合成
氮气氛围下将化合物BB-4D-2(1.00g，4.42mmol)和3-甲酰基苯硼酸(663.13mg，4.42mmol)溶于1,4-二氧六环(10mL)中，随后加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(360.95mg，4.42mmol)、碳酸钾(916.33mg，6.63mmol)和水(3mL)。将反应混合物加热至80℃，于氮气氛围下中搅拌12小时。反应完毕后，将混合物冷却至室温，减压浓缩所得残留物经柱层析(洗脱剂：乙酸乙酯/石油醚＝1/100–1/20)纯化得到目标化合物BB-4D(黄色液体，489.00mg，收率：44.02％)。
1H NMR(400MHz,CDCl3)δ：10.08(s,1H),8.07(s,1H),7.83(d,J＝7.8Hz,1H),7.75(d,J＝7.8Hz,1H),7.58-7.52(m,3H),6.66(d,J＝8.8Hz,2H),3.39-3.32(m,4H),2.05(td,J＝3.4,6.5Hz,4H)
参考例52：BB-4H
Figure PCTCN2017115453-appb-000127
合成路线：
Figure PCTCN2017115453-appb-000128
步骤1：化合物BB-4H-3的合成
氮气氛围下将化合物BB-4H-1(4.00g，15.16mmol)和化合物BB-4H-2(2.80g，14.40mmol)溶于1,4-二氧六环(50mL)中，随后加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(1.24g，1.52mmol)、碳酸钾(3.14g，22.74mmol)和水(15mL)。在氮气保护下将反应混合物于室温中搅拌12小时。反应完毕后，向混合物中加入饱和食盐水(50mL)淬灭反应，用乙酸乙酯(30mL x 3)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经柱层析(洗脱剂：乙酸乙酯/石油醚＝0/10-1/10)纯化得到目标化合物BB-4H-3(3.40g，收率：89.31％)。1H NMR(400MHz,CDCl3)δ：10.04(s,1H),7.95(d,J＝2.3Hz,1H),7.57(dd,J＝2.1,8.4Hz,1H),7.18(d,J＝8.4Hz,1H),5.69(quin,J＝2.2Hz,1H),2.68(qt,J＝2.3,7.4Hz,2H),2.53(qt,J＝2.4,7.5Hz,2H),2.02(quin,J＝7.5Hz,2H)
步骤2：化合物BB-4H-5的合成
氮气氛围下将化合物BB-4H-3(2.00g，7.96mmol)和化合物BB-4H-5(2.68g，8.36mmol)溶于1,4-二氧六环(45mL)中，随后加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(650.05mg,796.00μmol)、碳酸钾(1.65g,11.94mmol)和水(15mL)。在氮气保护下将反应混合物加热至80℃并搅拌10小时。反应完毕后冷却至室温，向混合物中加入饱和食盐水(100mL)淬灭反应，用乙酸乙酯(30mL x3)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经快速硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝0/10-1/10)纯化得到目标化合物BB-4H-5(1.89g，收率：65.14％)。
1H NMR(400MHz,CDCl3)δ：10.25(s,1H),8.11(d,J＝1.8Hz,1H),7.75(dd,J＝2.0,8.0Hz,1H),7.57(d,J＝8.8Hz,2H),7.43(d,J＝8.0Hz,1H),7.02(d,J＝8.8Hz,2H),5.86-5.72(m,1H),4.29-4.10(m,2H),3.86-3.79(m,2H),3.56(t,J＝6.7Hz,2H),2.80(dt,J＝2.0,7.5Hz,2H),2.63(dt,J＝2.4,7.3Hz,2H),2.12(quin,J＝7.5Hz,2H),1.66-1.59(m,2H),1.46-1.37(m,2H),0.94(t,J＝7.3Hz,3H)
步骤3：化合物BB-4H的合成
室温下将化合物BB-4H-5(1.89g，5.19mmol)溶于甲醇(100mL)中，向其中加入湿钯碳催化剂(70.00mg，钯含量10％，水含量50％)。置换氩气3次后，向其中置换氢气3次。反应混合物在氢气氛围(30psi)中于室温下搅拌24小时。过滤除去催化剂，滤液减压浓缩得粗产品BB-4H(白色固体，1.70g，收率88.89％)。粗产品不经纯化即可直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ：7.55(d,J＝2.0Hz,1H),7.54-7.51(m,2H),7.49(dd,J＝2.0,8.0Hz,1H),7.38(d,J＝8.0Hz,1H),6.99(d,J＝8.5Hz,2H),4.82(d,J＝5.8Hz,2H),4.19-4.15(m,2H),3.84-3.80(m,2H),3.56(t,J＝6.7Hz,2H),3.38-3.27(m,1H),2.13-2.06(m,2H),1.92-1.83(m,2H),1.79-1.70(m,2H),1.67-1.63(m,2H),1.61(br d,J＝8.0Hz,2H),1.40(qd,J＝7.4,14.9Hz,2H),0.94(t,J＝7.4Hz,3H)
参考例53：BB-5A
Figure PCTCN2017115453-appb-000129
合成路线
Figure PCTCN2017115453-appb-000130
步骤1：化合物BB-5A的合成
氮气氛围下将化合物BB-5A-1(800.00mg，2.08mmol)和三甲基三氟甲基硅烷(887.62mg，6.24mmol)溶于甲苯(10mL)中，随后加入三氟甲磺酸银(2.67g，10.40mmol)、1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(1.47g,4.16mmol)、氟化铯(948.24mg,6.24mmol)和2-氟吡啶(1.01g,10.40mmol)。在氮气保护下将反应混合物于室温中搅拌12小时。反应完毕后，向混合物中加入饱和食盐水(20mL)淬灭反应，用乙酸乙酯(10mL x 3)萃取。合并有机相，用饱和食盐水(30mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经柱层析(洗脱剂：乙酸乙酯/石油醚＝1/50-1/5)纯化得到目标化合物BB-5A(黄色油状液体，122.00mg，收率：12.96％)。
1H NMR(400MHz,CDCl3)δ：7.95(d,J＝16.1Hz,1H),7.80(d,J＝2.3Hz,1H),7.57(dd,J＝2.3,8.8Hz,1H),7.49(d,J＝8.8Hz,2H),7.34(dd,J＝1.3,8.5Hz,1H),7.03(d,J＝8.8Hz,2H),6.56(d,J＝16.1Hz,1H),4.30(q,J＝7.3Hz,2H),4.22-4.14(m,2H),3.87-3.78(m,2H),3.57(t,J＝6.7Hz,2H),1.68-1.60(m,2H),1.47-1.39(m,2H),1.36(t,J＝7.2Hz,3H),0.94(t,J＝7.4Hz,3H)
参考例54：BB-5B
Figure PCTCN2017115453-appb-000131
合成路线
Figure PCTCN2017115453-appb-000132
步骤1：化合物BB-5B的合成
将化合物BB-5B-1(400.00mg,903.73μmol,1.00eq)溶于二氯甲烷(5.00mL)中，室温下加入间氯过氧苯甲酸((779.78mg,3.61mmol,80％purity,4.00eq)。室温反应3小时后加入8mL饱和亚硫酸钠淬灭。加入水(20mL)，用二氯甲烷(50mL x 3)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。所得残留物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝50/1,3/1)纯化得到目标化合物BB-5B(400.00mg,842.80μmol,93.26％yield)。
MS–ESI m/z:497.2[M+Na]+
1H NMR(400MHz,CHLOROFORM-d)δ＝8.64(d,J＝16.1Hz,1H),8.08(d,J＝8.3Hz,1H),7.85(d,J＝1.5Hz,1H),7.72(dd,J＝1.8,8.3Hz,1H),7.63-7.51(m,2H),7.10-6.99(m,2H),6.46(d,J＝15.8Hz,1H),4.31(q,J＝7.0Hz,2H),4.22-4.17(m,2H),3.86-3.80(m,2H),3.57(t,J＝6.7Hz,2H),3.25(td,J＝6.8,13.7Hz,1H), 1.67-1.61(m,3H),1.45-1.39(m,2H),1.36(t,J＝7.2Hz,4H),1.31(d,J＝7.0Hz,6H),0.94(t,J＝7.3Hz,3H)参考例55：BB-5C
Figure PCTCN2017115453-appb-000133
合成路线
Figure PCTCN2017115453-appb-000134
步骤1：化合物BB-5C-2的合成
0℃下将三氯氧磷(4.62mL，49.74mmol)小心加入N,N-二甲基乙酰胺(6.91mL，74.61mmol)中，将该混合物置于0℃下搅拌0.5小时。随后向上述混合物中加入化合物BB-5C-1(5.00g，24.87mmol)。加料完毕后，将反应混合物加热至70℃并搅拌3小时。反应完毕后，将混合物冷却至室温，向其中加入饱和碳酸氢钠溶液(30mL)后，加热至60℃并搅拌0.5小时以淬灭反应。随后再次冷却至室温，加入浓盐酸调节pH值至2，用二氯甲烷(15mL x 3)萃取。合并有机相，用水(50mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/50-1/5)纯化得到目标化合物BB-5C-2(1.50g，收率：26.80％)。
1H NMR(400MHz,CDCl3)δ：7.71-7.61(m,3H),7.27-7.22(m,1H),6.48(br d,J＝9.5Hz,1H)
步骤2：化合物BB-5C-4的合成
氮气氛围下将化合物BB-5C-2(1.00g，4.44mmol)和化合物BB-5C-3(1.56g，4.88mmol)溶于1,4-二氧六环(15mL)中，随后向其中加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(362.59mg,444.00μmol)，碳酸钾(920.48mg，6.66mmol)和水(3.00mL)。加料完毕后，将反应混合物加热至80℃并搅拌4小时。反应完毕后，向混合物中加入饱和食盐水(40mL)淬灭反应，用乙酸乙酯(15mL x 3)萃取。合并有机相，用水(50mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/40-1/2)纯化得到目标化合物BB-5C-4(1.25g，收率：83.19％)。1H NMR(400MHz,CDCl3)δ：7.74(br dd,J＝9.2,18.4Hz,2H),7.63(s,1H),7.51(br d,J＝7.8Hz,2H),7.39(br d,J＝8.3Hz,1H),7.03(br d,J＝7.5Hz,2H),6.47(br d,J＝9.5Hz,1H),4.18(br s,2H),3.83(br s,2H),3.57(br t,J＝6.4Hz,2H),1.68-1.59(m,2H),1.41(qd,J＝7.1,14.5Hz,2H),0.94(br t,J＝7.2Hz,3H) 步骤3：化合物BB-5C的合成
室温下将化合物BB-5C-4(150.00mg，443.26μmol)溶于二甲亚砜(1mL)中，随后向其中加入氢氧化钡八水合物(279.66mg，886.52μmol)。加料完毕后，将反应混合物小心加热至40℃并搅拌3小时。随后向上述混合物中加入碘甲烷(251.67mg，1.77mmol)，加料完毕后继续在该温度下搅拌0.5小时。反应完毕后，将反应混合物冷却至室温，向其中鼓入氮气以除去过量碘甲烷，再加入饱和食盐水(20mL)淬灭反应，用乙酸乙酯(5mL x 3)萃取。合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩得到目标化合物BB-5C(148.00mg，收率：86.85％)。
1H NMR(400MHz,CDCl3)δ：7.78(d,J＝2.3Hz,1H),7.52-7.46(m,3H),7.20(d,J＝12.5Hz,1H),6.98(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,1H),6.02(d,J＝12.5Hz,1H),4.19-4.13(m,2H),3.87(s,3H),3.83-3.79(m,2H),3.69(s,3H),3.56(t,J＝6.7Hz,2H),1.66-1.60(m,2H),1.40(qd,J＝7.5,14.9Hz,2H),0.94(t,J＝7.3Hz,3H)
实施例1：WX017
Figure PCTCN2017115453-appb-000135
合成路线：
Figure PCTCN2017115453-appb-000136
步骤1：化合物WX017-2的合成
氮气氛围下，将磷酰基乙酸三乙酯(25.02g,111.60mmol)溶于四氢呋喃中，0℃下分批加入60％纯度的氢化钠(4.46g,111.60mmol)。在0-5℃下搅拌半小时后，加入化合物BB-2A(16.00g,74.40mmol)的四氢呋喃(20.00mL)溶液。氮气保护下反应混合物在室温中搅拌1.5小时。反应完毕后，
将反应液缓慢倒入50毫升饱和氯化铵水溶液中。油水两相分离，将水相用乙酸乙酯(40mL*3)萃取。 合并有机相，用饱和食盐水(120mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，得到产物WX017-2(21.00g,收率98.99％)。
1H NMR(400MHz,CDCl3)δ＝7.89(d,J＝16.3Hz,1H),7.61(d,J＝2.5Hz,1H),7.43(dd,J＝2.5,8.8Hz,1H),6.80(d,J＝9.0Hz,1H),6.49(d,J＝16.1Hz,1H),4.27(q,J＝7.3Hz,2H),3.87(s,3H),1.34-1.31(m,3H)
步骤2：化合物WX017-3的合成
氮气氛围下将化合物WX017-2(10.00g,35.07mmol)，化合物BB-1A(10.11g,31.56mmol)和碳酸钾(14.54g,105.21mmol)溶于1,4-二氧六环(80.00mL)和水(15.00mL)中，随后加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(2.57g,3.51mmol)。在氮气保护下将反应混合物加热至80℃并搅拌5小时。反应完毕后冷却至室温，向混合物中加入水(60mL)，用乙酸乙酯(60mL x 2)萃取。合并有机相，用饱和食盐水(120mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝100/1,20/1)纯化得到目标化合物WX017-3(8.60g,收率58.89％)。MS–ESI m/z:399.1(M+H)+
1H NMR(400MHz,CHLOROFORM-d)δ＝7.95(d,J＝16.3Hz,1H),7.60(d,J＝2.3Hz,1H),7.44(dd,J＝2.3,8.5Hz,1H),7.40-7.35(m,2H),6.94-6.86(m,3H),6.52(d,J＝16.1Hz,1H),4.20(q,J＝7.0Hz,2H),4.11-4.06(m,2H),3.84(s,3H),3.75-3.71(m,2H),3.48(t,J＝6.8Hz,2H),1.56-1.49(m,2H),1.32(dd,J＝7.4,15.2Hz,2H),1.27(t,J＝7.2Hz,3H),0.86(t,J＝7.4Hz,3H)
步骤3：化合物WX017-4的合成
将化合物WX017-3溶于甲醇，四氢呋喃和水中，室温下加入氢氧化钠。反应化合物在室温下搅拌15小时。反应完毕后，减压浓缩除去溶剂。加入10毫升水和4M盐酸调节到pH＝4到5，然后用乙酸乙酯(15mL*3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，得到化合物WX017-4(600.00mg,收率40.29％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.16(d,J＝16.3Hz,1H),7.71(d,J＝2.3Hz,1H),7.57(dd,J＝2.3,8.5Hz,1H),7.57-7.55(m,2H),7.02–6.98(m,3H),6.63(d,J＝16.1Hz,1H),4.17(q,J＝7.0Hz,2H),3.95(s,3H),3.84–3.81(m,2H),3.58-3.55(m,2H),1.66-1.59(m,2H),1.43-1.38(m,2H),0.94(t,J＝7.4Hz,3H).
步骤4：化合物WX017的合成
室温下将化合物WX017-4(80.00mg,215.96μmol)溶于二氯甲烷(5mL)中，冷却至0℃，向上述溶液中加入N,N-二甲基甲酰胺(789.23ug,10.80μmol)和草酰氯(82.24mg,647.88μmol)。氮气氛围下，反应混合物于0-5℃搅拌0.5小时。反应完毕后，向混合物中鼓入氮气以除去有机溶剂，并将其混合在3毫升四氢呋喃中。0℃下，将其滴加到化合物BB-3A(56.21mg,213.43μmol)和三乙胺(64.79mg,640.29μmol)的四氢呋喃(5mL)混合物中。加完后将反应混合物升至室温，于氮气氛围中搅拌15小时。反应完毕后向混合物中加入甲醇(5mL)淬灭反应，减压浓缩，所得残留物经制备级高效液相色 谱纯化得到化合物WX017。
MS–ESI m/z:616.1；617.1[M+H]+.
1H NMR(400MHz,CDCl3)δ：9.33(s,1H),8.05(d,J＝15.6Hz,1H),7.80(d,J＝8.8Hz,2H),7.61(d,J＝2.3Hz,1H),7.50(br d,J＝2.3Hz,1H),7.48(s,1H),7.44-7.39(m,2H),7.29(d,J＝8.8Hz,2H),6.98-6.93(m,3H),6.88(d,J＝15.8Hz,1H),6.55(s,1H),4.15(d,J＝4.8Hz,2H),4.14-4.13(m,1H),4.13(d,J＝2.8Hz,1H),3.97(d,J＝14.1Hz,1H),3.86(s,3H),3.83-3.79(m,1H),3.79-3.79(m,1H),3.76(dt,J＝4.0,7.3Hz,2H),3.56(t,J＝6.8Hz,2H),1.73-1.66(m,2H),1.65-1.57(m,2H),1.45-1.35(m,2H),0.93(t,J＝7.4Hz,2H),0.87(t,J＝7.4Hz,3H)。
参照实施例1中步骤1～4的合成方法，合成下表中参考例。
Figure PCTCN2017115453-appb-000137
Figure PCTCN2017115453-appb-000138
Figure PCTCN2017115453-appb-000139
Figure PCTCN2017115453-appb-000140
Figure PCTCN2017115453-appb-000141
Figure PCTCN2017115453-appb-000142
Figure PCTCN2017115453-appb-000143
Figure PCTCN2017115453-appb-000144
Figure PCTCN2017115453-appb-000145
Figure PCTCN2017115453-appb-000146
Figure PCTCN2017115453-appb-000147
Figure PCTCN2017115453-appb-000148
Figure PCTCN2017115453-appb-000149
Figure PCTCN2017115453-appb-000150
Figure PCTCN2017115453-appb-000151
Figure PCTCN2017115453-appb-000152
Figure PCTCN2017115453-appb-000153
Figure PCTCN2017115453-appb-000154
实施例37：WX039,WX040
Figure PCTCN2017115453-appb-000155
步骤1：化合物WX039和WX040的合成
化合物WX039-1经过超临界流体色谱(分离条件Column:Chiralpak AD-3 50*4.6mm I.D.,3um流动相:40％of ethanol(0.05％DEA)in CO2，流速:4mL/min，柱温:40℃波长:220nm)分离，得到异构体WX039(保留时间1.982分钟)和WX040(保留时间2.416分钟)。
MS–ESI m/z:603.1；604.1；605.1[M+H]+
1H NMR(WX039,400MHz,CDCl3)δ:9.37(s,1H)8.05(d,J＝15.5Hz,1H),7.80(d,J＝8.8Hz,2H),7.61(d,J＝2.3Hz,1H),7.51(s,1H),7.49(dd,J＝8.7Hz,J＝2.4Hz,1H),7.41(d,J＝8.8Hz,2H),7.29(d,J＝8.5Hz,2H),6.96-6.92(m,3H),6.88(d,J＝15.5Hz,1H),6.55(s,1H),4.15-4.13(m,2H),4.11-3.94(m,2H),3.86(s,3H),3.84-3.82(m,2H),3.80-3.69(m,2H),3.56(t,J＝6.8Hz,2H),1.63-1.59(m,2H),1.42-1.38(m,3H),1.36-1.32(m,2H),0.93(t,J＝7.4Hz,3H).
1H NMR(WX040,400MHz,CDCl3)δ:9.07(br s,1H)8.05(d,J＝15.5Hz,1H),7.80(d,J＝8.3Hz,2H),7.62(d,J＝2.3Hz,1H),7.53(s,1H),7.50(dd,J＝8.7Hz,J＝2.1Hz,1H),7.43(d,J＝8.5Hz,2H),7.30(d,J＝8.3Hz,2H),6.97-6.94(m,3H),6.88(d,J＝15.5Hz,1H),6.56(br s,1H),4.16-4.13(m,2H),4.11-3.95(m,2H),3.88(s,3H),3.85-3.74(m,4H),3.56(t,J＝6.8Hz,2H),1.63-1.59(m,2H),1.42-1.36(m,3H),1.36-1.32(m,2H),0.93(t,J＝7.4Hz,3H).
实施例86：WX086
Figure PCTCN2017115453-appb-000156
步骤1：化合物WX086的合成
将化合物WX086-1经过超临界流体色谱(分离条件Column:ChiralPaK AD-3 50*4.6mm I.D.,3um流动相:A:CO2B:40％Ethanol(0.05％DEA)，流速:4mL/min，柱温:40℃，波长:220nm)分离，得到异构体WX086’(保留时间2.247分钟)和WX086(保留时间3.248分钟).
MS–ESI m/z:613.0,614.0,615.0[M+H]+
1H NMR(400MHz,CDCl3)δ:8.35(d,J＝5.0Hz,1H),8.02(d,J＝16.1Hz,1H),7.97(s,1H),7.87(d,J＝9.0Hz,2H),7.77(d,J＝2.0Hz,1H),7.60(dd,J＝2.0,8.5Hz,1H),7.53(d,J＝8.5Hz,2H),7.44(d,J＝9.0Hz,2H),7.32(d,J＝5.0Hz,1H),7.12(d,J＝9.0Hz,1H),7.02(d,J＝8.5Hz,2H),6.97(d,J＝15.6Hz,1H),4.43-4.24(m,2H),4.19-4.11(m,2H),3.97(s,3H),3.82-3.78(m,2H),3.57(s,2H),2.73-2.55(m,2H),1.64-1.55(m,2H),1.48-1.38(m,2H),1.21(t,J＝7.5Hz,3H),0.95(t,J＝7.3Hz,3H)
实施例87：WX087
Figure PCTCN2017115453-appb-000157
步骤1：化合物WX087的合成
将化合物WX087-1经过超临界流体色谱(分离条件Column:ChiralPaK AD-3 50*4.6mm I.D.,3um流动相:A:CO2B:40％Ethanol(0.05％DEA)，流速:4mL/min，柱温:40℃，波长:220nm)分离，得到异构体WX087’(保留时间2.409分钟)和WX087(保留时间3.392分钟).
MS–ESI m/z:627.2,628.2,629.2[M+H]+
1H NMR(400MHz,CDCl3)δ:8.41(br d,J＝4.5Hz,1H),8.06(d,J＝15.6Hz,1H),7.94(br d,J＝10.3Hz,2H),7.76(br d,J＝8.5Hz,2H),7.67(d,J＝1.8Hz,1H),7.53(dd,J＝2.0,8.5Hz,1H),7.46(d,J＝8.5Hz,2H),7.36(br d,J＝8.3Hz,2H),7.12(br d,J＝4.5Hz,1H),6.99(dd,J＝2.9,8.7Hz,3H),6.78(d,J＝15.6Hz,1H),4.23-4.14(m,3H),4.10-4.04(m,1H),3.93(s,3H),3.82(t,J＝4.8Hz,2H),3.57(t,J＝6.7Hz,2H),2.61-2.53(m,2H),1.64-1.58(m,4H),1.44-1.37(m,2H),1.01-0.96(m,2H),0.96-0.91(m,3H)
实施例40：WX006
Figure PCTCN2017115453-appb-000158
合成路线：
Figure PCTCN2017115453-appb-000159
步骤1：化合物WX006-2的合成
氮气氛围下将化合物WX006-1(500.00mg，1.89mmol)和异丙烯基三氟硼酸钾(195.78mg，1.32mmol)溶于1,4-二氧六环(10mL)中，随后加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(154.34mg，189.00μol.0)、碳酸钾(522.43mg，3.78mmol)和水(4mL)。在氮气保护下将反应混合物加热至50℃，搅拌12小时。反应完毕后冷却至室温，向混合物中加入水(50mL)淬灭反应，用乙酸乙酯(50mL x 2)萃取。合并有机相，用饱和食盐水(50mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经快速硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/9)(洗脱剂：乙酸乙酯/石油醚＝0/9–1/9)纯化得到目标化合物WX006-2(无色液体，500.00mg，收率：77.78％)。
1H NMR(400MHz,CDCl3)δ：10.07(s,1H),7.96(s,1H),7.59-7.57(d,J＝6Hz,1H),7.17-7.15(d,J＝8Hz,1H),5.38(s,1H),4.85(s,1H),2.11(s,3H)
步骤2：化合物WX006-4的合成
氮气氛围下将化合物WX006-2(500.00g，1.47mmol)和化合物WX006-3(616.18mg,1.91mmol)溶于1,4-二氧六环(6mL)中，随后加入(1,1'–双(二苯基膦)二茂铁)二氯化钯二氯甲烷配合物(120.05mg,147.00μmol)、碳酸钾(406.34g,2.94mmol)和水(3mL)。在氮气保护下将反应混合物加热至50℃并搅拌16小时。反应完毕后冷却至室温，向混合物中加入水(50mL)淬灭反应，用乙酸乙酯(50mL x 2)萃取。合并有机相，用饱和食盐水(50mL x 2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩。过滤除去不溶物，所得残留物经快速硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1/9)纯化得到目标化合物WX006-4(黄色油状液体，232.00mg，收率：46.63％)。
1H NMR(400MHz,CDCl3)δ：10.26(s,1H),8.12(d,J＝1.8Hz,1H),7.78-7.74(m,1H),7.57(d,J＝7.5Hz,2H),7.47(d,J＝7.7Hz,1H),7.41(d,J＝8.0Hz,1H),7.27(s,1H),7.05-7.00(m,2H),5.46(t,J＝1.6Hz,1H),4.97-4.94(m,1H),4.19-4.16(m,2H),4.15(s,1H),3.83(d,J＝5.0Hz,2H),3.59-3.55(m,2H),2.22(s,3H),1.66-1.61(m,2H),1.61-1.57(m,5H),1.46-1.36(m,3H),1.34(s,1H),0.98-0.95(m,1H),0.96-0.93(m,1H),0.95-0.93(m,1H)
步骤3：化合物WX006-5的合成
室温下将化合物WX006-4(120.00mg,354.57μmol)溶于乙酸乙酯(3mL)中，向其中加入湿钯碳催化剂(100.00mg，钯含量10％，水含量50％)。置换氩气3次后，向其中置换氢气3次。反应混合物加热至50℃，在氢气氛围(15psi)中搅拌4小时。过滤除去催化剂，滤液减压浓缩得到目标化合物WX006-5(浅黄色油状液体，110.00mg)。粗产品不经纯化即可直接用于下一步。
步骤4：化合物WX006-6的合成
室温下将化合物WX006-5(100.00mg,292.00μmol)溶于二氯甲烷(3mL)中，向其中加入活性二氧化锰(253.86mg,2.92mmol)。氮气保护下将反应混合物于室温中搅拌16小时。反应完毕后过滤除去二氧化锰，滤液减压浓缩，所得残留物经制备级薄层色谱(展开剂：乙酸乙酯/石油醚＝1/15)纯化得到目标化合物WX006-6(浅黄色固体，170.00mg，收率85.50％)。1H NMR(400MHz,CDCl3)δ:10.43(s,1H),8.01(d,J＝2.0Hz,1H),7.75(dd,J＝2.1,8.2Hz,1H),7.58-7.45(m,2H),7.38-7.32(m,1H),7.05-6.96(m,2H),4.20-4.14(m,2H),4.04-3.94(m,1H),3.85-3.79(m,2H),3.60-3.52(m,2H),1.70-1.57(m,2H),1.51-1.37(m,2H),1.35(d,J＝6.8Hz,4H),1.04-0.98(m,1H),0.98-0.88(m,3H)
步骤5：化合物WX006-8的合成
室温下将化合物WX008-7(210.72mg,939.94μmol)溶于四氢呋喃(2mL)中，冷却至0℃，向上述溶液中加入氢化钠(22.56mg,939.94μmol，纯度60％)。反应混合物升至室温并搅拌0.5小时。向上述混合物中加入由化合物WX006-6(160.00mg,469.97μmol)和四氢呋喃(2mL)配制而成的溶液，加完后混合物继续搅拌5小时。反应完毕后，向混合物中加入水(25mL)淬灭反应，用乙酸乙酯(20mL x3)萃取。合并有机相，用水(20mL x 3)洗涤，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，所得残留物经制备级薄层色谱(展开剂：乙酸乙酯/石油醚＝1/15)纯化得到目标化合物WX006-8(浅黄色固体，160.00mg，收率82.93％)。
步骤6：化合物WX006-9的合成
室温下将化合物WX006-8(150.00mg,365.37μmol)溶于乙醇(2mL)中，向上述溶液中加入8M氢氧化钠水溶液(1.5mL)。将反应混合物加热至50℃并搅拌4小时。反应完毕后冷却至室温，用4M盐酸溶液调节pH值至4，过滤收集沉淀，沉淀经制备级薄层色谱(展开剂：乙酸乙酯/石油醚＝1/15)纯化得到目标化合物WX006-9(浅黄色固体，90.00mg，收率64.40％)。
1H NMR(400MHz,CDCl3)δ:8.36-8.24(m,1H),7.73(s,1H),7.64-7.46(m,3H),7.46-7.36(m,1H),7.08-6.98(m,2H),6.45(d,J＝15.8Hz,1H),4.26-4.10(m,2H),3.91-3.73(m,2H),3.57(t,J＝6.7Hz,2H),3.47-3.30(m,1H),1.79-1.52(m,2H),1.46-1.37(m,2H),1.37-1.21(m,6H),0.94(t,J＝7.4Hz,3H)
步骤7：化合物WX006的合成
室温下将化合物WX006-9(60.00mg,227.83μmol)溶于二氯甲烷(2mL)中，冷却至0℃。向上述溶液中加入草酰氯(74.57mg，587.46μmol)和N,N-二甲基甲酰胺(21.47mg,293.73μmol)。加料完毕后，将反应混合物升至室温，在氮气氛围中搅拌2.5小时。向反应混合物中鼓入氮气流以除去溶剂，所得残留物溶于四氢呋喃(1mL)中，将其加入到由化合物BB-3A(69.62mg，264.36μmol)、三乙胺(59.45mg,587.46μmol)和四氢呋喃(1mL)配置而成的溶液。加料完毕后，将反应混合物在室温下搅拌2.5小时。反应完毕后，向混合物中加入甲醇(2mL)淬灭反应，减压浓缩，所得残留物经制备级高效液相色谱纯化得到化合物WX006。
MS–ESI m/z:628.1；629.1；630.1[M+H]+.
1H NMR(400MHz,CDCl3)δ：8.84(br s,1H),8.33-8.20(m,1H),7.80(d,J＝8.5Hz,2H),7.67-7.29(m,8H),6.99(d,J＝8.8Hz,2H),6.61(d,J＝15.1Hz,1H),6.53(s,1H),4.23-4.11(m,3H),3.99(d,J＝14.1Hz,1H),3.87-3.74(m,4H),3.57(t,J＝6.8Hz,2H),3.45-3.36(m,1H),1.79-1.65(m,1H),1.41(qd,J＝7.3,14.9Hz,2H),1.29(d,J＝7.0Hz,5H),1.26(br s,1H),1.00-0.83(m,6H)
参照实施例40中步骤1～7的合成方法，合成下表中实施例。
Figure PCTCN2017115453-appb-000160
参照实施例40中步骤4～7的合成方法，合成下表中实施例。
Figure PCTCN2017115453-appb-000161
Figure PCTCN2017115453-appb-000162
Figure PCTCN2017115453-appb-000163
参照实施例40中步骤6～7的合成方法，合成下表中实施例。
Figure PCTCN2017115453-appb-000164
各实施例的NMR和MS数据
Figure PCTCN2017115453-appb-000165
Figure PCTCN2017115453-appb-000166
Figure PCTCN2017115453-appb-000167
Figure PCTCN2017115453-appb-000168
Figure PCTCN2017115453-appb-000169
Figure PCTCN2017115453-appb-000170
Figure PCTCN2017115453-appb-000171
Figure PCTCN2017115453-appb-000172
Figure PCTCN2017115453-appb-000173
Figure PCTCN2017115453-appb-000174
Figure PCTCN2017115453-appb-000175
Figure PCTCN2017115453-appb-000176
Figure PCTCN2017115453-appb-000177
Figure PCTCN2017115453-appb-000178
Figure PCTCN2017115453-appb-000179
实验例1：CCR2/CCR5体外测试
实验目的：
通过FLIPR检测细胞内钙信号变化,以化合物的IC50值为指标，来评价化合物对CCR2和CCR5受体的抑制作用。
实验材料:
1、细胞系：将细胞接种并在37℃，5％CO 2培养箱中温育过夜
CCR2/CCR5密度:1M(20k/well)
Target Clone# Passage# Host
CCR2 C7 P6 HEK293
CCR5 C13 P4 HEK293
2、试剂：Fluo-4 Direct,(Invitrogen,Cat#F10471)
3、装置设备：
384 well Poly-D-Lysine protein coating plate,Greiner#781946
384 compound plate,Greiner#781280
FLIPR,Molecular Device
ECHO,Labcyte
4、化合物：
将化合物溶解于DMSO制备成10mM溶液，并将化合物溶液放置在氮气箱中。
Compound_ID Purity Amount_In_mg
Cenicriviroc 97.00 1.15
激动剂参考化合物：
MCP-1 Sigma SRP3109 10uM stock in H2O
RANTES Sigma SRP3269 10uM stock in H2O
实验步骤和方法：
在FLIPR测定缓冲液中制备丙磺舒：向77mg丙磺舒中加入1mL FLIPR测定缓冲液，制成250mM溶液。每天新鲜制备。
2X(8uM)Fluo-4DirectTM上样缓冲液(每10mL)
·解冻一瓶Fluo-4DirectTM晶体(F10471)
·向样品瓶中加入10mL FLIPR测定缓冲液.
·向每10mL的Fluo-Direct中加入0.2mL的丙磺舒。最终测定浓度为2.5mM
·旋转，放置>5分钟(避光)
·每天新鲜制备
实验步骤：
a)激动剂化合物制备：
将MCP-1在FLIPR测定缓冲液1：2中稀释10个点，从0.5uM(最终100nM)开始。将RANTES在FLIPR测定缓冲液1：3中稀释10个点，从0.5uM(最终100nM)开始。根据化合物板图，将20uL连续稀释的化合物缓冲液加入DRC板的每个孔中。
b)拮抗剂化合物制备：拮抗剂参考化合物将标准化合物在DMSO 1:3中稀释11个点，从1mM开始。将受试化合物在DMSO 1:3中稀释11个点，从2mM开始。使用Echo将250nL化合物溶液转移至细胞板(Greiner#781946)
c)从培养箱中取出细胞板，并使用移液器轻轻地分配20uL 2X Fluo-4Direct无洗涤上样缓冲液到384孔细胞培养板。最终细胞板中为体积40μL
d)在37℃5％CO2下孵育50分钟，室温10分钟
e)从培养箱中取出细胞板，并将其放入FLIPR。将复合板和吸头盒放入FLIPR
f)对于DRC板：
1)在FLIPRTETRA上运行方案
2)读取荧光信号
3)将10μL的化合物从DRC板转移到细胞板
4)读取荧光信号
5)计算从Read 90到最大允许的“最大-最小”。使用FLIPR计算每个细胞株的EC80值
6)准备激动剂参考化合物的5X EC80浓度
g)对于复合板(1-添加)：
1)在FLIPRTETRA上运行方案
2)转移10微升的5X EC80浓度的激动剂参考化合物从复合板到细胞板。
3)读取荧光信号。
4)计算从Read 90到最大允许的“最大-最小”
h)使用Prism分析数据，计算化合物的IC50值。
实验结果见表1：
表1FLIPR检测IC50(nM)测试结果
化合物 CCR2 CCR5 化合物 CCR2 CCR5
WX001 29.9 9.3 WX047 8.2 6.7
WX002 318.6 113.2 WX048 11.8 2.6
WX003 21.6 3.0 WX049 13.3 9.2
WX004 152.8 7.1 WX050 12.6 20.8
WX005 12.1 3.4 WX051 5.5 1.4
WX006 32.1 3.3 WX052 80.8 11.9
WX007 65.2 6.4 WX053 5.9 1.3
WX008 17.3 1.5 WX054 43.4 9.2
WX009 63.2 9.4 WX055 7.6 6.4
WX010 214.2 17.2 WX056 71.1 16.6
WX011 61.0 2.6 WX057 24.7 3.5
WX012 51.0 5.4 WX058 28.2 5.7
WX013 983.7 14.2 WX059 9.9 8.5
WX014 257.8 7.9 WX060 18.5 4.1
WX015 62.0 65.1 WX061 8.9 15.2
WX016 75.1 4.5 WX062 84.5 20.5
WX017 13.0 7.9 WX063 9.4 1.4
WX018 43.5 7.3 WX064 12.8 6.1
WX019 9.3 50.9 WX065 49.6 68.0
WX020 68.1 8.2 WX066 6.5 10.1
WX021 64.5 8.8 WX067 16.8 0.9
WX022 204.9 10.1 WX068 36.0 18.4
WX023 37.1 53.3 WX069 35.3 1.0
WX024 63.1 1.3 WX070 39.2 8.4
WX025 127.0 7.4 WX071 4.5 3.4
WX026 175.4 3.2 WX072 11.9 5.9
WX027 207.2 13.6 WX073 11.9 6.5
WX028 86.4 15.5 WX074 5.4 3.5
WX029 167.5 34.2 WX075 17.3 2.4
WX030 300.3 15.9 WX076 42.2 8.5
WX031 237.3 95.9 WX078 25.4 1.3
WX032 28.6 8.1 WX079 5.6 5.8
WX033 56.3 11.8 WX080 25.1 15.1
WX034 30.0 10.0 WX081 12.5 5.5
WX035 214.6 16.1 WX082 53.4 11.4
WX036 64.9 13.3 WX083 28.9 2.1
WX037 62.2 44.2 WX084 51.2 4.6
WX038 42.5 12.5 WX085 5.2 5.6
WX039 70.1 760.0 WX086 13.0 1.8
WX040 11.3 10.5 WX087 66.0 2.1
WX041 22.5 21.4 WX088 3.5 4.3
WX042 52.8 4.0 WX089 15.0 ND
WX043 249.6 9.1 WX090 5.5 6.9
WX044 293.2 16.1 WX091 4.7 4.4
WX045 77.6 14.8 WX092 3.9 10.1
WX046 1.1 2.8      
结论：本发明化合物对CCR2和CCR5受体的拮抗作用显著。
实验例2 大鼠药代动力学对比试验
本研究选用SD雄性大鼠受试动物，应用LC/MS/MS法定量测定了大鼠分别静脉注射或口服给予测试化合物WX017，WX047，WX079,WX088和参比化合物不同时间点的血浆中的药物浓度，以评价这两个受试药物在大鼠体内的药代动力学特征。
将试验化合物的澄清溶液经尾静脉注射到SD大鼠体内(过夜禁食，7-10周龄)，将试验化合物灌胃给予到SD大鼠(过夜禁食，7-10周龄)。动物均于给药后0.0833,0.25,0.5,1,2,4,6,8和24小时从颈静脉或尾静脉采血约200μL置于添加了EDTA-K2的抗凝管中，4℃，3000g离心15min取血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlinTMVersion 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
表2展示了测试化合物WX017，WX047，WX079和参比化合物在大鼠中的药代动力学参数。
表2
Figure PCTCN2017115453-appb-000180
实验结果表明，WX017，WX047，WX079和WX088的血浆清除率比参比化合物低，分别为参比化合物的25％，33％，14％和21％；WX017，WX047，WX079和WX088的口服血浆系统暴露量(AUC0-inf)分别为参比化合物的10.4倍，6.4倍，12.6倍和3.8倍。因此在啮齿动物大鼠中，WX017，WX047，WX079和WX088的药代动力学显著优于参比化合物。
实验例3 食蟹猴药代动力学对比试验
本研究受试动物选用雄性食蟹猴，应用LC/MS/MS法定量测定了食蟹猴静脉注射或口服给予测试化合物WX047和参比化合物不同时间点的血浆中的药物浓度，以评价这两个受试药物在食蟹猴体内的药代动力学特征。
将试验化合物的澄清溶液经头静脉或隐静脉注射到食蟹猴体内(过夜禁食，2.5-7kg)，将试验化合物灌胃给予食蟹猴。动物均于给药后0.0833,0.25,0.5,1,2,4,6,8,12和24小时从外周静脉采血约400μL转移至含有0.85-1.15 mg的K2 EDTA*2H2O抗凝剂商品化离心管中，4℃，3000 g离心10min取血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlinTMVersion 6.3(Pharsight,MountainView,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
表3展示了测试化合物WX047和参比化合物在食蟹猴中的药代动力学参数。
表3
Figure PCTCN2017115453-appb-000181
实验结果表明，WX047的口服生物利用度是参比化合物的7.6倍，WX047的口服血浆系统暴露量(AUC0-inf)为参比化合物的10.8倍，因此WX047在食蟹猴中的药代动力学显著优于参比化合物。
实验例4 人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用
将CYP的5种同工酶的一共5个特异性探针底物非那西丁(Phenacetin，CYP1A2)、双氯芬酸(Diclofenac，CYP2C9)、(S)-美芬妥英((S)-Mephenytoin，CYP2C19)、右美沙芬 (Dextromethorphan，CYP2D6)、咪达唑仑(Midazolam，CYP3A4)分别与人肝微粒体以及测试化合物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后对样品处理并采用液相色谱串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的8种代谢产物对乙酰氨基酚(Acetaminophen)、4’-羟基双氯芬酸(4’-Hydroxydiclofenac)、4’-羟基美芬妥英(4’-Hydroxymephenytoin)、右啡烷(Dextrorphan)、1’-羟基咪达唑仑(1’-Hydroxymidazolam)的浓度，以计算相应的半抑制浓度(IC50)。
表4
Figure PCTCN2017115453-appb-000182
实验结论：参比化合物对CYP3A4有弱抑制作用，而WX047和WX079对人肝微粒体细胞色素P450的5种同工酶(CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4)都不存在抑制风险，优于参比化合物。

Claims (24)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2017115453-appb-100001
    其中，
    R1选自任选被1、2或3个R取代的：C1-6烷氧基、5～6元杂环烷基；
    R2、R3、R4分别独立地选自H、卤素、OH、CN，或分别独立地选自任选被1、2或3个R取代的：C1- 6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基-S(＝O)-、C1-6烷基-S(＝O)2-、C3-6环烷基；
    R5、R6分别独立地选自H，或分别独立地选自任选被1、2或3个R取代的C1-3烷基；
    环A选自：
    Figure PCTCN2017115453-appb-100002
    R7选自任选被1、2或3个R取代的：C1-6烷基；
    R8选自H，或选自任选被1、2或3个R取代的：C1-6烷基；
    L选自：-S(＝O)-或-S(＝O)2-；
    R选自卤素、OH，或选自任选被1、2或3个R’取代的：C1-6烷基、C1-6杂烷基、C3-6环烷基；
    R’选自F、Cl、Br、I、OH、CH2F、CHF2、CF3；
    所述5～6元杂环烷基之“杂”分别独立选自：-NH-、-O-、N；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R选自F、Cl、Br、I、OH，或选自任选被1、2或3个R’取代的：C1-3烷基、C1-4烷氧基、C3-6环烷基。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R选自F、Cl、Br、I、OH，或选自任选被1、2或3个R’取代的：Me、
    Figure PCTCN2017115453-appb-100003
  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，R选自F、Cl、Br、I、OH、CH3、CH2F、CHF2、CF3、
    Figure PCTCN2017115453-appb-100004
  5. 根据权利要求1～4任意一项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：C1-4烷氧基、吡咯烷基。
  6. 根据权利要求5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 PCTCN2017115453-appb-100005
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，R1选自：
    Figure PCTCN2017115453-appb-100006
    Figure PCTCN2017115453-appb-100007
  8. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，R2、R3、R4分别独立地选自H、卤素、OH、CN，或分别独立地选自任选被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烷基-S(＝O)-、C1-3烷基-S(＝O)2-、C4-5环烷基。
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，R2、R3、R4分别独立地选自H、F、Cl、Br、I、OH、CN，或分别独立地选自任选被1、2或3个R取代的：Me、
    Figure PCTCN2017115453-appb-100008
    Figure PCTCN2017115453-appb-100009
  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，R2、R3、R4分别独立地选自H、F、Cl、Br、I、OH、CN、Me、
    Figure PCTCN2017115453-appb-100010
    Figure PCTCN2017115453-appb-100011
  11. 根据权利要求10所述化合物或其药学上可接受盐，其中，R2选自：H、F、Cl、OH、CN、Me、
    Figure PCTCN2017115453-appb-100012
    Figure PCTCN2017115453-appb-100013
  12. 根据权利要求10所述化合物或其药学上可接受盐，其中，R3选自：H、F、Cl、Me、
    Figure PCTCN2017115453-appb-100014
  13. 根据权利要求10所述化合物或其药学上可接受盐，其中，R4选自：H、Cl。
  14. 根据权利要求1～4任意一项所述化合物或其药学上可接受盐，其中，R5、R6分别独立地选自H或Me。
  15. 根据权利要求1～4任意一项所述化合物或其药学上可接受盐，其中，R7选自任选被1、2或3个R取代的：Me、
    Figure PCTCN2017115453-appb-100015
  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，R7选自：Me、
    Figure PCTCN2017115453-appb-100016
    Figure PCTCN2017115453-appb-100017
  17. 根据权利要求1～4任意一项所述化合物或其药学上可接受盐，其中，R8选自H，或选自任选被1、2或3个R取代的：Me、
    Figure PCTCN2017115453-appb-100018
  18. 根据权利要求17所述化合物或其药学上可接受的盐，其中，R8选自H、Me、
    Figure PCTCN2017115453-appb-100019
  19. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，环A选自：
    Figure PCTCN2017115453-appb-100020
    Figure PCTCN2017115453-appb-100021
  20. 根据权利要求1～19任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017115453-appb-100022
    其中，
    R1、R2、R3、R4、R5、R6、R7和R8如权利要求1～19所定义。
  21. 下式所示化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017115453-appb-100023
    Figure PCTCN2017115453-appb-100024
    Figure PCTCN2017115453-appb-100025
    Figure PCTCN2017115453-appb-100026
    Figure PCTCN2017115453-appb-100027
    Figure PCTCN2017115453-appb-100028
    Figure PCTCN2017115453-appb-100029
  22. 根据权利要求21所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017115453-appb-100030
    Figure PCTCN2017115453-appb-100031
    Figure PCTCN2017115453-appb-100032
    Figure PCTCN2017115453-appb-100033
    Figure PCTCN2017115453-appb-100034
    Figure PCTCN2017115453-appb-100035
    Figure PCTCN2017115453-appb-100036
    Figure PCTCN2017115453-appb-100037
    Figure PCTCN2017115453-appb-100038
    Figure PCTCN2017115453-appb-100039
    Figure PCTCN2017115453-appb-100040
    Figure PCTCN2017115453-appb-100041
    Figure PCTCN2017115453-appb-100042
  23. 一种药物组合物，其含有治疗有效量的根据权利要求1～22任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  24. 根据权利要求1～22任意一项所述的化合物或其药学上可接受的盐或根据权利要求23所述的药物组合物在制备治疗与CCR2和/或CCR5相关疾病药物中的应用。
PCT/CN2017/115453 2016-12-09 2017-12-11 作为ccr2/ccr5受体拮抗剂的联苯化合物 WO2018103757A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CN201780074929.0A CN110023286B (zh) 2016-12-09 2017-12-11 作为ccr2/ccr5受体拮抗剂的联苯化合物
US16/468,127 US11155523B2 (en) 2016-12-09 2017-12-11 Biphenyl compound as CCR2/CCR5 receptor antagonist
ES17877947T ES2906992T3 (es) 2016-12-09 2017-12-11 Compuesto de bifenilo como antagonista del receptor CCR2/CCR5
JP2019530756A JP7086075B2 (ja) 2016-12-09 2017-12-11 Ｃｃｒ２／ｃｃｒ５受容体拮抗剤としてのビフェニル化合物
EP17877947.6A EP3567028B1 (en) 2016-12-09 2017-12-11 Biphenyl compound as ccr2/ccr5 receptor antagonist

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201611137560.7 2016-12-09
CN201611137560 2016-12-09
CN201710037028.6 2017-01-17
CN201710037028 2017-01-17

Publications (1)

Publication Number Publication Date
WO2018103757A1 true WO2018103757A1 (zh) 2018-06-14

Family

ID=62491744

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/115453 WO2018103757A1 (zh) 2016-12-09 2017-12-11 作为ccr2/ccr5受体拮抗剂的联苯化合物

Country Status (6)

Country Link
US (1) US11155523B2 (zh)
EP (1) EP3567028B1 (zh)
JP (1) JP7086075B2 (zh)
CN (1) CN110023286B (zh)
ES (1) ES2906992T3 (zh)
WO (1) WO2018103757A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019238041A1 (zh) * 2018-06-12 2019-12-19 南京明德新药研发有限公司 一种丙烯酰胺类化合物的晶型及其制备方法
WO2020259620A1 (zh) 2019-06-24 2020-12-30 南京明德新药研发有限公司 作为ccr2/ccr5拮抗剂的杂环烷基类化合物
WO2023143112A1 (zh) * 2022-01-26 2023-08-03 无锡瓴方生物医药科技有限公司 氮杂苯并八元环化合物的盐型、晶型及其应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20230013101A (ko) * 2020-05-22 2023-01-26 메드샤인 디스커버리 아이엔씨. 피리딘 유도체 및 이의 용도

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1282243A (zh) * 1997-12-19 2001-01-31 武田药品工业株式会社 用于拮抗ccr5的含n－酰苯胺衍生物的药物组合物
WO2004069808A1 (ja) * 2003-02-07 2004-08-19 Takeda Pharmaceutical Company Limited アクリルアミド誘導体、その製造法および用途

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2373073A1 (en) * 1999-05-07 2000-11-16 Takeda Chemical Industries, Ltd. Cyclic compounds and uses thereof
JP2001026586A (ja) 1999-05-07 2001-01-30 Takeda Chem Ind Ltd 環状化合物およびその用途
WO2001041808A1 (fr) * 1999-12-10 2001-06-14 Takeda Chemical Industries, Ltd. Compositions medicinales a usage par voie orale
US6890919B2 (en) 2001-06-26 2005-05-10 Shitij Kapur Atypical antipsychotic agents having low affinity for the D2 receptor
JP2003119191A (ja) 2001-08-08 2003-04-23 Takeda Chem Ind Ltd ベンゾアゼピン誘導体、その製造法および用途
WO2003014110A1 (fr) * 2001-08-08 2003-02-20 Takeda Chemical Industries, Ltd. Derive de benzazepine, son procede de preparation et d'utilisation
CA2459172C (en) 2001-08-08 2011-07-05 Takeda Chemical Industries, Ltd. Bicyclic compound, production and use thereof
JP2004256530A (ja) 2003-02-07 2004-09-16 Takeda Chem Ind Ltd アクリルアミド誘導体、その製造法および用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1282243A (zh) * 1997-12-19 2001-01-31 武田药品工业株式会社 用于拮抗ccr5的含n－酰苯胺衍生物的药物组合物
WO2004069808A1 (ja) * 2003-02-07 2004-08-19 Takeda Pharmaceutical Company Limited アクリルアミド誘導体、その製造法および用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
J. MED. CHEM., vol. 49, 2006, pages 2037 - 2048
See also references of EP3567028A4
SETO, M. ET AL.: "Highly Potent and Orally Active CCR 5 Antagonists anti-HIV-1 Agents Synthesis and Biological Activities of 1-Benzazocine Derivatives Containing a Sulfoxide Moiety", J. MED. CHEM., vol. 49, no. 6, 1 March 2006 (2006-03-01), pages 2037 - 2048, XP055460609, DOI: doi:10.1021/jm0509703 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019238041A1 (zh) * 2018-06-12 2019-12-19 南京明德新药研发有限公司 一种丙烯酰胺类化合物的晶型及其制备方法
WO2020259620A1 (zh) 2019-06-24 2020-12-30 南京明德新药研发有限公司 作为ccr2/ccr5拮抗剂的杂环烷基类化合物
CN114096245A (zh) * 2019-06-24 2022-02-25 深圳市瓴方生物医药科技有限公司 作为ccr2/ccr5拮抗剂的杂环烷基类化合物
CN114096245B (zh) * 2019-06-24 2023-02-28 深圳市瓴方生物医药科技有限公司 作为ccr2/ccr5拮抗剂的杂环烷基类化合物
EP3988098A4 (en) * 2019-06-24 2023-06-07 Shenzhen Lingfang Biotech Co., Ltd HETEROCYCLO-ALKYL COMPOUNDS USED AS CCR2/CCR5 ANTAGONISTS
WO2023143112A1 (zh) * 2022-01-26 2023-08-03 无锡瓴方生物医药科技有限公司 氮杂苯并八元环化合物的盐型、晶型及其应用

Also Published As

Publication number Publication date
EP3567028A1 (en) 2019-11-13
ES2906992T3 (es) 2022-04-21
US11155523B2 (en) 2021-10-26
CN110023286B (zh) 2021-06-01
CN110023286A (zh) 2019-07-16
JP2020500908A (ja) 2020-01-16
US20200223801A1 (en) 2020-07-16
EP3567028B1 (en) 2022-01-05
JP7086075B2 (ja) 2022-06-17
EP3567028A4 (en) 2020-03-25

Similar Documents

Publication Publication Date Title
EP3719012B1 (en) N-[4-[(2-amino-4-pyridinyl)oxy]-3-fluorophenyl]-3-(4-fluorophenyl)-1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamide derivatives as c-met/axl inhibitors for the treatment of tumors
EP3290418B1 (en) Janus kinase (jak) inhibitors
WO2018103757A1 (zh) 作为ccr2/ccr5受体拮抗剂的联苯化合物
WO2018184590A1 (zh) 作为A 2A受体抑制剂的[1,2,4]三唑并[1,5-c]嘧啶衍生物
WO2016192563A1 (zh) Janus激酶抑制剂
WO2016116025A1 (zh) Jak抑制剂
WO2019085933A1 (zh) 作为Wee1抑制剂的大环类化合物及其应用
TWI628180B (zh) 作為ＰＩ３Ｋ抑制劑的吡啶并［１，２－ａ］嘧啶酮類似物
WO2018108167A1 (zh) Cdk4/6抑制剂
WO2019062803A1 (zh) 作为a2a受体抑制剂的并环类衍生物
WO2018036469A1 (zh) Pde4抑制剂
WO2017177974A1 (zh) 用于治疗纤维化和炎性疾病的含杂原子环丁烷取代基的吡啶酮衍生物
WO2019056950A1 (zh) 噻吩并二氮杂卓衍生物及其应用
WO2021104488A1 (zh) 作为jak抑制剂的三并杂环类化合物及其应用
WO2018157820A1 (zh) 氮杂环丁烷衍生物
WO2019134661A1 (zh) 异吲哚啉酮及其衍生物作为csf-1r抑制剂
EP3988098B1 (en) Heterocyclo alkyl compounds used as ccr2/ccr5 antagonists
EP3719013B1 (en) Pyrimidine sulfamide derivative and preparation method and medical application thereof
WO2019134662A1 (zh) 作为csf-1r抑制剂的杂环化合物及其应用
TWI633107B (zh) 作為ｐａｒｐ抑制劑的稠合四或五環二氫二氮呯并咔唑酮
TW202126646A (zh) 作為蛋白激酶抑制劑的取代的吡咯並[2,3-b]吡啶及吡唑並[3,4-b]吡啶衍生物
JP2023549273A (ja) プロテインキナ－ゼ阻害剤としての置換されたピロロ［２，３－ｂ］ピリジン及びピラゾロ［３，４－ｂ］ピリジン誘導体
WO2018014867A1 (zh) 作为crth2抑制剂的三并环类化合物

Legal Events

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

Ref document number: 17877947

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019530756

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017877947

Country of ref document: EP

Effective date: 20190709