WO2018157820A1 - 氮杂环丁烷衍生物 - Google Patents

氮杂环丁烷衍生物 Download PDF

Info

Publication number
WO2018157820A1
WO2018157820A1 PCT/CN2018/077583 CN2018077583W WO2018157820A1 WO 2018157820 A1 WO2018157820 A1 WO 2018157820A1 CN 2018077583 W CN2018077583 W CN 2018077583W WO 2018157820 A1 WO2018157820 A1 WO 2018157820A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
phenyl
compound
cycloalkyl
Prior art date
Application number
PCT/CN2018/077583
Other languages
English (en)
French (fr)
Inventor
熊剑
谢程
陈新海
徐雄彬
张雪瑾
龚珍
黎健
陈曙辉
张爱明
江竹莲
张喜全
田心
Original Assignee
正大天晴药业集团股份有限公司
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
Priority to US16/489,282 priority Critical patent/US11014943B2/en
Priority to EP18760796.5A priority patent/EP3590944B1/en
Application filed by 正大天晴药业集团股份有限公司, 南京明德新药研发股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to SG11201907945YA priority patent/SG11201907945YA/en
Priority to AU2018228555A priority patent/AU2018228555B2/en
Priority to MX2019010108A priority patent/MX2019010108A/es
Priority to BR112019017844-9A priority patent/BR112019017844B1/pt
Priority to ES18760796T priority patent/ES2928298T3/es
Priority to CA3054459A priority patent/CA3054459A1/en
Priority to KR1020197028203A priority patent/KR102547709B1/ko
Priority to CN201880017090.1A priority patent/CN110461855B/zh
Priority to JP2019547081A priority patent/JP7083836B2/ja
Priority to EA201991932A priority patent/EA201991932A1/ru
Publication of WO2018157820A1 publication Critical patent/WO2018157820A1/zh
Priority to PH12019550154A priority patent/PH12019550154A1/en
Priority to IL268967A priority patent/IL268967B2/en
Priority to ZA2019/05646A priority patent/ZA201905646B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present application relates to a class of compounds for treating multiple myeloma or a pharmaceutically acceptable salt thereof, and to the use thereof in the manufacture of a medicament for the treatment of a disease associated with multiple myeloma.
  • MM Multiple myeloma
  • M protein monoclonal immunoglobulin or its fragment
  • Bortezomib is a reversible proteasome inhibitor that achieves the goal of treating multiple myeloma by promoting apoptosis of myeloma cells.
  • some patients with multiple myeloma have developed resistance to bortezomib. Therefore, there is still a need for new and safe drugs for the treatment of multiple myeloma.
  • the application provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof
  • Ring A is selected from C 3-6 cycloalkyl, phenyl or 5- to 10-membered heteroaryl;
  • n is selected from 0, 1, 2 or 3;
  • R 1 is each independently selected from halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 heteroalkyl or phenyl, wherein the C 1-3 alkyl, C 1-3 heteroalkane Each of the phenyl or phenyl is optionally substituted by 1, 2 or 3 R;
  • R 2 and R 3 are each independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 naphthenic a group -(CH 2 ) 1-3 - or phenyl-(CH 2 ) 1-3 - wherein the C 1-6 alkyl group, the C 1-6 heteroalkyl group, the C 3-6 cycloalkyl group, C 3-6 cycloalkyl-(CH 2 ) 1-3 - or phenyl-(CH 2 ) 1-3 - each optionally substituted by 1, 2 or 3 R;
  • R 2 , R 3 together with the carbon atom to which they are attached form a 3 to 6 membered ring;
  • R 4 is selected from C 1-6 alkyl or C 3-6 cycloalkyl - (CH 2) 1-3 -, wherein said C 1-6 alkyl or C 3-6 cycloalkyl - (CH 2) 1-3 - each optionally substituted by 1, 2 or 3 R;
  • R 5 is selected from H or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R;
  • Each R is independently selected from the group consisting of F, Cl, Br, I, OH, Me, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ;
  • hetero in the C 1-3 heteroalkyl group, the C 1-6 heteroalkyl group and the 5- to 10-membered heteroaryl group are each independently selected from -O-, -S-, -NH- or N. And in any of the above cases, the number of heteroatoms or groups containing heteroatoms is independently selected from 1, 2 or 3.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof, and a pharmaceutically acceptable An acceptable carrier, excipient or adjuvant.
  • the application provides a method of preventing or treating multiple myeloma comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometry thereof
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometry thereof
  • the isomer, or a pharmaceutical composition thereof is administered to an individual in need thereof.
  • the application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof, or a pharmaceutical composition thereof, for use in the preparation of Use in medicines for preventing or treating multiple myeloma.
  • the application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof, for use in the prevention or treatment of multiple myeloma , or a pharmaceutical composition thereof.
  • the application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof, or a pharmaceutical composition thereof, in the prophylaxis or treatment Use in multiple myeloma.
  • the application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof,
  • Ring A is selected from C 3-6 cycloalkyl, phenyl or 5- to 10-membered heteroaryl;
  • n is selected from 0, 1, 2 or 3;
  • R 1 is each independently selected from halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 heteroalkyl or phenyl, wherein the C 1-3 alkyl, C 1-3 heteroalkane Each of the phenyl or phenyl is optionally substituted by 1, 2 or 3 R;
  • R 2 and R 3 are each independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 naphthenic a group -(CH 2 ) 1-3 - or phenyl-(CH 2 ) 1-3 - wherein the C 1-6 alkyl group, the C 1-6 heteroalkyl group, the C 3-6 cycloalkyl group, C 3-6 cycloalkyl-(CH 2 ) 1-3 - or phenyl-(CH 2 ) 1-3 - each optionally substituted by 1, 2 or 3 R;
  • R 2 , R 3 together with the carbon atom to which they are attached form a 3 to 6 membered ring;
  • R 4 is selected from C 1-6 alkyl or C 3-6 cycloalkyl-(CH 2 ) 1-3 - wherein the C 1-6 alkyl or C 3-6 cycloalkyl-(CH 2 ) 1-3 - each optionally substituted by 1, 2 or 3 R;
  • R 5 is selected from H or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R;
  • Each R is independently selected from the group consisting of F, Cl, Br, I, OH, Me, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ;
  • hetero in the C 1-3 heteroalkyl group, the C 1-6 heteroalkyl group and the 5- to 10-membered heteroaryl group are each independently selected from -O-, -S-, -NH- or N. And in any of the above cases, the number of heteroatoms or groups containing heteroatoms is independently selected from 1, 2 or 3.
  • n is selected from 0, 1, or 2.
  • the term "hetero" in the C 1-3 heteroalkyl group and the C 1-6 heteroalkyl group are each independently selected from -O-, -S- or -NH-, and The term “hetero” in the 5- to 10-membered heteroaryl group is selected from N, -O- or -S-. In some embodiments of the present application, the term “hetero” in the C1-3 heteroalkyl and C1-6 heteroalkyl is -O-, and the term in the 5- to 10-membered heteroaryl. "Mi" is selected from N or -S-.
  • R 1 is each independently selected from halogen, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, or phenyl, wherein said C 1-3 alkane
  • the group, C 1-3 alkoxy or phenyl is each optionally substituted by 1, 2 or 3 R; preferably, R 1 is independently selected from halogen, OH, NH 2 , CN, C 1-3 alkane, respectively.
  • R 1 are each independently selected from halogen, OH, NH 2, CN, C 1-3 alkoxy, or phenyl optionally substituted with 1, 2 or 3 F C 1-3 alkyl group; even more preferably, R 1 is independently a C 1-3 alkyl group selected from halogen, CN, phenyl or optionally substituted with 3 F; most preferably, R 1 is independently selected from F, Cl, CN, phenyl or optionally 3 F substituted methyl groups.
  • R 1 is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, Where the Me, It is optionally substituted by 1, 2 or 3 R.
  • R 1 is independently selected from the group consisting of F, Cl, Br, I, CN, Me, or Where the Me or Optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and I substituents; preferably, R 1 is independently selected from F, Cl, Br, I, CN, Or Me optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br and I; further more preferably, R 1 is independently selected from the group consisting of F, Cl, Br, I, CN , Or Me optionally substituted by 1, 2 or 3 F; most preferably, R 1 is independently selected from the group consisting of F, Cl, Br, I, CN, Or Me optionally substituted by 3 F.
  • R 1 is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 .
  • R 1 is independently selected from the group consisting of F, Cl, CN, Or CF 3 .
  • Ring A is selected from phenyl or 5- to 10-membered heteroaryl.
  • Ring A is selected from cyclopropyl, phenyl, five-membered heteroaryl, six-membered heteroaryl, seven-membered heteroaryl, eight-membered heteroaryl, nine-membered heteroaryl or ten a heteroaryl group; preferably, ring A is selected from cyclopropyl, phenyl, five-membered heteroaryl, six-membered heteroaryl or nine-membered heteroaryl; more preferably, ring A is selected from cyclopropyl, benzene Base, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thienyl, pyrazolyl, imidazolyl or 1H-carbazolyl.
  • Ring A is selected from cyclopropyl, phenyl, pyridyl, pyrimidinyl, thiazolyl or pyridazinyl; more preferably, Ring A is selected from phenyl, pyridyl, pyrimidinyl, Thiazolyl or pyridazinyl.
  • Ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,4-oxadiazolyl, thiazolyl, imidazolyl or 1H-carbazolyl;
  • the ring A is selected from a phenyl group, a pyridyl group or a pyrimidinyl group; more preferably, the ring A is selected from a phenyl group.
  • the structural unit Selected from Further more preferably, the structural unit Selected from Most preferably, the structural unit Selected from
  • the structural unit From:
  • the structural unit From:
  • R 2 and R 3 are each independently selected from H, halo, OH, NH 2 , CN, C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkyl -OC 1-3 alkyl-, C 3-6 cycloalkyl-CH 2 - or phenyl-CH 2 - wherein C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkyl -OC 1-3 alkyl-, C 3-6 cycloalkyl-CH 2 - or phenyl-CH 2 - are each optionally substituted by 1, 2 or 3 R, or R 2 , R 3 and The carbon atoms to which they are bonded together form a 3- to 6-membered cycloalkyl group; preferably, R 2 and R 3 are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-3 alkoxy, C 1-3 Alkyl-OC 1-3 alkyl-, C 3-6 cycloalkyl-
  • R 3 is H
  • R 2 is selected from the group consisting of H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkyl -OC 1-3 alkyl-, C 3-6 cycloalkyl-CH 2 - or phenyl-CH 2 - wherein C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkyl -OC 1-3 alkyl-, C 3-6 cycloalkyl-CH 2 - or phenyl-CH 2 - are each optionally substituted by 1, 2 or 3 R; preferably, R 3 above is H, R 2 is selected from H, C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkyl-OC 1-3 alkyl-, C 3-6 cycloalkyl-CH 2 - or phenyl -CH 2 -, wherein C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkyl-OC 1-3 al
  • R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, Et, Me, Et, It is optionally substituted by 1, 2 or 3 R.
  • R 2 and R 3 are each independently selected from H, Me,
  • R 2 is selected from the group consisting of H, Me, And R 3 is H.
  • R 2 , R 3 and the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group.
  • R 4 is selected from C 1-6 alkyl or C 3-6 cycloalkyl-CH 2 - wherein C 1-6 alkyl or C 3-6 cycloalkyl-CH 2 - Each is optionally substituted by 1, 2 or 3 R; preferably, R 4 is selected from C 1-6 alkyl or C 3-6 cycloalkyl-CH 2 -; more preferably, R 4 is selected from C 1 -4 alkyl or C 3-6 cycloalkyl-CH 2 -; further more preferably, R 4 is selected from C 3-4 alkyl or C 3-4 cycloalkyl-CH 2 -; most preferably, R 4 is selected from C 4 alkyl or C 4 cycloalkyl-CH 2 -.
  • R 4 is selected from among them Each is optionally substituted by 1, 2 or 3 R; preferably, R 4 is selected from More preferably, R 4 is
  • R 5 is selected from H or C 1-3 alkyl; preferably, R 5 is selected from H, Me or Et; more preferably, R 5 is selected from H or Me; most preferably, R 5 is H.
  • each R is independently selected from the group consisting of F, Cl, Br, I, OH, Me, or NH 2 ; preferably, each R is independently selected from the group consisting of F, Cl, Br, OH, or Me; More preferably, each R is independently selected from F or OH.
  • the compound of formula (I) is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the present application also provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer or a geometric isomer thereof,
  • rings A, n, R 1 , R 2 and R 5 are as defined above.
  • the structural unit As defined above.
  • the present application also provides a compound of formula (III) or a compound of formula (IV), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer or a geometric isomer thereof,
  • n, R 1 , R 2 and R 5 are as defined above; and ring C is selected from cyclopropyl, five-membered heteroaryl or six-membered heteroaryl.
  • the present application also provides a compound of formula (V) or a compound of formula (VI), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof,
  • n, R 1 , R 2 and ring C are as defined above.
  • ring C is selected from the group consisting of cyclopropyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,4- Oxadiazolyl, thiazolyl, isothiazolyl, thienyl, pyrazolyl or imidazolyl; preferably, ring C is selected from cyclopropyl, pyridyl, pyrimidinyl, thiazolyl or pyridazinyl; more preferably, Ring C is selected from pyridinyl, pyrimidinyl, thiazolyl or pyridazinyl.
  • a structural unit Selected from in a compound of formula (IV) or a compound of formula (VI), a structural unit Selected from Preferably, the structural unit Selected from More preferably, the structural unit Selected from Most preferably, the structural unit Selected from
  • the present application also provides a compound of the formula (I-a) or formula (I-b), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a geometric isomer thereof,
  • ring A, n, R 1 , R 2 , R 3 , R 4 or R 5 is as defined above.
  • the structural unit As defined above.
  • the present application also provides a compound of formula (II-a) or formula (II-b), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a geometric isomer thereof,
  • rings A, n, R 1 , R 2 and R 5 are as defined above.
  • the structural unit As defined above.
  • the present application also provides a compound of the formula (III-a), formula (III-b), formula (IV-a) or (IV-b), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a geometrical difference thereof Structure,
  • n, R 1 , R 2 , R 5 and ring C are as defined above.
  • the structural unit As defined above.
  • the present application also provides a compound of the formula (V-a), formula (V-b), formula (VI-a) or (VI-b), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a geometric isomer thereof,
  • n, R 1 , R 2 and ring C are as defined above.
  • the structural unit As defined above.
  • the application also provides a compound selected from the group consisting of the following structural formulas, pharmaceutically acceptable salts thereof, tautomers thereof, stereoisomers thereof or geometric isomers thereof:
  • the compound of formula (I) is selected from the group consisting of
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof.
  • the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable adjuvant, carrier or diluent.
  • the present application provides a method of treating multiple myeloma in a mammal comprising administering to a mammal, preferably a human in need thereof, a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof , a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof, or a pharmaceutical composition thereof.
  • the present application provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof, or a pharmaceutical composition thereof, for use in the preparation thereof Use in the prevention or treatment of multiple myeloma drugs.
  • the present application provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or a geometric isomer thereof, or a pharmaceutical composition thereof, in the prophylaxis or Use in the treatment of multiple myeloma.
  • the present application provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or geometrical isomerism thereof for use in the prevention or treatment of multiple myeloma Body, or a pharmaceutical composition thereof.
  • the compounds of formula (I) of the present application can be prepared by one skilled in the art by the following general route and employing standard methods in the art:
  • the compound of the present application has a good antitumor effect on multiple myeloma and has good oral bioavailability, and has therapeutic potential for multiple myeloma resistant to bortezomib.
  • pharmaceutically acceptable is in the sense of those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • Dotted line in the structural unit or group in the present application Represents a covalent bond.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention prepared from a compound having a particular substituent found herein and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a sufficient amount of a base with such a compound.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonium or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a sufficient amount of an acid with such a compound.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts",
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the parent 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 present application 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 with 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, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid , hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthoic acid, isethionic acid, lactic acid, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxy Naphthoic acid, pantothenic acid, phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present application 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 free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of a prodrug.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the claimed compounds.
  • prodrugs can be converted to the claimed compounds by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the present application 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 present invention.
  • Certain compounds of the present application may have asymmetric carbon atoms (stereocenters) or double bonds. Thus, racemates, diastereomers, enantiomers, geometric isomers, and individual isomers are included within the scope of the present application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present application, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, All of these are within the scope of this application. Additional asymmetric carbon atoms may be present in the substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.
  • 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 one enantiomer of a compound of the present application 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 purity. 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 application 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). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable carrier means that the organism is not significantly irritating and does not impair the biological activity and properties of the active compound.
  • compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, lozenges, ointments, syrups, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, lozenges, ointments, syrups, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present application, a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, or permeable.
  • Preferred routes of administration are oral administration and injection administration.
  • the pharmaceutical composition of the present application can be prepared by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, and a freeze-drying method.
  • the pharmaceutical compositions of the present application are in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients or excipients known in the art. These excipients or excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, powders, granules, liquids, syrups, emulsions, gels, slurries, suspensions Etc., for oral administration to a patient.
  • Solid pharmaceutical compositions suitable for oral administration can be prepared by conventional methods of mixing, filling or tabletting.
  • an oral composition in solid form can be obtained by mixing the active compound with a solid excipient or excipient, optionally grinding the resulting mixture, if necessary, adding other suitable excipients or excipients, and then The mixture is processed into granules to give the core of a tablet or dragee.
  • suitable excipients or excipients include, but are not limited to, fillers, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions, emulsions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compound of the formula (I) of the present application can be administered daily at a dose of from 0.01 mg/kg body weight to 200 mg/kg body weight, administered in a single dose or in divided doses.
  • pharmaceutically acceptable carrier refers to any agent or carrier or medium that is capable of delivering an effective amount of the active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient.
  • Representative carriers include water, oils and minerals, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, suspending agents, tackifiers, transdermal enhancers and the like. Their reagents are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient or "auxiliary” 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.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing Or an amount of a compound of the present application that delays the onset of one or more symptoms of a particular disease, condition, or condition described herein.
  • the amount of a compound of the present application constituting a “therapeutically effective amount” will vary depending on the compound, the disease, the disease state or condition and its severity, the mode of administration, and the age of the mammal to be treated, but may be routinely Those skilled in the art will determine from their own knowledge and the present disclosure.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable e.g., R or R 1
  • its definition on each occurrence is independent.
  • the group may optionally be substituted at most by two R, and each case has an independent option;
  • Structural units Each of R 1 is independent and they may be the same or different.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of linking groups is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • C 3-6 cycloalkyl-(CH 2 ) 1-3 - includes C 3-6 cycloalkyl-CH 2 -, C 3-6 cycloalkyl-(CH 2 ) 2 - and C 3-6 cycloalkyl-(CH 2 ) 3 -; likewise, phenyl-(CH 2 ) 1-3 - includes phenyl-CH 2 -, phenyl-(CH 2 ) 2 - and phenyl-( CH 2 ) 3 -.
  • 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, such as in A-L-Z, where L represents a single bond, indicating that the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • the recited substituents do not indicate which atom is attached to the substituted group, such a substituent may be bonded through any of its atoms. For example, a pyridyl group as a substituent may be passed through any 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 middle 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 group containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and groups containing these heteroatoms, including, for example, oxygen.
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include monocyclic, bicyclic, bicyclic, spiro, bicyclic, fused or bridged rings. The number of ring atoms is generally defined as the number of members constituting the ring. For example, "5 to 7-membered ring” means a ring composed of 5 to 7 atoms. 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 heterocyclic” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 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 atoms may 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 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 atoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. 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, nonen
  • 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 a phenyl group, a naphthyl group 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, cyclohexyl, (cyclohexyl)methyl, cyclic A propylmethyl group, and a homologue or isomer of an atomic group such as n-pentyl, n-hexyl, n-heptyl or 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-propynyl and 3-propynyl, 3-butynyl, etc., and higher homologs And isomers.
  • 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 consisting of a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term denotes a stable straight chain, branched hydrocarbon radical or combination thereof, consisting of 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 atom is 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 suitable heterocycloalkyl or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl)
  • a heterocyclic alkynyl group, etc. by itself or in combination with other terms, denotes a cyclic “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.
  • heterocycloalkyl 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).
  • C 1-3 alkyl means an alkyl group having 1 to 3 carbon atoms ( For example, methyl, ethyl, n-propyl, isopropyl); for example, the term “ C1-6 alkyl” refers to an alkyl group containing from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl , 2-methylpentyl, etc.).
  • C 1-3 alkyl means an alkyl group having 1 to 3 carbon atoms ( For example, methyl, ethyl, n-propyl, isopropyl); for example, the term “ C1-6 alkyl” refers to an alkyl group containing from 1 to
  • a cycloalkyl group includes any stable monocyclic 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 containing 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 (F), chlorine (Cl), bromine (Br) or iodine (I) 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.
  • heteroalkyl is a straight or branched alkyl group which preferably has from 1 to 14 carbons, more preferably from 1 to 10 carbons, still more preferably from 1 to 6 carbons, most preferably from 1 to 1 in the chain. Three carbons, one or more of which are substituted by a hetero atom selected from the group consisting of S, O and N.
  • heteroalkyl groups include alkyl ethers, secondary alkyl amines and tertiary alkyl amines, amides, alkyl sulfides, and the like, including alkoxy groups, alkylthio groups, alkylamino groups; unless otherwise specified, C 1- 6 heteroalkyl groups include C 1, C 2, C 3 , C 4, C 5 heteroalkyl and C 6, for example, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino .
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and Alkoxy group of C 6 .
  • 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.
  • the aryl group preferably has 6 to 15 carbon atoms; more preferably 6 to 12 carbon atoms.
  • heteroaryl refers to an aryl group containing one to four heteroatoms.
  • the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction such as a nucleophilic substitution reaction.
  • representative leaving 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”, “carboxy protecting group”, “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions from occurring at the nitrogen position of the amino group.
  • 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-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl)
  • hydroxy protecting group refers to a protecting group suitable for preventing the side reaction of a hydroxyl group.
  • 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), Methoxybenzyl (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), Methoxybenzyl (PMB),
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the solvent used in the present application is commercially available.
  • This application uses 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 benzyloxycarbon
  • Mobile phase A: carbon dioxide; B: ethanol (containing 0.1% ammonia), elution gradient B%: 15% to 15%
  • Compound WX-193 is the second peak in high performance chiral liquid chromatography.
  • Mobile phase A: carbon dioxide; B: ethanol (containing 0.05% diethanolamine), elution gradient B%: 5% to 40%
  • N,N-Diisopropylethylamine (22.02 g, 170.40 mmol, 2.20 eq) was added to compound 3-1 (10 g, 77.46 mmol, 1.00 eq) and compound 3-2 (20.13 g, 77.46). Methyl, 1.00 eq) in acetonitrile (200 mL). The reaction mixture was stirred at 100 ° C for 16 hours then cooled to room temperature then added to ethyl acetate.
  • Mobile phase A: carbon dioxide; B: methanol, elution gradient B%: 30%-30%
  • the peak order of the compound WX-333 is the second peak appearing in the high performance chiral liquid chromatography.
  • the retention time of the compound WX-407 was 9.5 min in high performance liquid chromatography.
  • This experiment investigated the effect of compounds on cell proliferation by measuring the effect of compounds on cell viability in tumor cell line MM1.S in vitro.
  • MM1.S cells were seeded at a density of 7,000 cells per well into black 96-well cell culture plates, and then the plates were incubated overnight at 37 ° C, 5% CO 2 and 100% relative humidity incubator.
  • the test compound in DMSO solution was added to the cell culture well at a concentration (0.3-2000 nM), then the plate was returned to the incubator and a vehicle control (with DMSO added, no compound) and a blank control were set up.
  • the plates were incubated for 2 days in an incubator at 37 ° C, 5% CO 2 and 100% relative humidity.
  • RLU represents the relative luminescence intensity
  • WX-317 0.0320 WX-327 0.0242 WX-329 0.0115 WX-351 0.0459 WX-355 0.0288 WX-365 0.0906 WX-367 0.1831 WX-373 0.0267 WX-379 0.0240 WX-381 0.1194 WX-385 0.1045 WX-391 0.0054
  • Test compounds were incubated with CD-1 mice, SD rats, and human liver microsomes for stability assessment of test compounds.
  • Test Compound Solution 10 mM of the DMSO solution (5 ⁇ L) of the Example compound was added to DMSO (45 ⁇ L) in a mixed solvent of methanol and water (450 ⁇ L, volume ratio of methanol to water was 1:1) to prepare 100 ⁇ M.
  • Test compound solution 50 ⁇ L of 100 ⁇ M test compound solution was added to 450 ⁇ L of 100 mM potassium phosphate buffer to obtain a 10 ⁇ M test compound solution.
  • test compound solution 10 ⁇ M was pre-incubated with the microflora of the three species for 10 minutes, and then the reduced nicotinamide adenine dinucleotide phosphate (NADPH) regeneration system working solution was added to the incubation plate at each time point. The reaction was started, and finally, at 0, 5, 10, 20, 30, and 60 minutes, a stop solution (100% ACN) was added to the reaction plate to terminate the reaction. Test compounds were assayed by LC-MS/MS. The liver microsome stability test results of the test compounds are shown in Table 2.
  • H stands for human
  • R stands for rat
  • M stands for mouse
  • Test compounds were evaluated for cell membrane permeability on MDR1-MDCK II cells.
  • Papp A to B indicates the rate at which the compound enters the cell
  • Papp B to A indicates the rate at which the cell excludes the compound
  • Efflux Ratio Papp B to A/Papp A to B

Landscapes

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

Abstract

本申请公开了式(I)所示的化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，以及其在制备用于治疗或预防多发性骨髓瘤的药物中的用途。

Description

氮杂环丁烷衍生物
相关申请的引用
本申请要求于2017年02月28日向中华人民共和国知识产权局提交的申请号为201710112350.0的中国发明专利申请的权益，以及于2017年09月08日向中华人民共和国知识产权局提交的申请号为201710805883.7的中国发明专利申请的权益，在此将它们的全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及一类治疗多发性骨髓瘤的化合物或其药学上可接受的盐，以及其在制备用于治疗与多发性骨髓瘤相关的疾病的药物中的应用。
背景技术
多发性骨髓瘤(multiple myeloma,MM)是浆细胞恶性增殖性疾病，其特征是骨髓中克隆型浆细胞异常增生，破坏造血功能，刺激骨骼发生溶骨性损害，在血清和/或尿液中检查到单克隆免疫球蛋白或其片段(M蛋白)，临床表现为骨痛、贫血、高钙血症、肾功能损害、感染以及出血等。硼替佐米是一种可逆性蛋白酶体抑制剂，其通过促进骨髓瘤细胞凋亡达到治疗多发性骨髓瘤的目的。但是，在长期的治疗过程中，已有部分的多发性骨髓瘤患者出现对硼替佐米的耐药性。因此，仍然需要新的安全的治疗多发性骨髓瘤的药物。
发明概述
一方面，本申请提供了式(Ⅰ)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体
Figure PCTCN2018077583-appb-000001
其中，
环A选自C 3-6环烷基、苯基或5～10元杂芳基；
n选自0、1、2或3；
R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷基、C 1-3杂烷基或苯基，其中所述C 1-3烷基、C 1-3杂烷基或苯基各自任选地被1、2或3个R取代；
R 2和R 3分别独立地选自H、卤素、OH、NH 2、CN、C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、C 3-6环烷基-(CH 2) 1-3-或苯基-(CH 2) 1-3-，其中所述C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、C 3-6环烷基-(CH 2) 1-3-或苯基-(CH 2) 1-3-各自任选地被1、2或3个R取代；
或者，R 2、R 3和与它们相连的碳原子一起形成一个3～6元环；
R 4选自C 1-6烷基或C 3-6环烷基-(CH 2) 1-3-，其中所述C 1-6烷基或C 3-6环烷基-(CH 2) 1-3-各自任选地被1、2或3个R取代；
R 5选自H或任选地被1、2或3个R取代的C 1-3烷基；
每个R独立地选自F、Cl、Br、I、OH、Me、NH 2、NH(CH 3)或N(CH 3) 2；
其中所述C 1-3杂烷基、C 1-6杂烷基和5～10元杂芳基中的术语“杂”分别独立地选自-O-、-S-、-NH-或N；以及在任何一种上述情况下，杂原子或含有杂原子的基团的数目分别独立地选自1、2或3。
另一方面，本申请提供了药物组合物，其包含式(Ⅰ)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，以及药学上可接受的载体、赋形剂或辅料。
再一方面，本申请提供了预防或治疗多发性骨髓瘤的方法，其包括将式(Ⅰ)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体、或其药物组合物向有需要的个体给药。
再一方面，本申请提供了式(Ⅰ)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，或其药物组合物在制备用于预防或治疗多发性骨髓瘤的药物中的用途。
还一方面，本申请提供了用于预防或治疗多发性骨髓瘤的式(Ⅰ)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，或其药物组合物。
还一方面，本申请提供了式(Ⅰ)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，或其药物组合物在预防或治疗多发性骨髓瘤中的用途。
发明详述
本申请提供了式(Ⅰ)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，
Figure PCTCN2018077583-appb-000002
其中，
环A选自C 3-6环烷基、苯基或5～10元杂芳基；
n选自0、1、2或3；
R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷基、C 1-3杂烷基或苯基，其中所述C 1-3烷基、C 1-3杂烷基或苯基各自任选地被1、2或3个R取代；
R 2和R 3分别独立地选自H、卤素、OH、NH 2、CN、C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、C 3-6环烷基-(CH 2) 1-3-或苯基-(CH 2) 1-3-，其中所述C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、C 3-6环烷基-(CH 2) 1-3-或苯基-(CH 2) 1-3-各自任选地被1、2或3个R取代；
或者，R 2、R 3和与它们相连的碳原子一起形成一个3～6元环；
R 4选自C 1-6烷基或C 3-6环烷基-(CH 2) 1-3-，其中所述C 1-6烷基或C 3-6环烷基-(CH 2) 1-3-各自任选地被1、2或3个R取代；
R 5选自H或任选地被1、2或3个R取代的C 1-3烷基；
每个R独立地选自F、Cl、Br、I、OH、Me、NH 2、NH(CH 3)或N(CH 3) 2；
其中所述C 1-3杂烷基、C 1-6杂烷基和5～10元杂芳基中的术语“杂”分别独立地选自-O-、-S-、-NH-或N；以及在任何一种上述情况下，杂原子或含有杂原子的基团的数目分别独立地选自1、2或3。
本申请的一些实施方案中，n选自0、1或2。
本申请的一些实施方案中，所述C 1-3杂烷基和C 1-6杂烷基中的术语“杂”分别独立地选自-O-、-S-或-NH-，以及所述5～10元杂芳基中的术语“杂”选自N、-O-或-S-。本申请的一些实施方案中，所述C 1-3杂烷基和C 1-6杂烷基中的术语“杂”为-O-，以及所述5～10元杂芳基中的术语“杂”选自N或-S-。
本申请的一些实施方案中，R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基或苯基，其中所述C 1-3烷基、C 1-3烷氧基或苯基各自任选地被1、2或3个R取代；优选地，R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷氧基、苯基或任选地被1、2或3个独立地选自F、Cl、Br和I的取代基取代的C 1-3烷基；更优选地，R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷氧基、苯基或任选地被1、2或3个F取代的C 1-3烷基；进一步更优选地，R 1分别独立地选自卤素、CN、苯基或任选地被3个F取代的C 1-3烷基；最优选地，R 1分别独立地选自F、Cl、CN、苯基或任选地被3个F取代的甲基。
本申请的一些实施方案中，R 1分别独立地选自F、Cl、Br、I、OH、NH 2、CN、Me、
Figure PCTCN2018077583-appb-000003
其中所述Me、
Figure PCTCN2018077583-appb-000004
任选地被1、2或3个R取代。
本申请的一些优选实施方案中，R 1分别独立地选自F、Cl、Br、I、CN、Me或
Figure PCTCN2018077583-appb-000005
其中所述Me或
Figure PCTCN2018077583-appb-000006
任选地被1、2或3个独立地选自F、Cl、Br和I的取代基取代；优选地，R 1分别独立地选自F、Cl、Br、I、CN、
Figure PCTCN2018077583-appb-000007
或任选地被1、2或3个独立地选自F、Cl、Br和I的取代基取代的Me；进一步更优选地，R 1分别独立地选自F、Cl、Br、I、CN、
Figure PCTCN2018077583-appb-000008
或任选被1、2或3个F取代的Me；最优选地，R 1分别独立地选自F、Cl、Br、I、CN、
Figure PCTCN2018077583-appb-000009
或任选地被3个F取代的Me。
本申请的一些优选实施方案中，R 1分别独立地选自F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、
Figure PCTCN2018077583-appb-000010
Figure PCTCN2018077583-appb-000011
优选地，R 1分别独立地选自F、Cl、CN、
Figure PCTCN2018077583-appb-000012
或CF 3。
本申请的一些实施方案中，环A选自苯基或5～10元杂芳基。
本申请的一些实施方案中，环A选自环丙基、苯基、五元杂芳基、六元杂芳基、七元杂芳基、八元杂芳基、九元杂芳基或十元杂芳基；优选地，环A选自环丙基、苯基、五元杂芳基、六元杂芳基或九元杂芳基；更优选地，环A选自环丙基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、1,3,4-噁二唑基、噻唑基、异噻唑基、噻吩基、吡唑基、咪唑基或1H-吲唑基。
本申请的一些优选实施方案中，环A选自环丙基、苯基、吡啶基、嘧啶基、噻唑基或哒嗪基；更优选地，环A选自苯基、吡啶基、嘧啶基、噻唑基或哒嗪基。
本申请的一些优选实施方案中，环A选自苯基、吡啶基、嘧啶基、吡嗪基、1,3,4-噁二唑基、噻唑基、咪唑基或1H-吲唑基；优选地，环A选自苯基、吡啶基或嘧啶基；更优选地，环A选自苯基。
本申请的一些实施方案中，式(I)化合物的结构单元
Figure PCTCN2018077583-appb-000013
选自
Figure PCTCN2018077583-appb-000014
Figure PCTCN2018077583-appb-000015
本申请的一些优选实施方案中，结构单元
Figure PCTCN2018077583-appb-000016
选自
Figure PCTCN2018077583-appb-000017
Figure PCTCN2018077583-appb-000018
更优选地，结构单元
Figure PCTCN2018077583-appb-000019
选自
Figure PCTCN2018077583-appb-000020
Figure PCTCN2018077583-appb-000021
本申请的一些优选实施方案中，结构单元
Figure PCTCN2018077583-appb-000022
选自
Figure PCTCN2018077583-appb-000023
Figure PCTCN2018077583-appb-000024
本申请的一些具体实施方案中，结构单元
Figure PCTCN2018077583-appb-000025
选自
Figure PCTCN2018077583-appb-000026
本申请的一些更优选实施方案中，结构单元
Figure PCTCN2018077583-appb-000027
选自
Figure PCTCN2018077583-appb-000028
Figure PCTCN2018077583-appb-000029
Figure PCTCN2018077583-appb-000030
进一步更优选地，结构单元
Figure PCTCN2018077583-appb-000031
选自
Figure PCTCN2018077583-appb-000032
Figure PCTCN2018077583-appb-000033
Figure PCTCN2018077583-appb-000034
最优选地，结构单元
Figure PCTCN2018077583-appb-000035
选自
Figure PCTCN2018077583-appb-000036
Figure PCTCN2018077583-appb-000037
本申请的一些更优选实施方案中，结构单元
Figure PCTCN2018077583-appb-000038
选自
Figure PCTCN2018077583-appb-000039
Figure PCTCN2018077583-appb-000040
本申请的一些具体实施方案中，结构单元
Figure PCTCN2018077583-appb-000041
选自：
Figure PCTCN2018077583-appb-000042
Figure PCTCN2018077583-appb-000043
本申请的一些优选的具体实施方案中，结构单元
Figure PCTCN2018077583-appb-000044
选自：
Figure PCTCN2018077583-appb-000045
Figure PCTCN2018077583-appb-000046
Figure PCTCN2018077583-appb-000047
更优选地，结构单元
Figure PCTCN2018077583-appb-000048
选自：
Figure PCTCN2018077583-appb-000049
Figure PCTCN2018077583-appb-000050
Figure PCTCN2018077583-appb-000051
进一步更优选地，结构单元
Figure PCTCN2018077583-appb-000052
选自：
Figure PCTCN2018077583-appb-000053
Figure PCTCN2018077583-appb-000054
本申请的一些优选的具体实施方案中，结构单元
Figure PCTCN2018077583-appb-000055
选自：
Figure PCTCN2018077583-appb-000056
Figure PCTCN2018077583-appb-000057
本申请的一些实施方案中，R 2和R 3分别独立地选自H、卤素、OH、NH 2、CN、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个R取代，或者，R 2、R 3和与它们相连的碳原子一起形成一个3～6元环烷基；优选地，R 2和R 3分别独立地选自H、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个独立地选自F、Cl、Br、I和羟基的取代基取代；更优选地，R 2和R 3分别独立地选自H、C 1-6烷基、C 1-3烷氧基、C 3-6环烷基-CH 2-或苯基-CH 2-；进一步更优选地，R 2和R 3分别独立地选自H、C 1-6烷基、C 3-6环烷基-CH 2-或苯基-CH 2-；最优选地，R 2和R 3分别独立地选自H、Me、
Figure PCTCN2018077583-appb-000058
本申请的一些优选实施方案中，R 3为H，R 2选自H、卤素、OH、NH 2、CN、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个R取代；优选地，上述R 3为H，R 2选自H、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个独立地选自F、Cl、Br、I和羟基的取代基取代；更优选地，上述R 3为H，R 2选自H、C 1-6烷基、C 1-3烷氧基、C 3-6环烷基-CH 2-或苯基-CH 2-；更优选地，R 3为H，R 2选自H、C 1-6烷基、C 3-6环烷基-CH 2-或苯基-CH 2-；最优选地，R 3为H，R 2选自H、Me、
Figure PCTCN2018077583-appb-000059
本申请的一些实施方案中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me、Et、
Figure PCTCN2018077583-appb-000060
其中Me、Et、
Figure PCTCN2018077583-appb-000061
任 选地被1、2或3个R取代。
本申请的一些实施方案中，R 2和R 3分别独立地选自H、Me、
Figure PCTCN2018077583-appb-000062
Figure PCTCN2018077583-appb-000063
本申请的一些具体实施方案中，R 2选自H、Me、
Figure PCTCN2018077583-appb-000064
Figure PCTCN2018077583-appb-000065
以及R 3为H。
本申请的一些方案中，R 2、R 3和与它们相连的碳原子一起形成一个3～6元环烷基。
本申请的一些实施方案中，结构单元
Figure PCTCN2018077583-appb-000066
选自
Figure PCTCN2018077583-appb-000067
本申请的一些实施方案中，R 4选自C 1-6烷基或C 3-6环烷基-CH 2-，其中C 1-6烷基或C 3-6环烷基-CH 2-各自任选地被1、2或3个R取代；优选地，R 4选自C 1-6烷基或C 3-6环烷基-CH 2-；更优选地，R 4选自C 1-4烷基或C 3-6环烷基-CH 2-；进一步更优选地，R 4选自C 3-4烷基或C 3-4环烷基-CH 2-；最优选地，R 4选自C 4烷基或C 4环烷基-CH 2-。
本申请的一些实施方案中，R 4选自
Figure PCTCN2018077583-appb-000068
其中
Figure PCTCN2018077583-appb-000069
各自任选地被1、2或3个R取代；优选地，R 4选自
Figure PCTCN2018077583-appb-000070
更优选地，R 4为
Figure PCTCN2018077583-appb-000071
本申请的一些实施方案中，R 5选自H或C 1-3烷基；优选地，R 5选自H、Me或Et；更优选地，R 5选自H或Me；最优选地，R 5为H。
本申请的一些实施方案中，每个R独立地选自F、Cl、Br、I、OH、Me或NH 2；优选地，每个R独立地选自F、Cl、Br、OH或Me；更优选地，每个R独立地选自F或OH。
应当理解，本申请中的上述变量n、R、R 1、R 2、R 3、R 4、R 5以及环A可以以任意方式组合形成多个实施方案；以及上述变量R、R 2、R 3、R 4、R 5以及结构单元
Figure PCTCN2018077583-appb-000072
也可以以任意方式组合形成多个实施方案。
本申请的一些实施方案中，式(I)化合物选自：
Figure PCTCN2018077583-appb-000073
Figure PCTCN2018077583-appb-000074
或其药学上可接受的盐、其互变异构体、其立体异构体或几何异构体，
其中，R 1、R 2、R 3、R 4和R 5如上文所定义。
本申请还提供了式(II)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或几何异构体，
Figure PCTCN2018077583-appb-000075
其中，环A、n、R 1、R 2和R 5如上文所定义。
在一些实施方案中，结构单元
Figure PCTCN2018077583-appb-000076
如上文所定义。
本申请还提供了式(III)化合物或式(IV)化合物或其药学上可接受的盐、其互变异构体、其立体异构体或几何异构体，
Figure PCTCN2018077583-appb-000077
其中，n、R 1、R 2和R 5如上述上文所定义；以及环C选自环丙基、五元杂芳基或六元杂芳基。
本申请还提供了式(V)化合物或式(VI)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，
Figure PCTCN2018077583-appb-000078
其中n、R 1、R 2和环C如上述所定义。
本申请的一些实施方案中，在式(IV)化合物或式(VI)化合物中，环C选自环丙基、吡啶基、嘧啶基、吡嗪基、哒嗪基、1,3,4-噁二唑基、噻唑基、异噻唑基、噻吩基、吡唑基或咪唑基；优选地，环C选自环丙基、吡啶基、嘧啶基、噻唑基或哒嗪基；更优选地，环C选自吡啶基、嘧啶基、噻唑基或哒嗪基。
本申请的一些实施方案中，在式(IV)化合物或式(VI)化合物中，结构单元
Figure PCTCN2018077583-appb-000079
选自
Figure PCTCN2018077583-appb-000080
优选地，结构单元
Figure PCTCN2018077583-appb-000081
选自
Figure PCTCN2018077583-appb-000082
Figure PCTCN2018077583-appb-000083
更优选地，结构单元
Figure PCTCN2018077583-appb-000084
选自
Figure PCTCN2018077583-appb-000085
Figure PCTCN2018077583-appb-000086
最优选地，结构单元
Figure PCTCN2018077583-appb-000087
选自
Figure PCTCN2018077583-appb-000088
Figure PCTCN2018077583-appb-000089
本申请还提供了式(I-a)或式(I-b)化合物、其药学上可接受的盐、其立体异构体或其几何异构体，
Figure PCTCN2018077583-appb-000090
其中，环A、n、R 1、R 2、R 3、R 4或R 5如上文所定义。
在一些实施方案中，结构单元
Figure PCTCN2018077583-appb-000091
如上文所定义。
本申请还提供了式(II-a)或式(II-b)化合物、其药学上可接受的盐、其立体异构体或其几何异构体，
Figure PCTCN2018077583-appb-000092
其中，环A、n、R 1、R 2和R 5如上文所定义。
在一些实施方案中，结构单元
Figure PCTCN2018077583-appb-000093
如上文所定义。
本申请还提供了式(III-a)、式(III-b)、式(IV-a)或(IV-b)化合物、其药学上可接受的盐、其立体异构体或其几何异构体，
Figure PCTCN2018077583-appb-000094
Figure PCTCN2018077583-appb-000095
其中n、R 1、R 2、R 5和环C如上文所定义。
在一些实施方案中，结构单元
Figure PCTCN2018077583-appb-000096
如上文所定义。
本申请还提供了式(V-a)、式(V-b)、式(VI-a)或(VI-b)化合物、其药学上可接受的盐、其立体异构体或其几何异构体，
Figure PCTCN2018077583-appb-000097
其中n、R 1、R 2和环C如上述上文所定义。
在一些实施方案中，结构单元
Figure PCTCN2018077583-appb-000098
如上文所定义。
本申请还提供了选自以下结构式的化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体：
Figure PCTCN2018077583-appb-000099
Figure PCTCN2018077583-appb-000100
Figure PCTCN2018077583-appb-000101
Figure PCTCN2018077583-appb-000102
本申请的一些实施方案中，式(I)化合物选自：
Figure PCTCN2018077583-appb-000103
Figure PCTCN2018077583-appb-000104
Figure PCTCN2018077583-appb-000105
Figure PCTCN2018077583-appb-000106
Figure PCTCN2018077583-appb-000107
或其药学上可接受的盐。
另一方面，本申请还提供了药物组合物，其包含式(I)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料、载体或稀释剂。
另一方面，本申请还提供了治疗哺乳动物的多发性骨髓瘤的方法，包括对需要该治疗的哺乳动物，优选人，给予治疗有效量的式(I)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何 异构体，或其药物组合物。
另一方面，本申请还提供了式(I)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，或其药物组合物在制备用于预防或治疗多发性骨髓瘤的药物中的用途。
另一方面，本申请还提供了式(I)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，或其药物组合物在预防或治疗多发性骨髓瘤中的用途。
另一方面，本申请还提供了用于预防或治疗多发性骨髓瘤的式(I)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，或其药物组合物。
再一方面，本申请的式(I)化合物可以由本领域技术人员通过以下通用路线并采用本领域的标准方法来制备：
<通用路线1>
Figure PCTCN2018077583-appb-000108
<通用路线2>
Figure PCTCN2018077583-appb-000109
<通用路线3>
Figure PCTCN2018077583-appb-000110
<通用路线4>
Figure PCTCN2018077583-appb-000111
<通用路线5>
Figure PCTCN2018077583-appb-000112
<通用路线6>
Figure PCTCN2018077583-appb-000113
本申请的化合物对多发性骨髓瘤具有良好的抑瘤效果，并具有良好的口服生物利用度，对耐-硼替佐米的多发性骨髓瘤具有治疗的潜力。
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活性成分。
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。
本申请中的结构单元或者基团中的虚线
Figure PCTCN2018077583-appb-000114
表示共价键。
本申请中的某些结构单元或者基团中的共价键(例如，
Figure PCTCN2018077583-appb-000115
中的虚线
Figure PCTCN2018077583-appb-000116
)未与具体的原子连接时，表示该共价键可以与该结构单元或者基团中的任意原子连接，只要不违背价键连接规则。因此，例如，结构单元
Figure PCTCN2018077583-appb-000117
包括
Figure PCTCN2018077583-appb-000118
术语“药学上可接受的盐”是指本申请化合物的盐，由本申请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。当本申请的化合物中含有相对酸性的功能团时，可以通过用足够量的碱与这类化合物进行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盐、钾盐、钙盐、铵盐、有机铵盐或镁盐或类似的盐。当本申请的化合物中含有相对碱性的官能团时，可以通过用足够量的酸与这类化合物进行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))。本申请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加成盐或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的母体形式。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”属于本申请化合物的衍生物，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盐或有机酸盐、酸根比如羧酸的碱金属盐或有机盐等等。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，例如与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、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟萘酸、羟乙磺酸、乳酸、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、多聚半乳糖醛酸、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、单宁酸、酒石酸和对甲苯磺酸。
本申请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，经由游离的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，本申请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申请的化合物。此外，前药可以在体内环境中通过化学或生化方法被转化成本申请的化合物。
本申请的某些化合物可以以非溶剂化形式或溶剂化形式存在，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，都包含在本发明本申请的范围之内。
本申请的某些化合物可以具有不对称碳原子(立体中心)或双键。因此，外消旋体、非对映异构体、对映异构体、几何异构体和单个异构体都包括在本申请的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2018077583-appb-000119
表示立体中心的绝对构型，用波浪线
Figure PCTCN2018077583-appb-000120
表示立体中心的绝对构型之一(例如
Figure PCTCN2018077583-appb-000121
或
Figure PCTCN2018077583-appb-000122
之一)，用
Figure PCTCN2018077583-appb-000123
表示立体中心的相对构型。当本申请的化合物含有烯属双键或其它几何不对称中心时，除非另有规定，它们包括E和Z几何异构体。同样地，所有的互变异构形式均包括在本申请的范围之内。
本申请的化合物可以存在特定的几何异构体或立体异构体形式。本申请设想所有的这类化合物，包括互变异构体、顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、 (L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些都属于本申请的范围之内。烷基等取代基中可以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申请的范围之内。
可以通过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。如果想得到本申请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)。
本申请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)。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的载体”、“药学上可接受的赋形剂”或者“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些载体、赋形剂或辅料。合适的载体、赋形剂或辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括/包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、锭剂、膏剂、糖浆剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
本申请化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体或其药物组合物的典型的给药途径包括但不限于口服、直肠、透黏膜、局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下和静脉内给药。优选的给药途径是口服给药和注射给药。
本申请的药物组合物可以采用本领域已知的方法制备，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法和冷冻干燥法等。
在一些实施方案中，本申请的药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料或赋形剂混合来配制该药物组合物。这些辅料或赋形剂能使本申请的化 合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、粉剂、颗粒剂、液体、糖浆剂、乳剂、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备适于口服给药的固体药物组合物。例如，可通过下述方法获得固体形式的口服组合物：将活性化合物与固体辅料或赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料或赋形剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。合适的辅料或赋形剂包括但不限于：填充剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
本申请的药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂、乳剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本申请的式(Ⅰ)化合物可以以0.01mg/kg体重到200mg/kg体重的剂量进行每天给药，以单独剂量或分开剂量的形式施用。
术语“药学上可接受的载体”是指能够递送本申请的有效量的活性物质、不干扰该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试剂或载体或介质。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、助悬剂、增粘剂、透皮促进剂等。它们的试剂为化妆品领域或局部药物领域的技术人员所熟知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”或“辅料”通常是指配制有效的药物组合物所需要的载体、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。对于本申请中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或疾病状态，但尚未被诊断为已患有该疾病或疾病状态时；
(ii)抑制疾病或疾病状态，即，遏制其发展；
(iii)缓解疾病或疾病状态，即，使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗或预防特定疾病、疾病状态或病症，(ii)减轻、改善或消除特定 疾病、疾病状态或病症的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、疾病状态或病症的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病、疾病状态或病症及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“任选的”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
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，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。当取代基为氧代(即＝O)时，意味着两个氢原子被取代。氧代不会发生在芳香基上。术语“任选地被取代的”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或R 1)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；再如，结构单元
Figure PCTCN2018077583-appb-000124
中的每一个R 1都是独立的，它们可以相同也可以不同。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。
当连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
除非另有规定，C 3-6环烷基-(CH 2) 1-3-包括C 3-6环烷基-CH 2-、C 3-6环烷基-(CH 2) 2-和C 3-6环烷基-(CH 2) 3-；同样的，苯基-(CH 2) 1-3-包括苯基-CH 2-、苯基-(CH 2) 2-和苯基-(CH 2) 3-。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中，L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018077583-appb-000125
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的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，则其连接方向是任意的，例如，
Figure PCTCN2018077583-appb-000126
中连接基团L为-M-W-，此时-M-W-既可以按照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 PCTCN2018077583-appb-000127
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 PCTCN2018077583-appb-000128
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(即含有杂原子的基团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的基团，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-，以及任选地被取代的-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、双环、联环、螺环、并环、稠合环或桥环。环原子的数目通常被定义为组成环的成员的数目，例如，“5～7元环”是指由5～7个原子组成环。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元杂环基”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。氮原子和硫原子可任选被氧化(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)。氮原子和硫原子可任选被氧化(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。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、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、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、异噁唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、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、酚噁嗪基、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、吡啶并噁唑、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、噻吩并噁唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯基、萘基等。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、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叁键，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-丙炔基和3-丙炔基，3-丁炔基等，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，由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，由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，其中氮原子和硫原子任选地被氧化，氮原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环状的“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。杂环烃基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等；例如，术语“C 1-3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、正丙基、异丙基)；例如，术语“C 1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。
除非另有规定，环烷基包括任何稳定的单环状或多环状烃基，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-碳叁键，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”或“卤素”本身或作为另一取代基的一部分表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基和五氯乙基。
术语“杂烷基”是直链或者支链烷基，其在链中优选具有1至14个碳、更优选1至10个碳，进一步更优选为1至6个碳，最优选为1至3个碳，其中一个或多个碳被选自S、O和N的杂原子取代。示例性杂烷基包括烷基醚、仲烷基胺和叔烷基胺、酰胺、硫醚(alkyl sulfide)等，包括烷氧基、烷硫基、烷氨基；除非另有规定，C 1-6杂烷基包括C 1、C 2、C 3、C 4、C 5和C 6的杂烷基，例如C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基。
术语“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。芳基优选地具有6-15个碳原子；更优选地具有6-12个碳原子。
术语“杂芳基”是指含有一个至四个杂原子的芳基。在一个示范性实例中，杂原子选自B、N、O和S，其中氮原子和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。
芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、噁唑基、苯基-噁唑基、异噁唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、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(例如亲核取代反应)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”、“羧基保护基”“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适用于阻止氨基的氮位上发生副反应的保护基团。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”是指适用于阻止羟基发生副反应的保护基。代表性的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。
本申请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申请的实施例。
本申请所使用的溶剂可经市售获得。本申请采用下述缩略词：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，是一种氨基保护基团；BOC代表叔丁氧羰基，是一种氨基保护基团；HOAc/AcOH代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二碳酸二叔丁酯；TFA代表三氟乙酸；FA代表甲酸；ACN代表乙腈；Hepes代表4-(2-羟乙基)-1-哌嗪乙磺酸；HBSS代表Hank's平衡盐溶液；DIPEA/DIEA代表二异丙基乙胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表四丁基氟化铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基氨基锂；IPA代表异丙醇；DEA代表二乙胺；DCE代表二氯乙烷；TMSCl代表三甲基氯硅烷；TBTU代表O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸；TEA代表三乙胺。
市售化合物采用供应商目录名称。
实施例
下面通过实施例对本申请进行详细描述，但并不意味着对本申请任何不利限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
参考例1：片段BB-1
Figure PCTCN2018077583-appb-000129
合成路线：
Figure PCTCN2018077583-appb-000130
步骤1：化合物BB-1-2的合成
在冰浴下向化合物BB-1-1(50.00g,344.59mmol,45.05mL,1.00eq)的DCM(300.00mL)溶液中加入环己胺(68.35g,689.18mmol,78.56mL,2.00eq)和氯化钙(38.24g,344.59mmol,1.00eq)。将反应混合物升温，并在室温下搅拌12小时，然后过滤。滤液经减压浓缩得到粗产品，然后利用甲醇(50mL)进行重结晶，得到化合物BB-1-2。
步骤2：化合物BB-1-3的合成
在冰浴下向N,N,N',N'-四甲基甲二胺(2.55g,24.96mmol,3.40mL,1.10eq)的DCE(50.00mL)溶液中滴加乙酰氯(1.23g,24.96mmol,1.10eq)。将反应混合物在0℃下搅拌1小时，然后将化合物BB-1-2(5.00g,22.69mmol,1.00eq)加入到此反应混合物中。将所得反应混合物升至室温，并继续搅拌12小时，然后减压浓缩得到粗产品，经硅胶柱色谱法(流动相：二氯甲烷：甲醇＝50:1～20:1)纯化得到化合物BB-1-3。
步骤3：化合物BB-1-6的合成
在室温下向化合物BB-1-4(25.00g,290.26mmol,31.65mL,1.20eq)的DCM(600.00mL)溶液中加入化合物BB-1-5(30.00g,247.52mmol,1.02eq)、无水硫酸镁(145.58g,1.21mol,5.00eq)和对甲基苯磺酸(6.08g,24.19mmol,0.10eq)。反应混合物加热至40℃，并继续搅拌12小时，然后过滤。滤液经减压浓缩得到粗产品，经硅胶柱色谱法(流动相：石油醚：乙酸乙酯＝100:1～20:1)纯化得到化合物BB-1-6。
步骤4：化合物BB-1-7的合成
在室温下向化合物BB-1-6(38.00g,200.72mmol,1.00eq)的甲苯(300.00mL)溶液中加入双联频哪醇硼酸酯(56.07g,220.79mmol,1.10eq)、化合物BB-1-3(2.70g,10.04mmol,0.05eq)和叔丁醇钠(5.79g,60.22mmol,0.30eq)。反应混合物在氮气的保护下室温搅拌96小时，然后减压浓缩得到粗产品，经硅 胶柱色谱法(流动相：石油醚：乙酸乙酯＝100:1～20:1)纯化得到化合物BB-1-7。
步骤5：化合物BB-1的合成
在室温下向化合物BB-1-7(46.00g,144.97mmol,1.00eq)的二氧六环(120.00mL)溶液中加入盐酸的二氧六环溶液(4M,80.00mL,2.21eq)。反应混合物在室温搅拌12小时，然后减压浓缩得到粗产品。向粗产品中加入石油醚和乙酸乙酯的混合溶剂(石油醚：乙酸乙酯＝5：1,100mL)，搅拌15分钟，过滤，滤饼用甲基叔丁基醚(100mL)洗涤，得到化合物BB-1。 1H NMR(400MHz,DMSO-d6):δ7.97(s,3H),2.62-2.66(m,1H),1.51-1.72(m.,1H),1.43-1.50(m.,2H),1.23(s,12H),0.85(d,J＝6.4Hz,6H)。
实施例1
Figure PCTCN2018077583-appb-000131
合成路线：
Figure PCTCN2018077583-appb-000132
步骤1：化合物1-2的合成：
在0℃下向化合物1-1(15.00g,74.55mmol,1.00eq)和甲醇(150.00mL)的混合溶液中加入TMSCl(40.49g,372.75mmol,47.08mL,5.00eq)，然后将反应混合物在氮气保护下室温搅拌12小时。减压浓缩反应混合物，得到粗产品，即化合物1-2。 1HNMR:(400MHz,METHANOL-d 4)δ5.18(t,J＝9.03Hz,1H),4.15(q,J＝9.29Hz,1H),3.88-4.00(m,1H),3.79-3.86(m,3H),2.60-2.87(m,1H),2.60-2.87(m,1H)。
步骤2：化合物1-3的合成：
在室温下向对氟苯硼酸(2.21g,15.83mmol,1.20eq)的乙腈(35.00mL)溶液中加入化合物1-2(2.00g,13.19mmol,1.00eq,盐酸盐)、4A分子筛(1.00g)、Cu(OAc) 2(2.64g,14.51mmol,1.10eq)和TEA(5.34g,52.76mmol,7.32mL,4.00eq)。将反应混合物加热至80℃，并继续搅拌12小时。过滤反应混合物，滤液浓缩，所得残渣经硅胶柱色谱法(流动相：石油醚:乙酸乙酯＝10:1)纯化，得到化合物1-3。 1HNMR:(400 MHz,CHLOROFORM-d)δ6.87-6.97(m,2H),6.44-6.52(m,2H),4.45(dd,J＝7.65,8.66Hz,1H),4.00(ddd,J＝3.76,6.78,8.53Hz,1H),3.82(s,3H),3.62-3.71(m,1H),2.49-2.69(m,2H)。MS(ESI)m/z:210.0[M+1]。
步骤3：化合物1-4的合成：
在冰浴下向化合物1-3(400.00mg,1.91mmol,1.00eq)的甲醇(2.00mL)、四氢呋喃(2.00mL)和水(1.00mL)的混合溶液中加入LiOH.H 2O(401.11mg,9.56mmol,5.00eq)。将反应混合物在室温下搅拌1小时，然后用1N的稀盐酸调节至pH＝3。浓缩混合液，乙酸乙酯萃取，合并有机相并浓缩，得到粗产品化合物1-4，直接用于下一步反应。MS(ESI)m/z:195.9[M+1]。
步骤4：化合物1-5的合成：
在-10℃下向化合物1-4(370.00mg,1.90mmol,1.00eq)的DMF(5.00mL)溶液中加入苯丙氨酸甲酯盐酸盐(491.75mg,2.28mmol,1.20eq)、TBTU(732.06mg,2.28mmol,1.20eq)和DIEA(982.22mg,7.60mmol,1.33mL,4.00eq)。将反应混合物在-10℃至0℃下搅拌1小时，然后向反应混合物中加入饱和氯化铵水溶液(10mL)。水相经乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，并浓缩，得到的粗产物经硅胶柱色谱法(流动相：石油醚:乙酸乙酯＝1:1)纯化，得到化合物1-5。 1HNMR:(400MHz,CHLOROFORM-d)δ7.21-7.33(m,4H),7.13-7.19(m,2H),6.87-6.95(m,2H),6.38-6.46(m,2H),4.88-4.96(m,1H),4.20(dd,J＝7.78,9.03Hz,1H),3.82(ddd,J＝3.39,6.96,8.47Hz,1H),3.71(s,3H),3.60-3.67(m,1H),3.29(dd,J＝5.65,13.93Hz,1H),3.07(dd,J＝7.78,14.05Hz,1H),2.45-2.56(m,1H),2.03-2.17(m,1H)。MS(ESI)m/z:357.1[M+1]
步骤5：化合物1-6的合成
在室温下向化合物1-5(500.00mg,1.40mmol,1.00eq)的THF(2.00mL)、MeOH(2.00mL)和H 2O(1.00mL)的混合溶液中加入LiOH.H 2O(293.72mg,7.00mmol,5.00eq)。将反应混合物在室温下搅拌12小时，然后用1N的稀盐酸调节至pH＝3。浓缩混合液，乙酸乙酯萃取，合并有机相并浓缩，得到粗产品化合物1-6，直接用于下一步反应。MS(ESI)m/z:343.1[M+1]。
步骤6：化合物1-7的合成
在-10℃下向化合物1-6(250.00mg,730.23μmol,1.00eq)的DMF(5.00mL)溶液中加入化合物BB-1(218.70mg,876.27μmol,1.20eq,HCl)、TBTU(304.80mg,949.29μmol,1.30eq)和DIEA(377.50mg,2.92mmol,510.13μL,4.00eq)。将反应混合物在-10℃至0℃下搅拌1小时，然后向反应混合物中加入饱和氯化铵水溶液(10mL)。水相经乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，并浓缩，得到粗产品化合物1-7。MS(ESI)m/z:538.3[M+1]。
步骤7：化合物WX-193的合成
在冰浴下向化合物1-7(390.00mg,725.62μmol,1.00eq)的甲醇(5.00mL)溶液中加入异丁基硼酸(517.79mg,5.08mmol,7.00eq)和HCl(1M,51.87μL,2.00eq)水溶液。将反应混合物升至室温，并继续搅 拌4小时。减压浓缩反应混合物，得粗品，然后经制备HPLC(0.225％FA)分离纯化，随后经SFC分离纯化，得到化合物WX-193。 1HNMR:(400MHz,METHANOL-d 4)δ7.33-7.14(m,5H),6.86(br t,J＝8.7Hz,2H),6.63-6.45(m,2H),4.77(br t,J＝8.0Hz,1H),4.66-4.58(m,1H),4.52-4.41(m,1H),3.17-2.97(m,4H),2.65(br t,J＝7.5Hz,1H),2.24-1.98(m,2H),1.34(dt,J＝6.7,13.2Hz,1H),1.13(br t,J＝7.4Hz,2H),0.83(br t,J＝6.7Hz,6H)。MS(ESI)m/z:(M-17)438.2。
SFC分离方法：
色谱柱：AD 250mm×30mm，5μm
流动相：A：二氧化碳；B：乙醇(含0.1％氨水)，洗脱梯度B％:15％～15％
流速：50mL/min
柱温：40℃
化合物WX-193在高效手性液相柱色谱中为第二个峰。
化合物WX-268、WX-301、WX-351、WX-355、WX-365、WX-373、WX-381和WX-385均采用相同的方法合成得到，分离条件如下：
Figure PCTCN2018077583-appb-000133
Figure PCTCN2018077583-appb-000134
Figure PCTCN2018077583-appb-000135
实施例2
Figure PCTCN2018077583-appb-000136
合成路线：
Figure PCTCN2018077583-appb-000137
步骤1：化合物2-2的合成
在室温下向化合物1-2(1.00g,6.60mmol,1.00eq)和2-氯-4-苯基-嘧啶(1.26g,6.60mmol,1.00eq)的EtOH(20.00mL)溶液中加入DIPEA(2.56g,19.80mmol,3.46mL,3.00eq)和Na 2CO 3(2.10g,19.80mmol,3.00eq)。将反应混合物加热到40℃，并搅拌12小时。然后，减压旋蒸除去溶剂，加入水(20mL)稀释残余物，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。残余物经制备色谱法分离(流动相：石油醚/乙酸乙酯＝5/1)，得到化合物2-2。MS(ESI)m/z:269.9[M+1]。
步骤2：化合物2-3的合成
在室温下向化合物2-2(150.00mg,0.56mmol,1.00eq)的MeOH(3.00mL)和H 2O(0.50mL)的混合溶液中加入LiOH.H 2O(23.37mg,0.57mmol,1.00eq)。将反应混合物在室温下搅拌4小时，然后用1N的稀盐酸调节pH至6-7，浓缩混合液，得到粗产品化合物2-3，直接用于下一步反应。MS(ESI)m/z:255.9[M+1]。
步骤3：化合物2-4的合成
在-20℃下向化合物2-3(150.00mg,0.59mmol,1.00eq)的DMF(2.00mL)溶液中加入苯丙氨酸甲酯盐酸盐(126.37mg,0.71mmol,1.20eq)、TBTU(377.34mg,1.18mmol,2.00eq)和DIPEA(303.77mg,2.35mmol,0.41mL,4.00eq)。将反应混合物在-20℃至0℃下搅拌2小时，然后向反应混合物中加入水(10mL)。水相经乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，经无水硫酸钠干燥，过滤，浓缩，得到粗产物，经制备色谱法分离(流动相：石油醚:乙酸乙酯＝2:1)纯化，得到化合物2-4。
步骤4：化合物2-5的合成
在室温下向化合物2-4(250.00mg,600.28μmol,1.00eq)的水(1.00mL)和MeOH(2.00mL)的混合溶液中加入LiOH.H 2O(75.56mg,1.80mmol,3.00eq)，在室温下搅拌反应混合物12小时，然后用1N的稀盐酸调节至pH＝3左右。浓缩混合液，乙酸乙酯萃取，合并有机相并浓缩，得到粗产品化合物2-5，直接用于下一步反应。MS(ESI)m/z:403.5[M+1]。
步骤5：化合物2-6的合成
在-10℃下向化合物2-5(260.00mg,646.06μmol,1.00eq)的DMF(5.00mL)溶液中加入化合物BB-1(193.49mg,775.27μmol,1.20eq)、TBTU(311.15mg,969.09μmol,1.50eq)和DIPEA(333.99mg,2.58mmol,451.33μL,4.00eq)。将反应混合物在-10℃至0℃下搅拌1小时，然后向反应混合物中加入饱和氯化铵水溶液(10mL)，水相经乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到粗产品化合物2-6。MS(ESI)m/z:599.2[M+1]。
步骤6：化合物WX-174的合成
在0℃下向化合物2-6(380.00mg,634.88μmol,1.00eq)的MeOH(3.00mL)溶液中加入异丁基硼酸(478.92mg,4.70mmol,7.40eq)和HCl(1M,1.27mL,2.00eq)水溶液。将反应混合物在0℃至20℃下搅拌1小时，然后减压浓缩得到粗品，经制备HPLC(0.225％FA)分离，得到化合物WX-174。 1HNMR(400MHz,METHANOL-d4)δ8.38(br d,J＝5.3Hz,1H),8.21-8.03(m,2H),7.59-7.45(m,3H),7.36-7.05(m,6H),4.20-3.95(m,2H),3.23-2.93(m,2H),2.67-2.44(m,2H),2.23(br s,1H),1.49-1.07(m,3H),0.83(br t,J＝6.0Hz,6H)。MS(ESI)m/z:497.9[M-17]。
WX-174的SFC分析方法：
色谱柱：AS 150mm×4.6mm，5μm
流动相：A：二氧化碳；B：乙醇(含0.05％二乙醇胺)，洗脱梯度B％:5％～40％
流速：3mL/min
柱温：40℃
化合物WX-174在高效手性液相柱色谱中的保留时间为2.592min。
化合物WX-260，WX-306，WX-308，WX-311，WX-313，WX-317，WX-319，WX-327，WX-329，WX-367，WX-379，WX-387和WX-393均采用相同的方法合成得到，分离条件如下：
Figure PCTCN2018077583-appb-000138
Figure PCTCN2018077583-appb-000139
Figure PCTCN2018077583-appb-000140
Figure PCTCN2018077583-appb-000141
实施例3
Figure PCTCN2018077583-appb-000142
合成路线：
Figure PCTCN2018077583-appb-000143
步骤1：化合物3-3的合成
在室温下将N,N-二异丙基乙胺(22.02g，170.40mmol,2.20eq)加入到含有化合物3-1(10g,77.46mmol,1.00eq)和化合物3-2(20.13g,77.46mmol,1.00eq)的乙腈(200mL)溶液中。将反应混合物在100℃下搅拌16小时，然后冷却到室温，随后加入到乙酸乙酯中。有机层分别用水和饱和食盐水洗涤，用无水硫酸钠干燥，过滤。滤液浓缩后经硅胶柱色谱法(流动相：石油醚:乙酸乙酯＝10:1)纯化，得到化合物3-3。MS(ESI)m/z:227.9[M+1]。
步骤2：化合物3-4的合成
在0℃下向化合物3-3(7.2g,31.69mmol,1.00eq)的甲醇(20mL)、四氢呋喃(20mL)和水(10mL)的混合溶液中加入LiOH.H 2O(6.65g,158.45mmol,5.00eq)。将反应混合物在室温下搅拌1小时，然后减压浓缩，并用水和乙酸乙酯稀释，分液。水层用1N盐酸调节至pH＝6，然后用乙酸乙酯萃取。合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤。滤液浓缩得到化合物3-4，直接用于下一步反应。MS(ESI)m/z:213.9[M+1]。
步骤3：化合物3-5的合成
在-10℃下向化合物3-4(1.5g,7.04mmol,1.00eq)的二氯甲烷(50mL)溶液中加入甘氨酸甲酯盐酸盐(1.06g,8.44mmol,1.20eq,盐酸盐)、TBTU(2.71g,8.44mmol,1.20eq)和N,N-二异丙基乙胺(3.64g,28.15mmol,4.90mL,4.00eq)。将反应混合物在-10℃至0℃下搅拌3小时，然后用水(40mL)稀释，并用二氯甲烷萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤。滤液浓缩后经硅胶柱色谱法(流动相：石油醚:乙酸乙酯＝5:1)纯化，得到化合物3-5。MS(ESI)m/z:284.9[M+1]
步骤4：化合物3-6的合成：
在0℃下向化合物3-5(0.5g,1.76mmol,1.00eq)的四氢呋喃(2mL)、甲醇(2mL)和水(1mL)的混合溶液中加入LiOH.H 2O(369.03mg,8.79mmol,5.00eq)。将反应混合物在0℃至20℃下搅拌2小时，然后浓缩，并用水(3mL)稀释，分液。水层用1N盐酸调节至pH＝6，并用乙酸乙酯萃取。合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥，过滤。滤液浓缩得到化合物3-6，直接用于下一步反应。MS(ESI) m/z:270.9[M+1]
步骤5：化合物3-8的合成
在-10℃下向化合物3-6(0.26g,962.14μmol,1.00eq)、化合物3-7(437.84mg,1.15mmol,1.20eq)和TBTU(370.71mg,1.15mmol,1.20eq)的二氯甲烷(10mL)溶液中加入N,N-二异丙基乙胺(273.56mg,2.12mmol,2.20eq)。将反应混合物缓慢升至室温，并继续搅拌2小时，然后将反应混合物加入到水(10mL)中稀释，并用二氯甲烷萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤。滤液浓缩后经硅胶柱色谱法纯化(流动相：石油醚:乙酸乙酯＝1:1)，得到化合物3-8。MS(ESI)m/z:518.2[M+1]
步骤6：化合物WX-333的合成
在0℃向化合物3-8(0.17g,328.56μmol,1.00eq)的甲醇(4mL)和正己烷(6mL)的混合溶液中加入异丁基硼酸(234.45mg,2.30mmol,7.00eq)和1M HCl(1.31mL,4.00eq)。将反应混合物缓慢升温至室温，并继续搅拌12小时，然后减压浓缩得到残留物。残留物经制备HPLC纯化，再经SFC分离，得到化合物WX-333。 1H NMR(400MHz,METHANOL-d4)δ6.83(br s,2H),6.61(br s,1H),4.49(br s,1H),4.10(br s,3H),3.84(br s,1H),2.75(br s,1H),2.59(br s,1H),2.48(br s,1H),1.62(br s,1H),1.30(br s,2H),0.92(br s,6H)。MS(ESI)m/z:366.1[M-17].
WX-333的制备HPLC分离方法：
色谱柱：Xtimate C18 150×25mm，5μm；
流动相：水(0.225％FA)-MeOH
保留时间：9.5min
WX-333的制备SFC分离方法：
色谱柱：C2 250mm×30mm,10μm
流动相：A：二氧化碳；B：甲醇，洗脱梯度B％:30％-30％
流速：60mL/min
化合物WX-333的出峰顺序为高效手性液相柱色谱中出现的第二个峰。
化合物WX-391采用相同的方法合成得到，分离条件如下：
Figure PCTCN2018077583-appb-000144
Figure PCTCN2018077583-appb-000145
实施例4
Figure PCTCN2018077583-appb-000146
合成路线：
Figure PCTCN2018077583-appb-000147
步骤1：化合物4-3的合成：
向化合物4-2(4.37g,24.68mmol,2.84mL,1.00eq)的DMSO(40mL)溶液中加入化合物1-2(5g,32.98mmol,1.34eq)和DIEA(9.57g,74.03mmol,3.00eq)。将反应混合物加热至110℃并继续搅拌3小时，然后向反应混合物中加入水(20mL)。水相经乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残留物经硅胶柱色谱法纯化(流动相：石油醚:乙酸乙酯＝1:0-5:1)，得到化合物4-3。MS(ESI)m/z:272.9[M+1]。
步骤2：化合物4-4的合成
在室温下，向化合物4-3(5.2g,19.10mmol,1.00eq)的THF(50mL)溶液中加入10％Pd/C(1g,9.55mmol,0.5eq)。将反应混合物在H 2(15psi)下反应12小时，然后过滤。浓缩滤液，残留物经硅胶柱色谱 法纯化(流动相：石油醚:乙酸乙酯＝1:0-1:1)，得到化合物4-4。MS(ESI)m/z:242.9[M+1]。
步骤3：化合物4-5的合成
在0℃下向化合物4-4(3.2g,13.21mmol,1.00eq)的乙醇(30.00mL)溶液中加入氟硼酸(7.73g,42.28mmol,含量48％,3.20eq)和亚硝酸异戊酯(1.70g,14.53mmol,1.10eq)。将反应混合物在0℃下搅拌1.5小时，然后加入水(20mL)，用乙酸乙酯萃取。合并有机相，经饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残留物经硅胶柱色谱法纯化(流动相：石油醚:乙酸乙酯＝1:0-3:1)，得到化合物4-5。MS(ESI)m/z:228.3[M+1]。
步骤4：化合物4-6的合成
在0℃下向化合物4-5(1.1g,4.84mmol,1.00eq)的THF(4.00mL)、MeOH(4.00mL)和H 2O(2.00mL)的混合溶液中加入LiOH.H 2O(1.02g,24.21mmol,5.00eq)。将反应混合物缓慢升温至室温，并继续搅拌1小时，然后将反应混合物用1N的稀盐酸调节至pH＝5左右。浓缩混合液，用乙酸乙酯萃取，合并有机相并浓缩，得到粗产品化合物4-6，直接用于下一步反应。MS(ESI)m/z:214.0[M+1]
步骤5：化合物4-7的合成
在-10℃下，向化合物4-6(0.68g,3.19mmol,1.00eq)的DCM(10.00mL)溶液中加入化合物甘氨酸甲酯盐酸盐(480.59mg,3.83mmol,1.20eq)、TBTU(1.23g,3.83mmol,1.20eq)和DIEA(1.65g,12.76mmol,4.00eq)。将反应混合物在-10℃至0℃下搅拌0.5小时，然后加入15mL水，用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，经无水硫酸钠干燥，过滤，并浓缩。粗产物经硅胶柱色谱法纯化(流动相：石油醚:乙酸乙酯＝1:0-3:1)得到化合物4-7。MS(ESI)m/z:284.9[M+1]。
步骤6：化合物4-8的合成
在0℃下向化合物4-7(0.5g,1.76mmol,1.00eq)的THF(2.00mL)、MeOH(2.00mL)和H 2O(1.00mL)的混合溶液中加入LiOH.H 2O(369.03mg,8.79mmol,5.00eq)。将反应混合物缓慢升温至室温，并继续搅拌1小时，然后将反应混合物用1N的稀盐酸调节至pH＝5左右。浓缩混合液，用乙酸乙酯萃取，合并有机相并浓缩，得到粗产品化合物4-8，直接用于下一步反应。MS(ESI)m/z:270.9[M+1]。
步骤7：化合物4-9的合成
在-10℃下向化合物4-8(0.5g,1.85mmol,1.00eq)的DMF(8.00mL)溶液中加入化合物3-7(841.99mg,2.22mmol,1.20eq)、TBTU(712.90mg,2.22mmol,1.20eq)和DIEA(526.08mg,4.07mmol,2.20eq)。将反应混合物在-10℃至0℃下搅拌0.5小时，然后加入10mL水，用乙酸乙酯萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，并浓缩。粗产物经硅胶柱色谱法纯化，得到化合物4-9。MS(ESI)m/z:518.2[M+1]。
步骤8：化合物WX-407的合成
在0℃下向化合物4-9(0.42g,811.73μmol,1.00eq)的MeOH(3.00mL)和正己烷(3.00mL)的混合溶 液中加入异丁基硼酸(579.23mg,5.68mmol,7.00eq)和HCl(1M,1.62mL,2.00eq)。将反应混合物缓慢升温至室温，并继续搅拌12小时，然后加入5.00mL正己烷。混合液用甲醇(10mL)萃取，甲醇层用饱和碳酸氢钠水溶液调节pH至5-6，用乙酸乙酯萃取。合并有机相，经无水硫酸钠干燥，过滤，并浓缩。粗产品经制备HPLC纯化，得到化合物WX-407。MS(ESI)m/z:366.1[M-17]。
1H NMR(400MHz,METHANOL-d 4)δ6.96(ddd,J＝5.02,8.91,12.17Hz,1H),6.40-6.58(m,1H),6.34(ddd,J＝3.14,7.15,10.04Hz,1H),4.49-4.70(m,2H),4.12(s,3H),3.78-4.00(m,1H),2.57-2.79(m,2H),2.40-2.53(m,1H),1.57-1.76(m,1H),1.25-1.46(m,2H),0.81-1.01(m,6H)。
WX-407的制备HPLC分离方法：
色谱柱：Xtimate C18 150*25mm*5μm
流动相：A：水(0.225％FA)；B：MeOH，洗脱梯度B％:59％-89％
在高效液相柱色谱中，化合物WX-407的保留时间为9.5min。
实验例1：对MM1.S细胞的体外抗增殖试验
本实验通过测定化合物在肿瘤细胞系MM1.S中在体外对细胞活性的影响来研究化合物抑制细胞增殖的作用。
将MM1.S细胞以7,000个细胞每孔的密度接种入黑色96孔细胞培养板中，然后将培养板在37℃,5％CO 2及100％相对湿度的培养箱中培养过夜。将测试化合物的DMSO溶液以一定浓度(0.3-2000nM)加入细胞培养孔中，然后将培养板放回培养箱中，并设置溶媒对照(加入DMSO，不含化合物)和空白对照。将培养板在37℃,5％CO 2及100％相对湿度的培养箱中培养2天。采用Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7571)标准方法处理样品，在SpectraMax i3x of Molecular Devices读板器上检测发光信号。将原始数据用下列公式来计算测试化合物的抑制率：
Figure PCTCN2018077583-appb-000148
RLU表示相对发光强度。
测试化合物对MM1.S细胞的体外抗增殖试验结果见表1。
表1
化合物 IC 50(μM)
WX-174 0.0058
WX-193 0.0082
WX-333 0.0010
WX-260 0.0110
WX-301 0.0058
WX-306 0.0082
WX-308 0.0089
WX-313 0.0245
WX-317 0.0320
WX-327 0.0242
WX-329 0.0115
WX-351 0.0459
WX-355 0.0288
WX-365 0.0906
WX-367 0.1831
WX-373 0.0267
WX-379 0.0240
WX-381 0.1194
WX-385 0.1045
WX-391 0.0054
实验例2：化合物的肝微粒体稳定性测试
将测试化合物与CD-1小鼠、SD大鼠和人肝微粒体孵育以对测试化合物进行稳定性评估。
测试化合物溶液样品的制备：10mM的实施例化合物的DMSO溶液(5μL)加入到DMSO(45μL)与甲醇和水的混合溶剂(450μL，甲醇和水的体积比为1：1)中，制备成100μM的测试化合物溶液；取50μL的100μM的测试化合物溶液加入到450μL的100mM磷酸钾缓冲液中，得到10μM的测试化合物溶液。
将10μM的测试化合物溶液与三个种属的微粒体预孵育10分钟，然后在每个时间点的孵育板中加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)再生体系工作液以起始反应，最后分别在0、5、10、20、30和60分钟时，将终止液(100％ACN)加入到反应板中以终止反应。测试化合物用LC-MS/MS法进行测定。测试化合物的肝微粒体稳定性测试结果见表2。
表2
化合物 肝微粒体稳定性(T 1/2,min)
WX-174 3.5(H)，1.6(R)，0.8(M)
WX-193 4.8(H)，4.6(R)，2.7(M)
WX-333 67.4(H)，43.1(R)，67.4(M)
WX-260 107.9(H)，>145(R)，84.8(M)
WX-301 74.3(H)，42.1(R)，43.5(M)
WX-306 17.8(H)，37.4(R)，14.0(M)
WX-308 27.4(H)，26.8(R)，20.1(M)
WX-313 >145(H)，57.2(R)，52.5(M)
WX-317 77.0(H)，35.5(R)，27.1(M)
WX-327 75.0(H)，26.5(R)，37.7(M)
WX-329 51.5(H)，43.3(R)，40.3(M)
注：H代表human(人)，R代表rat(大鼠)，M代表mouse(小鼠)
实验例3：化合物的细胞膜渗透性测试
将测试化合物在MDR1-MDCK II细胞上进行了细胞膜渗透性评估。
将测试化合物(10mM的化合物的DMSO溶液)用转运缓冲液(具有10mM Hepes的HBSS,pH＝7.4)稀释，配制成终浓度为2μM的样品，然后双向(A-B和B-A)给药。给药后，将细胞板置于37℃，含5％CO 2及饱和湿度的孵箱中孵育150分钟。在150分钟的孵育结束后，收集样品，采用LC/MS/MS方法半定量检测测试化合物在转运样品中的浓度。测试化合物的细胞膜渗透性测试结果见表3。
表3
Figure PCTCN2018077583-appb-000149
注：Papp A to B表示化合物进入细胞的速度；Papp B to A表示细胞将化合物外排除去的速度；Efflux Ratio＝Papp B to A/Papp A to B

Claims (22)

  1. 式(Ⅰ)化合物、其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体
    Figure PCTCN2018077583-appb-100001
    其中，
    环A选自C 3-6环烷基、苯基或5～10元杂芳基；
    n选自0、1、2或3；
    R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷基、C 1-3杂烷基或苯基，其中所述C 1-3烷基、C 1-3杂烷基或苯基各自任选地被1、2或3个R取代；
    R 2和R 3分别独立地选自H、卤素、OH、NH 2、CN、C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、C 3-6环烷基-(CH 2) 1-3-或苯基-(CH 2) 1-3-，其中所述C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、C 3-6环烷基-(CH 2) 1-3-或苯基-(CH 2) 1-3-各自任选地被1、2或3个R取代；
    或者，R 2、R 3和与它们相连的碳原子一起形成一个3～6元环；
    R 4选自C 1-6烷基或C 3-6环烷基-(CH 2) 1-3-，其中所述C 1-6烷基或C 3-6环烷基-(CH 2) 1-3-各自任选地被1、2或3个R取代；
    R 5选自H或任选地被1、2或3个R取代的C 1-3烷基；
    每个R独立地选自F、Cl、Br、I、OH、Me、NH 2、NH(CH 3)或N(CH 3) 2；
    其中所述C 1-3杂烷基、C 1-6杂烷基和5～10元杂芳基中的术语“杂”分别独立地选自-O-、-S-、-NH-或N；以及在任何一种上述情况下，杂原子或含有杂原子的基团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述的化合物，其中n选自0、1或2。
  3. 根据权利要求1或2所述的化合物，R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷基、C 1-3烷氧基或苯基，其中所述C 1-3烷基、C 1-3烷氧基或苯基各自任选地被1、2或3个R取代；优选地，R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷氧基、苯基或任选地被1、2或3个独立地选自F、Cl、Br和I的取代基取代的C 1-3烷基；更优选地，R 1分别独立地选自卤素、OH、NH 2、CN、C 1-3烷氧基、苯基或任选地被1、2或3个F取代的C 1-3烷基；进一步更优选地，R 1分别独立地选自卤素、CN、苯基或任选地被3个F取代的C 1-3烷基；最优选地，R 1分别独立地选自F、Cl、CN、苯基或任选地被3个F取代的甲基。
  4. 根据权利要求1或2所述的化合物，其中R 1分别独立地选自F、Cl、Br、I、OH、NH 2、CN、 Me、
    Figure PCTCN2018077583-appb-100002
    其中所述Me、
    Figure PCTCN2018077583-appb-100003
    任选地被1、2或3个R取代；优选地，R 1分别独立地选自F、Cl、Br、I、CN、Me或
    Figure PCTCN2018077583-appb-100004
    其中所述Me或
    Figure PCTCN2018077583-appb-100005
    任选地被1、2或3个独立地选自F、Cl、Br和I的取代基取代；优选地，R 1分别独立地选自F、Cl、Br、I、CN、
    Figure PCTCN2018077583-appb-100006
    或任选地被1、2或3个独立地选自F、Cl、Br和I的取代基取代的Me；进一步更优选地，R 1分别独立地选自F、Cl、Br、I、CN、
    Figure PCTCN2018077583-appb-100007
    或任选被1、2或3个F取代的Me；最优选地，R 1分别独立地选自F、Cl、Br、I、CN、
    Figure PCTCN2018077583-appb-100008
    或任选地被3个F取代的Me；或者，R 1分别独立地选自F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、
    Figure PCTCN2018077583-appb-100009
    优选地，R 1分别独立地选自F、Cl、CN、
    Figure PCTCN2018077583-appb-100010
    或CF 3。
  5. 根据权利要求1-4中任一项所述的化合物，其中环A选自环丙基、苯基、五元杂芳基、六元杂芳基、七元杂芳基、八元杂芳基、九元杂芳基或十元杂芳基；优选地，环A选自环丙基、苯基、五元杂芳基、六元杂芳基或九元杂芳基；更优选地，环A选自环丙基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、1,3,4-噁二唑基、噻唑基、异噻唑基、噻吩基、吡唑基、咪唑基或1H-吲唑基；更优选地，环A选自环丙基、苯基、吡啶基、嘧啶基、噻唑基或哒嗪基；最优选地，环A选自苯基、吡啶基、嘧啶基、噻唑基或哒嗪基；或者，环A选自苯基或5～10元杂芳基；优选地，环A选自苯基、吡啶基、嘧啶基、吡嗪基、1,3,4-噁二唑基、噻唑基、咪唑基或1H-吲唑基；更优选地，环A选自苯基、吡啶基或嘧啶基；最优选地，环A选自苯基。
  6. 根据权利要求1所述的化合物，其中所述式(I)化合物中的结构单元
    Figure PCTCN2018077583-appb-100011
    选自
    Figure PCTCN2018077583-appb-100012
    Figure PCTCN2018077583-appb-100013
    优选地，结构单元
    Figure PCTCN2018077583-appb-100014
    选自
    Figure PCTCN2018077583-appb-100015
    Figure PCTCN2018077583-appb-100016
    更优选地，结构单元
    Figure PCTCN2018077583-appb-100017
    选自
    Figure PCTCN2018077583-appb-100018
    Figure PCTCN2018077583-appb-100019
    最优选地，所述结构单元
    Figure PCTCN2018077583-appb-100020
    选自
    Figure PCTCN2018077583-appb-100021
    Figure PCTCN2018077583-appb-100022
    Figure PCTCN2018077583-appb-100023
    或者，结构单元
    Figure PCTCN2018077583-appb-100024
    选自
    Figure PCTCN2018077583-appb-100025
    最优选地，结构单元
    Figure PCTCN2018077583-appb-100026
    选自
    Figure PCTCN2018077583-appb-100027
  7. 根据权利要求1所述的化合物，其中所述式(I)化合物中的结构单元
    Figure PCTCN2018077583-appb-100028
    选自
    Figure PCTCN2018077583-appb-100029
    Figure PCTCN2018077583-appb-100030
    Figure PCTCN2018077583-appb-100031
    更优选地，结构单元
    Figure PCTCN2018077583-appb-100032
    选自
    Figure PCTCN2018077583-appb-100033
    Figure PCTCN2018077583-appb-100034
    Figure PCTCN2018077583-appb-100035
    最优选地，所述结构单元
    Figure PCTCN2018077583-appb-100036
    选自
    Figure PCTCN2018077583-appb-100037
    Figure PCTCN2018077583-appb-100038
    Figure PCTCN2018077583-appb-100039
    或者，结构单元
    Figure PCTCN2018077583-appb-100040
    选自
    Figure PCTCN2018077583-appb-100041
    Figure PCTCN2018077583-appb-100042
  8. 根据权利要求1所述的化合物，其中所述式(I)化合物中的结构单元
    Figure PCTCN2018077583-appb-100043
    选自
    Figure PCTCN2018077583-appb-100044
    Figure PCTCN2018077583-appb-100045
    Figure PCTCN2018077583-appb-100046
    或者，结构单元
    Figure PCTCN2018077583-appb-100047
    选自：
    Figure PCTCN2018077583-appb-100048
    Figure PCTCN2018077583-appb-100049
  9. 根据权利要求1-8中任一项所述的化合物，其中R 2和R 3分别独立地选自H、卤素、OH、NH 2、CN、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个R取代，或者，R 2、R 3和与它们相连的碳原子一起形成一个3～6元环烷基；优选地，R 2和R 3分别独立地选自H、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个独立地选自F、Cl、Br、I和羟基的取代基取代；更优选地，R 2和R 3分别独立地选自H、C 1-6烷基、C 1-3烷氧基、C 3-6环烷基-CH 2-或苯基-CH 2-；进一步更优选地，R 2和R 3分别独立地选自H、C 1-6烷基、C 3-6环烷基-CH 2-或苯基-CH 2-； 最优选地，R 2和R 3分别独立地选自H、Me、
    Figure PCTCN2018077583-appb-100050
    或者，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me、Et、
    Figure PCTCN2018077583-appb-100051
    其中Me、Et、
    Figure PCTCN2018077583-appb-100052
    任选地被1、2或3个R取代。
  10. 根据权利要求1-8中任一项所述的化合物，其中R 3为H，R 2选自H、卤素、OH、NH 2、CN、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个R取代；优选地，上述R 3为H，R 2选自H、C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-，其中C 1-6烷基、C 1-3烷氧基、C 1-3烷基-O-C 1-3烷基-、C 3-6环烷基-CH 2-或苯基-CH 2-各自任选地被1、2或3个独立地选自F、Cl、Br、I和羟基的取代基取代；更优选地，上述R 3为H，R 2选自H、C 1-6烷基、C 1-3烷氧基、C 3-6环烷基-CH 2-或苯基-CH 2-；更优选地，R 3为H，R 2选自H、C 1-6烷基、C 3-6环烷基-CH 2-或苯基-CH 2-；最优选地，R 3为H，R 2选自H、Me、
    Figure PCTCN2018077583-appb-100054
  11. 根据权利要求1-10中任一项所述的化合物，其中R 4选自C 1-6烷基或C 3-6环烷基-CH 2-，其中C 1-6烷基或C 3-6环烷基-CH 2-各自任选地被1、2或3个R取代；优选地，R 4选自C 1-6烷基或C 3-6环烷基-CH 2-；更优选地，R 4选自C 1-4烷基或C 3-6环烷基-CH 2-；进一步更优选地，R 4选自C 3-4烷基或C 3-4环烷基-CH 2-；还进一步更优选地，R 4选自C 4烷基或C 4环烷基-CH 2-；甚至更优选地，R 4选自
    Figure PCTCN2018077583-appb-100055
    最优选地，R 4选自
    Figure PCTCN2018077583-appb-100056
  12. 根据权利要求1-11中任一项所述的化合物，其中R 5选自H或C 1-3烷基；优选地，R 5选自H、Me或Et；更优选地，R 5选自H或Me；最优选地，R 5为H。
  13. 根据权利要求1-12中任一项所述的化合物，其中每个R独立地选自F、Cl、Br、I、OH、Me或NH 2；优选地，每个R独立地选自F、Cl、Br、OH或Me；更优选地，每个R独立地选自F或OH。
  14. 根据权利要求1-13中任一项所述的化合物，其中所述式(I)化合物选自式(II)、式(III)、式(IV)、式(V)、式(VI)、式(I-a)、式(I-b)、式(II-a)、式(II-b)、式(III-a)、式(III-b)、式(IV-a)、式(IV-b)、式(V-a)、 式(V-b)、式(VI-a)或式(VI-b)化合物：
    Figure PCTCN2018077583-appb-100057
    Figure PCTCN2018077583-appb-100058
    其中，环C选自环丙基、五元杂芳基或六元杂芳基；优选地，环C选自环丙基、吡啶基、嘧啶基、吡嗪基、哒嗪基、1,3,4-噁二唑基、噻唑基、异噻唑基、噻吩基、吡唑基或咪唑基；优选地，环C选自环丙基、吡啶基、嘧啶基、噻唑基或哒嗪基；更优选地，环C选自吡啶基、嘧啶基、噻唑基或哒嗪基。
  15. 根据权利要求14所述的化合物，其中所述式(IV-a)、式(IV-b)、式(VI-a)或(VI-b)中的结构单元
    Figure PCTCN2018077583-appb-100059
    选自
    Figure PCTCN2018077583-appb-100060
    Figure PCTCN2018077583-appb-100061
    更优选地，结构单元
    Figure PCTCN2018077583-appb-100062
    选自
    Figure PCTCN2018077583-appb-100063
    Figure PCTCN2018077583-appb-100064
    进一步更优选地，结构单元
    Figure PCTCN2018077583-appb-100065
    选自
    Figure PCTCN2018077583-appb-100066
    最优 选地，结构单元
    Figure PCTCN2018077583-appb-100067
    选自
    Figure PCTCN2018077583-appb-100068
    Figure PCTCN2018077583-appb-100069
  16. 根据权利要求1-15中任一项所述的化合物，其中所述式(I)化合物选自
    Figure PCTCN2018077583-appb-100070
    Figure PCTCN2018077583-appb-100071
    Figure PCTCN2018077583-appb-100072
    或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体。
  17. 根据权利要求1-16中任一项所述的化合物，其中所述式(I)化合物选自
    Figure PCTCN2018077583-appb-100073
    Figure PCTCN2018077583-appb-100074
    Figure PCTCN2018077583-appb-100075
    Figure PCTCN2018077583-appb-100076
    Figure PCTCN2018077583-appb-100077
    Figure PCTCN2018077583-appb-100078
    或其药学上可接受的盐。
  18. 药物组合物，其包含权利要求1-17中任一项所述的化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体，以及药学上可接受的载体、赋形剂或辅料。
  19. 预防或治疗多发性骨髓瘤的方法，包括将权利要求1-17中任一项所述的化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体或权利要求18所述的药物组合物向有需要的个体给药。
  20. 权利要求1-17中任一项所述的化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体或权利要求18所述的药物组合物在制备用于预防或治疗多发性骨髓瘤的药物中的用途。
  21. 用于预防或治疗多发性骨髓瘤的权利要求1-17中任一项所述的化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体或权利要求18所述的药物组合物。
  22. 权利要求1-17中任一项所述的化合物或其药学上可接受的盐、其互变异构体、其立体异构体或其几何异构体或权利要求18所述的药物组合物在预防或治疗多发性骨髓瘤中的用途。
PCT/CN2018/077583 2017-02-28 2018-02-28 氮杂环丁烷衍生物 WO2018157820A1 (zh)

Priority Applications (15)

Application Number Priority Date Filing Date Title
KR1020197028203A KR102547709B1 (ko) 2017-02-28 2018-02-28 아제티딘 유도체
CA3054459A CA3054459A1 (en) 2017-02-28 2018-02-28 Azetidine derivative
SG11201907945YA SG11201907945YA (en) 2017-02-28 2018-02-28 Azetidine derivative
EP18760796.5A EP3590944B1 (en) 2017-02-28 2018-02-28 Azetidine derivative
MX2019010108A MX2019010108A (es) 2017-02-28 2018-02-28 Derivados de azetidina.
BR112019017844-9A BR112019017844B1 (pt) 2017-02-28 2018-02-28 Composto derivado de azetidina, composição farmacêutica que o compreende e uso dos mesmos
CN201880017090.1A CN110461855B (zh) 2017-02-28 2018-02-28 氮杂环丁烷衍生物
US16/489,282 US11014943B2 (en) 2017-02-28 2018-02-28 Azetidine derivative
AU2018228555A AU2018228555B2 (en) 2017-02-28 2018-02-28 Azetidine derivative
ES18760796T ES2928298T3 (es) 2017-02-28 2018-02-28 Derivado de azetidina
JP2019547081A JP7083836B2 (ja) 2017-02-28 2018-02-28 アゼチジン誘導体
EA201991932A EA201991932A1 (ru) 2017-09-08 2018-02-28 Производное азитидина
PH12019550154A PH12019550154A1 (en) 2017-02-28 2019-08-23 Azetidine derivative
IL268967A IL268967B2 (en) 2017-02-28 2019-08-27 Azetidine derivative
ZA2019/05646A ZA201905646B (en) 2017-02-28 2019-08-27 Azetidine derivative

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201710112350.0 2017-02-28
CN201710112350 2017-02-28
CN201710805883.7 2017-09-08
CN201710805883 2017-09-08

Publications (1)

Publication Number Publication Date
WO2018157820A1 true WO2018157820A1 (zh) 2018-09-07

Family

ID=63370561

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/077583 WO2018157820A1 (zh) 2017-02-28 2018-02-28 氮杂环丁烷衍生物

Country Status (14)

Country Link
US (1) US11014943B2 (zh)
EP (1) EP3590944B1 (zh)
JP (1) JP7083836B2 (zh)
KR (1) KR102547709B1 (zh)
CN (2) CN110461855B (zh)
AU (1) AU2018228555B2 (zh)
CA (1) CA3054459A1 (zh)
ES (1) ES2928298T3 (zh)
IL (1) IL268967B2 (zh)
MX (1) MX2019010108A (zh)
PH (1) PH12019550154A1 (zh)
SG (1) SG11201907945YA (zh)
WO (1) WO2018157820A1 (zh)
ZA (1) ZA201905646B (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020025037A1 (zh) * 2018-08-02 2020-02-06 正大天晴药业集团股份有限公司 氮杂环丁烷衍生物的硼酸酯
CN111039965A (zh) * 2018-10-12 2020-04-21 新发药业有限公司 一种法硼巴坦的简便制备方法
WO2023198060A1 (zh) * 2022-04-12 2023-10-19 正大天晴药业集团股份有限公司 蛋白酶体抑制剂与抗pd-1抗体的药物组合

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110790780B (zh) * 2018-08-02 2022-12-30 正大天晴药业集团股份有限公司 含硼的氮杂环丁烷衍生物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006086600A1 (en) * 2005-02-11 2006-08-17 Cephalon, Inc. Proteasome inhibitors and methods of using the same
CN105732683A (zh) * 2016-03-25 2016-07-06 南京林业大学 一类羧酸与α氨基酸组成的二肽硼酸及其酯类化合物、制备方法及其用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101120006A (zh) * 2005-02-11 2008-02-06 赛福伦公司 蛋白酶体抑制剂及其使用方法
MX350432B (es) 2012-01-19 2017-09-06 Agios Pharmaceuticals Inc Compuestos terapeuticamente activos y sus metodos de empleo.
SI3265448T1 (sl) 2015-03-03 2022-04-29 Biohaven Therapeutics Ltd. Predzdravila riluzola in njihova uporaba
CN110790780B (zh) * 2018-08-02 2022-12-30 正大天晴药业集团股份有限公司 含硼的氮杂环丁烷衍生物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006086600A1 (en) * 2005-02-11 2006-08-17 Cephalon, Inc. Proteasome inhibitors and methods of using the same
CN105732683A (zh) * 2016-03-25 2016-07-06 南京林业大学 一类羧酸与α氨基酸组成的二肽硼酸及其酯类化合物、制备方法及其用途

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT, WILLIAMS & WILKINS
BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, doi:10.1002/jps.2600660104
DOU, Q. PING: "Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System", CURRENT CANCER DRUG TARGETS, vol. 14, no. 6, 31 December 2014 (2014-12-31), pages 517 - 36, XP055605937 *
RUGGERI B.: "The development and pharmacology of proteasome inhibitors for the management and treatment of cancer", ADVANCES IN PHARMACOLOGY, vol. 57, 31 December 2009 (2009-12-31), San Diego , CA , United States, pages 91 - 135, XP009516635, DOI: 10.1016/S1054-3589(08)57003-7 *
See also references of EP3590944A4

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020025037A1 (zh) * 2018-08-02 2020-02-06 正大天晴药业集团股份有限公司 氮杂环丁烷衍生物的硼酸酯
CN112513052A (zh) * 2018-08-02 2021-03-16 正大天晴药业集团股份有限公司 氮杂环丁烷衍生物的硼酸酯
US11466036B2 (en) 2018-08-02 2022-10-11 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Borate of azetidine derivative
CN112513052B (zh) * 2018-08-02 2022-12-16 正大天晴药业集团股份有限公司 氮杂环丁烷衍生物的硼酸酯
CN111039965A (zh) * 2018-10-12 2020-04-21 新发药业有限公司 一种法硼巴坦的简便制备方法
CN111039965B (zh) * 2018-10-12 2020-12-01 新发药业有限公司 一种法硼巴坦的简便制备方法
WO2023198060A1 (zh) * 2022-04-12 2023-10-19 正大天晴药业集团股份有限公司 蛋白酶体抑制剂与抗pd-1抗体的药物组合

Also Published As

Publication number Publication date
IL268967B2 (en) 2023-03-01
KR102547709B1 (ko) 2023-06-23
JP2020509020A (ja) 2020-03-26
CN110461855A (zh) 2019-11-15
CN113061144A (zh) 2021-07-02
CN110461855B (zh) 2021-02-19
AU2018228555B2 (en) 2022-04-07
US11014943B2 (en) 2021-05-25
ZA201905646B (en) 2022-03-30
IL268967B (en) 2022-11-01
IL268967A (en) 2019-10-31
JP7083836B2 (ja) 2022-06-13
ES2928298T3 (es) 2022-11-16
BR112019017844A2 (pt) 2020-04-14
SG11201907945YA (en) 2019-09-27
KR20190125367A (ko) 2019-11-06
EP3590944A1 (en) 2020-01-08
MX2019010108A (es) 2020-01-13
EP3590944A4 (en) 2020-12-09
CA3054459A1 (en) 2018-09-07
US20200115392A1 (en) 2020-04-16
PH12019550154A1 (en) 2020-03-16
AU2018228555A1 (en) 2019-10-10
EP3590944B1 (en) 2022-09-14

Similar Documents

Publication Publication Date Title
KR102089234B1 (ko) Ask1 억제제로서의 피리딘 유도체 및 이의 제조방법과 용도
JP7233410B2 (ja) Ｅｇｆｒキナーゼ阻害薬としてのアリールホスフィンオキシド
WO2018041263A1 (zh) 抗流感病毒嘧啶衍生物
WO2018157820A1 (zh) 氮杂环丁烷衍生物
WO2018108064A1 (zh) 作为第四代egfr激酶抑制剂的螺环芳基磷氧化合物
JP7237010B2 (ja) Ｈｄａｃ６選択的阻害剤およびその製造方法と使用
WO2019085933A1 (zh) 作为Wee1抑制剂的大环类化合物及其应用
WO2018192493A1 (zh) 作为pcsk9抑制剂的哌啶类化合物
WO2018108167A1 (zh) Cdk4/6抑制剂
CN111542520A (zh) 作为a2a受体抑制剂的并环类衍生物
WO2019056950A1 (zh) 噻吩并二氮杂卓衍生物及其应用
WO2017118375A1 (zh) 地佐辛类似物
CN110023286B (zh) 作为ccr2/ccr5受体拮抗剂的联苯化合物
WO2018127207A1 (zh) 噻唑衍生物及其应用
CN109071469B (zh) 三环类化合物及其应用
CN111556869A (zh) 作为csf-1r抑制剂的杂环化合物及其应用
EP3498715B1 (en) Anti-hcmv virus compound
RU2772274C2 (ru) Селективные ингибиторы hdac6, способ их получения и их применение
BR112019017844B1 (pt) Composto derivado de azetidina, composição farmacêutica que o compreende e uso dos mesmos
EA040139B1 (ru) Производное азитидина
BR112019014152B1 (pt) Compostos inibidores seletivos de hdac6, composição farmacêutica compreendendo os referidos compostos e uso dos mesmos
WO2019001460A1 (zh) 作为 irak4 抑制剂的稠环化合物

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: 18760796

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3054459

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2019547081

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112019017844

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20197028203

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2018228555

Country of ref document: AU

Date of ref document: 20180228

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2018760796

Country of ref document: EP

Effective date: 20190930

ENP Entry into the national phase

Ref document number: 112019017844

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20190827