WO2019242625A1 - 制备来那度胺衍生物的方法 - Google Patents

制备来那度胺衍生物的方法 Download PDF

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Publication number
WO2019242625A1
WO2019242625A1 PCT/CN2019/091812 CN2019091812W WO2019242625A1 WO 2019242625 A1 WO2019242625 A1 WO 2019242625A1 CN 2019091812 W CN2019091812 W CN 2019091812W WO 2019242625 A1 WO2019242625 A1 WO 2019242625A1
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amino
dioxopiperidin
group
oxoisoindololin
alkylene
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PCT/CN2019/091812
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English (en)
French (fr)
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杨小宝
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孙宁
仇星
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上海科技大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure relates to a method for preparing a compound of formula (I), a lenalidomide derivative, and a compound of formula (I).
  • Thalidomide and its analogues pomalidomide and lenalidomide are currently commonly used immunomodulatory drugs, especially for multiple myeloma. 1
  • thalidomide and its analogs can specifically bind to Cereblon E3, and found that thalidomide and its derivatives can be used as E3 ligase to recognize small molecule ligands and successfully introduce them into protein degradation.
  • E3 ligase to recognize small molecule ligands and successfully introduce them into protein degradation.
  • PROTAD Proteolysis Targeting Drug
  • Ubiquitin-mediated protein degradation is the major negative regulation of intracellular proteins. Ubiquitinated degradation pathways are involved in regulating almost all life activities such as cell cycle, proliferation, apoptosis, and signal transmission.
  • the protein degradation targeted drug (PROTAD) technology platform uses the ubiquitin-protease system to degrade pathogenic target proteins. Specifically, the PROTAD molecule is composed of three parts: a small molecule inhibitor that binds to the target protein, a ligand that binds to the E3 ligase, and a chemical chain that links the two (as shown in the PROTAD structural formula of Figure 1). In cells, PROTAD works by establishing a ternary complex with the target protein and E3 ligase, making the target protein that could not be bound to E3 polyubiquitinated and subsequently degraded by the proteasome 4 .
  • CRBN ligand-based linker libraries need to be synthesized first, one end of which has functional groups such as carboxyl, amino, or halogen that can bind to small molecule inhibitors, and the other end remains bound to CRBN
  • the key structural unit of glutarimide is the key structural unit of glutarimide.
  • the library of pomalidomide-based linkers reported in the literature was constructed mainly by the aromatic nucleophilic substitution reaction and deprotection reaction of 4-fluoro-substituted thalidomide and alkylamines 6 (Scheme 1).
  • the first method is a reductive amination reaction 8 and the second method is an alkylation reaction 9 .
  • Scheme 3 is not suitable for industrial production and scale-up due to the use of the expensive and dangerous reducing agent sodium cyanoborohydride and the difficult to obtain and unstable aldehyde substrate.
  • Professor Bradner reported the reductive amination reaction of lenalidomide with aldehyde-substituted amines, and a lenalidomide-based linker was constructed, but the reaction required complicated operations, lacked versatility, and had low overall yield (46%, option 3).
  • the second method is to prepare the corresponding amino alkylated product 3a through the alkylation reaction of lenalidomide and alkyl bromide under the condition of inorganic base potassium carbonate in Li 10 in 2017. According to the reaction conditions in this document, we found compound 3a ' This is the true product structure under this reaction condition (Scheme 4), and the corresponding corresponding aminoalkylated product 3a is not obtained.
  • the applicant has devised a new method for the synthesis of lenalidomide derivatives, which includes the use of organic bases (such as, but not limited to, DIPEA or triethylamine) as acid binding agents.
  • organic bases such as, but not limited to, DIPEA or triethylamine
  • the lenalidomide can be reacted with a suitable alkylating agent to obtain the amino alkylation main product with high selectivity.
  • the applicant further extended this condition to a series of alkylation reactions of a alkylating reagent with a leaving group and lenalidomide to obtain a highly selective main alkylation product of aminoalkylation.
  • the method was applied in the development of protein degradation targeted drug technology.
  • the above object of the present disclosure is achieved by providing a method for preparing a compound of formula (I) of a lenalidomide derivative,
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: O, CONH, NHCO, NH, alkynylene, alkenylene Group, cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, And
  • the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group
  • the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or any combination thereof; or
  • the group U represents hydrogen
  • the method comprises: subjecting an amino group of a compound of formula (II) and a compound of formula (III) to an amino alkylation reaction in the presence of an organic base to selectively obtain a compound of formula (I),
  • R 1 represents a leaving group
  • LIN represents -alkylene-U
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: O, CONH, NHCO, NH, alkynylene, alkenylene Group, cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, And
  • the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group
  • the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or any combination thereof; or
  • the group U represents hydrogen.
  • the present disclosure also provides a compound of formula (I),
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: O, CONH, NHCO, NH, alkynylene, alkenylene Group, cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, And
  • the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group
  • the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or any combination thereof; or
  • the group U represents hydrogen.
  • the present disclosure provides a method for preparing a compound of formula (I), a lenalidomide derivative,
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: O, CONH, NHCO, NH, alkynylene, alkenylene Group, cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, And
  • the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group
  • the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or any combination thereof; or
  • the group U represents hydrogen
  • the method comprises: subjecting an amino group of a compound of formula (II) and a compound of formula (III) to an amino alkylation reaction in the presence of an organic base to selectively obtain a compound of formula (I),
  • R 1 represents a leaving group
  • LIN represents -alkylene-U
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: O, CONH, NHCO, NH, alkynylene, alkenylene Group, cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, And
  • the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group
  • the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or any combination thereof; or
  • the group U represents hydrogen.
  • the group in the LIN of the compound of the formula (III) may be protected by a method known in the art and an appropriate protecting group as necessary.
  • the group U in the LIN of the compound of formula (III) is protected by a protecting group (for example, the group U represents COOH, SO 3 H, or NH 2 protected by a protecting group)
  • the compound of formula (III) and The protecting group of the group U in the LIN of the corresponding compound of formula (I) prepared by aminoalkylation of the amino group of the compound of formula (II) may be retained or may be further passed by methods known in the art (as described below) ) For deprotection.
  • the organic base includes, but is not limited to, for example, triethylamine, dimethylamine, tri-tert-butylamine, N, N-dimethylaniline, DIPEA, N, N-diethylethylamine , DMAP, pyridine, quinoline, morpholine, and NMM, may also be one or more of these bases.
  • R 1 represents halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, or p-toluenesulfonyloxy.
  • the LIN represents:
  • n1, n2, n3, n4, n5, n6, m1, and m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
  • group U represents -COOH, -SO 3 H or -NH 2 optionally protected by a protecting group; or the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group , Heteroaryl or any combination thereof; or the group U represents hydrogen.
  • the LIN is preferably -C 1-30 alkylene-U. In one embodiment of the present disclosure, the LIN is preferably -methylene-U or -C 2-30 alkylene-U, wherein the C 2-30 alkylene is a linear or branched C 2-30 alkylene (preferably C 2 -C 29 alkylene chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 alkylene chain, C 2 -C 24 alkylene chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 alkylene chain, C 2 -C 19 alkylene chain, C 2 -C 18 alkylene chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 -C 15 alkylene chain, C 2 -C 14 alky
  • the LIN represents:
  • group U represents -COOH, SO 3 H or -NH 2 optionally protected by a protecting group, or the group U represents -N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group , Heteroaryl or any combination thereof; or the group U represents hydrogen.
  • the LIN represents:
  • group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group, or the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl Or any combination thereof; or the group U represents hydrogen.
  • the LIN is -alkylene-U, the alkylene (preferably a C 1-30 alkylene chain, particularly preferably a C 2 -C 29 alkylene chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 alkylene chain, C 2 -C 24 alkylene chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 alkylene chain, C 2 -C 19 alkylene chain, C 2 -C 18 alkylene chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 -C 15 alkylene chain, C 2 -C 14 alkylene chain, C 2 -C 13 alkylene chain, C 2 -C 12 alkylene chain, C 2 -C 11 alkylene chain, C 2 -C
  • the number of the substituents may be, for example, 1-30, 1-25, 1-20, or 1-15, 1-10, 1-9, 1-8. , 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 13, 12, 11, 10 , 9, 8, 7, 6, 5, 4, 3, 2, or 1.
  • the LIN represents -C 1-30 alkylene chain -U, and the C 1-30 alkylene chain is composed of one or more selected from a hydroxyl group, an amino group, a mercapto group, and a halogen.
  • the number of the substituents may be, for example, 1-30, 1-25, 1-20, or 1-15, 1-10, 1-9, 1-8. , 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 13, 12, 11, 10 , 9, 8, 7, 6, 5, 4, 3, 2, or 1.
  • the LIN represents:-(CH 2 ) n11 -triazolyl- (CH 2 ) n12 -U,-(CH 2 ) n11 -triazolyl- (CH 2 ) n12- (O (CH 2 ) n13 ) m11 -U,-(CH 2 ) n11- (O (CH 2 ) n12 ) m11 -O- (CH 2 ) n13 -triazolyl- (CH 2 ) n14- (O ( CH 2 ) n15 ) m12 -O- (CH 2 ) n16 -U,-(CH 2 ) n11 -triazolyl- (CH 2 ) n12- (O (CH 2 ) n13 ) m11 -O- (CH 2 ) n14 -U or- (CH 2 ) n11- (O (CH 2 ) n12 ) m11 -O- (CH 2 ) n14
  • n11, n12, n13, n14, n15, n16, m11, m12 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 An integer of 17, 17, 19, or 20;
  • group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group, or the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl Or any combination thereof; or the group U represents hydrogen.
  • the LIN represents:-(CH 2 ) 3 -triazolyl- (CH 2 ) 5 -U,-(CH 2 ) 2 -triazolyl- (CH 2 ) 5- U, -CH 2 -triazolyl- (CH 2 ) 5 -U,-(CH 2 ) 2 -triazolyl- (CH 2 ) 4 -U,-(CH 2 ) 3 -triazolyl- (CH 2 ) 2 -O (CH 2 ) 2 -U,-(CH 2 ) 2 -triazolyl- (CH 2 ) 2 -O (CH 2 ) 2 -U or -CH 2 -triazolyl- (CH 2 ) 2 -O (CH 2 ) 2 -U; where the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group, or the group U represents N 3 , alkenyl, alkynyl, ring Alkyl, aryl, hetero
  • the LIN represents: -CH 2 CONHCH 2 -U,-(CH 2 ) 2 CONH (CH 2 ) 2 -U,-(CH 2 ) 3 CONH (CH 2 ) 3- U,-(CH 2 ) 3 CONH (CH 2 ) 4 -U,-(CH 2 ) 4 CONH (CH 2 ) 4 -U,-(CH 2 ) 5 CONH (CH 2 ) 5 -U,-(CH 2 ) 6 CONH (CH 2 ) 7 -U,-(CH 2 ) 6 CONH (CH 2 ) 6 -U,-(CH 2 ) 7 CONH (CH 2 ) 7 -U,-(CH 2 ) 8 CONH ( CH 2 ) 8 -U,-(CH 2 ) 9 CONH (CH 2 ) 9 -U,-(CH 2 ) 10 CONH (CH 2 ) 10 -U,-(CH 2 ) 2 CONH (CH 2 ) 5- U,-(CH 2 )
  • the LIN represents: -CH 2 NHCOCH 2 -U,-(CH 2 ) 2 NHCO (CH 2 ) 2 -U,-(CH 2 ) 3 NHCO (CH 2 ) 3- U,-(CH 2 ) 3 NHCO (CH 2 ) 4 -U,-(CH 2 ) 4 NHCO (CH 2 ) 4 -U,-(CH 2 ) 5 NHCO (CH 2 ) 5 -U,-(CH 2 ) 6 NHCO (CH 2 ) 7 -U,-(CH 2 ) 6 NHCO (CH 2 ) 6 -U,-(CH 2 ) 7 NHCO (CH 2 ) 7 -U,-(CH 2 ) 8 NHCO ( CH 2 ) 8 -U,-(CH 2 ) 9 NHCO (CH 2 ) 9 -U,-(CH 2 ) 10 NHCO (CH 2 ) 10 -U,-(CH 2 ) 2 NHCO (CH 2 ) 10 -
  • the LIN represents -alkylene-U, wherein the alkylene is a linear or branched C 1-30 alkylene, and the group U represents N 3 , Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof.
  • the amount of the organic base in the reaction, based on the molar amount of the compound of formula (II), is 0.1 to 10 equivalents.
  • the amount of the organic base is 0.1 to 9 equivalents, preferably 0.5 to 8 equivalents, 0.5 to 7 equivalents, 0.5 to 6 equivalents, and 0.5 to 5 equivalents. Equivalents, 1 to 4 equivalents, and 1 to 3 equivalents.
  • the amount of the compound of formula (III) is 0.5 to 1.5 equivalents (preferably 0.5 equivalent, 0.6 equivalent). , 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1 equivalent, 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent, or 1.5 equivalent).
  • the reaction is performed with or without a solvent.
  • a solvent includes, but is not limited to, NMP, DMF, CH 3 CN.
  • the reaction is performed without adding a solvent, and the organic base is used as the sole solvent.
  • the reaction is performed at a temperature of 10-150 ° C. In one embodiment of the present disclosure, the temperature is 20-140 ° C, 70-130 ° C, 80-120 ° C, 90-110 ° C, or 80-100 ° C.
  • the method may further include first reacting the compound of formula (III) with NaI to react formula (III) The compounds are converted into iodides, ie
  • the compound of the formula (IV) further undergoes an aminoalkylation reaction with the amino group of the compound of the formula (II) in the presence of an organic base to selectively obtain the compound of the formula (I).
  • the method described in the present disclosure may further include performing the protected group U of the compound of the formula (I) Deprotection steps.
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: O, CONH, NHCO, NH, alkynylene, alkenylene Group, cycloalkylene, arylene, heterocycloalkylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, And
  • the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group
  • the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl or any combination thereof; or
  • the group U represents hydrogen.
  • the LIN represents:
  • n1, n2, n3, n4, n5, n6, m1, and m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
  • group U represents -COOH, -SO 3 H or -NH 2 optionally protected by a protecting group; or the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group , Heteroaryl or any combination thereof; or the group U represents hydrogen.
  • the LIN is preferably -C 1-30 alkylene-U.
  • the LIN is preferably -methylene-U or -C 2-30 alkylene-U, wherein the C 2-30 alkylene is a linear or branched C 2-30 alkylene (preferably C 2 -C 29 alkylene chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 alkylene chain, C 2 -C 24 alkylene chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 alkylene chain, C 2 -C 19 alkylene chain, C 2 -C 18 alkylene chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 -C 15 alkylene chain
  • the LIN represents:
  • group U represents -COOH, SO 3 H or -NH 2 optionally protected by a protecting group, or the group U represents -N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group , Heteroaryl or any combination thereof; or the group U represents hydrogen.
  • the LIN represents:
  • group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group, or the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl Or any combination thereof; or the group U represents hydrogen.
  • the LIN is -alkylene-U, and the alkylene (preferably a C 1-30 alkylene chain, particularly preferably C 2 -C 29 Alkylene chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 alkylene chain, C 2 -C 24 Alkylene chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 alkylene chain, C 2 -C 19 Alkylene chain, C 2 -C 18 alkylene chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 -C 15 alkylene chain, C 2 -C 14 Alkylene chain, C 2 -C 13 alkylene chain, C 2 -C 12 alkylene chain, C 2 -C 11 alkylene chain, C 2 -C 13 alkylene chain, C 2
  • the number of the substituents may be, for example, 1-30, 1-25, 1-20, or 1-15, 1-10, 1-9, 1-8. , 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 13, 12, 11, 10 , 9, 8, 7, 6, 5, 4, 3, 2, or 1.
  • the LIN represents -C 1-30 alkylene chain -U, and the C 1-30 alkylene chain is selected from one or more A linear or branched C 1-30 alkylene chain substituted with a substituent of a hydroxy, amino, mercapto, halogen, or combination thereof; wherein the group U represents COOH, SO 3 H, or NH 2, or the group U represents N 3, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; U represents hydrogen or a group.
  • the number of the substituents may be, for example, 1-30, 1-25, 1-20, or 1-15, 1-10, 1-9, 1-8. , 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 13, 12, 11, 10 , 9, 8, 7, 6, 5, 4, 3, 2, or 1.
  • the LIN represents:-(CH 2 ) n11 -triazolyl- (CH 2 ) n12 -U,-(CH 2 ) n11 -triazolyl -(CH 2 ) n12- (O (CH 2 ) n13 ) m11 -U,-(CH 2 ) n11- (O (CH 2 ) n12 ) m11 -O- (CH 2 ) n13 -triazolyl- (CH 2 ) n14- (O (CH 2 ) n15 ) m12 -O- (CH 2 ) n16 -U,-(CH 2 ) n11 -triazolyl- (CH 2 ) n12- (O (CH 2 ) n13 ) m11 -O- (CH 2 ) n14 -U or- (CH 2 ) n11- (O (CH 2 ) n12
  • n11, n12, n13, n14, n15, n16, m11, m12 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 An integer of 17, 17, 19, or 20;
  • group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group, or the group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl Or any combination thereof; or the group U represents hydrogen.
  • the LIN represents:-(CH 2 ) 3 -triazolyl- (CH 2 ) 5 -U,-(CH 2 ) 2 -triazolyl -(CH 2 ) 5 -U, -CH 2 -triazolyl- (CH 2 ) 5 -U,-(CH 2 ) 2 -triazolyl- (CH 2 ) 4 -U,-(CH 2 ) 3 -Triazolyl- (CH 2 ) 2 -O (CH 2 ) 2 -U,-(CH 2 ) 2 -triazolyl- (CH 2 ) 2 -O (CH 2 ) 2 -U or -CH 2- Triazolyl- (CH 2 ) 2 -O (CH 2 ) 2 -U; wherein the group U represents COOH, SO 3 H or NH 2 optionally protected by a protecting group, or the group U represents N 3 , Alkenyl, alkynyl,
  • the LIN represents: -CH 2 CONHCH 2 -U,-(CH 2 ) 2 CONH (CH 2 ) 2 -U,-(CH 2 ) 3 CONH (CH 2 ) 3 -U,-(CH 2 ) 3 CONH (CH 2 ) 4 -U,-(CH 2 ) 4 CONH (CH 2 ) 4 -U,-(CH 2 ) 5 CONH (CH 2 ) 5 -U,-(CH 2 ) 6 CONH (CH 2 ) 7 -U,-(CH 2 ) 6 CONH (CH 2 ) 6 -U,-(CH 2 ) 7 CONH (CH 2 ) 7 -U,- (CH 2 ) 8 CONH (CH 2 ) 8 -U,-(CH 2 ) 9 CONH (CH 2 ) 9 -U,-(CH 2 ) 10 CONH (CH 2 ) 10 -U,-(CH 2 ) 2 CONH (CH 2 ) 10 -U,-(CH 2 ) 2 CONH
  • the LIN represents: -CH 2 NHCOCH 2 -U,-(CH 2 ) 2 NHCO (CH 2 ) 2 -U,-(CH 2 ) 3 NHCO (CH 2 ) 3 -U,-(CH 2 ) 3 NHCO (CH 2 ) 4 -U,-(CH 2 ) 4 NHCO (CH 2 ) 4 -U,-(CH 2 ) 5 NHCO (CH 2 ) 5 -U,-(CH 2 ) 6 NHCO (CH 2 ) 7 -U,-(CH 2 ) 6 NHCO (CH 2 ) 6 -U,-(CH 2 ) 7 NHCO (CH 2 ) 7 -U,- (CH 2 ) 8 NHCO (CH 2 ) 8 -U,-(CH 2 ) 9 NHCO (CH 2 ) 9 -U,-(CH 2 ) 10 NHCO (CH 2 ) 10 -U,
  • the LIN represents: -alkylene-U, wherein the alkylene is a linear or branched C 1-30 alkylene, and The group U represents N 3 , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof.
  • the compounds of formula (I) described in the present disclosure are preferably selected from the compounds listed in Table 1:
  • halogen atom or halogen used alone or in combination means fluorine, chlorine, bromine or iodine, and is preferably I, Br or Cl.
  • alkyl refers to a linear or branched alkyl group.
  • C x -C y alkyl (x and y each being an integer) refers to a straight-chain or branched-chain alkyl group containing x to y carbon atoms.
  • C 1-10 alkyl used alone or in combination in this disclosure refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms.
  • the C 1-10 alkyl group of the present disclosure is preferably a C 1-9 alkyl group, more preferably a C 1-8 alkyl group, still more preferably a C 2-8 alkyl group, more preferably a C 1-7 alkyl group, and even More preferred is C 1-6 alkyl, C 1-5 alkyl, or C 1-4 alkyl.
  • Illustrative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • the term “C 1-3 alkyl” in the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms, and representative examples thereof include methyl, ethyl, n-propyl, and isopropyl.
  • alkylene (which is used interchangeably with “alkylene chain”) alone or in combination refers to a straight or branched chain divalent saturated hydrocarbon group composed of carbon and hydrogen atoms.
  • Cx- Cy alkylene or " Cx - y alkylene” (x and y are each an integer) refers to a straight or branched alkylene group containing x to y carbon atoms.
  • the C 1 -C 30 alkylene of the present disclosure is preferably C 1 -C 29 alkylene, C 1 -C 28 alkylene, C 1 -C 27 alkylene, C 1 -C 26 alkylene, C 1- C 25 alkylene, C 1 -C 24 alkylene, C 1 -C 23 alkylene, C 1 -C 22 alkylene, C 1 -C 21 alkylene, C 1 -C 20 alkylene Alkyl, C 1 -C 19 alkylene, C 1 -C 18 alkylene, C 1 -C 17 alkylene, C 1 -C 16 alkylene, C 1 -C 15 alkylene, C 1 -C 14 alkylene, C 1 -C 13 alkylene, C 1 -C 12 alkylene, C 1 -C 11 alkylene, C 1 -C 10 alkylene, C 1 -C 9 alkylene , C 1 -C 8 alkylene, C 1 -C 7 alkylene, C 1 -C
  • Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene , Neopentylidene, tetrapentylidene, hexylene, heptylene, octylyl, nonylidene, decylidene, undecylidene, dodecylidene, tridecylidene, decylidene Tetraalkyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, decadecane, eicosene, behenyl, icosene Dialkyl, behenylidene, behenylidene, pentadecylidene, hexadecylidene, icosandylid
  • arylene refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene or naphthalene Or arylene.
  • the "arylene” is an optionally substituted arylene.
  • a substituted arylene group refers to an arylene group substituted 1-3 times with a substituent, wherein the substituent is selected from C 1-3 alkyl, C 1-3 alkoxy, halogen, amino, or hydroxyl.
  • C 1-3 alkoxy refers to a straight or branched chain alkoxy group containing 1 to 3 carbon atoms.
  • Representative examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Preferred are methoxy and ethoxy.
  • cycloalkyl refers to a saturated or partially unsaturated (i.e., one or more double bonds, but not fully conjugated) monocyclic or Bicyclic cycloalkyl.
  • C 3 - 10 cycloalkyl means a monocyclic saturated and partially unsaturated having 3 to 10 carbon atoms (i.e., having one or more double bonds, but not fully conjugated) cyclic or bicyclic hydrocarbon.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthalene, octahydro Cyclopentadiene, octahydro-1H-indene, and spiro.
  • cycloalkylene refers to a monocyclic ring that is saturated and partially unsaturated (ie, has one or more double bonds, but is not fully conjugated) having 3 to 12 carbon atoms. Or a bicyclic cyclic hydrocarbon divalent group.
  • cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenyl, cyclohexylene, cyclohexenylene, cycloheptylene, cyclohexylene Octyl, decahydronaphthyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, spirocyclo.
  • heteroaryl alone or in combination, means one or more (e.g., 1 to 6 or 1 to 5 or 1 to 4 or 1 to 3) independently selected 5- to 10-membered monocyclic or bicyclic aromatic ring groups from heteroatoms of oxygen, nitrogen and sulfur.
  • heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, Imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, Indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo [2,1,3] Oxazolyl, benzo [2,1,3] thiadiazolyl, benzo [1,2,3] thiadiazolyl, quinolinyl, is
  • heteroarylene alone or in combination, means one or more (e.g., 1 to 6 or 1 to 5 or 1 to 4 or 1 to 3) independent A 5- to 10-membered monocyclic or bicyclic divalent aromatic ring group of a heteroatom selected from oxygen, nitrogen, and sulfur.
  • heteroarylene groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, Thiadiazolyl, pyrrolidyl, imidazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazinyl, indolyl, isoindolene Indolyl, benzofuranyl, isoisobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, phenylene Benzothiazolyl, Benzoisothiazolyl, Benzotriazolyl, Benzo [2,1,3] oxadiazolyl, Benzo [2,1,3] thiadiazolyl,
  • heterocyclyl refers to a 4- to 6-membered saturated monocyclic group containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen.
  • Representative examples of the heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, triazolyl, tetrahydrofuranyl, tetrahydrothienyl, Tetrahydrothienyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and dioxane.
  • the heterocyclyl may be unsubstituted or substituted as explicitly defined.
  • heterocyclylene refers to a 4- to 6-membered saturated divalent monocyclic group containing one or more groups independently selected from sulfur, oxygen, and nitrogen. Heteroatom.
  • Representative examples of the heterocycloalkylene group include, but are not limited to, azidocyclobutylene, oxecyclobutylene, pyrrolidinyl, imidazolidyl, pyrazolyl, triazolyl, Tetrahydrofuryl, tetrahydrothienyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and Dioxane.
  • the heterocyclylene may be unsubstituted or substituted as explicitly defined.
  • alkynylene refers to a straight group containing 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon triple bonds. Chain or branched divalent hydrocarbon group.
  • alkynylene include, but are not limited to, ethynylene, 1-propynyl, 1-butynyl, and 1,3-diynyl.
  • alkynyl refers to a straight chain containing 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon triple bonds. Or branched hydrocarbon.
  • alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-dialkynyl.
  • alkenylene refers to a straight containing two to ten (preferably two to six, more preferably two to four) carbon atoms having one or more carbon-carbon double bonds. Chain or branched divalent hydrocarbon group.
  • alkenyl used alone or in combination refers to a compound having one or more carbon-carbon double bonds (preferably containing 2 to 40 carbon atoms, more preferably 2 to 35, 2 to 30, 2 to 25 , 2 to 20, 2 to 15, 2 to 10, 2 to 6 or 2 to 5 carbon atoms, particularly preferably 2 to 4 or 2 to 3 carbon atoms) straight or branched chain hydrocarbon groups.
  • alkenyl examples include, but are not limited to, vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, pentenyl, n-pent-2, 4-dienyl, 1-methyl-but-1-enyl, 2-methyl-but-1-enyl, 3-methyl-but-1-enyl, 1-methyl-but-2 -Alkenyl, 2-methyl-but-2-enyl, 3-methyl-but-2-enyl, 1-methyl-but-3-enyl, 2-methyl-but-3-ene , 3-methyl-but-3-enyl, hexenyl, heptenyl, octenyl, n-oct-2-enyl, nonenyl, decenyl, n-dodecyl-2 -Alkenyl, isododecenyl, n-dodecen-2-enyl, n-octa
  • the term "leaving group” used alone or in combination is a term well known to those skilled in the art, which may also be referred to as a leaving group, which is carried from a reactant in a chemical reaction
  • a pair of electron-releasing molecular fragments is the term used in nucleophilic substitution reactions and elimination reactions.
  • Common ionic leaving group with a Cl -, Br -, I - and a sulfonate (such as tosylate, TsO -), the leaving group with a neutral molecule of water, ammonia and alcohols.
  • organic base used alone or in combination generally refers to an organic compound containing an amino group in the molecule, such as an amine compound.
  • the organic base includes, but is not limited to, triethylamine, dimethylamine, tri-tert-butylamine, N, N-dimethylaniline, DIPEA, N, N-diethylethylamine, DMAP, pyridine, quinine Morpholine, morpholine and NMM.
  • protecting group is an agent capable of protecting a certain group (eg, carboxyl, amino, sulfonyl).
  • a certain group eg, carboxyl, amino, sulfonyl.
  • the use of protecting groups in organic reactions is very common, and the protection of hydroxyl, amino and other groups is common.
  • room temperature refers to the ambient temperature, such as, but not limited to, a temperature of 20-30 ° C.
  • the method of the present disclosure can react the lenalidomide with an appropriate alkylating agent in the presence of an organic base to obtain an amino alkylation product with high selectivity.
  • the present disclosure provides examples of using a plurality of organic bases and inorganic bases, and the results show that the alkylation reaction of the method of the present disclosure in the presence of an organic base can obtain a desired amino alkylation product with high selectivity,
  • the alkylation reaction in the presence of an inorganic base cannot obtain the desired amino alkylation product, but only the N alkylation product of glutarimide, as shown in Scheme 5 and Table 2 below.
  • Solvents and reagents are processed as follows:
  • the solvents used in the reaction were DCM, DMF, NMP, anhydrous EtOH, anhydrous MeOH, etc. were purchased from Sinopharm Group;
  • HPLC preparation uses preparative grade CH 3 CN and deionized water
  • OTs-substituted tert-butyl ester (1equiv) and sodium iodide (2equiv) were added to a 25 mL egg-shaped bottle, followed by acetone (5 mL), and the mixture was refluxed at 60 ° C for 2 h.
  • the acetone was spin-dried, followed by the addition of NMP (3 mL), lenalidomide (0.8 equiv) and N, N-diisopropylethylamine (3 equiv).
  • the reaction was carried out at 110 ° C. for 12 h in an oil bath.
  • the reaction solution was cooled to room temperature, and then prepared using a C18 reversed-phase column.
  • acetonitrile / (water + 0.1% TFA) 10%-100%.
  • Acetonitrile was evaporated under reduced pressure.
  • the compound was then added to a 25 mL single-necked flask, 1 mL of dichloromethane and 3 mL of trifluoroacetic acid were sequentially added, and stirred at room temperature for 1 h.
  • the reaction solvent was evaporated under reduced pressure, and water was added to lyophilize to obtain the final target compound.
  • Acetonitrile was distilled off under reduced pressure. Intermediate; the compound was then added to a 25 mL single-necked flask, 1 mL of dichloromethane and 3 mL of trifluoroacetic acid were sequentially added, and stirred at room temperature for 1 h. The reaction solvent was evaporated under reduced pressure, and water was added to lyophilize to obtain the final target compound.
  • Example 1 Preparation of (2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) aminoacetic acid ((2- (2,6-dioxopiperidin- 3-yl) -1-oxoisoindolin-4-yl) glycine; SIAIS1204057)
  • Acetonitrile was distilled off under reduced pressure. Intermediate; the compound was then added to a 25 mL single-necked flask, 1 mL of dichloromethane and 3 mL of trifluoroacetic acid were sequentially added, and stirred at room temperature for 1 h.
  • Example 2 Preparation of 3-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) propanoic acid (3-((2 -(2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propanoic acid; SIAIS1204059)
  • the target compound SIAIS1204059 was prepared using the same method as in Example 1 under appropriate conditions understandable in the art, except that the bromo-tert-butyl ester used was tert-butyl 3-bromopropionate.
  • Example 3 Preparation of 4-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) butanoic acid (4-((2 -(2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) butanoic acid; SIAIS1204085)
  • the target compound SIAIS1204085 was prepared using the same method as in Example 1 under appropriate conditions understandable in the art, except that the bromo-tert-butyl ester used was tert-butyl 4-bromobutyrate.
  • Example 4 Preparation of 5-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) pentanoic acid (5-((2 -(2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) pentanoic acid; SIAIS184047)
  • the target compound SIAIS184047 was prepared using the same method as in Example 1 under appropriate conditions understandable in the art, except that the bromo-tert-butyl bromide used was tert-butyl 5-bromovalerate.
  • Example 5 Preparation of 6-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) hexanoic acid (6-((2 -(2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexanoic acid; SIAIS1204061)
  • the target compound SIAIS1204061 was prepared using the same method as in Example 1 under appropriate conditions understandable in the art, except that the bromo-tert-butyl ester used was tert-butyl 6-bromohexanoate.
  • Example 6 Preparation of 7-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) heptanoic acid (7-((2 -(2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) heptanoic acid; SIAIS1204063)
  • the target compound SIAIS1204063 was prepared using the same method as in Example 1 under appropriate conditions understandable in the art, except that the bromo-tert-butyl ester used was 7-bromoheptanoic acid tert-butyl ester.
  • Example 7 Preparation of 2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) ethoxy) acetic acid (2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid; SIAIS1204115)
  • tert-butyl 2- (2- (toluenesulfonyloxy) ethoxy) acetate (1equiv) and sodium iodide (2equiv) were added to a 25 mL egg-shaped bottle, followed by acetone ( 5mL), 60 ° C oil bath under reflux for 2h. The acetone was spin-dried, followed by the addition of NMP (3 mL), lenalidomide (0.8 equiv) and N, N-diisopropylethylamine (3 equiv). The reaction was carried out at 110 ° C. for 12 h in an oil bath.
  • the reaction solution was cooled to room temperature, and then prepared using a C18 reversed-phase column.
  • the eluent (v / v): acetonitrile / (water + 0.1% TFA) 10%-100%.
  • Acetonitrile was distilled off under reduced pressure.
  • the compound was then added to a 25 mL single-necked flask, 1 mL of dichloromethane and 3 mL of trifluoroacetic acid were sequentially added, and stirred at room temperature for 1 h.
  • Example 7-1 Preparation of 2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy ) Acetic acid (2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid; SIAIS1204115)
  • nalidamine (1equiv), 2- (2- (tosyloxy) ethoxy) acetic acid tert-butyl acetate (1.2equiv), and N, N-diisopropylethylamine ( 3equiv) was added to a 25 mL reaction tube, followed by NMP (5 mL), and reacted at 80 ° C. for 6 h in an oil bath.
  • the reaction solution was cooled to room temperature, and then prepared using a C18 reversed-phase column.
  • the eluent (v / v): acetonitrile / (water + 0.1% TFA) 10%-100%. Acetonitrile was distilled off under reduced pressure.
  • Example 8 Preparation of 2- (2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy ()) Ethoxy) acetic acid (2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) acetic acid; SIAIS1204123 )
  • the target compound SIAIS1204123 was prepared using the same method as in Example 7 under appropriate conditions understandable in the art, except that the tert-butyl ester substituted with OTs was 2- (2- (2- (toluene Sulfonyloxy) ethoxy) ethoxy) tert-butyl acetate.
  • the target compound SIAIS1204127 was prepared using the same method as in Example 7 under appropriate conditions understandable in the art, except that the tert-butyl ester substituted with OTs was 2- (2- (2- (2 -(Tosyloxy) ethoxy) ethoxy) ethoxy) t-butyl acetate.
  • Example 10 Preparation of 14-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) -3,6,9,12 -Tetraoxatetradecanoic acid (14-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12-tetraoxatetradecanoic acid; SIAIS1204131 )
  • the target compound SIAIS1204131 was prepared using the same method as in Example 7 under appropriate conditions understandable in the art, except that the tert-butyl ester substituted with OTs was 14- (toluenesulfonyloxy)- Tert-butyl 3,6,9,12-tetraoxatetradecanoate.
  • the obtained target compound SIAIS1204131 was a yellow liquid, 134 mg, and the yield was 79%.
  • Example 11 Preparation of 14-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) -3,6,9,12 -Tetraoxatetradecanoic acid (14-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12-tetraoxatetradecanoic acid; SIAIS1204135 )
  • the target compound SIAIS1204135 was prepared using the same method as in Example 7 under appropriate conditions understandable in the art, except that the tert-butyl ester substituted with OTs was 17- (toluenesulfonyloxy)- Tert-butyl 3,6,9,12,15-pentaoxahexadecanoate.
  • the obtained target compound SIAIS1204135 was a yellow liquid, 127 mg, and the yield was 75%.
  • Example 12 Preparation of 3- (4-((3-aminopropyl) amino) -1-oxoisoindololin-2-yl) piperidine-2,6-dione (3- (4- ( (3-aminopropyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS1204071)
  • nalidamine (259.3 mg, 1 mmol, 1 equiv), tert-butyl (3-bromopropyl) carbamate (1.2 mmol, 1.2 equiv), and N, N-diisopropylethylamine ( 387.7 mg, 3 mmol, 3 equiv) were added to a 25 mL reaction tube, followed by NMP (5 mL), and reacted at 110 ° C. in an oil bath for 12 h.
  • the reaction solution was cooled to room temperature, and then prepared using a C18 reversed-phase column.
  • acetonitrile / (water + 0.1% TFA) 10%-100%.
  • Acetonitrile was distilled off under reduced pressure.
  • the compound was then added to a 25 mL single-necked flask, 1 mL of dichloromethane and 3 mL of trifluoroacetic acid were sequentially added, and stirred at room temperature for 1 h.
  • Example 13 Preparation of 3- (4-((4-aminobutyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (3- (4- ( (4-aminobutyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS1204073)
  • the target compound SIAIS1204073 was prepared using the same method as in Example 12 under appropriate conditions understandable in the art, except that the N-tert-butoxycarbonyl-bromoalkylamine used was (4-bromo Butyl) tert-butyl carbamate.
  • Example 14 Preparation of 3- (4-((5-aminopentyl) amino) -1-oxoisoindololin-2-yl) piperidine-2,6-dione (3- (4- ( (5-aminopentyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS1204075)
  • the target compound SIAIS1204075 was prepared using the same method as in Example 12 under appropriate conditions understandable in the art, except that the N-tert-butoxycarbonyl-bromoalkylamine used was (5-bromo Amyl) tert-butyl carbamate.
  • Example 15 Preparation of 3- (4-((6-aminohexyl) amino) -1-oxoisoindololin-2-yl) piperidine-2,6-dione (3- (4-(( 6-aminohexyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS1204077)
  • the target compound SIAIS1204077 was prepared using the same method as in Example 12 under appropriate conditions understandable in the art, except that the N-tert-butoxycarbonyl-bromoalkylamine used was (6-bromo Hexyl) tert-butyl carbamate.
  • Example 16 Preparation of 3- (4-((7-aminoheptyl) amino) -1-oxoisoindololin-2-yl) piperidine-2,6-dione (3- (4- ( (7-aminoheptyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS1204079)
  • the target compound SIAIS1204079 was prepared using the same method as in Example 12 under appropriate conditions understandable in the art, except that the N-tert-butoxycarbonyl-bromoalkylamine used was (7-bromo Heptyl) tert-butyl carbamate.
  • Example 17 Preparation of 3- (4-((8-aminooctyl) amino) -1-oxoisoindololin-2-yl) piperidine-2,6-dione (3- (4- ( (8-aminooctyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS1204081)
  • the target compound SIAIS1204081 was prepared using the same method as in Example 12 under appropriate conditions understandable in the art, except that the N-tert-butoxycarbonyl-bromoalkylamine used was (8-bromo Octyl) tert-butyl carbamate.
  • Example 18 Preparation of 3- (1-oxo-4- (propylamino) isoindololin-2-yl) piperidine-2,6-dione (3- (1-oxo-4- (propylamino ) isoindolin-2-yl) piperidine-2,6-dione; SIAIS1204083A)
  • nalidamine (20 mg, 0.073 mmol, 1 equiv), n-propyl bromide (18.9 mg, 0.0876 mmol, 1.2 equiv), and N, N-diisopropylethylamine (29.9 mg, 0.219 mmol) 3equiv) were added to a 10 mL reaction tube, followed by NMP (2 mL), and reacted at 110 ° C. for 6 h in an oil bath.
  • the reaction solution was cooled to room temperature, and then prepared using a C18 reversed-phase column.
  • nalidamine (20 mg, 0.073 mmol, 1 equiv), n-propyl bromide (18.9 mg, 0.0876 mmol, 1.2 equiv), KI (3.8 mg, 0.0146 mmol, 0.2 equiv), and potassium carbonate (21.3 mg, 0.146 mmol, 3 equiv) were added together into a 10 mL reaction tube, followed by acetonitrile (2 mL), and the mixture was refluxed at 100 ° C for 2 h. The reaction solution was reduced to room temperature, and acetonitrile was distilled off under reduced pressure, and then prepared by using a C18 reversed-phase column.

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Abstract

提供了一种制备式(I)化合物的方法，所述方法包括：式(II)化合物的氨基与式(III)化合物在有机碱存在下发生氨基烷基化反应，选择性得到式(I)化合物。还提供了式(I)化合物。

Description

制备来那度胺衍生物的方法 技术领域
本公开涉及制备来那度胺衍生物式(I)化合物的方法以及所述式(I)化合物。
Figure PCTCN2019091812-appb-000001
背景技术
沙利度胺及其类似物泊马度胺、来那度胺是目前常用的免疫调节药物,尤其对多发性骨髓瘤具有较好疗效 1。研究发现,此类药物可以通过其戊二酰亚胺结构与CUL4-RBX1-DDB1-Cereblon(CRL4 CRBN)E3泛素连接酶复合物的底物受体Cereblon蛋白结合,促进转录因子IKZF1/3与Cereblon的结合,诱导IKZF1/3发生泛素化降解 2。近年来利用沙利度胺及其类似物可以与Cereblon E3特异性结合的特点,发现沙利度胺及其衍生物可以作为E3连接酶识别小分子配体，并将其成功的引入到蛋白降解靶向药物(PROTAD：Proteolysis Targeting Drug)开发中 3。
Figure PCTCN2019091812-appb-000002
[根据细则26改正23.08.2019]　
泛素介导的蛋白质降解是细胞内蛋白质最主要的负向调节方式，泛素化降解途径参与调节细胞周期、增殖、凋亡、信号传递等几乎一切生命活动。蛋白降解靶向药物(PROTAD)技术平台利用泛素-蛋白酶体系来降解致病的靶蛋白。具体来说，PROTAD分子由三部分构成：与靶蛋白结合的小分子抑制剂、与E3连接酶结合的配体，和连接两者的化学链(如图1的PROTAD结构式所示)。在细胞内，PROTAD可以通过与靶蛋白和E3连接酶建立三元复合物而起作用，使本来不能与E3结合的靶蛋白多泛素化，并随后通过蛋白酶体降解 4。
[根据细则26改正23.08.2019]　
近几年，将不同的靶蛋白小分子抑制剂通过连接基与沙利度胺或其类似物连接,设计合成了多个基于CRBN E3的蛋白降解靶向小分子化合物。Bradner 5、Crews 6、王少萌 7等课题组已经设计合成了如以下结构式表示的蛋白降解靶向小分子化合物，成功降解了BET蛋白和BCR-ABL融合蛋白。
Figure PCTCN2019091812-appb-000004
合成上述的蛋白降解靶向小分子化合物，需要首先合成一系列基于CRBN配体的连接物库，一端带有可以与小分子抑制剂结合的羧基、氨基或者卤素等官能团，另一端保留与CRBN结合的关键戊二酰亚胺的结构单元。
Bradner教授报道了靶向降解BAF复合物因子BRD9的蛋白降解靶向小分子化合物，并比较了泊马度胺和来那度胺充当CRBN配体部分的蛋白降解靶向小分子化合物的生物活性，发现如以下式(a)表示的基于来那度胺的蛋白降解靶向小分子化合物B具有更好的生物活性，而且在免疫调节药物的药效对比中，也具有相似的结果。因此，发展一种合成基于来那度胺的连接物库的方法是极有必要的。
Figure PCTCN2019091812-appb-000005
文献上报道的基于泊马度胺的连接物库，主要通过4-氟取代的沙利度胺与烷基胺的芳香亲核取代反应及脱保护反应构筑 6(方案1)。
Figure PCTCN2019091812-appb-000006
在此基础上，我们首先尝试通过关环反应构筑了4-氟取代的来那度胺衍生物，但是下一步的生成相应的氨基烷基化产物的亲核芳香取代反应并不能发生(方案2)，促使发展新的合成方法显得非常重要和迫切。
Figure PCTCN2019091812-appb-000007
通过文献调研发现，目前文献中该类相应的氨基烷基化化合物的合成方法有两种通用的方法，方法一为还原胺化反应 8、方法二为烷基化反应 9。方案3由于采用了价格昂贵以及危险的还原剂氰基硼氢化钠和不易得和不稳定的醛基底物反应得到，并不适合工业化生产和放大。如Bradner教授报道了来那度胺与醛基取代的胺的还原胺化反应，构筑了一个基于来那度胺的连接物，但是该反应需要复杂的操作，缺乏通用性并且总体收率较低(46％，方案3)。方法二为2017年Li 10采用无机碱碳酸钾条件下通过来那度胺与烷基溴的烷基化反应来制备相应的氨基烷基化产物3a，根据该文献反应条件，我们发现化合物3a'才是该反应条件下真正的产物结构(方案4)，并未得到所需要相应的氨基烷基化产物3a。
Figure PCTCN2019091812-appb-000008
因此，迫切需要开发一种新的合成来那度胺衍生物的方法。
发明内容
为了得到所需要的正确氨基烷基化产物，申请人设计了一种新的合成来那度胺衍生物的方法，其包括在有机碱(例如但不限于DIPEA或者三乙胺)作为缚酸剂的反应条件，使来那度胺与适当的烷基化试剂反应，可以高选择性的得到氨基烷基化主产物。申请人进一步将此条件扩充到一系列的带有离去基团的烷基化试剂与来那度胺的烷基化反应当中，得到了高选择性的氨基烷基化主产物，并将该方法应用于蛋白降解靶向药物技术开发中。
本公开的上述目的通过提供制备来那度胺衍生物式(I)化合物的方法得以实现，
Figure PCTCN2019091812-appb-000009
其中LIN表示-亚烷基-U，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
基团U表示氢；
所述方法包括：使式(II)化合物的氨基与式(III)化合物在有机碱存在下发生氨基烷基化反应，选择性得到式(I)化合物，
Figure PCTCN2019091812-appb-000010
R 1-LIN   式(III)
其中R 1表示离去基团，且LIN表示-亚烷基-U，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
基团U表示氢。
另一方面，本公开还提供一种式(I)化合物，
Figure PCTCN2019091812-appb-000011
其中，LIN表示-亚烷基-U，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组 合；或
基团U表示氢。
具体实施方式
因此，本公开提供一种制备来那度胺衍生物式(I)化合物的方法，
Figure PCTCN2019091812-appb-000012
其中LIN表示-亚烷基-U，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
基团U表示氢；
所述方法包括：使式(II)化合物的氨基与式(III)化合物在有机碱存在下发生氨基烷基化反应，选择性得到式(I)化合物，
Figure PCTCN2019091812-appb-000013
R 1-LIN   式(III)
其中R 1表示离去基团，且LIN表示-亚烷基-U，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
基团U表示氢。
在本公开中，对式(III)化合物的LIN中的基团，可根据需要，采用本领域公知的方法和适当的保护基进行保护。在式(III)化合物的LIN中的基团U被保护基团保护的情况下(例如基团U表示由保护基团保护的COOH、SO 3H或NH 2)，由式(III)化合物与式(II)化合物的氨基发生氨基烷基化反应制备得到的相应式(I)化合物的LIN中的基团U的保护基可以保留，或者可以进一步通过本领域公知的方法(如下文中所述方法)进行脱保护。
在本公开的一实施方式中，所述有机碱包括但不限于例如：三乙胺、二甲胺、三叔丁胺、N,N-二甲基苯胺、DIPEA、N,N-二乙基乙胺、DMAP、吡啶、喹啉、吗啉和NMM，也可以是这其中的一种或多种碱。
在本公开的一实施方式中，所述R 1表示卤素、甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基。
在本公开的一实施方式中，所述LIN表示：
-C 1-30亚烷基-U，-(CH 2) n1-(O(CH 2) n2) m1-U，-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-U，-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-U，-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-U，-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-U，-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-U，-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-U，由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的-亚烷基链-U，或其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-(CH 2) n1-(O(CH 2) n2) m1-U；
其中R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或支链的C 1- 10烷基或C 3- 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，或R a5、R a6、R a7、R a8、R a9、R a10，或R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；以及
n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；
其中基团U表示可选地由保护基团保护的-COOH、-SO 3H或-NH 2；或基团U表示 N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN优选是-C 1-30亚烷基-U。在本公开的一实施方式中，所述LIN优选是-亚甲基-U或-C 2-30亚烷基-U，其中所述C 2-30亚烷基是直链或支链的C 2-30亚烷基(优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)，以及基团U表示可选地由保护基团保护的-COOH、-SO 3H或-NH 2，或基团U表示-N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN表示：
-CH 2-U；-(CH 2) 2-U；-(CH 2) 3-U；-(CH 2) 4-U；-(CH 2) 5-U；-(CH 2) 6-U；-(CH 2) 7-U；-(CH 2) 8-U；-(CH 2) 9-U；-(CH 2) 10-U；-(CH 2) 11-U；-(CH 2) 12-U；-(CH 2) 13-U；-(CH 2) 14-U；-(CH 2) 15-U；-(CH 2) 16-U；-(CH 2) 17-U；-(CH 2) 18-U；-(CH 2) 19-U；-(CH 2) 20-U；-(CH 2) 21-U；-(CH 2) 22-U；-(CH 2) 23-U；-(CH 2) 24-U；-(CH 2) 25-U；-(CH 2) 26-U；-(CH 2) 27-U；-(CH 2) 28-U；-(CH 2) 29-U；或-(CH 2) 30-U。
其中基团U表示可选地由保护基团保护的-COOH、SO 3H或-NH 2，或基团U表示-N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN表示：
-CH 2-((CH 2) 2-O)-CH 2-U、-CH 2-((CH 2) 2-O) 2-CH 2-U、-CH 2-((CH 2) 2-O) 3-CH 2-U、-CH 2-((CH 2) 2-O) 4-CH 2-U、-CH 2-((CH 2) 2-O) 5-CH 2-U、-CH 2-((CH 2) 2-O) 6-CH 2-U、-CH 2-((CH 2) 2-O) 7-CH 2-U、-CH 2-((CH 2) 2-O) 8-CH 2-U、-CH 2-((CH 2) 2-O) 9-CH 2-U、-CH 2-((CH 2) 2-O) 10-CH 2-U、-CH 2-((CH 2) 2-O) 11-CH 2-U、-CH 2-((CH 2) 2-O) 12-CH 2-U、-CH 2-((CH 2) 2-O) 13-CH 2-U、-CH 2-((CH 2) 2-O) 14-CH 2-U、-CH 2-((CH 2) 2-O) 15-CH 2-U、-CH 2-((CH 2) 2-O) 16-CH 2-U、-CH 2-((CH 2) 2-O) 17-CH 2-U、-CH 2-((CH 2) 2-O) 18-CH 2-U、-CH 2-((CH 2) 2-O) 19-CH 2-U、-CH 2-((CH 2) 2-O) 20-CH 2-U、-((CH 2) 2-O)-CH 2-U、-((CH 2) 2-O) 2-CH 2-U、-((CH 2) 2-O) 3-CH 2-U、-((CH 2) 2-O) 4-CH 2-U、-((CH 2) 2-O) 5-CH 2-U、-((CH 2) 2-O) 6-CH 2-U、-((CH 2) 2-O) 7-CH 2-U、-((CH 2) 2-O) 8-CH 2-U、-((CH 2) 2-O) 9-CH 2-U、-((CH 2) 2-O) 10-CH 2-U、-((CH 2) 2-O) 11-CH 2-U、-((CH 2) 2-O) 12-CH 2-U、-((CH 2) 2-O) 13-CH 2-U、-((CH 2) 2-O) 14-CH 2-U、-((CH 2) 2-O) 15-CH 2-U、-((CH 2) 2-O) 16-CH 2-U、-((CH 2) 2-O) 17-CH 2-U、-((CH 2) 2-O) 18-CH 2-U、-((CH 2) 2-O) 19-CH 2-U、-((CH 2) 2-O) 20-CH 2-U、- CH 2-O-(CH 2) 2-U、-CH 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 2) 6-U、-CH 2-(O(CH 2) 2) 7-U、-CH 2-(O(CH 2) 2) 8-U、-CH 2-(O(CH 2) 2) 9-U、-CH 2-(O(CH 2) 2) 10-U、-(CH 2) 2-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-U、-(CH 2) 2-(O(CH 2) 2) 7-U、-(CH 2) 2-(O(CH 2) 2) 8-U、-(CH 2) 2-(O(CH 2) 2) 9-U、-(CH 2) 2-(O(CH 2) 2) 10-U、-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-U、-(CH 2) 3-(O(CH 2) 2) 7-U、-(CH 2) 3-(O(CH 2) 2) 8-U、-(CH 2) 3-(O(CH 2) 2) 9-U、-(CH 2) 3-(O(CH 2) 2) 10-U、-(CH 2) 4-O-(CH 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 3-U、-(CH 2) 4-(O(CH 2) 2) 4-U、-(CH 2) 4-(O(CH 2) 2) 5-U、-(CH 2) 4-(O(CH 2) 2) 6-U、-(CH 2) 4-(O(CH 2) 2) 7-U、-(CH 2) 4-(O(CH 2) 2) 8-U、-(CH 2) 4-(O(CH 2) 2) 9-U、-(CH 2) 4-(O(CH 2) 2) 10-U、-CH 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 3) 6-U、-CH 2-(O(CH 2) 3) 7-U、-CH 2-(O(CH 2) 3) 8-U、-CH 2-(O(CH 2) 3) 9-U、-CH 2-(O(CH 2) 3) 10-U、-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-U、-(CH 2) 2-(O(CH 2) 3) 7-U、-(CH 2) 2-(O(CH 2) 3) 8-U、-(CH 2) 2-(O(CH 2) 3) 9-U、-(CH 2) 2-(O(CH 2) 3) 10-U、-(CH 2) 3-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 3-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-U、-(CH 2) 3-(O(CH 2) 3) 7-U、-(CH 2) 3-(O(CH 2) 3) 8-U、-(CH 2) 3-(O(CH 2) 3) 9-U、-(CH 2) 3-(O(CH 2) 3) 10-U、-CH 2-O-(CH 2) 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-CH 2-O-(CH 2) 3-O-(CH 2) 2-U、-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-CH 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-(O(CH 2) 2) 2- O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-U、-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-U、或-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-U；
其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN是-亚烷基-U，所述亚烷基(优选C 1-30亚烷基链，尤其优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)是被一或多个取代基取代一或多次的直链或支链的亚烷基链，其中所述取代基选自羟基、氨基、巯基、卤素或其组合；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。在本公开的一子实施方式中，所述取代基的数目可以是例如1-30个，1-25个，1-20个，或者1-15，1-10，1-9，1-8，1-7，1-6，1-5，1-4，1-3，或1-2个，或是20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、或1个。
在本公开的一实施方式中，所述LIN表示-C 1-30亚烷基链-U，所述C 1-30亚烷基链是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-30亚烷基链；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。在本公开的一子实施方式中，所述取代基的数目可以是例如1-30个，1-25个，1-20个，或者1-15，1-10，1-9，1-8，1-7，1-6，1-5，1-4，1-3，或1-2个，或是20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、或1个。
在本公开的一实施方式中，所述LIN表示：-(CH 2) n11-三唑基-(CH 2) n12-U、-(CH 2) n11-三唑基-(CH 2) n12-(O(CH 2) n13) m11-U、-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-三唑基-(CH 2) n14-(O(CH 2) n15) m12-O-(CH 2) n16-U、-(CH 2) n11-三唑基-(CH 2) n12-(O(CH 2) n13) m11-O-(CH 2) n14-U或-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-三唑基-(CH 2) n14-U；以及
n11、n12、n13、n14、n15、n16、m11、m12分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示 N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN表示：-(CH 2) 3-三唑基-(CH 2) 5-U、-(CH 2) 2-三唑基-(CH 2) 5-U、-CH 2-三唑基-(CH 2) 5-U、-(CH 2) 2-三唑基-(CH 2) 4-U、-(CH 2) 3-三唑基-(CH 2) 2-O(CH 2) 2-U、-(CH 2) 2-三唑基-(CH 2) 2-O(CH 2) 2-U或-CH 2-三唑基-(CH 2) 2-O(CH 2) 2-U；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN表示：-CH 2CONHCH 2-U、-(CH 2) 2CONH(CH 2) 2-U、-(CH 2) 3CONH(CH 2) 3-U、-(CH 2) 3CONH(CH 2) 4-U、-(CH 2) 4CONH(CH 2) 4-U、-(CH 2) 5CONH(CH 2) 5-U、-(CH 2) 6CONH(CH 2) 7-U、-(CH 2) 6CONH(CH 2) 6-U、-(CH 2) 7CONH(CH 2) 7-U、-(CH 2) 8CONH(CH 2) 8-U、-(CH 2) 9CONH(CH 2) 9-U、-(CH 2) 10CONH(CH 2) 10-U、-(CH 2) 2CONH(CH 2) 5-U、-(CH 2) 2CONH(CH 2) 3-U、-(CH 2) 2CONH(CH 2) 4-U、或-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-U；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN表示：-CH 2NHCOCH 2-U、-(CH 2) 2NHCO(CH 2) 2-U、-(CH 2) 3NHCO(CH 2) 3-U、-(CH 2) 3NHCO(CH 2) 4-U、-(CH 2) 4NHCO(CH 2) 4-U、-(CH 2) 5NHCO(CH 2) 5-U、-(CH 2) 6NHCO(CH 2) 7-U、-(CH 2) 6NHCO(CH 2) 6-U、-(CH 2) 7NHCO(CH 2) 7-U、-(CH 2) 8NHCO(CH 2) 8-U、-(CH 2) 9NHCO(CH 2) 9-U、-(CH 2) 10NHCO(CH 2) 10-U、-(CH 2) 2NHCO(CH 2) 5-U、-(CH 2) 2NHCO(CH 2) 3-U、-(CH 2) 2NHCO(CH 2) 4-U、-(CH 2) 4NHCO(CH 2) 8-U或-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-U；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开的一实施方式中，所述LIN表示-亚烷基-U，其中所述亚烷基是直链或支链的C 1-30亚烷基，且所述基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合。
在本公开的一实施方式中，在所述反应中，基于所述式(II)化合物的摩尔量计算，有机碱的量为0.1当量至10当量。优选地，基于所述式(II)化合物的摩尔量计算，有机碱的量为0.1当量至9当量，优选0.5当量至8当量，0.5当量至7当量，0.5当量至6当量，0.5当量至5当量，1当量至4当量，1当量至3当量。
在本公开的一实施方式中，在所述反应中，基于所述式(II)化合物的摩尔量 计算，所述式(III)化合物的量为0.5当量至1.5当量(优选0.5当量，0.6当量，0.7当量，0.8当量，0.9当量，1当量，1.1当量，1.2当量，1.3当量，1.4当量，或1.5当量)。
在本公开的一实施方式中，所述反应在添加或不添加溶剂的情况进行。本领域技术人员可根据需要适当选择溶剂。优选地，溶剂包括但不限于NMP、DMF、CH 3CN。在本公开的一实施方式中，所述反应在不添加溶剂的情况进行，其中所述有机碱用作为唯一的溶剂。
在本公开的一实施方式中，所述反应是在10-150℃的温度进行。在本公开的一实施方式中，所述温度为20-140℃，70-130℃，80-120℃，90-110℃，或80-100℃。
在本公开的一实施方式中，当离去基团R 1表示对甲苯磺酰氧基时，所述方法还可包括先使所述式(III)化合物与NaI反应，以将式(III)化合物转换成碘代物，即
I-LIN   式(IV)；
所述式(IV)化合物进一步与式(II)化合物的氨基在有机碱存在下发生氨基烷基化反应，选择性得到式(I)化合物。
在本公开的一实施方式中，在式(III)化合物的基团U被保护基保护的情况下，本公开所述方法还可进一步包括对式(I)化合物的受保护的基团U进行脱保护的步骤。
本公开还提供式(I)化合物，
Figure PCTCN2019091812-appb-000014
其中，LIN表示-亚烷基-U，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：
-C 1-30亚烷基-U，-(CH 2) n1-(O(CH 2) n2) m1-U，-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-U，- (CR a1R a2) n1-(O(CR a3R a4) n2) m1-U，-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-U，-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-U，-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-U，-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-U，由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的-亚烷基链-U，或其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-(CH 2) n1-(O(CH 2) n2) m1-U；
其中R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或支链的C 1- 10烷基或C 3- 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，或R a5、R a6、R a7、R a8、R a9、R a10，或R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；以及
n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；
其中基团U表示可选地由保护基团保护的-COOH、-SO 3H或-NH 2；或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN优选是-C 1-30亚烷基-U。在本公开的一实施方式中，所述LIN优选是-亚甲基-U或-C 2-30亚烷基-U，其中所述C 2-30亚烷基是直链或支链的C 2-30亚烷基(优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)，以及基团U表示可选地由保护基团保护的-COOH、-SO 3H或-NH 2，或基团U表示-N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：
-CH 2-U；-(CH 2) 2-U；-(CH 2) 3-U；-(CH 2) 4-U；-(CH 2) 5-U；-(CH 2) 6-U；-(CH 2) 7-U；-(CH 2) 8-U；-(CH 2) 9-U；-(CH 2) 10-U；-(CH 2) 11-U；-(CH 2) 12-U；-(CH 2) 13-U；-(CH 2) 14-U；-(CH 2) 15-U；-(CH 2) 16-U；-(CH 2) 17-U；-(CH 2) 18-U；-(CH 2) 19-U；-(CH 2) 20-U；-(CH 2) 21-U；-(CH 2) 22-U；-(CH 2) 23-U；- (CH 2) 24-U；-(CH 2) 25-U；-(CH 2) 26-U；-(CH 2) 27-U；-(CH 2) 28-U；-(CH 2) 29-U；或-(CH 2) 30-U。
其中基团U表示可选地由保护基团保护的-COOH、SO 3H或-NH 2，或基团U表示-N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：
-CH 2-((CH 2) 2-O)-CH 2-U、-CH 2-((CH 2) 2-O) 2-CH 2-U、-CH 2-((CH 2) 2-O) 3-CH 2-U、-CH 2-((CH 2) 2-O) 4-CH 2-U、-CH 2-((CH 2) 2-O) 5-CH 2-U、-CH 2-((CH 2) 2-O) 6-CH 2-U、-CH 2-((CH 2) 2-O) 7-CH 2-U、-CH 2-((CH 2) 2-O) 8-CH 2-U、-CH 2-((CH 2) 2-O) 9-CH 2-U、-CH 2-((CH 2) 2-O) 10-CH 2-U、-CH 2-((CH 2) 2-O) 11-CH 2-U、-CH 2-((CH 2) 2-O) 12-CH 2-U、-CH 2-((CH 2) 2-O) 13-CH 2-U、-CH 2-((CH 2) 2-O) 14-CH 2-U、-CH 2-((CH 2) 2-O) 15-CH 2-U、-CH 2-((CH 2) 2-O) 16-CH 2-U、-CH 2-((CH 2) 2-O) 17-CH 2-U、-CH 2-((CH 2) 2-O) 18-CH 2-U、-CH 2-((CH 2) 2-O) 19-CH 2-U、-CH 2-((CH 2) 2-O) 20-CH 2-U、-((CH 2) 2-O)-CH 2-U、-((CH 2) 2-O) 2-CH 2-U、-((CH 2) 2-O) 3-CH 2-U、-((CH 2) 2-O) 4-CH 2-U、-((CH 2) 2-O) 5-CH 2-U、-((CH 2) 2-O) 6-CH 2-U、-((CH 2) 2-O) 7-CH 2-U、-((CH 2) 2-O) 8-CH 2-U、-((CH 2) 2-O) 9-CH 2-U、-((CH 2) 2-O) 10-CH 2-U、-((CH 2) 2-O) 11-CH 2-U、-((CH 2) 2-O) 12-CH 2-U、-((CH 2) 2-O) 13-CH 2-U、-((CH 2) 2-O) 14-CH 2-U、-((CH 2) 2-O) 15-CH 2-U、-((CH 2) 2-O) 16-CH 2-U、-((CH 2) 2-O) 17-CH 2-U、-((CH 2) 2-O) 18-CH 2-U、-((CH 2) 2-O) 19-CH 2-U、-((CH 2) 2-O) 20-CH 2-U、-CH 2-O-(CH 2) 2-U、-CH 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 2) 6-U、-CH 2-(O(CH 2) 2) 7-U、-CH 2-(O(CH 2) 2) 8-U、-CH 2-(O(CH 2) 2) 9-U、-CH 2-(O(CH 2) 2) 10-U、-(CH 2) 2-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-U、-(CH 2) 2-(O(CH 2) 2) 7-U、-(CH 2) 2-(O(CH 2) 2) 8-U、-(CH 2) 2-(O(CH 2) 2) 9-U、-(CH 2) 2-(O(CH 2) 2) 10-U、-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-U、-(CH 2) 3-(O(CH 2) 2) 7-U、-(CH 2) 3-(O(CH 2) 2) 8-U、-(CH 2) 3-(O(CH 2) 2) 9-U、-(CH 2) 3-(O(CH 2) 2) 10-U、-(CH 2) 4-O-(CH 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 3-U、-(CH 2) 4-(O(CH 2) 2) 4-U、-(CH 2) 4-(O(CH 2) 2) 5-U、-(CH 2) 4-(O(CH 2) 2) 6-U、-(CH 2) 4-(O(CH 2) 2) 7-U、-(CH 2) 4-(O(CH 2) 2) 8-U、-(CH 2) 4-(O(CH 2) 2) 9-U、-(CH 2) 4-(O(CH 2) 2) 10-U、-CH 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 3) 6-U、-CH 2-(O(CH 2) 3) 7-U、-CH 2-(O(CH 2) 3) 8-U、-CH 2-(O(CH 2) 3) 9-U、-CH 2-(O(CH 2) 3) 10-U、-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-U、-(CH 2) 2-(O(CH 2) 3) 7-U、-(CH 2) 2-(O(CH 2) 3) 8-U、-(CH 2) 2-(O(CH 2) 3) 9-U、-(CH 2) 2-(O(CH 2) 3) 10-U、-(CH 2) 3-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-U、 -(CH 2) 3-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-U、-(CH 2) 3-(O(CH 2) 3) 7-U、-(CH 2) 3-(O(CH 2) 3) 8-U、-(CH 2) 3-(O(CH 2) 3) 9-U、-(CH 2) 3-(O(CH 2) 3) 10-U、-CH 2-O-(CH 2) 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-CH 2-O-(CH 2) 3-O-(CH 2) 2-U、-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-CH 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-U、-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-U、或-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-U；
其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN是-亚烷基-U，所述亚烷基(优选C 1-30亚烷基链，尤其优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)是被一或多个取代基取代一或多次的直链或支链的亚烷基链，其中所述取代基选自羟基、氨基、巯基、卤素或其组合；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。在本公开的一子实施方式中，所述取代基的数目可以是例如1-30个，1-25个，1- 20个，或者1-15，1-10，1-9，1-8，1-7，1-6，1-5，1-4，1-3，或1-2个，或是20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、或1个。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示-C 1-30亚烷基链-U，所述C 1-30亚烷基链是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-30亚烷基链；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。在本公开的一子实施方式中，所述取代基的数目可以是例如1-30个，1-25个，1-20个，或者1-15，1-10，1-9，1-8，1-7，1-6，1-5，1-4，1-3，或1-2个，或是20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、或1个。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：-(CH 2) n11-三唑基-(CH 2) n12-U、-(CH 2) n11-三唑基-(CH 2) n12-(O(CH 2) n13) m11-U、-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-三唑基-(CH 2) n14-(O(CH 2) n15) m12-O-(CH 2) n16-U、-(CH 2) n11-三唑基-(CH 2) n12-(O(CH 2) n13) m11-O-(CH 2) n14-U或-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-三唑基-(CH 2) n14-U；以及
n11、n12、n13、n14、n15、n16、m11、m12分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：-(CH 2) 3-三唑基-(CH 2) 5-U、-(CH 2) 2-三唑基-(CH 2) 5-U、-CH 2-三唑基-(CH 2) 5-U、-(CH 2) 2-三唑基-(CH 2) 4-U、-(CH 2) 3-三唑基-(CH 2) 2-O(CH 2) 2-U、-(CH 2) 2-三唑基-(CH 2) 2-O(CH 2) 2-U或-CH 2-三唑基-(CH 2) 2-O(CH 2) 2-U；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：-CH 2CONHCH 2-U、-(CH 2) 2CONH(CH 2) 2-U、-(CH 2) 3CONH(CH 2) 3-U、-(CH 2) 3CONH(CH 2) 4-U、-(CH 2) 4CONH(CH 2) 4-U、-(CH 2) 5CONH(CH 2) 5-U、-(CH 2) 6CONH(CH 2) 7-U、-(CH 2) 6CONH(CH 2) 6-U、-(CH 2) 7CONH(CH 2) 7-U、-(CH 2) 8CONH(CH 2) 8-U、-(CH 2) 9CONH(CH 2) 9-U、-(CH 2) 10CONH(CH 2) 10-U、-(CH 2) 2CONH(CH 2) 5-U、-(CH 2) 2CONH(CH 2) 3-U、-(CH 2) 2CONH(CH 2) 4-U、或-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-U；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、 炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：-CH 2NHCOCH 2-U、-(CH 2) 2NHCO(CH 2) 2-U、-(CH 2) 3NHCO(CH 2) 3-U、-(CH 2) 3NHCO(CH 2) 4-U、-(CH 2) 4NHCO(CH 2) 4-U、-(CH 2) 5NHCO(CH 2) 5-U、-(CH 2) 6NHCO(CH 2) 7-U、-(CH 2) 6NHCO(CH 2) 6-U、-(CH 2) 7NHCO(CH 2) 7-U、-(CH 2) 8NHCO(CH 2) 8-U、-(CH 2) 9NHCO(CH 2) 9-U、-(CH 2) 10NHCO(CH 2) 10-U、-(CH 2) 2NHCO(CH 2) 5-U、-(CH 2) 2NHCO(CH 2) 3-U、-(CH 2) 2NHCO(CH 2) 4-U、-(CH 2) 4NHCO(CH 2) 8-U或-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-U；其中基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2，或基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或基团U表示氢。
在本公开所述式(I)化合物的一实施方式中，所述LIN表示：-亚烷基-U，其中所述亚烷基是直链或支链的C 1-30亚烷基，且所述基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合。
在本公开的一实施方式中，当所述式(I)化合物的LIN中的基团U表示SO 3H时，所述式(I)化合物的SO 3H可根据后续合成方案的需要被进一步转化成SO 2Cl。
本公开所述式(I)化合物优选选自表1中所列的化合物：
表1
Figure PCTCN2019091812-appb-000015
Figure PCTCN2019091812-appb-000016
Figure PCTCN2019091812-appb-000017
Figure PCTCN2019091812-appb-000018
Figure PCTCN2019091812-appb-000019
定义
在本文中，单独或组合使用的术语“卤素原子”或“卤素”是指氟、氯、溴或碘，且优选为I、Br或Cl。
在本文中，单独或组合使用的术语“烷基”是指直链或支链的烷基。术语“C x-C y烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链烷基。本公开中单独或组合使用的术语“C 1-10烷基”是指含有1至10个碳原子的直链或支链烷基。本公开的C 1-10烷基优选为C 1-9烷基，较优选为C 1-8烷基，还较优选为C 2-8烷基，更优选为C 1-7烷基，甚至更优选为C 1-6烷基，C 1-5烷基，或C 1-4烷基。表示性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基及叔丁基。本公开的术语“C 1-3烷基”是指含有1至3个碳原子的烷基，其表示性实例包括甲基、乙基、正丙基及异丙基。
在本文中，单独或组合使用的术语“亚烷基”(其与“亚烷基链”可互换使用)是指由碳和氢原子组成的直链或支链的二价饱和烃基团。术语“C x-C y亚烷基”或“C x- y亚烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链的亚烷基。本 公开的C 1-C 30亚烷基优选为C 1-C 29亚烷基，C 1-C 28亚烷基，C 1-C 27亚烷基，C 1-C 26亚烷基，C 1-C 25亚烷基，C 1-C 24亚烷基，C 1-C 23亚烷基，C 1-C 22亚烷基，C 1-C 21亚烷基，C 1-C 20亚烷基，C 1-C 19亚烷基，C 1-C 18亚烷基，C 1-C 17亚烷基，C 1-C 16亚烷基，C 1-C 15亚烷基，C 1-C 14亚烷基，C 1-C 13亚烷基，C 1-C 12亚烷基，C 1-C 11亚烷基，C 1-C 10亚烷基，C 1-C 9亚烷基，C 1-C 8亚烷基，C 1-C 7亚烷基，C 1-C 6亚烷基，C 1-C 5亚烷基，C 1-C 4亚烷基，C 1-C 3亚烷基，或C 1-C 2亚烷基。代表性实例包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚叔丁基、亚戊基、亚异戊基、亚新戊基、亚特戊基、亚己基、亚庚基、亚辛基、亚壬基、亚癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基、亚十六烷基、亚十七烷基、亚十八烷基、亚十九烷基、亚二十烷基、亚二十一烷基、亚二十二烷基、亚二十三烷基、亚二十四烷基、亚二十五烷基、亚二十六烷基、亚二十七烷基、亚二十八烷基、亚二十九烷基、和亚三十烷基。
在本文中，单独或组合使用的术语“亚芳基”是指包含5至14个碳原子并且可选地包含一个或多个稠合环的二价芳香烃基团，例如亚苯基或亚萘基或亚芴基。在本公开中，所述“亚芳基”是可选地经取代的亚芳基。经取代的亚芳基是指经取代基取代1-3次的亚芳基，其中取代基选自C 1-3烷基、C 1-3烷氧基、卤素、氨基或羟基。
在本文中，单独或组合使用的术语“C 1-3烷氧基”是指含有1至3个碳原子的直链或支链烷氧基。C 1-3烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基及异丙氧基。优选为甲氧基及乙氧基。
在本文中，单独或组合使用的术语“环烷基”是指具有3至12个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃基。术语“C 3- 10环烷基”是指具有3至10个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃基。环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘、八氢并环戊二烯、八氢-1H-茚、和螺环基。
在本文中，单独或组合使用的术语“亚环烷基”是指具有3至12个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃二价基团。亚环烷基的代表性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、亚螺环基。
在本文中，单独或组合使用的术语“杂芳基”是指含有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的5-至10-元单环或二环的芳香环基团。该种杂芳基基团的代表性实例包括但不限于呋喃基、 噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2,1,3]噁二唑基、苯并[2,1,3]噻二唑基、苯并[1,2,3]噻二唑基、喹啉基、异喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、4H-氟[3,2-b]吡咯基、吡咯并[2,1-b]噻唑基和咪唑并[2,1-b]噻唑基。根据明确的定义，所述杂芳基基团可未被取代或被取代。
在本文中，单独或组合使用的术语“亚杂芳基”是指含有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的5-至10-元单环或二环的二价芳香环基团。该种亚杂芳基基团的代表性实例包括但不限于亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基和咪唑并[2,1-b]噻唑亚基。根据明确的定义，所述亚杂芳基基团可未被取代或被取代。
在本文中，单独或组合使用的术语“杂环基”是指4-至6-元饱和的单环基团，其包含有一个或多个独立地选自硫、氧和氮的杂原子。所述杂环基的代表性实例包括但不限于氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、三唑基、四氢呋喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和二氧杂环己基。所述杂环基可以是未取代的或如明确定义的取代的。
在本文中，单独或组合使用的术语“亚杂环基”是指4-至6-元饱和的二价单环基团，其包含有一个或多个独立地选自硫、氧和氮的杂原子。所述亚杂环基的代表性实例包括但不限于亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚三唑基、亚四氢呋喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基和亚二氧杂环己基。所述亚杂环基可以是未取代的或如明确定义的取代的。
在本文中，单独或组合使用的术语“亚炔基”是指具有一个或多个碳碳叁键的包含2至10个(优选2至6个、较优选2至4个)碳原子的直链或支链二价烃基。优选亚炔基的实例包括但不限于亚乙炔基、1-丙炔亚基、1-丁炔亚基和1,3-二炔亚基。
在本文中，单独或组合使用的术语“炔基”是指具有一个或多个碳碳叁键的包含2至10个(优选2至6个、较优选2至4个)碳原子的直链或支链烃基。优选炔基的实例包括但不限于乙炔基、1-丙炔基、1-丁炔基和1,3-二炔基。
在本文中，单独或组合使用的术语“亚烯基”是指具有一个或多个碳碳双键的包含2至10个(优选2至6个、较优选2至4个)碳原子的直链或支链二价烃基。优选亚烯基的实例包括但不限于亚乙烯基(例如-CH＝CH-)、1-丙烯亚基、1-丁烯亚基。
文中，单独或组合使用的术语“烯基”是指具有一个或多个碳碳双键的(优选包含2至40个碳原子，较优选2至35个、2至30个、2至25个、2至20个、2至15个、2至10个、2至6个或2至5个碳原子，尤其优选2至4个或2至3个碳原子)直链或支链烃基。优选烯基的实例包括但不限于乙烯基、丙烯基、烯丙基、1-丁烯基、2-丁烯基、3-丁烯基、异丁烯基、戊烯基、正-戊-2,4-二烯基、1-甲基-丁-1-烯基、2-甲基-丁-1-烯基、3-甲基-丁-1-烯基、1-甲基-丁-2-烯基、2-甲基-丁-2-烯基、3-甲基-丁-2-烯基、1-甲基-丁-3-烯基、2-甲基-丁-3-烯基、3-甲基-丁-3-烯基、己烯基、庚烯基、辛烯基、正-辛-2-烯基、壬烯基、癸烯基、正-十二碳-2-烯基、异十二碳烯基、正-十二碳-2-烯基、正-十八碳-4-烯基或3,7,11,11-四甲基-2,6,10-十一碳三烯基。
在本文中，单独或组合使用的术语“离去基团(leaving group)”是本领域技术人员所熟知的术语，其还可称为离去基，是在化学反应中从一反应物中携带一对电子离去的分子片段(离子或中性分子)，是亲核取代反应与消除反应中应用的术语。常见离子性离去基有Cl -、Br -、I -和磺酸酯(如对甲苯磺酸酯，TsO -)，中性分子离去基有水、氨和醇。在本公开中，本领域技术人员可以根据需要选择适当的离去基团，例如但不限于卤素、甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基等。
在本文中，单独或组合使用的术语“有机碱”的定义一般情况下是指分子中含有氨基的有机化合物，例如胺类化合物。在本公开中，所述有机碱包括但不限于三乙胺、二甲胺、三叔丁胺、N,N-二甲基苯胺、DIPEA、N,N-二乙基乙胺、DMAP、吡啶、喹啉、吗啉和NMM。
在本文中，单独或组合使用的术语“保护基”是能保护某种基团(例如羧基、氨基、磺酰基)的试剂。保护基在有机反应中的使用是很常见的，常见的是对羟基、氨基等基团的保护。
本文的术语“室温”是指周围环境温度，例如但不限于20-30℃的温度。
与无机碱相比，本公开的方法在有机碱的存在下，使来那度胺与适当的烷基化试剂反应，可以高选择性的得到氨基烷基化产物。本公开提供了分别使用多种有机碱与无机碱的实施例，结果显示本公开的方法在有机碱的存在下发生的烷基化反应均能高选择性获得所期望的氨基烷基化产物，而在无机碱存在下发生的烷基化反应不能得到所期望的氨基烷基化产物，而只能得到戊二酰亚胺的N烷基化产物，如以下方案5以及表2所显示。
Figure PCTCN2019091812-appb-000020
表2
Figure PCTCN2019091812-appb-000021
aHPLC收率. b反应在110℃进行.
实施例
在下列说明中，为了提供对本公开的彻底了解而提出许多具体细节。本公开可在不具有部分或所有这些具体细节的情况下实施。在其他情况下，为了不对本公开造成不必要的混淆，不详述众所周知的过程操作。虽然本公开将结合具体实施例来进行说明，但应当理解的是，这并非旨在将本公开限制于这些实施例。
整个说明书及实施例中使用下列缩写：
Figure PCTCN2019091812-appb-000022
Figure PCTCN2019091812-appb-000023
在实施例中， 1H NMR谱采用Bruker-500MHz型核磁共振仪测定，用含0.1％TMS的CD 3OD做溶剂，其中 1H NMR谱以CD 3OD(δ＝3.31ppm)作为内标；或用含0.1％TMS的CDCl 3做溶剂，其中 1H NMR谱以CDCl 3(δ＝7.26ppm)作为内标；或使用含0.03％TMS的DMSO-d 6做溶剂，其中 1H NMR谱以DMSO-d 6(δ＝2.50ppm)作为内标；LRMS谱在AB Triple 4600型质谱仪上测定，HPLC制备在SHIMADZU LC-20AP型仪器上测定，HPLC纯度在SHIMADZU LC-30AP或Waters 1525型仪器上测定。所有反应未作特别说明均在空气氛围下进行；反应用TLC或LC-MS跟踪。
溶剂及试剂处理如下：
1.反应所用溶剂DCM、DMF、NMP、无水EtOH、无水MeOH等均购自国药集团；
2.HPLC制备所用的是制备级CH 3CN及去离子水；
3.来那度胺直接购买得到。
其它试剂和药品未经特别说明均从厂家买来直接使用。
通用合成方法
通用合成方案A：
末端羧酸取代的来那度胺烷基碳链系列衍生物的制备方法：
Figure PCTCN2019091812-appb-000024
将来那度胺(259.3mg,1mmol,1equiv)，溴代叔丁酯(1.2mmol,1.2equiv)和N,N-二异丙基乙胺(387.7mg,3mmol,3equiv)一起加入25mL的反应管中，随后加入NMP(5mL),110℃油浴反应12h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得最终目标化合物。
通用合成方案B1：
末端羧酸取代的来那度胺聚乙二醇(PEG)系列衍生物的制备方法1：
Figure PCTCN2019091812-appb-000025
将OTs取代的叔丁酯(1equiv)和碘化钠(2equiv)一起加入25mL的蛋形瓶中，随后加入丙酮(5mL),60℃油浴回流反应2h。将丙酮旋干，随后加入NMP(3mL)，来那度胺(0.8equiv)及N,N-二异丙基乙胺(3equiv)，110℃油浴反应12h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得最终的目标化合物。
通用合成方案B2：
末端羧酸取代的来那度胺聚乙二醇(PEG)系列衍生物的制备方法2：
Figure PCTCN2019091812-appb-000026
将来那度胺(1equiv)，OTs取代的叔丁酯(1.2equiv)和N,N-二异丙基乙胺(3equiv)一起加入25mL的反应管中，随后加入NMP(5mL),80℃油浴反应6h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得最终目标化合物。
通用合成方案C：
末端氨基取代的来那度胺烷基碳链系列衍生物的制备方法：
Figure PCTCN2019091812-appb-000027
将来那度胺(259.3mg,1mmol,1equiv)，N-叔丁氧羰基-溴代烷基胺(1.2mmol,1.2equiv)和N,N-二异丙基乙胺(387.7mg,3mmol,3equiv)一起加入25mL的反应管中，随后加入NMP(5mL),110℃油浴反应12h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得最终的目标化合物。
通用合成方案D：
Figure PCTCN2019091812-appb-000028
将来那度胺(20mg,0.073mmol,1equiv)，正丙基溴(18.9mg,0.0876mmol,1.2equiv)和N,N-二异丙基乙胺(29.9mg,0.219mmol,3equiv)一起加入10mL的反应管 中，随后加入NMP(2mL),110℃油浴反应6h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到最终的目标化合物。
实施例1：制备(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酸((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)glycine；SIAIS1204057)
根据方案A的方法，将来那度胺(259.3mg,1mmol,1equiv)，2-溴乙酸叔丁酯(1.2mmol,1.2equiv)和N,N-二异丙基乙胺(387.7mg,3mmol,3equiv)一起加入25mL的反应管中，随后加入NMP(5mL),110℃油浴反应12h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得目标化合物SIAIS1204057(黄色固体，203mg,收率64％)； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.28(t,J＝7.7Hz,1H),6.98(d,J＝7.3Hz,1H),6.66(d,J＝8.0Hz,1H),5.94(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.26(d,J＝17.0Hz,1H),4.16(d,J＝17.0Hz,1H),3.92(s,2H),2.98–2.85(m,1H),2.62(d,J＝17.3Hz,1H),2.39-2.26(m,1H),2.08-1.99(m,1H)；HRMS(ESI)m/z:计算值C 15H 16N 3O 5 +[M+H] +,318.1084；实测值,318.1098.
实施例2：制备3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酸(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propanoic acid；SIAIS1204059)
根据方案A，采用与实施例1相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204059，不同之处在于采用的溴代叔丁酯是3-溴丙酸叔丁酯。所得目标化合物SIAIS1204059为黄色固体，54mg,收率16％； 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.31(t,J＝7.7Hz,1H),6.96(d,J＝7.4Hz,1H),6.79(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.21(d,J＝17.0Hz,1H),4.12(d,J＝17.0Hz,1H),4.08(s,1H),3.37(t,J＝6.9Hz,2H),2.98–2.86(m,1H),2.65-2.57(m,1H),2.54(t,J＝6.9Hz,2H),2.33–2.26(m,1H),2.07–1.99(m,1H)；HRMS(ESI)m/z:计算值C 16H 18N 3O 5 +[M+H] +,332.1241；实测值,332.1259.
实施例3：制备4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酸(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoic acid；SIAIS1204085)
根据方案A，采用与实施例1相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204085，不同之处在于采用的溴代叔丁酯是4-溴丁酸叔丁酯。所得目标化合物SIAIS1204085为黄色固体，215mg,收率62％； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.28(t,J＝7.7Hz,1H),6.93(d,J＝7.3Hz,1H),6.77(d,J＝8.0Hz,1H),5.11(dd, J＝13.3,5.1Hz,1H),4.23(d,J＝17.0Hz,1H),4.13(d,J＝17.0Hz,1H),4.01(s,1H),3.14(t,J＝7.0Hz,2H),2.98–2.86(m,1H),2.66-2.58(d,J＝17.6Hz,1H),2.34(t,J＝7.3Hz,2H),2.32–2.24(m,1H),2.08-1.98(m,1H),1.85-1.75(m,2H)；HRMS(ESI)m/z:计算值C 17H 20N 3O 5 +[M+H] +,346.1379；实测值,346.1414.
实施例4：制备5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酸(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoic acid；SIAIS184047)
根据方案A，采用与实施例1相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS184047，不同之处在于采用的溴代叔丁酯是5-溴戊酸叔丁酯。所得目标化合物SIAIS184047为黄色固体，215mg,收率60％； 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.28(t,J＝7.7Hz,1H),6.92(t,J＝10.9Hz,1H),6.76(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),5.07(s,1H),4.23(d,J＝17.2Hz,1H),4.13(d,J＝17.1Hz,1H),3.13(d,J＝6.4Hz,2H),2.97–2.87(m,1H),2.61(d,J＝16.7Hz,1H),2.38–2.21(m,3H),2.06–1.98(m,1H),1.67–1.55(m,4H)；HRMS(ESI)m/z:计算值C 18H 22N 3O 5 +[M+H] +,416.2180；实测值,416.2189.
实施例5：制备6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酸(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoic acid；SIAIS1204061)
根据方案A，采用与实施例1相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204061，不同之处在于采用的溴代叔丁酯是6-溴己酸叔丁酯。所得目标化合物SIAIS1204061为黄色固体，268mg,收率72％； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.29(t,J＝7.7Hz,1H),6.94(d,J＝7.4Hz,1H),6.76(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.24(d,J＝17.0Hz,1H),4.14(d,J＝17.0Hz,1H),4.05(s,1H),3.12(t,J＝7.0Hz,2H),2.98–2.87(m,1H),2.66-2.58(m,1H),2.35–2.25(m,1H),2.22(t,J＝7.0Hz,2H),2.07-2.00(m,1H),1.63-1.50(m,4H),1.43-1.37(m,2H)；HRMS(ESI)m/z:计算值C 19H 24N 3O 5 +[M+H] +,374.1710；实测值,374.1720.
实施例6：制备7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酸(7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanoic acid；SIAIS1204063)
根据方案A，采用与实施例1相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204063，不同之处在于采用的溴代叔丁酯是7-溴庚酸叔丁酯。所得目标化合物SIAIS1204063为黄色固体，252mg,收率65％； 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.28(t,J＝7.7Hz,1H),6.93(d,J＝7.3Hz,1H),6.75(d,J＝8.0Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.23(d,J＝17.0Hz,1H),4.13(d,J＝17.0Hz,1H),3.11(t,J＝7.0Hz,2H),2.98–2.84(m,1H),2.67-2.57(m,1H),2.35-2.25(m,1H),2.20(t,J＝7.3Hz,2H),2.07 –1.99(m,1H),1.63-1.46(m,4H),1.42–1.27(m,4H)；HRMS(ESI)m/z:计算值C 20H 26N 3O 5 +[M+H] +,388.1867；实测值,388.1878.
实施例7：制备2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酸(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)acetic acid；SIAIS1204115)
根据方案B1的方法，将2-(2-(甲苯磺酰氧基)乙氧基)乙酸叔丁酯(1equiv)和碘化钠(2equiv)一起加入25mL的蛋形瓶中，随后加入丙酮(5mL),60℃油浴回流反应2h。将丙酮旋干，随后加入NMP(3mL)，来那度胺(0.8equiv)及N,N-二异丙基乙胺(3equiv)，110℃油浴反应12h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得目标化合物SIAIS1204115(黄色固体，134mg,收率77％)； 1H NMR(500MHz,DMSO)δ 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.29(t,J＝7.7Hz,1H),6.95(d,J＝6.9Hz,1H),6.80(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.24(d,J＝17.1Hz,1H),4.13(d,J＝17.0Hz,1H),4.02(s,2H),3.65(t,J＝5.9Hz,2H),3.32(t,J＝5.9Hz,2H),2.97–2.89(m,1H),2.65–2.58(m,1H),2.33-2.25(m,1H),2.06-2.02(m,1H)；HRMS(ESI)m/z:计算值C 17H 20N 3O 6 +[M+H] +,362.1347；实测值,362.1344.
实施例7-1：制备2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酸(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)acetic acid；SIAIS1204115)
根据方案B2的方法，将来那度胺(1equiv)，2-(2-(甲苯磺酰氧基)乙氧基)乙酸叔丁酯(1.2equiv)和N,N-二异丙基乙胺(3equiv)一起加入25mL的反应管中，随后加入NMP(5mL),80℃油浴反应6h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得最终目标化合物SIAIS1204115(黄色固体，11.1mg,收率40％)； 1H NMR(500MHz,DMSO)δ 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.27(t,J＝7.7Hz,1H),6.93(d,J＝6.9Hz,1H),6.78(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.12(d,J＝17.0Hz,1H),4.01(s,2H),3.63(t,J＝5.9Hz,2H),3.31(t,J＝5.9Hz,2H),2.96–2.88(m,1H),2.64–2.57(m,1H),2.33-2.23(m,1H),2.06-2.01(m,1H)；HRMS(ESI)m/z:计算值C 17H 20N 3O 6 +[M+H] +,362.1347；实测值,362.1339.
实施例8：制备2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基) 乙氧基)乙氧基)乙酸(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetic acid；SIAIS1204123)
根据方案B1，采用与实施例7相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204123，不同之处在于采用的OTs取代的叔丁酯是2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙酸叔丁酯。所得目标化合物SIAIS1204123为黄色液体，139mg,收率80％； 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.33–7.24(m,1H),6.94(t,J＝8.2Hz,1H),6.81(d,J＝7.9Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.14(d,J＝17.1Hz,1H),4.04–4.01(m,2H),3.62–3.56(m,6H),3.32(t,J＝5.9Hz,2H),2.95-2.88(m,1H),2.62(d,J＝17.6Hz,1H),2.35-2.28(m,1H),2.07–2.00(m,1H)；HRMS(ESI)m/z:计算值C 19H 24N 3O 7 +[M+H] +,406.1609；实测值,406.1618.
实施例9：制备2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙酸(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)acetic acid；SIAIS1204127)
根据方案B1，采用与实施例7相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204127，不同之处在于采用的OTs取代的叔丁酯是2-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯。所得目标化合物SIAIS1204127为黄色液体，124mg,收率72％； 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.29(t,J＝7.7Hz,1H),6.94(d,J＝7.4Hz,1H),6.81(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.13(d,J＝17.1Hz,1H),4.01(s,2H),3.60–3.51(m,10H),3.34-3.30(m,2H),2.97–2.87(m,1H),2.62(d,J＝16.9Hz,1H),2.36-2.28(m,1H),2.07-2.01(m,1H)；HRMS(ESI)m/z:计算值C 21H 28N 3O 8 +[M+H] +,450.1871；实测值,450.1879.
实施例10：制备14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酸(14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecanoic acid；SIAIS1204131)
根据方案B1，采用与实施例7相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204131，不同之处在于采用的OTs取代的叔丁酯是14-(甲苯磺酰氧基)-3,6,9,12-四氧杂十四烷酸叔丁酯。所得目标化合物SIAIS1204131为黄色液体，134mg,收率79％。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.29(t,J＝7.7Hz,1H),6.96(d,J＝7.3Hz,1H),6.82(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.1Hz,2H),4.24(d,J＝17.1Hz,1H),4.13(d,J＝17.1Hz,1H),4.01(s,2H),3.64–3.46(m,14H),3.32(t,J＝5.9Hz,2H),2.99–2.86(m,1H),2.62(d,J＝16.9Hz,1H),2.31(qd,J＝13.3,4.4Hz,1H),2.07–2.00(m,1H)；HRMS(ESI)m/z:计算值C 23H 32N 3O 9 +[M+H] +,494.2133；实测值,494.2144.
实施例11：制备14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酸(14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecanoic acid；SIAIS1204135)
根据方案B1，采用与实施例7相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204135，不同之处在于采用的OTs取代的叔丁酯是17-(甲苯磺酰氧基)-3,6,9,12,15-五氧杂十七烷酸叔丁酯。所得目标化合物SIAIS1204135为黄色液体，127mg,收率75％。 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.29(t,J＝7.7Hz,1H),6.95(d,J＝6.9Hz,1H),6.80(d,J＝6.9Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.24(d,J＝17.1Hz,1H),4.14(d,J＝17.1Hz,1H),4.01(s,2H),3.62–3.46(m,18H),3.32(t,J＝5.9Hz,2H),2.96-2.88(m,1H),2.62(d,J＝16.6Hz,1H),2.37–2.25(m,1H),2.08–2.00(m,1H)；HRMS(ESI)m/z:计算值C 25H 36N 3O 10 +[M+H] +,538.2395；实测值,538.2403.
实施例12：制备3-(4-((3-氨基丙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3-(4-((3-aminopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione；SIAIS1204071)
根据方案C的方法，将来那度胺(259.3mg,1mmol,1equiv)，(3-溴丙基)氨基甲酸叔丁酯(1.2mmol,1.2equiv)和N,N-二异丙基乙胺(387.7mg,3mmol,3equiv)一起加入25mL的反应管中，随后加入NMP(5mL),110℃油浴反应12h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到中间体；随后将该化合物加入25mL单口瓶中，依次加入1mL二氯甲烷和3mL三氟乙酸，室温搅拌1h。减压蒸去反应溶剂，加水冻干得目标化合物SIAIS1204071(黄色液体，159mg,50％) 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.93(s,1H),7.71(s,2H),7.31(t,J＝7.7Hz,1H),6.96(d,J＝7.4Hz,1H),6.79(d,J＝8.1Hz,1H),5.12(dd,J＝13.2,5.1Hz,1H),4.21(d,J＝17.0Hz,1H),4.12(d,J＝17.0Hz,1H),3.22(t,J＝6.4Hz,2H),2.98–2.92(m,1H),2.92–2.87(m,2H),2.67-2.58(m,1H),2.34-2.23(m,1H),2.08-2.00(m,1H),1.88-1.79(m,2H)；HRMS(ESI)m/z:计算值C 16H 21N 4O 3 +[M+H] +,317.1608；实测值,317.1616.
实施例13：制备3-(4-((4-氨基丁基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3-(4-((4-aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione；SIAIS1204073)
根据方案C，采用与实施例12相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204073，不同之处在于采用的N-叔丁氧羰基-溴代烷基胺是(4-溴丁基)氨基甲酸叔丁酯。所得目标化合物SIAIS1204073为黄色液体，60mg,收率18％； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.87(s,1H),7.69(s,2H),7.29(t,J＝7.7Hz,1H),6.94(d,J＝7.3Hz,1H),6.77(d,J＝8.0Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.22(d,J＝ 17.1Hz,1H),4.11(d,J＝17.1Hz,1H),3.25-3.12(m,2H),3.00–2.88(m,1H),2.88-2.75(m,2H),2.67-2.57(m,1H),2.33–2.22(m,1H),2.10–1.98(m,1H),1.66–1.50(m,4H)；HRMS(ESI)m/z:计算值C 17H 23N 4O 3 +[M+H] +,331.1765；实测值,331.1784.
实施例14：制备3-(4-((5-氨基戊基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3-(4-((5-aminopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione；SIAIS1204075)
根据方案C，采用与实施例12相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204075，不同之处在于采用的N-叔丁氧羰基-溴代烷基胺是(5-溴戊基)氨基甲酸叔丁酯。所得目标化合物SIAIS1204075为黄色液体，234mg,收率68％； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.69(s,3H),7.29(t,J＝7.7Hz,1H),6.94(d,J＝7.1Hz,1H),6.75(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.13(d,J＝17.1Hz,1H),3.13(t,J＝7.0Hz,2H),2.98–2.88(m,1H),2.84–2.75(m,2H),2.67-2.57(m,1H),2.35–2.22(m,1H),2.08-1.99(m,1H),1.65–1.51(m,4H),1.45–1.37(m,2H)；HRMS(ESI)m/z:计算值C 18H 25N 4O 3 +[M+H] +,345.1921；实测值,345.1939.
实施例15：制备3-(4-((6-氨基己基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3-(4-((6-aminohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione；SIAIS1204077)
根据方案C，采用与实施例12相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204077，不同之处在于采用的N-叔丁氧羰基-溴代烷基胺是(6-溴己基)氨基甲酸叔丁酯。所得目标化合物SIAIS1204077为黄色液体，243mg,收率76％； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.67(s,3H),7.29(t,J＝7.7Hz,1H),6.93(d,J＝6.9Hz,1H),6.75(d,J＝7.8Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.12(d,J＝17.1Hz,1H),3.13(t,J＝7.0Hz,2H),2.98-2.87(m,1H),2.82–2.72(m,2H),2.67-2.57(m,1H),2.35–2.23(m,1H),2.08–2.00(m,1H),1.62-1.49(m,4H),1.43–1.29(m,4H)；HRMS(ESI)m/z:计算值C 19H 27N 4O 3 +[M+H] +,359.2078；实测值,359.2090.
实施例16：制备3-(4-((7-氨基庚基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3-(4-((7-aminoheptyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione；SIAIS1204079)
根据方案C，采用与实施例12相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204079，不同之处在于采用的N-叔丁氧羰基-溴代烷基胺是(7-溴庚基)氨基甲酸叔丁酯。所得目标化合物SIAIS1204079为黄色液体，283mg,收率76％； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.68(s,3H),7.29(t,J＝7.7Hz,1H),6.93(t,J＝7.2Hz,1H),6.75(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.12(d,J＝17.1Hz,1H),3.12(t,J＝7.1Hz,2H),2.98–2.87(m,1H),2.83-2.72(m,2H),2.66-2.58(m,1H),2.35-2.23(m,1H),2.08–1.99(m,1H),1.62-1.55(m,2H),1.55-1.49(m,2H), 1.40-1.34(m,2H),1.34-1.29(m,4H)；HRMS(ESI)m/z:计算值C 20H 29N 4O 3 +[M+H] +,373.2234；实测值,373.2242.
实施例17：制备3-(4-((8-氨基辛基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(3-(4-((8-aminooctyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione；SIAIS1204081)
根据方案C，采用与实施例12相同的方法，在本领域可理解的适当条件下制备目标化合物SIAIS1204081，不同之处在于采用的N-叔丁氧羰基-溴代烷基胺是(8-溴辛基)氨基甲酸叔丁酯。所得目标化合物SIAIS1204081为黄色液体，274mg,收率71％； 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.66(s,3H),7.28(t,J＝7.7Hz,1H),6.93(d,J＝7.3Hz,1H),6.74(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.12(d,J＝17.1Hz,1H),3.20–3.01(m,2H),2.99–2.85(m,1H),2.83–2.69(m,2H),2.66-2.58(m,1H),2.35-2.23(m,1H),2.11–1.95(m,1H),1.65–1.43(m,4H),1.43-1.25(m,6H)；HRMS(ESI)m/z:计算值C 21H 31N 4O 3 +[M+H] +,387.2391；实测值,387.2382.
实施例18：制备3-(1-氧代-4-(丙基氨基)异吲哚啉-2-基)哌啶-2,6-二酮(3-(1-oxo-4-(propylamino)isoindolin-2-yl)piperidine-2,6-dione；SIAIS1204083A)
根据方案D的方法，将来那度胺(20mg,0.073mmol,1equiv)，正丙基溴(18.9mg,0.0876mmol,1.2equiv)和N,N-二异丙基乙胺(29.9mg,0.219mmol,3equiv)一起加入10mL的反应管中，随后加入NMP(2mL),110℃油浴反应6h。将反应液降至室温，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物SIAIS1204083A(黄色固体，18.5mg,84％)； 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.28(t,J＝7.7Hz,1H),6.92(d,J＝7.4Hz,1H),6.74(d,J＝8.0Hz,1H),5.58(s,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.23(d,J＝17.1Hz,1H),4.13(d,J＝17.1Hz,1H),3.09(t,J＝6.7Hz,2H),2.98–2.86(m,1H),2.66-2.58(m,1H),2.35-2..24(qd,J＝13.0,4.2Hz,1H),2.08–1.98(m,1H),1.64–1.52(m,2H),0.94(t,J＝7.4Hz,3H)；HRMS(ESI)m/z:计算值C 16H 20N 3O 3 +[M+H] +,302.1499；实测值,302.1508.
比较实施例：
Figure PCTCN2019091812-appb-000029
根据方案E，将来那度胺(20mg,0.073mmol,1equiv)，正丙基溴(18.9mg, 0.0876mmol，1.2equiv)，KI(3.8mg,0.0146mmol,0.2equiv)和碳酸钾(21.3mg,0.146mmol,3equiv)一起加入10mL的反应管中，随后加入乙腈(2mL),100℃油浴回流反应2h。将反应液降至室温，减压蒸去乙腈，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，冻干后得到化合物3-(4-氨基-1-氧代异吲哚啉-2-基)-1-丙基哌啶-2,6-二酮(3-(4-amino-1-oxoisoindolin-2-yl)-1-propylpiperidine-2,6-dione；SIAIS1204083B)(黄色固体，12.8mg,58％) 1H NMR(500MHz,DMSO)δ7.23(t,J＝7.6Hz,1H),6.98(d,J＝6.9Hz,1H),6.86(d,J＝7.6Hz,1H),5.18(dd,J＝13.4,5.1Hz,1H),4.22(d,J＝17.1Hz,1H),4.11(d,J＝17.1Hz,1H),3.68–3.50(m,2H),3.08-2.96(m,1H),2.83–2.71(m,1H),2.35-2.24(m,1H),2.09–1.99(m,1H),1.52-1.40(m,2H),0.83(t,J＝7.5Hz,3H)；HRMS(ESI)m/z:计算值C 16H 20N 3O 3 +[M+H] +,302.1499；实测值,302.1511.
本公开不受上面所显示和描述的实施例的限制，而是在权利要求的范围内可以改变。[参考文献]
1.X.Chang,Y.Zhu,C.Shi,et al.Acta.Biochim.Biophys.Sin,2014,46,240.
2.a)G.E.Winter,D.L.Buckley,J.Paulk,J.M.Roberts,A.Souza,S.Dhe-Paganon and J.E.Bradner,Science,2015,348,1376.b)E.S.Fischer,K.Bohm,J.R.Lydeard,H.Yang,M.B.Stadler,S.Cavadini,J.Nagel,F.Serluca,V.Acker,G.M.Lingaraju,R.B.Tichkule,M.Schebesta,W.C.Forrester,M.Schirle,U.Hassiepen,J.Ottl,M.Hild,R.E.J.Beckwith,J.W.Harper,J.L.Jenkins and N.H.
Figure PCTCN2019091812-appb-000030
Nature,2014,512,49.
3.For reviews,see:a)A.C.Lai,and C.M.Crews,Nature Reviews Drug Discovery,2017,16,101.b)T.K.Neklesa,J.D.Winkler and C.M.Crews,Pharmacology&Therapeutics,2017,
174,138.For papers,see:c)K.M.Sakamoto,K.B.Kim,A.Kumagai,F.Mercurio,C.M.Crews and R.J.Deshaies,Proc.Natl.Acad.Sci.U.S.A.2001,98,8554.
4.a)M.Toure and C.M.Crews,Angew.Chem.,Int.Ed.2016,55,1966.b)D.P.Bondeson,A.Mares,I.E.D.Smith,E.Ko,S.Campos,A.H.Miah,K.E.Mulholland,N.Routly,D.L.Buckley,J.L.Gustafson,N.Zinn,P.Grandi,S.Shimamura,G.Bergamini,M.Faelth-Savitski,M.Bantscheff,C.Cox,D.A.Gordon,R.R.Willard,J.J.Flanagan,L.N.Casillas,B.J.Votta,W.den Besten,K.Famm,L.Kruidenier,P.S.Carter,J.D.Harling,I.Churcher and C.M.Crews,Nat.Chem.Biol.2015,11,611.
5.G.E.Winter,D.L.Buckley,J.Paulk,J.M.Roberts,A.Souza,S.Dhe-Paganon and J.E.Bradner,Science,2015,348,1376.
6.a)J.Lu,Y.Qian,M.Altieri,H.Dong,J.Wang,K.Raina,J.Hines,J.D.Winkler,A.P.Crew,K.Coleman and C.M.Crews,Chemistry&Biology,2015,22,755.b)A.C.Lai,M.Toure,D.Hellerschmied,J.Salami,S.Jaime-Figueroa,E.Ko,J.Hines and C.M.Crews,Angew.Chem.Int.Ed.2016,55,807.
7.B.Zhou,J.Hu,F.Xu,Z.Chen,L.Bai,E.Fernandez-Salas,M.Lin,L.Liu,C.-Y.Yang,Y.Zhao,D.McEachern,S.Przybranowski,B.Wen,D.Sun and S.Wang,J.Med.Chem.,2018,61,462.
8.D.Remillard,D.L.Buckley,J.Paulk,G.L.Brien,M.Sonnett,H.Seo,S.Dastjerdi,M.Wghr,S.Dhe-Paganon,S.A.Armstrong and J.E.Bradner,Angew.Chem.Int.Ed.2017,56,5738.
9.S.Hu,L.Yuan,H.Yan,Z.Li,Bioorganic&Medicinal Chemistry Letters 2017,27,4075.

Claims (17)

  1. 制备式(I)化合物的方法，
    Figure PCTCN2019091812-appb-100001
    其中LIN表示-亚烷基-U，其中
    所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
    基团U表示可选地由保护基团保护的-COOH、-SO 3H或-NH 2；或
    基团U表示-N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
    基团U表示氢；
    所述方法包括使式(II)化合物的氨基与式(III)化合物在有机碱存在下发生氨基烷基化反应，选择性得到式(I)化合物，
    Figure PCTCN2019091812-appb-100002
    R 1-LIN          式(III)
    其中R 1表示离去基团，且LIN表示-亚烷基-U，其中
    所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
    基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
    基团U表示-N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
    基团U表示氢。
  2. 如权利要求1所述的方法，其中，所述有机碱选自以下中的一种或多种：三乙胺、二甲胺、三叔丁胺、N,N-二甲基苯胺、DIPEA、N,N-二乙基乙胺、DMAP、吡啶、喹啉、吗啉和NMM。
  3. 如权利要求1所述的方法，其中，所述R 1表示卤素、甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基。
  4. 如权利要求1-3中任一项所述的方法，其中，所述LIN表示：
    -C 1-30亚烷基-U，-(CH 2) n1-(O(CH 2) n2) m1-U，-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-U，-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-U，-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-U，-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-U，-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-U，-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-U，由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的-亚烷基链-U，或其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-(CH 2) n1-(O(CH 2) n2) m1-U；
    其中R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或支链的C 1- 10烷基或C 3- 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，或R a5、R a6、R a7、R a8、R a9、R a10，或R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；以及
    n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
  5. 如权利要求4所述的方法，其中，所述LIN表示：
    -CH 2-U；-(CH 2) 2-U；-(CH 2) 3-U；-(CH 2) 4-U；-(CH 2) 5-U；-(CH 2) 6-U；-(CH 2) 7-U；-(CH 2) 8-U；-(CH 2) 9-U；-(CH 2) 10-U；-(CH 2) 11-U；-(CH 2) 12-U；-(CH 2) 13-U；-(CH 2) 14-U；-(CH 2) 15-U；-(CH 2) 16-U；-(CH 2) 17-U；-(CH 2) 18-U；-(CH 2) 19-U；-(CH 2) 20-U；-(CH 2) 21-U；-(CH 2) 22-U；-(CH 2) 23-U；-(CH 2) 24-U；-(CH 2) 25-U；-(CH 2) 26-U；-(CH 2) 27-U；-(CH 2) 28-U；-(CH 2) 29-U；或-(CH 2) 30-U。
  6. 如权利要求4所述的方法，其中，所述LIN表示：
    -CH 2-((CH 2) 2-O)-CH 2-U、-CH 2-((CH 2) 2-O) 2-CH 2-U、-CH 2-((CH 2) 2-O) 3-CH 2-U、-CH 2-((CH 2) 2-O) 4-CH 2-U、-CH 2-((CH 2) 2-O) 5-CH 2-U、-CH 2-((CH 2) 2-O) 6-CH 2-U、-CH 2-((CH 2) 2-O) 7- CH 2-U、-CH 2-((CH 2) 2-O) 8-CH 2-U、-CH 2-((CH 2) 2-O) 9-CH 2-U、-CH 2-((CH 2) 2-O) 10-CH 2-U、-CH 2-((CH 2) 2-O) 11-CH 2-U、-CH 2-((CH 2) 2-O) 12-CH 2-U、-CH 2-((CH 2) 2-O) 13-CH 2-U、-CH 2-((CH 2) 2-O) 14-CH 2-U、-CH 2-((CH 2) 2-O) 15-CH 2-U、-CH 2-((CH 2) 2-O) 16-CH 2-U、-CH 2-((CH 2) 2-O) 17-CH 2-U、-CH 2-((CH 2) 2-O) 18-CH 2-U、-CH 2-((CH 2) 2-O) 19-CH 2-U、-CH 2-((CH 2) 2-O) 20-CH 2-U、-((CH 2) 2-O)-CH 2-U、-((CH 2) 2-O) 2-CH 2-U、-((CH 2) 2-O) 3-CH 2-U、-((CH 2) 2-O) 4-CH 2-U、-((CH 2) 2-O) 5-CH 2-U、-((CH 2) 2-O) 6-CH 2-U、-((CH 2) 2-O) 7-CH 2-U、-((CH 2) 2-O) 8-CH 2-U、-((CH 2) 2-O) 9-CH 2-U、-((CH 2) 2-O) 10-CH 2-U、-((CH 2) 2-O) 11-CH 2-U、-((CH 2) 2-O) 12-CH 2-U、-((CH 2) 2-O) 13-CH 2-U、-((CH 2) 2-O) 14-CH 2-U、-((CH 2) 2-O) 15-CH 2-U、-((CH 2) 2-O) 16-CH 2-U、-((CH 2) 2-O) 17-CH 2-U、-((CH 2) 2-O) 18-CH 2-U、-((CH 2) 2-O) 19-CH 2-U、-((CH 2) 2-O) 20-CH 2-U、-CH 2-O-(CH 2) 2-U、-CH 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 2) 6-U、-CH 2-(O(CH 2) 2) 7-U、-CH 2-(O(CH 2) 2) 8-U、-CH 2-(O(CH 2) 2) 9-U、-CH 2-(O(CH 2) 2) 10-U、-(CH 2) 2-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-U、-(CH 2) 2-(O(CH 2) 2) 7-U、-(CH 2) 2-(O(CH 2) 2) 8-U、-(CH 2) 2-(O(CH 2) 2) 9-U、-(CH 2) 2-(O(CH 2) 2) 10-U、-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-U、-(CH 2) 3-(O(CH 2) 2) 7-U、-(CH 2) 3-(O(CH 2) 2) 8-U、-(CH 2) 3-(O(CH 2) 2) 9-U、-(CH 2) 3-(O(CH 2) 2) 10-U、-(CH 2) 4-O-(CH 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 3-U、-(CH 2) 4-(O(CH 2) 2) 4-U、-(CH 2) 4-(O(CH 2) 2) 5-U、-(CH 2) 4-(O(CH 2) 2) 6-U、-(CH 2) 4-(O(CH 2) 2) 7-U、-(CH 2) 4-(O(CH 2) 2) 8-U、-(CH 2) 4-(O(CH 2) 2) 9-U、-(CH 2) 4-(O(CH 2) 2) 10-U、-CH 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 3) 6-U、-CH 2-(O(CH 2) 3) 7-U、-CH 2-(O(CH 2) 3) 8-U、-CH 2-(O(CH 2) 3) 9-U、-CH 2-(O(CH 2) 3) 10-U、-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-U、-(CH 2) 2-(O(CH 2) 3) 7-U、-(CH 2) 2-(O(CH 2) 3) 8-U、-(CH 2) 2-(O(CH 2) 3) 9-U、-(CH 2) 2-(O(CH 2) 3) 10-U、-(CH 2) 3-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 3-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-U、-(CH 2) 3-(O(CH 2) 3) 7-U、-(CH 2) 3-(O(CH 2) 3) 8-U、-(CH 2) 3-(O(CH 2) 3) 9-U、-(CH 2) 3-(O(CH 2) 3) 10-U、-CH 2-O-(CH 2) 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、- (CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-CH 2-O-(CH 2) 3-O-(CH 2) 2-U、-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-CH 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-U、-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-U、或-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-U。
  7. 如权利要求1-3中任一项所述的方法，其中，所述LIN表示-亚烷基-U，其中所述亚烷基是直链或支链的C 1-30亚烷基，且所述基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合。
  8. 如权利要求1-3中任一项所述的方法，其中，所述反应是在10-150℃的温度进行。
  9. 如权利要求1-3中任一项所述的方法，其中，在所述反应中，基于所述式(II)化合物的摩尔量计算，有机碱的量为0.1当量至10当量。
  10. 如权利要求1-3中任一项所述的方法，其中，在所述反应中，基于所述式(II)化合物的摩尔量计算，所述式(III)化合物的量为0.5当量至1.5当量。
  11. 如权利要求1-3中任一项所述的方法，其中，所述反应在不添加溶剂的情况进行，其中所述有机碱用作为唯一的溶剂。
  12. 式(I)化合物，
    Figure PCTCN2019091812-appb-100003
    其中，LIN表示-亚烷基-U，其中
    所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
    基团U表示可选地由保护基团保护的COOH、SO 3H或NH 2；或
    基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合；或
    基团U表示氢。
  13. 如权利要求12所述的式(I)化合物，其中，所述LIN表示：
    -C 1-30亚烷基-U，-(CH 2) n1-(O(CH 2) n2) m1-U，-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-U，-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-U，-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-U，-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-U，-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-U，-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-U，-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-U，-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-U，由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的-亚烷基链-U，或其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-(CH 2) n1-(O(CH 2) n2) m1-U；
    其中R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或支链的C 1- 10烷基或C 3- 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，或R a5、R a6、R a7、R a8、R a9、R a10，或R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；以及
    n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
  14. 如权利要求13所述的式(I)化合物，其中，所述LIN表示：
    -CH 2-U；-(CH 2) 2-U；-(CH 2) 3-U；-(CH 2) 4-U；-(CH 2) 5-U；-(CH 2) 6-U；-(CH 2) 7-U；-(CH 2) 8-U；-(CH 2) 9-U；-(CH 2) 10-U；-(CH 2) 11-U；-(CH 2) 12-U；-(CH 2) 13-U；-(CH 2) 14-U；-(CH 2) 15-U；-(CH 2) 16-U；-(CH 2) 17-U；-(CH 2) 18-U；-(CH 2) 19-U；-(CH 2) 20-U；-(CH 2) 21-U；-(CH 2) 22-U；-(CH 2) 23-U；-(CH 2) 24-U；-(CH 2) 25-U；-(CH 2) 26-U；-(CH 2) 27-U；-(CH 2) 28-U；-(CH 2) 29-U；或-(CH 2) 30-U。
  15. 如权利要求13所述的式(I)化合物，其中，所述LIN表示：
    -CH 2-((CH 2) 2-O)-CH 2-U、-CH 2-((CH 2) 2-O) 2-CH 2-U、-CH 2-((CH 2) 2-O) 3-CH 2-U、-CH 2-((CH 2) 2-O) 4-CH 2-U、-CH 2-((CH 2) 2-O) 5-CH 2-U、-CH 2-((CH 2) 2-O) 6-CH 2-U、-CH 2-((CH 2) 2-O) 7-CH 2-U、-CH 2-((CH 2) 2-O) 8-CH 2-U、-CH 2-((CH 2) 2-O) 9-CH 2-U、-CH 2-((CH 2) 2-O) 10-CH 2-U、-CH 2-((CH 2) 2-O) 11-CH 2-U、-CH 2-((CH 2) 2-O) 12-CH 2-U、-CH 2-((CH 2) 2-O) 13-CH 2-U、-CH 2-((CH 2) 2-O) 14-CH 2-U、-CH 2-((CH 2) 2-O) 15-CH 2-U、-CH 2-((CH 2) 2-O) 16-CH 2-U、-CH 2-((CH 2) 2-O) 17-CH 2-U、-CH 2-((CH 2) 2-O) 18-CH 2-U、-CH 2-((CH 2) 2-O) 19-CH 2-U、-CH 2-((CH 2) 2-O) 20-CH 2-U、-((CH 2) 2-O)-CH 2-U、-((CH 2) 2-O) 2-CH 2-U、-((CH 2) 2-O) 3-CH 2-U、-((CH 2) 2-O) 4-CH 2-U、-((CH 2) 2-O) 5-CH 2-U、-((CH 2) 2-O) 6-CH 2-U、-((CH 2) 2-O) 7-CH 2-U、-((CH 2) 2-O) 8-CH 2-U、-((CH 2) 2-O) 9-CH 2-U、-((CH 2) 2-O) 10-CH 2-U、-((CH 2) 2-O) 11-CH 2-U、-((CH 2) 2-O) 12-CH 2-U、-((CH 2) 2-O) 13-CH 2-U、-((CH 2) 2-O) 14-CH 2-U、-((CH 2) 2-O) 15-CH 2-U、-((CH 2) 2-O) 16-CH 2-U、-((CH 2) 2-O) 17-CH 2-U、-((CH 2) 2-O) 18-CH 2-U、-((CH 2) 2-O) 19-CH 2-U、-((CH 2) 2-O) 20-CH 2-U、-CH 2-O-(CH 2) 2-U、-CH 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 2) 6-U、-CH 2-(O(CH 2) 2) 7-U、-CH 2-(O(CH 2) 2) 8-U、-CH 2-(O(CH 2) 2) 9-U、-CH 2-(O(CH 2) 2) 10-U、-(CH 2) 2-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-U、-(CH 2) 2-(O(CH 2) 2) 7-U、-(CH 2) 2-(O(CH 2) 2) 8-U、-(CH 2) 2-(O(CH 2) 2) 9-U、-(CH 2) 2-(O(CH 2) 2) 10-U、-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-U、-(CH 2) 3-(O(CH 2) 2) 7-U、-(CH 2) 3-(O(CH 2) 2) 8-U、-(CH 2) 3-(O(CH 2) 2) 9-U、-(CH 2) 3-(O(CH 2) 2) 10-U、-(CH 2) 4-O-(CH 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 2-U、-(CH 2) 4-(O(CH 2) 2) 3-U、-(CH 2) 4-(O(CH 2) 2) 4-U、-(CH 2) 4-(O(CH 2) 2) 5-U、-(CH 2) 4-(O(CH 2) 2) 6-U、-(CH 2) 4-(O(CH 2) 2) 7-U、-(CH 2) 4-(O(CH 2) 2) 8-U、-(CH 2) 4-(O(CH 2) 2) 9-U、-(CH 2) 4-(O(CH 2) 2) 10-U、-CH 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 3) 6-U、-CH 2-(O(CH 2) 3) 7-U、-CH 2-(O(CH 2) 3) 8-U、-CH 2-(O(CH 2) 3) 9-U、-CH 2-(O(CH 2) 3) 10-U、-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-U、-(CH 2) 2-(O(CH 2) 3) 7-U、-(CH 2) 2-(O(CH 2) 3) 8-U、-(CH 2) 2-(O(CH 2) 3) 9-U、-(CH 2) 2-(O(CH 2) 3) 10-U、-(CH 2) 3-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 3-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-U、-(CH 2) 3-(O(CH 2) 3) 7-U、-(CH 2) 3-(O(CH 2) 3) 8-U、-(CH 2) 3-(O(CH 2) 3) 9-U、-(CH 2) 3-(O(CH 2) 3) 10-U、-CH 2-O-(CH 2) 2-O-(CH 2) 3-U、-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 2-(O(CH 2) 2) 3- (O(CH 2) 3) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-U、-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-U、-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-U、-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-U、-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-U、-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-U、-CH 2-O-(CH 2) 3-O-(CH 2) 2-U、-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-U、-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-U、-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-U、-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-U、-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-U、-CH 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-O-(CH 2) 2-O-CH 2-U、-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-U、-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-U、-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-U、或-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-U。
  16. 如权利要求12所述的式(I)化合物，其中，所述LIN表示：-亚烷基-U，其中所述亚烷基是直链或支链的C 1-30亚烷基，且所述基团U表示N 3、烯基、炔基、环烷基、芳基、杂环基、杂芳基或它们的任意组合。
  17. 如权利要求12所述的式(I)化合物，其选自：
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酸；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酸；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙酸；
    3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十七 酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酰氨基)丙酸；
    (2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基乙酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酸；
    7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酸；
    8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)辛酸；
    9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)壬酸；
    10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)癸酸；
    11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)十一酸；
    12-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)十二酸；
    13-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)十三酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)十四酸；
    15-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)十五酸；
    3-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰氨基)丙酸；
    3-(4-((2-(2-氨基乙氧基)乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-氨基-3,6,9,12-四氧杂十四烷基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-氨基-3,6,9,12,15-五氧杂十七烷基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙基)氨基)-4-氧代丁酸；
    3-(4-((2-氨基乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-氨基丙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-氨基丁基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-氨基戊基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-氨基己基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-氨基庚基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((8-氨基辛基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊基)氨基)-4-氧代丁酸；
    3-(4-((2-(2-叠氮基乙氧基)乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-叠氮基-3,6,9,12-四氧杂十四烷基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-叠氮基-3,6,9,12,15-五氧杂十七烷基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丁酸；
    3-(4-((2-叠氮基乙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-叠氮基丙基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-叠氮基丁基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-叠氮基戊基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-叠氮基己基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((8-叠氮基辛基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊基)-1H-1,2,3-三唑-4-基)丁酸；
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙烷-1-磺酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙烷-1-磺酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙烷-1-磺酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷-1-磺酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十七烷-1-磺酸；
    2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙烷-1-磺酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙烷-1-磺酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁烷-1-磺酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊烷-1-磺酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己烷-1-磺酸；和
    7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚烷-1-磺酸。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103396397A (zh) * 2013-08-14 2013-11-20 中国人民解放军军事医学科学院毒物药物研究所 来那度胺衍生物及其作为药物的用途
WO2015077058A2 (en) * 2013-11-08 2015-05-28 The Broad Institute, Inc. Compositions and methods for selecting a treatment for b-cell neoplasias
WO2017176958A1 (en) * 2016-04-06 2017-10-12 The Regents Of The University Of Michigan Monofunctional intermediates for ligand-dependent target protein degradation
WO2018085247A1 (en) * 2016-11-01 2018-05-11 Cornell University Compounds for malt1 degradation
WO2018106870A1 (en) * 2016-12-08 2018-06-14 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating cdk4/6-mediated cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9029548B2 (en) * 2011-05-06 2015-05-12 Catabasis Pharmaceuticals, Inc. Fatty acid lenalidomide derivatives and their uses
RU2704807C9 (ru) * 2015-06-04 2021-02-24 Арвинас, Инк. Модуляторы протеолиза на основе имидов и связанные с ними способы применения

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103396397A (zh) * 2013-08-14 2013-11-20 中国人民解放军军事医学科学院毒物药物研究所 来那度胺衍生物及其作为药物的用途
WO2015077058A2 (en) * 2013-11-08 2015-05-28 The Broad Institute, Inc. Compositions and methods for selecting a treatment for b-cell neoplasias
WO2017176958A1 (en) * 2016-04-06 2017-10-12 The Regents Of The University Of Michigan Monofunctional intermediates for ligand-dependent target protein degradation
WO2018085247A1 (en) * 2016-11-01 2018-05-11 Cornell University Compounds for malt1 degradation
WO2018106870A1 (en) * 2016-12-08 2018-06-14 Icahn School Of Medicine At Mount Sinai Compositions and methods for treating cdk4/6-mediated cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 3 November 2017 (2017-11-03), retrieved from STN Database accession no. 2138444-73-0 *
DATABASE REGISTRY 8 June 2017 (2017-06-08), retrieved from STN Database accession no. 2097970-92-6 *
HU , S. Q.: "Design, synthesis and biological evaluation of Lenalidomide derivatives as tumor angiogenesis inhibitor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 27, no. 17, 19 July 2017 (2017-07-19), pages 4075 - 4081, XP085166347 *

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