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WO2017088730A1 - 用于抗丙型肝炎病毒感染的含硅化合物 - Google Patents

用于抗丙型肝炎病毒感染的含硅化合物 Download PDF

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Publication number
WO2017088730A1
WO2017088730A1 PCT/CN2016/106781 CN2016106781W WO2017088730A1 WO 2017088730 A1 WO2017088730 A1 WO 2017088730A1 CN 2016106781 W CN2016106781 W CN 2016106781W WO 2017088730 A1 WO2017088730 A1 WO 2017088730A1
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Prior art keywords
compound
formula
bis
phenyl
independently selected
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PCT/CN2016/106781
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English (en)
French (fr)
Inventor
张寅生
刘保民
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Publication of WO2017088730A1 publication Critical patent/WO2017088730A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the present application belongs to the field of medicinal chemistry, and in particular to a silicon-containing compound for use against hepatitis C virus infection, a process for the preparation thereof, and a pharmaceutical composition containing the same.
  • the application also relates to the use of these compounds and pharmaceutical compositions for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • HCV is a positive-strand RNA virus belonging to the genus Hepatitis C in the Flaviviridae family. At least six major genotypes have been identified, including more than 50 subtypes.
  • the single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of approximately 3000 amino acids. In infected cells, the polyprotein is cleaved by cellular and viral proteases at multiple sites, resulting in both structural and non-structural (NS) proteins. In the case of HCV, the formation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B) is achieved by two viral proteases.
  • Treatment options for chronic HCV infection include: peginterferon- ⁇ combined with ribavirin in the treatment of HCV-infected patients and patients with cirrhosis, if the treatment fails, the interferon-containing treatment regimen is used again, and the sustained virological response rate will be As low as 14%, in addition, interferon-containing treatment regimens have increased toxic side effects in patients with cirrhosis; treatment with peginterferon- ⁇ , ribavirin and telaprevir or boceprevir may lead to serious deaths including death Complications, this program is not suitable for patients with cirrhosis with platelet count ⁇ 100000/ml and albumin level ⁇ 35g/L. Therefore, there is a need for a direct acting antiviral combination regimen that does not contain interferon to improve the efficacy and safety of patients with cirrhosis who are treated for HCV infection.
  • Ombitasvir (ABT-267) is an HCV NS5A protease inhibitor and a number of HCV NS5A inhibitors similar in structure to ABT-267 are currently under development.
  • the present application specifically selects ombitasvir as the mother nucleus to obtain a more excellent compound against hepatitis C virus infection.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof:
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, alkyl or aryl;
  • X is selected from -C(R 6 R 7 )- or -Si(R 6 R 7 )-;
  • Y is selected from -C(R' 6 R' 7 )- or -Si(R' 6 R' 7 )-;
  • R 4 is selected from -C(R 8 R 9 R 10 ) or -Si(R 8 R 9 R 10 );
  • R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 );
  • R 6 , R 7 , R' 6 and R' 7 are each independently selected from hydrogen or C 1-6 alkyl;
  • R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, and one or more A pharmaceutically acceptable carrier.
  • the application provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, for use in the manufacture of a medicament for the treatment of hepatitis C virus infection .
  • the present application provides the use of the above pharmaceutical composition for the manufacture of a medicament for the treatment of hepatitis C virus infection.
  • the application provides a method of treating a hepatitis C virus infection, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a pharmaceutically acceptable salt thereof A drug or a stereoisomer and a mixture thereof or a pharmaceutical composition as described above.
  • the application provides a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, for use in the treatment of hepatitis C virus infection, and combinations of the foregoing Things.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, alkyl or aryl;
  • X is selected from -C(R 6 R 7 )- or -Si(R 6 R 7 )-;
  • Y is selected from -C(R' 6 R' 7 )- or -Si(R' 6 R' 7 )-;
  • R 4 is selected from -C(R 8 R 9 R 10 ) or -Si(R 8 R 9 R 10 );
  • R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 );
  • R 6 , R 7 , R' 6 and R' 7 are each independently selected from hydrogen or C 1-6 alkyl;
  • R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • the relative stereochemistry of the 2 and 5 positions of the pyrrole ring (where N is the 1 position) to which the three benzene rings are directly attached may be cis or trans.
  • the 2- and 5-position configurations on the pyrrole ring include (2S, 5S), (2S, 5R), (2R, 5S), (2R, 5R).
  • the compound of formula I may be a stereoisomer or a mixture of two or more stereoisomers in any ratio.
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl. In the above embodiment, R 1 , R 2 and R 3 may be the same or different, and different cases include that all three are different and the two are different. For example, in the case where the two are different, R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • X is selected from -C (R 6 R 7) -
  • Y is selected from -C (R '6 R' 7 ) - or -Si (R '6 R' 7 ) -.
  • X is selected from -Si (R 6 R 7) -
  • Y is selected from -C (R '6 R' 7 ) - or -Si (R '6 R' 7 ) -.
  • R 4 is selected from -C(R 8 R 9 R 10 ), and R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ). In some embodiments, R 4 is selected from -Si(R 8 R 9 R 10 ); R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ).
  • R 6 , R 7 , R′ 6 and R′ 7 are each independently selected from hydrogen or C 1-4 alkyl. In some embodiments, R 6 , R 7 , R′ 6 and R′ 7 are each independently selected from hydrogen, methyl or ethyl. In the above embodiment, R 6 and R 7 may be the same or different, and R' 6 and R' 7 may be the same or different.
  • R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, methyl, ethyl, methoxy or ethoxy. In the above embodiment, R 8 , R 9 and R 10 may be the same or different, and R' 8 , R' 9 and R' 10 may be the same or different.
  • X and Y are both -CH 2 -; or X and Y are both -Si (CH 3) 2 -.
  • X is different from Y, for example, X is -Si(CH 3 ) 2 -, Y is -CH 2 -; or X is -CH 2 -; Y is -Si(CH 3 ) 2 -.
  • R 4 and R 5 are the same, for example, R 4 and R 5 are both -CH(CH 3 ) 2 ; or both -Si(CH 3 ) 3 ; or both -C(CH 3 ) 3 Or both are -CH(CH 3 )(OCH 3 ). In some embodiments, R 4 and R 5 are different, for example, R 4 is —C(CH 3 ) 3 ; R 5 is —CH(CH 3 ) 2 ; or R 4 is —Si(CH 3 ) 3 ; R 5 Is -CH(CH 3 ) 2 .
  • X is the same as Y, for example, at the same time -CH 2 -;
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or -CH (C 1-4) Alkyl)(C 1-4 alkoxy);
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl.
  • X is the same as Y, for example, simultaneously -CH 2 -;
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH (C 1 -4 alkyl)(C 1-4 alkoxy);
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl.
  • X is the same as Y, for example, simultaneously -CH 2 -;
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH (C 1 -4 alkyl)(C 1-4 alkoxy);
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, Isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different. For example, the two are different.
  • R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X and Y are both -CH 2 -;
  • R 4 is -C(C 1-4 alkyl) 3 ;
  • R 5 is -CH(C 1-4 alkyl) 2 or -C(C 1-4 alkyl) 3 ;
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X is -Si(C 1-4 alkyl) 2 -
  • Y is -CH 2 - or -Si(C 1-4 alkyl) 2 -
  • R 4 and R 5 are simultaneously -CH (C 1-4 alkyl) 2
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or benzene base.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X and Y are both -CH 2 -;
  • R 4 is -Si(C 1-4 alkyl) 3 ;
  • R 5 is -CH(C 1-4 alkyl) 2 or -Si(C 1-4 alkyl) 3 ;
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X and Y are independently selected from -CH 2 - or -Si (CH 3) 2 -;
  • R 4 and R 5 are independently selected from -CH (CH 3) 2, -C (CH 3) 3 , -Si(CH 3 ) 3 or -CH(CH 3 )(OCH 3 );
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and tertiary Butyl, n-butyl, isobutyl or phenyl.
  • X and Y are both -CH 2 -;
  • R 4 and R 5 are both -CH(CH 3 ) 2 , or both -C(CH 3 ) 3 , or both -Si(CH 3 3 or all are -CH(CH 3 )(OCH 3 ); and
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, and Butyl, isobutyl or phenyl.
  • X is -Si(CH 3 ) 2 -; Y is -CH 2 - or -Si(CH 3 ) 2 -; R 4 and R 5 are both -CH(CH 3 ) 2 ; 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • X and Y are both -CH 2 -;
  • R 4 is -C (CH 3) 3 or -Si (CH 3) 3;
  • R 5 is -CH (CH 3) 2; and
  • R 1, R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • the application provides a compound of Formula Ia, Formula Ib, Formula Ic, Formula Id, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • R 1 , R 2 , R 3 , X, Y, R 4 and R 5 in formula Ia, formula Ib, formula Ic and formula Id are as described above for R 1 , R 2 , R 3 , X, Y in formula I
  • the detailed descriptions of R 4 and R 5 are the same.
  • the application provides a compound of Formula II, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, alkyl or aryl;
  • R 4 is selected from -C(R 8 R 9 R 10 ) or -Si(R 8 R 9 R 10 );
  • R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 );
  • R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • the relative stereochemistry of the 2 and 5 positions of the pyrrole ring (where N is 1 position) directly linked to the three benzene rings It is cis or trans.
  • the 2- and 5-position configurations on the pyrrole ring include (2S, 5S), (2S, 5R), (2R, 5S), (2R, 5R).
  • the compound of formula II may be a stereoisomer or a mixture of two or more stereoisomers in any ratio.
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl. In the above embodiment, R 1 , R 2 and R 3 may be the same or different, and different cases include that all three are different and the two are different. For example, in the case where the two are different, R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • R 4 is selected from -C(R 8 R 9 R 10 ), and R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ). In some embodiments, R 4 is selected from -Si(R 8 R 9 R 10 ); R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ).
  • R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, methyl, ethyl, methoxy or ethoxy. In the above embodiment, R 8 , R 9 and R 10 may be the same or different, and R' 8 , R' 9 and R' 10 may be the same or different.
  • R 4 and R 5 are the same, for example, R 4 and R 5 are both -CH(CH 3 ) 2 ; or both -Si(CH 3 ) 3 ; or both -C(CH 3 ) 3 Or both are -CH(CH 3 )(OCH 3 ). In some embodiments, R 4 and R 5 are different, for example, R 4 is —C(CH 3 ) 3 ; R 5 is —CH(CH 3 ) 2 ; or R 4 is —Si(CH 3 ) 3 ; R 5 Is -CH(CH 3 ) 2 .
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH(C 1-4 alkyl)(C 1-4 alkoxy); R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl. In some specific embodiments, R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH(C 1-4 alkyl)(C 1-4 alkoxy) R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl.
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH(C 1-4 alkyl)(C 1-4 alkoxy)
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different. For example, the two are different.
  • R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • R 4 is -C(C 1-4 alkyl) 3
  • R 5 is -CH(C 1-4 alkyl) 2 or -C(C 1-4 alkyl) 3
  • R 1 R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, tert-butyl or Phenyl.
  • R 4 is -Si(C 1-4 alkyl) 3
  • R 5 is -CH(C 1-4 alkyl) 2 or -Si(C 1-4 alkyl) 3
  • R 1 R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • R 4 and R 5 are both -CH(CH 3 ) 2 , or both -C(CH 3 ) 3 , or both -Si(CH 3 ) 3 , or both -CH(CH 3 ) (OCH 3 ); and R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl or phenyl.
  • R 4 is -C(CH 3 ) 3 or -Si(CH 3 ) 3
  • R 5 is -CH(CH 3 ) 2
  • R 1 , R 2 and R 3 are each independently selected from Methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl or phenyl.
  • the present application provides a compound of Formula IIa, Formula IIb, Formula IIc, Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • the present application provides the following compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or stereoisomers thereof, and mixtures thereof:
  • Me is a methyl group
  • Et is an ethyl group
  • Ph is a phenyl group
  • t-Bu is a tert-butyl group
  • i-Pr is an isopropyl group.
  • compositions comprising a therapeutically effective amount of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula A compound of IId, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, and one or more pharmaceutically acceptable carriers.
  • compositions of the present application can be prepared by combining a compound of the present application, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, with a suitable pharmaceutically acceptable carrier.
  • a suitable pharmaceutically acceptable carrier for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, Microspheres and aerosols, etc.
  • Typical routes for administration of a compound of the present application, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, Administered by the intestine, or topical, transdermal, inhaled, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers such carriers.
  • pharmaceutically acceptable carriers such carriers.
  • These carriers enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules.
  • the core of a tablet or dragee. Suitable accessory package include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compound of the present application comprises a compound having a specific structure having hepatitis C virus (HCV) NS5A inhibitory activity, and can be used as an HCV NS5A inhibitor for the treatment of hepatitis C virus infection, specifically for causing hepatitis C virus infection. Treatment of liver diseases such as hepatitis and cirrhosis.
  • HCV hepatitis C virus
  • the compound of the present application includes a compound having a specific structure having hepatitis C virus (HCV) NS5A inhibitory activity, in particular, having excellent inhibitory activity against various gene subtypes of HCV, and these gene subtypes include 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 6a are preferably 1b, 3a, 4a, 5a, 6a.
  • HCV hepatitis C virus
  • the compounds of the present application including compounds of specific structure, also have excellent pharmacokinetic parameters, including stability in liver microsomes, good half-life and bioavailability, and good liver targeting.
  • the compounds of the present application include anti-HCV viral activity of compounds of specific structure and have significant advantages in terms of pharmacokinetics compared to ombitasvir; compounds of the present application include inhibitory activities of compounds of specific structure on various genetic subtypes of HCV and Compared with ombitasvir, it has significant advantages.
  • the present application provides a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate thereof, Use of prodrugs or stereoisomers and mixtures thereof for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the present application provides a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate thereof, Use of prodrugs or stereoisomers and mixtures thereof with at least one other active compound for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the present application provides a compound comprising Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • a pharmaceutical composition of a prodrug or a stereoisomer and a mixture thereof for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • the present application provides a compound comprising Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • a pharmaceutical composition of a prodrug or a stereoisomer and a mixture thereof with at least one other active compound for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • other active compounds include, but are not limited to, other compounds that are resistant to HCV activity.
  • other active compounds include, but are not limited to, immunomodulatory agents and other antiviral agents.
  • other active compounds include, but are not limited to, interferon or ribavirin, wherein the interferon is selected from the group consisting of interferon alpha 2B, PEGylation Interferon alpha, complex interferon (consensus interferon), interferon alpha 2A, and lymphoblastin interferon tau.
  • other active compounds include, but are not limited to, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of a type 1 helper T cell response, interfering RNA, antisense RNA, Imiqimod, Baverin, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
  • other active compounds are effective to inhibit the function of a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV Entry, HCV assembly, HCV release, HCV NS5A protein and IMPDH.
  • a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV Entry, HCV assembly, HCV release, HCV NS5A protein and IMPDH.
  • the HCV includes a plurality of genotypes thereof and a plurality of gene subtypes, such as 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 6a.
  • the application provides a method of treating a hepatitis C virus infection, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or a compound of Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof.
  • the therapeutically effective amount of the prodrug or stereoisomer and mixtures thereof is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId is determined by the needs of the individual patient, for example, once or twice per day, Or more times a day.
  • Administration can be intermittent, for example, wherein during a period of several days, the patient receives Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId A daily dose of the compound, followed by a period of several days or more, the patient does not receive Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId The daily dose of the compound.
  • the present application provides a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId for use in the treatment of hepatitis C virus infection or a pharmaceutically acceptable compound thereof Salts, hydrates, solvates, prodrugs or stereoisomers and mixtures thereof, as well as the above pharmaceutical compositions for the treatment of hepatitis C virus infection.
  • Cbz- means a benzyloxycarbonyl group, specifically PhOCO-.
  • EDCI refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.
  • HOBT refers to 1-hydroxybenzotriazole.
  • Ms- nail sulfonyl group, specifically CH 3 SO 2 -.
  • C mn means having mn carbon atoms in this moiety.
  • C1-6 alkyl means that the alkyl group has from 1 to 6 carbon atoms.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, ⁇ , ⁇ , etc.
  • the specific alkyl group includes all isomeric forms thereof, for example, the propyl group includes -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , for example, butyl includes -CH 2 CH 2 CH 2 CH 3 ,- CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 .
  • C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • the "alkyl”, “C 1-6 alkyl” or “C 1-4 alkyl” may be unsubstituted or substituted by one or more substituents selected from alkyl, hydroxy, halogen or amino groups. .
  • C1-6 alkoxy refers to an -O-alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkoxy refers to an -O-alkyl group having from 1 to 4 carbon atoms.
  • the "alkoxy”, “C 1-6 alkoxy” or “C 1-4 alkoxy” may be unsubstituted or selected from one or more selected from the group consisting of an alkyl group, a hydroxyl group, a halogen or an amino group. Substituent substitution.
  • aryl refers to an all-carbon monocyclic or polycyclic fused aromatic ring group having a conjugated ⁇ -electron system, preferably having from 6 to 14 carbon atoms, more preferably from 6 to 12 carbon atoms, most It preferably has 6 carbon atoms.
  • a monocyclic aromatic ring group is selected from phenyl
  • a bicyclic fused aromatic ring group consists of a phenyl group fused to a 4-6 membered aromatic or non-aromatic carbocyclic ring including a naphthyl group.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without biologically adverse effects.
  • a pharmaceutically acceptable salt for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned. .
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • hydrate refers to a complex formed by a compound of the present application and a stoichiometric amount of water molecules.
  • solvate refers to a compound comprising a compound of the present application and a stoichiometric amount of one or more pharmaceutically acceptable solvents.
  • a molecular complex of molecules such as ethanol.
  • prodrug refers to a compound obtained by chemically modifying a drug, which has no activity in vitro, and is converted into an original drug in an organism or a human body to exert a pharmacological effect; the original drug (original drug) is referred to as a parent drug, The structurally modified compound is a prodrug.
  • stereoisomer refers to isomers of the same molecular structure of the compound, but which differ in stereostructure, such as enantiomers and diastereomers.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • the compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • the compounds of the present application may contain asymmetrically substituted carbon atoms known as chiral centers. These compounds may, without limitation, be a single stereoisomer (eg, a single enantiomer or a single diastereomer), a mixture of stereoisomers (eg, a mixture of enantiomers or diastereomers). Or in the form of a racemic mixture.
  • Compounds identified herein as single stereoisomers are intended to describe compounds that are substantially free of other stereoisomers. "Substantially free” means that at least 95%, 96%, 97%, 98% or 99% of the compound in the composition is the stereoisomer described.
  • R 4 and R 5 may contain a chiral carbon atom, specifically When R 4 and R 5 are -CH(C 1-4 alkyl)(C 1-4 alkoxy), at least one of the chiral carbon atoms is -C*H(C 1-4 alkyl) (C 1-4 alkoxy), wherein C* is a chiral carbon atom, which may be in the S configuration or the R configuration, respectively, more specifically, R 4 and R 5 are -CH(CH 3 ) (OCH 3 ) When the specific configuration is:
  • stereoisomers of the compounds of the present application can be prepared using a variety of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, enantiomeric enantiomeric conversion of enantiomeric mixtures to diastereomers, and subsequent diastereomeric chromatography. Separation and regeneration of individual enantiomers, as well as enzymatic resolution.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the following Specific embodiments, their implementations in combination with other chemical synthesis methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments include, but are not limited to, embodiments of the present application.
  • reaction materials and reaction reagents of the present application can be obtained by purchase unless otherwise stated.
  • the compounds of formula I of the present application can be prepared by the following general methods in the art: wherein R 1 , R 2 , R 3 , X, Y, R 4 , R 5 , R 6 , R 7 , R' 6 , R' 7 , R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are as defined above.
  • Compound 5 reacts with compound 8 under the action of a base to form compound 9; compound 9 is reacted by reduction (using a catalyst such as platinum oxide) to form compound 10, compound 10 is reacted with amino acid derivative 11 to obtain compound 12; and compound 12 is deprotected from Cbz (The reaction conditions are, for example, under the action of a palladium carbon catalyst and hydrogen to give compound 13; compound 13 is then amidated with amino acid derivative 14 to give a compound of formula I.
  • Compound 5 is reacted with compound 8 under the action of a base to form compound 9; compound 9 is subjected to a reduction reaction (using a catalyst such as platinum oxide) to give compound 10, and compound 10 is reacted with amino acid-derived fragment 15 to give a compound of formula I.
  • a reduction reaction using a catalyst such as platinum oxide
  • the obtained compound 10 is sequentially reacted with the amino acid derivative 11X and the amino acid derivative 11Y to obtain a compound 12, which is then subjected to reduction and amidation to give a compound of the formula I.
  • the obtained compound 13 is sequentially reacted with the amino acid derivative 14-R4 and the amino acid derivative 14-R5 to prepare a compound of the formula I.
  • the obtained compound 10 is sequentially reacted with the amino acid derivative 11X and the amino acid derivative 11Y to obtain the compound 12, which is then subjected to a reduction reaction, and is sequentially amidated with the amino acid derivative 14-R4 and the amino acid derivative 14-R5 to obtain a compound of the formula I. .
  • the compound 10 can be subjected to chromatography to obtain an optically active compound 10a, a compound 10b, and a compound 10c.
  • Compound 1 reacts with Compound 2 under Lewis acid mediated conditions to form Compound 3;
  • Compound 3 can be, for example, boron Reduction of sodium hydride produces compound 4, which reacts with methylsulfonyl chloride to form compound 5 under the action of a base.
  • Compound 5 is a mixture of various configurations comprising 5a (RR), 5b (SS), 5c (SR). It can be synthesized according to the preparation methods reported in the literature (J. Med. Chem, 2014, 57, 2047-2057; Synthesis, 2009, 1739-1743; Synthesis, 2000, 1259-1262).
  • Compound 5 can be subjected to chiral column chromatography to give optically active compound 5a, compound 5b, and compound 5c.
  • the preparation method of the intermediate compound 8 is as follows:
  • the synthesis of the silicon-containing aniline compound 8 can be carried out according to the preparation method reported in the literature (Journal of Organic Chemistry, 73 (17), 2008, 6671-6678). Different methods may use different silane derivatives such as Me 3 SiMe 3 , Et 3 SiH, Me 3 SiCl, Et 3 SiCl, Me 2 EtSiCl, Me 2 PhSiH, Me 2 PhSiCl and the like, which are commercially available.
  • Intermediate 11 (including 11X and 11Y) can be prepared according to methods reported in the literature.
  • the intermediate 11 containing silicon can be obtained by a method reported in the literature (Eur. J. Org. Chem. 2000, 8072811 J. Am. Chem. Soc. 2006, 128, 8479-8483), (ICH 2 ) 2 Si (R) 6 R 7 ) can be obtained, for example, from the purchase of Aldrich.
  • Intermediate 14 (including 14-R4 and 14-R5) can be prepared according to methods reported in the literature.
  • the intermediate 14 containing silicon can be reported in the literature (Tetrahedron, 61(1), 43-50; 2005, Angew. Chem. Int. ed. 2009, 39, 2288-2290).
  • the method is then obtained by further chiral separation. Examples are as follows:
  • the starting material compound 21 and other silane analogs which are differently substituted on the silicon atom can be obtained, for example, from Aldrich.
  • the intermediate 25 may be purchased or obtained by a method disclosed in the literature, or may be obtained by removing the protecting group from the intermediate 11.
  • the present application also provides a process for the preparation of the compounds of Formula Ia, Formula Ib, Formula Ic, and Formula Id.
  • the compounds of the formula Ia, the formula Ib, the formula Ic and the formula Id of different configurations can be obtained directly by chromatography column chromatography.
  • the compound of the formula Ia, the formula Ib, the formula Ic and the formula Id can be further synthesized by the optically active compound 10a, the compound 10b, and the compound 10c, respectively, in a similar manner to the above-mentioned preparation of the compound of the formula I.
  • the compound of the formula Ia, the formula Ib, the formula Ic and the formula Id can be further synthesized by the optically active compound 5a, the compound 5b, and the compound 5c, respectively, in a similar manner to the above-mentioned preparation of the compound of the formula I.
  • a mixture of the optically active compound 10a and the compound 10b may be isolated to obtain a mixture of the compound of the formula Ia and the compound of the formula Ib, which is then chromatographed to obtain a compound of the formula Ia of different configuration but of the same structure, formula Ib.
  • Compound. Methods of preparation of such similar means are included within the scope of the present application.
  • the compound of formula Ic is prepared using compound 10c or compound 5c, which will first give the cis configuration of the compound of formula I, which can be further isolated to give a compound of formula Ic, formula Id.
  • the corresponding compound of formula II (compound of formula IIa, formula IIb, formula IIc, formula IId) can be prepared according to the process for the preparation of a compound of formula I (compounds of formula Ia, formula Ib, formula Ic, formula Id).
  • a mixture of trans isomers 10a (SS) and 10b (RR) is reacted with amino acid derivative 11 to obtain a mixture of 12a (SS) and 12b (RR); a mixture of 12a (SS) and 12b (RR) is Removal of Cbz protecting group by palladium-carbon catalyst and hydrogen to obtain a mixture of 13a (SS) and 13b (RR); 13a (SS), 13b (RR) and amidation of amino acid derivative 14 to obtain a mixture of Ia and Ib Ia and Ib can be separated by column chromatography to obtain a compound of a single configuration of Ia and Ib.
  • Nuclear magnetic resonance chromatography was measured using a Varian VNMR S-400 nuclear magnetic resonance spectrometer; LC/MS was performed using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18, Mm, 5 microns, 35 ° C), using ESI (+) ion mode.
  • THF refers to tetrahydrofuran.
  • DCM dichloromethane.
  • DMSO means dimethyl sulfoxide.
  • DIPEA means N,N-diisopropylethylamine.
  • DMF means N,N-dimethylformamide.
  • MOC-L-proline means N-(methoxycarbonyl)-L-proline.
  • Room temperature means that the reaction temperature is between 25 and 30 °C.
  • Step 1 Add p-chloronitrobenzene (30 g, 190.4 mmol), hexamethyldisilane (119.57 g, 86.82 mmol), tetrakis-(triphenylphosphine)palladium (8.8 g, 7.616 mmol) to a pressure tube. The reaction was stirred at 170 ° C under a nitrogen atmosphere with xylene (90 mL). After 7 hours, the reaction was completed, and the reaction mixture was cooled to room temperature, then celite was filtered, and the filtrate was concentrated to give trimethyl(4-nitrophenyl)-silane (32 g).
  • Step 2 Add trimethyl(4-nitrophenyl)-silane (32 g, 163.86 mmol), absolute ethanol (500 mL), 10% Pd/C (4.78 g, 4.5 mmol) in a single-neck flask, and pass nitrogen. The substitution was carried out 3 times, the hydrogen was replaced 3 times to remove the air, and the reaction was carried out at room temperature overnight under a hydrogen pressure of 1 atm. After the completion of the reaction, the reaction mixture was filtered with EtOAc EtOAc (EtOAc)EtOAc.
  • Step 1 Toluene (300 mL), anhydrous zinc chloride (54.6 g, 0.4 mol) were added to a three-necked flask, and the reaction was stirred at room temperature under nitrogen atmosphere, then triethylamine (32 mL) and tert-butanol (28 mL) were slowly added. Stirring was continued for 1.5 hours at room temperature. Then, 2-bromo-4-nitroacetophenone (48.8 g, 0.2 mol) and 4-nitroacetophenone (49.6 g, 0.3 mol) were further added, and stirred at room temperature overnight.
  • Step 2 Add 1,4-bis-(4-nitrophenyl)butane-1,4-dione (30 g, 91.39 mmol) and THF (500 mL) in a one-neck flask, under nitrogen, at 0 ° C Sodium borohydride (10.72 g, 283.3 mmol) was added, and after reacting for 30 minutes, the mixture was heated to 60 ° C to react overnight. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with water, and the mixture was washed with water, and then the mixture was added with 500 ml of water, and the mixture was extracted with ethyl acetate. (4-Nitrophenyl)butane-1,4-diol (13.2 g), a mixture of three configurations of SS, RR, and SR.
  • Step 3 Add a mixture of three configurations of SS, RR, SR of 1,4-bis(4-nitrophenyl)butane-1,4-diol in a three-necked flask (13 g, 39.12 mmol), DCM (300 mL), triethylamine (16.31 mL, 117.36 mmol) was added dropwise at 0 ° C under nitrogen atmosphere. After stirring, stirring was continued for 20 minutes, then methanesulfonyl chloride (7.57 mL, 97.8 mmol) was slowly added dropwise. The reaction was continued for 2.5 hours to 3.5 hours after completion.
  • Butane-1,4-disubstituted dimethoyl ester (10.5 g) is a mixture of three configurations of SS, RR, SR.
  • Step 1 Add sodium hydroxide (2.4 g, 60.08 mmol) to 60 mL water, then add O-methyl-L-threonine (8.0 g, 60.08 mmol) and sodium carbonate (3.30 g, 31.2 mmol), 0 ° C Stirring to dissolve the solid, the solution became clarified and then became turbid. Methyl chloroformate (8.48g, 90.12mmol) was slowly added to the reaction solution. After the addition was completed, it was moved to room temperature overnight. After the reaction, the ice water bath was cooled.
  • Step 2 Add (2S,3R)-3-methoxy-2-((methoxy)amino)butyric acid (11.5 g, 60.15 mmol) to 150 mL of ethyl acetate and then add N-hydroxysuccinyl Imine (6.92g, 60.15mmol), stirred at 0 ° C, solid dissolved, diisopropylcarbodiimide (7.59g, 60.15mmol) was slowly added to the reaction solution, resulting in white turbidity, after the end of the addition, 0 ° C After stirring for 1 hour, the reaction mixture was allowed to react to room temperature overnight.
  • Step 3 L-valine (4.98 g, 43.37 mmol) was added to a mixed solvent of 40 mL of water and 40 mL of acetonitrile, then N,N-diisopropylethylamine (10.68 g, 82.60 mmol) was added and stirred at room temperature The solid was dissolved by (2S,3R)-2,5-dioxopyrrolidin-1-yl-3-methoxy-2-((methoxy)amino)butyrate (11.90 g, 41.30 mmol Dissolved in 40 mL of acetonitrile, and then slowly added to the above reaction solution.
  • Example 1 Dimethyl((2S,2'S)-((2S,2'S)-2,2'-((((2S,5S)-1-(4-(trimethylsilyl))phenyl) Pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl)) bis ( 3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ia-1)
  • Step 1 Add a mixture of 1,4-bis(4-nitrophenyl)butane-1,4-disubstituted dimesyl ester SS, RR, SR in a three-necked flask (4.5 g, 9.2mmol), DMF (24mL), triethylamine (9.32g, 92.1mmol), the mixture was heated to 60 ° C under nitrogen, then slowly added trimethylsilylaniline (10.66g, 64.47mmol), and the reaction was stirred overnight. . After completion of the reaction, the reaction mixture was cooled, and then added with 50 mL of water and ethyl acetate.
  • Step 2 Add 2,5-bis-(4-nitro-phenyl)-1-(4-trimethylsilyl-phenyl)-pyrrolidine SS, RR, SR to the autoclave.
  • the celite was filtered, and the filter cake was washed with dichloromethane.
  • Step 3 Add 4,4'-(1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine trans isomer SS, RR in a single vial Mixture (450 mg, 1.12 mmol), DMF (15 mL), N-benzyloxycarbonyl-L-valine (1.34 g, 5.6 mmol), EDCI (869.34mg, 5.6mmol), HOBT (756.67mg, 5.6mmol) N-methylmorpholine (566.44 mg, 5.6 mmol) was stirred at room temperature under nitrogen overnight.
  • Step 4 Add (2S,2'S)-dibenzyl-2,2'-((((2S,5S)-1-(4-(trimethylsilyl)phenyl)pyrrolidine) to the autoclave. 2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) and (2S,2'S)-di Benzyl-2,2'-((((2R,5R)-1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis(4,1- sub) a mixture of phenyl))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) (790 mg, 0.914 mmol), then ethanol (30 mL), partially dissolved, then added Methanol (5 mL), all solids were dissolved, then 10% anhydrous
  • Step 5 Compound (Ia-1) and Compound (Ib-1)
  • Example 2 Dimethyl ((2S, 2S')-((2S, 2S')-2, 2'-((((2S,5R)-1-(4-(trimethylsilyl)) Phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1-diyl) )) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ic-1)
  • Step 1 (2S, 2'S)-dibenzyl-2,2'-((((2S,5R)-1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5- Diyl) bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate)
  • Step 2 (2S,2'S)-N,N'-(((2S,5R)-1-(4-(Trimethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis (4 , 1-phenylene)) bis(pyrrolidine-2-carboxamide)
  • Example 3 dimethyl ((2S, 2S')-((2S, 2S')-2, 2'-(((((2S,5S)-1-(4-(triethylsilyl))) Phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1-diyl) )) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ia-2)
  • Step 1 Referring to Step 1 in Example 1, trimethylsilylaniline was replaced with triethylsilylaniline (13.37 g, 64.47 mmol) to give 2,5-bis-(4-nitro-phenyl)- A mixture of three configurations of 1-(4-triethylsilyl-phenyl)-pyrrolidine SS, RR, SR. HRMS (ESI) m/z 504.2312 (M+H) + .
  • Step 2 Referring to Step 2 in Example 1, 4,4'-(1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine is trans isomerized. Bulk SS, RR mixture (850 mg), cis single isomer SR (1.0 g).
  • step 5 of Example 1 a mixture of Ia-2 and Ib-2 was obtained, a total of 490 mg, and the ratio of the two isomers was 1:1.
  • the two isomers were separated on a C-18 column, and Ia-2 was isolated first, and then Ib-2 was isolated.
  • Example 4 dimethyl ((2S, 2S')-((2S, 2S')-2, 2'-((((2S,5R)-1-(4-(triethylsilyl))) Phenyl) Pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1-diyl)) double (3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ic--2)
  • Step 1 (2S,2'S)-dibenzyl-2,2'-((((2S,5R)-1-(4-(triethylsilyl)phenyl)pyrrolidine-2,5- Diyl) bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate)
  • Step 2 (2S, 2'S)-N,N'-(((2S,5R)-1-(4-(Triethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis (4 , 1-phenylene)) bis(pyrrolidine-2-carboxamide)
  • Example 5 Dimethyl((2S,2S')-((2S,2S')-2,2'-(((((2S,5S)-1-(4-(tert-butyldimethyl)) Silyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1 -diyl)) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ia-3)
  • step 1
  • (2S, 2'S)-N,N'-((2S,5S)-1-(4-(tert-butyldimethylsilyl)phenyl)pyrrolidine-2 was obtained.
  • 2,5-diyl)bis(4,1-phenylene))bis(pyrrolidine-2-carboxamide) and (2S,2'S)-N,N'-((2R,5R)-1-( a mixture of 4-(tert-butyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene)bis(pyrrolidine-2-carboxamide) 350mg.
  • Step 5 Compound (Ia-3) and Compound (Ib-3)
  • a mixture of Ia-3 and Ib-3 was obtained in a total of 350 mg, and the ratio of the two isomers was 1:1.
  • the two isomers were separated by a C-18 column, and Ia-3 was isolated and then separated to obtain Ib-3.
  • Example 6 Dimethyl((2S,2S')-((2S,2S')-2,2'-(((((2S,5R)-1-(4-(tert-butyldimethyl)) Silyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1 -diyl)) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ic-3)
  • step 1
  • Example 7 Dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2S,5S))) Ethylsilyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2 ,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-15)
  • step 1
  • Example 8 dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2), 5S)) Butyl dimethyl Silyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1 -diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-16)
  • Step 1 (2S,5S)-2,5-bis-(4-nitro-phenyl)-1-(4-tert-butyldimethylsilyl-phenyl)-pyrrolidine
  • Example 9 dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2), 5S)) Dimethylsilyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl) -2,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-17)
  • Step 1 (2S,5S)-2,5-bis-(4-nitro-phenyl)-1-(4-ethyldimethylsilyl-phenyl)-pyrrolidine
  • Step 2 4,4'-((2S,5S)-1-(4-(ethyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine
  • Example 10 dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2S,5S)-1-(4-(3) Methylsilyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2 ,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-18)
  • Step 2 4,4'-((2S,5S)-1-(4-(Trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine
  • Example 11 In vitro drug efficacy test and cytotoxicity test
  • the Huh7 cell line is stably transferred into the HCV genotype 1a replicon or the 1b replicon.
  • Test compound 10 mM mother liquor prepared with 100% DMSO was temporarily stored in a nitrogen cabinet, and the compound list is shown in Table 2.
  • the compound DMSO stock solution was diluted according to the dilution information of the compound of Table 2 and added to a 96-well experimental plate at a final concentration of 0.5% DMSO.
  • HCV 1a replicon cells or 1b replicon cells were seeded in the above 96-well cell plates, followed by incubation at 37 ° C for 3 days in a 5% CO 2 incubator.
  • the cell viability test can be carried out by adding a cell growth fluorescent titration detection reagent to each well. After incubating the cells for 1 hour at 37 ° C in a 5% CO 2 incubator, the Luminescence signal value is detected by a spectrophotometer detection system Envision, and the raw data is used for the calculation of the compound cytotoxicity. .
  • the inhibitory effect of the compound of the present application on HCV replication can be determined by measuring the activity of the luciferase reporter gene. The luciferase luminescent substrate Bright-Glo was added to each well, and the Luminescence signal value was detected within 5 minutes using the chemiluminescence detection system Envision. The raw data was used for the calculation of the compound inhibitory activity.
  • the raw data is processed as a percentage of cell viability using the following formula:
  • the raw data is processed as a percent inhibition using the following formula:
  • CPD represents the signal value of the compound pore
  • HPE Haundred percent effect
  • ZPE Zero percent effect
  • CPD represents the signal value of the compound pore
  • HPE Haundred percent effect
  • HPE 100% effective control well signal value, only DMEM medium in the well
  • ZPE Zero percent effect
  • the percentage of cell viability, the percent inhibition were introduced into GraphPad Prism software for data processing and the curve corresponding compound derived cytotoxicity (CC 50) and the replicon inhibitory activity against HCV (EC 50) values.
  • Ic-1 >1 0.008 nM 4
  • Ia-2 >1 0.003 nM 5
  • Ib-2 >1 0.006 nM 6
  • Ic-2 >1 0.007 nM 7
  • Ia-3 >1 0.003 nM
  • Example 12 Inhibitory activity of HCV different genotype NS5A chimeric replicon and determination of anti-infective disease hepatitis virus (HCVcc, JFH-1, GT2a) activity
  • DMEM cell culture solution Invitrogen Fetal bovine serum Corning L-glutamine Invitrogen Penicillin-streptomycin Invitrogen Phosphate buffer Corning Trypsin Invitrogen Dimethyl sulfoxide (DMSO) Sigma Plasmid extraction kit Qiagen SpeI-HF enzyme NEB PCR product purification kit Qiagen In vitro transcription kit Promega RNA purification kit Qiagen DEPC treatment of water Invitrogen Phosphate buffer PBS pH 7.4 (Ca2+Mg2+free) Invitrogen Bright-Glo detection reagent Promega
  • the HCV replicon RNA was transiently transfected into huh7 cells by electroporation; the cells were then seeded into 96-well plates (10,000 cells/well), and then placed in a 37 ° C, 5% CO 2 incubator. 3 days.
  • Anti-HCV replicon activity assay The luciferase luminescent substrate Bright-Glo was added to each well, and the Luminescence signal value was detected by the chemiluminescence detection system Envision within 5 minutes. The raw data (RLU) was used for the calculation of the compound inhibitory activity.
  • CPD Signal value of the compound well.
  • HPE 100% effective control well signal value, only DMEM medium in the well.
  • ZPE Zero percent effect: Ineffective control cell signal value, with 0.5% DMSO instead of compound.
  • Huh-7.5.1 cells were seeded into 96-well plates (7,000 cells/well) and subsequently cultured overnight at 37 ° C in a 5% CO 2 incubator.
  • HCVcc was added to a 96-well assay plate at a concentration of MOI 0.1 per well. It was then placed in a 37 ° C, 5% CO 2 incubator for 3 days. The luciferase luminescent substrate was added to each well, and the Luminescence signal value was detected by the chemiluminescence detection system Envision. The raw data (RLU) was used for the calculation of the compound inhibitory activity.
  • the raw data was processed as percent inhibition activity using the following formula:

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Abstract

本申请提供用于抗丙型肝炎病毒感染的含硅化合物，具体涉及如式Ⅰ所示的新的具有HCV NS5A蛋白酶抑制活性的化合物及其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物、其制备方法及其药物组合物。本申请还涉及所述化合物及其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物和其药物组合物治疗丙型肝炎病毒感染的用途。

Description

用于抗丙型肝炎病毒感染的含硅化合物
相关申请的交叉引用
本申请要求于2015年11月23日向中国国家知识产权局提交的第201510814757.9号中国专利申请以及于2016年08月12日向中国国家知识产权局提交的第201610669653.8号中国专利申请的优先权和权益，所述专利申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于药物化学领域，具体涉及用于抗丙型肝炎病毒感染的含硅化合物、其制备方法、含有这些化合物的药物组合物。本申请还涉及这些化合物和药物组合物用于治疗丙型肝炎病毒(HCV)感染的用途。
背景技术
HCV是一种正链RNA病毒，属于黄病毒科中的丙型肝炎病毒属，已经鉴定出至少6个主要的基因型，包含50多个亚型。单链HCV RNA基因组长度约为9500个核苷酸，具有单个可读框(ORF)，编码单个约3000个氨基酸的大型多聚蛋白。在感染细胞中，该多聚蛋白在多个位点上被细胞蛋白酶和病毒蛋白酶切割，产生结构和非结构(NS)蛋白。就HCV而言，成熟非结构蛋白(NS2、NS3、NS4A、NS4B、NS5A、NS5B)的形成是通过两种病毒蛋白酶实现的。
慢性HCV感染的治疗方案包括：聚乙二醇干扰素-α与利巴韦林组合治疗HCV感染患者和肝硬化患者，若治疗失败后再次使用含干扰素的治疗方案，持续病毒学应答率将低至14％，此外，含干扰素的治疗方案对肝硬化患者的毒副作用增加；聚乙二醇干扰素-α、利巴韦林和telaprevir或boceprevir的治疗方案可能导致包括死亡在内的严重并发症，该方案不适于治疗血小板计数＜100000/ml、白蛋白水平＜35g/L的肝硬化患者。因此，需要不含干扰素的直接作用抗病毒药联合方案，用来改善治疗HCV感染的肝硬化患者的疗效和安全性。
德克萨斯大学健康科学中心-肝病研究所的Poordad博士等用ABT-450、ombitasvir(ABT-267)、dasabuvir(ABT-333)和利巴韦林联合方案治疗HVC基因-1型感染同时伴有代偿性肝硬化的成人患者，治疗周期为12周和24周，观察该联合方案的疗效和安全性。结果显示，该不含干扰素的联合方案治疗HCV基因1型代偿性肝硬化患者安全且有效，可达到较 高的持续病毒学应答率。
Ombitasvir(ABT-267)是一种HCV NS5A蛋白酶抑制剂，目前还有多种与ABT-267结构类似的HCV NS5A抑制剂在开发中。本申请特异性地选择ombitasvir为母核得到了更优异的抗丙型肝炎病毒感染的化合物。
发明概述
一方面，本申请提供了式Ⅰ的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物：
Figure PCTCN2016106781-appb-000001
其中：
R1、R2和R3分别独立地选自氢、烷基或芳基；
X选自-C(R6R7)-或-Si(R6R7)-；
Y选自-C(R’6R’7)-或-Si(R’6R’7)-；
R4选自-C(R8R9R10)或-Si(R8R9R10)；
R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)；
R6、R7、R’6和R’7分别独立地选自氢或C1-6烷基；以及
R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-6烷基或C1-6烷氧基。
另一方面，本申请提供了药物组合物，其包含式I的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，以及一种或多种药学上可接受的载体。
又一方面，本申请提供了式I的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物在制备治疗丙型肝炎病毒感染的药物中的用途。
另一方面，本申请提供了上述药物组合物在制备治疗丙型肝炎病毒感染的药物中的用途。
再一方面，本申请提供了治疗丙型肝炎病毒感染的方法，所述方法包括给予需要治疗的患者治疗有效量的式I的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物或者上述药物组合物。
又一方面，本申请提供了用于治疗丙型肝炎病毒感染的式I的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物以及上述药物组合物。
发明详述
本申请提供了式Ⅰ的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，
Figure PCTCN2016106781-appb-000002
其中：
R1、R2和R3分别独立地选自氢、烷基或芳基；
X选自-C(R6R7)-或-Si(R6R7)-；Y选自-C(R’6R’7)-或-Si(R’6R’7)-；
R4选自-C(R8R9R10)或-Si(R8R9R10)；R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)；
R6、R7、R’6和R’7分别独立地选自氢或C1-6烷基；以及
R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-6烷基或C1-6烷氧基。
其中与三个苯环直接相连的吡咯环(其中N为1位)的2位和5位的相对立体化学可以是顺式或反式。在一些具体的实施方案中，该吡咯环上2位和5位构型包括(2S,5S)、(2S,5R)、(2R,5S)、(2R,5R)。式Ⅰ的化合物可以是一种立体异构体，也可以是两种或两种以上立体异构体任意比例的混合物。
在一些实施方案中，R1、R2和R3分别独立地选自氢、C1-6烷基或C6-12芳基。在一些实施方案中，R1、R2和R3分别独立地选自氢、C1-4烷基、苯基或萘基。在一些实施方案中，R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同的情况包括三者均不相同和两者不相同。举例来说，两者不相同的情况有R1与R2相同而R3与R1、R2不同。
在一些实施方案中，X选自-C(R6R7)-，Y选自-C(R’6R’7)-或-Si(R’6R’7)-。在一些实施方案中，X选自-Si(R6R7)-，Y选自-C(R’6R’7)-或-Si(R’6R’7)-。
在一些实施方案中，R4选自-C(R8R9R10)，R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)。在一些 实施方案中，R4选自-Si(R8R9R10)；R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)。
在一些实施方案中，R6、R7、R’6和R’7分别独立地选自氢或C1-4烷基。在一些实施方案中，R6、R7、R’6和R’7分别独立地选自氢、甲基或乙基。在上述实施方案中，R6和R7可以相同也可以不同，R’6和R’7可以相同也可以不同。
在一些实施方案中，R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-4烷基或C1-4烷氧基。在一些实施方案中，R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、甲基、乙基、甲氧基或乙氧基。在上述实施方案中，R8、R9和R10可以相同也可以不同，R’8、R’9和R’10可以相同也可以不同。
在一些实施方案中，X与Y相同，例如X和Y均为-CH2-；或者X和Y均为-Si(CH3)2-。在一些实施方案中，X与Y不同，例如X为-Si(CH3)2-，Y为-CH2-；或者X为-CH2-；Y为-Si(CH3)2-。
在一些实施方案中，R4和R5相同，例如R4和R5均为-CH(CH3)2；或者均为-Si(CH3)3；或者均为-C(CH3)3；或者均为-CH(CH3)(OCH3)。在一些实施方案中，R4和R5不同，例如R4为-C(CH3)3；R5为-CH(CH3)2；或者R4为-Si(CH3)3；R5为-CH(CH3)2。
在一些实施方案中，X与Y相同，例如同时为-CH2-；R4和R5相同，例如同时为-CH(C1-4烷基)2或同时为-CH(C1-4烷基)(C1-4烷氧基)；R1、R2和R3分别独立地选自氢、C1-6烷基或C6-12芳基。在一些具体的实施方案中，X与Y相同，例如同时为-CH2-；R4和R5相同，例如同时为-CH(C1-4烷基)2或同时为-CH(C1-4烷基)(C1-4烷氧基)；R1、R2和R3分别独立地选自氢、C1-4烷基、苯基或萘基。在一些具体的实施方案中，X与Y相同，例如同时为-CH2-；R4和R5相同，例如同时为-CH(C1-4烷基)2或同时为-CH(C1-4烷基)(C1-4烷氧基)；R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同情况包括三者均不相同和两者不相同。举例来说两者不相同的情况有R1与R2相同而R3与R1、R2不同。例如，R1、R2和R3相同，均为甲基或均为乙基；或者R1与R2相同，均为甲基或乙基，而R3为异丙基、叔丁基或苯基。
在一些实施方案中，X和Y同时为-CH2-；R4为-C(C1-4烷基)3；R5为-CH(C1-4烷基)2或-C(C1-4烷基)3；R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同情况包括三者均不相同和两者不相同。例如，R1、R2和R3相同，均为甲基或均为乙基；或者R1与R2相同，均为甲基或乙基，而R3为异丙基、叔丁基或苯基。
在一些实施方案中，X为-Si(C1-4烷基)2-，Y为-CH2-或-Si(C1-4烷基)2-；R4和R5同时为 -CH(C1-4烷基)2；R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同情况包括三者均不相同和两者不相同。例如，R1、R2和R3相同，均为甲基或均为乙基；或者R1与R2相同，均为甲基或乙基，而R3为异丙基、叔丁基或苯基。
在一些实施方案中，X和Y同时为-CH2-；R4为-Si(C1-4烷基)3；R5为-CH(C1-4烷基)2或者-Si(C1-4烷基)3；R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同情况包括三者均不相同和两者不相同。例如，R1、R2和R3相同，均为甲基或均为乙基；或者R1与R2相同，均为甲基或乙基，而R3为异丙基、叔丁基或苯基。
在一些实施方案中，X和Y独立地选自-CH2-或-Si(CH3)2-；R4和R5独立地选自-CH(CH3)2、-C(CH3)3、-Si(CH3)3或-CH(CH3)(OCH3)；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
在一些实施方案中，X和Y均为-CH2-；R4和R5均为-CH(CH3)2，或均为-C(CH3)3，或均为-Si(CH3)3，或均为-CH(CH3)(OCH3)；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
在一些实施方案中，X为-Si(CH3)2-；Y为-CH2-或-Si(CH3)2-；R4和R5均为-CH(CH3)2；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
在一些实施方案中，X和Y均为-CH2-；R4为-C(CH3)3或-Si(CH3)3；R5为-CH(CH3)2；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
进一步地，本申请提供式Ⅰa、式Ⅰb、式Ⅰc、式Ⅰd的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，
Figure PCTCN2016106781-appb-000003
Figure PCTCN2016106781-appb-000004
式Ia、式Ib、式Ic和式Id中的R1、R2、R3、X、Y、R4和R5与上述针对式I中的R1、R2、R3、X、Y、R4和R5的详细描述相同。
进一步地，本申请提供式II的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，
Figure PCTCN2016106781-appb-000005
其中：
R1、R2和R3分别独立地选自氢、烷基或芳基；
R4选自-C(R8R9R10)或-Si(R8R9R10)；R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)；以及
R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-6烷基或C1-6烷氧基。
其中与三个苯环直接相连的吡咯环(其中N为1位)的2位和5位的相对立体化学可以 是顺式或反式。在一些具体的实施方案中，该吡咯环上2位和5位构型包括(2S,5S)、(2S,5R)、(2R,5S)、(2R,5R)。式II的化合物可以是一种立体异构体，也可以是两种或两种以上立体异构体任意比例的混合物。
在一些实施方案中，R1、R2和R3分别独立地选自氢、C1-6烷基或C6-12芳基。在一些实施方案中，R1、R2和R3分别独立地选自氢、C1-4烷基、苯基或萘基。在一些实施方案中，R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同的情况包括三者均不相同和两者不相同。举例来说，两者不相同的情况有R1与R2相同而R3与R1、R2不同。
在一些实施方案中，R4选自-C(R8R9R10)，R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)。在一些实施方案中，R4选自-Si(R8R9R10)；R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)。
在一些实施方案中，R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-4烷基或C1-4烷氧基。在一些实施方案中，R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、甲基、乙基、甲氧基或乙氧基。在上述实施方案中，R8、R9和R10可以相同也可以不同，R’8、R’9和R’10可以相同也可以不同。
在一些实施方案中，R4和R5相同，例如R4和R5均为-CH(CH3)2；或者均为-Si(CH3)3；或者均为-C(CH3)3；或者均为-CH(CH3)(OCH3)。在一些实施方案中，R4和R5不同，例如R4为-C(CH3)3；R5为-CH(CH3)2；或者R4为-Si(CH3)3；R5为-CH(CH3)2。
在一些实施方案中，R4和R5相同，例如同时为-CH(C1-4烷基)2或同时为-CH(C1-4烷基)(C1-4烷氧基)；R1、R2和R3分别独立地选自氢、C1-6烷基或C6-12芳基。在一些具体的实施方案中，R4和R5相同，例如同时为-CH(C1-4烷基)2或同时为-CH(C1-4烷基)(C1-4烷氧基)；R1、R2和R3分别独立地选自氢、C1-4烷基、苯基或萘基。在一些具体的实施方案中，R4和R5相同，例如同时为-CH(C1-4烷基)2或同时为-CH(C1-4烷基)(C1-4烷氧基)；R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同情况包括三者均不相同和两者不相同。举例来说两者不相同的情况有R1与R2相同而R3与R1、R2不同。例如，R1、R2和R3相同，均为甲基或均为乙基；或者R1与R2相同，均为甲基或乙基，而R3为异丙基、叔丁基或苯基。
在一些实施方案中，R4为-C(C1-4烷基)3；R5为-CH(C1-4烷基)2或-C(C1-4烷基)3；R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同情况包括三者均不相同和两者不相同。例如，R1、R2和R3相同，均为甲基或均为乙基；或者R1与R2相同，均为甲基或乙基，而 R3为异丙基、叔丁基或苯基。
在一些实施方案中，R4为-Si(C1-4烷基)3；R5为-CH(C1-4烷基)2或者-Si(C1-4烷基)3；R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。在上述实施方案中，R1、R2和R3可以相同也可以不同，不同情况包括三者均不相同和两者不相同。例如，R1、R2和R3相同，均为甲基或均为乙基；或者R1与R2相同，均为甲基或乙基，而R3为异丙基、叔丁基或苯基。
在一些实施方案中，R4和R5均为-CH(CH3)2，或均为-C(CH3)3，或均为-Si(CH3)3，或均为-CH(CH3)(OCH3)；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
在一些实施方案中，R4为-C(CH3)3或-Si(CH3)3；R5为-CH(CH3)2；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
更进一步地，本申请提供式IIa、式IIb、式IIc、式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，
Figure PCTCN2016106781-appb-000006
Figure PCTCN2016106781-appb-000007
式IIa、式IIb、式IIc、式IId中的R1、R2、R3、R4和R5与上述针对式II中的R1、R2、R3、R4和R5的详细描述相同。
具体地，本申请提供了如下化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物：
其中，Me为甲基，Et为乙基，Ph为苯基，t-Bu为叔丁基，i-Pr为异丙基。
Figure PCTCN2016106781-appb-000008
Figure PCTCN2016106781-appb-000009
Figure PCTCN2016106781-appb-000010
本申请另一方面提供了一种药物组合物，该药物组合物包含治疗有效量的式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，以及一种或多种药学上可接受的载体。
本申请的药物组合物可通过将本申请的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物与适宜的药学上可接受的载体组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合来配制该药物组合物。这些载体能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包 括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
再一方面，本申请的化合物包括具体结构的化合物具有丙型肝炎病毒(HCV)NS5A抑制活性，可作为HCV NS5A抑制剂用于丙型肝炎病毒感染的治疗，具体可用于丙型肝炎病毒感染引起的肝炎、肝硬化等肝病的治疗。
具体地，本申请化合物包括具体结构的化合物具有丙型肝炎病毒(HCV)NS5A抑制活性，特别地，具有对HCV的多种基因亚型具有优异的抑制活性，这些基因亚型包括1a、1b、2a、2b、3a、3b、4a、4b、5a、6a，优选的是1b、3a、4a、5a、6a。
同时，本申请化合物包括具体结构的化合物也具有优异的药代动力学参数，包括在肝微粒体中稳定，具有好的半衰期和生物利用度，以及好的肝靶向性。
本申请化合物包括具体结构的化合物的抗HCV病毒活性和在药物代谢动力学方面与ombitasvir相比具有显著的优越性；本申请化合物包括具体结构的化合物对HCV的多种基因亚型的抑制活性与ombitasvir相比具有显著优越性。
本申请提供了式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物在制备治疗丙型肝炎病毒(HCV)感染的药物中的用途。
本申请提供了式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物与至少一种其他活性化合物在制备治疗丙型肝炎病毒(HCV)感染的药物中的用途。
本申请提供了含有式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物的药物组合物在制备治疗丙型肝炎病毒(HCV)感染的药物中的用途。
本申请提供了包含式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物与至少一种其他活性化合物的药物组合物在制备治疗丙型肝炎病毒(HCV)感染的药物中的用途。
在一些实施方式中，其他活性化合物包括但不限于抗HCV活性的其它化合物。在一些实施方式中，其他活性化合物包括但不限于免疫调节剂例和其他抗病毒药。在一些实施方式中，其他活性化合物包括但不限于干扰素或利巴韦林，其中干扰素选自干扰素α2B、聚乙二醇化 干扰素α、复合α干扰素(consensus interferon)、干扰素α2A和成淋巴细胞干扰素τ。在一些实施方式中，其他活性化合物包括但不限于白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德(Imiqimod)、利巴韦林、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺(amantadine))和金刚乙胺(rimantadine)。在一些实施方式中，其他活性化合物包括但不限于其它化合物有效抑制选自以下靶标的功能以治疗HCV感染：HCV金属蛋白酶、HCV丝氨酸蛋白酶、HCV聚合酶、HCV解旋酶、HCV NS4B蛋白、HCV进入、HCV装配、HCV释放、HCV NS5A蛋白和IMPDH。
所述的HCV包括其多种基因型以及多种基因亚型，例如1a、1b、2a、2b、3a、3b、4a、4b、5a、6a。
本申请提供了治疗丙型肝炎病毒感染的方法，所述方法包括给予需要治疗的患者治疗有效量的式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物。
本申请所述的式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物的每日剂量，接着在若干天或更多天的期间，患者不接受式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物的每日剂量。
本申请提供了用于治疗丙型肝炎病毒感染的式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，以及用于治疗丙型肝炎病毒感染的上述药物组合物。
有关定义：
除非另有说明，本文所用的下列术语和短语具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。
“Cbz-”指苄氧羰基，具体为PhOCO-。
“EDCI”指1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐。
“HOBT”指1-羟基苯并三唑。
“Ms-”指甲磺酰基，具体为CH3SO2-。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
本文所用的Cm-n指该部分中具有m-n个碳原子。例如，“C1-6烷基”指该烷基具有1-6个碳原子。
本文中的数字范围，是指给定范围中的各个整数。例如“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和脂肪烃基团，例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基等。所述特定烷基包括其所有同分异构体形式，例如丙基包括-CH2CH2CH3、-CH(CH3)2，例如丁基包括-CH2CH2CH2CH3、-CH(CH3)(CH2CH3)、-C(CH3)3、-CH2CH(CH3)2。
术语“C1-6烷基”指具有1-6个碳原子的烷基。术语“C1-4烷基”指具有1-4个碳原子的烷基。所述“烷基”、“C1-6烷基”或“C1-4烷基”可以是非取代的或是被一个或多个选自烷基、羟基、卤素或氨基等的取代基取代。
术语“C1-6烷氧基”指具有1-6个碳原子的-O-烷基基团。术语“C1-4烷氧基”指具有1-4个碳原子的-O-烷基基团。所述“烷氧基”、“C1-6烷氧基”或“C1-4烷氧基”可以是非取代的或是被一个或多个选自烷基、羟基、卤素或氨基等的取代基取代。
术语“芳基”是指具有共轭的π电子体系的全碳单环或多环稠合的芳香环基团，优选具有6-14个碳原子，更优选具有6-12个碳原子，最优选具有6个碳原子。例如单环芳香环基团选自苯基，双环稠合的芳香环基团由与4-6元芳族或非芳族碳环稠合的苯基组成包括萘基。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
本申请的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“水合物”指本申请的化合物和化学计量的水分子形成的复合物。
术语“溶剂化物”指包含本申请的化合物和化学计量的一种或多种药学上可接受的溶剂 分子(如乙醇)的分子复合物。
术语“前药”指：药物经化学结构修饰得到的化合物，其在体外没有活性，在生物体或人体内转化为原来的药物而发挥药效；称原来的药物(原药)为母体药物，结构修饰后的化合物为药物前药。
术语“立体异构体”指化合物分子的构造相同，但是立体结构不同而产生的异构体，例如対映异构体和非对映异构体。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本申请中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本申请的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
本申请的化合物可以包含被称为手性中心的被不对称取代的碳原子。这些化合物可以，在没有限制的情况下，以单个立体异构体(例如单个对映体或单个非对映体)，立体异构体的混合物(例如对映体或非对映体的混合物)，或外消旋混合物的形式存在。本申请作为单个立体异构体被识别的化合物意图描述以基本上没有其它立体异构体的形式存在的化合物。“基本上没有”是指组合物中至少95％、96％、97％、98％或99％的化合物是所描述的立体异构体。在手性碳的立体化学没有在化合物的化学结构中规定的情况下，该化学结构意图包括含手性中心的任一立体异构体的化合物。例如，式Ⅰ或式Ⅰa或式Ⅰb或式Ⅰc或式Ⅰd或式II或式IIa或式IIb或式IIc或式IId的化合物中，R4和R5可含有手性碳原子，具体来说，当R4和R5为-CH(C1-4烷基)(C1-4烷氧基)时，其中至少有一个手性碳原子，为-C*H(C1-4烷基)(C1-4烷氧基)，其中C*为手性碳原子，分别可以为S构型或R构型，更具体的，R4和R5为-CH(CH3)(OCH3)时，具体的构型有：
Figure PCTCN2016106781-appb-000011
本申请的化合物的单独的立体异构体可以使用各种本领域已知的方法来制备。这些方法包括但不限于立体有择合成，非对映体的色谱分离，对映体的色谱拆分，对映体混合物中的对映体转化为非对映体、随后非对映体的色谱分离和单独对映体的再生，以及酶拆分。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举 的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
除非另有说明，本申请的反应原料和反应试剂均可通过购买获得。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本申请的式Ⅰ化合物可以由如下路线用本领域的常用方法来制备：其中，R1、R2、R3、X、Y、R4、R5、R6、R7、R’6、R’7、R8、R9、R10、R’8、R’9、R’10如上定义。
1、当X，Y相同，且R4，R5也相同时，式Ⅰ化合物的制备方法：
Figure PCTCN2016106781-appb-000012
化合物5与化合物8在碱的作用下反应生成化合物9；化合物9经还原反应(使用催化剂例如氧化铂)生成化合物10，化合物10与氨基酸衍生物11反应得化合物12；化合物12脱Cbz保护基(反应条件例如在钯碳催化剂及氢气的作用下)得到化合物13；化合物13再与氨基酸衍生物14发生酰胺化反应得到式Ⅰ化合物。
2、当X，Y相同，且R4，R5也相同时，式Ⅰ化合物的另一种制备方法：
Figure PCTCN2016106781-appb-000013
化合物5与化合物8在碱的作用下反应生成化合物9；化合物9经还原反应(使用催化剂例如氧化铂)生成化合物10，化合物10与氨基酸衍生片段15反应得到式Ⅰ化合物。
3、当X，Y不相同，且R4，R5相同时，式Ⅰ化合物的制备方法：
Figure PCTCN2016106781-appb-000014
制得的化合物10依次与氨基酸衍生物11X和氨基酸衍生物11Y反应制得化合物12后，再经还原、酰胺化得到式Ⅰ化合物。
4、当X，Y相同，且R4，R5不相同时，式Ⅰ化合物的制备方法：
Figure PCTCN2016106781-appb-000015
制得的化合物13依次与氨基酸衍生物14-R4和氨基酸衍生物14-R5反应制得式Ⅰ化合物。
5、当X，Y不相同，且R4，R5不相同时，式Ⅰ化合物的制备方法：
制得的化合物10依次与氨基酸衍生物11X和氨基酸衍生物11Y反应制得化合物12后，再经还原反应，并依次与氨基酸衍生物14-R4和氨基酸衍生物14-R5酰胺化得到式Ⅰ化合物。
其中，化合物10可经色谱柱层析得到光学活性化合物10a、化合物10b、和化合物10c。
Figure PCTCN2016106781-appb-000016
其中，化合物5的制备方法：
Figure PCTCN2016106781-appb-000017
化合物1与化合物2在路易斯酸介导的条件下反应生成化合物3；化合物3可被例如硼 氢化钠还原生成化合物4，化合物4与甲基磺酰氯在碱的作用下生成化合物5，化合物5是多种构型的混合物，包含5a(RR)、5b(SS)、5c(SR)。可按文献报道的制备方法合成(J.Med.Chem,2014,57,2047-2057；Synthesis,2009,1739-1743；Synthesis,2000,1259-1262)。
化合物5可经手性色谱柱层析得到光学活性化合物5a、化合物5b、和化合物5c。
Figure PCTCN2016106781-appb-000018
其中中间体化合物8的制备方法：
Figure PCTCN2016106781-appb-000019
含硅苯胺类化合物8的合成可按文献报道的制备方法合成(Journal of Organic Chemistry,73(17),2008,6671-6678)。不同方法可用不同的硅烷衍生物如:Me3SiMe3,Et3SiH,Me3SiCl,Et3SiCl,Me2EtSiCl,Me2PhSiH,Me2PhSiCl等，这些硅烷衍生物可以通过购买获得。
其中中间体11(包括11X和11Y)可按照文献报道的方法制备。例如含硅的中间体11可按文献报道(Eur.J.Org.Chem.2000,8072811J.Am.Chem.Soc.2006,128,8479-8483)的方法获得，(ICH2)2Si(R6R7)可以通过例如Aldrich公司购买获得。
Figure PCTCN2016106781-appb-000020
其中中间体14(包括14-R4和14-R5)可按照文献报道的方法制备。例如含硅的中间体14可按文献报道(Tetrahedron,61(1),43-50；2005,Angew.Chem.Int.ed.2009,39,2288-2290) 的方法，再通过进一步手性拆分获得。举例如下：
Figure PCTCN2016106781-appb-000021
其中的起始原料化合物21及其他硅原子上不同取代的硅烷类似物可通过例如Aldrich公司购买获得。
其中化合物15的制备方法：
Figure PCTCN2016106781-appb-000022
其中的中间体25可以购买获得也可以按照文献公开的方法制备得到，或者通过中间体11脱去保护基制得。
本申请还提供了式Ⅰa、式Ⅰb、式Ⅰc、式Ⅰd化合物的制备方法。
在制得式Ⅰ化合物的基础上，可直接通过色谱柱层析分离得到不同构型的式Ⅰa、式Ⅰb、式Ⅰc、式Ⅰd化合物。
也可以分别通过光学活性化合物10a、化合物10b、和化合物10c，按照上述制备式Ⅰ化合物类似的方法，进一步合成得到式Ⅰa、式Ⅰb、式Ⅰc、式Ⅰd化合物。
也可以分别通过光学活性化合物5a、化合物5b、和化合物5c，按照上述制备式Ⅰ化合物类似的方法，进一步合成得到式Ⅰa、式Ⅰb、式Ⅰc、式Ⅰd化合物。
可以选择地，可先分离得到光学活性化合物10a和化合物10b的混合物制得式Ⅰa化合物和式Ⅰb化合物的混合物，再经色谱柱层析分离得到不同构型但结构相同的式Ⅰa化合物、式Ⅰb化合物。如此类似手段的制备方法均包含在本申请的范围内。
当式Ⅰ化合物为非对称结构时，使用化合物10c或者化合物5c制备式Ⅰc化合物时，会先得到式Ⅰ化合物的顺式构型，可进一步分离得到式Ⅰc、式Ⅰd化合物。
依据制备式I的化合物(式Ⅰa、式Ⅰb、式Ⅰc、式Ⅰd的化合物)的制备方法可以制备相应的式II的化合物(式IIa、式IIb、式IIc、式IId的化合物)。
举例来说，当X，Y相同，且R4，R5也相同时，式Ⅰa、Ⅰb化合物的制备方法：
Figure PCTCN2016106781-appb-000023
反式异构体10a(SS)、10b(RR)的混和物与氨基酸衍生物11反应得12a(SS)、12b(RR)的混和物；12a(SS)、12b(RR)的混和物在钯碳催化剂及氢气的作用下脱Cbz保护基得到13a(SS)、13b(RR)的混合物；13a(SS)、13b(RR)再与氨基酸衍生物14发生酰胺化反应得到Ⅰa、Ⅰb的混合物，Ⅰa、Ⅰb可通过色谱柱层析分离，得到Ⅰa及Ⅰb单一构型的化合物。
具体实施方式
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。本领域技术人员应该理解：还有形成本申请化合物的其它合成途径，下面提供的是非限制性的实施例。
除非另有说明，本申请使用的原料都是市场上直接买到，未经进一步纯化直接使用的。
凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)。薄层色谱采用E.Merck公司生产的预制板(硅胶60PF254,0.25毫米)。手性化合物分离采用色谱柱：Waters XBridge C18，
Figure PCTCN2016106781-appb-000024
毫米，5 微米和手性色谱柱：CHIRALPAK IA
Figure PCTCN2016106781-appb-000025
毫米，5微米。核磁共振色谱(NMR)使用Varian VNMRS-400核磁共振仪测定；液质连用(LC/MS)使用FINNIGAN Thermo LCQ Advantage MAX，Agilent LC 1200series(柱子：Waters Symmetry C18，
Figure PCTCN2016106781-appb-000026
毫米，5微米，35℃)，采用ESI(+)离子模式。
“THF”指四氢呋喃。“DCM”是指二氯甲烷。“DMSO”是指二甲基亚砜。“DIPEA”是指N，N-二异丙基乙胺。“DMF”是指N，N-二甲基甲酰胺。“MOC-L-缬氨酸”是指N-(甲氧羰基)-L-缬氨酸。“室温”是指反应温度在25-30℃。
试验部分
中间体：4-(三甲基硅基)苯胺
Figure PCTCN2016106781-appb-000027
步骤1：在耐压管中加入对氯硝基苯(30g，190.4mmol)、六甲基二硅烷(119.57g，86.82mmol)、四-(三苯基磷)钯(8.8g，7.616mmol)和二甲苯(90mL)，氮气保护下于170℃搅拌反应。7小时后反应结束，将反应液冷却至室温，然后硅藻土助滤，滤液浓缩得到三甲基(4-硝基苯基)-硅烷(32g)。
1H-NMR(400MHz,DMSO-d6):δ＝8.19-8.16(d,J＝8.19Hz,2H),7.83-7.80(d,J＝8.22Hz,2H),0.30(s,9H)。
步骤2：在单口烧瓶中加入三甲基(4-硝基苯基)-硅烷(32g，163.86mmol)、无水乙醇(500mL)、10％Pd/C(4.78g，4.5mmol)，通过氮气置换3次，氢气置换3次排除空气，在1atm氢气压力下，室温反应过夜。反应结束后，反应液用硅藻土助滤，滤液浓缩，浓缩液用硅胶柱色谱分离(石油醚：乙酸乙酯＝10：1)得4-(三甲基硅基)苯胺(12g)。
1H-NMR(300MHz,DMSO-d6):δ＝7.13-7.10(d,J＝7.83Hz,2H),6.55-6.52(d,J＝7.83Hz,2H),0.13(s,9H)。
中间体：4-(三乙基硅基)苯胺
Figure PCTCN2016106781-appb-000028
在双口瓶中加入对碘苯胺(15g，68.49mmol)、双三苯基磷氯化羰基铑(2.36g，3.42mmol)、磷酸钾(43.6g，205.47mmol)和NMP(100mL)，氮气保护并且避光反应，反应 液中缓慢加入三乙基硅烷(15.93g，136.98mmol)，反应于室温下搅拌4天。反应结束后，加入100mL水淬灭反应，反应液用乙酸乙酯萃取(100mL×3)，合并有机相，有机相用水洗涤(150mL×3)，并用无水硫酸镁干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得4-(三乙基硅基)苯胺(7.2g)。
1H-NMR(300MHz,DMSO-d6):δ＝7.11-7.09(d,J＝8.1Hz,2H),6.57-6.54(d,J＝8.13Hz,2H)，5.10(s,2H)，0.91-0.86(m,9H),0.70-0.62(m,6H)。
HRMS(ESI)m/z 208.1510(M+H)+。
中间体：4-(叔丁基二甲基硅基)苯胺
Figure PCTCN2016106781-appb-000029
在双口瓶中加入对碘苯胺(8.37g，38.2mmol)、双三苯基磷氯化羰基铑(1.32g，1.91mmol)、磷酸钾(24.32g，114.6mmol)和NMP(100mL)，氮气保护并且避光反应，反应液中缓慢加入叔丁基二甲基硅烷(13.32g，114.6mmol)，反应于室温下搅拌4天。反应结束后，加入100mL水淬灭反应，反应液用乙酸乙酯萃取(100mL×3)，合并有机相，有机相用水洗涤(150mL×3)，并用无水硫酸镁干燥，把有机相旋转蒸发去除乙酸乙酯，残留物用硅胶柱色谱分离得4-(叔丁基二甲基硅基)苯胺(7.92g)。
1H-NMR(300MHz,DMSO-d6):δ＝7.14-7.12(d,J＝8.28Hz,2H),6.58-6.55(d,J＝8.25Hz,2H)，5.11(s,2H)，0.82(s,9H),0.16(s,6H)。
HRMS(ESI)m/z208.1505(M+H)+。
中间体：1，4-双(4-硝基苯基)丁烷-1，4-二取代二甲磺酰酯
Figure PCTCN2016106781-appb-000030
步骤1：在三口烧瓶中加入甲苯(300mL)，无水氯化锌(54.6g，0.4mol)，氮气保护下于室温搅拌反应，然后缓慢加入三乙胺(32mL)和叔丁醇(28mL)，室温下继续搅拌1.5小时。 然后再加入2-溴-4-硝基苯乙酮(48.8g，0.2mol)和4-硝基苯乙酮(49.6g，0.3mol)，室温下搅拌过夜。反应结束后，加入500mL水搅拌，析出大量固体，过滤，滤饼用二氯甲烷洗涤，干燥，得1,4-双-(4-硝基苯基)丁烷-1,4-二酮(61g)。
1H-NMR(300MHz,DMSO-d6):δ＝8.38-8.35(d,J＝8.19Hz,4H),8.26-8.24(d,J＝8.22Hz,4H),3.52(s,4H)。
HRMS(APCI)m/z 327.0613(M-H)-。
步骤2：在单口烧瓶中加入1,4-双-(4-硝基苯基)丁烷-1,4-二酮(30g，91.39mmol)和THF(500mL)，氮气保护下，于0℃加入硼氢化钠(10.72g，283.3mmol)，反应30分钟后，升温至60℃反应过夜。反应结束后，将反应液过滤，滤饼用水洗涤，滤液中加入500mL水，然后用乙酸乙酯萃取多次，合并有机层，无水硫酸钠干燥，过滤，滤液浓缩，得1,4-双(4-硝基苯基)丁烷-1,4-二醇(13.2g)，为SS、RR、SR三种构型的混合物。
1H-NMR(300MHz,DMSO-d6):δ＝8.18-8.15(d,J＝8.34Hz,4H),7.57-7.54(d,J＝8.07Hz,4H),5.48(s,2H),4.67(s,2H),1.67-1.56(m,4H)。
HRMS(APCI)m/z 331.0936(M-H)-。
步骤3：在三口瓶中加入1,4-双(4-硝基苯基)丁烷-1,4-二醇的SS、RR、SR三种构型的混合物(13g，39.12mmol)，DCM(300mL)，氮气保护下，于0℃滴加三乙胺(16.31mL,117.36mmol)，滴加完毕后继续搅拌20分钟，然后缓慢滴加甲磺酰氯(7.57mL，97.8mmol)，滴加完毕后继续反应2.5小时至3.5小时。反应结束后，于室温下加入50mL饱和氯化铵溶液搅拌20分钟，然后用100mL水洗涤2次，析出固体，过滤，滤饼烘干后得1,4-双(4-硝基苯基)丁烷-1,4-二取代二甲磺酰酯(10.5g)，为SS、RR、SR三种构型的混合物。
1H-NMR(300MHz,DMSO-d6):δ＝8.26-8.24(d,J＝8.19Hz,4H),7.70-7.67(d,J＝8.28Hz,4H),5.84(s,2H),3.12(s,6H),1.96(s,4H)。
HRMS(APCI)m/z 487.0487(M-H)-。
中间体：(1R,4S)-1,4-双(4-硝基苯基)丁烷-1,4-二醇
Figure PCTCN2016106781-appb-000031
在三口烧瓶中加入(S)-二苯基脯氨醇(126.67mg，0.5mmol)与THF(10mL)，氮气保护下，于23℃搅拌反应，然后加入硼酸三甲酯(67.5mg，0.65mmol)，继续反应1小时；将温度降低至15℃，缓慢加入N，N二异丙氨硼烷络合物(1.0g，6.15mmol)，15分钟后，将温度降至11℃，将1,4-双(4-硝基苯基)丁烷-1,4-二酮(1.0g，3.0mmol)加入反应瓶中， 再加入10mL THF，反应升温至35℃搅拌过夜。反应结束后，将温度降至5℃，加入甲醇(779mg)，搅拌20分钟，然后室温搅拌至固体溶解，往溶液中加入20mL乙酸乙酯，10mL 1M HCl，乙酸乙酯萃取多次，合并有机相，有机相分别用10mL 1M HCl洗底两次，水洗涤两次，饱和氯化钠溶液洗涤两次，无水硫酸镁干燥，过滤浓缩，浓缩液中加入5ml乙酸乙酯，50℃下搅拌，于15分钟内缓慢滴加30mL正庚烷，溶液中缓慢析出淡黄色固体，继续室温搅拌30分钟，过滤，滤饼用乙酸乙酯：正庚烷＝1：3溶液洗涤，干燥，得(1R,4S)-1,4-双(4-硝基苯基)丁烷-1,4-二醇(500mg)。
1H-NMR(300MHz,DMSO-d6):δ＝8.18-8.15(d,J＝8.61Hz,4H)，7.57-7.54(d,J＝8.61Hz,4H)，5.50(s,2H),4.70(s,2H),1.65-1.64(m,4H)。
HRMS(APCI)m/z 331.0936(M-H)-。
中间体：(S)-1-((2S,3R)-3-甲氧基-2-((甲氧酰基)氨基)丁酰基)吡咯烷-2-羧酸
Figure PCTCN2016106781-appb-000032
步骤1：将氢氧化钠(2.4g，60.08mmol)加入60mL水中，然后加入O-甲基-L-苏氨酸(8.0g，60.08mmol)和碳酸钠(3.30g，31.2mmol)，0℃搅拌使固体溶解，溶液先变澄清后又变混浊，取氯甲酸甲酯(8.48g，90.12mmol)缓慢加入反应液中，滴加结束后，移至室温反应过夜，反应结束后，冰水浴冷却，用浓盐酸调节pH为1-2，二氯甲烷萃取，有机相用无水硫酸镁干燥，过滤，浓缩，固体干燥，得(2S,3R)-3-甲氧基-2-((甲氧酰基)氨基)丁酸(11.50g)。
1H-NMR(500MHz,CDCl3):δ＝5.47-5.45(d,J＝10Hz,1H),4.41-4.39(m,1H),4.04-4.00(m,1H),3.73(s,3H),3.37(s,3H),1.24-1.23(d,J＝5Hz,3H)。
HRMS(ESI)m/z 190.0543[M-H]-。
步骤2：将(2S,3R)-3-甲氧基-2-((甲氧酰基)氨基)丁酸(11.5g，60.15mmol)加入150mL乙酸乙酯中，再加入N-羟基丁二酰亚胺(6.92g，60.15mmol)，0℃搅拌，固体溶解，取二异丙基碳二亚胺(7.59g，60.15mmol)缓慢加入反应液中，产生白色浑浊，滴加结束后，0℃搅拌1小时,移至室温反应过夜，反应结束后，过滤，滤饼用乙酸乙酯洗涤，浓缩滤液，浓缩物中加入150mL异丙醇，于50℃下搅拌至固体溶解，冷却重结晶，过滤，干燥，得(2S,3R)-2,5-二氧代吡咯烷-1-基-3-甲氧基-2-((甲氧酰基)氨基)丁酸酯(11.90g)。
1H-NMR(500MHz，DMSO-d6)：δ＝7.85-7.84(d,J＝5Hz,1H),4.63-4.60(m,1H),3.86-3.84(m,1H),3.58(s,3H),3.28(s,3H),2.81(s,4H),1.19-1.18(m,3H)。
HRMS(ESI)m/z 289.1034[M+H]+。
步骤3：将L-脯氨酸(4.98g，43.37mmol)加入40mL水与40mL乙腈的混合溶剂中，然后加入N,N-二异丙基乙胺(10.68g，82.60mmol)，室温下搅拌使固体溶解，将(2S,3R)-2,5-二氧代吡咯烷-1-基-3-甲氧基-2-((甲氧酰基)氨基)丁酸酯(11.90g，41.30mmol)溶解于40mL乙腈中，然后缓慢加入上述反应液中，滴加结束后，室温反应过夜，反应结束后，浓缩除去乙腈，用6mol/L HCl溶液调节pH至1-2，25％氯化钠溶液洗涤，再用乙酸乙酯多次萃取，干燥过滤，浓缩，得(S)-1-((2S,3R)-3-甲氧基-2-((甲氧酰基)氨基)丁酰基)吡咯烷-2-羧酸(9.50g)。
1H-NMR(500MHz，DMSO-d6)：δ＝5.83-5.82(d,J＝5Hz,1H),5.82-4.58(m,1H),4.50-4.48(m,1H),3.83-3.81(m,1H),3.80-3.77(m,3H),3.74-3.72(m,2H),3.37(s,3H),2.23-2.10(m,2H),2.09-2.06(m,2H),1.19-1.18(m,3H)。
HRMS(ESI)m/z 289.1400[M+H]+。
实施例1：二甲基((2S,2'S)-((2S,2'S)-2,2'-(((((2S,5S)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰa-1)
二甲基((2S,2'S)-((2S,2'S)-2,2'-(((((2R,5R)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰb-1)
Figure PCTCN2016106781-appb-000033
步骤1：在三口瓶中加入1,4-双(4-硝基苯基)丁烷-1,4-二取代二甲磺酰酯SS、RR、SR三种构型的混合物(4.5g，9.2mmol)，DMF(24mL)，三乙胺(9.32g，92.1mmol)，氮气保护下，反应液升温至60℃，再缓慢加入三甲基硅苯胺(10.66g，64.47mmol)，反应搅拌过夜。反应结束后，将反应液冷却，加入50mL水，乙酸乙酯萃取3次，合并有机相，有机相用无水硫酸镁干燥，过滤，浓缩，得2,5-双-(4-硝基-苯基)-1-(4-三甲基硅烷基-苯基)-吡咯烷SS、RR、SR三种构型的混合物。HRMS(ESI)m/z462.1910(M+H)+。
步骤2：高压釜中加入2,5-双-(4-硝基-苯基)-1-(4-三甲基硅烷基-苯基)-吡咯烷SS、RR、SR三种构型的混合物(12g)，氧化铂(4g，17.61mmol)，THF(80mL)，氮气置换空气4次，氢气置换4次，氢气压力10atm下反应48小时。反应结束后，硅藻土助滤，滤饼用二氯甲烷洗涤，浓缩滤液，然后硅胶柱层析分离(洗脱剂为石油醚：乙酸乙酯＝10：1-1：1)。分离得4,4’-(1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)二苯胺反式异构体SS、RR混合物(560mg)，顺式单一异构体SR(860mg)。
反式异构体SS、RR混合物：1H-NMR(300MHz,DMSO-d6):δ＝7.03-7.00(d,J＝8.22Hz,2H)，6.83-6.80(d,J＝8.13Hz,4H)，6.48-6.46(d,J＝8.13Hz,4H)，6.28-6.26(d,J＝8.28Hz,2H)，5.00-4.98(d,J＝6.3Hz,2H)，4.86(s,4H)，2.38-2.36(d,J＝6.03Hz,2H)，1.57-1.55(d,J＝5.67Hz,2H),0.08(s,9H)；HRMS(ESI)m/z 402.2363(M+H)+。
顺式单一异构体SR：1H-NMR(300MHz,DMSO-d6):δ＝7.12-7.08(m,6H)，6.56-6.54(d,4H)， 6.44-6.41(d,J＝8.04Hz,2H)，4.92(s,4H)，4.53(s,2H)，2.26(s,2H)，1.81-1.74(m,2H),0.10(s,9H)；HRMS(ESI)m/z 402.2362(M+H)+。
步骤3：在一单口瓶中加入4,4’-(1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)二苯胺反式异构体SS、RR混合物(450mg，1.12mmol)，DMF(15mL)，N-苄氧羰基-L-脯氨酸(1.34g，5.6mmol)，EDCI(869.34mg，5.6mmol)，HOBT(756.67mg，5.6mmol)，N-甲基吗啡啉(566.44mg，5.6mmol)，氮气保护下室温搅拌过夜。反应结束后，反应液中加入50mL水，搅拌，析出固体，过滤，滤液用二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤浓缩，硅胶柱层析分离(展开剂为石油醚：乙酸乙酯＝1：2)，分离得(2S,2'S)-二苄基-2，2'-(((((2S,5S)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)和(2S,2'S)-二苄基-2，2'-(((((2R,5R)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)的混合物，共790mg。
1H-NMR(300MHz,DMSO-d6):δ＝9.99(s,2H)，7.53-7.50(d,J＝7.2Hz,4H)，7.36(d,4H)，7.20-7.01(m,12H)，6.34-6.25(m,2H)，5.22(s,2H)，5.10-4.90(m,4H)，4.33(s,2H),3.48-3.44(m,4H),2.88-2.22(m,4H),1.90-1.67(m,8H),0.08(s,9H)；
HRMS(ESI)m/z 864.3637(M+H)+。
步骤4：高压釜中加入(2S,2'S)-二苄基-2，2'-(((((2S,5S)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)和(2S,2'S)-二苄基-2，2'-(((((2R,5R)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)的混合物(790mg，0.914mmol)，然后加入乙醇(30mL)，部分固体溶解，再加入甲醇(5mL)，固体全部溶解，然后加入10％无水钯碳(97.2mg，0.0914mmol)，DIPEA(236mg，1.828mmol)，氮气置换3次，氢气置换3次，10atm氢气压力下室温反应30小时。反应结束后，硅藻土助滤，浓缩滤液，得(2S,2'S)-N,N’-(((2S,5S)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)和(2S,2'S)-N,N’-(((2R,5R)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)的混合物，共410mg。
1H-NMR(300MHz,DMSO-d6):δ＝9.80(s,2H),7.50-7.47(d,J＝8.07Hz,4H),7.06-7.04(d,J＝8.07Hz,4H),6.97-6.94(d,J＝7.92Hz,2H)，6.34-6.25(m,2H)，6.20-6.17(d,J＝7.98Hz,2H),5.13-5.12(d,J＝5.1Hz,2H),3.60-3.55(m,2H),2.81-2.77(m,4H),1.97-1.15(m,12H),0.0009(s,9H)；
HRMS(ESI)m/z 596.3479(M+H)+。
步骤5：化合物(Ⅰa-1)和化合物(Ⅰb-1)
在单口瓶中加入(2S,2'S)-N,N’-(((2S,5S)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)和(2S,2'S)-N,N’-(((2R,5R)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)的混合物(400mg，0.67mmol)，DMF(15mL)，MOC-L-缬氨酸(586.85mg，3.35mmol)，EDCI(520mg，3.35mmol)，HOBT(452.65mg，3.35mmol)和N-甲基吗啡啉(338.85mg，3.35mmol)。氮气保护下室温搅拌过夜。反应结束后，加入50mL水，搅拌，析出白色固体，将固体复溶后用硅胶柱层析分离(展开剂为石油醚：乙酸乙酯＝1：2)，分离得Ⅰa-1和Ⅰb-1的混合物，共358mg，两种异构体的比例为1：1。C-18柱分离两种异构体，先分离得到Ⅰa-1再分离得到Ⅰb-1。
Ⅰa-1：1H-NMR(300MHz,DMSO-d6):δ＝9.96(s,2H),7.51-7.48(d,J＝8.22Hz,4H),7.29-7.26(d,J＝8.01Hz,2H)，7.14-7.11(d,J＝8.22Hz,4H)，7.06-7.03(d,J＝8.04Hz,2H)，6.27-6.24(d,J＝8.04Hz,2H),5.19(s,2H),4.45-4.40(m,2H),4.06-4.00(m,2H),3.79(m,2H),3.62(m,2H),3.52(s,6H),2.13(m,2H),1.97-1.65(m,10H),0.94-0.87(m,12H),0.07(s,9H)；
HRMS(ESI)m/z 910.4685(M+H)+。
Ⅰb-1：1H-NMR(300MHz,DMSO-d6):δ＝9.96(s,2H),7.51-7.48(d,J＝8.25Hz,4H),7.28-7.25(d,J＝7.92Hz,2H)，7.13-7.11(d,J＝8.22Hz,4H)，7.06-7.03(d,J＝8.25Hz,2H)，6.27-6.24(d,J＝8.25Hz,2H),5.19(s,2H),4.45-4.40(m,2H),4.05-4.00(m,2H),3.78-3.76(m,2H),3.58(m,2H),3.52(s,6H),2.12(m,2H),1.98-1.23(m,10H),0.92-0.85(m,12H),0.07(s,9H)；
HRMS(ESI)m/z 910.4685(M+H)+。
实施例2：二甲基((2S,2S’)-((2S,2S’)-2,2’-(((((2S,5R)-1-(4-(三甲基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰc-1)
Figure PCTCN2016106781-appb-000034
步骤1：(2S,2'S)-二苄基-2，2'-(((((2S,5R)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)
参照实施例1中的步骤3，得到目标化合物。
1H-NMR(300MHz,DMSO-d6):δ＝10.05(s,2H)，7.60-7.58(d,J＝6.48Hz,4H)，7.45-7.42(d,J＝7.92Hz,4H)，7.36-7.10(m,12H)，6.42-6.40(m,2H),5.12-4.92(m,4H)，4.73(s,2H)，4.38-4.33(m,2H),3.49-3.45(m,4H),2.40-2.23(m,4H),1.89-1.85(m,8H),0.10(s,9H)；
HRMS(ESI)m/z 864.3637(M+H)+。
步骤2：(2S,2'S)-N,N’-(((2S,5R)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)
参照实施例1中的步骤4，得到目标化合物。
1H-NMR(300MHz,DMSO-d6):δ＝10.06(s,2H),7.65-7.63(d,J＝8.34Hz,4H),7.43-7.40(d,J＝8.4Hz,4H)，7.14-7.11(d,J＝8.31Hz,2H)，6.40-6.37(d,J＝5.52Hz,2H)，4.72(d,2H),3.80-3.75(m,2H),2.35-2.07(m,4H),2.02-1.72(m,8H),1.08(m,4H),0.10(s,9H)；
HRMS(ESI)m/z 596.3479(M+H)+。
步骤3：
参照实施例1中的步骤5，得到化合物(Ⅰc-1)。
1H-NMR(300MHz,DMSO-d6):δ＝10.03(s,2H),7.60-7.57(d,J＝8.25Hz,4H),7.43-7.40(d,J＝8.4Hz,4H)，7.32-7.30(d,J＝7.29Hz,2H)，7.14-7.11(d,J＝8.13Hz,2H)，6.39-6.36(d,J＝8.34Hz,2H),4.70(s,2H),4.45(m,2H),4.06-4.00(m,2H),3.80(m,2H),3.64(m,2H),3.53(s,6H),2.04-1.90(m,12H),0.94-0.88(m,12H),0.10(s,9H)；
HRMS(ESI)m/z 910.4740(M+H)+。
实施例3：二甲基((2S,2S’)-((2S,2S’)-2,2’-(((((2S,5S)-1-(4-(三乙基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰa-2)
二甲基((2S,2S’)-((2S,2S’)-2,2’-(((((2R,5R)-1-(4-(三乙基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰb-2)
Figure PCTCN2016106781-appb-000035
Figure PCTCN2016106781-appb-000036
步骤1：参照实施例1中的步骤1，将三甲基硅苯胺替换成三乙基硅苯胺(13.37g，64.47mmol),得2,5-双-(4-硝基-苯基)-1-(4-三乙基硅烷基-苯基)-吡咯烷SS、RR、SR三种构型的混合物。HRMS(ESI)m/z 504.2312(M+H)+。
步骤2：参照实施例1中的步骤2，得4,4’-(1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)二苯胺反式异构体SS、RR混合物(850mg)，顺式单一异构体SR(1.0g)。
反式异构体SS、RR混合物：1H-NMR(300MHz,DMSO-d6):δ＝7.00-6.98(d,J＝8.16Hz,2H)，6.84-6.81(d,J＝8.13Hz,4H)，6.49-6.46(d,J＝8.1Hz,4H)，6.30-6.27(d,J＝8.25Hz,2H)，5.00-4.98(d,J＝5.97Hz,2H)，4.86(s,4H)，2.12-2.11(d,J＝3.93Hz,2H)，1.56-1.54(d,J＝5.79Hz,2H),0.93-0.83(m,9H),0.72-0.63(m,6H)；HRMS(ESI)m/z444.2829(M+H)+。
顺式单一异构体SR：1H-NMR(300MHz,DMSO-d6):δ＝7.14-7.11(d,J＝8.19Hz,4H)，7.08-7.06(d,J＝8.16Hz,2H)，6.58-6.55(d,J＝8.16Hz,4H)，6.46-6.44(d,J＝8.19Hz,2H),4.92(s,4H)，4.54(s,2H)，2.26-2.11(m,2H),1.82-1.74(m,2H),0.91-0.77(m,9H),0.70-0.66(m,6H)；HRMS(ESI)m/z 444.2808(M+H)+。
步骤3：
参照实施例1的步骤3，得(2S,2'S)-二苄基-2，2'-(((((2S,5S)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)和(2S,2'S)-二苄基-2，2'-(((((2R,5R)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)双(4,1- 亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)的混合物，共1.0g。
1H-NMR(300MHz,DMSO-d6):δ＝9.99(s,2H),7.54-7.51(d,J＝6.42Hz,4H)，7.42-7.18(m,12H),7.05-7.03(d,J＝6.81Hz,4H),6.33-6.30(d,J＝8.13Hz,2H),5.22(s,2H)，5.11-4.90(m,4H),4.35(s,2H),2.88(s,2H),2.73(s,2H),2.21(s,2H),1.98-1.84(m,8H),1.66(s,2H),0.93-0.79(m,9H),0.63-0.49(m,6H)；
HRMS(ESI)m/z 906.4700(M+H)+。
步骤4：
参照实施例1的步骤4，得(2S,2'S)-N,N’-(((2S,5S)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)和(2S,2'S)-N,N’-(((2R,5R)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)的混合物，共700mg。
1H-NMR(300MHz,DMSO-d6):δ＝9.93(s,2H),7.57-7.54(d,J＝8.34Hz,4H),7.16-7.13(d,J＝8.25Hz,4H)，7.02-6.99(d,J＝8.16Hz,2H)，6.29-6.26(d,J＝8.28Hz,2H)，5.21-5.20(d,J＝5.58Hz,2H)，3.73-3.45(m,2H),2.92-2.89(m,4H),2.07-1.98(m,2H),1.82-1.63(m,8H),1.05-1.01(m,2H),0.84-0.79(m,9H),0.63-0.55(m,6H)；
HRMS(ESI)m/z 638.3875(M+H)+。
步骤:5：化合物(Ⅰa-2)和化合物(Ⅰb-2)
参照实施例1的步骤5，得得Ⅰa-2和Ⅰb-2的混合物，共490mg，两种异构体的比例为1：1。C-18柱分离两种异构体，先分离得到Ⅰa-2，再分离得到Ⅰb-2。
Ⅰa-2：1H-NMR(300MHz,DMSO-d6):δ＝9.98(s,2H),7.52-7.49(d,J＝8.19Hz,4H),7.31-7.29(d,J＝8.16Hz,2H)，7.15-7.12(d,J＝8.22Hz,4H)，7.03-7.00(d,J＝8.1Hz,2H)，6.28-6.25(d,J＝8.09Hz,2H),5.19(s,2H),4.44-4.41(m,2H),4.05-4.00(m,2H),3.84-3.77(m,2H),3.60(m,2H),3.52(s,6H),2.13(m,2H),2.19-1.87(m,8H),1.63-1.61(m,2H)，0.94-0.89(m,12H),0.87-0.79(m,9H),0.62-0.54(m,6H)；HRMS(ESI)m/z 952.5343(M+H)+。
Ⅰb-2：1H-NMR(300MHz,DMSO-d6):δ＝9.98(s,2H),7.51-7.49(d,J＝8.19Hz,4H),7.31-7.28(d,J＝8.28Hz,2H)，7.14-7.12(d,J＝8.19Hz,4H)，7.03-7.00(d,J＝8.07Hz,2H)，6.27-6.25(d,J＝8.13Hz,2H),5.19(s,2H),4.44-4.40(m,2H),4.05-3.99(m,2H),3.84-3.78(m,2H),3.65-3.58(m,2H),3.52(s,6H),2.17-2.12(m,2H),2.04-1.86(m,8H),1.63-1.62(m,2H),0.92-0.84(m,12H),0.81-0.79(m,9H),0.62-0.55(m,6H)；HRMS(ESI)m/z 952.5343(M+H)+。
实施例4：二甲基((2S,2S’)-((2S,2S’)-2,2’-(((((2S,5R)-1-(4-(三乙基硅基)苯基) 吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰc--2)
Figure PCTCN2016106781-appb-000037
步骤1：(2S,2'S)-二苄基-2，2'-(((((2S,5R)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)
参照实施例1中的步骤3，得到目标化合物。
1H-NMR(300MHz,DMSO-d6):δ＝10.03(s,2H),7.60-7.58(d,J＝7.35Hz,4H)，7.46-7.43(d,J＝7.8Hz,4H),7.31-7.10(m,12H),6.45-6.43(d,J＝5.94Hz,2H),5.12-5.08(m,4H),4.74(s,2H)，4.39-4.34(m,2H)，2.88(s,2H),2.73(s,2H),1.98(s,2H),1.92-1.85(m,10H),0.91-0.81(m,9H),0.65-0.58(m,6H)；
HRMS(ESI)m/z 906.4700(M+H)+。
步骤2：(2S,2'S)-N,N’-(((2S,5R)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)
参照实施例1中的步骤4，得到目标化合物。
1H-NMR(300MHz,DMSO-d6):δ＝9.97(s,2H),7.65-7.63(d,J＝8.46Hz,4H),7.44-7.41(d,J＝8.28Hz,4H)，7.11-7.08(d,J＝8.31Hz,2H),6.42-6.39(d,J＝8.31Hz,2H),4.73(s,2H),3.74-3.71(m,2H),3.30-2.91(m,4H),2.11-2.00(m,4H),1.84-1.61(m,8H),0.86-0.81(m,9H),0.65-0.58(m,6H)；
HRMS(ESI)m/z 638.3876(M+H)+。
步骤3：
参照实施例1中的步骤5，得到化合物(Ⅰc-2)。
1H-NMR(300MHz,DMSO-d6):δ＝10.03(s,2H),7.60-7.57(d,J＝8.37Hz,4H),7.44-7.41(d,J＝8.31Hz,4H)，7.32-7.30(d,J＝7.86Hz,2H)，7.11-7.08(d,J＝8.22Hz,2H)，6.41-6.38(d,J＝ 8.01Hz,2H),4.71(s,2H),4.48-4.44(m,2H),4.06-4.01(m,2H),3.83-3.78(m,2H),3.69-3.62(m,2H),3.59(s,6H),2.38-1.82(m,12H),0.95-0.88(m,12H),0.86-0.80(m,9H),0.65-0.57(m,6H)；
HRMS(ESI)m/z 952.5335(M+H)+。
实施例5：二甲基((2S,2S’)-((2S,2S’)-2,2’-(((((2S,5S)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰa-3)
二甲基((2S,2S’)-((2S,2S’)-2,2’-(((((2R,5R)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰb-3)
Figure PCTCN2016106781-appb-000038
步骤1：
参照实施例1中的步骤1，将三甲基硅苯胺替换成叔丁基二甲基硅苯胺(8.0g，38.57mmol),得2,5-双-(4-硝基-苯基)-1-(4-叔丁基二甲基硅烷基-苯基)-吡咯烷SS、RR、SR三种构型的混合物。HRMS(ESI)m/z 504.2323(M+H)+。
步骤2：
参照实施例1中的步骤2，得4,4’-(1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)二苯胺反式异构体SS、RR混合物(310mg)，顺式单一异构体SR(660mg)。
反式异构体SS、RR混合物：1H-NMR(300MHz,DMSO-d6):δ＝7.02-6.99(d,J＝8.4Hz,2H)，6.84-6.81(d,J＝8.31Hz,4H)，6.49-6.46(d,J＝8.28Hz,4H)，6.29-6.27(d,J＝8.49Hz,2H)，5.00-4.98(d,J＝6.39Hz,2H)，4.87(s,4H)，1.56-1.54(d,J＝5.76Hz,2H)，1.25-1.17(m,2H),0.75(s,9H),0.08-0.07(m,6H)；HRMS(ESI)m/z 444.2723(M+H)+。
顺式单一异构体SR：1H-NMR(300MHz,DMSO-d6):δ＝7.13-7.04(m,4H)，6.91-6.84(m,2H)，6.57-6.54(d,J＝8.28Hz,4H)，6.48-6.31(m,2H),4.99-4.97(m,4H)，4.55(s,2H)，1.82-1.74(m,2H),1.57-1.45(m,2H),0.77(s,9H),0.10(s,6H)；HRMS(ESI)m/z 444.2825(M+H)+。
步骤3：
参照实施例1的步骤3，得(2S,2'S)-二苄基-2，2'-(((((2S,5S)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)和(2S,2'S)-二苄基-2，2'-(((((2R,5R)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)的混合物，共980mg。
1H-NMR(300MHz,DMSO-d6):δ＝9.98(s,2H),7.52-7.50(d,J＝7.47Hz,4H)，7.39-7.36(m,6H),7.17-7.12(m,6H),7.05-7.01(m,4H),6.31-6.29(d,J＝7.92Hz,2H),5.10-4.99(m,4H)，4.35-4.32(m,2H),3.59-3.56(m,4H),2.88(s,2H),2.23(m,2H),1.90-1.82(m,6H),1.65(s,2H),1.25-1.23(m,2H),0.74(s,9H),0.08(s,6H)；
HRMS(ESI)m/z 906.4705(M+H)+。
步骤4：
参照实施例1的步骤4，得(2S,2'S)-N,N’-(((2S,5S)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)和(2S,2'S)-N,N’-(((2R,5R)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)的混合物，共350mg。
1H-NMR(300MHz,DMSO-d6):δ＝9.93(s,2H),7.57-7.55(d,J＝8.4Hz,4H),7.15-7.09(m,4H)，7.04-7.01(d,J＝8.28Hz,2H)，6.29-6.26(d,J＝8.37Hz,2H),3.72-3.67(m,2H),2.91-2.87(m,4H),2.14-1.62(m,12H),0.74(s,9H),0.08(s,6H)；
HRMS(ESI)m/z 638.3901(M+H)+。
步骤5：化合物(Ⅰa-3)和化合物(Ⅰb-3)
参照实施例1的步骤5，得得Ⅰa-3和Ⅰb-3的混合物，共350mg，两种异构体的比例为1：1。C-18柱分离两种异构体，先分离得到Ⅰa-3再分离得到Ⅰb-3。
Ⅰa-3：1H-NMR(300MHz,DMSO-d6):δ＝9.96(s,2H),7.51-7.49(d,J＝8.19Hz,4H),7.29-7.27(d,J＝8.19Hz,2H)，7.15-7.12(d,J＝8.19Hz,4H)，7.05-7.02(d,J＝8.07Hz,2H)，6.27-6.25(d,J＝7.98Hz,2H),5.19(s,2H),4.44-4.43(m,2H),4.05-4.00(m,2H),3.79(s,2H),3.62-3.60(m,2H),3.52(s,6H),2.12-2.08(m,2H),1.99-1.89(m,8H),1.63-1.61(m,2H),0.94-0.82(m,12H),0.73(s,9H),0.07-0.06(m,6H)；HRMS(ESI)m/z 952.5405(M+H)+。
Ⅰb-3：1H-NMR(300MHz,DMSO-d6):δ＝9.96(s,2H),7.51-7.48(d,J＝8.31Hz,4H),7.29-7.26(d,J＝7.89Hz,2H)，7.14-7.11(d,J＝8.28Hz,4H)，7.05-7.02(d,J＝8.16Hz,2H)，6.27-6.24(d,J＝8.25Hz,2H),5.19(s,2H),4.42(s,2H),4.05-3.99(m,2H),3.78(s,2H),3.63(s,2H),3.52(s,6H),2.12-2.08(m,2H),2.00-1.75(m,8H),1.64-1.62(m,2H),0.92-0.85(m,12H),0.73(s,9H),0.07-0.06(m,6H)；HRMS(ESI)m/z 952.5404(M+H)+。
实施例6：二甲基((2S,2S’)-((2S,2S’)-2,2’-(((((2S,5R)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ⅰc-3)
Figure PCTCN2016106781-appb-000039
步骤1：
参照实施例1中的步骤3，得到(2S,2'S)-二苄基-2，2'-(((((2S,5R)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷-1-羧酸酯)。
1H-NMR(300MHz,DMSO-d6):δ＝10.04(s,2H),7.63-7.58(m,4H)，7.45-7.43(m,4H),7.36-7.09(m,12H),6.44-6.42(d,J＝6.51Hz,2H),5.13-5.08(m,4H),4.74(s,2H)，4.36-4.34(m,4H)，2.26-1.88(m,14H),0.76(s,9H),0.10(s,6H)；
HRMS(ESI)m/z 906.4704(M+H)+。
步骤2：
参照实施例1中的步骤4，得到(2S,2'S)-N,N’-(((2S,5R)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)双(4,1-亚苯基))双(吡咯烷-2-甲酰胺)。
1H-NMR(300MHz,DMSO-d6):δ＝9.93(s,2H),7.65-7.63(d,J＝8.46Hz,4H),7.43-7.40(d,J＝8.4Hz,4H)，7.14-7.07(m,2H)，6.42-6.39(d,J＝8.31Hz,2H)，3.70-3.63(m,2H),2.90-2.86(m,4H),2.07-1.53(m,12H),0.76(s,9H),0.09(s,6H)；
HRMS(ESI)m/z 638.3888(M+H)+。
步骤3：化合物(Ⅰc-3)
参照实施例1中的步骤5，得到化合物(Ⅰc-3)。
1H-NMR(300MHz,DMSO-d6):δ＝10.01(s,2H),7.59-7.57(d,J＝8.1Hz,4H),7.43(m,4H)，7.28(d,J＝8.28Hz,2H)，7.10(m,2H)，6.40-6.37(d,J＝7.53Hz,2H),5.74-5.73(m,2H),4.71(m,2H),4.45(m,2H),4.03(m,2H),3.80(m,2H),3.52(s,6H),2.12(m,2H),1.89(m,10H),0.93-0.87(m,12H),0.76-0.74(m,9H),0.09-0.07(m,6H)；
HRMS(ESI)m/z 952.5400(M+H)+。
实施例7：二甲基((2S,2S’,3R,3R’)-((2S,2S’)-2,2’-(((((2S,5S)-1-(4-(三乙基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ia-15)
Figure PCTCN2016106781-appb-000040
步骤1：
将中间体(1R,4R)-1，4-双(4-硝基苯基)丁烷-1，4-二取代二甲磺酰酯(11.20g，22.90mmol)加入DMF(80mL)中，再加入N,N-二异丙基乙胺(29.60g，229.00mmol)，三乙基硅基苯胺(38g，183.23mmol)，油浴加热100℃，反应12小时，反应结束后，加入80mL水，再用乙酸乙酯多次萃取，无水硫酸镁干燥有机相，过滤，浓缩，得到黄色油状液体，柱层析分 离，洗脱剂为石油醚：乙腈＝200：1，最后分离得到(2S,5S)-2,5-双-(4-硝基-苯基)-1-(4-三乙基硅烷基-苯基)-吡咯烷(5.0g)。
1H-NMR(500MHz,DMSO-d6):δ＝8.21-8.20(d,4H)，7.55-7.53(d,4H)，7.07-7.06(d,2H)，6.30-6.28(d,2H)，5.52-5.51(d,2H),1.76-1.75(d,2H)，1.27-1.23(m,2H),0.85-0.80(m,6H)，0.62-0.58(m,9H)。
MS(ESI)m/z 504.2[M+H]+。
步骤2：
将(2S,5S)-2,5-双-(4-硝基-苯基)-1-(4-三乙基硅烷基-苯基)-吡咯烷(4.2g，8.35mmol)、二氧化铂(3.79g，16.70mmol)加入THF(50mL)溶液中，氮气置换4次，氢气置换4次，氢气压力1atm，反应6小时，反应结束后，硅藻土助滤，二氯甲烷洗涤，浓缩滤液，得到黄色油状液体，柱层析分离，洗脱剂为石油醚：乙酸乙酯＝10：1～1：1进行梯度洗脱。分离出第一组分为4,4’-((2S,5S)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)二苯胺(2.80g)。
1H-NMR(300MHz,DMSO-d6):δ＝7.00-6.98(d,J＝8.16Hz,2H)，6.84-6.81(d,J＝8.13Hz,4H)，6.49-6.46(d,J＝8.1Hz,4H)，6.30-6.27(d,J＝8.25Hz,2H)，5.00-4.98(d,J＝5.97Hz,2H)，4.86(s,4H)，2.12-2.11(d,J＝3.93Hz,2H)，1.56-1.54(d,J＝5.79Hz,2H)，0.93-0.83(m,9H)，0.72-0.63(m,6H)。
HRMS(ESI)m/z 444.2829[M+H]+。
步骤3：化合物(Ia-15)
将4,4’-((2S,5S)-1-(4-(三乙基硅基)苯基)吡咯烷-2,5-二基)二苯胺(600mg,1.35mmol)加入DMF(10.00mL)溶液中，再加入(S)-1-((2S,3R)-3-甲氧基-2-((甲氧酰基)氨基)丁酰基)吡咯烷-2-羧酸(1.23g，4.05mmol)，EDC(628.7mg，4.05mmol)，HOBT(540.48mg，4.05mmol)，N-甲基吗啡啉(682.70g，6.75mmol),氮气保护下，于60℃反应4小时，反应结束后，反应液中缓慢加入10.00mL水，搅拌，用二氯甲烷多次萃取，有机相用无水硫酸镁干燥，过滤，浓缩，干燥，得产物(800g)，C18柱制备分离，先出峰的第一组分为目标产物。
1H-NMR(500MHz,DMSO-d6):δ＝9.92(s,2H),7.51-7.49(d,4H),7.30-7.28(d,2H)，7.15-7.14(d,4H)，7.03-7.02(d,2H)，6.28-6.26(d,2H),4.44-4.42(m,2H),4.29-4.26(m,2H),3.83-3.82(m,2H),3.69-3.64(m,2H),3.53(s,6H),3.49-3.46(m,4H)3.25(s,6H),2.16-2.15(m,2H)，2.01-1.98(m,2H)，1.91-1.85(m,4H)，1.64-1.62(m,2H)，1.24(s,2H)，1.14-1.13(m,6H),0.84-0.81(m,9H),0.62-0.57(m,6H)。
HRMS(ESI)m/z 984.5245[M+H]+。
实施例8：二甲基((2S,2S’,3R,3R’)-((2S,2S’)-2,2’-(((((2S,5S)-1-(4-(叔丁基二甲基 硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ia-16)
Figure PCTCN2016106781-appb-000041
步骤1：(2S,5S)-2,5-双-(4-硝基-苯基)-1-(4-叔丁基二甲基硅烷基-苯基)-吡咯烷
参照实施例7的步骤1，将三乙基硅基苯胺替换成叔丁基二甲基苯胺，得到目标化合物。步骤2：4,4’-((2S,5S)-1-(4-(叔丁基二甲基硅基)苯基)吡咯烷-2,5-二基)二苯胺
参照实施例7的步骤2，得到目标化合物。
步骤3：化合物(Ia-16)
参照实施例7的步骤3，得到化合物(Ia-16)(收率57％)。
1H-NMR(500MHz,CDCl3):δ＝8.90(s,2H),7.43(d,4H,J＝8.0Hz),7.12–7.09(m,6H),6.29(d,2H,J＝8.0Hz),5.12(d,2H,J＝5.0Hz),4.81(s,2H),4.67(s,2H),3.78–3.68(m,10H),3.40–3.33(m,6H),2.49–2.44(m,4H),2.09–2.03(m,8H),1.74(d,2H,J＝4.5Hz),1.20(d,6H,J＝4.0Hz),0.78(s,9H),0.13(s,3H),0.11(s,3H)。
13C-NMR(125MHz,CDCl3):δ＝170.3,169.0,156.8,145.2,139.7,136.6,135.0,126.5,121.9,120.0,113.3,62.6,60.8,57.4,55.5,52.4,48.0,32.2,27.5,26.6,24.9,17.1,14.7,14.2,-6.1。
LC-MS(ESI)m/z 1006.5(M+Na)+。
实施例9：二甲基((2S,2S’,3R,3R’)-((2S,2S’)-2,2’-(((((2S,5S)-1-(4-(乙基二甲基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ia-17)
Figure PCTCN2016106781-appb-000042
步骤1：(2S,5S)-2,5-双-(4-硝基-苯基)-1-(4-乙基二甲基硅烷基-苯基)-吡咯烷
参照实施例7的步骤1，将三乙基硅基苯胺替换成乙基二甲基苯胺，得到目标化合物。
步骤2：4,4’-((2S,5S)-1-(4-(乙基二甲基硅基)苯基)吡咯烷-2,5-二基)二苯胺
参照实施例7的步骤2，得到目标化合物。
步骤3：化合物(Ia-17)
参照实施例7的步骤3，得到化合物(Ia-17)(收率57％)。
1H-NMR(500MHz,CDCl3):δ＝8.89(s,2H),7.43(d,4H,J＝8.5Hz),7.12(d,4H,J＝8.0Hz),6.97(m,2H),6.31(d,2H,J＝8.0Hz),5.74(d,2H,J＝8.0Hz),5.13(d,2H,J＝6.5Hz),4.81(d,2H,J＝2.5Hz),4.68(m,2H),3.79-3.69(m,12H),3.34(s,6H),2.49-2.45(m,4H),2.06-2.01(m,6H),1.75(d,2H,J＝5.5Hz),1.21(s,6H),0.91-0.89(m,3H),0.60-0.58(m,2H),0.13(s,6H)。
13C-NMR(125MHz,CDCl3):δ＝170.2,169.0,156.8,144.8,139.6,136.6,128.6,126.6,126.4,120.2,120.0,115.6,113.9,113.5,62.6,60.8,57.4,55.5,52.4,48.0,32.3,27.6,24.9,14.8,14.1,9.5,6.6,-0.8。
LC-MS(ESI)m/z 978.5(M+Na)+。
实施例10：二甲基((2S,2S’,3R,3R’)-((2S,2S’)-2,2’-(((((2S,5S)-1-(4-(三甲基硅基)苯基)吡咯烷基-2,5-二基)双(4,1-亚苯基))双(氮烷二基))双(羰基))双(吡咯烷基-2,1-二基))双(3-甲氧基-1-氧代丁烷-2,1-二基))二氨基甲酸酯(Ia-18)
Figure PCTCN2016106781-appb-000043
步骤1：(2S,5S)-2,5-双-(4-硝基-苯基)-1-(4-三甲基硅烷基-苯基)-吡咯烷
参照实施例7的步骤1，将三乙基硅基苯胺替换成三甲基苯胺，得到目标化合物。
步骤2：4,4’-((2S,5S)-1-(4-(三甲基硅基)苯基)吡咯烷-2,5-二基)二苯胺
参照实施例7的步骤2，得到目标化合物。
步骤3：化合物(Ia-18)
参照实施例7的步骤3，得到化合物(Ia-18)。
1H-NMR(500MHz,CDCl3):δ＝8.87(s,2H),7.44–7.42(m,4H),7.13–7.11(m,4H),6.99–6.96(m,2H),6.33–6.31(m,2H),5.73–5.71(m,2H),5.14–5.13(m,2H),4.83–4.81(m,2H),4.69–4.67(m,2H),3.79–3.77(m,2H),3.75–3.72(m,4H),3.75–3.72(s,6H),3.34(s,6H),2.50–2.45(m,4H),2.06–2.01(m,8H),1.20(d,6H,J＝6Hz),0.16(s,6H),0.08(s,3H)。
13C-NMR(125MHz,CDCl3):δ＝170.2,169.0,156.8,136.6,128.6,126.6,120.0,114.0,62.7,60.8,60.4,57.4,55.5,52.4,48.0,32.3,27.6,24.9,14.7,1.92,1.32。
LC-MS(ESI)m/z 964.5(M+Na)+。
实施例11：体外药效检测及细胞毒性实验
1.实验材料
1.1HCV 1a复制子细胞和1b复制子细胞：即Huh7细胞系稳定转入HCV基因型1a复制子或1b复制子。
1.2试剂：试剂列表及供应商见表1。
表1.试剂列表
Figure PCTCN2016106781-appb-000044
Figure PCTCN2016106781-appb-000045
1.3待测化合物：用100％DMSO配制成10mM母液暂存于氮气柜中，化合物列表见表2。
2.实验方法
根据表2化合物稀释信息，对化合物DMSO母液进行稀释并加入96孔实验板中，DMSO终浓度为0.5％。
表2.化合物列表
Figure PCTCN2016106781-appb-000046
在上述96孔细胞板中种入HCV 1a复制子细胞或者1b复制子细胞(8,000细胞/孔)，随后置于37℃，5％CO2培养箱中培养3天。细胞活性测试可在每孔加入细胞生长荧光滴定检测试剂，37℃，5％CO2培养箱培养细胞1小时后，用分光光度仪检测系统Envision检测Luminescence信号值，原始数据用于化合物细胞毒性计算。通过测量荧光素酶报道基因的活性，可以确定本 申请化合物对HCV复制的抑制效果。每孔加荧光素酶发光底物Bright-Glo，5分钟内用化学发光检测系统Envision检测Luminescence信号值，原始数据用于化合物抑制活性计算。
使用如下公式将原始数据处理为细胞活力百分比：
Figure PCTCN2016106781-appb-000047
使用如下公式将原始数据处理为抑制百分数：
Figure PCTCN2016106781-appb-000048
其中CPD代表化合物孔的信号值；HPE(Hundred percent effect)代表100％有效作用对照孔信号值，孔中只有DMEM培养液；ZPE(Zero percent effect)代表无效作用对照孔信号值，用0.5％DMSO代替化合物。将细胞活力百分数、抑制百分数分别导入GraphPad Prism软件进行数据处理得出化合物对应的曲线及其细胞毒性(CC50)和对HCV复制子的抑制活性(EC50)数值。
3.实验结果
表3.化合物抗HCV 1a复制子的EC50值和对HCV1a复制子细胞的CC50值
编号 化合物名称 CC50 EC50 单位
1 Ⅰa-1 ＞0.5 0.014 nM
2 Ⅰb-1 ＞0.5 0.118 nM
3 Ⅰc-1 ＞0.5   nM
4 Ⅰa-2 ＞0.5 0.007 nM
5 Ⅰb-2 ＞0.5 0.041 nM
6 Ⅰc-2 ＞0.5   nM
7 Ⅰa-3 ＞0.5 0.011 nM
表4.化合物抗HCV 1b复制子的EC50值和对HCV1b复制子细胞的CC50值
编号 化合物名称 CC50 EC50 单位
1 Ⅰa-1 ＞1 0.004 nM
2 Ⅰb-1 ＞1 0.007 nM
3 Ⅰc-1 ＞1 0.008 nM
4 Ⅰa-2 ＞1 0.003 nM
5 Ⅰb-2 ＞1 0.006 nM
6 Ⅰc-2 ＞1 0.007 nM
7 Ⅰa-3 ＞1 0.003 nM
实施例12：HCV不同基因型NS5A嵌合复制子的抑制活性和抗感染性病型肝炎病毒(HCVcc，JFH-1，GT2a)活性的测定
1.实验材料
1.1Huh-7细胞、HCV复制子和HCVcc(GT2a)病毒感染系统。
1.2试剂：试剂列表及供应商见表5。
表5
试剂名称 供应商
DMEM细胞培养液 Invitrogen
胎牛血清 Corning
L-谷氨酰胺 Invitrogen
青霉素-链霉素 Invitrogen
磷酸盐缓冲液 Corning
胰酶 Invitrogen
二甲基亚砜(DMSO) Sigma
质粒提取试剂盒 Qiagen
SpeI-HF酶 NEB
PCR产物纯化试剂盒 Qiagen
体外转录试剂盒 Promega
RNA纯化试剂盒 Qiagen
DEPC处理水 Invitrogen
磷酸盐缓冲液PBS pH 7.4(Ca2+Mg2+free) Invitrogen
Bright-Glo检测试剂 Promega
2.试验方法
2.1瞬时转染法检测化合物对HCV不同基因型NS5A嵌合复制子的抑制活性
2.1.1根据表6化合物监测浓度信息，对Ia-1、Ia-2、Ia-3、ombitasvi的DMSO母液进行稀释并加入96孔实验板中，DMSO终浓度为0.5％。
表6
Figure PCTCN2016106781-appb-000049
2.1.2细胞处理：采用电击方法将HCV复制子RNA瞬时转染入huh7细胞；然后将细胞种入96孔板(10,000细胞/孔)，随后置于37℃，5％CO2培养箱中培养3天。
2.1.3抗HCV复制子活性检测：每孔加荧光素酶发光底物Bright-Glo，5分钟内用化学发光检测系统Envision检测Luminescence信号值，原始数据(RLU)用于化合物抑制活性计算。
2.1.4使用如下公式将原始数据处理为抑制百分数：
Figure PCTCN2016106781-appb-000050
CPD：化合物孔的信号值。
HPE(Hundred percent effect):100％有效作用对照孔信号值，孔中只有DMEM培养液。
ZPE(Zero percent effect):无效作用对照孔信号值，用0.5％DMSO代替化合物。
2.1.5将抑制百分数分别导入GraphPad Prism软件进行数据处理得出化合物对应的曲线及其对HCV复制子的抑制活性(EC50)数值。
2.2测定化合物抗感染性病型肝炎病毒(HCVcc，JFH-1，GT2a)活性
2.2.1细胞处理：将Huh-7.5.1细胞种入96孔板(7,000细胞/孔)，随后置于37℃，5％CO2培养箱中培养过夜。
2.2.2化合物处理：对化合物DMSO母液进行稀释并加入96孔实验板中。DMSO终浓度为
0.5％。化合物检测浓度见表7。
表7.化合物HCVcc检测浓度信息
2.2.3接种HCVcc：将HCVcc以每孔MOI0.1的浓度加入96孔实验板中。随后置于37℃，5％CO2培养箱中培养3天。每孔加入荧光素酶发光底物，用化学发光检测系统Envision检测Luminescence信号值，原始数据(RLU)用于化合物抑制活性计算。
2.2.4细胞毒性测定：细胞和化合物处理方法同以上3步，但培养基替代病毒加入实验板中。同样条件37℃，5％CO2培养箱中培养3天后，加入细胞活力检测试剂Alamar Blue，用分光光度仪检测Fluorescence信号值。原始数据(RFU)用于化合物细胞毒性计算。
2.2.5数据处理：使用如下公式将原始数据处理为细胞活力百分比：
Figure PCTCN2016106781-appb-000052
使用如下公式将原始数据处理为抑制活性百分数：
Figure PCTCN2016106781-appb-000053
将细胞活力百分数、抑制百分数分别导入GraphPad Prism软件进行数据处理得出化合物对应的曲线及其细胞毒性(CC50)和对HCV的抑制活性(EC50)数值。
3.试验结果
表8化合物对HCV不同基因型复制子的EC50值
Figure PCTCN2016106781-appb-000054
表9.化合物抗HCV GT2aHCVcc的EC50值和对Huh-7.5.1细胞的CC50值
化合物 EC50 CC50 单位
Ia-1 0.002575 >1 nM
Ia-2 0.000804 >1 nM
Ia-3 0.001115 >1 nM

Claims (16)

  1. 式Ⅰ的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物：
    Figure PCTCN2016106781-appb-100001
    其中：
    R1、R2和R3分别独立地选自氢、烷基或芳基；
    X选自-C(R6R7)-或-Si(R6R7)-；
    Y选自-C(R’6R’7)-或-Si(R’6R’7)-；
    R4选自-C(R8R9R10)或-Si(R8R9R10)；
    R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)；
    R6、R7、R’6和R’7分别独立地选自氢或C1-6烷基；以及
    R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-6烷基或C1-6烷氧基。
  2. 如权利要求1所述的化合物，其为式Ia的化合物、式Ib的化合物、式Ic的化合物或式Id的化合物：
    Figure PCTCN2016106781-appb-100002
    Figure PCTCN2016106781-appb-100003
    其中R1、R2、R3、X、Y、R4和R5如权利要求1所定义。
  3. 如权利要求1所述的化合物，其为式II的化合物：
    Figure PCTCN2016106781-appb-100004
    其中，
    R1、R2和R3分别独立地选自氢、烷基或芳基；
    R4选自-C(R8R9R10)或-Si(R8R9R10)；
    R5选自-C(R’8R’9R’10)或-Si(R’8R’9R’10)；以及
    R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-6烷基或C1-6烷氧基。
  4. 如权利要求3所述的化合物，其为式IIa的化合物、式IIb的化合物、式IIc的化合物或式IId的化合物：
    Figure PCTCN2016106781-appb-100005
    Figure PCTCN2016106781-appb-100006
    其中R1、R2、R3、R4和R5如权利要求3所定义。
  5. 如权利要求1-4中任一项所述的化合物，其中R1、R2和R3分别独立地选自氢、C1-6烷基或C6-12芳基。
  6. 如权利要求1或2所述的化合物，其中R6、R7、R’6和R’7分别独立地选自氢或C1-4烷基。
  7. 如权利要求1-4中任一项所述的化合物，其中R8、R9、R10、R’8、R’9和R’10分别独立地选自氢、C1-4烷基或C1-4烷氧基。
  8. 如权利要求1或2所述的化合物，其中X和Y独立地选自-CH2-或-Si(CH3)2-；R4和R5独立地选自-CH(CH3)2、-C(CH3)3、-Si(CH3)3或-CH(CH3)(OCH3)；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
  9. 如权利要求1或2所述的化合物，其中X为-Si(CH3)2-；Y为-CH2-或-Si(CH3)2-；R4和R5均为-CH(CH3)2；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
  10. 如权利要求3或4所述的化合物，其中R4和R5均为-CH(CH3)2，或均为-C(CH3)3，或均为-Si(CH3)3，或均为-CH(CH3)(OCH3)；且R1、R2和R3分别独立地选自甲基、乙基、正 丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
  11. 如权利要求3或4所述的化合物，其中R4为-C(CH3)3或-Si(CH3)3；R5为-CH(CH3)2；且R1、R2和R3分别独立地选自甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基或苯基。
  12. 如权利要求1所述的化合物，选自下列化合物：
    Figure PCTCN2016106781-appb-100007
    Figure PCTCN2016106781-appb-100008
  13. 药物组合物，其包含治疗有效量的权利要求1-12中任一项所述的化合物或其药学上可接 受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，以及一种或多种药学上可接受的载体。
  14. 权利要求1-12中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，或权利要求13所述的药物组合物在制备治疗丙型肝炎病毒感染的药物中的用途。
  15. 治疗丙型肝炎病毒感染的方法，所述方法包括给予需要治疗的患者治疗有效量的权利要求1-12中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物、或权利要求13所述的药物组合物。
  16. 用于治疗丙型肝炎病毒感染的权利要求1-12中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、前药或立体异构体及其混合物，或用于治疗丙型肝炎病毒感染的权利要求13所述的药物组合物。
PCT/CN2016/106781 2015-11-23 2016-11-22 用于抗丙型肝炎病毒感染的含硅化合物 Ceased WO2017088730A1 (zh)

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US5214176A (en) * 1988-04-20 1993-05-25 Rhone-Poulenc Chimie Organosilicon compounds
CN103172620A (zh) * 2009-06-11 2013-06-26 雅培制药有限公司 抗病毒化合物
CN103209686A (zh) * 2010-06-10 2013-07-17 雅博维巴哈马有限公司 固体组合物

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US5214176A (en) * 1988-04-20 1993-05-25 Rhone-Poulenc Chimie Organosilicon compounds
CN103172620A (zh) * 2009-06-11 2013-06-26 雅培制药有限公司 抗病毒化合物
CN103209686A (zh) * 2010-06-10 2013-07-17 雅博维巴哈马有限公司 固体组合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114656389A (zh) * 2022-04-27 2022-06-24 河南大学 一种1-苯基吡咯烷的合成方法
CN114656389B (zh) * 2022-04-27 2023-12-15 河南大学 一种1-苯基吡咯烷的合成方法

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