WO2017088730A1 - Silicone-containing compound for resisting hepatitis c virus infection - Google Patents

Abstract

The present application provides a silicone-containing compound for resisting hepatitis c virus infection, and in particular relates to a new compound which is as shown in formula I and has HCV NS5A protease inhibition activity, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or stereoisomers of the new compound as well as a mixture of pharmaceutically acceptable salts, hydrates, solvates, prodrugs and stereoisomers of the new compound, and a preparation method and a pharmaceutical composition of the new compound. The present application also relates to use of the compound, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or stereoisomers of the compound, a mixture of pharmaceutically acceptable salts, hydrates, solvates, prodrugs and stereoisomers of the compound, and a pharmaceutical composition of the compound in treatment of hepatitis c virus infection.

Description

Silicon-containing compound for anti-hepatitis C virus infection

Cross-reference to related applications

This application claims the priority of the Chinese Patent Application No. 201510814757.9, filed on November 23, 2015, and the Chinese Patent Application No. 201610669653.8, filed on August 12, 2016 with the Chinese State Intellectual Property Office. The disclosure of the patent application is hereby incorporated by reference in its entirety.

Technical field

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.

Background technique

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-α 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-α, 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.

Dr. Poordad from the University of Texas Health Science Center-Hepatology Institute used ABT-450, ombitasvir (ABT-267), dasabuvir (ABT-333) and ribavirin to treat HVC-1 infection. In adults with compensated cirrhosis, the treatment cycle was 12 weeks and 24 weeks, and the efficacy and safety of the combination regimen was observed. The results show that the interferon-free combination regimen is safe and effective in the treatment of patients with HCV genotype 1 compensated cirrhosis. High sustained virological response rate.

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.

Summary of invention

In one aspect, the application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof:

among them:

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.

In another aspect, the application provides 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.

In a further aspect, 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 .

In another aspect, 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.

In a further aspect, 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.

In a further aspect, 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.

Detailed description of the invention

The application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,

among them:

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. In some specific embodiments, 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.

In some embodiments, 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 .

In some embodiments, X is selected from _{-C (R 6 R 7) -} , Y is selected from _{-C (R '6 R' 7} ) - or _{-Si (R '6 R' 7} ) -. In some embodiments, X is selected from _{-Si (R 6 R 7) -} , Y is selected from _{-C (R '6 R' 7} ) - or _{-Si (R '6 R' 7} ) -.

In some embodiments, 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 ).

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the same as X and Y, for example, X and Y are both -CH ₂ -; or X and Y are both -Si (CH _{3) 2} -. In some embodiments, 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 -.

In some embodiments, 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 .

In some embodiments, 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. In some specific embodiments, 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. In some specific embodiments, 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. In the above embodiment, 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 . For example, 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.

In some embodiments, 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. In the above embodiment, 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, 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.

In some embodiments, 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. In the above embodiment, 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, 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.

In some embodiments, 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. In the above embodiment, 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, 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.

In some embodiments, 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 ); and 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

Further, 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.

Further, the application provides a compound of Formula II, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,

among them:

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 ); and

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. In some specific embodiments, 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.

In some embodiments, 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 .

In some embodiments, 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 ).

In some embodiments, 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.

In some embodiments, 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 .

In some 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 _1-6 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. 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 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 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 . For example, 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.

In some embodiments, 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. In the above embodiment, 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, 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.

In some embodiments, 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. In the above embodiment, 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, 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.

In some embodiments, 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.

In some embodiments, 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, tert-butyl, n-butyl, isobutyl or phenyl.

Still further, 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,

R ₁ , R ₂ , R ₃ , R ₄ and R _{5 in} formula IIa, formula IIb, formula IIc, formula IId and the above details for R ₁ , R ₂ , R ₃ , R ₄ and R ₅ in formula II The description is the same.

In particular, the present application provides the following compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or stereoisomers thereof, and mixtures thereof:

Wherein Me is a methyl group, Et is an ethyl group, Ph is a phenyl group, t-Bu is a tert-butyl group, and i-Pr is an isopropyl group.

Another aspect of the present application provides a pharmaceutical composition 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.

The pharmaceutical 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. , 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.

For oral administration, the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically 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 These 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.

The pharmaceutical 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.

In a further aspect, 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.

Specifically, 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.

At the same time, 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.

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.

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 Use of 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 Use of 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.

In some embodiments, other active compounds include, but are not limited to, other compounds that are resistant to HCV activity. In some embodiments, other active compounds include, but are not limited to, immunomodulatory agents and other antiviral agents. In some embodiments, 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. In some embodiments, 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. In some embodiments, other active compounds, including but not limited to other 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.

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.

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 as described herein, or a pharmaceutically acceptable salt, hydrate or solvate 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.

Related definitions:

The following terms and phrases used herein have the following meanings unless otherwise indicated. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense.

"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 -.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance.

As used herein, C _mn means having mn carbon atoms in this moiety. For example, " _C1-6 alkyl" means that the alkyl group has from 1 to 6 carbon atoms.

The numerical range in this document refers to each integer in a given range. For example, " _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.

The term "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,壬基, 癸基, 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 .

The term " _C1-6 alkyl" refers to an alkyl group having from 1 to 6 carbon atoms. The term "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. .

The term " _C1-6 alkoxy" refers to an -O-alkyl group having from 1 to 6 carbon atoms. The term "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.

The term "aryl" refers to an all-carbon monocyclic or polycyclic fused aromatic ring group having a conjugated π-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. For example, a monocyclic aromatic ring group is selected from phenyl, and 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.

The term "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.

The term "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. As the 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. In general, 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. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

The term "hydrate" refers to a complex formed by a compound of the present application and a stoichiometric amount of water molecules.

The term "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.

The term "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.

The term "stereoisomer" refers to isomers of the same molecular structure of the compound, but which differ in stereostructure, such as enantiomers and diastereomers.

The term "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. For an oral dosage form of the present application, 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. For example, 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. Where the stereochemistry of the chiral carbon is not specified in the chemical structure of the compound, the chemical structure is intended to include compounds containing any stereoisomer of the chiral center. For example, in 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, 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:

Individual 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.

The reaction materials and reaction reagents of the present application can be obtained by purchase unless otherwise stated.

The chemical reactions of the specific embodiments of the present application are accomplished in a suitable solvent which is suitable for the chemical changes of the present application and the reagents and materials required thereof. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the prior embodiments.

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.

1. When X, Y are the same, and R ₄ and R ₅ are also the same, the preparation method of the compound of formula I:

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.

2. Another method for preparing a compound of formula I when X, Y are the same and R ₄ and R ₅ are also the same:

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.

3. When X, Y are not the same, and R ₄ and R ₅ are the same, the preparation method of the compound of formula I:

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.

4. When X, Y are the same, and R ₄ and R ₅ are different, the preparation method of the compound of 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.

5. When X, Y are not the same, and R ₄ and R ₅ are different, the preparation method of the compound of 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. .

Among them, the compound 10 can be subjected to chromatography to obtain an optically active compound 10a, a compound 10b, and a compound 10c.

Among them, the preparation method of compound 5:

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. For example, 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. For example, 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 preparation method of compound 15 is as follows:

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.

On the basis of the preparation of the compound of the formula I, 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.

Further, 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.

Further, 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.

Alternatively, 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.

When the compound of formula I is of asymmetric structure, 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).

For example, when X, Y are the same, and R ₄ and R ₅ are also the same, the preparation method of the compound of formula Ia, Ib:

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.

detailed description

The following specific embodiments are intended to enable those skilled in the art to understand and practice the invention. They should not be considered as limiting the scope of the application, but are merely exemplary and typical representations of the application. Those skilled in the art will appreciate that there are other synthetic routes to form the compounds of the present application, and non-limiting examples are provided below.

Unless otherwise indicated, the materials used in this application were purchased directly from the market and used without further purification.

All operations involving materials that are susceptible to oxidation or hydrolysis are carried out under nitrogen. Column chromatography was performed using silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. Thin layer chromatography was carried out using a prefabricated board (silica gel 60 PF254, 0.25 mm) manufactured by E. Merck. The chiral compound was separated using a column: Waters XBridge C18,

Millimeter, 5 micron and chiral columns: CHIRALPAK IA

Mm, 5 microns. Nuclear magnetic resonance chromatography (NMR) 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" means 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.

Test part

Intermediate: 4-(trimethylsilyl)aniline

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).

¹ H-NMR (400 MHz, DMSO-d6): δ = 8.19 - 8.16 (d, J = 8.19 Hz, 2H), 7.83 - 7.80 (d, J = 8.22 Hz, 2H), 0.30 (s, 9H).

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.

¹ H-NMR (300 MHz, DMSO-d6): δ = 7.13 - 7.10 (d,J = 7.83 Hz, 2H), 6.55 - 6.52 (d, J = 7.83 Hz, 2H), 0.13 (s, 9H).

Intermediate: 4-(triethylsilyl)aniline

Add p-iodoaniline (15g, 68.49mmol), bistriphenylphosphine carbonyl ruthenium (2.36g, 3.42mmol), potassium phosphate (43.6g, 205.47mmol) and NMP (100mL) in a two-necked bottle, nitrogen protection And protected from light, reaction Triethylsilane (15.93 g, 136.98 mmol) was slowly added to the solution, and the mixture was stirred at room temperature for 4 days. After the reaction was completed, the reaction was quenched with water (100 mL), and the mixture was evaporated to ethyl acetate (100 mL×3), and the organic phase was washed with water (150 mL×3) and dried over anhydrous magnesium sulfate. Ethyl acetate was removed, and the residue was purifiedjjjjjjjjjj

¹ H-NMR (300 MHz, DMSO-d6): δ = 7.11 - 7.09 (d, J = 8.1 Hz, 2H), 6.57 - 6.54 (d, J = 8.13 Hz, 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) ⁺ .

Intermediate: 4-(tert-butyldimethylsilyl)aniline

Add p-iodoaniline (8.37 g, 38.2 mmol), bistriphenylphosphine carbonyl ruthenium (1.32 g, 1.91 mmol), potassium phosphate (24.32 g, 114.6 mmol) and NMP (100 mL) in a two-necked bottle, nitrogen The reaction was protected and protected from light. tert-butyldimethylsilane (13.32 g, 114.6 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 4 days. After the reaction was completed, the reaction was quenched with water (100 mL), and the mixture was evaporated to ethyl acetate (100 mL×3), and the organic phase was washed with water (150 mL×3) and dried over anhydrous magnesium sulfate. Ethyl acetate was removed, and the residue was purifiedjjjjjjjjj

^{1 H-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/z 208.1505 (M+H) ⁺ .

Intermediate: 1,4-bis(4-nitrophenyl)butane-1,4-disubstituted dimesyl ester

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. After completion of the reaction, 500 mL of water was added to stir, a large amount of solid was precipitated, and the mixture was filtered, and the cake was washed with dichloromethane and dried to give 1,4-bis-(4-nitrophenyl)butane-1,4-dione ( 61g).

¹ H-NMR (300 MHz, DMSO-d6): δ = 8.38 - 8.35 (d, J = 8.19 Hz, 4H), 8.26 - 8.24 (d, J = 8.22 Hz, 4H), 3.52 (s, 4H).

HRMS (APCI) m/z 327.0613 (MH) ^- .

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.

^{1 H-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 (MH) ^- .

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. After the reaction was completed, 50 mL of a saturated ammonium chloride solution was added thereto at room temperature for 20 minutes, and then washed twice with 100 mL of water to precipitate a solid, which was filtered, and the filter cake was dried to obtain 1,4-bis(4-nitrophenyl). Butane-1,4-disubstituted dimethoyl ester (10.5 g) is a mixture of three configurations of SS, RR, SR.

¹ H-NMR (300 MHz, DMSO-d6): δ = 8.26 - 8.24 (d, J = 8.19 Hz, 4H), 7.70 - 7.67 (d, J = 8.28 Hz, 4H), 5.84 (s, 2H), 3.12 (s, 6H), 1.96 (s, 4H).

HRMS (APCI) m/z 487.0487 (MH) ^- .

Intermediate: (1R,4S)-1,4-bis(4-nitrophenyl)butane-1,4-diol

(S)-Diphenyldecanol (126.67 mg, 0.5 mmol) and THF (10 mL) were added to a three-necked flask, and the reaction was stirred at 23 ° C under nitrogen, then trimethyl borate (67.5 mg, 0.65 mmol) was added. The reaction was continued for 1 hour; the temperature was lowered to 15 ° C, and N,N diisopropylammonium borane complex (1.0 g, 6.15 mmol) was slowly added. After 15 minutes, the temperature was lowered to 11 ° C, and 1, 4-bis(4-nitrophenyl)butane-1,4-dione (1.0 g, 3.0 mmol) was added to the reaction flask. An additional 10 mL of THF was added and the reaction was warmed to 35 ° C and stirred overnight. After the reaction was completed, the temperature was lowered to 5 ° C, methanol (779 mg) was added, and the mixture was stirred for 20 minutes, and then stirred at room temperature until the solid was dissolved. 20 mL of ethyl acetate was added to the solution, 10 mL of 1 M HCl and ethyl acetate. The organic phase was washed twice with 10 mL of 1 M HCl, washed twice with water, twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated by filtration, and 5 ml of ethyl acetate was added to the concentrate and stirred at 50 ° C 30mL of n-heptane was slowly added dropwise in 15 minutes, the solution was slowly precipitated as a pale yellow solid, and the mixture was stirred at room temperature for 30 minutes, filtered, and the filter cake was washed with ethyl acetate: n-heptane = 1:3, and dried. 1R,4S)-1,4-bis(4-nitrophenyl)butane-1,4-diol (500 mg).

^{1 H-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 (MH) ^- .

Intermediate: (S)-1-((2S,3R)-3-methoxy-2-((methoxy))amino)butyryl)pyrrolidine-2-carboxylic acid

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. The pH is adjusted to 1-2 with concentrated hydrochloric acid, extracted with dichloromethane, and the organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated and dried to give (2S,3R)-3-methoxy-2- ((A) Oxylyl)amino)butyric acid (11.50 g).

¹ H-NMR (500 MHz, CDCl ₃ ): δ = 5.47-5.45 (d, J = 10 Hz, 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 = 5 Hz, 3H).

HRMS (ESI) m/z 190.0543 [MH] ^- .

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. After the reaction was completed, the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated, and 150 mL of isopropanol was added to the concentrate, and the mixture was stirred at 50 ° C until the solid was dissolved, cooled and recrystallized, filtered. After drying, (2S,3R)-2,5-dioxopyrrolidin-1-yl-3-methoxy-2-((methoxy)amino)butyrate (11.90 g) was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.85 - 7.84 (d, J = 5 Hz, 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] ⁺ .

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. After the completion of the dropwise addition, the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the acetonitrile was concentrated to remove the pH, and the pH was adjusted to 1-2, 25% sodium chloride with a 6 mol/L HCl solution. The solution is washed, extracted with ethyl acetate multiple times, dried and filtered and concentrated to give (S)-1-((2S,3R)-3-methoxy-2-((methoxy)amino)butanoyl) Pyrrolidine-2-carboxylic acid (9.50 g).

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ=5.83-5.82 (d, J=5 Hz, 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] ⁺ .

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)

Dimethyl ((2S,2'S)-((2S,2'S)-2,2'-((((2R,5R)-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 (Ib-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. The mixture was combined, and the organic phase was combined, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give 2,5-bis-(4-nitro- A mixture of three configurations of phenyl)-1-(4-trimethylsilyl-phenyl)-pyrrolidine SS, RR, SR. HRMS (ESI) m/z 4621.19 (M+H) ⁺ .

Step 2: Add 2,5-bis-(4-nitro-phenyl)-1-(4-trimethylsilyl-phenyl)-pyrrolidine SS, RR, SR to the autoclave. The mixture (12 g), platinum oxide (4 g, 17.61 mmol), THF (80 mL), was replaced with nitrogen four times with hydrogen, four times with hydrogen, and reacted at a hydrogen pressure of 10 atm for 48 hours. After the completion of the reaction, the celite was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated and then purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1). 4,4'-(1-(4-(Trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine trans isomer SS, RR mixture (560 mg), cis Single isomer SR (860 mg).

The mixture of the trans isomers SS and RR: ¹ H-NMR (300 MHz, DMSO-d6): δ=7.03-7.00 (d, J = 8.22 Hz, 2H), 6.83-6.80 (d, J = 8.13 Hz, 4H ), 6.48-6.46 (d, J = 8.13 Hz, 4H), 6.28-6.26 (d, J = 8.28 Hz, 2H), 5.00 - 4.98 (d, J = 6.3 Hz, 2H), 4.86 (s, 4H) , 2.38-2.36 (d, J = 6.03 Hz, 2H), 1.57-1.55 (d, J = 5.67 Hz, 2H), 0.08 (s, 9H); HRMS (ESI) m/z 402.2363 (M+H) ⁺ .

Cis single isomer SR: ¹ H-NMR (300MHz, DMSO-d6): δ=7.12-7.08 (m, 6H), 6.56-6.54 (d, 4H), 6.44-6.41 (d, J=8.04 Hz , 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) ⁺ .

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. After the completion of the reaction, 50 mL of water was added to the reaction mixture, and the mixture was stirred, and the solid was separated, filtered, and the filtrate was extracted with methylene chloride. Ethyl acetate = 1:2), isolated (2S,2'S)-dibenzyl-2,2'-(((((2),5S)-1-(4-(trimethylsilyl)phenyl) Pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) and (2S, 2'S)-dibenzyl-2,2'-((((2R,5R)-1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis (4 , a mixture of 1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate), a total of 790 mg.

^{1 H-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) ⁺ .

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 palladium on carbon (97.2 mg, 0.0914 mmol), DIPEA (236 mg, 1.828 mmol), 3 times with nitrogen, 3 times with hydrogen, 3 at room temperature under hydrogen pressure 30 hour. After the reaction, the diatomaceous earth was filtered, and the filtrate was concentrated to give (2S,2'S)-N,N'-((2S,5S)-1-(4-(trimethylsilyl)phenyl)pyrrolidine. -2,5-diyl)bis(4,1-phenylene))bis(pyrrolidine-2-carboxamide) and (2S,2'S)-N,N'-(((2R,5R)-1 a mixture of -(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(pyrrolidine-2-carboxamide), 410 mg in total .

^{1 H-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 = 7.92 Hz, 2H), 6.34 - 6.25 (m, 2H), 6.20-6.17 (d, J = 7.98 Hz, 2H), 5.13-5.12 (d, J = 5.1 Hz, 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) ⁺ .

Step 5: Compound (Ia-1) and Compound (Ib-1)

Add (2S,2'S)-N,N'-((2S,5S)-1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl) double to a one-neck bottle (4,1-phenylene))bis(pyrrolidine-2-carboxamide) and (2S,2'S)-N,N'-(((2R,5R)-1-(4-(trimethylsilane) a mixture of phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene)bis(pyrrolidine-2-carboxamide) (400 mg, 0.67 mmol), DMF (15 mL) MOC-L-proline (586.85 mg, 3.35 mmol), EDCI (520 mg, 3.35 mmol), HOBT (452.65 mg, 3.35 mmol) and N-methylmorpholine (338.85 mg, 3.35 mmol). Stir at room temperature overnight under nitrogen. After completion of the reaction, 50 mL of water was added thereto, and the mixture was stirred to precipitate a white solid. The solid was re-dissolved and then separated by silica gel column chromatography (developing solvent: petroleum ether: ethyl acetate = 1:2), and Ia-1 and Ib-1 were isolated. The mixture was 358 mg in total and the ratio of the two isomers was 1:1. The two isomers were separated by a C-18 column, and Ia-1 was isolated and then separated to obtain Ib-1.

Ia-1: ¹ H-NMR (300MHz, DMSO-d6): δ = 9.96 (s, 2H), 7.51-7.48 (d, J = 8.22 Hz, 4H), 7.29-7.26 (d, J = 8.01 Hz, 2H), 7.14-7.11 (d, J=8.22 Hz, 4H), 7.06-7.03 (d, J=8.04 Hz, 2H), 6.27-6.24 (d, J=8.04 Hz, 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 910.4 </RTI> (M+H) ⁺ .

Ib-1: ¹ H-NMR (300MHz, DMSO-d6): δ = 9.96 (s, 2H), 7.51-7.48 (d, J = 8.25 Hz, 4H), 7.28-7.25 (d, J = 7.92 Hz, 2H), 7.13-7.11 (d, J=8.22 Hz, 4H), 7.06-7.03 (d, J=8.25 Hz, 2H), 6.27-6.24 (d, J=8.25 Hz, 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 910.4 </RTI> (M+H) ⁺ .

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)

Referring to step 3 in Example 1, the target compound was obtained.

^{1 H-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) ⁺ .

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)

Referring to step 4 in Example 1, the target compound was obtained.

¹ H-NMR (300 MHz, DMSO-d6): δ = 10.06 (s, 2H), 7.65 - 7.63 (d, J = 8.34 Hz, 4H), 7.43 - 7.40 (d, J = 8.4 Hz, 4H), 7.14 -7.11 (d, J = 8.31 Hz, 2H), 6.40-6.37 (d, J = 5.52 Hz, 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) ⁺ .

Step 3:

Referring to the step 5 in Example 1, the compound (Ic-1) was obtained.

¹ H-NMR (300 MHz, DMSO-d6): δ = 10.03 (s, 2H), 7.60-7.57 (d, J = 8.25 Hz, 4H), 7.43-7.40 (d, J = 8.4 Hz, 4H), 7.32 -7.30 (d, J = 7.29 Hz, 2H), 7.14 - 7.11 (d, J = 8.13 Hz, 2H), 6.39-6.36 (d, J = 8.34 Hz, 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) ⁺ .

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)

Dimethyl ((2S,2S')-((2S,2S')-2,2'-((((2R,5R)-1-(4-(triethylsilyl)phenyl)pyrrole Alkyl-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 (Ib-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).

The mixture of the trans isomers SS and RR: ¹ H-NMR (300 MHz, DMSO-d6): δ = 7.00-6.98 (d, J = 8.16 Hz, 2H), 6.84-6.81 (d, J = 8.13 Hz, 4H ), 6.49-6.46 (d, J = 8.1 Hz, 4H), 6.30-6.27 (d, J = 8.25 Hz, 2H), 5.00 - 4.98 (d, J = 5.97 Hz, 2H), 4.86 (s, 4H) , 2.12-2.11 (d, J = 3.93 Hz, 2H), 1.56-1.54 (d, J = 5.79 Hz, 2H), 0.93-0.83 (m, 9H), 0.72-0.63 (m, 6H); HRMS (ESI) ) m/z 444.2829 (M+H) ⁺ .

Cis single isomer SR: ¹ H-NMR (300 MHz, DMSO-d6): δ = 7.14 - 7.11 (d, J = 8.19 Hz, 4H), 7.08 - 7.06 (d, J = 8.16 Hz, 2H), 6.58-6.55 (d, J = 8.16 Hz, 4H), 6.46-6.44 (d, J = 8.19 Hz, 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) ⁺ .

Step 3:

Referring to step 3 of Example 1, (2S, 2'S)-dibenzyl-2,2'-((((2S,5S)-1-(4-(triethylsilyl)phenyl)pyrrole) was obtained. Alkano-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) and (2S,2'S) -dibenzyl-2,2'-((((2R,5R)-1-(4-(triethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis (4,1 - A mixture of phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate), a total of 1.0 g.

¹ H-NMR (300 MHz, DMSO-d6): δ = 9.99 (s, 2H), 7.54 - 7.51 (d, J = 6.42 Hz, 4H), 7.42 - 7.18 (m, 12H), 7.05 - 7.03 (d, J = 6.81 Hz, 4H), 6.33-6.30 (d, J = 8.13 Hz, 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) +.

Step 4:

Referring to step 4 of Example 1, (2S, 2'S)-N,N'-((2S,5S)-1-(4-(triethylsilyl)phenyl)pyrrolidine-2,5- Diyl) bis(4,1-phenylene))bis(pyrrolidine-2-carboxamide) and (2S,2'S)-N,N'-((2R,5R)-1-(4-( A mixture of triethylsilyl)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene)bis(pyrrolidine-2-carboxamide), total 700 mg.

^{1 H-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 = 8.16 Hz, 2H), 6.29-6.26 (d, J = 8.28 Hz, 2H), 5.21-5.20 (d, J = 5.58 Hz, 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) ⁺ .

Step: 5: Compound (Ia-2) and Compound (Ib-2)

Referring to 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.

Ia-2: ¹ H-NMR (300MHz, DMSO-d6): δ=9.98 (s, 2H), 7.52-7.49 (d, J = 8.19 Hz, 4H), 7.31-7.29 (d, J = 8.16 Hz, 2H), 7.15-7.12 (d, J = 8.22 Hz, 4H), 7.03-7.00 (d, J = 8.1 Hz, 2H), 6.28-6.25 (d, J = 8.09 Hz, 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: ¹ H-NMR (300MHz, DMSO-d6): δ=9.98 (s, 2H), 7.51-7.49 (d, J = 8.19 Hz, 4H), 7.31-7.28 (d, J = 8.28 Hz, 2H), 7.14-7.12 (d, J = 8.19 Hz, 4H), 7.03-7.00 (d, J = 8.07 Hz, 2H), 6.27-6.25 (d, J = 8.13 Hz, 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) ⁺ .

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)

Referring to step 3 in Example 1, the target compound was obtained.

¹ H-NMR (300 MHz, DMSO-d6): δ = 10.03 (s, 2H), 7.60-7.58 (d, J = 7.35 Hz, 4H), 7.46-7.43 (d, J = 7.8 Hz, 4H), 7.31 -7.10 (m, 12H), 6.45-6.43 (d, J = 5.94 Hz, 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) +.

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)

Referring to step 4 in Example 1, the target compound was obtained.

^{1 H-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 = 8.31 Hz, 2H), 6.42 - 6.39 (d, J = 8.31 Hz, 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) ⁺ .

Step 3:

Referring to the step 5 in Example 1, the compound (Ic-2) was obtained.

¹ H-NMR (300 MHz, DMSO-d6): δ = 10.03 (s, 2H), 7.60 - 7.57 (d, J = 8.37 Hz, 4H), 7.44 - 7.41 (d, J = 8.31 Hz, 4H), 7.32 -7.30 (d, J = 7.86 Hz, 2H), 7.11 - 7.08 (d, J = 8.22 Hz, 2H), 6.41-6.38 (d, J = 8.01 Hz, 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) ⁺ .

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)

Dimethyl ((2S,2S')-((2S,2S')-2,2'-((((2R,5R)-1-(4-(tert-butyldimethylsilyl)benzene) 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 (Ib-3)

step 1:

Referring to step 1 in Example 1, trimethylsilylaniline was replaced with tert-butyldimethylsilylaniline (8.0 g, 38.57 mmol) to give 2,5-bis-(4-nitro-phenyl)- A mixture of three configurations of 1-(4-tert-butyldimethylsilyl-phenyl)-pyrrolidine SS, RR, SR. HRMS (ESI) m/z 504.2323 (M+H) ⁺ .

Step 2:

Referring to step 2 in Example 1, 4,4'-(1-(4-(tert-butyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine is trans isomerized. Bulk SS, RR mixture (310 mg), cis single isomer SR (660 mg).

Trans isomer SS, RR mixture: ¹ H-NMR (300 MHz, DMSO-d6): δ = 7.02-6.99 (d, J = 8.4 Hz, 2H), 6.84-6.81 (d, J = 8.31 Hz, 4H ), 6.49-6.46 (d, J = 8.28 Hz, 4H), 6.29-6.27 (d, J = 8.49 Hz, 2H), 5.00 - 4.98 (d, J = 6.39 Hz, 2H), 4.87 (s, 4H) , 1.56-1.54 (d, J = 5.76 Hz, 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) ⁺ .

Cis single isomer SR: ¹ H-NMR (300MHz, DMSO-d6): δ = 7.13 - 7.04 (m, 4H), 6.91-6.84 (m, 2H), 6.57-6.54 (d, J = 8.28 Hz) , 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) ⁺ .

Step 3:

Referring to step 3 of Example 1, (2S, 2'S)-dibenzyl-2,2'-((((2S,5S)-1-(4-(tert-butyldimethylsilyl)benzene) Pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) and (2S , 2'S)-dibenzyl-2,2'-((((2R,5R)-1-(4-(tert-butyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl a mixture of bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate), a total of 980 mg.

^{1 H-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 = 7.92 Hz, 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 906.4 s (M+H) ⁺ .

Step 4:

Referring to step 4 of Example 1, (2S, 2'S)-N,N'-((2S,5S)-1-(4-(tert-butyldimethylsilyl)phenyl)pyrrolidine-2 was obtained. ,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.

^{1 H-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 = 8.28 Hz, 2H), 6.29-6.26 (d, J = 8.37 Hz, 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) ⁺ .

Step 5: Compound (Ia-3) and Compound (Ib-3)

Referring to step 5 of Example 1, 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.

Ia-3: ¹ H-NMR (300MHz, DMSO-d6): δ = 9.96 (s, 2H), 7.51-7.49 (d, J = 8.19 Hz, 4H), 7.29-7.27 (d, J = 8.19 Hz, 2H), 7.15-7.12 (d, J=8.19 Hz, 4H), 7.05-7.02 (d, J=8.07 Hz, 2H), 6.27-6.25 (d, J=7.98 Hz, 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: ¹ H-NMR (300MHz, DMSO-d6): δ = 9.96 (s, 2H), 7.51-7.48 (d, J = 8.31 Hz, 4H), 7.29-7.26 (d, J = 7.89 Hz, 2H), 7.14-7.11 (d, J = 8.28 Hz, 4H), 7.05-7.02 (d, J = 8.16 Hz, 2H), 6.27-6.24 (d, J = 8.25 Hz, 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) ⁺ .

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:

Referring to step 3 in Example 1, (2S, 2'S)-dibenzyl-2,2'-(((((2S,5R)-1-(4-(tert-butyldimethylsilyl))) Phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate).

¹ H-NMR (300 MHz, 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 = 6.51 Hz, 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) ⁺ .

Step 2:

Referring to step 4 in Example 1, (2S, 2'S)-N,N'-((2S,5R)-1-(4-(tert-butyldimethylsilyl)phenyl)pyrrolidine- 2,5-diyl)bis(4,1-phenylene))bis(pyrrolidine-2-carboxamide).

^{1 H-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 = 8.31 Hz, 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) ⁺ .

Step 3: Compound (Ic-3)

Referring to the step 5 in Example 1, the compound (Ic-3) was obtained.

^{1 H-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 = 7.53 Hz, 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) ⁺ .

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:

The intermediate (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-disubstituted dimethylsulfonyl ester (11.20 g, 22.90 mmol) was added to DMF (80 mL). Further, N,N-diisopropylethylamine (29.60 g, 229.00 mmol), triethylsilylaniline (38 g, 183.23 mmol) was added, and the mixture was heated at 100 ° C for 12 hours in an oil bath. After the reaction was completed, 80 mL of water was added. And extracting with ethyl acetate multiple times, drying the organic phase with anhydrous magnesium sulfate, filtering and concentrating to obtain a yellow oily liquid, column chromatography The eluent was petroleum ether: acetonitrile = 200:1, and finally (2S,5S)-2,5-bis-(4-nitro-phenyl)-1-(4-triethylsilyl) was isolated. -Phenyl)-pyrrolidine (5.0 g).

¹ H-NMR (500 MHz, 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] ⁺ .

Step 2:

(2S,5S)-2,5-bis-(4-nitro-phenyl)-1-(4-triethylsilyl-phenyl)-pyrrolidine (4.2 g, 8.35 mmol), dioxide Platinum (3.79 g, 16.70 mmol) was added to a solution of THF (50 mL), replaced with nitrogen four times, hydrogen was replaced four times, hydrogen pressure was 1 atm, and the reaction was carried out for 6 hours. After the reaction was completed, the diatomaceous earth was filtered, washed with dichloromethane, and concentrated. The filtrate obtained a yellow oily liquid, which was separated by column chromatography. The eluting solvent was petroleum ether: ethyl acetate = 10:1 to 1:1. The first component was isolated as 4,4'-((2S,5S)-1-(4-(triethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine (2.80 g) .

^{1 H-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 = 8.1 Hz, 4H), 6.30-6.27 (d, J = 8.25 Hz, 2H), 5.00-4.98 (d, J = 5.97 Hz, 2H), 4.86 (s, 4H), 2.12-2.11 (d, J = 3.93) Hz, 2H), 1.56-1.54 (d, J = 5.79 Hz, 2H), 0.93-0.83 (m, 9H), 0.72-0.63 (m, 6H).

HRMS (ESI) m/z 444.2829 [M+H] ⁺ .

Step 3: Compound (Ia-15)

Add 4,4'-((2S,5S)-1-(4-(triethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine (600 mg, 1.35 mmol) to DMF (10.00) (mL) 1-((2S,3R)-3-methoxy-2-((methoxy))))- yl) pyrrolidine-2-carboxylic acid (1.23 g, 4.05mmol), EDC (628.7mg, 4.05mmol), HOBT (540.48mg, 4.05mmol), N-methylmorpholine (682.70g, 6.75mmol), reacted under nitrogen for 4 hours at 60 ° C, after the reaction the reaction solution was slowly added 10.00mL of water, stirred, and extracted several times with methylene chloride, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated and dried to give the product (800g), C ₁₈ preparative separation column, the first peak The first component is the target product.

^{1 H-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] ⁺ .

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

Referring to step 1 of Example 7, triethylsilylaniline was replaced with tert-butyldimethylaniline to give the target compound. Step 2: 4,4'-((2S,5S)-1-(4-(tert-Butyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine

Referring to step 2 of Example 7, the target compound was obtained.

Step 3: Compound (Ia-16)

Referring to the step 3 of Example 7, the compound (Ia-16) was obtained (yield: 57%).

^{1 H-NMR (500MHz, CDCl} 3): δ = 8.90 (s, 2H), 7.43 (d, 4H, J = 8.0Hz), 7.12-7.09 (m, 6H), 6.29 (d, 2H, J = 8.0 Hz), 5.12 (d, 2H, J = 5.0 Hz), 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 = 4.5 Hz), 1.20 (d, 6H, J = 4.0 Hz), 0.78 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H).

¹³ C-NMR (125 MHz, CDCl ₃ ): 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) +.

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

Referring to step 1 of Example 7, triethylsilylaniline was replaced with ethyldimethylaniline to obtain the target compound.

Step 2: 4,4'-((2S,5S)-1-(4-(ethyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine

Referring to step 2 of Example 7, the target compound was obtained.

Step 3: Compound (Ia-17)

Referring to the step 3 of Example 7, the compound (Ia-17) was obtained (yield: 57%).

¹ H-NMR (500MHz, CDCl ₃ ): δ=8.89 (s, 2H), 7.43 (d, 4H, J = 8.5 Hz), 7.12 (d, 4H, J = 8.0 Hz), 6.97 (m, 2H) , 6.31 (d, 2H, J = 8.0 Hz), 5.74 (d, 2H, J = 8.0 Hz), 5.13 (d, 2H, J = 6.5 Hz), 4.81 (d, 2H, J = 2.5 Hz), 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 = 5.5 Hz ), 1.21 (s, 6H), 0.91 - 0.89 (m, 3H), 0.60 - 0.58 (m, 2H), 0.13 (s, 6H).

¹³ C-NMR (125 MHz, CDCl ₃ ): 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) +.

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 1: (2S,5S)-2,5-bis-(4-nitro-phenyl)-1-(4-trimethylsilyl-phenyl)-pyrrolidine

Referring to step 1 of Example 7, triethylsilylaniline was replaced with trimethylaniline to give the target compound.

Step 2: 4,4'-((2S,5S)-1-(4-(Trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine

Referring to step 2 of Example 7, the target compound was obtained.

Step 3: Compound (Ia-18)

Referring to the step 3 of Example 7, the compound (Ia-18) was obtained.

¹ H-NMR (500MHz, CDCl ₃ ): 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 = 6 Hz), 0.16 (s, 6H), 0.08 (s, 3H).

¹³ C-NMR (125 MHz, CDCl ₃ ): 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) +.

Example 11: In vitro drug efficacy test and cytotoxicity test

Experimental material

1.1 HCV 1a replicon cells and 1b replicon cells: the Huh7 cell line is stably transferred into the HCV genotype 1a replicon or the 1b replicon.

1.2 Reagents: The list of reagents and suppliers are shown in Table 1.

Table 1. Reagent List

1.3 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.

2. Experimental methods

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.

Table 2. List of compounds

HCV 1a replicon cells or 1b replicon cells (8,000 cells/well) 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:

Wherein CPD represents the signal value of the compound pore; HPE (Hundred percent effect) represents the 100% effective control well signal value, only DMEM medium in the well; ZPE (Zero percent effect) represents the invalid control well signal value, using 0.5% DMSO Instead of a compound. 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.

3. Experimental results

Table 3. Compound anti-HCV 1a replicon EC ₅₀ and CC ₅₀ values of values of replicon cells HCV1a

Numbering	Compound name	CC 50	EC 50	unit
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

Table 4. Compound anti-HCV 1b replicon EC ₅₀ value of CC replicon cells HCV1b ₅₀ values

Numbering	Compound name	CC 50	EC 50	unit
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

Example 12: Inhibitory activity of HCV different genotype NS5A chimeric replicon and determination of anti-infective disease hepatitis virus (HCVcc, JFH-1, GT2a) activity

Experimental material

1.1 Huh-7 cells, HCV replicon and HCVcc (GT2a) virus infection system.

1.2 Reagents: The list of reagents and suppliers are shown in Table 5.

table 5

Reagent name	supplier
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

2. Test method

2.1 Transient transfection assay for the inhibitory activity of compounds on HCV different genotype NS5A chimeric replicons

2.1.1 According to the monitoring concentration information of the compound of Table 6, the DMSO mother liquor of Ia-1, Ia-2, Ia-3, ombitasvi was diluted and added to a 96-well experimental plate with a final concentration of DMSO of 0.5%.

Table 6

2.1.2 Cell treatment: 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.

2.1.3 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.

2.1.4 Process the raw data as a percentage of inhibition using the following formula:

CPD: Signal value of the compound well.

HPE (Hundred percent effect): 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.

2.1.5 The percent inhibition were introduced into GraphPad Prism software for data processing and the curve corresponding compound derived replication promoter inhibitory activity (EC ₅₀₎ values for HCV.

2.2 Determination of compound anti-infectious disease hepatitis virus (HCVcc, JFH-1, GT2a) activity

2.2.1 Cell treatment: 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.

2.2.2 Compound Treatment: The compound DMSO stock solution was diluted and added to a 96-well assay plate. The final concentration of DMSO is

0.5%. The concentrations of the compounds tested are shown in Table 7.

Table 7. Compound HCVcc detection concentration information

2.2.3 Inoculation of HCVcc: 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.

2.2.4 Cytotoxicity assay: The cell and compound treatment methods were the same as the above 3 steps, but the medium was replaced with the virus and added to the experimental plate. After culturing for 3 days at 37 ° C in a 5% CO ₂ incubator, the cell viability assay reagent Alamar Blue was added, and the Fluorescence signal value was detected by a spectrophotometer. Raw data (RFU) was used for compound cytotoxicity calculations.

2.2.5 Data Processing: The raw data is processed as a percentage of cell viability using the following formula:

The raw data was processed as percent inhibition activity using the following formula:

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₎ of HCV inhibitory activity (EC ₅₀₎ values.

3. Test results

Table 8 Compound ₅₀ values for different genotypes of HCV replicon EC

Table 9. Compound of anti-HCV GT2aHCVcc EC ₅₀ value of Huh-7.5.1 and CC ₅₀ values of the cells

Compound	EC50	CC50	unit
Ia-1	0.002575	>1	nM
Ia-2	0.000804	>1	nM
Ia-3	0.001115	>1	nM

Claims (16)

1. a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof and mixtures thereof:

   

   among them:

   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.
2. A compound according to claim 1 which is a compound of formula Ia, a compound of formula Ib, a compound of formula Ic or a compound of formula Id:

   

   

   Wherein R ₁ , R ₂ , R ₃ , X, Y, R ₄ and R _{5 are} as defined in claim 1.
3. A compound according to claim 1 which is a compound of formula II:

   

   among them,

   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.
4. A compound according to claim 3 which is a compound of formula IIa, a compound of formula IIb, a compound of formula IIc or a compound of formula IId:

   

   

   Wherein R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} as defined in claim 3.
5. The compound according to any one of claims 1 to 4, wherein R ₁ , R ₂ and R ₃ are each independently selected from hydrogen, C _1-6 alkyl or C _6-12 aryl.
6. The compound according to claim 1 or 2, wherein R ₆ , R ₇ , R' ₆ and R' ₇ are each independently selected from hydrogen or C _1-4 alkyl.
7. The compound according to any one of claims 1 to 4, wherein 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.
8. The compound according to claim 1 or 2, wherein 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 ); 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.
9. The compound according to claim 1 or 2, wherein 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 ; 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.
10. The compound according to claim 3 or 4, wherein 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, n-butyl, iso Butyl or phenyl.
11. The compound according to claim 3 or 4, wherein 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, tert-butyl, n-butyl, isobutyl or phenyl.
12. The compound of claim 1 selected from the group consisting of:

    

    
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-12 or a pharmaceutically acceptable compound thereof Salts, hydrates, solvates, prodrugs or stereoisomers and mixtures thereof, and one or more pharmaceutically acceptable carriers.
14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, or the pharmaceutical composition of claim 13 Use in the preparation of a medicament for the treatment of hepatitis C virus infection.
15. 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 any one of claims 1-12, or a pharmaceutically acceptable salt, hydrate, solvate thereof, Prodrug or stereoisomer and mixtures thereof, or the pharmaceutical composition of claim 13.
16. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, for use in the treatment of a hepatitis C virus infection, or A pharmaceutical composition according to claim 13 for the treatment of hepatitis C virus infection.