CN115806570B

CN115806570B - Peptoid derivative, pharmaceutical composition and application thereof

Info

Publication number: CN115806570B
Application number: CN202211423074.7A
Authority: CN
Inventors: 张天舒; 姜龙; 侯雯; 潘伟
Original assignee: Nanjing Zhihe Medical Technology Co ltd
Current assignee: Nanjing Zhihe Medical Technology Co ltd
Priority date: 2021-11-15
Filing date: 2022-11-15
Publication date: 2023-09-12
Anticipated expiration: 2042-11-15
Also published as: CN115806570A

Abstract

The invention discloses a novel peptoid derivative, a pharmaceutical composition and application thereof, wherein the novel peptoid derivative is shown as a formula (I) ₀ -1) is shown; the compound can be used for preparing antiviral drugs.

Description

Peptoid derivative, pharmaceutical composition and application thereof

Technical Field

The invention relates to the technical field of pharmaceutical chemistry, in particular to a peptidomimetic derivative, a pharmaceutical composition and application thereof.

Background

Coronavirus-19 (COVID-19, also known as SARS-CoV-2) belongs to the family of single positive strand RNA viruses, and the family of coronaviruses mainly includes novel coronaviruses (SARS-CoV-2), SARS coronaviruses (SARS-CoV), middle east respiratory syndrome coronaviruses (MERS-CoV), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU. Coronaviruses often cause respiratory and intestinal diseases, neurological symptoms and myocarditis.

There is an urgent need to develop various specific inhibitors with different mechanisms of action to treat new coronaviruses.

Disclosure of Invention

The present inventors have developed a peptidomimetic derivative which can be used for the preparation of antiviral drugs.

One aspect of the present invention provides a method as described in (I ₀ -the peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof shown in 1):

Formula (I) ₀ In the step of-1), the step of,

n ₁ selected from 0, 1,2, 3, 4;

represented as a bond or not;

R _1a and R is _1b Each independently selected from hydrogen, the following substituted or unsubstituted with group a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl;

R _2a and R is _2b Are independently selected from hydrogen, CF ₃ Or by one or more basesC1-C8 alkyl, C2-C8 alkenyl substituted or unsubstituted by group A;

R ₃ selected from hydrogen, halogen, hydroxy, nitro, amino, CN, CF ₃ 、Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein,,

g is selected from O or Se;

R _a selected from hydrogen, hydroxy, amino, CF ₃ Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl;

R _b selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A;

R ₄ selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, orWherein,,

R _a as defined above;

Y ₁ selected from O, S or Se;

Y ₂ selected from the group consisting ofWherein,,

X ₀ selected from O, S or Se;

t ₁ selected from 1,2 or 3;

t ₂ Selected from 0,1,2,3 or 4;

R ₅ selected from hydrogen,Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein the method comprises the steps of，R _b As defined above;

R _6a and R is _6b Are each independently selected from CH ₂ O, S or NH;

R ₇ selected from hydrogen, halogen, nitro, amino, CN, CF ₃ 、Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein,,

R _a and R is _b As defined above;

R _8a and R is _8b Are each independently selected from hydrogen, mercapto, halogen, nitro, amino, cyano, Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein,,

R _a and R is _b As defined above;

Y ₃ selected from hydrogen, orWherein,,

n ₂ selected from 1,2,3, 4;

g is selected from

Wherein,,

X ₁ 、X ₂ and X ₃ Each independently selected from O or S;

R _c and R is _d Each independently selected from the group consisting of cations, hydrogen, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C18 aryl, C6-C18 heteroaryl; or,

R _c And R is _d Is connected with P and R together _c 、R _d O which are respectively connected together form a multi-ring;

R _e selected from hydroxyl, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxy, C6-C18 heteroaryl, C6-C18 heteroaryloxy;

R _f1 and R is _f2 Each independently selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A;

m ₁ and m ₂ Each independently selected from 0, 1, 2, 3, 4;

R _g1 and R is _g2 Each independently selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl;

Y ₄ selected from N, C, or CH;

in particular the number of the elements to be processed,

when Y is ₂ Is thatAnd Y is ₁ When S is, Y ₃ Is not hydrogen;

when Y is ₄ Is N, andwhen expressed as a bond, R ₄ Absence of;

the group A is: C1-C8 alkyl,NR _g1 R _g2 、/> Mercapto C1-C8 alkyl, halogen, cyano, aldehyde, nitro, trifluoromethyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C6-C18 aryl, C6-C18 aryloxy; wherein R is _a 、R _b 、R _e 、R _g1 And R is _g2 As defined above.

In some embodiments, the invention provides a compound of formula (I ₀ -2) a peptidomimetic derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salts thereof:

formula (I) ₀ The substituents in-2) are as defined in formula (I) ₀ -1) said.

In some embodiments, the invention provides a compound of formula (I ₀ -3) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₀ The substituents in 3) are as defined in formula (I) ₀ -1) said.

In some embodiments, the invention provides a compound of formula (I ₀ -4) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₀ The substituents in-4) are as defined for formula (I) ₀ -1) said.

In some embodiments, the invention provides a compound of formula (I ₀ -5) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₀ The substituents in-5) are as defined in formula (I) ₀ -1) said.

In some embodiments, the invention provides a compound of formula (I ₀ -6) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

Formula (I) ₀ The substituents in 6) are as defined for formula (I) ₀ -1) said.

In some embodiments, the invention provides a compound of formula (I ₀ -7) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₀ The substituents in 7) are as defined in formula (I) ₀ -1) said.

In some embodiments, the invention provides a compound of formula (I ₀ -8) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₀ -8) the substituents are as defined in formula (I) ₀ -1) said.

In some embodiments, the invention provides a compound of formula (I ₁ -peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof of 1):

formula (I) ₁ In the step of-1), the step of,

n ₁ selected from 0, 1, 2, 3, 4;

represented as a bond or not;

or R is _1a And R is _1b Are connected together to form a ternary ring, a quaternary ring, a five-membered ring, a six-membered ring or a seven-membered ring with the adjacent carbon;

R ₂ selected from hydrogen, C1-C8 alkyl substituted or unsubstituted by the radical A, or Wherein,,

R _a selected from hydrogen, hydroxy, amino, CF ₃ The following groups, substituted or unsubstituted with group a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl;

R ₃ selected from hydrogen, halogen, hydroxy, nitro, amino, CN, CF ₃ 、The following groups, substituted or unsubstituted with group a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein,,g is selected from O or Se; r is R _a As defined above;

R _b selected from hydrogen, C1-C8 alkyl substituted or unsubstituted by group A;

Y ₁ selected from S or Se; in particular, when Y ₁ When S is, Y ₃ Is not hydrogen;

Y ₂ selected from C, N, or CH; when Y is ₂ Is N, andr is R when bond is formed ₂ Absence of;

Y ₃ selected from hydrogen, orWherein,,

n ₂ selected from 1, 2, 3, 4;

a is selected from Wherein,,

X ₁ 、X ₂ and X ₃ Each independently selected from O or S;

R _e selected from the following groups, substituted or unsubstituted with group a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxy, C6-C18 heteroaryl, C6-C18 heteroaryloxy;

R _f1 And R is _f2 Independently selected from hydrogen, C1-C8 alkyl substituted or unsubstituted with group A;

m ₁ and m ₂ Each independently selected from 0, 1, 2, 3, 4;

R _g1 and R is _g2 Each independently selected from hydrogen, the following substituted or unsubstituted with group a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl;

the group A is: C1-C8 alkyl, hydroxy, NR _g1 R _g2 、 Mercapto, halogen, cyano, aldehyde, nitro, trifluoromethyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C6-C18 aryl, C6-C18 aryloxy; wherein R is _g1 And R is _g2 As defined above.

In some embodiments, the invention provides a compound of formula (I ₁ -2) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₁ The substituents in-2) are as defined in formula (I) ₁ -1) said.

In some embodiments, the invention provides a compound of formula (I ₁ -3) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₁ The substituents in 3) are as defined in formula (I) ₁ -1) said.

In some embodiments, the invention provides a compound of formula (I ₁ -4) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

Formula (I) ₁ The substituents in-4) are as defined for formula (I) ₁ -1) said.

In some embodiments, the invention provides a compound of formula (I ₂ -peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof of 1):

formula (I) ₂ In the step of-1), the step of,

n ₁ selected from 0, 1, 2, 3, 4.

R ₁ Selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl.

R _2a And R is _2b Are independently selected from hydrogen, CF ₃ Or C1-C8 alkyl, C2-C8 alkenyl substituted or unsubstituted with one or more groups A.

g is selected from O or Se;

R _a selected from hydrogen, hydroxy, amino, CF ₃ Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkylC2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl;

R _b selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A.

R ₄ Selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl or Wherein,,

R _a as defined above.

Y ₁ Selected from O, S or Se.

Y ₂ Selected from the group consisting ofWherein,,

X ₀ selected from S, or Se;

t ₁ selected from 1,2 or 3;

t ₂ selected from 0,1,2,3 or 4, when t ₂ When 0, R is ₇ Is not present.

R ₅ Selected from hydrogen,Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein R is _b As defined above;

R _6a and R is _6b Are each independently selected from CH ₂ O, S or NH;

R _a and R is _b As defined aboveSense and meaning;

R _a and R is _b As defined above.

Y ₃ Selected from H orWherein n is ₂ Selected from 1,2,3, 4, when Y ₃ When H is the same as X ₀ Is not O;

g is selected from

Wherein,,

X ₁ 、X ₂ and X ₃ Each independently selected from O or S;

R _e selected from hydroxyl, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxyA radical, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxy, C6-C18 heteroaryl, C6-C18 heteroaryloxy;

R _f1 and R is _f2 Each independently selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A.

m ₁ And m ₂ Each independently selected from 0, 1, 2, 3, 4;

R _g1 and R is _g2 Each independently selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl.

In some embodiments, the invention provides a compound of formula (I ₂ -2) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₂ The substituents in-2) are as defined in formula (I) ₂ -1) said.

In some embodiments, the invention provides a compound of formula (I ₂ -3) peptidomimetic derivativesBiology, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₂ The substituents in 3) are as defined in formula (I) ₂ -1) said.

In some embodiments, the invention provides a compound of formula (I ₂ -4) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₂ The substituents in-4) are as defined for formula (I) ₂ -1) said.

In some embodiments, the invention provides a compound of formula (I ₂ -5) peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₂ The substituents in-5) are as defined in formula (I) ₂ -1) said.

In some embodiments, the above formula (I ₀ -1)-(I ₀ In the step-5), the step of,represented as a bond;

in some embodiments, the above formula (I ₀ -1) and/or (I) ₀ -6)-(I ₀ In the step of-8), the step of,represented as a bond or not; preferably, the + >Represented as a key. />

In some embodiments, the above formula (I ₀ -1)-(I ₀ -8), n ₁ Selected from 0, 1, 2, 3, 4; preferably n ₁ Selected from 0, 1 or 2; more preferably, n ₁ 1.

In some embodiments, the above formula (I ₀ -1)-(I ₀ -8) in R _1a And R is _1b Each independently selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C6-C18 aryl; preferably, R _1a And R is _1b Each independently selected from hydrogen, or C1-C8 alkyl; more preferably, R _1a And R is _1b One of which is hydrogen and the other is isobutyl;

in some embodiments, the above formula (I ₀ -1)-(I ₀ -5) in R _2a And R is _2b Are independently selected from hydrogen, CF ₃ Or C1-C8 alkyl substituted or unsubstituted with one or more groups A; preferably, R _2a And R is _2b Are all hydrogen.

In some embodiments, the above formula (I ₀ -1)-(I ₀ -8) in R ₃ Selected from H, halogen, hydroxy, nitro, amino, CN, CF ₃ 、Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; preferably, R ₃ Selected from hydrogen, halogen, hydroxy,Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C3-C8 cycloalkyl; more preferably, R ₃ Selected from hydrogen, halogen, hydroxy, or +.>Wherein,,

g is selected from O or Se;

r is as described above _a Selected from hydrogen, hydroxy, amino, CF ₃ Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl;

r is as described above _b Selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A.

In some embodiments, the above formula (I ₀ -1)-(I ₀ -8) in R ₄ Selected from hydrogen, or C1-C8 alkyl or unsubstituted by one or more groups APreferably, R ₄ Selected from hydrogen, or C1-C8 alkyl; wherein,,

r is as described above _a Selected from hydrogen, hydroxy, amino, CF ₃ Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkoxy.

In some embodiments, the above formula (I ₀ -1)-(I ₀ -8) in Y ₁ Selected from O, S or Se; preferably Y ₁ Selected from S, or Se.

In some embodiments, the above formula (I ₀ -1)-(I ₀ -2) in Y ₂ Is thatWherein X is as described above ₀ Selected from O, S or Se;

in some embodiments, the above formula (I ₀ -1) and/or (I) ₀ -3) in Y ₂ Is thatWherein R is as described above ₅ Selected from hydrogen, & lt & gt>Or the following groups, which are optionally substituted by one or more groups A : C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C3-C8 cycloalkyl; preferably, R ₅ Selected from hydrogen, & lt & gt>Or C1-C8 alkyl substituted or unsubstituted with one or more groups A; wherein R is as described above _b Selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A; />

In some embodiments, the above formula (I ₀ -1) and/or (I) ₀ -4) in Y ₂ Is thatWherein R is as described above _6a And R is _6b Are each independently selected from CH ₂ O, S or NH; preferably, R _6a And R is _6b Each independently selected from S, or NH;

r is as described above ₇ Selected from hydrogen, halogen, nitro, amino, CN, CF ₃ 、Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; preferably, R ₇ Selected from hydrogen, halogen, CN, & lt/EN & gt> Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; more preferably, R is as defined above ₇ Selected from hydrogen, halogen, CN, & lt/EN & gt>Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C3-C8 cycloalkyl; wherein R is as described above _a And R is _b As defined above;

T is as described above ₁ Selected from 1, 2 or 3; preferably t ₁ Selected from 1, or 2;

t is as described above ₂ Selected from 0, 1, 2, 3 or 4; preferably t ₁ Selected from 1, or 2;

in some embodiments, the above formula (I ₀ -1) and/or (I) ₀ -5) in Y ₂ Is thatWherein,,

r is as described above _8a And R is _8b Are each independently selected from hydrogen, mercapto, halogen, nitro, amino, cyano, Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; preferably, R _8a And R is _8b Are each independently selected from hydrogen, mercapto, amino, cyano,Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; more preferably, R _8a And R is _8b Independently selected from hydrogen, mercapto, cyano,/->Wherein R is as described above _a And R is _b As defined above.

In some embodiments, the above formula (I ₀ -1)-(I ₀ -5) in Y ₃ Is hydrogen, in which case X ₀ Not being O, i.e. Y ₂ Not be of

In some embodiments, the above formula (I ₀ -1)-(I ₀ -8) in Y ₃ Is thatWherein n is as above ₂ Selected from 1, 2, 3, 4; preferably n ₂ Selected from 1, 2 or 3; more preferably, n ₂ Selected from 1, or 2; />

G is represented by formula (I) ₀ -1)-(I ₀ -6) isWherein,,

X ₁ selected from O or S;

R _c and R is _d Each independently selected from the group consisting of cations, hydrogen, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C18 aryl, C6-C18 heteroaryl; alternatively, R _c And R is _d Is connected with P and R together ₃ 、R ₄ O which are respectively connected together form a multi-ring; preferably, R _c And R is _d Each independently selected from alkali metal cations, alkaline earth metal cations, quaternary ammonium salts, amine ions, zinc ions, silver ions; alternatively, R _c And R is _d Is connected with P and R together _c 、R _d O which are respectively connected together form a multi-ring; more preferably, R _c And R is _d Are independently selected from Li ⁺ 、Na ⁺ 、K ⁺ 、Zn ⁺ 、Mg ²⁺ 、Ca ²⁺ 、Ag ⁺ Ammonium ion, or N (C) ₁ -C ₄ -alkyl group ₄ ⁺ The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R _c And R is _d Is connected with P and R together _c 、R _d O which are respectively connected together form a 5-7 membered ring; further, more preferably, R _c And R is _d Are respectively and independently selected from hydrogen, na ⁺ 、Mg ²⁺ 、Ca ²⁺ Or substituted or unsubstituted by one or more groups ASubstituted C1-C8 alkyl; or R is _c And R is _d Is connected with P and R together _c And R is _d O which are respectively connected together form a 5-7 membered ring.

G is represented by formula (I) ₀ -1)-(I ₀ -5) and/or (I) ₀ -7) isWherein,,

m is as above ₁ Selected from 0, 1, 2, 3, 4; preferably, m ₁ Is 2;

m is as above ₂ Selected from 0, 1, 2, 3, 4; preferably, m ₂ Selected from 0, 1, or 2; more preferably, m ₂ Selected from 1, or 2;

above X ₂ Selected from O or S;

r is as described above _f1 And R is _f2 Each independently selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A; preferably, R _f1 And R is _f2 Are all hydrogen, or R _f1 And R is _f2 One of which is hydrogen and the other of which is selected from C1-C8 alkyl;

r is as described above _e Selected from hydroxyl, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxy, C6-C18 heteroaryl, C6-C18 heteroaryloxy; preferably, R _e Selected from hydroxyl, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxy; more preferably, R _e Selected from hydroxyl, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkoxy;

G is represented by formula (I) ₀ -1)-(I ₀ -5) and/or (I) ₀ -8) isWherein,,

m ₁ 、m ₂ 、R _f1 and R is _f2 As defined above;

above X ₃ Selected from O or S;

r is as described above _g1 And R is _g2 Each independently selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl; preferably, R _g1 And R is _g2 Each independently selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl; more preferably, R _g1 And R is _g2 Each independently selected from hydrogen, or C1-C8 alkyl substituted or unsubstituted with one or more groups A.

In some embodiments, the above formula (I ₀ -1)-(I ₀ -5) in Y ₄ Is C;

in some embodiments, the above formula (I ₀ -1) and/or (I) ₀ -6)-(I ₀ -8) in Y ₄ C, N, or CH, in particular, when Y ₄ Is N, andwhen expressed as a bond, R ₄ Absence of;

In some embodiments, the present invention provides the above-described peptidomimetic derivatives selected from the following compounds:

/>

In another aspect, in some embodiments, the present invention provides pharmaceutical compositions comprising the above-described peptidomimetic derivatives, tautomers, stereoisomers, solvates, and pharmaceutically acceptable salts thereof.

In some embodiments, the invention discloses a pharmaceutical composition, which is composed of the compound, isomer or pharmaceutically acceptable salt thereof of the invention as an active ingredient or a main active ingredient, and a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides that the above pharmaceutical compositions are useful for the treatment and prevention of diseases associated with antiviral disorders.

In some embodiments, the present invention provides the use of the above pharmaceutical composition for the preparation of an antiviral drug.

In yet another aspect, the present invention provides a pharmaceutical composition comprising the above for use in the treatment of any viral-caused disease in a human or animal; such viruses include, but are not limited to: arenaviridae, filoviridae, and coronaviridae, and the like, including, but not limited to, adenovirus, rhinovirus, hepatitis a virus, hepatitis c virus, pneumo virus b, pneumo virus c, HIV virus, polio virus, measles virus, ebola virus, coxsackie virus, west nile virus, smallpox virus, yellow fever virus, dengue virus, influenza virus, lassa virus, respiratory syncytial virus, severe acute respiratory syndrome virus, parainfluenza virus, coronavirus, and the like.

Further, the influenza viruses include, but are not limited to, influenza a virus, influenza b virus, and the like;

further, the above coronaviruses include, but are not limited to, SARS virus, MERS virus, covd-19 virus, etc.;

in some embodiments, the peptidomimetic derivatives of the invention can be formulated as pharmaceutical compositions for administration to a patient in a variety of suitably selected modes of administration, including systemic, e.g., oral, inhaled, or parenteral, by intravenous, intramuscular, transdermal, subcutaneous, or the like.

In some embodiments, the peptidomimetic derivatives of the invention can be formulated as pharmaceutical compositions including, but not limited to, tablets, capsules or solutions for oral administration, or solutions, sprays, emulsions, ointments, emulsions or gels for transdermal administration.

The present invention discloses compounds having stronger 2019-nCoV-3CLpro inhibition and better anti-neocoronavirus activity and higher selection index than the compound ZJT4, and lower cardiotoxicity.

The compound disclosed by the invention has higher tissue distribution of liver, kidney and lung than the compound ZJT4, especially has more prominent tissue distribution in the lung, and is more beneficial to resisting pulmonary virus infection.

In addition, the disclosed compounds have a higher effect of passing through the blood brain barrier than the compound ZJT4, and it has been reported that the novel coronavirus may enter the brain through the nasal cavity, thereby causing long-term brain damage, so that the disclosed compounds can play a role in brain antiviral.

The compounds of the invention can be used as antiviral drugs with novel structures.

Definition:

the following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

Certain compounds of the invention may exist in unsolvated forms or solvated forms such as, for example, hydrated, ethanolic forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.

The term "substituted" means that one, two or three or more hydrogen atoms thereon are independently substituted with a substituent, which may be the same or different when substituted with more than one substituent.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic ammonia, or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.

The term "alkyl" means a saturated aliphatic radical, including straight and branched chain groups, alkyl groups which may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.

The term "alkenyl" means an aliphatic radical having an unsaturated carbon-carbon double bond, and includes straight and branched chain alkyl groups which may be substituted or unsubstituted. The carbon-carbon double bond may be one or more.

The term "cycloalkyl" means a single or fused ring of all carbons ("fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system), wherein one or more of the rings does not have a fully attached pi-electron system, examples of cycloalkyl (without limitation) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl groups may be substituted and unsubstituted.

The term "aryl" means an all-carbon monocyclic or fused multicyclic group of 1 to 12 carbon atoms having a fully conjugated pi-electron system. Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl. Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two.

The term "arylalkyl" denotes an alkyl group substituted with an aryl group.

The term "heteroaryl" means a multi-atom monocyclic or fused ring radical containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, additionally having a fully conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole.

The term "alkoxy" refers to a group in which an alkyl group is attached to oxygen, where the alkyl group may be straight chain, branched or cyclic alkyl.

The term "hydroxy" denotes an-OH group.

The term "amino" means-NH ₂ A group.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, including water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like.

The term "stereoisomer" refers to a compound that has the same chemical constitution but differs in the arrangement of atoms or groups in space.

By "solvate" is meant that certain compounds may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present application.

The numerical ranges stated herein, e.g., "C1-C8", means that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 8 carbon atoms.

The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present application.

Detailed Description

A number of exemplary methods for preparing the compounds of the present invention are provided in the examples below. The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. Certain compounds of the invention can be used as intermediates for preparing other compounds of the invention, all of which have structures determined by MS.

Various commonly used solvents and catalysts used in the present invention are commercially available.

Example 1: synthesis of Compound ZJT1

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of Compound ZJT 1-01:

l-leucine tert-butyl ester (18.7 g,100 mmol) was dissolved in N, N-dimethylformamide (200 mL), and 4-methoxyindole-2-carboxylic acid (22.9 g,120 mmol), 1-hydroxybenzotriazole (HOBt, 14.9g,110 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 21.1g,110 mmol) were then added to the above system in order. After the addition was completed, the system was cooled to 0℃and triethylamine (21.2 g,210 mmol) was then added dropwise; after the addition, the temperature was raised to room temperature, the mixture was stirred for 2 hours, a large amount of water was added to the system, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed 2 times with 5% citric acid and 2 times with 5% sodium bicarbonate, washed 2 times with saturated saline, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue was purified on a silica gel column to give Compound ZJT1-01 (23.2 g), yield 64.5%. ESI-MS (+): m/z= 361.20.

Step 2: preparation of compound ZJT 1:

compound ZJT1-01 (23.0 g,50 mmol) was added to dichloromethane (50 mL), cooled to about 0deg.C, then a trifluoroacetic acid/water (10:1, 75 mL) mixed solution was slowly added to the above system, and after the addition was completed, the reaction was allowed to proceed to room temperature for 1 hour, and concentrated to dryness under reduced pressure, the remainder was compound ZJT1 (13.3 g), the yield was 87.3%. ESI-MS (-) m/z= 303.14.

Example 2: synthesis of Compound ZJT2

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of Compound ZJT 2-04:

acetyl chloride (7.9 g,100 mmol) and aluminum chloride (1.07 g,7.6 mmol) were added sequentially to anhydrous 1, 2-dichloroethane (250 mL) and then ethyl 5-methoxyindole-2-carboxylate (21.9 g,100 mmol) was added slowly to the mixture in portions. The reaction mixture was heated at reflux for 2.5 hours. After cooling, the reaction mixture was poured onto crushed ice, acidified with hydrochloric acid, extracted 3 times with dichloromethane, combined with dichloromethane, washed 3 times with saturated brine, and the organic phase dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified on a silica gel column to give compound ZJT2-04 (16.0 g) in 61.2% yield. ESI-MS (+): m/z= 262.10.

Step 2: preparation of Compound ZJT 2-03:

A mixture of compound ZJT2-04 (13.1 g,50 mmol), triethylsilane (23.3 g,400 mmol) and ethyl 2, 2-trifluoroacetate (300 mL) was stirred at room temperature for 5 hours. After quenching with a saturated sodium carbonate solution, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by passing through a column to give the compound ZJT2-03 (4.9 g) in 39.8% yield. ESI-MS (+): m/z= 248.12.

Step 3: compound ZJT2-02 preparation:

compound ZJT2-03 (4.5 g,18.2 mmol) is added to tetrahydrofuran (50 mL) at room temperature, followed by an aqueous solution (20 mL) of lithium hydroxide monohydrate (5.5 g,130 mmol). After stirring for 3 hours, the solvent was concentrated to remove tetrahydrofuran, the residue was made acidic with 1M hydrochloric acid, extracted 3 times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column to give Compound ZJT2-02 (2.4 g) in 59.8% yield. ESI-MS (-) m/z= 218.10.

Step 3: preparation of Compound ZJT 2-01:

referring to the procedure of step 1 in example 1, compound ZJT2-01 (1.2 g) was prepared in a yield of 79.1%. ESI-MS (+): m/z= 361.20.

Step 4: compound ZJT2 preparation:

Referring to the procedure of step 2 in example 1, compound ZJT2 (2.1 g) was produced in 59.8% yield. ESI-MS (-) m/z= 303.14.

Example 3: synthesis of Compound ZJT3

The reaction formula:

the preparation method comprises the following steps:

step 1: compound ZJT3-04 preparation:

l-glutamic acid (29.4 g,0.2 mol) was dissolved in methanol (600 mL), cooled to about 0deg.C, and trimethylchlorosilane (TMSCI, 87.0g,0.8 mol) was slowly added, and the mixture was warmed to room temperature, stirred overnight, and TLC was used to detect the completion of the reaction. Triethylamine (131.5 g,1.3 mol) and di-tert-butyl dicarbonate ((Boc) 2O,48.0g,0.22 mol) were slowly added to the system. After the completion of the addition, the reaction was carried out at room temperature, and the completion of the reaction was detected by TLC. The residue was purified by silica gel column chromatography to give the compound ZJT3-04 (44.7 g) in a yield of 81.1%. ESI-MS (+): m/z= 276.14.

Step 2: preparation of Compound ZJT 3-03:

tetrahydrofuran (200 mL) was added to a three-necked flask under argon atmosphere, cooled to-78deg.C, ZJT3-04 (41.3 g,0.15 mol) was then added to the above system, stirred for 5 minutes, and hexamethyldisilazide (55.2 g,0.33 mol) was slowly added, and the reaction was maintained at-78deg.C for 2 hours with stirring. Then bromoacetonitrile (27.0 g,0.225 mol) was added thereto over 1 hour while maintaining the temperature, and the reaction was stirred for 2 hours, followed by TLC detection. The reaction was quenched by adding pre-chilled methanol to the system. The resulting methoxide was then quenched by addition of a pre-chilled acetic acid/tetrahydrofuran solution (1:7, 50 mL). After ten minutes, the temperature was raised to about 0℃and the system was introduced into saturated saline. The organic phase was separated and concentrated to dryness. The residue was purified by column chromatography on silica gel to give Compound ZJT3-03 (25.6 g) in 54.3% yield. ESI-MS (+): m/z= 315.15.

Step 3: compound ZJT3-02 preparation:

compound ZJT3-03 (25.0 g,79.5 mmol) and 10% palladium on carbon (2.5 g) are dissolved in acetic acid (500 mL), air is removed by vacuum, hydrogen is filled to 5atm, the reaction is carried out for about 30 hours, diatomite of the system is filtered, the filtrate is concentrated under reduced pressure, the remainder is dissolved in tetrahydrofuran (200 mL), triethylamine (20 mL) is then added, stirring is carried out at 60 ℃ overnight, water is added to the system for quenching, the organic phase is separated, the aqueous phase is extracted once with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the remainder is purified by a silica gel column, thus obtaining compound ZJT3-02 (10.4 g) with a yield of 47.9%. ESI-MS (+): m/z= 287.15.

Step 4: preparation of Compound ZJT 3-01:

compound ZJT3-02 (10.0 g,34.9 mmol) was dissolved in methanol (50 mL) at room temperature, 4mol/L sodium hydroxide (44 mL,174.5 mmol) was added, and the reaction was stirred at room temperature for 4 hours. After the TLC detection, the reaction was completed, methanol was removed by concentration, the reaction was neutralized with 2mol/L hydrochloric acid, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound ZJT3-01 (8.4 g), yield 88.8%. ESI-MS (-) m/z= 271.14.

Step 5: compound ZJT3-00 preparation:

Compound ZJT3-01 (8.0 g,29.4 mmol) is added to N, N-dimethylformamide (80 mL) at room temperature, then 1-hydroxybenzotriazole (HOBt, 4.8g,35.3 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 6.8g,35.3 mmol) and N, O-dimethylhydroxylamine hydrochloride (3.5 g,35.3 mmol) are added sequentially, cooled to 0℃after the addition, and triethylamine (3.6 g,35.3 mmol) is then slowly added. After the completion of the addition, N-dimethylformamide was removed by high vacuum concentration for 2 hours, ethyl acetate was added to the residue, which was washed with 5% citric acid, 5% sodium hydrogencarbonate and saturated brine, respectively, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to give Compound ZJT3-00 (6.4 g) in a yield of 68.7%. ESI-MS (+): m/z= 316.18.

Step 6: compound ZJT3 preparation:

to a solution of benzothiazole (13.5 g,100 mmol) in tetrahydrofuran (150 mL) at-78deg.C, 2mol/L of n-butyllithium tetrahydrofuran solution (17 mL) was added over 20 minutes, and the mixture was stirred for 1 hour after the addition. Then, a solution (50 mL) of the compound ZJT3-00 (6.3 g,20 mmol) in tetrahydrofuran was added to the above system over 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride at-78℃for 3 hours. The system was concentrated to remove tetrahydrofuran, the residue was added, washed with ethyl acetate, saturated brine and water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column to give compound ZJT3 (5.8 g) in 74.2% yield. ESI-MS (+): m/z= 290.14.

Example 4: synthesis of Compound ZJT4

The reaction formula:

the preparation method comprises the following steps:

compound ZJT3 (5.5 g,14.1 mmol) is dissolved in dichloromethane (100 mL), cooled to about 0deg.C, and trifluoroacetic acid/water (10:1, 55 mL) is added and stirred for 1 hour. Dichloromethane and trifluoroacetic acid were removed by concentrating under reduced pressure, N-dimethylformamide (100 mL) was added to the residue, diisopropylethylamine (1.4 g,10.8 mmol) and O-benzotriazol-tetramethyluronium hexafluorophosphate (HBTU, 4.1g,10.8 mmol) were then added sequentially with stirring, the temperature was lowered to 0 ℃, compound ZJT1 (3.3 g,10.8 mmol) was added, the addition was completed, the reaction was warmed to room temperature, stirring was carried out for 2 hours, TLC detection was completed, N-dimethylformamide was distilled off under high vacuum, ethyl acetate was added to the residue, each was washed with 5% citric acid, 5% sodium bicarbonate and saturated brine, an organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to obtain compound ZJT4 (4.9 g) in 78.2% yield. ESI-MS (+): m/z= 576.22.

Example 5: synthesis of Compound ZJT5

The reaction formula:

the preparation method comprises the following steps:

under the protection of nitrogen, the compound ZJT5 (2.9 g,5.0 mmol) is dissolved in tetrahydrofuran (50 mL), potassium carbonate (3.5 g,25 mmol) is added, then formaldehyde aqueous solution (35-40%, 2.5 g) is slowly added, the temperature is raised to 55 ℃ for 8h of reaction, TLC detection reaction is complete, the system is concentrated, water and methylene dichloride are added, shaking is carried out, the liquid phase is separated, methylene dichloride is extracted again, methylene dichloride phases are combined, anhydrous sodium sulfate is dried, filtration is carried out, and residues are purified and separated by a column, thus obtaining the compound ZJT5 (0.57 g), and the yield is 18.7%. ESI-MS (+): m/z= 606.23.

Example 6: synthesis of PYDD87-01

The reaction formula:

the preparation method comprises the following steps:

step 1: synthesis of PYDD87-0101

Compound ZJT4 (1.15 g,2.0 mmol) is dissolved in N, N-dimethylformamide (20 mL), sodium hydride (0.14 g,6 mmol) is slowly added, stirring is carried out at room temperature for 1 hour, di-tert-butyl chloromethyl phosphate (1.55 g,6.0 mmol) is added, reaction is continued at room temperature for 12 hours, ice water (60 mL) is added, ethyl acetate extraction (80 mL×2) is carried out, the organic phases are combined, anhydrous sodium sulfate is dried, concentrated, and the remainder is purified and separated by column to obtain compound PYDD87-0101 (0.40 g), yield: 24.9%. ESI-MS (+): m/z= 798.32.

Step 2: synthesis of PYDD87-01

Under the protection of nitrogen, the compound PYDD87-0101 (0.34 g,0.43 mmol) is dissolved in acetonitrile (10 mL), trifluoroacetic acid (1.0 mL) is added, the temperature is raised to 60 ℃ for reaction for 2 hours, the system is concentrated, acetonitrile is added into the residue for concentration again, and the trifluoroacetic acid is removed as much as possible; the residue was then dissolved in dichloromethane (5 mL), methyl tert-butyl ether (25 mL) was slowly added dropwise under ice bath, stirred at this temperature for 3 hours, filtered, and methyl tert-butyl ether rinsed to give the compound PYDD87-01 (0.08 g), yield: 26.4%. ESI-MS (-) m/z= 684.20.

Example 7: synthesis of PYDD87-02

The reaction formula:

the preparation method comprises the following steps:

compound PYDD87-01 (0.2 g,0.3 mmol) is dissolved in acetonitrile (10 mL), thionyl chloride (0.11 g,0.9 mmol) is added for reaction at 60 ℃ for 2 hours under nitrogen atmosphere, the temperature is reduced to 0-5 ℃, ethanol (1 mL) and triethylamine (0.12 g,1.2 mmol) are slowly added for reaction at 60 ℃ for 2 hours under nitrogen atmosphere, the temperature is reduced to room temperature, the concentration is carried out, the product is dissolved in dichloromethane, the water washing is carried out, the organic phase is dried, filtered and concentrated, and the residue is separated by column chromatography to obtain compound PYDD87-02 (69.9 mg), and the yield is 31.4%. ESI-MS (+): m/z= 742.26.

Example 8: synthesis of PYDD87-04

The reaction formula:

the preparation method comprises the following steps:

step 1: synthesis of PYDD87-0401

Freshly distilled phosphorus oxychloride (10.0 g,65.2 mmol) was dissolved in cold dichloromethane (80 mL) under argon, then anhydrous triethylamine (13.2 g,130.4 mmol) was added, cooled to 0-5℃after the addition was completed, and then a dichloromethane solution (150 mL) in which 1, 3-propanediol (5.0 g,65.2 mmol) was slowly added dropwise to the system. After the addition was completed, the system was stirred overnight at room temperature. The system was filtered, rinsed with dichloromethane and the filtrate concentrated to give cyclophosphamide chloride (compound ZJT9,8.6 g) in a yield of 84.2%.

Step 2: synthesis of PYDD87-04

Compound ZJT5 (0.61 g,1 mmol) is dissolved in dry dichloromethane (50 mL) at 0-5℃under nitrogen, and then the compound PYDD87-0401 (0.31 g,2 mmol) and 1-methylimidazole (0.17 g,2 mmol) are added sequentially to the system under stirring. After the addition was complete, stirring was continued at room temperature for 16h and tlc monitored complete. The system was concentrated, the residue was dissolved in methylene chloride (30 mL), and washed successively with saturated aqueous sodium hydrogencarbonate and water, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to isolate the compound PYDD87-04 (0.26 g) in a yield of 35.8%. ESI-MS (+): m/z= 726.23.

Example 9: synthesis of PYDD87-07

The reaction formula:

the preparation method comprises the following steps:

the compound PYDD87-01 (0.34 g,0.5 mmol) is added into 15ml ethanol, cooled to 0-10 ℃, 5ml of aqueous solution of sodium bicarbonate (0.08 g,1.0 mmol) is added dropwise for carrying out a temperature maintaining reaction, after the reaction is finished, the ethanol is distilled off under reduced pressure at 20-30 ℃, 10ml of acetone is added, crystallization, filtration and drying are carried out, and the compound PYDD87-07 (0.29 g) is obtained, and the yield is 85.4%. ESI-MS (-) m/z= 684.20.

Example 10: synthesis of PYDD87-11

The reaction formula:

the preparation method comprises the following steps:

to the reaction flask was added compound ZJT5 (0.3 g,0.5 mmol), cesium carbonate (0.33 g,1 mmol), sodium iodide (0.19 g,1.25 mmol), N, N-dimethylacetamide (10 mL) and water (40 mL), and the system was stirred and warmed to 60℃and a solution of chloromethyl dimethyl carbonate (0.09 g,0.75 mmol) in N, N-dimethylacetamide (5 mL) was added. The system reacts for 8 hours at 55 ℃, is cooled to room temperature, is added with ethyl acetate, is washed by saturated ammonium chloride, water and saturated saline water in sequence, is separated into liquid and is dried by anhydrous sodium sulfate; the organic phase was concentrated and evaporated to dryness, and the residue was purified by column to give the compound PYDD87-11 (0.14 g) in 40.1% yield. ESI-MS (+): m/z= 694.25.

Example 11: synthesis of PYDD87-12

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of Compound SM1

The synthesis of compound SM1 was performed as described in the synthetic references (Pharmaceutical Research,2005, vol.22, #3, p.390-396). Chloromethyl chloroformate (5.4 g,45 mmol) was added to methylene chloride (50 mL), cooled to 0 ℃, and a solution of dimethylamine in tetrahydrofuran (24 mL) was slowly added dropwise thereto, and the system was allowed to react at room temperature for 24 hours. Concentrated to dryness, dichloromethane and water were added, and the organic phase was separated and washed 3 times with 5% nahco3 solution. The organic phase was concentrated to dryness to give compound SM1 (2.60 g) in a yield of 41.9%. ESI-MS (+): m/z= 138.02.

Step 2: preparation of the Compound PYDD87-12

The compound ZJT4 (0.29 g,0.5 mmol), naH (24 mg,1.0 mmol), SM1 (0.21 g,1.5 mmol), and potassium iodide (0.12 g,0.75 mmol) were added sequentially to N, N-dimethylformamide (30 mL) at room temperature. After reaction was completed in TLC at 50-55deg.C for 24 hours, ethyl acetate (200 mL) was added to the reaction system, followed by washing with water, washing with saturated brine, separating out an organic phase, drying over anhydrous sodium sulfate, filtering, concentrating, and column-chromatography to give Compound PYDD87-12 (72 mg), yield 21.3%. ESI-MS (+): m/z= 677.27.

Example 12: synthesis of PYDD87-19

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of the Compound PYDD87-1902

Referring to the procedure of the step of example 4, substituting compound ZJT2 for compound ZJT1 gave compound PYDD87-1902 (3.10 g), yield 75.1%. ESI-MS (+): m/z= 604.25.

Step 2: preparation of the Compound PYDD87-1901

Referring to the procedure of step 1 in example 6, compound PYDD87-1901 (0.53 g) was produced in a yield of 21.9%. ESI-MS (+): m/z= 826.35.

Step 3: preparation of the Compound PYDD87-19

Referring to the procedure of step 2 in example 6, compound PYDD87-19 (0.11 g) was produced in a yield of 22.2%. ESI-MS (-) m/z= 712.23.

Example 13: synthesis of PYDD87-20

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of lithium methyl selenide

Selenium powder (0.8 g) was added to tetrahydrofuran (10 mL) at room temperature under nitrogen, and then methyllithium (1.6 mol/L diethyl ether solution, 1.1 mol) was added dropwise to the above system, followed by stirring for 15 minutes to obtain a white suspension for use.

Step 2: preparation of the Compound PYDD87-2003

A solution of 4-chloro-1H-indole-2-carboxylic acid (2.0 g,10 mmol) in N, N-dimethylformamide (30 mL) was slowly added to the suspension of lithium methylselenide, heated to 120℃and stirred for 8 hours, then cooled to room temperature, methyl iodide (1.4 g,10 mmol) was added, stirred for 1 hour, monitored by TLC, and the reaction was completed, and the system was poured into water. Extracting with methyl tert-butyl ether for 3 times, mixing the organic phases, washing with water for 3 times, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue with column to obtain the compound PYDD87-2003 (0.91 g) with a yield of 35.7%. ESI-MS (+): m/z= 256.00.

Step 3: preparation of the Compound PYDD87-2002

Referring to the procedure of step 1 in example 1, compound PYDD87-2002 (0.51 g) was produced in a yield of 60.2%. ESI-MS (+): m/z= 425.13.

Step 4: preparation of the Compound PYDD87-2001

Referring to the procedure of step 2 in example 1, compound PYDD87-2001 (0.44 g) was produced in a yield of 81.5%. ESI-MS (+): m/z= 367.06.

Step 5: preparation of the Compound PYDD87-20

Referring to the procedure of the step of example 4, compound PYDD87-20 (0.15 g) was produced in a yield of 71.1%. ESI-MS (+): m/z= 367.06.

Example 14: synthesis of PYDD87-21

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of benzoselenazole

Bis (2-aminophenyl) diselenide (3.4 g,10 mmol) was dissolved in anhydrous toluene (50 mL) under nitrogen and n-tributylphosphine (6.1 g,30 mmol) was added with stirring. After the completion of the addition, stirring at room temperature for 15 minutes, adding formic acid (0.5 g,10 mmol), heating to 100 ℃, reacting for 2 hours under the irradiation power of 100W, after TLC detection, cooling the reaction liquid to room temperature, adding saturated sodium bicarbonate, separating liquid, extracting aqueous dichloromethane for 3 times, combining organic phases, drying anhydrous sodium sulfate, filtering, concentrating, and purifying the residue by a column to obtain benzoselenazole (1.0 g), wherein the yield is 54.9%.

Step 2: preparation of the Compound PYDD87-2101

Referring to the procedure of step 6 in example 3, compound PYDD87-2101 (0.55 g) was produced in a yield of 69.1%. ESI-MS (+): m/z= 438.09.

Step 3: preparation of the Compound PYDD87-2101

With reference to the procedure of the step of example 4, compound PYDD87-21 (0.19 g) was produced in a yield of 70.3%. ESI-MS (+): m/z= 624.16.

Example 15: synthesis of PYDD87-28

The reaction formula:

the preparation method comprises the following steps:

referring to the procedure of step 2 in example 11, compound PYDD87-28 (0.21 g) was produced in 18.3% yield. ESI-MS (+): m/z= 707.28.

Example 16: synthesis of PYDD92-01

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of the compound PYDD 92-0101:

to a solution of compound ZJT3 (1.95 g,5 mmol) in anhydrous treated toluene (20 mL) under argon at room temperature was added Lawson reagent (2.5 g,6.2 mmol), the reaction was allowed to proceed at 110℃for 5 hours, TLC was followed by completion of the reaction, and cooling to room temperature. The reaction solution was filtered through a silica gel pad, the filtrate was concentrated, and the residue was purified by silica gel column to give the compound PYDD92-0101 (0.83 g) in a yield of 41.2%. ESI-MS (+): m/z= 406.12.

Step 2: preparation of the Compound PYDD92-01

Compound PYDD92-0101 (0.8 g,1.97 mmol) was dissolved in dichloromethane (10 mL), cooled to about 0deg.C, trifluoroacetic acid/water (10:1, 5 mL) was added and stirred for 1 hour. The dichloromethane was removed by concentrating under reduced pressure, N-dimethylformamide (10 mL) was added to the residue, diisopropylethylamine (0.2 g,1.51 mmol) and O-benzotriazol-tetramethyluronium hexafluorophosphate (HBTU, 0.59g,1.51 mmol) were then added sequentially with stirring, the temperature was lowered to 0℃and Compound ZJT1 (0.47 g,1.51 mmol) was added, the addition was completed, the temperature was raised to room temperature, the reaction was stirred for 2 hours, TLC was checked for completion, N-dimethylformamide was distilled off under high vacuum, ethyl acetate was added to the residue, and the organic phase was separated by washing with 5% citric acid, 5% sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to give Compound PYDD92-01 (0.61 g), yield 68.4%.

Example 17: synthesis of PYDD92-02

The reaction formula:

step 1: preparation of Compound PYDD 92-0201:

to a solution of compound ZJT3 (2.34 g,6 mmol) in anhydrous toluene (20 mL) under argon, woollins reagent (1.07 g,2 mmol) was added at room temperature, the temperature was raised to 120℃for 2 hours, and TLC was followed by completion of the reaction and cooled to room temperature. The reaction solution was filtered through a silica gel pad, the filtrate was concentrated, and the residue was purified by silica gel column to give the compound PYDD92-0201 (0.58 g) in a yield of 64.2%. ESI-MS (+): m/z= 454.06.

Step 2: preparation of the Compound PYDD92-02

Referring to the procedure of step 2 in example 4, compound PYDD92-02 (0.13 g) was produced in a yield of 33.6%. ESI-MS (+): m/z= 640.14.

Example 18: synthesis of PYDD92-03

The reaction formula:

the preparation method comprises the following steps:

compound ZJT4 (0.58 g,1.0 mmol) and hydroxylamine hydrochloride (0.42 g,6 mmol) are added sequentially to ethanol (50 mL) at room temperature, diisopropylethylamine (DIPEA, 0.78g,6 mmol) is added dropwise with stirring, and the temperature is raised to reflux for 8 hours. After TLC reaction, the temperature was lowered to room temperature, the system was poured into water, stirred for 1 hour, filtered, and the crude product was purified by column to give the compound PYDD92-03 (0.13 g) in 22.4% yield. ESI-MS (+): m/z= 591.23.

Example 19: synthesis of PYDD92-04

The reaction formula:

the preparation method comprises the following steps:

with reference to the procedure of the step of example 18, compound PYDD92-04 (0.22 g) was produced in a yield of 34.1%. ESI-MS (+): m/z= 605.25.

Example 20: synthesis of PYDD92-08

The reaction formula:

the preparation method comprises the following steps:

compound ZJT4 (0.58 g,1.0 mmol) is dissolved in 25mL ethanol, 10mg of p-toluenesulfonic acid is added, the temperature is raised to 40 ℃, an ethanol solution (20 mL) in which methyl cysteine (0.14 g,1.0 mmol) is dissolved is dripped into the above system, the reaction is carried out for 30min, ethanol is distilled off under reduced pressure, and the remainder is purified by column, thus obtaining compound PYDD92-08 (72 mg) with a yield of 10.4%. ESI-MS (+): m/z= 693.25.

Example 21: synthesis of PYDD92-10

The reaction formula:

the preparation method comprises the following steps:

compound ZJT4 (0.58 g,1.0 mmol) is dissolved in 25ml methanol, cooled to-10deg.C, saturated with hydrogen chloride gas, cooled to-50deg.C, charged with hydrogen sulfide gas for 10-2 hours, monitored by TLC, and the reaction is complete. The system was bubbled with argon to remove excess hydrogen chloride and hydrogen sulfide, methyl t-butyl ether was added to the system, and the mixture was rapidly washed with ice water, the organic phase was separated, dried, filtered, concentrated, and the residue was rapidly purified by passing through a column to give the compound PYDD92-10 (57 mg) in 9.5% yield. ESI-MS (+): m/z= 610.21.

Example 22: synthesis of PYDD92-11

The reaction formula:

the preparation method comprises the following steps:

compound ZJT4 (0.58 g,1.0 mmol) was dissolved in 25ml of isopropyl alcohol, and after bubbling with hydrogen sulfide gas for 15min, the mixture was stirred at room temperature for 65 hours; then, hydrogen sulfide gas was removed by bubbling with nitrogen, sodium borohydride (57 mg,1.5 mmol) was added, the temperature was raised to 80℃for 2 hours, TLC was monitored, the reaction was completed, the temperature was lowered to room temperature, isopropanol was removed by concentration under reduced pressure, and the residue was purified by column to give the compound PYDD92-11 (80 mg), yield 13.5%. ESI-MS (+): m/z= 594.21.

Example 23: synthesis of PYDD92-12

The reaction formula:

the preparation method comprises the following steps:

with reference to the procedure of the step of example 18, compound PYDD92-12 (0.17 g) was produced in a yield of 21.3%. ESI-MS (+): m/z= 649.26.

Example 24: synthesis of PYDD92-13

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of the Compound PYDD92-1303

3-mercapto-1-propylamine (9.1 g,100 mmol) and triethylamine (10.1 g,100 mmol) were dissolved in dichloromethane (200 mL). Di-tert-butyldicarbonate (24.0 g,110 mmol) was dissolved in dichloromethane (100 mL) and gradually added dropwise to the above system with stirring at room temperature for 10 min. After stirring overnight at room temperature, the system was washed with saturated sodium bicarbonate and water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound PYDD92-1303 (17.5 g) in 91.4% yield. ESI-MS (+): m/z= 192.10.

Step 2: preparation of the Compound PYDD92-1302

PYDD92-13-SM (22.0 g,97.8 mmol), compound PYDD92-1302 (17.0 g,88.9 mmol) and sodium bicarbonate (7.5 g,88.9 mmol) were added to tetrahydrofuran: in water (7:1, 100 mL), stirring at room temperature for 1 hour, concentrating, dissolving the residue in ethyl acetate, washing with saturated sodium bicarbonate and water respectively, separating an organic phase, drying over anhydrous sodium sulfate, filtering, concentrating, and recrystallizing the residue with dichloromethane/n-hexane to obtain a compound PYDD92-1302 (22.9 g) in a yield of 87.1%. ESI-MS (+): m/z= 296.12.

Step 3: preparation of the Compound PYDD92-1301

Compound PYDD92-1302 (20.0 g,67.7 mmol) was dissolved in dichloromethane (100 mL), cooled to about 0deg.C, and trifluoroacetic acid/water (10:1, 55 mL) was added and stirred for 1 hour. The methylene chloride was removed by concentration under reduced pressure, and the residue was slurried with methyl tert-butyl ether to give the compound PYDD92-1301 (10.8 g) in a yield of 81.6%. ESI-MS (+): m/z= 196.07.

Step 4: preparation of the Compound PYDD92-13

With reference to the procedure of the step of example 18, compound PYDD92-13 (0.17 g) was produced in a yield of 22.1%. ESI-MS (+): m/z= 753.28.

Example 25: synthesis of PYDD92-14

The reaction formula:

The preparation method comprises the following steps:

with reference to the procedure of the step of example 18, compound PYDD92-14 (0.12 g) was produced in a yield of 18.4%. ESI-MS (+): m/z= 707.26.

Example 26: synthesis of PYDD92-24

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of the Compound PYDD92-2401

Compound ZJT3 (1.95 g,5 mmol) is dissolved in dichloromethane (10 mL), cooled to about 0deg.C, trifluoroacetic acid/water (10:1, 20 mL) is added, and stirred for 1 hour. The dichloromethane was removed by concentrating under reduced pressure, N-dimethylformamide (40 mL) was added to the residue, diisopropylethylamine (0.49 g,3.68 mmol) and O-benzotriazol-tetramethyluronium hexafluorophosphate (HBTU, 1.22g,3.68 mmol) were then added sequentially with stirring, the temperature was lowered to 0℃and Compound ZJT2 (1.15 g,3.68 mmol) was added, the addition was completed, the temperature was raised to room temperature, the reaction was stirred for 2 hours, TLC was checked for completion, N-dimethylformamide was distilled off under high vacuum, ethyl acetate was added to the residue, and the organic phase was separated by washing with 5% citric acid, 5% sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to give Compound PYDD92-2401 (1.85 g) in 61.2% yield.

Step 2: preparation of the Compound PYDD92-24

With reference to the procedure of the step of example 18, compound PYDD92-24 (0.57 g) was produced in a yield of 13.4%. ESI-MS (+): m/z= 677.29.

Example 27: synthesis of PYDD92-25

The reaction formula:

the preparation method comprises the following steps:

step 1: preparation of the Compound PYDD92-2501

Compound ZJT3 (5.1 g,13.0 mmol) is dissolved in dichloromethane (100 mL), cooled to about 0deg.C, and trifluoroacetic acid/water (10:1, 55 mL) is added and stirred for 1 hour. The dichloromethane was removed by concentrating under reduced pressure, N-dimethylformamide (100 mL) was added to the residue, diisopropylethylamine (1.3 g,10.0 mmol) and O-benzotriazol-tetramethyluronium hexafluorophosphate (HBTU, 3.8g,10.0 mmol) were then added sequentially with stirring, the temperature was lowered to 0℃and Compound ZJT1 (3.0 g,10.0 mmol) was added, the addition was completed, the temperature was raised to room temperature, the reaction was stirred for 2 hours, TLC detection was completed, N-dimethylformamide was distilled off under high vacuum, ethyl acetate was added to the residue, and the organic phase was separated by washing with 5% citric acid, 5% sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to give Compound PYDD92-2501 (4.68 g) in 81.2% yield. ESI-MS (+): m/z= 576.22.

Step 2: preparation of the Compound PYDD92-25

To the reaction flask was added PYDD92-2501 (0.29 g,0.5 mmol), cesium carbonate (0.33 g,1 mmol), sodium iodide (0.19 g,1.25 mmol), N, N-dimethylacetamide (10 mL) and water (40 mL), and the system was stirred and warmed to 60℃and a solution of chloromethyl pivalate (0.11 g,0.75 mmol) in N, N-dimethylacetamide (5 mL). The system reacts for 8 hours at 55 ℃, is cooled to room temperature, is added with ethyl acetate, is washed by saturated ammonium chloride, water and saturated saline water in sequence, is separated into liquid and is dried by anhydrous sodium sulfate; the organic phase was concentrated and evaporated to dryness, and the residue was purified by column to give the compound PYDD92-25 (0.11 g) in a yield of 31.9%. ESI-MS (+): m/z= 690.29.

The following examples were synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from the commercially available compounds.

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Example 28:2019-nCoV-3CLpro inhibition assay

The inhibition of 2019-nCoV3CLpro enzyme activity by each compound sample was determined using fluorescence resonance energy transfer method. The volume of the whole enzymatic reaction system was 120. Mu.L, the final concentration of protease was 30nM and the final concentration of substrate was 50. Mu.M. The buffer of the reaction system included 50mM Tris pH7.3, 1mM EDTA. 2019-nCoV3CLpro enzyme and compound samples with different concentrations are added to a 96-well plate, incubated for 10min at 30 ℃, substrate is added and rapidly placed into an microplate reader for reading. The excitation light and the emission light were 340nm and 405nm, respectively. The test time was 10min, and fluorescence values were read every 30 s. The final results were fitted to the read out values for the first 2min to the reaction rate and compared to the control group (DMSO) to calculate the inhibition. IC was obtained by fitting with software GraphPad Prism 8 ₅₀ Values. The results are shown in Table 1.

TABLE 1 2019-nCoV3CLpro enzyme Activity test IC ₅₀ Results

Compounds of formula (I)	IC ₅₀ (mM)	Compounds of formula (I)	IC ₅₀ (mM)	Compounds of formula (I)	IC ₅₀ (mM)
						PYDD87-01	0.36	PYDD87-20	0.26	PYDD92-09	0.41
PYDD87-02	0.34	PYDD87-21	0.32	PYDD92-10	0.31
						PYDD87-03	0.54	PYDD87-22	0.37	PYDD92-11	0.36
PYDD87-04	0.34	PYDD87-23	0.63	PYDD92-12	0.37
						PYDD87-05	0.64	PYDD87-24	0.60	PYDD92-13	0.48
PYDD87-06	0.59	PYDD87-25	0.54	PYDD92-14	0.33
						PYDD87-07	0.48	PYDD87-26	0.53	PYDD92-15	0.54
PYDD87-08	0.32	PYDD87-27	0.58	PYDD92-16	0.46
						PYDD87-09	0.66	PYDD87-28	0.31	PYDD92-17	0.49
PYDD87-10	0.28	PYDD87-29	0.46	PYDD92-18	0.52
						PYDD87-11	0.33	PYDD87-30	0.41	PYDD92-19	0.56
PYDD87-12	0.32	PYDD92-01	0.29	PYDD92-20	0.61
						PYDD87-13	0.45	PYDD92-02	0.34	PYDD92-21	0.73
PYDD87-14	0.50	PYDD92-03	0.33	PYDD92-22	0.64
						PYDD87-15	0.68	PYDD92-04	0.37	PYDD92-23	0.34
PYDD87-16	0.71	PYDD92-05	0.57	PYDD92-24	0.38
						PYDD87-17	0.54	PYDD92-06	0.65	PYDD92-25	0.32
PYDD87-18	0.61	PYDD92-07	0.57	PYDD92-26	0.51
						PYDD87-19	0.54	PYDD92-08	0.36	ZJT4	0.87

From the above results, the compounds disclosed by the invention have better inhibitory effects on the activity of 2019-nCoV3CLpro enzyme than the positive control compound ZJT4, wherein the inhibitory activity of the compounds PYDD87-01, PYDD87-02, PYDD87-03, PYDD87-04, PYDD87-10, PYDD87-11, PYDD87-12, PYDD87-20, PYDD87-21, PYDD87-22, PYDD87-28, PYDD87-30, PYDD92-01, PYDD92-02, PYDD92-03, PYDD92-04, PYDD92-08, PYDD92-09, PYDD92-10, PYDD92-11, PYDD92-12, PYDD92-20, PYDD92-21, PYDD92-22, PYDD92-28, PYDD92-30 on 2019-nCoV3CLpro enzyme is 2-3 times that of ZJT 4.

Example 29: determination of anti-coronavirus Activity

Vero cells were inoculated into 96 well plates and placed in 5% CO ₂ Culturing at 37 ℃. During the cell index growth period, maintaining liquid containing test compound and positive control medicine in different dilutions is added, and 3 compound wells are set in each concentration while normal cell control wells are set. After the sample was added, the sample was cultured for 72 hours, and the cytotoxicity test of the sample was performed by the CPE method.

Inoculating Vero cells into 96-well cell culture plate, culturing at 37deg.C in 5% CO2 incubator for 24 hr, removing culture solution, adding 0.1 pfu/cell complex number of recombinant COVID-19 virus solution expressing green fluorescent protein (COVID-19 RFP), culturing at 37deg.C in 5% CO2 for 3 hr, removing virus solution, washing top surface of Vero cells with 500 μl 1×PBS for 3 times, and removing residual virus; the maintenance solution containing the test compound and the positive control agent at different dilutions was added and the culture was continued for 48h. The antiviral test of the tested sample is carried out by a CPE method, and when the pathological change degree (CPE) of the virus control group reaches 4+, the cytopathic change degree (CPE) of each group is observed.

The cells were assessed by fluorescence imaging of the cell cultures for infection with the virus and the level of intracellular viral replication. The half-toxic concentration of the sample on cells (CC 50) and the effective concentration of the drug (EC 50) to suppress 50% of the cytopathic effect were calculated by the Reed-Muench method, respectively, and the Therapeutic Index (TI) was calculated as CC50/EC 50. The results are shown in Table 2.

TABLE 2 determination of anti-coronavirus Activity

From the above results, it was found that all test compounds had outstanding activity against the COVID-19 virus. In particular, the activity against the COVID-19 virus is superior to that of the positive control compound ZJT4, and all test compounds have higher selectivity than that of the ZJT 4. These results indicate that the disclosed compounds treat diseases of coronaviridae infections with smaller doses and lower side effects.

Example 30: hERG assay

To investigate the risk of QT interval prolongation by test compounds, the effect of delayed rectifier k+ current (IKr) on important roles in ventricular repolarization was studied using HEK293 cells expressing the human ether-a-go-go related gene (hERG) channel.

The IKr induced by the depolarization stimulus given 2 seconds +50mV and the repolarization stimulus given 2 seconds-50 mV was further given using a fully automatic patch clamp system after the cells were maintained at a membrane potential of-80 mV by whole cell patch clamp method recording. After the generated current was stabilized, a test compound solution dissolved in an extracellular solution (NaCl: 137mmol/L, KCl:4mmol/L, caCl2:1.8mmol/L, mgCl2-6H2O:1mmol/L, glucose: 10mmol/L, HEPES:10mmol/L, pH 7.4.4) was applied to the cells at room temperature for 10 minutes. From the resulting IKr, the absolute value of the maximum tail current was measured using analytical software with reference to the current value of the resting membrane potential. Further, the inhibition ratio with respect to the maximum tail current before application of the test compound was calculated, and the influence of the test substance on IKr was evaluated in comparison with the vehicle-applied group (0.1% dmso solution). The results are shown in Table 3.

Table 3 average inhibition at 200. Mu. Mol/L of Compound

Numbering of compounds	Inhibition ratio (%)	Numbering of compounds	Inhibition ratio (%)
				PYDD87-01	5.8	PYDD92-02	5.5
PYDD87-02	7.0	PYDD92-03	5.8
				PYDD87-04	7.2	PYDD92-08	6.8
PYDD87-10	6.5	PYDD92-10	6.7
				PYDD87-20	6.3	PYDD92-14	5.3
PYDD87-21	6.1	PYDD92-25	5.2
				PYDD92-01	5.6	ZJT4	15.6

The IKr inhibition rate of the disclosed compounds is obviously smaller than that of ZJT4 at 200 mu mol/L, and the inhibition rate is between 0.33 and 0.46 compared with that of ZJT4, so that all the test compounds are lower in cardiotoxicity than the compound ZJT 4. Demonstrating that the disclosed compounds have greatly reduced cardiotoxicity.

Example 31: parallel artificial membrane permeation model (PAMPA) test of the disclosed compounds

Diluting the compound with a buffer solution with pH of 7.4 to 25 mug/mL; dissolving pig brain lipid extract (PBL) in dodecane to prepare 20mg/mL solution as phospholipid membrane; dropping 4 mu L of PBL solution on a polyvinyl fluoride film of a 96-hole filter plate to form a phospholipid film simulating the brain environment; 300. Mu.L/well buffer was added above the phospholipid membrane as acceptor tube, and another 96-well plate was added with 150. Mu.L/well of 25. Mu.g/mL compound solution as donor tube, three wells per drug were in parallel; overlapping the two plates to enable the phospholipid membrane to be in contact with donor liquid to form a sandwich structure, and placing the sandwich structure in a constant temperature environment at 37 ℃ for 18 hours; the solution in the 96-well filter plate was removed and transferred to a blank 96-well plate, and OD was measured at 340 nm. Experiments were performed in parallel 3 times. The permeability Pe values were calculated according to the literature (Kiyohiko S., et al, optimized conditions of bio-mimetic artificial membrane permeation assay [ J ]. Int. J. Pharm.,2001,228,181-188). The results are shown in Table 4.

TABLE 4 Artificial Membrane permeation model (PAMPA) test results

Numbering of compounds	Pe value (10) ^-6 cm/s)	Numbering of compounds	Pe value (10) ^-6 cm/s)
				PYDD87-01	10.60	PYDD92-02	10.27
PYDD87-02	9.12	PYDD92-03	6.45
				PYDD87-03	9.55	PYDD92-04	6.23
PYDD87-04	9.79	PYDD92-08	7.53
				PYDD87-10	10.33	PYDD92-09	9.66
PYDD87-11	9.64	PYDD92-10	10.32
				PYDD87-12	10.88	PYDD92-11	10.68
PYDD87-20	10.61	PYDD92-12	8.24
				PYDD87-21	10.45	PYDD92-14	8.65
PYDD87-22	10.98	PYDD92-23	6.62
				PYDD87-28	8.87	PYDD92-24	6.68
PYDD87-30	8.55	PYDD92-25	10.35
				PYDD92-01	9.26	ZJT4	1.75

The data show that the ability of the disclosed compounds to penetrate through the blood brain barrier is higher than that of a control compound ZJT4 by 3 times, wherein the ability of the compounds PYDD87-01, PYDD87-10, PYDD87-12, PYDD87-20, PYDD87-21, PYDD87-22, PYDD92-02, PYDD92-10, PYDD92-11 and PYDD92-25 to penetrate through the blood brain barrier is more than 5.8 times that of the ZJT 4. It has been reported that the novel coronavirus may enter the brain through the nasal cavity, causing long-term brain damage, so that the disclosed compounds can play an antiviral role in the brain.

Example 32: tissue distribution test

80 male CD-1 mice were randomly assigned to 5 groups, group A (16, randomly assigned to 4 groups, each group of 4, 4 mice were each given 75mg/kg of compound PYDD 87-01) by gavage, group B (16, randomly assigned to 4 groups, each group of 4, 4 mice were each given 75mg/kg of compound PYDD 87-02) group C (16, randomly assigned to 4 groups, each group of 4, 4 mice were each given 75mg/kg of compound PYDD 92-01) group D (16, randomly assigned to 4 groups, each group of 4, 4 groups of mice were each given 75mg/kg of compound PYDD 92-04) group E (16, randomly assigned to 4 groups, each group of 4 mice was given 75mg/kg of compound ZJT4 by gavage). Fasted for 12 hours before the experiment, and the water is freely drunk; unified feeding is performed 2h after administration. After administration for 0.33h, 0.75h, 5h and 9h, the mice were anesthetized, and liver, kidney and lung tissue samples were collected, and the distribution of the test substances in each tissue was determined by HPLC-MS/MS (test substances of the compounds PYDD87-01 and PYDD87-01 were prototypes, and test substances of the compounds PYDD92-01 and PYDD92-04 were ZJT 4). The results are shown in Table 5.

TABLE 5 tissue distribution of test substances after oral administration of Compound (75 mg/kg) to mice

In vivo tissue distribution experiments of mice show that after the compounds PYDD87-01, PYDD87-02, PYDD92-01 and PYDD92-04 disclosed by the invention are orally taken for 0.33h, the distribution of the substances to be tested in the liver, the lung, the kidney and the middle is larger than that of the control compound ZJT4, and unexpectedly, the distribution of the compounds disclosed by the invention in the lung of the mice at all time points is far higher than that of the compounds disclosed by the invention in the liver and the kidney, which proves that the compounds disclosed by the invention have better lung tissue distribution and are more favorable for resisting pulmonary virus infection.

While the invention has been described with reference to the preferred embodiments, it is not intended to limit the invention thereto, and it is to be understood that other modifications and improvements may be made by those skilled in the art without departing from the spirit and scope of the invention, which is therefore defined by the appended claims.

Claims

1. A kind of liquid crystal display (I) ₀ -1) a peptidomimetic derivative as depicted and pharmaceutically acceptable salts thereof:

formula (I) ₀ In the step of-1), the step of,

n ₁ selected from 0 or 1;

represented as a bond or not;

R _1a and R is _1b Each independently selected from hydrogen or C1-C8 alkyl;

R _2a and R is _2b Selected from hydrogen;

R ₃ selected from hydrogen, halogen orWherein,,

g is selected from O or Se;

R _b selected from hydrogen or C1-C8 alkyl;

R ₄ selected from hydrogen or C1-C8 alkyl;

Y ₁ Selected from the group consisting ofS or Se;

Y ₂ selected from the group consisting ofWherein,,

X ₀ selected from O, S or Se;

t ₁ selected from 1;

t ₂ selected from 0 or 1;

R ₅ selected from the group consisting ofOr the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl; wherein R is _b As defined above;

R _6a and R is _6b Each independently selected from S or NH;

R ₇ selected from hydrogen,Wherein,,

R _a selected from C1-C8 alkoxy;

R _8a and R is _8b Each independently selected from mercapto, hydrogen or hydroxy;

Y ₃ selected from hydrogen, orWherein,,

n ₂ selected from 1, 2, 3, 4;

g is selected from

Wherein,,

X ₁ selected from O or S, X ₂ And X ₃ Each independently selected from O;

R _c and R is _d Are respectively and independently selected from Na ⁺ 、Ca ²⁺ 、Mg ²⁺ Hydrogen, C1-C8 alkyl or C6-C18 aryl; or,

R _c and R is _d Is connected with P and R together _c 、R _d O which are respectively connected together form a six-membered ring;

R _e selected from C1-C8 alkyl or C1-C8 alkoxy;

R _f1 and R is _f2 Each independently selected from hydrogen;

m ₁ and m ₂ Each independently selected from 0 or 1; r is R _g1 And R is _g2 Each independently selected from C1-C8 alkyl; y is Y ₄ Selected from N, C, or CH;

when Y is ₂ Is thatAnd Y is ₁ When S is, Y ₃ Is not hydrogen;

when Y is ₄ Is N, andwhen expressed as a bond, R ₄ Absence of;

the group A is: mercapto C1-C8 alkyl,Wherein R is _a As defined above.

2. The peptidomimetic derivative according to claim 1, having the structure of formula (I) ₀ -2)：

Formula (I) ₀ -2) the substituents are as defined in formula (I) of claim 1 ₀ -1) as defined.

3. The peptidomimetic derivative according to claim 1, having the structure of formula (I) ₀ -3)：

Formula (I) ₀ -3) the substituents are as defined in formula (I) of claim 1 ₀ -1) as defined.

4. The peptoid derivative of claim 1 or 3, having the structure of formula (I) ₀ -4)：

Formula (I) ₀ -4) the substituents are as defined in formula (I) of claim 1 ₀ -1) as defined.

5. The peptidomimetic derivative according to claim 1, having the structure of formula (I) ₀ -5)：

Formula (I) ₀ -5) the substituents are as defined in formula (I) of claim 1 ₀ -1) as defined.

6. The peptidomimetic derivative according to claim 1, having the structure of formula (I) ₀ -6)：

Formula (I) ₀ -6) the substituents are as defined in formula (I) of claim 1 ₀ -1) as defined.

7. The peptidomimetic derivative according to claim 1, having the structure of formula (I) ₀ -7)：

Formula (I) ₀ -7) the substituents are as defined in formula (I) of claim 1 ₀ -1) as defined.

8. The peptidomimetic derivative according to claim 1, having the structure of formula (I) ₀ -8)：

Formula (I) ₀ -8) the substituents are as defined in formula (I) of claim 1 ₀ -1) as defined.

9. The peptoid derivative of claim 1, and pharmaceutically acceptable salts thereof, wherein said peptoid derivative comprises the following compounds:

10. a pharmaceutical composition comprising the peptidomimetic derivative according to any one of claims 1 to 9, and pharmaceutically acceptable salts thereof.

11. Use of a peptidomimetic derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the preparation of an anti-coronavirus medicament.

12. Use according to claim 11, characterized in that the virus is a covd-19 virus.