CN115806570A

CN115806570A - Novel peptide-like derivative, and pharmaceutical composition and application thereof

Info

Publication number: CN115806570A
Application number: CN202211423074.7A
Authority: CN
Inventors: 张天舒; 姜龙; 侯雯; 潘伟
Original assignee: Zhihe Shandong Pharmaceutical Factory Co ltd
Current assignee: Nanjing Zhihe Medical Technology Co ltd
Priority date: 2021-11-15
Filing date: 2022-11-15
Publication date: 2023-03-17
Anticipated expiration: 2042-11-15
Also published as: CN115806570B

Abstract

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

Description

Novel peptide-like derivative, and pharmaceutical composition and application thereof

Technical Field

The invention relates to but is not limited to the technical field of pharmaceutical chemistry, and particularly relates to a novel peptidomimetic derivative, and a pharmaceutical composition and application thereof.

Background

Coronaviruses belong to the single positive-strand RNA virus, 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, and HCoV-HKU. Coronaviruses commonly cause respiratory and intestinal diseases, neurological symptoms, and myocarditis.

In order to reduce the incidence, severity and mortality of SARS-CoV-2 infection, it is imperative to develop a variety of specific inhibitors with different mechanisms of action to treat the new coronavirus.

Disclosure of Invention

The inventor develops a novel peptide analogue derivative which can be used for preparing antiviral medicaments.

In one aspect of the present invention there is provided a compound of formula (I) ₀ -1) novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereofAcceptable salts:

formula (I) ₀ In the step (1) of (a) to (b),

n ₁ selected from 0,1,2,3, 4;

indicates bonding or not;

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

R _2a and R _2b Each independently selected from hydrogen, CF ₃ Or C1-C8 alkyl, C2-C8 alkenyl which are unsubstituted or substituted by one or more groups A;

R ₃ selected from hydrogen, halogen, hydroxyl, 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 the content of the first and second substances,

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 by 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, the first and the second end of the pipe are connected with each other,

R _a as defined aboveOf (1);

Y ₁ selected from O, S or Se;

Y ₂ is selected from

Wherein the content of the first and second substances,

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 by 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 _6b Are each independently selected from CH ₂ O, S or NH;

R ₇ selected from hydrogen, halogen, nitro, amino, CN, CF ₃ 、

R _a and R _b As defined above;

R _8a and R _8b Each independently selected from hydrogen, mercapto, halogen, nitro, amino, cyano,

Or the following groups substituted or unsubstituted by one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein the content of the first and second substances,

R _a and R _b As defined above;

Y ₃ selected from hydrogen, or

Wherein the content of the first and second substances,

n ₂ selected from 1,2,3, 4;

g is selected from

Wherein the content of the first and second substances,

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

R _c and R _d Each independently selected from the group consisting of a cation, hydrogen, or the following groups 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, the first and second electrodes may be,

R _c and R _d Are linked together with P and with R _c 、R _d The O connected with each other form a polycyclic ring together;

R _e selected from hydroxyl, 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, 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 _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 _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, it is possible to provide a device,

when Y is ₂ Is composed of

And Y is ₁ When is S, Y ₃ Is not hydrogen;

when Y is ₄ Is N, and

when it represents a bond, R ₄ Is absent;

the group A is: C1-C8 alkyl,

NR _g1 R _g2 、

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

In some embodiments, the invention provides a compound of formula (I) ₀ -2) novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

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

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

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

In some embodiments, the invention provides a compound of formula (I) ₀ -4) multiple novel 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) a polytypically peptidomimetic derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salt thereof:

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

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

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

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

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

At one endIn some embodiments, the invention provides a compound of formula (I) ₀ -8) and pharmaceutically acceptable salts thereof:

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

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

formula (I) ₁ In the step (1) of (a) to (b),

n ₁ selected from 0,1,2,3, 4;

indicates bonding or not;

or R _1a And R _1b Connected together with adjacent carbons to form a three-, four-, five-, six-or seven-membered ring;

R ₂ selected from hydrogen, C1-C8 alkyl which is substituted or unsubstituted by a radical A or

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, hydroxyl, 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 _a As defined above;

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

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

Y ₂ selected from C, N, or CH; when Y is ₂ Is N, and

when forming a bond, R ₂ Is absent;

Y ₃ selected from hydrogen, or

Wherein the content of the first and second substances,

n ₂ selected from 1,2,3, 4;

a is selected from

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

R _e selected from hydroxy, quilt groupA is the following substituted or unsubstituted group: 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 _f2 Each independently selected from hydrogen, C1-C8 alkyl substituted or unsubstituted with a group A;

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

R _g1 and R _g2 Each independently selected from hydrogen, the following groups 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 group, nitro, trifluoromethyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C6-C18 aryl, C6-C18 aryloxy; wherein R is _g1 And R _g2 As defined above.

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

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

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

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

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

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

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

formula (I) ₂ In the step (1) of (a) to (b),

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 _2b Each independently selected from hydrogen, CF ₃ Or C1-C8 alkyl, C2-C8 alkenyl which are unsubstituted or substituted by one or more groups A.

R ₃ Selected from hydrogen, halogen, hydroxyl, nitro, amino, CN, CF ₃ 、

Or the following groups substituted or unsubstituted by one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C1-C8 alkoxy, C3-C8 cycloalkyl; wherein, the first and the second end of the pipe are connected with each other,

g is selected from O or Se;

R _a selected from hydrogen, hydroxy, amino, CF ₃ Or the following groups substituted or unsubstituted by 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, optionally substituted 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 the content of the first and second substances,

R _a as defined above.

Y ₁ Selected from O, S or Se.

Y ₂ Is selected from

Wherein the content of the first and second substances,

X ₀ selected from S, or Se;

t ₁ selected from 1,2 or 3;

t ₂ is selected from 0,1,2,3 or 4 when t is ₂ When is 0, R ₇ Is absent.

R ₅ Selected from hydrogen,

R _6a and R _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 alkylaminoC1-C8 alkoxy, C3-C8 cycloalkyl; wherein the content of the first and second substances,

R _a and R _b As defined above;

R _a and R _b As defined above.

Y ₃ Is selected from H or

Wherein n is ₂ Selected from 1,2,3, 4, when Y ₃ When it is H, X ₀ Is not O;

g is selected from

Wherein the content of the first and second substances,

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

R _c and R _d Each independently selected from the group consisting of a cation, hydrogen, or the following groups 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, the first and second liquid crystal display panels may be,

R _e selected from hydroxyl, 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, C3-C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxyC6-C18 heteroaryl, C6-C18 heteroaryloxy;

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

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

R _g1 and R _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.

The group A is: C1-C8 alkyl,

NR _g1 R _g2 、

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

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

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

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

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

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

In some embodiments, the invention provides a compound of formula (I) ₂ -5) a multiple novel peptidomimetic derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salt thereof:

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

In some embodiments, the above formula (I) ₀ -1)-(I ₀ In (1) of (5) above,

represents a bond;

in some embodiments, the above formula (I) ₀ -1) and/or (I) ₀ -6)-(I ₀ In (1) of (1) to (8),

indicates bonded or not bonded; preferably, the first and second electrodes are formed of a metal,

denoted as a bond.

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

In some embodiments, the above formula (I) ₀ -1)-(I ₀ In-8), R _1a And R _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 _1b Each independently selected from hydrogen, or C1-C8 alkyl; more preferably, R _1a And R _1b One of which is hydrogen and the other is isobutyl;

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

In some embodiments, the above formula (I) ₀ -1)-(I ₀ In-8), R ₃ Selected from H, halogen, hydroxyl, 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 the content of the first and second substances,

g is selected from O or Se;

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

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

In some embodiments, the above formula (I) ₀ -1)-(I ₀ In-8), R ₄ Selected from hydrogen, or C1-C8 alkyl which is substituted or unsubstituted by one or more groups A or

Preferably, R ₄ Selected from hydrogen, or C1-C8 alkyl; wherein, the first and the second end of the pipe are connected with each other,

r is as defined above _a Selected from hydrogen, hydroxy, amino, CF ₃ Or the following groups substituted or unsubstituted by 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 In-8), 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 In (2) Y ₂ Is composed of

Wherein, X is ₀ Selected from O, S or Se;

in some embodiments, the above formula (I) ₀ -1) and/or (I) ₀ In-3) Y ₂ Is composed of

Wherein R is as defined above 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, C3-C8 cycloalkyl; preferably, R ₅ Selected from hydrogen,

Or C1-C8 alkyl which is unsubstituted or substituted by one or more radicals A; wherein R is as defined above _b Selected from hydrogen, or C1-C substituted or unsubstituted by one or more groups A8 alkyl group;

in some embodiments, the above formula (I) ₀ -1) and/or (I) ₀ In-4), Y ₂ Is composed of

Wherein R is as defined above _6a And R _6b Are each independently selected from CH ₂ O, S or NH; preferably, R _6a And R _6b Each independently selected from S, or NH;

r is as defined 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,

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,

Or the following groups substituted or unsubstituted by one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C3-C8 cycloalkyl; wherein R is as defined above _a And R _b As defined above;

t above ₁ Selected from 1,2 or 3; preferably, t ₁ Selected from 1, or 2;

t 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 In-5), Y ₂ Is composed of

Wherein the content of the first and second substances,

r is as defined above _8a And R _8b 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 _8b Each independently selected from hydrogen, mercapto, amino, cyano,

Or the following groups substituted or unsubstituted by 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 _8b Each independently selected from hydrogen, mercapto, cyano,

Wherein R is as defined above _a And R _b As defined above.

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

In some embodiments, the above formula (I) ₀ -1)-(I ₀ In-8), Y ₃ Is composed of

Wherein n is as defined 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 in the formula (I) ₀ -1)-(I ₀ In-6) is

Wherein the content of the first and second substances,

X ₁ selected from O or S;

R _c and R _d Each independently selected from the group consisting of a cation, hydrogen, or the following groups 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 _d Are linked together with P and with R ₃ 、R ₄ The O connected with each other form a polycyclic ring together; preferably, R _c And R _d Each independently selected from alkali metal cations, alkaline earth metal cations, quaternary ammonium salts, amine ions, zinc ions, and silver ions; or, R _c And R _d Are linked together with P and with R _c 、R _d The O connected with each other form a polycyclic ring together; more preferably, R _c And R _d Are each independently selected from Li ⁺ 、Na ⁺ 、K ⁺ 、Zn ⁺ 、Mg ²⁺ 、Ca ²⁺ 、Ag ⁺ Ammonium ion, or N (C) ₁ -C ₄ -alkyl groups) ₄ ⁺ (ii) a Or, R _c And R _d Are linked together with P and with R _c 、R _d The O connected with each other form a 5-7 membered ring together; further, more preferably, R _c And R _d Each independently selected from hydrogen and Na ⁺ 、Mg ²⁺ 、Ca ²⁺ Or C1-C8 alkyl which is unsubstituted or substituted by one or more radicals A; or R _c And R _d Are linked together with P and with R _c And R _d The O's connected respectively form a 5-7 membered ring.

G is in the formula (I) ₀ -1)-(I ₀ -5) and/or (I) ₀ In-7) is

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

m 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 defined above _f1 And R _f2 Each independently selected from hydrogen, or C1-C8 alkyl optionally substituted with one or more groups A; preferably, R _f1 And R _f2 Are both hydrogen, or R _f1 And R _f2 One of which is hydrogen and the other is selected from C1-C8 alkyl;

r is as defined above _e Selected from hydroxyl, 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, 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 groups 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 groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkoxy;

g is in the formula (I) ₀ -1)-(I ₀ -5) and/or (I) ₀ In-8) are

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

above X ₃ Selected from O or S;

r is as defined above _g1 And R _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 _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 _g2 Each independently selected from hydrogen, or C1-C8 alkyl optionally substituted with one or more groups A.

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

in some embodiments, the above formula (I) ₀ -1) and/or (I) ₀ -6)-(I ₀ In-8), Y ₄ Is C, N, or CH, especially when Y ₄ Is N, and

when it represents a bond, R ₄ Is absent;

the group A is: C1-C8 alkyl,

NR _g1 R _g2 、

In some embodiments, the present invention provides the above novel peptidomimetic derivatives selected from the group consisting of:

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

In some embodiments, the present invention discloses a pharmaceutical composition comprising the compound, isomer or pharmaceutically acceptable salt thereof of the present invention as an active ingredient or a main active ingredient, in combination with a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides that the above-described pharmaceutical compositions can be used for the treatment and prevention of diseases associated with antiviral disorders.

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

In a further aspect, the present invention provides in some embodiments pharmaceutical compositions containing the above for use in the treatment of any viral-induced 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, pneumonia virus b, pneumonia virus c, HIV virus, poliovirus, 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 above influenza viruses include, but are not limited to, influenza a virus, influenza b virus, and the like;

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

in some embodiments, the novel peptidomimetic derivatives of the invention can be prepared as pharmaceutical compositions for administration to a patient according to a variety of suitably selected modes of administration including systemically, e.g., orally, by inhalation, or parenterally, intravenously, intramuscularly, transdermally, or subcutaneously, and the like.

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

The compound disclosed by the invention has stronger 2019-nCoV-3CLpro inhibition effect and better anti-new coronavirus activity and higher selection index than a compound ZJT4, and has 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 lung, and is more favorable for resisting lung virus infection.

In addition, the compound disclosed by the invention has higher effect of passing through a blood brain barrier than the compound ZJT4, and has been reported that the new coronavirus can enter the brain through a nasal cavity, so that long-term brain injury is caused, and the compound disclosed by the invention can play a role in resisting the virus of the brain.

The compound can be used as an antiviral drug with a novel structure.

Defining:

as used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.

Certain compounds of the invention may exist in unsolvated forms as well as solvated forms, such as hydrated, ethanolic forms. In general, the solvated forms are equivalent to unsolvated forms and 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 are independently substituted by a substituent, which when substituted by more than one substituent, may be the same or different.

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 salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat 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 compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat 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 salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.

The term "alkyl" denotes saturated aliphatic groups, including straight and branched chain groups, alkyl groups 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" denotes aliphatic hydrocarbon groups containing unsaturated carbon-carbon double bonds, including straight and branched chain groups, alkyl groups may be substituted or unsubstituted. The carbon-carbon double bond may be one or more.

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

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

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

The term "heteroaryl" denotes a multiple atom monocyclic or fused ring group containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, in addition to having a completely 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" denotes a group wherein an alkyl group, which may be straight chain, branched or cyclic, is attached to the oxygen.

The term "hydroxy" denotes an-OH group.

The term "amino" denotes-NH ₂ A group.

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

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent, and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such bases include suspending agents, viscosity increasing agents, skin penetration enhancers, and the like.

The term "stereoisomers" refers to compounds that have the same chemical constitution, but differ in the arrangement of atoms or groups in space.

The term "solvate" means that certain compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Reference herein to a numerical range, such as "C1-C8," means that the group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and the like, up to and including 8 carbon atoms.

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

Detailed Description

A number of exemplary methods of 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 limited to any of the disadvantages of the present invention. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Certain compounds of the present invention can be used as intermediates for the preparation of other compounds of the present invention, all of which have structures determined by MS.

Various conventional dissolving agents and catalysts used in the present invention are commercially available.

Example 1: synthesis of compound ZJT1

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of Compound ZJT 1-01:

tert-butyl L-leucine (18.7g, 100mmol) was dissolved in N, N-dimethylformamide (200 mL) and 4-methoxyindole-2-carboxylic acid (22.9g, 120mmol), 1-hydroxybenzotriazole (HOBt, 14.9g, 110mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,21.1g, 110mmol) were added to the above system in this order. After the addition was complete, the system was cooled to 0 ℃ and triethylamine (21.2g, 210mmol) was added dropwise; after the addition, the temperature is raised to room temperature, the mixture is stirred for 2 hours, a large amount of water is added into the system, the mixture is extracted by ethyl acetate for 3 times, organic phases are combined, washed by 5 percent citric acid for 2 times, 5 percent sodium bicarbonate for 2 times and saturated salt water for 2 times, an organic layer is separated, dried by anhydrous sodium sulfate, filtered, decompressed and evaporated to dryness, and the remainder is purified by a silica gel column to obtain a compound ZJT1-01 (23.2 g) with the yield of 64.5 percent. ESI-MS (+): m/z =361.20.

Step 2: preparation of compound ZJT 1:

adding the compound ZJT1-01 (23.0 g, 50mmol) into dichloromethane (50 mL), cooling to about 0 ℃, then slowly adding a trifluoroacetic acid/water (10, 1, 75mL) mixed solution into the system, after the addition is finished, heating to room temperature, reacting for 1 hour, and concentrating under reduced pressure to dryness, wherein the compound ZJT1 (13.3 g) is obtained as the residue, and the yield is 87.3%. ESI-MS (-): m/z =303.14.

Example 2: synthesis of Compound ZJT2

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of Compound ZJT 2-04:

acetyl chloride (7.9g, 100mmol) and aluminum chloride (1.07g, 7.6mmol) were added sequentially to dry 1, 2-dichloroethane (250 mL), and then ethyl 5-methoxyindole-2-carboxylate (21.9g, 100mmol) was added to the mixture slowly in portions. The reaction mixture was heated at reflux for 2.5 hours. After cooling, the reaction mixture was poured onto crushed ice, made acidic with hydrochloric acid, extracted 3 times with dichloromethane, combined with dichloromethane, washed 3 times with saturated brine, dried over anhydrous sodium sulfate for the organic phase, filtered, concentrated, and purified with silica gel column as the residue 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 (13.1g, 50mmol), triethylsilane (23.3g, 400mmol) and ethyl 2, 2-trifluoroacetate (300 mL) was stirred at room temperature for 5 hours. After quenching with 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 column chromatography to give compound ZJT2-03 (4.9 g) with a yield of 39.8%. ESI-MS (+): m/z =248.12.

And step 3: preparation of compound ZJT 2-02:

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

And 3, 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 79.1% yield. ESI-MS (+): m/z =361.20.

And 4, step 4: preparation of compound ZJT 2:

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

Example 3: synthesis of compound ZJT3

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of Compound ZJT 3-04:

dissolving L-glutamic acid (29.4g, 0.2mol) in methanol (600 mL), cooling to about 0 ℃, slowly adding trimethylchlorosilane (TMSCI, 87.0g, 0.8mol), after the addition is finished, heating to room temperature, stirring overnight, and detecting by TLC to finish the reaction. Triethylamine (131.5g, 1.3 mol) and di-tert-butyl dicarbonate ((Boc) 2O,48.0g, 0.22mol) were slowly added to the system. After the addition, the reaction is carried out at room temperature, and the TLC detection shows that the reaction is finished. Filtering with diatomite, eluting with petroleum ether, concentrating the filtrate, and purifying the residue with silica gel column chromatography to obtain compound ZJT3-04 (44.7 g) with yield of 81.1%. ESI-MS (+): m/z =276.14.

Step 2: preparation of compound ZJT 3-03:

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

And step 3: preparation of compound ZJT 3-02:

dissolving a compound ZJT3-03 (25.0 g,79.5 mmol) and 10% palladium carbon (2.5 g) in acetic acid (500 mL), vacuumizing to remove air, introducing hydrogen to 5atm, reacting for about 30 hours, filtering a system by using kieselguhr, concentrating a filtrate under reduced pressure, dissolving a residue in tetrahydrofuran (200 mL), adding triethylamine (20 mL), stirring overnight at 60 ℃, adding water to the system for quenching, separating an organic phase, extracting an aqueous phase once by using dichloromethane, combining the organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating, and purifying the residue by using a silica gel column to obtain a compound ZJT3-02 (10.4 g), wherein the yield is 47.9%. ESI-MS (+): m/z =287.15.

And 4, 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 (44mL, 174.5 mmol) was added, and the reaction was stirred at room temperature for 4 hours. After TLC detection reaction, concentrating to remove methanol, adjusting to neutral with 2mol/L hydrochloric acid, extracting with ethyl acetate for 3 times, combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain compound ZJT3-01 (8.4 g), with the yield of 88.8%. ESI-MS (-): m/z =271.14.

And 5: preparation of compound ZJT 3-00:

the compound ZJT3-01 (8.0g, 29.4mmol) was added to N, N-dimethylformamide (80 mL) at room temperature, followed by the sequential addition of 1-hydroxybenzotriazole (HOBt, 4.8g, 35.3mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,6.8g, 35.3mmol) and N, O-dimethylhydroxylamine hydrochloride (3.5g, 35.3mmol), cooling to 0 ℃ and then triethylamine (3.6g, 35.3mmol) was slowly added. After the addition was completed, the reaction was carried out for 2 hours, and the reaction mixture was concentrated under high vacuum to remove N, N-dimethylformamide, and the residue was washed with ethyl acetate, 5% citric acid, 5% sodium hydrogencarbonate and saturated brine, respectively, to separate the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to give a compound ZJT3-00 (6.4 g), with a yield of 68.7%. ESI-MS (+): m/z =316.18.

And 6: preparation of compound ZJT 3:

to a tetrahydrofuran solution (150 mL) containing benzothiazole (13.5g, 100mmol) at-78 ℃, a 2mol/L n-butyllithium tetrahydrofuran solution (17 mL) was added over 20 minutes, and the mixture was stirred for 1 hour. Then, a tetrahydrofuran solution (50 mL) containing the compound ZJT3-00 (6.3 g, 20mmol) was added to the above system over 20 minutes. The reaction was carried out at-78 ℃ for 3 hours and quenched with saturated aqueous ammonium chloride. The system was concentrated to remove tetrahydrofuran, the residue was added, washed with ethyl acetate, saturated brine and water respectively, 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 is as follows:

the preparation method comprises the following steps:

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

Example 5: synthesis of Compound ZJT5

The reaction formula is as follows:

the preparation method comprises the following steps:

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

Example 6: synthesis of Compound PYDD87-01

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: synthesis of PYDD87-0101 Compound

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

Step 2: synthesis of Compound PYDD87-01

Under the protection of nitrogen, dissolving a compound PYDD87-0101 (0.34g, 0.43mmol) in acetonitrile (10 mL), adding trifluoroacetic acid (1.0 mL), heating to 60 ℃, reacting for 2 hours, concentrating the system, adding acetonitrile into the residue, concentrating to dryness again, and removing trifluoroacetic acid as much as possible; the residue was then dissolved in dichloromethane (5 mL), methyl tert-butyl ether (25 mL) was slowly added dropwise in an ice bath, the temperature was maintained and stirred for 3 hours, filtered, and the methyl tert-butyl ether was rinsed to give compound PYDD87-01 (0.08 g), yield: 26.4 percent. ESI-MS (-): m/z =684.20.

Example 7: synthesis of Compound PYDD87-02

The reaction formula is as follows:

the preparation method comprises the following steps:

dissolving a compound PYDD87-01 (0.2g, 0.3 mmol) in acetonitrile (10 mL), adding thionyl chloride (0.11g, 0.9mmol), reacting at 60 ℃ under a nitrogen atmosphere for 2 hours, cooling to 0-5 ℃, slowly adding ethanol (1 mL) and triethylamine (0.12g, 1.2mmol), continuously reacting at 60 ℃ under the nitrogen atmosphere for 2 hours, cooling to room temperature, concentrating, dissolving a product in dichloromethane, washing with water, drying an organic phase, filtering, concentrating, and performing column chromatography on a residue to obtain a compound PYDD87-02 (69.9 mg) with the yield of 31.4%. ESI-MS (+): m/z =742.26.

Example 8: synthesis of Compound PYDD87-04

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: synthesis of PYDD87-0401 Compound

Under the protection of argon, freshly distilled phosphorus oxychloride (10.0 g, 65.2mmol) is dissolved in cold dichloromethane (80 mL), then anhydrous triethylamine (13.2 g,130.4 mmol) is added, after the addition is finished, the temperature is reduced to 0-5 ℃, and then a dichloromethane solution (150 mL) dissolved with 1, 3-propylene glycol (5.0 g, 65.2mmol) is slowly added dropwise into the system. After the addition was complete, the system was stirred overnight at room temperature. The system is filtered, methylene dichloride is leached, and filtrate is concentrated to obtain the cyclic phosphoryl chloride (the compound ZJT9,8.6 g) with the yield of 84.2 percent.

And 2, step: synthesis of Compound PYDD87-04

The compound ZJT5 (0.61g, 1mmol) was dissolved in dry dichloromethane (50 mL) at 0 to 5 ℃ under a nitrogen atmosphere, and then the compound PYDD87-0401 (0.31g, 2mmol) and 1-methylimidazole (0.17g, 2mmol) were added to the system in this order with stirring. After the addition was complete, stirring was continued at room temperature for 169h and the reaction was monitored by TLC for completion. The system was concentrated, the residue was dissolved in dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate and water in that order, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated by column purification to give the compound PYDD87-04 (0.26 g) with a yield of 35.8%. ESI-MS (+): m/z =726.23.

Example 9: synthesis of Compound PYDD87-07

The reaction formula is as follows:

the preparation method comprises the following steps:

adding a compound PYDD87-01 (0.34g, 0.5 mmol) into 15ml of ethanol, cooling to 0-10 ℃, dropwise adding 5ml of aqueous solution in which sodium bicarbonate (0.08g, 1.0 mmol) is dissolved, maintaining the temperature for reaction, evaporating the ethanol at 20-30 ℃ under reduced pressure after the reaction is finished, adding 10ml of acetone, crystallizing, filtering and drying to obtain a compound PYDD87-07 (0.29 g), wherein the yield is 85.4%. ESI-MS (-): m/z =684.20.

Example 10: synthesis of Compound PYDD87-11

The reaction formula is as follows:

the preparation method comprises the following steps:

the reaction flask was charged with compound ZJT5 (0.3 g,0.5 mmol), cesium carbonate (0.33g, 1mmol), sodium iodide (0.19g, 1.25mmol), N, N-dimethylacetamide (10 mL) and water (40 mL), the system was stirred to warm to 60 deg.C, and a solution of chloromethyl dimethyl carbonate (0.09g, 0.75mmol) in N, N-dimethylacetamide (5 mL) was added. Reacting the system at 55 ℃ for 8 hours, cooling to room temperature, adding ethyl acetate, washing with saturated ammonium chloride, water and saturated salt solution in sequence, separating liquid, and drying an organic phase with anhydrous sodium sulfate; the organic phase was concentrated to dryness and the residue was purified by column chromatography to give the compound PYDD87-11 (0.14 g) with a yield of 40.1%. ESI-MS (+): m/z =694.25.

Example 11: synthesis of Compound PYDD87-12

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of Compound SM1

Synthesis reference of Compound SM1 (Pharmaceutical Research,2005, vol.22, #3, p.390-396). Chloromethyl chloroformate (5.4 g, 45mmol) was added to methylene chloride (50 mL), the temperature was lowered to 0 ℃, dimethylamine tetrahydrofuran solution (24 mL) was slowly dropped, and the reaction system was reacted at room temperature for 24 hours. Concentrating to dryness, adding dichloromethane and water, separating the organic phase, washing the organic phase with 5% NaHCO3 solution 3 times. The organic phase was concentrated to dryness to give compound SM1 (2.60 g) in 41.9% yield. ESI-MS (+): m/z =138.02.

Step 2: preparation of Compound PYDD87-12

The compound ZJT4 (0.29g, 0.5mmol), naH (24mg, 1.0 mmol), SM1 (0.21g, 1.5mmol) and potassium iodide (0.12g, 0.75mmol) were added in this order to N, N-dimethylformamide (30 mL) at room temperature. Reacting for 24 hours at 50-55 ℃, after TLC detection reaction is finished, adding ethyl acetate (200 mL) into the system, washing with water and saturated saline respectively, separating out an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and carrying out column chromatography to obtain a compound PYDD87-12 (72 mg) with the yield of 21.3%. ESI-MS (+): m/z =677.27.

Example 12: synthesis of Compound PYDD87-19

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of Compound PYDD87-1902

Referring to the procedure of the step of example 4, compound ZJT2 was used instead of compound ZJT1 to give PYDD87-1902 (3.10 g) in a yield of 75.1%. ESI-MS (+): m/z =604.25.

Step 2: preparation of Compound PYDD87-1901

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

And step 3: preparation of compound PYDD87-19

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

Example 13: synthesis of PYDD87-20 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of lithium methyl selenide

Selenium powder (0.8 g) is added into tetrahydrofuran (10 mL) under the condition of room temperature and nitrogen, then methyllithium (1.6 mol/L diethyl ether solution, 1.1 mol) is dripped into the system, and after stirring for 15 minutes, white suspension is obtained for standby.

Step 2: preparation of compound PYDD87-2003

Slowly adding N, N-dimethylformamide (30 mL) solution dissolved with 4-chloro-1H-indole-2-carboxylic acid (2.0 g,10 mmol) into the suspension of the lithium methyl selenide, heating to 120 ℃, stirring for 8 hours, then cooling to room temperature, adding methyl iodide (1.4 g,10 mmol), stirring for 1 hour, monitoring by TLC, completely reacting, and pouring the system into water. Extracting with methyl tert-butyl ether for 3 times, mixing organic phases, washing with water for 3 times, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue with a column to obtain PYDD87-2003 (0.91 g) with a yield of 35.7%. ESI-MS (+): m/z =256.00.

And step 3: preparation of PYDD87-2002 Compound

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

And 4, step 4: preparation of PYDD87-2001 Compound

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

And 5: preparation of PYDD87-20 Compound

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

Example 14: synthesis of PYDD87-21 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of benzoselenazole

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

Step 2: preparation of compound PYDD87-2101

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

And step 3: preparation of compound PYDD87-2101

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

Example 15: synthesis of Compound PYDD87-28

The reaction formula is as follows:

the preparation method comprises the following steps:

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

Example 16: synthesis of PYDD92-01 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of compound PYDD 92-0101:

under the protection of argon, lawson's reagent (2.5g, 6.2mmol) was added to a solution of compound ZJT3 (1.95g, 5 mmol) dissolved in anhydrous treated toluene (20 mL) at room temperature, the temperature was raised to 110 ℃ for 5 hours, the reaction was followed by TLC, and the reaction was cooled to room temperature. The reaction solution was filtered through a silica gel pad, the filtrate was concentrated, and the residue was subjected to silica gel column separation and purification to obtain a compound PYDD92-0101 (0.83 g) with a yield of 41.2%. ESI-MS (+): m/z =406.12.

Step 2: preparation of compound PYDD92-01

The compound PYDD92-0101 (0.8g, 1.97mmol) was dissolved in methylene chloride (10 mL), cooled to about 0 ℃ and stirred for 1 hour with trifluoroacetic acid/water (10. Concentrating under reduced pressure to remove dichloromethane, adding N, N-dimethylformamide (10 mL) into the residue, then sequentially adding diisopropylethylamine (0.2g, 1.51mmol) and O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU, 0.59g, 1.51mmol) under stirring, cooling to 0 ℃, adding a compound ZJT1 (0.47g, 1.51mmol), heating to room temperature after the addition is finished, stirring for reaction for 2 hours, distilling N, N-dimethylformamide under high vacuum after TLC detection reaction is finished, adding ethyl acetate into the residue, washing with 5% citric acid, 5% sodium bicarbonate and saturated salt water respectively, separating out an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, purifying the residue by a column to obtain a compound DD92-01 (0.61 g), and obtaining the yield of 68.4%.

Example 17: synthesis of PYDD92-02 Compound

The reaction formula is as follows:

step 1: preparation of compound PYDD 92-0201:

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

Step 2: preparation of compound PYDD92-02

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

Example 18: synthesis of PYDD92-03 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

the compound ZJT4 (0.58g, 1.0 mmol) and hydroxylamine hydrochloride (0.42g, 6 mmol) were added to ethanol (50 mL) in this order at room temperature, diisopropylethylamine (DIPEA, 0.78g,6 mmol) was added dropwise with stirring, and after completion of the addition, the mixture was heated to reflux for 8 hours. And after the TLC reaction is finished, cooling to room temperature, pouring the system into water, stirring for 1 hour, filtering, and purifying a crude product through a column to obtain a compound PYDD92-03 (0.13 g) with the yield of 22.4%. ESI-MS (+): m/z =591.23.

Example 19: synthesis of PYDD92-04 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

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

Example 20: synthesis of Compound PYDD92-08

The reaction formula is as follows:

the preparation method comprises the following steps:

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

Example 21: synthesis of PYDD92-10 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

dissolving ZJT4 (0.58g, 1.0 mmol) in 25ml methanol, cooling to-10 deg.C, charging hydrogen chloride gas to saturate, cooling to-50 deg.C, charging hydrogen sulfide gas for 10-2 hr, TLC monitoring, and reacting completely. Argon bubbling is used for removing redundant hydrogen chloride and hydrogen sulfide, methyl tert-butyl ether is added into the system, ice water is used for quickly washing the system, an organic phase is separated out, drying, filtering and concentrating are carried out, and residue is quickly purified by a column to obtain the compound PYDD92-10 (57 mg) with the yield of 9.5%. ESI-MS (+): m/z =610.21.

Example 22: synthesis of Compound PYDD92-11

The reaction formula is as follows:

the preparation method comprises the following steps:

dissolving ZJT4 (0.58g, 1.0 mmol) in 25ml isopropanol, bubbling with hydrogen sulfide gas for 15min, maintaining hydrogen sulfide environment, and stirring at room temperature for 65 hr; then, nitrogen bubbling is used for removing hydrogen sulfide gas, sodium borohydride (57mg, 1.5 mmol) is added, the temperature is raised to 80 ℃ for reaction for 2 hours, TLC monitoring is carried out, the temperature is reduced to room temperature after the reaction is finished, isopropanol is removed through decompression and concentration, and the remainder is purified through a column, so that the compound PYDD92-11 (80 mg) is obtained, and the yield is 13.5%. ESI-MS (+): m/z =594.21.

Example 23: synthesis of PYDD92-12 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

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

Example 24: synthesis of Compound PYDD92-13

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of Compound PYDD92-1303

3-mercapto-1-propylamine (9.1g, 100mmol) and triethylamine (10.1g, 100mmol) were dissolved in dichloromethane (200 mL). After stirring at room temperature for 10 minutes, di-t-butyldicarbonate (24.0 g, 110mmol) was dissolved in methylene chloride (100 mL) and gradually added dropwise to the above system. 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 PYDD92-1303 (17.5 g) in 91.4% yield. ESI-MS (+): m/z =192.10.

And 2, step: preparation of compound PYDD92-1302

PYDD92-13-SM (22.0g, 97.8mmol), the compound PYDD92-1302 (17.0g, 88.9mmol) and sodium hydrogencarbonate (7.5g, 88.9mmol) were added to tetrahydrofuran: water (7. ESI-MS (+): m/z =296.12.

And step 3: preparation of compound PYDD92-1301

Compound PYDD92-1302 (20.0 g, 67.7mmol) was dissolved in dichloromethane (100 mL), cooled to about 0 ℃, trifluoroacetic acid/water (10, 1, 55 mL) was added and stirred for 1 hour. The dichloromethane 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 81.6% yield. ESI-MS (+): m/z =196.07.

And 4, step 4: preparation of compound PYDD92-13

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

Example 25: synthesis of PYDD92-14 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

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

Example 26: synthesis of Compound PYDD92-24

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of compound PYDD92-2401

Compound ZJT3 (1.95g, 5 mmol) was dissolved in dichloromethane (10 mL), cooled to about 0 ℃, trifluoroacetic acid/water (10. Concentrating under reduced pressure to remove dichloromethane, adding N, N-dimethylformamide (40 mL) into the residue, then adding diisopropylethylamine (0.49g, 3.68mmol) and O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU, 1.22g, 3.68mmol) in sequence with stirring, cooling to 0 ℃, adding a compound ZJT2 (1.15g, 3.68mmol), raising the temperature to room temperature after the addition is finished, stirring for reaction for 2 hours, distilling N, N-dimethylformamide under high vacuum after TLC detection reaction is finished, adding ethyl acetate into the residue, washing with 5% citric acid, 5% sodium bicarbonate and saturated saline respectively, separating out an organic phase, drying anhydrous sodium sulfate, filtering, concentrating, and purifying the residue by a column to obtain a compound PYDD92-2401 (1.85 g) with the yield of 61.2%.

Step 2: preparation of compound PYDD92-24

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

Example 27: synthesis of PYDD92-25 Compound

The reaction formula is as follows:

the preparation method comprises the following steps:

step 1: preparation of compound PYDD92-2501

Compound ZJT3 (5.1g, 13.0 mmol) was dissolved in dichloromethane (100 mL), cooled to about 0 ℃, and trifluoroacetic acid/water (10. The dichloromethane was removed by concentration 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 sequentially added with stirring, the temperature was reduced to 0 ℃ and the compound ZJT1 (3.0 g,10.0 mmol) was added, after the addition was completed, the temperature was raised to room temperature, the reaction was stirred for 2 hours, after the TLC detection reaction was completed, N-dimethylformamide was distilled off under high vacuum, ethyl acetate was added to the residue, and the mixture was washed with 5% citric acid, 5% sodium bicarbonate and saturated brine, respectively, to separate the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to give the compound DD92-2501 (4.68 g) in 81.2% yield. ESI-MS (+): m/z =576.22.

Step 2: preparation of compound PYDD92-25

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

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

Example 28:2019-nCoV-3CLpro inhibition assay

And (3) determining the inhibition effect of each compound sample on the activity of 2019-nCoV3CLpro enzyme by using a 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 solution of the reaction system includes 50mM Tris pH7.3, 1mM EDTA. 2019-nCoV3CLpro enzyme and compound samples of different concentrations were added to 96-well plates, incubated at 30 ℃ for 10min, substrate added and read quickly in a microplate reader. The excitation and emission light were 340nm and 405nm, respectively. The test time was 10min and the fluorescence was read every 30 s. The final result was obtained by fitting the previous 2min readings to the reaction rate and comparing it with the control (DMSO) to calculate the inhibition rate. IC was obtained by fitting with the software GraphPad Prism 8 ₅₀ The value is obtained. The results are shown in Table 1.

TABLE 1 2019-nCoV3CLpro enzyme Activity test IC ₅₀ As a result, the

Compound (I)	IC ₅₀ (mM)	Compound (I)	IC ₅₀ (mM)	Compound (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

The results show that the compound disclosed by the invention has better inhibiting effect on the activity of 2019-nCoV3CLpro enzyme than positive control compound ZJT4, wherein the inhibiting activity of the compound 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 and PYDD92-30 on the 2019-nCoV3CLpro enzyme is 2-3 times as compared with the inhibiting activity of ZJT 4.

Example 29: determination of anti-coronavirus Activity

Inoculating Vero cells into 96-well culture plate, and adding 5% CO ₂ And cultured at 37 ℃. During the exponential growth phase of the cells, maintenance solutions containing test compounds with different dilutions and positive control drugs were added, 3 multiple wells were set for each concentration, and normal cell control wells were set at the same time. After adding the sample, the sample was cultured for 72 hours, and the cytotoxicity test of the sample was performed by the CPE method.

Further, vero cells were seeded in a 96-well cell culture plate, cultured in a 5% CO2 incubator at 37 ℃ for 24 hours, the culture solution was discarded, a virus solution of recombinant COVID-19 expressing green fluorescent protein (COVID-19 RFP) at a multiplicity of cell infection of 0.1 pfu/cell was added, the virus solution was discarded after culturing for 3 hours at 37 ℃ for 5% CO2, the apical surface of Vero cells was washed 3 times with 500. Mu.L 1 XPBS, and residual viruses were removed; adding maintenance solution containing test compound and positive control drug at different dilutions, and culturing for 48 hr. The antiviral test of the test sample is carried out by CPE method, and the degree of cytopathic effect (CPE) of each group is observed when the degree of cytopathic effect (CPE) of the virus control group reaches 4 +.

Whether cells are infected with virus and the level of intracellular viral replication is assessed by fluorescence imaging of the cell culture. The half toxic concentration of the sample on the cells (CC 50) and the effective concentration of the drug inhibiting 50% of the cytopathic effect (EC 50) 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, all the test compounds showed outstanding activity against COVID-19 virus. Especially, compared with positive control compound ZJT4, the test compound has better anti-COVID-19 virus activity, and all test compounds have higher selectivity than ZJT 4. These results indicate that the compounds disclosed in the present invention are useful for treating diseases infected by the family coronaviridae, and are administered at lower doses and with lower side effects.

Example 30: hERG assay

To investigate the risk of QT interval prolongation by test compounds, the effect of delayed rectified K + current (IKr), which plays an important role in ventricular repolarization, was studied using HEK293 cells expressing the human ether-a-go-go related gene (hERG) channel.

IKr induced upon administration of depolarizing stimulation at 2 seconds +50mV, further repolarizing stimulation at 2 seconds-50 mV, after cells were held at a membrane potential of-80 mV, was recorded by whole cell patch clamp method using a fully automated patch clamp system. After the generated current was stabilized, a test compound solution dissolved in an extracellular fluid (NaCl: 137mmol/L, KCl:4mmol/L, caCl2:1.8mmol/L, mgCl2-6H2O 1mmol/L, glucose: 10mmol/L, HEPES:10mmol/L, pH 7.4) was applied to the cells at room temperature for 10 minutes. From the obtained 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 effect of the test compound on IKr was evaluated in comparison with the medium application group (0.1% DMSO solution). The results are shown in Table 3.

TABLE 3 average inhibition of the compound at 200. Mu. Mol/L

Compound numbering	Inhibition ratio (%)	Compound numbering	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 compounds disclosed in the present invention have significantly less inhibition of IKr than ZJT4 at 200 μmol/L, between 0.33 and 0.46 compared to ZJT4, indicating that all tested compounds are less cardiotoxic than compound ZJT 4. Indicating that the compounds disclosed in the present invention have greatly reduced cardiotoxicity.

Example 31: the Compound parallel Artificial Membrane permeation model (PAMPA) test disclosed in the invention

Diluting the compound with a buffer solution with pH 7.4 to a solution of 25. Mu.g/mL; dissolving pig brain lipid extract (PBL) in dodecane to obtain 20mg/mL solution as phospholipid membrane; dripping 4 mu L of PBL solution on a polyfluortetraethylene membrane of a 96-hole filter plate to form a phospholipid membrane simulating the environment in the brain; adding 300 mu L/hole buffer solution above the phospholipid membrane as a receptor tube, adding 150 mu L/hole compound solution of 25 mu g/mL as a donor tube into another 96-hole plate, and paralleling three holes for each drug; superposing the two plates to enable the phospholipid membrane to contact donor liquid to form a sandwich structure, and placing the sandwich structure in a constant temperature environment of 37 ℃ for 18 hours; the solution was removed from the 96-well filter plate and transferred to a blank 96-well plate, and the OD was measured at 340 nm. Experiments were performed in parallel for 3 times. The permeability Pe value is calculated according to the literature (Kiyohiko S., et al. Optimized conditions of bio-electrochemical characterization evaluation [ J ]. Int. J. Pharm.,2001,228, 181-188). The results are shown in Table 4.

TABLE 4 test results of the artificial Membrane permeation model (PAMPA)

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

Example 32: tissue distribution test

80 male CD-1 mice, randomly divided into 5 groups, group A (16, randomly divided into 4 groups, each group of 4, 4 groups of mice being gavage administered 75mg/kg of the compound PYDD 87-01), group B (16, randomly divided into 4 groups, each group of 4, 4 groups of mice being gavage administered 75mg/kg of the compound PYDD 87-02), group C (16, randomly divided into 4 groups, each group of 4, 4 groups of mice being gavage administered 75mg/kg of the compound PYDD 92-01), group D (16, randomly divided into 4 groups, each group of 4, 4 groups of mice being gavage administered 75mg/kg of the compound PYDD 92-04), group E (16, randomly divided into 4 groups, each group of 4, 4 groups of mice being gavage administered 75mg/kg of the compound ZJT 4). Fasting for 12h before the experiment, and freely drinking water; meals were uniformly administered 2h after dosing. After administration for 0.33h, 0.75h, 5h and 9h, mice were anesthetized, and liver, kidney and lung tissue samples were collected, and distribution of the analyte in each tissue was measured by HPLC-MS/MS (the analyte of the compounds PYDD87-01 and PYDD87-01 was its prototype, and the analyte of the compounds PYDD92-01 and PYDD92-04 was 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

The tissue distribution test in a mouse shows 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 an object to be tested in the liver, the lung, the kidney and the middle is larger than that of a control compound ZJT4, and unexpectedly, the distribution of the compounds disclosed by the invention in the lung of the mouse at each time point is far higher than that of the liver and the kidney, which shows that the compounds disclosed by the invention have better lung tissue distribution and are more favorable for resisting lung virus infection.

Although the present invention has been described with respect to one or more embodiments thereof, it will be understood by those skilled in the art that the foregoing and various other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention.

Claims

1. A compound of formula (I) ₀ -1) novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof:

formula (I) ₀ In the step (1) of (a) to (b),

n ₁ selected from 0,1,2,3, 4;

indicates bonded or not bonded;

R _2a and R _2b Each independently selected from hydrogen, CF ₃ Or C1-C8 alkyl, C2-C8 alkenyl which is unsubstituted or substituted by one or more groups A;

R ₃ selected from hydrogen, halogen, hydroxyl, nitro, amino, CN, CF ₃ 、

g is selected from O or Se;

Wherein the content of the first and second substances,

R _a as defined above;

Y ₁ selected from O, S or Se;

Y ₂ is selected from

Wherein the content of the first and second substances,

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,

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

R ₇ selected from hydrogen, halogen, nitro, amino, CN, CF ₃ 、

R _a and R _b As defined above;

R _a and R _b As defined above;

Y ₃ selected from hydrogen, or

n ₂ selected from 1,2,3, 4;

g is selected from

Wherein the content of the first and second substances,

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

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

m ₁ and m ₂ Each independently selected from 0,1,2,3, 4; r is _g1 And R _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, it is possible to provide a device,

when Y is ₂ Is composed of

And Y is ₁ When is S, Y ₃ Is not hydrogen;

when Y is ₄ Is N, and

when it represents a bond, R ₄ Is absent;

the group A is: C1-C8 alkyl,

NR _g1 R _g2 、

2. The novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to claim 1, having the structure of formula (I) ₀ -2)：

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

3. The novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to claim 1, having the structure of formula (I) ₀ -3)：

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

4. The novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to claim 1 or 3, having the structure of formula (I) ₀ -4)：

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

5. The novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to claim 1, having the structure of formula (I) ₀ -5)：

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

6. The novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to claim 1, having the structure of formula (I) ₀ -6)：

Formula (I) ₀ The substituents in (A) to (B) are as defined in claim 1 for formula (I) ₀ -1) as defined.

7. The novel peptidomimetic derivative, tautomer, or stereoisomer of claim 1The structure of the isomer, solvate and pharmaceutically acceptable salt thereof is as shown in formula (I) ₀ -7)：

8. The novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to claim 1, having the structure of formula (I) ₀ -8)：

9. The novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof of claims 1 to 8, wherein the compounds include but are not limited to the following compounds:

10. a pharmaceutical composition comprising the novel peptidomimetic derivative, tautomer, stereoisomer, solvate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

11. Use of the novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 for the preparation of an antiviral medicament.

12. Use of the novel peptidomimetic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 10, wherein the medicament is prepared for administration to a patient according to a variety of suitably selected modes of administration including systemically, e.g., orally, inhaled or parenterally, intravenously, intramuscularly, transdermally or subcutaneously, or the like for the prevention and/or treatment of diseases caused by viruses; 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, pneumovirus b, pneumovirus c, HIV virus, poliovirus, 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.

13. The use of claim 12, wherein the influenza and coronavirus include but are not limited to: influenza A virus, influenza B virus, SARS virus, MERS virus, and COVID-19 virus.