CN115108970B - Diamide derivative and pharmaceutical application thereof - Google Patents

Diamide derivative and pharmaceutical application thereof Download PDF

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CN115108970B
CN115108970B CN202111494340.0A CN202111494340A CN115108970B CN 115108970 B CN115108970 B CN 115108970B CN 202111494340 A CN202111494340 A CN 202111494340A CN 115108970 B CN115108970 B CN 115108970B
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hydrogen
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CN115108970A (en
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杨胜勇
李琳丽
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West China Hospital of Sichuan University
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract

The invention provides a diamide derivative and pharmaceutical application thereof, belonging to the technical field of organic synthetic drugs. Specifically provided are compounds represented by formula I, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or optical isomers thereof, or deuterated compounds thereof. The compound can effectively inhibit SARS-CoV-2M pro Activity, can be used for preparing SARS-CoV-2M pro Inhibitors, which block the replication and transcription of SARS-CoV-2 virus in a patient. Preparation of SARS-CoV-2M by the Compounds of the invention pro The inhibitor, the medicine for resisting SARS-CoV-2 and the medicine for preventing and/or treating novel coronavirus pneumonia have very good application prospect.

Description

Diamide derivative and pharmaceutical application thereof
Technical Field
The present invention belongs to the field of organic synthetic medicine technology, and is especially one kind of SARS-CoV-2M medicine pro An inhibitory activity diamide derivative, and its preparation method and application are provided.
Background
In 2019, coronavirus pneumonia (covd-19, also known as novel coronavirus pneumonia) is pneumonia caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2, also known as novel coronavirus), and no clinically effective antiviral drug for preventing and treating covd-19 infection exists at present. Although interferon-alpha and anti-HIV drug lopinavir/ritonavir have been used clinically But the efficacy is still very limited and may have toxic side effects. Gilea sciences company (Gilea)d Sciences, inc.) the broad-spectrum antiviral drug, adefovir, was also being explored for the treatment of covd-19, but more data was needed to demonstrate its efficacy. Thus, there is a need to develop safe and effective anti-SARS-CoV-2 drugs.
The genomic RNA of coronavirus is about 30knt in length, has a 5 'cap structure and a 3' -poly-a tail, and contains at least 6 Open Reading Frames (ORFs). The first ORF (ORF 1 a/b) is approximately two-thirds the length of the genome, translating two polyproteins directly: a-1 frameshift exists between pp1a and pp1ab, ORF1a and ORF1 b. These polyproteins are composed of a main protease (abbreviated as M pro The method comprises the steps of carrying out a first treatment on the surface of the Also known as 3C-like protease (3 CL pro ) Processed with one or two papain-like proteases (PLPs) to convert to 16 nonstructural proteins. These nonstructural proteins are involved in the production of subgenomic RNAs, encoding four major structural proteins (envelope (E), membrane (M), spinous process (S) and nucleocapsid (N) proteins) and other auxiliary proteins to complete viral replication and invasion processes.
M pro Proteolytic cleavage of the overlapping pp1a and pp1ab multimers into functional proteins is a key step in the viral replication process. Enzymes essential for replication of viruses such as RdRp or nsp13 cannot function completely to complete replication without prior proteolytic release. Thus, inhibiting viral M pro Can prevent the generation of infectious viral particles, thereby alleviating disease symptoms.
M pro Is conserved among coronaviruses, and M among different coronaviruses pro Has some common features: the amino acids from N-terminal to C-terminal are numbered (-P4-P3-P2-P1 ∈P1'-P2' -P3 ') in paired form, with cleavage sites between P1 and P1'. In particular, M pro Unique substrate preference for glutamine at the P1 site (Leu-Gln ∈ (Ser, ala, gly)), which is absent in the host protease, suggests that viral M is targeted pro It is possible to achieve high selectivity. Thus, the absolute dependence of the virus on the correct function of this protease, combined with the lack of homologous human proteases, results in M pro Becomes an ideal antiviral target point.
Thus, it is urgentIt is necessary to develop an M capable of effectively inhibiting SARS-CoV-2 virus pro Enzymatically active pharmaceuticals.
Disclosure of Invention
The invention aims to provide a novel diamide derivative and pharmaceutical application thereof.
The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof:
wherein R is 4 Selected from hydrogen, CR 4a R 4b R 4c Substituted or unsubstituted C 1～8 Alkyl, substituted or unsubstituted 3-8 membered saturated cycloalkyl, substituted or unsubstituted 3-8 membered saturated heterocyclyl, LR 4d 、LCOOR 4f The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from C 1～8 Alkyl, halogen, C 1～8 An alkoxy group;
R 4a 、R 4b each independently selected from hydrogen, substituted or unsubstituted: c (C) 1～8 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, fused ring alkyl, heterofused ring group, said substituents being selected from halogen, hydroxy, C 1～8 Alkyl, C 1～8 An alkoxy group; alternatively, R 4a 、R 4b Connected into a ring;
R 4c selected from hydrogen, C 1～8 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl;
l is selected from C 1～3 An alkylene group;
R 4d selected from unsubstituted or substituted R 4e The substituted following groups: 5-6 membered aryl, 5-6 membered heteroaryl, R 4e Selected from halogen, C 1～8 Alkyl, C 1～8 An alkoxy group;
R 4f selected from halogen, C 1～8 Alkyl, C 1～8 An alkoxy group;
R 0 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～8 An alkyl group;
R 5 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～8 Alkyl, unsubstituted or deuterated C 1～8 Alkoxy, halogen;
w is selected from none, C 1～5 An alkylene group;
R 1 selected from hydrogen, C 1～8 Alkyl, C 1～8 Alkoxy, halogen, 5-6 membered aryl, 5-6 membered heteroaryl, 3-8 membered saturated heterocyclyl, 3-8 membered saturated cycloalkyl, NHCOR 1a ；R 1a Selected from C 1～8 Alkyl, unsubstituted or halogenated: 3-8 membered saturated heterocyclic group, 3-8 membered saturated cycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl;
Z is selected from none, C 1～5 An alkylene group;
R 2 selected from the following substituted or unsubstituted: 5-6 membered aryl, 5-6 membered heteroaryl, 3-8 membered saturated heterocyclic group, 3-8 membered saturated cycloalkyl, condensed ring alkyl, hetero condensed ring group, bicycloalkyl, hetero-linked ring group; the substituents are selected from deuterium, halogen, halogenated or unsubstituted C 1～8 Alkyl, halogenated or unsubstituted C 1～8 Alkoxy, unsubstituted or substituted by R 9 The substituted following groups: 3-8 membered saturated heterocyclic group, 3-8 membered saturated cycloalkyl group, 5-6 membered aryl group, 5-6 membered heteroaryl group, OR 11 ；R 11 Is phenyl; r is R 9 Selected from deuterium, C 1～5 Alkyl, C 1～5 Alkoxy, halogen, cyano;
m is selected from integers of 0 to 5;
R 3 selected from hydrogen, halogen, halogenated or unsubstituted C 1～8 Alkyl, halogenated or unsubstituted C 1～8 An alkoxy group;
the A ring is selected from 5-6 membered aryl, 5-6 membered heteroaryl, 3-8 membered saturated heterocyclic group, 3-8 membered saturated cycloalkyl, condensed ring alkyl and hetero condensed ring group.
Further, the structure of the compound is shown as a formula II:
wherein R is 4a Selected from hydrogen, substituted or unsubstituted C 1～5 Alkyl, the substituent is selected from halogen, hydroxy; r is R 4b Selected from hydrogen, substituted or unsubstituted: c (C) 1～8 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, fused ring alkyl, heterofused ring group, said substituents being selected from halogen, C 1～5 Alkyl, C 1～5 An alkoxy group; alternatively, R 4a 、R 4b Connected into a ring;
R 0 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～5 An alkyl group;
R 5 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～5 Alkyl, unsubstituted or deuterated C 1～5 Alkoxy, halogen;
R 1 selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen;
R 2a 、R 2b each independently selected from hydrogen, unsubstituted or substituted by R 9 The substituted following groups: 5-6 membered aryl, 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, R 9 Selected from deuterium, C 1～5 Alkyl, C 1～5 Alkoxy, halogen, cyano; alternatively, R 2a 、R 2b Are connected to form a ring, preferably a fused ring or a heterofused ring;
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 each independently selected from N, CR 10 ；R 10 Selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen.
Further, the structure of the compound is shown as a formula III-1 or a formula III-2:
wherein R is 4a Selected from hydrogen, substituted or unsubstituted C 1～5 Alkyl, the substituent is selected from halogen, hydroxy; r is R 4b Selected from hydrogen, substituted or unsubstitutedThe group: c (C) 1～8 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, fused ring alkyl, heterofused ring group, said substituents being selected from halogen, C 1～5 Alkyl, C 1～5 Alkoxy, cyano; alternatively, R 4a 、R 4b Connected into a ring;
R 5 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～5 Alkyl, unsubstituted or deuterated C 1～5 Alkoxy, halogen;
R 1 selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen;
x is selected from O, S, CO, CR 6 R 7 、NR 8 ，R 6 、R 7 、R 8 Each independently selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen.
Further, the R 4a Selected from hydrogen, substituted or unsubstituted C 1～2 Alkyl, wherein the substituent is hydroxyl; r is R 4b Selected from hydrogen, substituted or unsubstituted: phenyl, naphthyl, said substituents being selected from halogen, C 1～2 Alkyl, C 1～2 Alkoxy, cyano; alternatively, R 4a 、R 4b Is linked to be unsubstituted or substituted by R 13 A substituted ring which is a condensed ring, a 3-8 membered saturated ring or a 3-8 membered unsaturated ring, R 13 Selected from phenyl, C 1～5 Alkyl, C 1～5 Alkoxy, halogen;
R 5 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～2 Alkyl, deuterium, unsubstituted or deuterated C 1～2 Alkoxy, halogen;
R 1 selected from hydrogen, C 1～2 Alkyl, C 1～2 Alkoxy, halogen;
x is selected from O, S, CO, CR 6 R 7 、NR 8 ，R 6 、R 7 、R 8 Each independently selected from hydrogen, C 1～2 An alkyl group.
Further, the structure of the compound is shown as a formula III-3 or a formula III-4:
further, R 5 Selected from hydrogen, deuterium or CD 3 。
Further, the structure of the compound is shown as a formula IV-1 or a formula IV-2:
wherein R is 4a Selected from hydrogen, substituted or unsubstituted C 1～5 Alkyl, the substituent is selected from halogen, hydroxy; r is R 4b Selected from hydrogen, substituted or unsubstituted: 5-6 membered aryl, 5-6 membered heteroaryl, fused ring alkyl, heterofused ring group, said substituents being selected from halogen, C 1～5 Alkyl, C 1～5 An alkoxy group; alternatively, R 4a 、R 4b Connected into a ring;
R 5 selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen;
R 1 selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen;
R 2a selected from hydrogen, unsubstituted or substituted by R 9 The substituted following groups: 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclyl, R 9 Selected from deuterium, C 1～5 Alkyl, C 1～5 Alkoxy, halogen, cyano;
R 12 selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen.
Further, the R 4a Selected from hydrogen, C 1～2 Alkyl, R 4b Selected from hydrogen, substituted or unsubstituted: cyclohexyl, phenyl, naphthyl, said substituents being selected from halogen, C 1～2 Alkyl, C 1～2 An alkoxy group; alternatively, R 4a 、R 4b The rings are connected into a ring, and the ring is a condensed ring, a 3-8 membered saturated ring or a 3-8 membered unsaturated ring;
R 5 selected from hydrogen, C 1～2 Alkyl, C 1～2 Alkoxy, halogen;
R 1 selected from hydrogen, C 1～2 Alkyl, C 1～2 Alkoxy, halogen;
R 2a selected from unsubstituted or substituted by R 9 The substituted following groups: benzene ring, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclic group, R 9 Selected from deuterium, C 1～2 Alkyl, C 1～2 Alkoxy, halogen.
Further, the structure of the compound is shown as a formula IV-3 or a formula IV-4:
further, R 5 Selected from hydrogen, deuterium or CD 3 。
Further, the compound is selected from:
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the invention also provides a pharmaceutical composition which is a preparation prepared by taking the compound, or pharmaceutically acceptable salt, or stereoisomer, or optical isomer, or deuterated compound thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound, or pharmaceutically acceptable salt, or stereoisomer, or optical isomer, or deuterated compound thereof in preparing coronavirus proteolytic enzyme inhibitor; preferably, the coronavirus proteolytic enzyme is a coronavirus main protease; more preferably, the coronavirus proteolytic enzyme is SARS-COV-2M pro 。
Further, the coronavirus proteolytic enzyme inhibitor is an anti-coronavirus drug, preferably SARS-CoV-2, SARS-CoV, MERS-CoV, hcov-229E, hcoV-NL63, hcov-HKU1 or Hcov-OC43, more preferably SARS-CoV-2.
Further, the coronavirus proteolytic enzyme inhibitor is used for preventing and/or treating SARS-COV-2M pro Medicine for related diseases, SARS-COV-2M pro The disease of interest is preferably novel coronavirus pneumonitis covd-19.
Further, the coronavirus proteolytic enzyme inhibitor is capable of inhibiting SARS-COV-2M pro And/or can inhibit SARS-COV-2 infection of cells.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1～8 Alkyl refers to straight or branched chain alkyl groups containing 1 to 8 carbon atoms.
"alkylene" refers to a group after one atom of an alkyl group has been lost. For example, C 1～3 Alkylene means C 1～3 Alkyl groups lose one atom of the group.
"substituted" herein refers to the replacement of 1, 2 or more hydrogen atoms in a molecule with other different atoms or molecules, including 1, 2 or more substitutions on a co-or an ectopic atom in the molecule.
"deuterated compound" refers to a compound in which one or more hydrogens in the compound are replaced with protium.
By "pharmaceutically acceptable" is meant that the carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
"salts" are acidic and/or basic salts formed with inorganic and/or organic acids and/or bases of a compound or stereoisomer thereof, and also include zwitterionic salts (inner salts) and also include quaternary ammonium salts, for example alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of an acid or base. These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
The "pharmaceutically acceptable salt" may be the hydrochloride, sulfate, citrate, besylate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salt of the compound.
Halogen is fluorine, chlorine, bromine or iodine.
"aryl" refers to an all-carbon monocyclic or fused-polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl. The aryl group does not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be on a carbon atom on the ring with conjugated pi-electron system. Aryl groups may be substituted or unsubstituted. "5-to 6-membered aryl" refers to an aryl group having 5 or 6 ring carbon atoms.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, and the like. The heteroaryl group may be optionally substituted or unsubstituted. "5-to 6-membered heteroaryl" refers to heteroaryl groups having 5 or 6 ring atoms.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent. For example, "3-to 8-membered saturated cycloalkyl" refers to a saturated cycloalkyl group having 3 to 8 ring carbon atoms.
"heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; and the cyclic hydrocarbon carries at least one ring heteroatom (including but not limited to O, S or N). For example, the "3-to 8-membered saturated heterocyclic group" means a saturated heterocyclic group having 3 to 8 ring atoms.
"fused ring alkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.
"heterofused ring group" refers to a polycyclic heterocyclic group containing at least 1 heteroatom, wherein two rings share two adjacent carbon atoms or heteroatoms.
"Bicycloalkyl" refers to a polycyclic cycloalkyl group in which two rings are joined by a single bond.
"heterobicyclic" refers to a polycyclic heterocyclic group in which two rings are joined by a single bond.
“CD 3 "means methyl substituted with 3 deuterium.
Unless otherwise indicated, the "ring linked" as used herein includes both unsubstituted and substituted rings. For example, "R 4a 、R 4b Connected in a ring "," R 2a 、R 2b Connected into a ring.
Experimental results show that the invention providesProvides a novel coronavirus main protease M which can effectively inhibit pro Active compound can effectively block the replication and transcription of SARS-CoV-2 virus in patient, inhibit SARS-COV-2 infection in cell, and provide powerful support for resisting SARS-COV-2.
Meanwhile, the compound provided by the invention also has good in vivo safety and pharmacokinetics property; has low cardiotoxicity, and is not easy to induce acute arrhythmia or sudden death after administration.
The compound of the invention can effectively inhibit SARS-CoV-2M pro Activity, antiviral activity against SARS-CoV-2 wild-type virus strain (in vitro) and mutant virus strain (in vivo and in vitro) in vitro and in vivo.
Preparation of SARS-CoV-2M by the Compounds of the invention pro The inhibitor, the medicine for resisting SARS-CoV-2 and the medicine for preventing and/or treating novel coronavirus pneumonia have very good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 shows the inhibitory activity of Compound 113 on the enzyme activity of SARS-COV-2 MPro.
FIG. 2 shows the inhibitory activity of Compound 118 on the enzyme activity of SARS-COV-2 MPro.
FIG. 3 shows the inhibitory activity of compound 152 on SARS-COV-2 MPro.
FIG. 4 shows the enzyme activity inhibitory activity of compound 190 against SARS-COV-2 MPro.
FIG. 5 shows the results of RT-qPCR assay of compound 152 at the cellular level.
FIG. 6 shows the results of a cell viability assay for compound 152 at the cellular level.
FIG. 7 shows the results of plaque assay of compound 152 antiviral activity at the cellular level.
FIG. 8 shows the results of viral load detection in vivo experiments.
Fig. 9 shows plaque assay results of in vivo experiments.
FIG. 10 shows the results of the in vivo experiments in terms of histopathological analysis and immunohistochemical staining.
Figure 11 is animal survival and weight recording data for in vivo experiments.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The preparation operating conditions of the diamide derivative comprise:
a. ethyl formate, 80 degree
b. Pragues reagent, dichloromethane, 0 degree
c. Methanol, room temperature
d. Dessmartin oxidant, 0 degree, room temperature
e. Chiral resolution
Example 1 preparation of Compounds 84, 113 and 114
Step a: preparation of intermediate 1 ((S) -N- (1-phenethyl) carboxamide).
The raw material (S) -1-phenethylamine (2.42 g,20 mmol) is added into a round bottom flask, ethyl formate (15 mL) is added for reaction for 6 hours at 80 ℃, and then intermediate 1 is obtained after decompression concentration, white solid is directly used for the next reaction
Step b: preparation of intermediate 2 ((S) - (1-isocyanatoethyl) benzene).
Intermediate 1 (149 mg,1 mmol) was dissolved in dichloromethane (2 mL), and under ice bath, a Prague reagent (284 mg,1.2 mmol) was added, and after the addition was completed, the reaction was continued under ice bath for 30 minutes, after the TLC detection reaction was completed, intermediate 2 was obtained by concentrating under reduced pressure, and colorless oil was directly used for the next reaction.
Step c: preparation of intermediate 3 (N- ([ [1,1' -biphenyl ] -4-yl ] -2-hydroxy-N- (2-oxo-2- ((((S) -1-phenethyl) amino) -1- (pyrazin-2-yl) ethyl) propionamide)
Pyrazine-2-carbaldehyde (108 mg,1 mmol), 4-aminobiphenyl (169 mg,1 mmol) was added to a reaction flask, dissolved in methanol (2 mL), reacted at room temperature for 20 minutes, lactic acid (90 mg,1 mmol) was added, intermediate 2 (131 mg,1 mmol) was added, reacted at room temperature for 20 hours after the addition was completed, concentrated under reduced pressure after the reaction was completed, diluted with ethyl acetate (5 mL) and washed with saturated sodium bicarbonate (5 mL), dried, filtered and concentrated, and purified by column chromatography to give intermediate 3 as a yellow solid in 55% yield.
1 H NMR(400MHz,Chloroform-d)δ8.75-8.68(m,1H),8.54-847(m,2H),7.56-7.44(m,7H),7.39-7.31(m,6H),7.25-7.23(m,1H),6.09-5.82(m,1H),5.25-5.14(m,1H),4.34-4.22(m,1H),3.19-3.16(m,1H),1.55-1.50(m,3H),1.28-1.26(m,3H).
Step d: preparation of Compound 84 (N- ([ [1,1' -biphenyl ] -4-yl ] -2-oxo-N- (2-oxo-2- (((S) -1-phenylethyl) amino) -1- (pyrazin-2-yl) ethyl) propionamide)
Intermediate 3 (240 mg,0.5 mmol) was dissolved in dichloromethane (2 mL), stirred in an ice bath, dessert-martin oxidant (318 mg,0.75 mmol) was added in portions, the reaction was allowed to warm to room temperature after addition, stirring was continued for 2 hours, after completion of the reaction, diluted with dichloromethane (5 mL), extracted sequentially with saturated sodium thiosulfate (5 mL) and saturated sodium bicarbonate (5 mL), the organic phase was collected, dried, filtered, concentrated under reduced pressure and isolated by column chromatography to give compound 84 as a pale yellow solid in 65% yield.
1 H NMR(400MHz,Chloroform-d)δ8.76-8.72(m,1H),8.51-8.47(m,2H),7.82(s,1H),7.51-7.27(m,13H),7.22-7.21(m,1H),6.07-6.02(m,1H),5.21-5.12(m,1H),2.23(s,3H),1.51-1.42(m,3H).
Step e: chiral resolution of Compound 84, preparation of chiral Compounds 113 and 114
Splitting experiment:
chiral resolution instrument and model Shimadzu LC-20AT type high performance liquid chromatograph
Chiral analytical column: CHIRALPAK AD-H,250×4.6um×5 μm
Software: shimadzu workstation
Mobile phase: n-hexane (phase A) ethanol (phase B)
Flow rate: 1.0mL/min
A detector: SPD-20A
Column temperature: 30 DEG C
Injection volume: 10uL
Concentration: 1mg/mL
The detection method comprises the following steps: phase A: phase B = 50:50
Preparation experiment:
chiral preparation instrument and equipment and model: innovative LC-3000
Chiral preparation column: uniChiral AD-5H,250x4.6umx5 μm
Mobile phase: n-hexane (phase A) ethanol (phase B)
Column temperature: room temperature
Flow rate: 15.0mL/min
Detection wavelength: 210nm of
Injection volume: 3mL of
Concentration: 1mg/mL
The detection method comprises the following steps: phase A: phase B = 60:40
Experimental results:
diastereoisomer 1: compound 113 retention time (min): 7.6 40mg of white solid
Diastereoisomer 2: compound 114 retention time (min): 12.5 45mg of white solid
Compound 113: 1 H NMR(400MHz,Chloroform-d)δ8.79(s,1H),8.57-8.48(m,2H),7.77(s,1H),7.52-7.48(m,4H),7.43(t,J＝7.5Hz,2H),7.38-7.27(m,7H),7.25-7.20(m,1H),5.96(s,1H),5.17(p,J＝7.0Hz,1H),2.26(s,3H),1.45(d,J＝6.9Hz,3H).
compound 114: 1 H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.54-8.50(m,2H),7.71(s,1H),7.60-7.40(m,6H),7.40-7.27(m,4H),7.24-7.21(m,2H),6.00(s,1H),5.22-5.15(m,1H),2.25(s,3H),1.54(d,J＝6.9Hz,3H).
EXAMPLE 2 preparation of Compounds 117, 118 and 119
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The preparation operating conditions of the diamide derivative shown in the formula I comprise:
a. ethyl formate, 80 degree
b. (1) Prague reagent, dichloromethane, 0 degree
(2) Phosphorus oxychloride, triethylamine, dichloromethane, -40 degree
c. Methanol, room temperature
d. Dessmartin oxidant, 0 degree, room temperature
e. Chiral resolution
Step a: preparation of intermediate 1 ((S) -N- (1-phenylpropyl) carboxamide).
The starting material (S) -1-amphetamine (2.7 g,20 mmol) was added to a round bottom flask, followed by ethyl formate (15 mL), reacted at 80℃for 6 hours, and then concentrated under reduced pressure to give intermediate 1 as a white solid which was directly used in the next reaction.
Step b: preparation of intermediate 2 ((S) - (1-isopropyl) benzene).
Intermediate 1 (1.49 g,10 mmol) was dissolved in dichloromethane (10 mL), and a bergs reagent (2.86 g,12 mmol) was added under ice bath, and after the addition was completed, the reaction was continued under ice bath for 30 minutes, after TLC detection was completed, the reaction was concentrated under reduced pressure to obtain a mixture containing intermediate 2, which was directly used for the next reaction.
Or adding the intermediate 1 (1.49 g,10 mmol) into a 100mL round bottom flask, adding dichloromethane (20 mL), placing in a low-temperature reactor at-40 ℃, adding triethylamine (3.03 g,30 mmol) after 10min, cooling for 10min, slowly dropwise adding phosphorus oxychloride (15 mmol), and keeping at-40 ℃ for continuous reaction for 3h. After the reaction, the reaction mixture was poured into ice water (100 mL), extracted, and the organic phase was dried and concentrated to obtain intermediate 2.
Step c: preparation of intermediate 3N- (diphenyl [ b, d ] benzofuro-3-yl) -2-hydroxy-N- (2-oxo-2- (((S) -1-phenylpropyl) amino) -1- (pyridin-3-yl) ethyl) propionamide
Pyridine-3-carbaldehyde (107 mg,1 mmol) was added to a reaction flask, followed by methanol (107 mg,1 mmol) and 4-aminobiphenyl (169 mg,1 mmol) and lactic acid (90 mg,1 mmol) were added thereto, followed by intermediate 2 (131 mg,1 mmol) and reaction at room temperature for 20 hours, respectively, and after completion of the reaction, ethyl acetate (20 mL) was diluted and washed with saturated sodium hydrogencarbonate (5 mL), dried, filtered and concentrated, and purified by column chromatography to give 294mg of intermediate 3 as a yellow solid in 58% yield.
MS(ESI)m/z:508.2[M+H] + .
Step d: preparation of Compound 117N- (benz [ b, d ] benzofuran-3-yl) -2-oxo-N- (2-oxo-2- (((S) -1-phenylpropyl) amino) -1- (pyridin-3-yl) ethyl) propanamide
Intermediate 3 (255 mg,0.5 mmol) was dissolved in dichloromethane (10 mL), stirred under ice bath, dessert-martin oxidant (318 mg,0.75 mmol) was added in portions, after addition, the reaction was allowed to warm to room temperature, stirred for 2 hours, after completion of the reaction, diluted with dichloromethane (10 mL), extracted sequentially with saturated sodium thiosulfate (5 mL) and saturated sodium bicarbonate (5 mL), the organic phase was collected, dried, filtered, concentrated under reduced pressure and isolated by column chromatography to give compound 117 (151 mg) as a pale yellow solid in 60% yield.
1 H NMR(400MHz,Chloroform-d)δ8.49-8.35(m,2H),7.92-7.81(m,1H),7.75-7.61(m,1H),7.59-7.26(m,8H),7.25-6.84(m,4H),6.65-6.45(m,1H),6.21-6.10(m,1H),5.03-4.88(m,1H),2.27-2.11(m,3H),1.93-1.76(m,2H),0.98-0.84(m,3H).
Step e: chiral resolution of compound 117 to prepare chiral compounds 118 and 119
Resolution experiment conditions: same as in example 1
Resolution results:
compound 118: 1 H NMR(400MHz,Chloroform-d)δ8.50-8.47(m,2H),7.87(d,J＝7.7Hz,1H),7.68(d,J＝8.2Hz,1H),7.54-7.45(m,3H),7.42-7.32(m,6H),7.24(s,1H),7.08-7.05(m,1H),6.88(d,J＝6.9Hz,1H),6.41(d,J＝7.8Hz,1H),6.16(s,1H),4.95(q,J＝7.5Hz,1H),2.17(s,3H),1.83(p,J＝7.2Hz,2H),0.86(t,J＝7.4Hz,3H).
compound 119: 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H),8.39(d,J＝6.1Hz,1H),7.86(d,J＝7.6Hz,1H),7.69(d,J＝8.1Hz,1H),7.53-7.44(m,3H),7.34-7.26(m,5H),7.16-7.14(m,2H),7.04(s,1H),6.94(dd,J＝7.9,4.8Hz,1H),6.34(d,J＝7.6Hz,1H),6.16(s,1H),4.96(q,J＝7.5Hz,1H),2.21(s,3H),1.95-1.81(m,2H),0.97(t,J＝7.4Hz,3H).
example 3 preparation of Compound 149
Step a: preparation of Compound 149N- (dibenzofuran-3-yl) -2-oxo-N- ((R) -2-oxo-2- (((S) -1-phenylpropyl) amino) -1- (pyridin-3-yl) ethyl) propionamide
Compound 118 (101 mg,0.2 mmol) was dissolved in dichloromethane (5 mL), 4M hydrogen chloride dioxane solution (0.1 mL,0.4 mmol) was added with stirring at room temperature, stirring was continued for 2 hours, the precipitate was filtered off, the filter cake was washed with petroleum ether, and the compound 149 was obtained as a yellow solid in 65% yield
1 H NMR(400MHz,DMSO-d 6 )δ8.91(d,J＝8.3Hz,1H),8.81(s,1H),8.60(d,J＝5.3Hz,1H),8.09(d,J＝7.7Hz,1H),8.03(d,J＝8.1Hz,1H),7.99-7.90(m,1H),7.73(s,1H),7.68(d,J＝8.3Hz,1H),7.65-7.58(m,1H),7.58-7.50(m,1H),7.45-7.38(m,1H),7.38-7.29(m,4H),7.26-7.22(m,1H),7.20-7.10(m,1H),6.42(s,1H),4.80(q,J＝7.8Hz,1H),2.20(s,3H),1.75-1.53(m,2H),0.67(t,J＝7.2Hz,3H).
EXAMPLE 4 preparation of Compound 152
Step a: preparation of intermediate 1 (S) -N- (1- (4-fluorophenyl) ethyl) carboxamide.
The starting material (S) -1- (4-fluorophenyl) ethylamine (2.8 g,20 mmol) was added to a round bottom flask, followed by ethyl formate (15 mL) and after reaction at 80℃for 6 hours, intermediate 1 was obtained after concentration under reduced pressure as a white solid and was used directly in the next reaction.
Step b: preparation of intermediate 2 (S) -1-fluoro-4- (1-isocyanatoethyl) benzene.
Intermediate 1 (1.67 g,10 mmol) was dissolved in dichloromethane (10 mL), and a bergs reagent (2.86 g,12 mmol) was added under ice bath, and after the addition was completed, the reaction was continued under ice bath for 30 minutes, after TLC detection was completed, the reaction was concentrated under reduced pressure to obtain a mixture containing intermediate 2, which was directly used for the next reaction.
Or adding the intermediate 1 (1.67 g,10 mmol) into a 100mL round bottom flask, adding dichloromethane (20 mL), placing in a low-temperature reactor at-40 ℃, adding triethylamine (3.03 g,30 mmol) after 10min, cooling for 10min, slowly dropwise adding phosphorus oxychloride (15 mmol), and keeping at-40 ℃ for continuous reaction for 3h. After the reaction, the reaction mixture was poured into ice water (100 mL), extracted, and the organic phase was dried and concentrated to obtain intermediate 2.
Step c: preparation of intermediate 3-deuterated-3-pyridine formaldehyde
3-Pyridinecarboxaldehyde (40 g,374 mmol) was dissolved in 100mL of deuterated methanol, and sodium borodeuteride (1.57 g,374 mmol) was added in portions and stirred at room temperature after the addition. After the TLC detection reaction is finished, adding ammonium chloride solution to quench the reaction, and separating and purifying by column chromatography to obtain deuterated 3-pyridine methanol (37 g). Deuterated 3-pyridinemethanol (37 g,333 mmol) was dissolved in 400mL of methylene chloride, and dessert-martin oxidant (141 g,333 mmol) was added in portions, and stirred at room temperature for 3 hours after the addition. After the TLC detection was completed, saturated sodium thiosulfate and saturated sodium carbonate were added, and extracted with dichloromethane. Combining the organic phasesDrying, filtering and spin drying to obtain an intermediate 3, and repeating the steps to obtain the intermediate 3 with high deuteration rate. 1 H NMR(400MHz,CDCl 3 )δ9.17-9.05(m,1H),8.86(dd,J＝4.8,1.7Hz,1H),8.19(dt,J＝7.9,1.9Hz,1H),7.50(ddd,J＝7.9,4.8,0.8Hz,1H).MS(ESI)m/z:109.1[M+H] + .
Step d: preparation of intermediate 4N- (dibenzofuran-3-yl) -2-hydroxy-N- (2-oxo-2- (((S) - (1- (4-fluorophenyl) ethyl) amino) -1- (pyridin-3-yl) ethyl) propanamide
Pyridine-3-carbaldehyde (107 mg,1 mmol) was added to a reaction flask, followed by methanol (107 mg,1 mmol) and 4-aminobiphenyl (169 mg,1 mmol) and lactic acid (90 mg,1 mmol) were added thereto, followed by intermediate 2 (131 mg,1 mmol) and reaction at room temperature for 20 hours, respectively, and after completion of the reaction, ethyl acetate (20 mL) was diluted and washed with saturated sodium hydrogencarbonate (5 mL), dried, filtered and concentrated, and then purified by column chromatography to give 317mg of intermediate 4 as a yellow solid in 62% yield.
MS(ESI)m/z:512.2[M+H] + .
Step e: preparation of Compound 152
Intermediate 4 (256 mg,0.5 mmol) was dissolved in dichloromethane (10 mL), stirred in an ice bath, dessert-martin oxidant (318 mg,0.75 mmol) was added in portions, the reaction was continued for 2 hours after the addition was completed, diluted with dichloromethane (10 mL), then extracted sequentially with saturated sodium thiosulfate (5 mL) and saturated sodium bicarbonate (5 mL), the organic phase was collected, dried, filtered, concentrated under reduced pressure and separated by column chromatography to give compound 152 and its diastereomer mixture (153 mg) as a pale yellow solid in 60% yield. Further chiral resolution to obtain a compound 152, wherein the resolution experimental conditions are as follows: as in example 1. 1 H NMR(400MHz,CDCl 3 )δ8.57-8.39(m,2H),7.87(d,J＝7.6Hz,1H),7.70(d,J＝8.1Hz,1H),7.55-7.46(m,3H),7.43-7.26(m,4H),7.07(q,J＝7.0,5.4Hz,3H),6.93(brs,1H),6.28(d,J＝7.1Hz,1H),5.18(p,J＝6.9Hz,1H),2.19(s,3H),1.47(d,J＝6.9Hz,3H).
EXAMPLE 5 preparation of Compound 187
Intermediate 2 was prepared as in example 4, steps a and b.
Step c: preparation of intermediate 3 (N- (dibenzo [ b, d ] furan-3-) -1- (pyridin-3-yl) ethan-1-imine).
Dibenzo [ b, d]Furan-3-amine (1.91 g,10 mmol), 3-acetylpyridine (1.21 g,10 mmol),Molecular sieve and catalytic amount of titanium tetrachloride are dissolved in 100mL of 1, 2-dichloroethane, reflux reaction is carried out for 24h, after TLC detection reaction is finished, filtration is carried out, filtrate is concentrated to obtain intermediate 3, brown solid is directly used in the next step. />
Step d: preparation of intermediate 4 (N- (dibenzo [ b, d ] furan-3-yl) -N- (2- (((S) -1- (4-fluorophenyl) ethyl) amino) -2-oxo-1- (pyridin-3-yl) ethyl) -2-hydroxypropionamide)
Intermediate 3 (284 mg,1 mmol) was added to the reaction flask, lactic acid (90 mg,1 mmol) was added, dissolved in methanol (2 mL), and reacted at room temperature for 30 minutes, and intermediate 2 (131 mg,1 mmol) was added and reacted at room temperature for 20 hours. After the TLC detection reaction is finished, concentrating under reduced pressure, separating and purifying by column chromatography to obtain an intermediate 4(133 mg) as a yellow solid, 25% yield, MS (ESI) m/z:526.2[ M+H ]] + .
Step e: preparation of Compound 187
Intermediate 4 (128 mg,0.25 mmol) was dissolved in dichloromethane (2 mL), stirred in an ice bath, dessert-martin oxidant (128 mg,0.3 mmol) was added in portions, the reaction was allowed to warm to room temperature after completion of the addition, stirring was continued for 2 hours, after completion of the reaction, diluted with dichloromethane (5 mL), then extracted sequentially with saturated sodium thiosulfate (5 mL), saturated sodium bicarbonate (5 mL), the organic phases were combined, dried, filtered, concentrated under reduced pressure and separated by column chromatography to give compound 187 and a mixture of its diastereomers (85 mg) as a pale yellow solid in 65% yield. Further chiral resolution to obtain a compound 187, resolution experimental conditions: as in example 1. 1 H NMR(400MHz,Chloroform-d)δ8.74(d,J＝2.6Hz,1H),8.60(dd,J＝4.8,1.5Hz,1H),7.93(dd,J＝13.7,7.8Hz,2H),7.82(ddd,J＝8.1,2.7,1.6Hz,2H),7.58(d,J＝8.3Hz,1H),7.51(ddd,J＝8.3,7.2,1.3Hz,1H),7.43-7.28(m,4H),7.14(td,J＝7.5,1.2Hz,1H),7.07(ddd,J＝11.0,8.1,1.2Hz,1H),6.94(d,J＝8.0Hz,1H),5.40(p,J＝7.1Hz,1H),2.20(s,3H),1.55(d,J＝6.9Hz,6H).
EXAMPLE 6 preparation of Compound 190
Intermediate 2 was prepared as in example 4, steps a and b.
Step c: intermediate 3 (1- (pyridin-3-yl) ethan-1-one-2, 2-d 3 ) Is prepared by the following steps.
3-Acetylpyridine (1.21 g,10 mmol) was dissolved in 15mL of dioxane solvent, 15mL of heavy water was added, pyrrolidine (71 mg,1 mmol) was added, and after stirring at room temperature for 12 hours, water (100 mL) was added and extracted with ethyl acetate (2X 10 mL). The organic phases were combined, washed with water and brine, dried, filtered and concentrated to afford intermediate 3.
Step d: preparation of intermediate 4 deuterated (N- (dibenzo [ b, d ] furan-3-) -1- (pyridin-3-yl) ethan-1-imine).
The starting materials dibenzo [ b, d]Furan-3-amine (1.91 g,10 mmol), intermediate 3 (1.24 g,10 mmol),Molecular sieve and catalytic amount of titanium tetrachloride are dissolved in 100mL of 1, 2-dichloroethane, reflux reaction is carried out for 24h, after TLC detection reaction is finished, filtration is carried out, filtrate is concentrated to obtain intermediate 4, brown solid is directly used in the next step.
Step e: preparation of intermediate 5 deuterated (N- (dibenzo [ b, d ] furan-3-yl) -N- (2- (((S) -1- (4-fluorophenyl) ethyl) amino) -2-oxo-1- (pyridin-3-yl) ethyl) -2-hydroxypropionamide)
Intermediate 4 (289 mg,1 mmol) was added to a reaction flask, lactic acid (90 mg,1 mmol) was added, dissolved in methanol (2 mL), and reacted at room temperature for 30 minutes, and intermediate 2 (131 mg,1 mmol) was added thereto, followed by reaction at room temperature for 20 hours. After TLC detection was completed, the reaction was concentrated under reduced pressure and purified by column chromatography to give intermediate 5 (106 mg), a yellow solid, 20% yield, MS (ESI) m/z:529.2[ M+H ] ] + .
Step e: preparation of Compound 190
Intermediate 4 (100 mg,0.19 mm)ol) was dissolved in dichloromethane (2 mL), stirred in an ice bath, dessert-martin oxidant (107 mg,0.25 mmol) was added in portions, after addition was allowed to cool to room temperature, stirring was continued for 2 hours, after completion of the reaction, diluted with dichloromethane (5 mL), extracted sequentially with saturated sodium thiosulfate (5 mL), saturated sodium bicarbonate (5 mL), the organic phases were combined, dried, filtered, concentrated under reduced pressure and separated by column chromatography to give compound 190 and its mixture of diastereomers (70 mg) as a pale yellow solid in 71% yield. Further chiral resolution to obtain a compound 190, resolution experimental conditions: as in example 1. 1 H NMR(400MHz,Chloroform-d)δ8.71(s,1H),8.57(s,1H),7.93(dd,J＝13.9,7.8Hz,2H),7.77(dd,J＝8.2,2.2Hz,1H),7.59(d,J＝8.3Hz,1H),7.56-7.46(m,1H),7.38(t,J＝7.5Hz,1H),7.36-7.27(m,4H),7.05(t,J＝8.6Hz,2H),6.78(d,J＝7.5Hz,1H),5.21(p,J＝7.0Hz,1H),2.18(s,3H),1.52(d,J＝7.0Hz,3H).
EXAMPLE 7 preparation of Compound 193
Step a: preparation of intermediate 1 (2-bromo-2- (pyridin-3-yl) acetic acid ethyl ester).
3-pyridine ethyl acetate (1.65 g,10 mmol) was dissolved in tetrahydrofuran, placed in an ice bath, DBU (1.67 g,11 mmol) was added under nitrogen protection, stirred at room temperature for 30min, then stirred at-78 ℃, carbon tetrabromide (3.32 g,10 mmol) in tetrahydrofuran was slowly added dropwise, and the reaction was continued for 1-2 hours under heat preservation. After the TLC detection reaction was completed, saturated ammonium chloride was added to quench, and after the organic phase was concentrated, ethyl acetate was diluted, extracted, the organic phase was dried, filtered and intermediate 1 (1.71 g) was concentrated, and the yield was 70% and used directly in the next reaction.
Step b: preparation of intermediate 2 (ethyl 2- (dibenzo [ b, d ] furan-3-ylamino) -2- (pyridin-3-yl) acetate).
Intermediate 1 (1.71g,7 mmol) in tetrahydrofuran, triethylamine (784 mg,7.7 mmol) was added, dibenzo [ b, d]Furan-3-amine (1.3 g,7 mmol) was reacted overnight at 60 ℃ under nitrogen. After TLC detection reaction, the reaction solution was concentrated, and column chromatography was performed to obtain intermediate 2 (1.22 g), yield 50%, MS (ESI) m/z 347.1[ M+H ]] + .
Step c: preparation of intermediate 3 (2- (dibenzo [ b, d ] furan-3-ylamino) -2- (pyridin-3-yl) acetic acid).
Intermediate 2 (1.22 g,3.5 mmol) was dissolved in methanol/tetrahydrofuran solution (10 mL/10 mL) and 2mL of 2M sodium hydroxide solution was added and reacted at room temperature for 2 hours. After the TLC detection reaction was completed, the pH was adjusted to 5-6 with dilute hydrochloric acid, followed by extraction with ethyl acetate, and the organic phases were combined, dried, filtered and concentrated to give intermediate 3 (1.07 g), 95% yield, which was used directly in the next reaction.
Step d: preparation of intermediate 4 (2- (dibenzo [ b, d ] furan-3-ylamino) -2- (pyridin-3-yl) acetic acid).
Intermediate 3 (159 mg,0.5 mmol) was dissolved in dichloromethane and (S) -N-methyl-1-phenylethane-1-amine (88 mg,0.65 mmol), HATU (275 mg,0.75 mmol), DIPEA (136 mg,1.05 mmol) were added sequentially and reacted overnight at room temperature. After the TLC detection reaction is finished, saturated ammonium chloride and saturated sodium bicarbonate are sequentially used for extraction, organic phases are combined, dried, filtered and concentrated, and column chromatography separation and purification are carried out, thus obtaining intermediate 4 (175 mg) with the yield of 80%. MS (ESI) m/z 436.2[ M+H ] ] + .
Step e: preparation of intermediate 5 (2-oxopropionyl chloride).
Pyruvic acid (352 mg,4 mmol) was dissolved in 5mL of dichloromethane, oxalyl chloride (508 mg,4 mmol) was added under ice bath stirring, 1 drop of DMF was stirred at room temperature for 3 hours to obtain the final product, which was directly used for the next reaction.
Step f: preparation of compound 193 (N- (dibenzo [ b, d ] furan-3-yl) -N- (2- (methyl ((S) -1-phenylethyl) amino) -2-oxo-1- (pyridin-3-yl) ethyl) -2-oxopropanamide).
Intermediate 4 (175 mg,0.4 mmol) was dissolved in 5mL of dichloromethane, triethylamine (60 mg,0.6 mmol) was slowly added under ice-bath stirring, and the dichloromethane solution of intermediate 5 was slowly added dropwise to the reaction solution, followed by stirring at room temperatureAfter stirring for 2 hours, the reaction mixture was concentrated and separated by column chromatography to give compound 193 and its diastereomer (163 mg) as a pale yellow solid in 80% yield. Further chiral resolution gives compound 193, resolution experimental conditions: as in example 1. 1 H NMR(400MHz,DMSO-d 6 )δ8.78(d,J＝2.1Hz,1H),8.57(d,J＝5.2Hz,1H),8.12(m,2H),7.99(d,J＝8.4Hz,1H),7.79-7.67(m,2H),7.62-7.51(m,2H),7.42(t,J＝7.2Hz,2H),7.36-7.19(m,4H),7.18-7.12(m,1H),6.74(s,1H),5.92(q,J＝7.1Hz,1H),2.60(s,3H),2.28(s,3H),1.40(d,J＝7.1Hz,3H).
Other target compounds of the present invention were prepared by the method of examples 1-7. The structure and characterization data of the resulting target compounds are shown in table 1.
TABLE 1 Structure and characterization data for the compounds of the invention
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The beneficial effects of the compounds of the invention are demonstrated below by experimental examples.
Experimental example 1 Compound pair M of the invention pro Testing of enzyme Activity inhibition level
(1) Experimental method
Recombinant SARS-CoV-2M pro (final concentration 750 nM) was mixed with serial dilutions of each compound in 25. Mu.L assay buffer (20 mM Tris-HCl, pH 7.5, 150mM NaCl,1mM EDTA,2mM DTT) and incubated for 10 min. The reaction was initiated by adding 25. Mu.L of fluorogenic substrate (MCA-AVLQ ∈ SGFR-Lys (Dnp) -Lys-NH 2) at a final concentration of 20. Mu.M and measuring the fluorescent signal at 320nm (excitation)/405 nm (emission) with a microplate reader. The Vmax of the reactions with different concentrations of compound added and the Vmax of the reactions with DMSO added were calculated and used to generate IC 50 A curve. anti-SARS-CoV-2M was measured at 9 concentrations and 3 independent replicates for each compound pro Is of (2) 50 Values. All experimental data were analyzed using GraphPad Prism software.
(2) Experimental results
Compound of table 2 vs SARS-COV-2M Pro Is effective in inhibiting the activity of enzyme activity
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As can be seen from Table 2 and FIGS. 1 to 4, the compounds of the present invention are effective in inhibiting SARS-CoV-2M Pro In particular compounds 42, 84, 86-96, 99, 104, 109-111, 113, 115, 117-118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148-161, 166-168, 175, 177-181, 186-192, 196, for SARS-CoV-2M Pro Is of (2) 50 Are all below 0.1. Mu.M. The compounds of the present invention can be used to prepare SARS-CoV-2M Pro Inhibitors, medicaments for resisting novel coronaviruses and medicaments for preventing and/or treating novel coronavirus pneumonia.
Experimental example 2: toxicity test of Compounds on Vero E6 cells
(1) Experimental method
Cytotoxicity assessment of compounds was performed using Vero E6 cells. The specific experimental scheme is as follows: vero E6 cells were grown at a cell density of 2X 10 4 Cells/well, 100. Mu.L/well seeded in 96-well plates at 37℃with 5% CO 2 Incubators were incubated overnight. The next day, 200 μl of drug-containing medium was added per well, the compound was diluted 5-fold in gradient at 200 μΜ as the initial concentration, 6 gradients were added, 3 duplicate wells were set for each concentration, and negative and blank controls without drug were set for each set of experiments. After 72h of drug treatment, cell viability was measured using CCK-8 kit, and toxicity and cell half-toxicity concentration (CC 50 ) Values. All experimental data were analyzed using GraphPad Prism software.
(2) Experimental results
TABLE 3 toxicity of the inventive compounds on Vero E6 cells
Compounds of formula (I) CC 50 (μM)
117 >500
130 >500
132 >500
126 >500
138 >500
146 103.8
115 >500
122 >500
118 >500
175 >500
178 >500
84 >500
152 >500
195 >500
As can be seen from Table 3, the compounds of the present invention have very low toxicity to Vero E6 cells.
Experimental example 3: in vivo pharmacokinetic profile assessment of Compounds on rats
(1) Dosing regimen
Male Sprague-Dawley (SD) rats 66, body weight 200-230g; 6 male beagle dogs with weight of 9-12kg; male Institute of Cancer Research (ICR) 6 animals, 18-20g in weight. All animals were randomly grouped, 3 per group, and the series of test compounds were administered as gastric (p.o.), venous (i.v.), and intraperitoneal (i.p.) separately according to the following table 4 protocol. Fasted for 12 hours before the experiment, and the water is freely drunk. Unified feeding is performed 2h after administration.
The intragastric, intravenous and intraperitoneal administration solutions were formulated in DMSO/HS15/NaCl (5/3/92, v/v/v). The drug was administered at the dosing amounts shown in table 4, the dosing times were recorded, and blood was collected via the jugular vein or other suitable means at the time points set forth above, with about 0.20mL of each sample taken, heparin sodium anticoagulated, and placed on ice after collection. And the plasma was centrifuged within 1 hour (centrifugation conditions: 6800g,6 minutes, 2-8 ℃). The plasma samples were stored in a-80 ℃ freezer prior to analysis. The grouping and bleeding time points are shown in table 4, with 3 animals at each time point.
In vivo pharmacokinetic profile evaluation of the compounds of Table 4 on rats
(2) Experimental results
Principal pharmacokinetic parameters of the compounds of Table 5
The present invention conducted pharmacokinetic studies on compounds 84, 178, 175, 146, 115, 122, 117, 138, 130, 132 and 126. Wherein, the oral exposure of compound 84 was 2479h ng/mL and the bioavailability was 35.4%. The oral exposure of compound 178 was 1782h ng/mL and the bioavailability was 20.4%. The oral exposure of compound 175 was 509.61h ng/mL and the bioavailability was 10.11%. Compound 146 had an oral exposure of 126.7047h ng/mL and a bioavailability of 5.63%. The oral exposure of compound 115 was 119.7460h ng/mL and the bioavailability was 4.07%. Compound 122 was orally exposed to 85.4325h ng/mL with a bioavailability of 3.77%. The oral exposure of compound 117 was 4310.2917h ng/mL and the bioavailability was 58.44%. Compound 138 was orally exposed at 633.65h ng/mL with a bioavailability of 10.81%. The oral exposure of compound 130 was 231.59h ng/mL and the bioavailability was 4.59%. The oral exposure of compound 132 was 75.915h ng/mL and the bioavailability was 2.51%. The oral exposure of compound 126 was 1556.565h ng/mL with a bioavailability of 36.12%.
Table 6 major pharmacokinetic parameters of compound 152 in SD rats, ICR mice and beagle dogs
Experimental results show that compound 152 of the present invention has good pharmacokinetics in SD rats, ICR mice and beagle dogs.
Experimental example 4: experiment of Effect of Compound 113 on hERG Potassium ion channel
(1) Purpose of experiment
Rapid activation of human delayed rectifier outward potassium current (IKr) is mediated primarily by hERG ion channels, involved in human cardiomyocyte repolarization. Blocking this current with drugs will lead to the clinical appearance of QT interval prolongation syndrome, which is prone to induce acute arrhythmias and even sudden death. The experimental example uses a manual patch clamp method to test the effect of compound 113 on hERG potassium current on stable cell lines transfected with hERG potassium channels, thereby determining whether the test substance has an inhibitory effect on hERG ion channels.
(2) Experimental method
After HEK-293-hERG cells are subcultured to a proper state, digestion separation is carried out by using pancreatin and the cells are stored in a centrifuge tube, supernatant is discarded after centrifugation, the cells are resuspended for standby by using extracellular fluid, and before patch clamp recording, the cells are dripped into a culture dish to ensure that the cells have a certain density and are in a single separation state.
hERG current was recorded using whole cell patch clamp technique. The cell suspension was taken and placed in a small petri dish on an inverted microscope stage. After the cells are attached, the extracellular fluid is used for perfusion, and the flow rate is 1-2mL/min. The glass microelectrode is drawn by a microelectrode drawing instrument in two steps, and the resistance value of water inlet is 2-5MΩ after filling the electrode inner liquid.
After establishing the whole cell recording mode, the clamp potential was maintained at-80 mV. Depolarization voltage was given to +60mV for 850ms, then repolarization was performed to-50 mV for 1275ms to draw hERG tail current. Such a set of pulse sequences was repeated every 15 seconds throughout the experiment.
And after the current is stabilized, the mode of extracellular continuous perfusion administration from low concentration to high concentration is adopted. From low concentration, continuous perfusion until the drug effect is stable, i.e. the current value of the last 5 stimulus strips of each concentration administration phase changes by less than 10% of the mean value (when the current is greater than or equal to 200 pA) or less than 30% of the mean value (when the current is less than 200 pA), and then perfusion of the next concentration is performed. Test subjects (0.3,1,3, 10, 30 μm) and positive control Terfenadine (Terfenadine) were tested for their blocking effect on hERG tail current, respectively. Stimulus emission and signal acquisition are carried out through PatchMaster or Clampex 10.6 software; the patch clamp amplifier amplifies the signal. Further data analysis and curve fitting were performed using FitMaster or Clampfit 10.6,EXCEL,Graphpad Prism and SPSS 21.0, etc. Data are expressed as mean, standard deviation.
(3) Experimental results
Under the experimental condition, the positive reference substance Terfenadine has concentration dependence on hERG current inhibition effect, and the IC thereof 50 A value of 0.039 μm, indicating that the test results were reliable; compound 113 has concentration dependence on the effect of hERG potassium channel, IC of its inhibition of hERG current 50 The value was 24.68. Mu.M.
Experimental results show that the compound 113 has low inhibition activity (10 mu M) on the hERG ion channel, has low cardiotoxicity, and is not easy to induce acute arrhythmia or even sudden death after administration.
Experimental example 5: preliminary evaluation of in vivo safety of Compounds 118 and 152 on rats
(1) Experimental method
The compound was dissolved in 10% (v/v) DMSO (Sigma-Aldrich), 42% PEG400 (Shanghai Biotechnology), 3% (v/v) polyether F188 (Shanghai microphone) and 45% physiological saline. SPF SD rats (age: 7-11 weeks) female 190-220 g male (body weight 200-230 g) were each half. Compound 118 was tested according to the dosing regimen of table 7 and compound 152 was tested according to the dosing regimen of table 8 and clinical observations were made for all animals. And at the end of the experiment, samples of heart, liver, spleen, lung, kidney and the site of administration were collected. The test results are shown in tables 7 and 8.
(2) Experimental results
Table 7 preliminary evaluation of in vivo safety of compound 118 on rats
Table 8 preliminary evaluation of in vivo safety of compound 152 on rats
The experimental results show that the compound 118 and the compound 152 of the invention have good in vivo safety to rats.
Experimental example 6: RT-qPCR method for determining antiviral activity of compound 152 at cell level
Wild-type SARS-CoV-2 or SARS-CoV-2 mutant strain (B.1.1.7, B.1.617.1, P.3) was infected with Vero E6-TMPRSS2 and Calu3 cells at MOI values of 0.01 and 1, respectively. Compound 152 was 5-fold diluted from 0.0013 μm to 20 μm and cells were treated with solvent DMSO and adefovir (0.8 μm, 4 μm and 20 μm). Cell lysates were collected at 24hpi for RT-qPCR analysis.
The experimental results are shown in FIG. 5. The results indicate that compound 152 is capable of inhibiting replication of wild-type and mutant SARS-CoV-2 (B.1.1.7, B.1.617.1, P.3) in Vero E6-TMPRSS2 and Calu3 cells.
Experimental example 7: determination of Compound 152 antiviral Activity at the cellular level by cell viability
Wild-type SARS-CoV-2 or SARS-CoV-2 mutant strain (B.1.1.7, B.1.617.1, P.3) was infected with Vero E6-TMPRSS2 cells at an MOI value of 1. Compound 152 was 5-fold diluted from 0.0013 μm to 20 μm and cells were treated with solvent DMSO and adefovir (0.8 μm, 4 μm and 20 μm). After 48h, cell viability was quantified using CellTiter-Glo luminescent cell viability assay kit (G7572, promega) according to the manufacturer's manual and assayed using a multifunctional microplate reader Victor X3 (Perkin-Elmer).
The experimental results are shown in FIG. 6. The results demonstrate that compound 152 is capable of reducing cell death caused by infection of Vero E6-TMPRSS2 cells with wild-type and mutant SARS-CoV-2 (b.1.1.7, b.1.617.1, P.3).
Experimental example 8: plaque assay compound 152 antiviral activity at the cellular level
Wild-type SARS-CoV-2 or SARS-CoV-2 mutant strain (B.1.1.7, B.1.617.1, P.3) was infected with Vero E6-TMPRSS2 cells in 12-well plates at 50-70 PFU/well. Cells were washed with PBS and covered with 2% agarose/PBS and mixed with 2 XDMEM/2% FBS at a 1:1 ratio, compound 152 was diluted 5-fold from 0.0013. Mu.M to 20. Mu.M, and the cells were treated with solvent DMSO. After 48h, cells were fixed and stained with 0.5% crystal violet in 25% ethanol/distilled water for 10 min and stained plaques were quantified.
The experimental results are shown in FIG. 7. The results demonstrate that compound 152 is capable of reducing the cytopathic effects of wild-type and mutant SARS-CoV-2 (B.1.1.7, B.1.617.1, P.3) infection of Vero E6-TMPRSS2 cells.
Experimental example 9: evaluation of in vivo antiviral Activity of Compound 152 in K18-hACE2 transgenic mice
(1) Experimental protocol
The K18-hACE2 transgenic mice (6-8 weeks old) were purchased from The Jackson Laboratory, and the use of animals met all relevant ethical regulations and were approved by the living animal Committee for use in university of hong Kong teaching and research. Intranasal (i.n.) inoculation of 250PFU B.1.1.7 or 1X 10 in hACE2 mice 5 PFU b.1.617.1. Compound 152 was dissolved in 5% (v/v) DMSO (Sigma-Aldrich), 3% (v/v) HS15 (GLPBIO) and 92% physiological saline, and compound 152 (treatment group) or solvent solution (control group) was administered twice daily for 8 days or until sample collection or animal death. For the prophylactic treatment group, compound 152 treatment was started 1 hour prior to viral infection, while the administration of the therapeutic treatment group was delayed to 6 hours post-infection, with mice survival monitored daily during the trial. Mice were sacrificed at the indicated time points and samples of organ tissue were taken for virologic and histopathological analysis.
The specific experimental scheme for viral load detection is: transgenic mouse tissue samples were lysed using RLT buffer (Qiagen) and extracted with RNeasy Mini kit (74106, qiagen). After RNA extraction, transcriptor First Strand cDNA Synthesis Kit (04897030001, roche), quantiNova SYBR Green RT-PCR kit (208154, qiagen) or QuantiNova Probe RT-PCR kit (208354, qiagen) was used for RT-qPCR analysis.
The specific experimental scheme of the plaque method is as follows: vero E6-TMPRSS2 cells were seeded in 12-well plates 1 day prior to infection. Supernatants from harvested tissue samples were serially diluted in gradient and inoculated into cells at 37 ℃ for 1 hour. After inoculation, cells were washed 3 times with PBS and mixed with 2% agarose/PBS and 2 XDMEM/2% FBS at a ratio of 1:1. After 48 hours cells were fixed and stained with 0.5% crystal violet in 25% ethanol/distilled water for 10 minutes for plaque quantification.
The specific protocols for histopathological analysis and immunohistochemical staining were: the transgenic mice turbinates and lung tissue soaked with formate were fixed overnight in 10% formalin. The fixed samples were then embedded in paraffin using a TP1020 Leica semi-closed bench tissue processor and sectioned at 5 μm. Tissue sections were fished out and dried at 37 ℃ and fixed on Thermo Fisher Scientific Superfrost Plus slides overnight. The sections were sequentially diluted with xylene, ethanol, double distilled water, dewaxed and dehydrated, treated with antigen blocking solution (H-3300,Vector Laboratories), and heated at 85℃for 90s for antigen exposure, then blocked with 0.3% hydrogen peroxide for 30 minutes, then with 1% BSA for 30 minutes. Internal rabbit anti-SARS-CoV-2-N immune serum and goat anti-rabbit IgG antibodies (BA-1000-1.5,Vector Laboratories) were used as primary and secondary antibodies, respectively. The DAB (3, 3' -diaminobenzidine) substrate kit (SK-4100,Vector Laboratories) was used to generate the signal. Nuclei were labeled with gilsonin. Slides were mounted with a fade resistant mounting agent (H-1200,Vector Laboratories) with DAPI. For H & E staining, infected tissue sections were stained with Gill hematoxylin and eosin Y (Thermo Fisher Scientific). Images were taken using an Olympus BX53 optical microscope (Olympus Life Science).
(2) Experimental results
As shown in fig. 8, the experimental results of the viral load detection show that in the b.1.1.7-infected K18-hACE2 transgenic mice, both prophylactic and therapeutic treatment with compound 152 enabled significant reduction of viral load in nasal turbinates and lung tissues of the transgenic mice at days 2 and 4 compared to the vector group.
As shown in fig. 9, the specific experimental results of the plaque assay show that in b.1.1.7-infected K18-hACE2 transgenic mice, both prophylactic and therapeutic treatment with compound 152 enabled significant reduction of infectious viral titers in nasal turbinates and lung tissue of the transgenic mice at days 2 and 4 compared to the vehicle group.
The results of specific experiments for histopathological analysis and immunohistochemical staining are shown in FIG. 10. In B.1.1.7 infected K18-hACE2 transgenic mice, prophylactic and therapeutic treatment of compound 152 significantly inhibited the expression of viral nucleocapsid proteins in the lung and nasal turbinates and ameliorated the histopathological lesions caused by viral infection.
Animal survival and body weight recordings data As shown in FIG. 11, in B.1.617.1-infected K18-hACE2 transgenic mice, prophylactic and therapeutic treatment with compound 152 significantly improved the survival and weight loss of transgenic mice against B.1.617.1 infection.
Experimental results show that the compound 152 of the invention can effectively resist SARS-COV-2B.1.1.7 or B.1.617.1 infection of transgenic mice in vivo.
In summary, the invention provides a diamide derivative which can effectively inhibit SARS-CoV-2M pro Activity, the compound can be used for preparing SARS-CoV-2M pro Inhibitors, which block the replication and transcription of SARS-CoV-2 virus in patients, provide powerful support for combating SARS-COV-2. The compound has low inhibition activity on hERG ion channel, low cardiac toxicity and less possibility of inducing acute arrhythmia or even sudden death after administration. The compound 152 has good in vivo safety and pharmacokinetics, and can effectively inhibit SARS-CoV-2M pro The activity of the recombinant strain has antiviral activity on SARS-CoV-2 wild-type virus strain (in vitro experiment) and mutant virus strain (in vivo and in vitro experiment). In the preparation of SARS-CoV-2M by the compound of the invention pro The inhibitor, the medicine for resisting SARS-CoV-2 and the medicine for preventing and/or treating novel coronavirus pneumonia have very good application prospect.

Claims (20)

1. A compound of formula II or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated compound thereof:
Wherein R is 4a Selected from hydrogen, substituted or unsubstituted C 1～5 Alkyl groups, said substituents being selected from halogen, hydroxyA base; r is R 4b Selected from hydrogen, substituted or unsubstituted: c (C) 1～8 Alkyl, phenyl, said substituents being selected from halogen, C 1～5 Alkyl, C 1～5 An alkoxy group;
R 0 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～5 An alkyl group;
R 5 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～5 An alkyl group;
R 1 selected from hydrogen, C 1～5 An alkyl group;
R 2a 、R 2b each independently selected from hydrogen, unsubstituted or substituted by R 9 The substituted following groups: phenyl, 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, R 9 Selected from deuterium, C 1～5 Alkyl, C 1～5 Alkoxy, halogen, cyano;
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 each independently selected from N, CR 10 ；R 10 Selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen.
2. A compound of formula III-1 or formula III-2 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated compound thereof:
wherein R is 4a Selected from hydrogen, substituted or unsubstituted C 1～5 Alkyl, the substituent is selected from halogen, hydroxy; r is R 4b Selected from hydrogen, substituted or unsubstituted: c (C) 1～8 Alkyl, phenyl, said substituents being selected from halogen, C 1～5 Alkyl, cyano;
R 5 selected from hydrogen, deuterium, unsubstituted or deuteratedC 1～5 An alkyl group;
R 1 selected from hydrogen, C 1～5 An alkyl group;
X is selected from O, CO and CH 2 、C(CH 3 ) 2 。
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, wherein: the R is 4a Selected from hydrogen, substituted or unsubstituted C 1～2 Alkyl, wherein the substituent is hydroxyl; r is R 4b Selected from hydrogen, substituted or unsubstituted: phenyl, said substituents being selected from halogen, C 1～2 Alkyl, cyano;
R 5 selected from hydrogen, deuterium, unsubstituted or deuterated C 1～2 An alkyl group;
R 1 selected from hydrogen, C 1～2 An alkyl group;
x is selected from O, CO and CH 2 、C(CH 3 ) 2 。
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, wherein: the structure of the compound is shown as a formula III-3 or a formula III-4:
wherein R is 4a 、R 4b 、R 5 、R 1 Radicals and R in claim 3 4a 、R 4b 、R 5 、R 1 The groups are in one-to-one correspondence.
5. The compound according to claim 4, wherein：R 5 Selected from hydrogen, deuterium or CD 3 。
6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, wherein: the structure of the compound is shown as a formula IV-1 or a formula IV-2:
wherein R is 4a Selected from hydrogen, substituted or unsubstituted C 1～5 Alkyl, the substituent is selected from halogen, hydroxy; r is R 4b Selected from hydrogen, substituted or unsubstituted: phenyl, said substituents being selected from halogen, C 1～5 Alkyl, C 1～5 An alkoxy group;
R 5 selected from hydrogen, C 1～5 An alkyl group;
R 1 selected from hydrogen, C 1～5 An alkyl group;
R 2a selected from hydrogen, unsubstituted or substituted by R 9 Substituted phenyl, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclyl, R 9 Selected from deuterium, C 1～5 Alkyl, C 1～5 Alkoxy, halogen, cyano;
R 12 selected from hydrogen, C 1～5 Alkyl, C 1～5 Alkoxy, halogen.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, wherein: the R is 4a Selected from hydrogen, C 1～2 Alkyl, R 4b Selected from hydrogen, substituted or unsubstituted: phenyl, said substituents being selected from halogen, C 1～2 Alkyl, C 1～2 An alkoxy group;
R 5 selected from hydrogen, C 1～2 An alkyl group;
R 1 selected from hydrogen, C 1～2 An alkyl group;
R 2a selected from the group consisting ofSubstituted or by R 9 The substituted following groups: benzene ring, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclic group, R 9 Selected from deuterium, C 1～2 Alkyl, C 1～2 Alkoxy, halogen.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, wherein: the structure of the compound is shown as a formula IV-3 or a formula IV-4:
Wherein R is 4a 、R 4b 、R 5 、R 1 Radicals and R in claim 7 4a 、R 4b 、R 5 、R 1 The groups are in one-to-one correspondence.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, wherein: r is R 5 Selected from hydrogen, deuterium or CD 3 。
10. A compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated compound thereof, characterized in that: the compound is selected from:
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11. a pharmaceutical composition characterized by: the pharmaceutical composition is a preparation prepared by taking the compound, the pharmaceutically acceptable salt, the stereoisomer or the deuterated compound thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated compound thereof and/or a pharmaceutical composition according to claim 11 for the preparation of a coronavirus proteolytic enzyme inhibitor.
13. Use according to claim 12, characterized in that: the coronavirus proteolytic enzyme is a coronavirus main protease.
14. Use according to claim 13, characterized in that: the coronavirus proteolytic enzyme is SARS-COV-2M pro 。
15. Use according to claim 12, characterized in that: the coronavirus proteolytic enzyme inhibitor is an anti-coronavirus drug.
16. Use according to claim 15, characterized in that: the coronavirus is SARS-CoV-2, SARS-CoV, MERS-CoV, hcov-229E, hcoV-NL63, hcov-HKU1 or Hcov-OC43.
17. Use according to claim 15, characterized in that: the coronavirus is SARS-CoV-2.
18. Use according to claim 12, characterized in that: the coronavirus proteolytic enzyme inhibitor is used for preventing and/or treating SARS-COV-2M pro Medicaments for related diseases.
19. Use according to claim 18, characterized in that: the coronavirus proteolytic enzyme inhibitor is a medicament for preventing and/or treating novel coronavirus pneumonia.
20. Use according to claim 18 or 19, characterized in that: the coronavirus proteolytic enzyme inhibitor can inhibit SARS-COV-2 infection of cells.
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AU2004248859A1 (en) * 2003-06-26 2004-12-29 Biotron Limited Antiviral acylguanidine compounds and methods
CN111518094A (en) * 2019-02-01 2020-08-11 四川大学华西医院 Anti-influenza small molecule compound and preparation method and application thereof
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