WO2023272571A1 - Medical use of 2,3-epoxy succinyl derivative - Google Patents

Abstract

A compound as represented by formula 1 that has an inhibitory effect on the novel coronavirus 2019-nCoV; a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; and the use thereof in the preparation of a medicament for treating the COVID-2019 disease caused by the novel coronavirus 2019-nCoV infection, and in a pharmaceutical composition containing same. In the formula, R1 is independently selected from hydrogen or ethyl; R2 is selected from a C3-C6 alkyl, or a C3-C6 alkyl containing an S atom; R3 and R4 are independently selected from a C1-C6 alkyl, and a C1-C6 alkyl substituted by R5, wherein R5 is a benzene ring which is unsubstituted or monosubstituted by halogen; and R3 and R4 can form a six-membered saturated heterocyclic ring, wherein the six-membered saturated heterocyclic ring can be monosubstituted by a benzene ring.

Description

The medical application of 2,3-epoxysuccinyl derivatives technical field

The invention relates to novel coronavirus nCoV-2019 inhibitors and their use in the preparation of drugs for treating COVID-2019, a disease caused by novel coronavirus nCoV-2019 infection, and pharmaceutical compositions containing them.

Background technique

In mid-January 2020, the full genome of the new coronavirus nCoV-2019 was first published by Chinese researchers. This full-length 29903 genome (GenBank ID: MN908947.3) provides important information for the selection of drug targets. With the progress of bioinformatics analysis, a series of potential targets have been proposed, including S-spike protein, RdRp enzyme, Papain enzyme, 3Cl protease, etc., but the targeted active molecules have not been reported yet. At present, there are drugs for the treatment of COVID-2019, which are mainly potential drugs identified through drug repositioning in clinical research, including Chloroquine Phosphate (Chloroquine), Remdesivir (Remdesivir), Favipiravir (Favipiravir), Lopina The targets of lopinavir and ritonavir include RdRp enzyme and protein integrase, and most of the specific mechanisms have yet to be confirmed. However, the structures of the above-mentioned drugs are quite different, and the clinical efficacy is still unclear. Therefore, the research on targeted inhibitors of the new coronavirus nCoV-2019 is still in the initial stage, and there is very little information to learn from, and it is difficult to have a systematic structure-activity relationship and commonality. Structure-guided discovery of highly active compounds.

Contents of the invention

The present invention relates to a compound represented by formula I with inhibitory effect on novel coronavirus nCoV-2019, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof, and its preparation for treating novel coronavirus Use of COVID-2019 medicines for diseases caused by nCoV-2019 infection and pharmaceutical compositions containing them.

Therefore, in the first aspect of the present invention, the present invention provides the compound shown in formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt in the preparation for the treatment of viral infection Pneumonia caused by novel coronavirus 2019-nCoV infection, such as COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, low oxygen respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.), or in the preparation of drugs as novel coronavirus 2019-nCoV inhibitors, or in the preparation of drugs for inhibiting Use of novel coronavirus 2019-nCoV in a medicine for replicating or multiplying in cells (e.g. mammalian cells),

in,

R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;

R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;

Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;

所述苯环任选被卤素单取代，或者，R3、R4和与它们直接相连的N原子一起组成

Preferably, R3, R4 are each independently selected from hydrogen,

The benzene ring is optionally monosubstituted by halogen, or, R3, R4 and the N atom directly connected to them form together

In the second aspect of the present invention, the present invention provides a pharmaceutical composition used in the preparation of pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to Simple infection such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.), or in the Use in the preparation of medicines as 2019 novel coronavirus (2019-nCoV) inhibitors, or in the preparation of medicines for inhibiting the replication or reproduction of 2019 novel coronavirus (2019-nCoV) in cells (such as mammalian cells) use,

Wherein the pharmaceutical composition comprises the compound represented by formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt,

in,

R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;

R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;

Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;

或者，R3、R4和与它们直接相连的N原子 一起组成

所述苯环任选被卤素单取代； Preferably, R3, R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The benzene ring is optionally monosubstituted by halogen;

Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, preferably, the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration. formulations of micronized suspensions or solutions, ointments, ointments, lotions or creams for topical application on the skin, sterile injectable aqueous or oily suspensions or sterile injectable solutions for injection.

In some embodiments, the compound of formula 1 is selected from:

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]epoxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamino)butane]formamido]epoxy Succinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]carboxamido]epoxysuccinate acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamido]ring oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]carboxamido]cyclo oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamido] ring oxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxy Succinic acid

(2s,3s)-3-[2-[(s)-4-Methyl-1-carbonyl-1-(3-methylbutylamino)pentane]carboxamido]epoxysuccinic acid.

In a third aspect of the present invention, the present invention provides a method of treating and/or preventing disease in a mammal in need or inhibiting the replication or reproduction of 2019 novel coronavirus (2019-nCoV) in a mammal in need A method, the method comprising administering a therapeutically and/or preventively effective amount of a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof to a mammal in need A pharmaceutical composition comprising a compound represented by formula 1, a racemate or an optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof in a therapeutically and/or preventively effective amount,

in,

R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;

R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;

Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;

或者，R3、R4和与它们直接相连的N原子一起组成

所述苯环任选被卤素单取代； Preferably, R3, R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The benzene ring is optionally monosubstituted by halogen;

The diseases mentioned therein include pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, pneumonia, Acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.);

Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, preferably, the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration. formulations of micronized suspensions or solutions, ointments, ointments, lotions or creams for topical application on the skin, sterile injectable aqueous or oily suspensions or sterile injectable solutions for injection.

In some embodiments, the compound of formula 1 is selected from:

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]epoxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamino)butane]formamido]epoxy Succinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]carboxamido]epoxysuccinate acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamido]ring oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]carboxamido]cyclo oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamido] ring oxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxy Succinic acid

(2s,3s)-3-[2-[(s)-4-Methyl-1-carbonyl-1-(3-methylbutylamino)pentane]carboxamido]epoxysuccinic acid.

In the fourth aspect of the present invention, the present invention provides a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof or a compound represented by formula 1, its A pharmaceutical composition of a rotator or an optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, as a 2019 novel coronavirus (2019-nCoV) inhibitor, or for inhibiting a 2019 novel coronavirus (2019-nCoV) nCoV) replicates or reproduces in cells (such as mammalian cells), or it is used to treat pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple Sexual infections such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.)

in,

R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;

R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;

Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;

或者，R3、R4和与它们直接相连的N原子一起组成

所述苯环任选被卤素单取代； Preferably, R3, R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The benzene ring is optionally monosubstituted by halogen;

Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, preferably, the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration. formulations of micronized suspensions or solutions, ointments, ointments, lotions or creams for topical application on the skin, sterile injectable aqueous or oily suspensions or sterile injectable solutions for injection.

In some embodiments, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof or comprises a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 is selected from:

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]epoxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamino)butane]formamido]epoxy Succinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]carboxamido]epoxysuccinate acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamido]ring oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]carboxamido]cyclo oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamido] ring oxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxy Succinic acid

(2s,3s)-3-[2-[(s)-4-Methyl-1-carbonyl-1-(3-methylbutylamino)pentane]carboxamido]epoxysuccinic acid.

In the fifth aspect of the present invention, the present invention provides a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof, for the preparation of treating, delaying or alleviating virus Infection-induced pneumonia drugs and uses of pharmaceutical compositions containing them,

in,

R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;

R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;

Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;

或者，R3、R4和与它们直接相连的N原子 一起组成

所述苯环任选被卤素单取代。 Preferably, R3, R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The phenyl ring is optionally monosubstituted with halogen.

In a specific embodiment of the present invention, the compound of formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically or physiologically acceptable salt, wherein the compound is selected from:

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]epoxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxysuccinic acid ( 2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamido)butane]formamido]epoxysuccinate acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]carboxamido]epoxysuccinate acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamido]ring oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]carboxamido]cyclo oxysuccinic acid

(2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamido] ring oxysuccinic acid

(2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxy Succinic acid

(2s,3s)-3-[2-[(s)-4-Methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxysuccinic acid

The present invention relates to compounds represented by formula I, which have significant in vitro anti-nCoV-2019 virus-infected cells, and the EC50 of the preferred compounds are respectively 4.5 μM and 6.25 μM.

Another aspect of the present invention relates to a pharmaceutical composition, which contains the racemate or optical isomer of the compound of the present invention and at least one pharmaceutically acceptable carrier, which can be used for in vivo therapy and has biocompatibility. The pharmaceutical composition can be prepared in various forms according to different administration routes. The compound mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts, and the said pharmaceutical composition of the present invention can be used for preventing and/or treating pneumonia caused by novel coronavirus (nCoV-2019) infection ( COVID-2019) treatment.

The pharmaceutical composition involved in the present invention refers to comprising an effective dose of the compound of formula I of the present invention or a pharmaceutically acceptable salt or hydrate thereof and one or more suitable pharmaceutically acceptable carriers. The pharmaceutical carriers here include but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate, saturated vegetable Partial glyceride mixtures of fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fibers Vegetable substances, macrogol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin.

The pharmaceutical compositions of the compounds of this invention can be administered in any of the following ways: oral, inhalation spray, rectal, nasal, buccal, topical, parenteral, e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Intravenous, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.

When administered orally, the compounds of the present invention may be prepared in any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. Wherein, the carrier that tablet uses generally comprises lactose and cornstarch, also can add lubricant such as magnesium stearate in addition. Diluents used in capsule formulations generally include lactose and dried cornstarch. Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral preparation forms.

When used locally, especially when treating the affected areas or organs that are easily accessible by local external application, such as eye, skin or lower intestinal neuropathy, the compound of the present invention can be made into different topical preparations according to different affected areas or organs The format is specified as follows:

When administered topically to the eye, the compounds of the present invention may be formulated as a micronized suspension or solution in the form of an isotonic sterile saline solution of pH with or without the addition of a preservative such as benzyl chloride. alkyl alkoxides. For ophthalmic use, the compound may also be formulated in the form of an ointment such as petrolatum ointment.

When applied topically to the skin, the compounds of the invention may be formulated in suitable ointments, lotions or creams, wherein the active ingredients are suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil Oil, Sorbitan Monostearate, Tween 60, Cetyl Ester Wax, Cetyl Aryl Alcohol, 2-Octyldodecanol, Benzyl Alcohol and Water.

The compounds of the present invention can also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions. Among them, the carrier and solvent that can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterile fixed oils, such as mono- or diglycerides, may be employed as a solvent or suspending medium.

In addition, it should be pointed out that the dose and method of use of the compound of the present invention depend on many factors, including the patient's age, body weight, sex, natural health status, nutritional status, activity intensity of the compound, time of administration, metabolic rate, severity of the disease, and The subjective judgment of the treating physician. The preferred dosage ranges from 0.01 to 100 mg/kg body weight/day, and the optimal dosage is 1 mg/kg-50 mg/kg body weight/day.

It should be noted that the term "C1-C6 alkyl containing an S atom" refers to a group formed after one C atom in the C1-C6 alkyl is replaced by an S atom, for example, "n-propane containing an S atom base" can be

The term "C1-C6 alkyl" refers to any straight chain or branched chain group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.

The term "C1-C4 alkyl" refers to any straight chain or branched chain group containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base, tert-butyl, etc.

The term "C1-C3 alkyl" refers to any straight-chain or branched-chain group containing 1-3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.

The term "C3-C6 alkyl" refers to any straight chain or branched chain group containing 3-6 carbon atoms, such as n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.

The term "five-six-membered saturated heterocyclic ring" refers to a 5- or 6-membered saturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of five- to six-membered ring saturated heterocycles include pyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, piperidine base, piperazinyl, morpholinyl, thiomorpholinyl, etc. Non-limiting examples of six-membered ring saturated heterocyclic groups are, for example, pyranyl, piperidinyl, piperazinyl, morpholinyl, and the like.

detailed description

Embodiments of the present invention are described in detail below, and the embodiments described below are exemplary and intended to explain the present invention, but should not be construed as limiting the present invention.

The essence and beneficial effects of the present invention will be further described below in conjunction with the examples. The examples are only used to illustrate the present invention and not to limit the present invention.

The melting point of the compound was determined by RY-1 melting point apparatus, and the thermometer was not corrected. The specific rotation was measured by a precision automatic polarimeter, Polar 3005 from OA Company, and the mass spectrum was measured by a Micromass ZabSpec high-resolution mass spectrometer (resolution 1000). 1H NMR is measured by JNM-ECA-400 superconducting NMR instrument, working frequency 1H NMR 400MHz, 13C NMR 100MHz.

Preparation of intermediates

Intermediate 1 : Preparation of (2S,3S)-oxirane-2,3-dicarboxylic acid

(+/-)-trans-epoxysuccinic acid (178 g, 1.35 mol) was dissolved in 2600 ml methanol. Add (234.9g, 1.35mol) L-arginine in 650ml water, heat to dissolve, then add dropwise in the methanol solution of (+/-)-trans-epoxysuccinic acid while stirring, finally will A large amount of insoluble material appeared. After the addition was complete, it was stirred overnight at room temperature. The precipitate was obtained by suction filtration, and the precipitate was washed with methanol/water (4:1) mixed solvent (1000ml) to obtain 201.2g of crude product. The crude product was recrystallized with about 3000ml of methanol water (2:1) to obtain 170.2g of (+)-trans-epoxysuccinic acid with a yield of 82.5%.

¹ H-NMR (400MHz, D ₂ O) 1.54-2.02 (4H, m), 3.22 (2H, t), 3.48 (2H, s), 3.84 (1H, t); [α] _D +54.7 (c= 1.00, H ₂ 0); EI-MS (m/z): [M+H] ⁺ 133.

Intermediate 2 : Preparation of (2S,3S)-2,3-dicarboethoxy-oxirane

At room temperature, add (+/-)-trans-epoxysuccinic acid (107.1g, 0.35mol) into 1050ml ethanol solution for suspension, stir, then add 95% concentrated sulfuric acid (102.9g, 1.05mol) dropwise After the addition was complete, the mixture was stirred at reflux for 4.5 hours. After the reaction, the solvent in the mixture was removed by rotary evaporation, and the residue in the bottle was poured into 200ml of ice water, and extracted 3 times with ethyl acetate (300ml*3). The extracted ester layers were combined, washed successively with saturated aqueous sodium bicarbonate solution (200ml*2) and saturated brine (200ml*2), dried with anhydrous magnesium sulfate, filtered with suction, and spin-dried to obtain the crude product, which was analyzed by chromatography The column obtained pure product, 50.4 g of colorless oily liquid, yield 76.6%.

¹ H-NMR (400MHz, CDCl ₃ ) 1.31 (6H, t), 3.66 (2H, s), 4.28 (4H, dq); [α] _D +110.5 (c=1.12, EtOH); EI-MS (m /z):[M+H] ⁺ 189.

Intermediate 3 : Preparation of (2S,3S)-3-carboethoxy-oxirane-2-carboxylic acid

85% potassium hydroxide (6.72g, 0.1mol) was added to 67ml of ethanol to form potassium hydroxide ethanol solution. Add intermediate 2 (18.8g, 0.1mol) to 150ml ethanol, stir, and control the temperature in an ice bath at 4-6°C, then add potassium hydroxide ethanol solution dropwise, and continue stirring at 4-6°C for 1 hours, then warmed to room temperature and stirred for 4 hours. After the reaction was completed, the solvent was evaporated, and 50ml of water was added to form a solution, which was washed with ethyl acetate (50ml*2). The aqueous layer was separated and placed in an ice bath. The aqueous layer was acidified to pH=2 with 6N hydrochloric acid and extracted with ethyl acetate (70ml*3). The collected ester layer was washed with saturated brine (70ml*2), dried over anhydrous magnesium sulfate, filtered with suction, and the solvent in the solution was removed to obtain the crude intermediate 3 (13.1g), a colorless oil. No purification required, directly to the next step.

¹ H-NMR (400MHz, CDCl ₃ ) 1.27-1.31 (3H, t), 3.59-3.62 (2H, s), 4.23-4.25 (2H, dq); EI-MS (m/z): [M+H ] ⁺ 161.

Intermediate 4 : Preparation of (2S,3S)-3-(4-nitrophenoxycarbonyl)-oxirane-2-carboxylic acid ethyl ester

DCC (12.9 g, 0.0625 mol) was dissolved in ethyl acetate (26 ml) to form an ethyl acetate solution. Dissolve 10g of intermediate 3 and p-nitrophenol (8.69g, 0.0625mol) in 55ml of ethyl acetate solution, keep the temperature at 4-5°C and stir, slowly drop into the prepared DCC ethyl acetate solution, and react at low temperature 3 hours, rise to room temperature and react for 1 hour. After the reaction was completed, the residue was filtered, the organic layer was washed with ethyl acetate (20ml), the ethyl acetate was filtered again, and the solvent was rotary evaporated to obtain a crude product, which was recrystallized with ethyl acetate-cyclohexane to obtain intermediate 4 (14.1g, yield 65.8%), which are yellow needles.

¹ H-NMR (400MHz, DMSO) 1.26(3H,t), 4.06(1H,d), 4.08(1H,d), 4.24(2H,q), 7.58(2H,d), 8.36(2H,d) ; [α] _D + 114.8 (c=1.00, AcOEt); EI-MS (m/z): [M+H] ⁺ 282.

Example 1 (2s, 3s) -2-ethyl ester -3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]ring oxysuccinic acid

1 Dissolve DCC (10.32g, 0.05mol) in 20ml of ethyl acetate to form an ethyl acetate solution. Dissolve (12.49g, 0.05mol) N-(tert-butoxycarbonyl)-L-methionine, (4.36g, 0.05mol) isoamylamine and (6.76g, 0.05mol) HOBt in 35ml ethyl acetate, stir, Ice bath 3-8°C. Then add the previously prepared DCC ethyl acetate solution dropwise. Keep stirring at 3-8°C for 1.5 hours, then warm to room temperature for 2.5 hours. After the reaction was completed, impurities were filtered off, the precipitate was washed with 40ml of ethyl acetate, and the filtrates were combined, washed successively with 5% hydrochloric acid (100ml), saturated brine (100ml), saturated sodium bicarbonate (100ml), and saturated brine (100ml). The organic layer was dried with anhydrous magnesium sulfate, and rotary evaporated to obtain 14.45 g of crude product, with a yield of 96.1%. directly to the next step without purification.

2. The crude product from the previous step (18.5 g, 0.062 mol) was dissolved in 65 ml of 10% HCl-AcOEt solution, and stirred for 2.5 hours. Rotate the solvent, add 50ml of water to the residue, wash with 50ml of ethyl acetate, basify the aqueous layer with 25% sodium hydroxide to pH>10, and extract with ethyl acetate (50ml*1, 25ml*2). The combined organic layers were dried over anhydrous magnesium sulfate and spin-dried. Get the crude product, go directly to the next step.

3 Mix the crude product (4.39g, 0.32mol) from the previous step, intermediate 3 (3g, 0.32mol), HOBt2.54g and 30ml ethyl acetate, and add 3.87g DCC and 10ml ethyl acetate dropwise under ice-cooling, React in ice bath for 3 hours. Rise to room temperature and react for 12 hours. The insoluble matter was filtered off, washed with ethyl acetate, and washed successively with 5% hydrochloric acid, saturated brine, saturated sodium bicarbonate, and saturated brine. Dry over anhydrous magnesium sulfate. The crude product was spin-dried under reduced pressure, and compound 1 was obtained by recrystallization from absolute ethanol. Yellow needle powder 3.1g. Yield 42%

¹ H-NMR (400MHz, DMSO) 0.86 (6H, d) 1.20-1.31 (5H, m) 1.54 (1H, m) 1.79-1.88 (2H, m) 2.03 (3H, s) 2.42 (2H, m) 2.90 -3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI -MS(m/z):361[M+H] ⁺

Example 2 (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxy Succinic acid

Using hexylamine and intermediate 3 as raw materials, the operation was the same as in Example 1 to obtain compound 5 as a white needle-like powder.

¹ H-NMR (400MHz, DMSO) 0.86 (3H, t) 1.17-1.35 (11H, m) 1.79-1.88 (2H, m) 2.03 (3H, s) 2.42 (2H, m) 2.90-3.20 (2H, m )3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z ):375[M+H] ⁺ .

Example 3 (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamino)butane]formamide ]epoxysuccinic acid

Using 3-amphetamine and intermediate 3 as raw materials, the operation was the same as in Example 1 to obtain compound 8 as a yellow needle-like powder.

¹ H-NMR(400MHz,DMSO)1.21-1.3(5H,m)1.50-1.88(4H,m)2.03(3H,s)2.42(2H,m)3.00-3.10(2H,m)3.61(1H,d )3.72(1H,d)4.16-4.17(2H,m)4.33-4.37(1H,m)7.17-7.27(5H,m)8.13(1H,t)8.63(1H,d)EI-MS(m/z ):409[M+H] ⁺ .

Example 4 (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]formamido] epoxy succinic acid

Using 4-phenylpiperidine and intermediate 3 as raw materials, the operation was the same as in Example 1 to obtain compound 13 as a colorless needle-like powder.

¹ H-NMR(400MHz,DMSO)1.21(3H,t)1.50-1.90(6H,m)2.03(3H,s)2.42(2H,m)2.65(1H,t)2.75(2H,t)3.15(2H ,t)3.60(1H,m)3.72(1H,d)4.12-4.15(2H,m)4.41-4.51(1H,m)7.10-7.38(5H,m)8.81(1H,d)EI-MS(m /z):435[M+H] ⁺ .

Example 5 (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamide base]epoxysuccinic acid

Using 3-fluorophenethylamine and intermediate 3 as raw materials, the operation was the same as in Example 1 to obtain compound 34 as a yellow solid.

¹ H-NMR(400MHz,DMSO)1.21-1.3(3H,t)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.70-2.75(2H,m)3.61-3.72(4H ,m)4.16-4.17(2H,m)4.28-4.32(1H,m)7.05(3H,m)7.30(1H,m)8.17(1H,t)8.63(1H,d)EI-MS(m/z ):413[M+H] ⁺ .

Example 6 (2s, 3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]formamide base]epoxysuccinic acid

Using 3-aminopentane and intermediate 3 as raw materials, the operation was the same as in Example 1 to obtain compound 39 as a white needle-like powder.

¹ H-NMR (400MHz, DMSO) 0.86 (6H, t) 1.21-1.43 (7H, m) 1.79-1.88 (2H, m) 2.03 (3H, s) 2.42 (2H, m) 3.49-3.52 (1H, m )3.59(1H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.77(1H,t)8.63(1H,d)EI-MS(m/z): 361[M+H] ⁺ .

Example 7 (2s, 3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamide base]epoxysuccinic acid

Using 4-phenylbutylamine and intermediate 3 as raw materials, the operation was the same as in Example 1 to obtain compound 40 as a white solid.

¹ H-NMR(400MHz,DMSO)1.21-1.3(3H,m)1.35-1.51(4H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.53(2H,t )3.00-3.10(2H,m)3.57(1H,d)3.67(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.17-7.27(5H,m)8.06-8.09(1H ,t)8.63(1H,d)EI-MS(m/z):423[M+H] ⁺ .

Example 8 (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamide ]epoxysuccinic acid

Using isoamylamine, N-(tert-butoxycarbonyl)-L-leucine and intermediate 3 as raw materials, the operation was the same as in Example 1 to obtain compound 40 as a white solid.

¹ H-NMR (400MHz, DMSO) 0.85-1.04 (12H, m), 1.32 (3H, t, J = 7Hz), 1.41 (2H, q, J = 7Hz), 1.47-1.76 (4H, m), 3.11 -3.47(2H,m),3.48(1H,d,J=2Hz),3.69(1H,d,J=2Hz),4.27(2H,dq,J=7.2Hz),4.35-4.50(1H,m) , 6.16-6.30 (1H, m), 6.8 (1H, d, J=8Hz). EI-MS (m/z): 343 [M+H] ⁺ .

Example 9 (2s, 3s)-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxysuccinic acid

The (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido] ring Oxysuccinic acid was operated according to intermediate 3 to obtain the compound as a white solid.

¹ H-NMR (400MHz, DMSO) 0.85-1.04 (12H, m), 1.41 (2H, q, J=7Hz), 1.47-1.76 (4H, m), 3.11-3.47 (2H, m), 3.48 (1H , d, J = 2Hz), 3.69 (1H, d, J = 2Hz), 4.35-4.50 (1H, m), 6.16-6.30 (1H, m), 6.8 (1H, d, J = 8Hz). EI-MS (m/z): 314 [M+H] ⁺ .

The test of embodiment 10 compound against nCovV-2019 coronavirus infection

The EC50 of the drug was determined by CPE method and nucleic acid quantitative method. Drugs were formulated with 2% FBS in DMEM maintenance solution, 100, 50, 25, 12.5, 10, 6.25, 3.125 μM. Vero cells were inoculated into 96-well plates at a concentration of 10000/well one day in advance. Discard the cell culture supernatant, add 100 TCID50 novel coronavirus liquid, adsorb and culture at 37°C for 2 hours, discard the virus liquid, add different concentrations of drugs (200 μl/well) to each well, and use 4 replicate wells for each drug, and set up virus control and normal The cell control group was cultured in a 5% CO ₂ incubator at 37° C., and cytopathic changes (CPE) were observed every day. Two days after infection, 50 μl of cell supernatant was taken from each well to extract nucleic acid, and the viral load was detected by quantitative RT-PCR. The new coronavirus is a Beijing isolate (2019-nCoV BetaCoV/Beijing/AMMS01/2020), which is kept by the biosafety level III laboratory of the Academy of Military Medical Sciences. All evaluations were completed in a biosafety level III laboratory. The results are shown in Table 1 and Table 2. The evaluation results of viral load showed that the EC50 of Example 8 and Example 9 were 6.25 μM and 4.5 μM, respectively.

Table 1 Preliminary screening results of compounds

"×" indicates that the drug is toxic to Vero cells, "+" indicates mild cytopathy,

"++" means moderate cytopathy, "+++" means complete cytopathy, "-" means no lesion

Table 2 Determination of Compound EC50

"×" indicates that the drug is toxic to Vero cells, "+" indicates mild cytopathy,

"++" means moderate cytopathy, "+++" means complete cytopathy, "-" means no lesion

The specific embodiments described above have further described the purpose, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above descriptions are only specific embodiments of the present invention and are not intended to limit the scope of the present invention. Protection scope, within the spirit and principles of the present invention, any modifications, equivalent replacements, improvements, etc., shall be included in the protection scope of the present invention.

Claims (7)

The compound shown in formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt is used for the treatment of pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.), or in the preparation of drugs as novel coronavirus 2019-nCoV inhibitors, or in the preparation of drugs for inhibiting novel coronavirus 2019-nCoV in cells (such as mammalian cells) Use in medicines for copying or reproduction,

in, R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl; R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5; Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen; Preferably, R3 and R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The phenyl ring is optionally monosubstituted with halogen. The pharmaceutical composition is prepared for the treatment of pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, etc., Pneumonia, acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.), or in the preparation of 2019 novel coronavirus (2019-nCoV) inhibitor The purposes in the medicine of agent, or the purposes in the medicine that is used for the preparation of the 2019 novel coronavirus (2019-nCoV) to suppress in cell (for example mammalian cell) to replicate or multiply, Wherein the pharmaceutical composition comprises the compound represented by formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt,

in, R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl; R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5; Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen; Preferably, R3, R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The benzene ring is optionally monosubstituted by halogen; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, preferably, the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration. formulations of micronized suspensions or solutions, ointments, ointments, lotions or creams for topical application on the skin, sterile injectable aqueous or oily suspensions or sterile injectable solutions for injection. The use according to claim 1 or 2, wherein said compound of formula 1 is selected from: (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]epoxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamino)butane]formamido]epoxy Succinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]carboxamido]epoxysuccinate acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamido]ring oxysuccinic acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]carboxamido]cyclo oxysuccinic acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamido] ring oxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxy Succinic acid (2s,3s)-3-[2-[(s)-4-Methyl-1-carbonyl-1-(3-methylbutylamino)pentane]carboxamido]epoxysuccinic acid. A method of treating and/or preventing disease in a mammal in need or a method of inhibiting the replication or reproduction of 2019 novel coronavirus (2019-nCoV) in a mammal in need, the method comprising giving breastfeeding to a need Animals are administered a therapeutically and/or preventively effective amount of a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof, or a therapeutically and/or preventively effective amount of a compound represented by formula 1 A pharmaceutical composition of the compound shown in 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof,

in, R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl; R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5; Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen; Preferably, R3 and R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The benzene ring is optionally monosubstituted by halogen; The diseases mentioned therein include pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, pneumonia, Acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.); Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, preferably, the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration. formulations of micronized suspensions or solutions, ointments, ointments, lotions or creams for topical application on the skin, sterile injectable aqueous or oily suspensions or sterile injectable solutions for injection. The method according to claim 4, wherein said compound of formula 1 is selected from: (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]epoxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamino)butane]formamido]epoxy Succinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]carboxamido]epoxysuccinate acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamido]ring oxysuccinic acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]carboxamido]cyclo oxysuccinic acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamido] ring oxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxy Succinic acid (2s,3s)-3-[2-[(s)-4-Methyl-1-carbonyl-1-(3-methylbutylamino)pentane]carboxamido]epoxysuccinic acid. The compound shown in formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt or comprising the compound shown in formula 1, its racemate or optical isomer, its solvate, or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, as a 2019 novel coronavirus (2019-nCoV) inhibitor, or for inhibiting 2019 novel coronavirus (2019-nCoV) from replicating in cells (such as mammalian cells) Or reproduction, or for the treatment of pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, pneumonia , acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.)

in, R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl; R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from isopropyl or

R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5; Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen; Preferably, R3, R4 are each independently selected from hydrogen,

Alternatively, R3, R4 and the N atom directly connected to them form together

The benzene ring is optionally monosubstituted by halogen; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant, preferably, the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration. formulations of micronized suspensions or solutions, ointments, ointments, lotions or creams for topical application on the skin, sterile injectable aqueous or oily suspensions or sterile injectable solutions for injection. The compound represented by formula 1 according to claim 6, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof or comprising the compound represented by formula 1, its racemate or optical isomer Construct, its solvate, or the pharmaceutical composition of pharmaceutically acceptable salt thereof, wherein said compound of formula 1 is selected from: (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(isoamylamino)butane]formamido]epoxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(hexylamino)butane]formamido]epoxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-benzamino)butane]formamido]epoxy Succinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(phenylpiperidinyl)butane]carboxamido]epoxysuccinate acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-fluorophenethylamino)butane]formamido]ring oxysuccinic acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(3-aminopentyl)butane]carboxamido]cyclo oxysuccinic acid (2s,3s)-2-ethyl ester-3-[2-[(s)-4-methylthio-1-carbonyl-1-(4-phenylbutylamino)butane]formamido] ring oxysuccinic acid (2s,3s)-2-Ethyl ester-3-[2-[(s)-4-methyl-1-carbonyl-1-(3-methylbutylamino)pentane]formamido]epoxy Succinic acid (2s,3s)-3-[2-[(s)-4-Methyl-1-carbonyl-1-(3-methylbutylamino)pentane]carboxamido]epoxysuccinic acid.