3CL protease small molecule inhibitors for treating or preventing coronavirus infection and uses thereof

Abstract

The present application relates to a small molecule inhibitor of 3CL protease for treating or preventing coronavirus infection and its use. Specifically, the present application relates to a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and its use in the preparation of a drug for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to the Chinese patent application with application number CN202110882817.6 filed on August 2, 2021 and the PCT patent application with application number PCT / CN2021 / 128089 filed on November 2, 2021, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to the field of biomedicine, and in particular to 3CL protease small molecule inhibitors and uses thereof for treating or preventing coronavirus infection. Background Art

[0004] The new coronavirus (SARS-CoV-2) is a positive-strand RNA virus with the largest genome among the currently known RNA viruses. Studies have found that the new coronavirus mainly infects cells through the human respiratory mucosal system. After entering the cell, the viral gene is cleaved by proteases to begin translation and replication of the required proteins. 3CL proteases recognize specific cleavage sites and cut polyprotein precursors into multiple non-structural proteins. They are essential for the life cycle of the virus and are excellent targets for antiviral drugs. Many marketed antiviral drugs target 3CL proteases such as HIV and HCV. Among them, HIV 3CL protease inhibitors lopinavir and ritonavir have certain interactions with the 3CL protease of the new coronavirus in vitro, but have been shown to have no positive effects on patients infected with the new coronavirus in clinical tests. Therefore, strong inhibitors specific for the 3CL protease of the new coronavirus are particularly important. Summary of the invention

[0005] In the first aspect, the present application provides a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

[0006]

[0007] in,

[0008] P1 is selected from unsubstituted or optionally substituted five- to ten-membered heteroaryl groups with R1, wherein the heteroaryl group contains at least one heteroatom selected from N, O or S;

[0009] P2 together with the two adjacent carbon atoms forms an unsubstituted or optionally C 1 -C 3Alkyl or halogen-substituted three- to six-membered cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains at least one heteroatom selected from N, O or S;

[0010] P3 is selected from

[0011] Further, among them,

[0012] R1 is selected from hydrogen, deuterium, halogen, cyano, oxo, nitro, C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 4 Alkoxy, C 5 -C 10 Aryl or 5- to 10-membered heteroaryl;

[0013] R2 is selected from C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy or C 5 -C 10 Aryl;

[0014] R3 is selected from C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy, C 5 -C 10 Aryl or 5- to 10-membered heteroaryl;

[0015] Ring A is selected from unsubstituted or optionally halogen-substituted C 5 -C 10 aryl or a 5- to 10-membered heteroaryl, wherein the heteroaryl contains at least one heteroatom selected from N, O or S;

[0016] X is selected from

[0017] In one embodiment of the present invention, the compound of formula (I) may more particularly have the following formula (II):

[0018]

[0019] In one embodiment of the present invention, the compound of formula (I) may more particularly have the following formula (III):

[0020]

[0021] In another embodiment of the present invention,

[0022] P1 may be selected from unsubstituted or optionally substituted by a group R1, a five- to six-membered monocyclic or eight- to ten-membered bicyclic heteroaryl group, wherein the heteroaryl group contains one to three heteroatoms selected from N, O or S;

[0023] P2 may form, together with two adjacent carbon atoms, an unsubstituted or optionally substituted three- to six-membered cycloalkyl or heterocycloalkyl group with methyl, ethyl, fluorine or chlorine, wherein the heterocycloalkyl group contains one to two heteroatoms selected from N, O or S;

[0024] P3 can be selected from

[0025] Further, among them,

[0026] R1 can be selected from hydrogen, deuterium, halogen, cyano, oxo, nitro, C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 4 Alkoxy, C 5 -C 10 Aryl or 5- to 10-membered heteroaryl;

[0027] R2 can be selected from C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy or C 5 -C 10 Aryl;

[0028] R3 can be selected from C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy, C 5 -C 10 Aryl or 5- to 10-membered heteroaryl;

[0029] Ring A may be selected from unsubstituted or optionally halogen-substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furanyl or thienyl;

[0030] X can be selected from

[0031] In another embodiment of the present invention,

[0032] P1 can be selected from

[0033] P2 can be selected from Together with two adjacent carbon atoms, they respectively form a cyclopropyl group substituted with two methyl groups, a cyclopropyl group substituted with two fluorine groups, or a cyclopentyl group;

[0034] P3 can be selected from

[0035] Further, among them,

[0036] R1 can be selected from hydrogen, deuterium, halogen, cyano, nitro, C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl or C 1 -C 4 Alkoxy, C 5 -C 10 Aryl or 5- to 10-membered heteroaryl;

[0037] R2 can be selected from C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy or C 5 -C 10 Aryl;

[0038] R3 can be selected from C 1 -C 5 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkoxy, C 5 -C 10 Aryl or 5- to 10-membered heteroaryl;

[0039] Ring A may be selected from phenyl which is unsubstituted or optionally substituted by fluorine, chlorine or bromine;

[0040] X can be selected from

[0041] In a preferred embodiment of the present invention,

[0042] R1 can be selected from hydrogen, deuterium, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl or pyridyl;

[0043] R2 can be selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl or halophenyl;

[0044] R3 can be selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl or pyridyl.

[0045] In a preferred embodiment of the present invention,

[0046] R1 may be selected from hydrogen, bromine, cyano, methyl, phenyl, benzyl, pyridyl or pyrazolyl;

[0047] R2 can be selected from isopropyl, tert-butyl, phenyl or chlorophenyl;

[0048] R3 may be selected from methyl, trifluoromethyl, cyclopropyl, tert-butoxy, tolyl, chlorophenyl, aminophenyl or amidophenyl.

[0049] In a preferred embodiment of the present invention, the compound of formula (I) may in particular have the following formula:

[0050]

[0051]

[0052] For the sake of simplicity, the "compound of formula (I)" or "compound of the present application" mentioned below may also include any isotope-labeled compound of the compound of formula (I), or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites.

[0053] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may exist in the R configuration or the S configuration, and the various isomers thus constituted are optical isomers. Optical isomers include all diastereomers, enantiomers, mesomers, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0054] The term "geometric isomer" means that when a double bond exists in a compound, the compound may exist as cis isomers, trans isomers, E isomers and Z isomers. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or a mixture thereof.

[0055] The term "tautomer" refers to an isomer that is produced by the rapid movement of an atom in a molecule between two positions. Those skilled in the art will understand that tautomers can transform into each other and may reach an equilibrium state and coexist under a certain state.

[0056] Unless otherwise indicated, references herein to "compounds of formula (I)" or "compounds of the present invention" also encompass isotope-labeled compounds in which any atom in the compound is replaced by its isotope atom. The present invention includes all pharmaceutically acceptable isotope-labeled compounds of compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number as the atoms usually found in nature but with a different atomic mass or mass number.

[0057] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C. 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O. 17 O and 18 O, and isotopes of sulfur such as 35 S.

[0058] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used in an analogous manner to the methods described in the Examples and Preparations appended herein.

[0059] The compounds of formula (I) may exist in the form of pharmaceutically acceptable salts, for example, acid addition salts and / or base addition salts of the compounds of formula (I). Unless otherwise indicated, "pharmaceutically acceptable salts" as used herein include acid addition salts or base addition salts that may occur in the compounds of formula (I).

[0060] Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, hexadecanoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemi-salts of acids and bases, such as hemi-sulfate and hemi-calcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahland Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0061] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, compounds of formula (I) are encompassed within the scope of the present invention regardless of whether they exist in solvated or unsolvated forms.

[0062] Certain compounds of the present invention may exist in different crystalline or amorphous forms. Regardless of the form in which they exist, the compounds of formula (I) are included within the scope of the present invention.

[0063] To avoid ambiguity, the following definitions are given for the terms used in this article. Unless otherwise specified, the meanings of the terms used in this article are as follows.

[0064] The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to humans. Preferably, the term refers to any national regulatory agency certified by regulatory agencies such as CFDA (China), EMEA (Europe), FDA (USA) for use in mammals, preferably humans.

[0065] "Prodrug" refers to a derivative that is converted into the compound of the present invention by reaction with an enzyme, gastric acid, etc. under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc., each catalyzed by an enzyme.

[0066] "Metabolites" refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

[0067] The term "cyano" refers to -CN.

[0068] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

[0069] As used herein, the term "independently" means that when there are more than one substituent, the substituents may be the same or different.

[0070] As used herein, the term "optional" or "optionally" means that the event it describes can or cannot occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

[0071] As used herein, the term "heteroatom" refers to oxygen (O), nitrogen (N), or S (O). m (wherein m can be 0, 1 or 2, i.e., sulfur atom S, or sulfoxide group SO, or sulfonyl group S(O) 2 ).

[0072] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, the alkyl group has 1-8, or 1-6, or 1-3 carbon atoms. For example, the term "C 1-8 "Alkyl" refers to a straight or branched chain radical having 1 to 8 carbon atoms. 1-8 The term "alkyl" includes in its definition the term "C 1-6 Alkyl", "C 1 -C 3 Alkyl" and "C 1 -C 4Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0073] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl group having m carbon atoms forming a ring and (nm) heteroatoms forming a ring, the heteroatoms being selected from O, S and N. For example, 3-7 membered heterocycloalkyl groups include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine, oxepane, thiepane, azeptan. Heterocycloalkyl groups may be optionally substituted with one or more suitable substituents.

[0074] As used in this article, the term “C 5-7 The term "aryl" refers to an aromatic group having an aromatic ring containing 5 to 7 carbon atoms, preferably phenyl.

[0075] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from O, S and N. For example, 5-7 membered heteroaryl includes, but is not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine. The heteroaryl group may be optionally substituted with one or more suitable substituents.

[0076] As used in this article, the term “C 7-11 The term "bicyclic aryl" refers to a bicyclic aryl group having 7 to 11 carbon atoms, such as naphthalene, indene, etc. The bicyclic aryl group may be optionally substituted by one or more suitable substituents.

[0077] As used herein, the term "n-membered bicyclic heteroaryl" refers to a bicyclic heteroaryl having m carbon atoms forming an aromatic bicyclic ring and (nm) heteroatoms forming an aromatic bicyclic ring, wherein the heteroatoms are selected from O, S and N. For example, 7-11 membered bicyclic heteroaryl includes, but is not limited to, quinoline, isoquinoline, benzothiazole, etc. The bicyclic heteroaryl may be optionally substituted with one or more suitable substituents.

[0078] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). For example, the term "C 1-6 "Haloalkyl" refers to a C 1-6An alkyl group (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). 1-4 "Haloalkyl" refers to a C 1-4 Alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); the term "C 1-3 "Haloalkyl" refers to a C 1-3 alkyl group (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); and the term "C 1-2 "Haloalkyl" refers to a C 1-2 An alkyl group (i.e., methyl or ethyl) (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C 1 "Haloalkyl" refers to a methyl group having 1, 2 or 3 halogen substituents. Examples of haloalkyl groups include: CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl et al.

[0079] Herein, the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent a list of all integers within the range, and the ranges are only used as a simplified representation. For example, "1-4 substituents" means 1, 2, 3, or 4 substituents; "3-8 ring atoms" means 3, 4, 5, 6, 7, or 8 ring atoms. Therefore, the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also include any subranges thereof, and each subrange is also deemed to be disclosed herein.

[0080] The compounds of the present application can be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those skilled in the art can refer to the synthetic routes of the specific compounds of the specific embodiments of the present application and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain synthetic methods for other compounds.

[0081] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

[0082] Pharmaceutically acceptable carriers can be organic or inorganic inert carrier materials, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, mannitol, cellulose, cellulose derivatives, saccharin sodium, glucose, sucrose, magnesium carbonate, saline, glycerol, ethanol, etc. In addition, the pharmaceutical composition may also contain other pharmaceutical additives, such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, disintegrants, lubricants, glidants, etc.

[0083] The dosage form of the pharmaceutical composition of the present application can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form can be a solution (including a true solution and a colloidal solution), an emulsion (including an o / w type, a w / o type and a multiple emulsion), a suspension, an injection (including a water injection, a powder injection and an infusion), an eye drop, a nasal drop, a lotion and an liniment, etc.; the solid dosage form can be a tablet (including a common tablet, an enteric-coated tablet, a lozenge, a dispersible tablet, a chewable tablet, an effervescent tablet, an orally disintegrating tablet), a capsule (including a hard capsule, a soft capsule, an enteric-coated capsule), a granule, a powder, a pill, a suppository, a film, a patch, an aerosol, a spray, etc.; the semi-solid dosage form can be an ointment, a gel, a paste, etc. The pharmaceutical composition of the present application can be made into a common preparation, a sustained-release preparation, a controlled-release preparation, a targeted preparation and various microparticle delivery systems.

[0084] In some embodiments, the dosage form of the pharmaceutical composition is selected from tablets, granules, powders, syrups, inhalants and injections.

[0085] Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may also include: (a) fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar); The invention can be prepared by mixing (a) agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarder (e.g., paraffin); (f) absorption promoter (e.g., quaternary ammonium compounds); (g) wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) adsorbents (e.g., kaolin and bentonite) and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

[0086] Preparations suitable for parenteral administration, such as injections, may include aqueous and non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions. The parenteral formulations provided herein are optionally contained in unit dose or multi-dose sealed containers (e.g., ampoules), and can be stored under freeze drying (lyophilization) conditions that require only the addition of a sterile liquid carrier (e.g., water for injection) just before use. Examples of suitable diluents for reconstructing pharmaceutical compositions (e.g., before injection) include antibacterial water for injection, 5% glucose aqueous solution, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.

[0087] Sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Inhalants may contain excipients such as lactose, or aqueous solutions containing, for example, polyethylene oxide-9-lauryl ether, glycocholate and deoxycholate, or oily solutions administered as nasal drops or sprays, or in the form of gels.

[0088] The content of the compound of the present application in its pharmaceutical composition can be adjusted according to actual needs (such as dosage form, administration method, administration object, etc.), for example, 0.1-95% by weight, such as 1-95% by weight, 5-90% by weight, 10-80% by weight, etc.

[0089] Specifically, the pharmaceutical composition of the present application may specifically contain 0.01-10 g (eg, 0.05 g, 0.1 g, 0.5 g, 1 g or 5 g, etc.) of the compound of the present application.

[0090] In a third aspect, the present application provides the use of a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a drug for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus in a subject in need thereof. A compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof can be used to treat or prevent coronavirus infection or a disease or symptom caused by coronavirus in a subject in need thereof.

[0091] The term "subject" as used herein refers to any human or non-human organism that can potentially benefit from treatment with a compound of formula (I). Exemplary subjects include humans or mammals of any age. Preferably, the subject is a human.

[0092] As used herein, the term "treatment" includes treating a disease or symptom in a mammal, particularly a human, and includes: (a) inhibiting an infection, disease or symptom, i.e., arresting or delaying the development of an infection, disease or symptom; (b) alleviating an infection, disease or symptom, i.e., causing regression of the disease or symptom, and / or (c) curing an infection, disease or symptom.

[0093] As used herein, the term "prevention" includes prophylactic therapy in mammals, especially humans, to reduce the likelihood of infection, disease or symptoms. Patients who receive prophylactic therapy can be selected based on their increased risk of infection or disease or symptoms compared to the general population. "Prevention" can include treatment of subjects who have not yet presented with an infection or clinical condition, and preventing the second occurrence of the same or similar infection or clinical condition.

[0094] The inventors of the present application have found that the compounds of the present application can inhibit coronavirus infection, for example, they can act as reversible covalent small molecule inhibitors against the 3CL protease of the new coronavirus (i.e., 3CL protease inhibitors), thereby inhibiting the viral replication of the coronavirus. Therefore, the compounds of the present application can be used to prevent or treat coronavirus infection or diseases or symptoms caused by coronavirus.

[0095] In some embodiments, the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV), and a coronavirus with a homology of greater than 85% and viral activity with any of the above coronaviruses. In some embodiments, the coronavirus is novel coronavirus (SARS-CoV-2).

[0096] In some embodiments, the diseases or symptoms caused by the coronavirus include respiratory infections, acute respiratory syndrome (SARS), pneumonia (including severe pneumonia), gastroenteritis (including acute gastroenteritis), cough, fever, chills, vomiting, headache, chills, shortness of breath, cytokine storm, etc. caused by the virus.

[0097] In a fourth aspect, the present application provides a method for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

[0098] In some embodiments, the compounds of the present invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, or through the oral mucosa, ocularly, through the lungs, through the respiratory tract, through the vagina, through the rectum, intraperitoneally, intralesionally, or around the lesion.

[0099] "Therapeutically effective amount" refers to an amount of the compound of the present application that is effective in treating or preventing coronavirus infection or diseases or symptoms caused by coronavirus when administered alone or in combination.

[0100] The specific dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors that the attending physician generally considers when determining the individual regimen and dosage level that is most suitable for a particular patient. For example, the daily dose of the compound of the present application can be particularly 0.001-150 mg / kg body weight (e.g., 0.1 mg / kg body weight, 1 mg / kg body weight, 10 mg / kg body weight or 100 mg / kg body weight, etc.).

[0101] The specific administration frequency can be determined by technicians in the relevant field, for example, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, twice a day, three times a day, etc.

[0102] In a fifth aspect, the present application provides a method for preparing a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, as follows:

[0103]

[0104] The compound of formula (I-1) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, is prepared by condensation reaction with the compound of formula (I-2) to obtain the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, wherein P1, P2 and P3 are as defined in formula (I).

[0105] In a preferred embodiment of the present invention, the condensation reaction is carried out in the presence of a condensing agent and an alkaline agent.

[0106] In a preferred embodiment of the present invention, the condensing agent is selected from one or more of a carbodiimide condensing agent, an onium salt condensing agent and an organic phosphorus condensing agent.

[0107] In a preferred embodiment of the present invention, the condensing agent is selected from one or more of DCC, DIC, EDCI, HOBt, DMAP, HOAt, HATU, HBTU, HCTU, TBTU, BOP, pyBOP, DPP-Cl, DPPA and BOP-Cl.

[0108] In a preferred embodiment of the present invention, the alkaline agent is selected from an organic base or an inorganic base.

[0109] In a preferred embodiment of the present invention, the alkaline agent is selected from one or more of DIEA, NMM and triethylamine.

[0110] In a preferred embodiment of the present invention, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, can be resolved to obtain the compound of formula (II) and the compound of formula (III) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt,

[0111]

[0112] Those skilled in the art will appreciate that the definitions and preferences described in one aspect of the present application are equally applicable to other aspects. Those skilled in the art will appreciate that the embodiments of various aspects of the present application can be combined in various ways without departing from the subject matter and ideas of the present application, and these combinations are also included in the scope of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0113] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the following specific embodiments, they are used to explain the present invention but do not constitute a limitation of the present invention. In the accompanying drawings:

[0114] Figure 1 The pharmacokinetic (PK) data of the oral administration of compound GDI-001 (15 mg / kg) to rats is shown;

[0115] Figure 2 The pharmacokinetic (PK) data of the oral administration of compound GDI-006 (15 mg / kg) to rats are shown;

[0116] Figure 3 The pharmacokinetic (PK) data of the compound GDI-011 (15 mg / kg) orally administered to rats are shown;

[0117] Figure 4 The pharmacokinetic (PK) data of the compound GDI-012 (15 mg / kg) orally administered to rats are shown; and

[0118] Figure 5 The pharmacokinetic (PK) data of the compound GDI-014 (15 mg / kg) administered orally to rats are shown. DETAILED DESCRIPTION

[0119] The compounds of formula (I) of the present application can be synthesized by various methods familiar to those skilled in the art of organic synthesis. Some exemplary synthesis methods of compounds of formula (I) are given in the following specific examples, and these methods are well known in the field of synthetic chemistry. Obviously, referring to the exemplary schemes in this patent, those skilled in the art can easily design the synthesis routes of other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions and protecting groups.

[0120] The present invention is further described below with reference to the examples; however, these examples do not limit the scope of the present invention. Unless otherwise stated, all reactants used in the examples are obtained from commercial sources; the instruments and equipment used in the synthesis experiments and product analysis and detection are conventional instruments and equipment commonly used in organic synthesis.

[0121] Example 1: Preparation of Compound GDI-001 (tert-butyl ((2S)-1-((1R,2S,5S)-2-((5-bromopyridin-3-yl)(cyano)methyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-3,3-dimethyl-1-oxobutane-2-yl)carbamate)

[0122]

[0123] 1) Synthesis steps of compound GDI-001

[0124]

[0125] At 1.0°C, DIEA (701 mg, 5.43 mmol, 945 uL, 4 eq), HOBt (275 mg, 2.04 mmol,

[0126] 1.5eq) and BOP (900 mg, 2.04 mmol, 1.5eq) were added to a DMF (2mL) solution of Cpd.4 (0.50 g, 1.36 mmol, 1eq) and Cpd.6 (288 mg, 1.36 mmol, 1eq).

[0127] 2. Continue stirring for 2 hours.

[0128] 3. LC-MS showed the target product appeared.

[0129] 4. Filter the reaction solution and spin dry the filtrate.

[0130] 5. Direct purification using prep-HPLC (neutral conditions).

[0131] 6. Obtained white solid GDI-001 (320 mg, 553 μmol, 40.8% yield, 97.2% purity).

[0132] 1 H NMR (400 MHz, DMSO-d 6 )δ9.63–9.37(m,1H),8.76(d,J=3.1Hz,1H),8.66(d,J=7.7Hz,1H),8.09(s,1H),6.68(t,J=8.1Hz,1H),6.46–6.17(m,1H),4.24(s,1H),4.00( d,J=9.1Hz,1H),3.94–3.76(m,2H),1.60–1.49(m,1H),1.35(s,10H),1 .31–1.22(m,1H),1.06–0.98(m,3H),0.90(s,11H),0.91–0.83(m,10H).

[0133] Example 2: Preparation of compound GDI-002 ((1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-N-((5-bromopyridin-3-yl)(cyano)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide formate)

[0134]

[0135] 1) The operation of step 1 is the same as that of Example 1.

[0136] 2) Synthesis steps of compound GDI-002

[0137]

[0138] 1. Dissolve GDI-001 (280 mg, 498 μmol, 1 eq) in HCOOH (5.6 mL) at room temperature.

[0139] 2. React at 40°C for 1 hour.

[0140] 3. LC-MS showed that GDI-001 was completely consumed, and the main peak was the target product MS.

[0141] 4. Directly spin dry to obtain a crude solid.

[0142] 5. Use MeCN (10 mL) and H 2O (50 mL), and then lyophilized to remove excess HCOOH to obtain a crude product 0.26 g GDI-002.

[0143] 6. Direct prep-HPLC (FA conditions) purification and separation.

[0144] 7. Obtained white solid GDI-002 (0.23 g, 452 μmol, 90.9% yield, 100% purity, FA salt).

[0145] 1 H NMR (400 MHz, DMSO-d 6 )δ9.65–9.45(m,1H),8.76(s,1H),8.66(d,J=7.2Hz,1H),8.22(s,1H),8.11(d,J=10.2Hz,1H),6.49–6.22(m,1H),4.24(s,1H), 3.88–3.75(m,2H),3.70–3.62(m,1H),1.63–1.50(m,1H),1.41–1.24(m,1H),1.10–0.99(m,4H),0.95–0.89(m,5H),0.88(s,9H).

[0146] Example 3: Preparation of Compound 3 ((1R, 2S, 5S)-3-((S)-2-acetamide-3,3-dimethylbutyryl)-N-((5-bromopyridin-3-yl)(cyano)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0147]

[0148] 1) The operation of steps 1 and 2 is the same as in Example 2.

[0149] 2) Synthesis steps of compound GDI-003

[0150] Ac2O (32.1 mg, 315 μmol, 29.5 uL, 1 eq) was added to a solution of GDI-002 (160 mg, 315 μmol, 1 eq, FA) and TEA (63.7 mg, 629 μmol, 87.6 uL, 2 eq) in DCM (3.2 mL) at 1.0°C.

[0151] Stirring was continued at 2.0°C for 2 hours.

[0152] 3. LC-MS showed that GDI-002 had been completely consumed and the target product MS appeared.

[0153] 4. Spin dry the reaction solution.

[0154] 5. Purify directly using prep-HPLC (neutral conditions).

[0155] 6. Obtained pale yellow solid GDI-003 (87 mg, 172 μmol, 54.8% yield, 100% purity).

[0156] 1 H NMR (400 MHz, DMSO-d 6 )δ9.64–9.42(m,1H),8.76(d,J=2.1Hz,1H),8.67(d,J=8.6Hz,1H),8.08( s,1H),7.95–7.81(m,1H),6.48–6.21(m,1H),4.28(d,J=8.5Hz,1H),4.21 (d,J=3.1Hz,1H),3.94–3.73(m,2H),1.84(s,3H),1.60–1.48(m,1H),1.4 0–1.24(m,1H),1.06–0.98(m,3H),0.98–0.88(m,9H),0.88–0.82(m,3H).

[0157] Example 4: Preparation of Compound GDI-004 (tert-butyl ((2S)-1-((1R,2S,5S)-2-((cyano(5-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate)

[0158] Compound GDI-004 was obtained in a similar manner to Example 3.

[0159]

[0160] 1 H NMR (400 MHz, DMSO-d 6 )δ9.71–9.50(m,1H),9.08–9.00(m,1H),8.98(d,J=10.3Hz,1H),8.20(s,1H),6.73–6.61(m,1H),6.56–6.32(m,1H),4.30–4.20(m,1H) ,4.00(d,J=9.4Hz,1H),3.94–3.79(m,2H),1.60–1.51(m,1H),1.35(s,9H),1.32–1.21(m,1H),1.06–0.99(m,3H),0.97–0.82(m,12H).

[0161] Example 5: Preparation of compound GDI-005 ((1R,2S,5S)-3-((S)-2-acetamide-3,3-dimethylbutanoyl)-N-(cyano(5-methylpyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0162] 1) Synthesis steps of Cpd.8

[0163]

[0164] (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (174 mg, 616.20 μmol, 1 eq) was dissolved in DCM (3.48 mL) at 1.0 °C.

[0165] 2. TEA (124.70 mg, 1.23 mmol, 171.53 uL, 2 eq) was then added.

[0166] 3. Add and Ac in batches 2 O (75.49 mg, 739.44 μmol, 69.26 uL, 1.2 eq) was added to the above reaction solution.

[0167] Stirring was continued at 4.0°C for 2 hours.

[0168] 5. LC-MS showed the target product.

[0169] 6. Add saturated NH 4 Cl (300 mL) solution.

[0170] 7. Extract the reaction solution with EtOAc (300 mL*3).

[0171] 8. Combine the organic phases and spin dry.

[0172] 9. A colorless oil (1R, 2S, 5S)-3-[(2S)-2-acetylamino-3,3-dimethyl-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (0.18 g, 537.65 μmol, 87.25% yield) was obtained.

[0173] 2) Synthesis steps of Cpd.9

[0174]

[0175] Cpd.8 (0.18 g, 554.85 μmol, 1 eq) was added to MeOH (1.8 mL) and H at 1.0 °C.2 O (0.54 mL) was added to the mixed solution, followed by the addition of LiOH. 2 O (46.57 mg, 1.11 mmol, 2 eq).

[0176] 2. Continue stirring at 0°C for 2 hours.

[0177] 3. LC-MS showed the target product appeared.

[0178] The reaction was quenched with saturated NH4Cl solution (100 mL) at 4.0°C.

[0179] 5. At low temperature, adjust the pH to 5-6 with 2M citric acid solution.

[0180] 6. Extract the aqueous phase with EtOAc (20 mL*3).

[0181] 7. Combine the organic phases and spin dry.

[0182] 8. Obtained colorless liquid (1R, 2S, 5S)-3-[(2S)-2-acetylamino-3,3-dimethyl-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (130 mg, 418.83 μmol, 75.49% yield).

[0183] 3) Synthesis steps of compound GDI-005

[0184]

[0185] DIEA (108.26 mg, 837.66 μmol, 145.91 uL, 4 eq), HOBt (42.45 mg, 314.12 μmol, 1.5 eq) and BOP (138.93 mg, 314.12 μmol, 1.5 eq) were added to a solution of (1R,2S,5S)-3-[(2S)-2-acetylamino-3,3-dimethyl-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (65 mg, 209.42 μmol, 1 eq) and 2-amino-2-(5-methyl-3-pyridyl)acetonitrile (36.99 mg, 251.30 μmol, 1.2 eq) in DMF (1.3 mL) at 1.0°C.

[0186] 2. Continue stirring for 2 hours.

[0187] 3. LC-MS showed the target product appeared.

[0188] 4. Filter the reaction solution and spin dry the filtrate.

[0189] 5. Direct purification using prep-HPLC (neutral conditions).

[0190] 6. Obtained grayish yellow solid GDI-005 (27.1 mg, 61.65 μmol, 29.44% yield).

[0191] 1 H NMR (400 MHz, DMSO-d 6 )δ9.57–9.33(m,1H),8.55–8.37(m,2H),7.87(t,J=7.6Hz,1H),7.69(d,J=9.2Hz,1H),6.38–6.15(m,1H),4.29(d,J=8.7Hz,1H),4.23(s,1 H),3.93–3.73(m,2H),2.33(s,3H),1.84(s,3H),1.64–1.46(m,1H),1.40–1.19(m,1H),1.05–0.97(m,3H),0.93(s,9H),0.89–0.82(m,3H).

[0192] Example 6: Preparation of compound GDI-006 ((1R,2S,5S)-3-((S)-2-acetamide-3,3-dimethylbutanoyl)-N-(cyano(isoquinolin-4-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide) Compound GDI-006 was obtained in a manner similar to Example 5.

[0193]

[0194] 1 H NMR (400 MHz, DMSO-d 6 )δ9.59–9.44(m,1H),9.42(s,1H),8.72(d,J=7.0Hz,1H),8.29–8.16(m,1H),8.06– 7.95(m,1H),7.95–7.83(m,1H),7.83–7.70(m,2H),6.94–6.80(m,1H),4.35–4.24( m,1H),4.20(d,J=14.6Hz,1H),3.94–3.75(m,2H),1.88–1.78(m,3H),1.62–1.46(m ,1H),1.33–1.04(m,1H),1.04–0.96(m,3H),0.97–0.88(m,9H),0.85–0.77(m,3H).

[0195] Example 7: Preparation of Compound GDI-007 ((1R,2S,5S)-3-((S)-2-acetamide-3,3-dimethylbutanol)-N-(cyano(5-(trifluoromethyl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0196] Compound GDI-007 was obtained in a similar manner to Example 5.

[0197]

[0198] 1 H NMR (400 MHz, DMSO-d 6 )δ9.36–9.17(m,1H),9.07–8.93(m,1H),8.20(s,1H),7.97–7.74(m,1H),6.61–6.31(m,1H),4.31(dd,J=34.0,8.7Hz,1H),4.22(d,J=4.7 Hz,1H),3.96–3.76(m,2H),1.85(s,3H),1.63–1.51(m,1H),1.45–1.22(m,1H),1.05–1.00(m,3H),0.99–0.89(m,9H),0.89–0.85(m,3H).

[0199] Example 8: Preparation of Compound GDI-008 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(5-methoxypyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0200] Compound GDI-008 was obtained in a similar manner to Example 5.

[0201]

[0202] 1 H NMR (400 MHz, DMSO-d 6)δ9.56–9.38(m,1H),8.39–8.21(m,2H),7.95–7.79(m,1H),7.43(s,1H) ,6.42–6.18(m,1H),4.29(d,J=8.6Hz,1H),4.26–4.18(m,1H),3.86(s,3 H),3.85–3.76(m,2H),1.84(s,3H),1.65–1.44(m,1H),1.41–1.34(m,1H ),1.28–1.20(m,1H),1.06–0.98(m,3H),0.92(s,9H),0.88–0.82(m,3H).

[0203] Example 9: Preparation of Compound GDI-009 ((1R,2S,5S)-3-((S)-2-acetamide-3,3-dimethylbutanoyl)-N-((5-bromo-4-methylpyridin-3-yl)(cyano)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0204] Compound GDI-009 was obtained in a similar manner to Example 5.

[0205]

[0206] 1 H NMR (400 MHz, DMSO-d 6 )δ9.44–9.15(m,1H),8.83–8.72(m,1H),8.63(s,1H),7.92–7.78(m,1H),6.50–6.35(m,1H),4.26(t,J=10.1Hz,1H),4.19–4.09(m,1H), 3.93–3.72(m,2H),2.43–2.29(m,3H),1.89–1.75(m,3H),1.65–1.49(m,1H),1.31–1.18(m,1H),1.10–0.99(m,3H),0.99–0.77(m,12H).

[0207] Example 10: Preparation of Compound GDI-010 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(5-cyanopyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0208] Compound GDI-010 was obtained in a similar manner to Example 5.

[0209]

[0210] 1 H NMR (400 MHz, DMSO-d 6 )δ9.68–9.48(m,1H),9.07(d,J=5.0Hz,1H),8.94(d,J=9.7Hz,1H),8.31(d ,J=7.8Hz,1H),7.88(d,J=8.4Hz,1H),6.53–6.25(m,1H),4.27(d,J=8.5Hz, 1H),4.21(d,J=4.4Hz,1H),3.95–3.75(m,2H),1.85(s,3H),1.65–1.48(m, 1H),1.43–1.30(m,1H),1.07–1.00(m,3H),0.91(s,9H),0.88–0.83(m,3H).

[0211] Example 11: Preparation of Compound GDI-011 ((1R,2S,5S)-N-((5-bromopyridin-3-yl)(cyano)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0212] Compound GDI-011 was obtained in a similar manner to Example 5.

[0213]

[0214] 1 H NMR (400 MHz, DMSO-d 6 )δ9.66–9.46(m,1H),8.76(s,1H),8.67(d,J=5.3Hz,1H),8.09(s,1H), 6.48–6.22(m,1H),4.38(s,1H),4.25(s,1H),3.95–3.87(m,1H),3.75– 3.62(m,1H),3.21–3.04(m,1H),2.31–2.03(m,1H),1.64–1.51(m,1H), 1.37–1.26(m,1H),1.05–1.01(m,3H),0.97(s,9H),0.89–0.81(m,3H).

[0215] Example 12: Preparation of Compound GDI-012 ((1R,2S,5S)-N-(cyano(5-(trifluoromethyl)pyridin-3-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0216] Compound GDI-012 was obtained in a similar manner to Example 5.

[0217]

[0218] 1 H NMR (400 MHz, DMSO-d 6 )δ9.72–9.51(m,1H),9.48–9.32(m,1H),9.04(s,1H),8.98(d,J=8.4Hz,1H),8.21(s,1H),6.59–6.33(m,1H),4.37(d,J=7.3Hz,1H),4.25(s,1 H),3.99–3.80(m,1H),3.68(t,J=12.0Hz,1H),1.68–1.51(m,1H),1.52 –1.30(m,1H),1.06–1.01(m,3H),1.01–0.90(m,9H),0.89–0.84(m,3H).

[0219] Example 13: Preparation of Compound GDI-013 (2-chlorobenzyl (1R, 2S, 5S) -2- ((5-bromopyridin-3-yl)(cyano)methyl) carbamoyl) -6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-carboxylate)

[0220] Compound GDI-013 was obtained in a similar manner to Example 5.

[0221]

[0222] 1 H NMR (400 MHz, DMSO-d 6 )δ9.68–9.46(m,1H),8.83–8.59(m,2H),8.15–7.99(m,1H),7.50–7.17(m,4H),6.43–6.26(m,1H),5.25–4.93(m,2H),4.11(d,J= 22.8Hz,1H),3.77–3.61(m,1H),3.51–3.38(m,1H),1.55–1.44(m,1H),1.44–1.32(m,1H),1.09–0.99(m,3H),0.94–0.83(m,3H).

[0223] Example 14: Preparation of Compound GDI-014 ((1R,2S,5S)-N-(cyano(5-cyanopyridin-3-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0224] Compound GDI-014 was obtained in a similar manner to Example 5.

[0225]

[0226] 1 H NMR (400 MHz, DMSO-d 6 )δ9.74–9.52(m,1H),9.50–9.32(m,1H),9.11–9.03(m,1H),8.94(d,J= 6.0Hz,1H),8.38–8.27(m,1H),6.52–6.27(m,1H),4.37(s,1H),4.25(s, 1H),4.04–3.84(m,1H),3.69(t,J=12.3Hz,1H),1.66–1.54(m,1H),1.51 –1.33(m,1H),1.06–1.01(m,3H),1.00–0.91(m,9H),0.89–0.79(m,3H).

[0227] Example 15: Preparation of Compound GDI-015 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0228] Compound GDI-015 was obtained in a similar manner to Example 5.

[0229]

[0230] 1 H NMR (400 MHz, DMSO-d 6)δ9.72–9.51(m,1H),9.32–9.24(m,1H),8.93(d,J=6.8Hz,1H),8.52(s,1H),7.99–7.80(m,1H),6.59–6.39(m,1H),4.26(d,J=8.8Hz,1H),4.2 2(d,J=6.9Hz,1H),3.96–3.73(m,2H),2.47(s,3H),1.84(s,3H),1.59– 1.48(m,1H),1.41–1.25(m,1H),1.05–0.99(m,3H),0.97–0.82(m,12H).

[0231] Example 16: Preparation of Compound GDI-016 ((1R,2S,5S)-N-(cyano(5-(trifluoromethyl)pyridin-3-yl)methyl)-3-((S)-3,3-dimethyl-2-((4-methylphenyl)sulfonamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0232] Compound GDI-016 was obtained in a similar manner to Example 5.

[0233]

[0234] 1 H NMR (400 MHz, DMSO-d 6 )δ9.68–9.55(m,1H),9.02–8.91(m,2H),8.18(d,J=7.6Hz,1H),7.80–7.70(m,1H ),7.67–7.55(m,2H),7.30(d,J=7.9Hz,2H),6.50–6.27(m,1H),4.07(d,J=5.8Hz, 1H),3.77(td,J=10.5,5.6Hz,1H),3.58(s,1H),3.43(dd,J=17.4,10.1Hz,1H),2. 32(s,3H),0.95(d,J=17.3Hz,3H),0.75(d,J=2.8Hz,9H),0.57(d,J=22.5Hz,3H).

[0235] Example 17: Preparation of Compound GDI-017 ((1R,2S,5S)-N-(cyano(5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)methyl)-3-(S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0236] Compound GDI-017 was obtained in a similar manner to Example 5.

[0237]

[0238] 1 H NMR (400 MHz, DMSO-d 6 )δ9.67–9.62(m,1H),9.40–9.32(m,1H),9.23(dd,J=3.4,2.0Hz,1H),8.89(t,J=2.6Hz,1 H),8.49(dt,J=4.8,2.2Hz,1H),6.53–6.38(m,1H),4.33(t,J=6.7Hz,1H),4.21(d,J=5.1H z,1H),3.91–3.83(m,1H),3.68–3.60(m,1H),2.43(s,3H),1.53(dd,J=14.9,6.7Hz,1H), 1.39–1.27(m,1H),0.99(d,J=13.9Hz,3H),0.89(d,J=13.8Hz,9H),0.82(d,J=5.7Hz,3H).

[0239] Example 18: Preparation of Compound GDI-018 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(5-(methylcarbamoyl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0240] Compound GDI-018 was obtained in a similar manner to Example 5.

[0241]

[0242] 1 H NMR (400 MHz, DMSO-d 6 )δ9.56–9.45(m,1H),9.00(t,J=2.4Hz,1H),8.76(dt,J=6.2,3.2Hz,2H),8.38 –8.17(m,1H),7.94–7.78(m,1H),6.46–6.31(m,1H),4.36–4.19(m,2H),3.91–3 .73(m,2H),2.83(t,J=4.2Hz,3H),1.85(s,3H),1.59–1.49(m,1H),1.38–1.23 (m,1H),1.02(d,J=16.1Hz,3H),0.92(d,J=5.8Hz,9H),0.87(d,J=12.0Hz,3H).

[0243] Example 19: Preparation of Compound GDI-019 ((1R,2S,5S)-N-(cyano(5-(trifluoromethyl)pyridin-3-yl)methyl)-3-((S)-2-((4-(dimethylamino)phenyl)sulfonamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0244] Compound GDI-019 was obtained in a similar manner to Example 5.

[0245]

[0246] 1 H NMR (400 MHz, DMSO-d 6 )δ9.70–9.54(m,1H),9.00(d,J=8Hz,1H),8.93(d,J=8Hz,1H),8.21–8.15(m,1H),7.51( d,J=8.5Hz,2H),7.22(dd,J=16.1,8.8Hz,1H),6.68(d,J=8.8Hz,2H),6.51–6.27(m,1H) ,4.10(d,J=2.5Hz,1H),3.81–3.72(m,1H),3.54–3.39(m,2H),2.94(s,6H),1.55–1.50( m,1H),1.33–1.17(m,1H),0.96(d,J=16.4Hz,3H),0.74(s,9H),0.67(d,J=17.4Hz,3H).

[0247] Example 20: Preparation of Compound GDI-020 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0248] Compound GDI-020 was obtained in a similar manner to Example 5.

[0249]

[0250] 1 H NMR (400 MHz, DMSO-d 6)δ11.83(s,1H),9.38(t,J=7.5Hz,1H),8.31(dd,J=4.6,2.2Hz,1H),8.08(dd,J=6.8,2.2Hz, 1H),7.88(t,J=9.6Hz,1H),7.56(s,1H),6.50(ddd,J=8.7,3.4,1.8Hz,1H),6.34–6.24(m,1H) ,4.31(d,J=8.7Hz,1H),4.25(s,1H),3.91–3.74(m,2H),1.84(d,J=5.3Hz,3H),1.58–1.46(m, 1H),1.36–1.15(m,2H),1.00(d,J=27.2Hz,3H),0.94(d,J=2.9Hz,9H),0.85(d,J=8.3Hz,3H).

[0251] Example 21: Preparation of Compound GDI-021 ((1R,2S,5S)-N-((5-bromopyridin-3-yl)(cyano)methyl)-3-((S)-3,3-dimethyl-2-((4-methylphenyl)sulfonamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0252] Compound GDI-021 was obtained in a similar manner to Example 5.

[0253]

[0254] 1 H NMR (400 MHz, DMSO-d 6 )δ9.66–9.50(m,1H),8.80–8.62(m,2H),8.09(dt,J=4.6,2.2Hz,1H),7.78(t,J=8.0Hz, 1H),7.71–7.58(m,2H),7.34(d,J=8.0Hz,2H),6.45–6.21(m,1H),4.11(d,J=4.3Hz,1H), 3.88–3.75(m,1H),3.66–3.60(m,1H),3.54–3.41(m,1H),2.36(s,3H),1.62–1.48(m,1H ),1.35–1.20(m,1H),0.99(d,J=15.4Hz,3H),0.92–0.71(m,9H),0.61(d,J=17.7Hz,3H).

[0255] Example 22: Preparation of Compound GDI-022 ((1R,2S,5S)-N-(cyano(isoquinolin-4-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0256] Compound GDI-022 was obtained in a similar manner to Example 5.

[0257]

[0258] 1 H NMR (400 MHz, DMSO-d 6 )δ9.62–9.46(m,1H),9.44–9.30(m,2H),8.73(d,J=5.9Hz,1H),8.29–8.20(m,1 H),8.03–7.88(m,1H),7.80(td,J=6.7,3.5Hz,2H),6.92–6.83(m,1H),4.40(t,J =7.6Hz,1H),4.24(d,J=14.3Hz,1H),3.98–3.91(m,1H),3.75–3.66(m,1H),1.65 –1.50(m,1H),1.35(d,J=7.6Hz,1H),1.08–0.90(m,12H),0.81(d,J=7.0Hz,3H).

[0259] Example 23: Preparation of Compound GDI-023 ((1R,2S,5S)-N-(cyano(isoquinolin-4-yl)methyl)-3-((S)-3,3-dimethyl-2-((4-methylphenyl)sulfonamido)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0260] Compound GDI-023 was obtained in a similar manner to Example 5.

[0261]

[0262] 1 H NMR (400 MHz, DMSO-d 6)δ9.62–9.51(m,1H),9.42(d,J=3.0Hz,1H),8.71(d,J=6.4Hz,1H),8.25(dd,J=8.9,4.1Hz,1H), 8.03–7.72(m,4H),7.66(dd,J=12.6,8.1Hz,2H),7.31(t,J=8.8Hz,2H),6.90–6.80(m,1H),4.08( d,J=9.0Hz,1H),3.84(dt,J=13.1,6.7Hz,1H),3.65(d,J=8.4Hz,1H),3.53–3.40(m,1H),2.34(d, J=3.8Hz,3H),1.58–1.48(m,1H),1.35–1.18(m,1H),1.06–0.80(m,12H),0.54(d,J=11.5Hz,3H).

[0263] Example 24: Preparation of Compound GDI-024 ((1R,2S,5S)-3-((S)-2-acetylamino-3,3-dimethylbutyryl)-N-(cyano(1H-indol-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0264] Compound GDI-024 was obtained in a similar manner to Example 5.

[0265]

[0266] 1 H NMR (400 MHz, DMSO-d 6 )δ11.27(s,1H),9.17(dd,J=13.6,7.5Hz,1H),7.83(t,J=8.0Hz,1H),7.55(d,J=7.9Hz,1H),7.49(dd,J =6.1,2.5Hz,1H),7.39(dd,J=8.2,4.3Hz,1H),7.12(tdd,J=7.0,3.2,1.2Hz,1H),7.06–6.95(m,1H),6.2 5(dd,J=7.6,1.8Hz,1H),4.29(dd,J=8.7,1.7Hz,1H),4.24(d,J=2.6Hz,1H),3.86–3.76(m,2H),1.80(d ,J=6.6Hz,3H),1.53–1.41(m,1H),1.29–1.07(m,1H),0.99(d,44Hz,3H),0.93(s,9H),0.79(d,8Hz,3H).

[0267] Example 25: Preparation of Compound GDI-025 ((1R,2S,5S)-N-((5-bromopyridin-3-yl)(cyano)methyl)-3-((S)-3,3-dimethyl-2-((trifluoromethyl)sulfonamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0268] Compound GDI-025 was obtained in a similar manner to Example 5.

[0269]

[0270] 1 H NMR (400 MHz, DMSO-d 6 )δ9.81–9.50(m,2H),8.89–8.60(m,2H),8.10(dt,J=12.6,2.2Hz,1H),6.46–6.23(m,1H),4.28(d,J=4.3Hz,1H),3.89(d,J=8.0H z,2H),3.63–3.47(m,1H),1.64–1.54(m,1H),1.45–1.31(m,1H),1.04(d,J=12.8Hz,3H),1.0–0.96(m,9H),0.90(d,J=5.6Hz,3H).

[0271] Example 26: Preparation of Compound GDI-026 ((1R,2S,5S)-N-((5-bromopyridin-3-yl)(cyano)methyl)-3-((S)-2-((4-(dimethylamino)phenyl)sulfonamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0272] Compound GDI-026 was obtained in a similar manner to Example 5.

[0273]

[0274] 1 H NMR (400 MHz, DMSO-d 6)δ9.66–9.52(m,1H),8.76(dd,J=8.0,4.0Hz,1H),8.66(dd,J=8.0,4.0Hz,1H),8.10(q,J=2. 3Hz,1H),7.68–7.47(m,2H),7.27(dd,J=11.5,8.9Hz,1H),6.78–6.65(m,2H),6.45–6.22(m,1 H),4.15(d,J=2.1Hz,1H),3.85–3.77(m,1H),3.62–3.40(m,2H),2.99(s,6H),1.59–1.49(m,1 H),1.37–1.22(m,1H),1.00(d,J=15.0Hz,3H),0.82(d,J=3.1Hz,9H),0.70(d,J=14.5Hz,3H).

[0275] Example 27: Preparation of Compound GDI-027 ((1R,2S,5S)-N-(cyano(isoquinolin-4-yl)methyl)-3-((S)-2-((4-(dimethylamino)phenyl)sulfonyl)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0276] Compound GDI-027 was obtained in a similar manner to Example 5.

[0277]

[0278] 1 H NMR (400 MHz, DMSO-d 6 )δ9.62–9.50(m,1H),9.42(d,J=2.2Hz,1H),8.72(d,J=5.9Hz,1H),8.34–8.23(m,1H),8.05–7.70(m,3H) ,7.66–7.48(m,2H),7.32–7.22(m,1H),6.85(dd,J=15.3,7.8Hz,1H),6.76–6.54(m,2H),4.11(d,J=10.0 Hz,1H),3.93–3.73(m,1H),3.54(dd,J=9.1,3.4Hz,1H),3.46(dd,J=10.1,6.5Hz,1H),2.97(s,6H),1.60 –1.48(m,1H),1.28(d,J=7.7Hz,1H),1.01(d,J=2.7Hz,2H),0.96–0.72(m,10H),0.64(d,J=10.6Hz,3H).

[0279] Example 28: Preparation of Compound GDI-028 ((1R,2S,5S)-N-((5-(1H-pyrazol-1-yl)pyridin-3-yl)(cyano)methyl)-3-((S)-2-acetylamino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0280] Compound GDI-028 was obtained in a similar manner to Example 5.

[0281]

[0282] 1H NMR (400MHz, DMSO-d 6 )δ9.60–9.50(m,1H),9.17–9.14(m,1H),8.73–8.65(m,1H),8.62–8.59(m ,1H),8.34(q,J=2.6Hz,1H),7.97–7.70(m,2H),6.66–6.62(m,1H),6.50– 6.35(m,1H),4.32–4.20(m,2H),3.90–3.78(m,2H),1.85(s,3H),1.60–1. 48(m,1H),1.40–1.26(m,1H),1.02(d,J=17.3Hz,3H),0.94–0.83(m,12H).

[0283] Example 29: Preparation of Compound GDI-029 ((1R,2S,5S)-N-(cyano(isoquinolin-4-yl)methyl)-3-((S)-3,3-dimethyl-2-((trifluoromethyl)sulfonamido)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0284] Compound GDI-029 was obtained in a similar manner to Example 5.

[0285]

[0286] 1H NMR (400MHz, DMSO-d 6)δ9.76–9.52(m,2H),9.42(s,1H),8.79–8.69(m,1H),8.35–8.20(m,1H),8.10–7.65(m,3H),6.87–6.75(m,1H),4.23(d,J=14.5Hz,1H), 4.08(d,J=218.1Hz,3H),4.0–3.80(m,2H),1.7–1.5(m,1H),1.43–1.31(m,1H),1.21–1.27(m,2H),1.03–0.98(m,9H),0.94–0.80(m,4H).

[0287] Example 30: Preparation of Compound GDI-030 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0288] Compound GDI-030 was obtained in a similar manner to Example 5.

[0289]

[0290] 1H NMR (400MHz, DMSO-d 6 )δ9.54–9.38(m,1H),8.86(d,J=2.7Hz,1H),8.49(d,J=6.5Hz,1H),8.33(d,J=20.3Hz,1H),8.06–7.95(m,2H),7.86(t,J=8.4Hz,1H),6.41–6 .20(m,1H),4.30–4.22(m,2H),4.04–3.69(m,5H),1.86(s,3H),1.60–1 .48(m,1H),1.41–1.20(m,1H),1.06–0.98(m,3H),0.97–0.77(m,12H).

[0291] Example 31: Preparation of Compound GDI-031 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0292] Compound GDI-031 was obtained in a similar manner to Example 5.

[0293]

[0294] 1 H NMR (400 MHz, DMSO-d 6 )δ9.64–9.52(m,1H),9.26(s,1H),8.93(d,J=7.7Hz,1H),8.63–8.45(m,1H),7.84(t,J=9.0Hz,1H),6.55–6.41(m,1H),4.29–4.19(m,2H ),3.90–3.75(m,2H),3.25–3.07(m,1H),1.83(s,3H),1.62–1.50(m,1H),1.44–1.32(m,7H),1.02(d,J=14.0Hz,3H),0.98–0.72(m,12H).

[0295] Example 32: Preparation of Compound GDI-032 ((1R,2S,5S)-N-((5-(1H-pyrazol-4-yl)pyridin-3-yl)(cyano)methyl)-3-((S)-2-acetylamino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0296] Compound GDI-032 was obtained in a similar manner to Example 5.

[0297]

[0298] 1 H NMR (400 MHz, DMSO-d 6 )δ13.13(s,1H),9.52–9.38(m,1H),8.91(s,1H),8.59–8.30(m,2H),8.15–8.00(s,2H),7.90–7.80(m,1H),6.38–8.20 (m,1H),4.41–4.18(m,2H),3.90–3.78(m,2H),1.85(s,3H),1.69–1.51(m,1H),1.43–1.22(m,1H),1.11–0.75(m,15H).

[0299] Example 33: Preparation of Compound GDI-033 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(cyano(8-fluoroisoquinolin-4-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0300] Compound GDI-033 was obtained in a similar manner to Example 5.

[0301]

[0302] 1 H NMR (400 MHz, DMSO-d 6 )δ9.72–9.33(m,2H),8.83(d,J=8.1Hz,1H),8.06–7.73(m,3H),7.61(t,J=9.1Hz,1H),6.89(dd,J=11.0,8.1Hz,1H),4.27(t,J=8.2H z,1H),4.19(d,J=13.4Hz,1H),3.93–3.79(m,2H),1.82(d,J=9.8Hz,3H),1.60–1.48(m,1H),1.34–1.07(m,1H),1.06–0.76(m,15H).

[0303] Example 34: Preparation of Compound GDI-034 (5-((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)(cyano)methyl)nicotinate)

[0304] Compound GDI-034 was obtained in a similar manner to Example 5.

[0305]

[0306] 1 H NMR (400 MHz, DMSO-d 6 )δ9.59–9.48(m,1H),9.09(s,1H),8.89(dd,J=6.0,2.8Hz,1H),8.38(s,1H),7.85(t,J=8.0Hz,1H),6.52–6.36(m,1H),4.29–4.19(m,2H) ,3.92(s,3H),3.87–3.76(m,2H),2.07(s,1H),1.84(s,3H),1.65–1.42(m,1H),1.37–1.22(m,1H),1.02(d,J=13.6Hz,3H),0.88(m,12H).

[0307] Example 35: Preparation of Compound GDI-035 ((1R,2S,5S)-N-((5-(1H-pyrazol-5-yl)pyridin-3-yl)(cyano)methyl)-3-((S)-2-acetylamino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)

[0308] Compound GDI-035 was obtained in a similar manner to Example 5.

[0309]

[0310] 1 H NMR (400 MHz, DMSO-d 6 )δ13.15(s,1H),9.53–9.45(m,1H),9.04(s,1H),8.66–8.52(m,1H),8.28(s,1H),7.85(d,J=8.0Hz,2H),6.93–6.85(m,1H),6. 43–6.30(m,1H),4.32–4.23(m,2H),3.88–3.80(m,2H),1.85(s,3H),1.60–1.48(m,1H),1.38–1.22(m,1H),1.12–0.81(m,15H).

[0311] Example 36 and Example 37: Preparation of Compound GDI-036 and Compound GDI-037

[0312] Compound 6 was chiral resolved to give compounds GDI-036 and GDI-037.

[0313] The chiral column used YMC Cellulose-SC (10um 50*250mm) with hexane and ethanol in a ratio of 7:3 as the mobile phase. The separation volume was 300 mg, and the retention times were 2 minutes and 7.5 minutes, respectively.

[0314] 1 H NMR (400 MHz, DMSO-d 6 )δ=9.44(d,J=7.9Hz,1H),9.42-9.39(m,1H),8.73-8.69(m,1H),8.27-8.22(m,1H),8.02-7.97(m,1H),7.94-7.8 9(m,1H),7.88-7.83(m,1H),7.81-7.76(m,1H),6.87-6.83(m,1H),4.30-4.25(m,1H),4.23-4.19(m,1H),3.90-F 3.83(m,1H),3.82-3.76(m,1H),1.87-1.79(m,3H),1.54-1.46(m,1H),1.09-1.05(m,1H),0.92-0.87(m,12H),0.83-0.77(m,3H).

[0315] 1 H NMR (400 MHz, DMSO-d6 )δ=9.60-9.50(m,1H),9.45-9.36(m,1H),8.77-8.68(m,1H),8.26-8.19(m,1H ),8.00-7.93(m,1H),7.85-7.73(m,3H),6.94-6.84(m,1H),4.33-4.25(m,1H) ,4.19-4.13(m,1H),3.94-3.85(m,1H),3.84-3.77(m,1H),1.83-1.77(m,3H), 1.61-1.53(m,1H),1.34-1.27(m,1H),1.02(s,3H),0.95(s,9H),0.82(s,3H).

[0316] Test Example 1: Activity determination of compounds

[0317] SARS-CoV-2 / Hela-ACE Test

[0318] Compounds were transferred to 384-well plates (Greiner, Part. No. 781090-2B) and then added to Hela-ACE cells (cell density 5000 cells / 20 μl MEM with 2% FBS). Plates with cells were transferred to the BSL3 laboratory. SARS-CoV-2 (USA-WA1 / 2020 Vero E6 cells) was diluted to an MOI of 0.75 to 1 to achieve ~30–60% cell infection. After the test plates were incubated at 37°C 5% CO2 for 48 hours, formaldehyde was added to a final concentration of 4% to fix the cells. Human polyclonal serum antibodies were used as primary antibodies, and goat anti-human H+L conjugated Alexa 488 (Thermo Fisher Scientific A11013) was used as secondary antibodies. DAPI (Thermo Fisher Scientific D1306) DNA staining.

[0319] Uninfected cell toxicity assay

[0320] The compound was transferred to a 1536-well plate (Corning No.9006BC) and then added to Hela-ACE cells (cell density 600 cells / 5 μl MEM with 2% FBS). After the test plate was incubated at 37°C 5% CO2 for 48 hours, the cell activity was tested. 2 μL of 50% Cell-Titer Glo (Promega No G7573) water was diluted and added to the cell test plate, and the value was read using EnVision Plate Reader (Perkin Elmer).

[0321] Enzyme activity test

[0322] Inhibition assays were performed using 200 nM recombinant SARS-CoV-2 main protease and 15 μM fluorogenic substrate (Dabcyl-TSAVL QSGFRK-Glu (EDANS); Genscript). The assay buffer consisted of 50 mM Tris-HCl, pH 7.3, 1 mM EDTA. SARS-CoV-2 3CLpro was dissolved in 25 μL assay buffer and mixed with different concentrations of compounds. The mixture was incubated at 37 °C for 30 min. The substrate dissolved in 25 μL assay buffer was then added to initiate the reaction. The fluorescence signal at 350 nm (excitation) / 490 nm (emission) was immediately measured every 1 min for 10 min at 37°C using an M5 multi-mode microplate reader. The RFU at the 6th minute of the reaction with different concentrations of the compound was used to generate the IC 50 For each compound, the IC against SARS-CoV-2 3CLpro was measured at 12 concentrations. 50 The experimental data were analyzed by GraphPad Prism software.

[0323] The activity results of the exemplary compounds are shown in Table 1 below.

[0324] Table 1: Activity results of exemplary compounds

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331] Test Example 2: Oral Pharmacokinetics in Rats

[0332] Male SD rats were orally administered with 15 mg / kg of the compound of the present invention, and blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours. The samples were treated with anticoagulant EDTA-K2 and acetonitrile, and centrifuged. The drug concentration was analyzed by LC / MS / MS. The test results are shown in Table 1 and Figure 1-5 As shown, Figure 1 The PK profile of the oral compound GDI-001 in rats is shown; Figure 2 The PK profile of oral administration of compound GDI-006 in rats is shown; Figure 3 The PK profile of the oral administration of compound GDI-011 in rats is shown; Figure 4 shows the PK profile of the oral administration of compound GDI-012 to rats; and Figure 5 The PK profile of the oral compound GDI-014 in rats is shown.

[0333] Table 1

[0334]

Claims

1. A compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in, P1 is selected from P2 is Together with the two adjacent carbon atoms, it forms a cyclopropyl group substituted with two methyl groups; P3 is selected from Further, among them, R1 is selected from hydrogen, deuterium, halogen, cyano, oxo, nitro, C1-C5 alkyl, C1-C3 haloalkyl, C1-C4 alkoxy, C5-C 10 Aryl or 5- to 10-membered heteroaryl; R2 is selected from C1-C5 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy or C5-C 10 Aryl; R3 is selected from C1-C5 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C5-C 10 Aryl or 5- to 10-membered heteroaryl; Ring A is selected from unsubstituted or optionally halogen-substituted C5-C 10 aryl or a 5- to 10-membered heteroaryl, wherein the heteroaryl contains at least one heteroatom selected from N, O or S; X is selected from 2. The compound of formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, wherein: The compound of formula (I) has formula (II):

3. The compound of formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, wherein: The compound of formula (I) has formula (III):

4. A compound of formula (I) according to any one of claims 1 to 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from phenyl, pyridyl, pyrimidyl, pyrrolyl, furanyl or thienyl which are unsubstituted or optionally substituted by halogen.

5. A compound of formula (I) according to any one of claims 1 to 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, C1-C5 alkyl, C1-C3 haloalkyl, C1-C4 alkoxy, C5-C 10 Aryl or 5- to 10-membered heteroaryl; R2 is selected from C1-C5 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy or C5-C 10 Aryl; R3 is selected from C1-C5 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C5-C 10 Aryl or 5- to 10-membered heteroaryl; Ring A is selected from phenyl which is unsubstituted or optionally substituted by fluorine, chlorine or bromine; X is selected from 6. The compound of formula (I) according to any one of claims 1 to 3, or its tautomer, or its pharmaceutically acceptable salt, wherein: R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl or pyridyl; R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl or halophenyl; R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl or pyridyl.

7. A compound of formula (I) according to any one of claims 1 to 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from hydrogen, bromine, cyano, methyl, fluoromethyl, methoxy, phenyl, benzyl, pyridyl or pyrazolyl; R2 is selected from isopropyl, tert-butyl, phenyl or chlorophenyl; R3 is selected from methyl, trifluoromethyl, cyclopropyl, tert-butoxy, tolyl, chlorophenyl, aminophenyl or amidophenyl.

8. A compound of formula (I) according to any one of claims 1 to 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) has the following formula:

9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 8, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, wherein the dosage form is selected from the group consisting of tablets, granules, powders, syrups, inhalants and injections.

11. The use of a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a coronavirus infection or a disease or symptom caused by a coronavirus in a subject in need thereof.

12. The method of claim 11, wherein the coronavirus is selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV), and a coronavirus having a homology greater than 85% with any of the above coronaviruses and having viral activity.

13. The method of claim 11 or 12, wherein the disease or symptom caused by coronavirus is selected from one or more of the following: respiratory infection, acute respiratory syndrome (SARS), pneumonia, gastroenteritis, cough, fever, chills, vomiting, headache, chills, shortness of breath and cytokine storm.

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