3CL protease small molecule inhibitors for the treatment or prevention of coronavirus infections and uses thereof

Abstract

The present invention relates to 3C protease small molecule inhibitors and their use for treating or preventing coronavirus infections. Specifically, the present invention relates to a compound of formula (I) or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or mixture of isomers, or its pharma- ceutically acceptable salt, or its precursor drug, or its metabolite, and their use in preparing a medicament for treating or preventing coronavirus infections or coronavirus diseases or symptoms. [Formula 1] JPEG2024529062000093.jpg3135 formula (I)

Description

[Technical Field]

[0001] Cross-reference to related applications This application claims priority to a Chinese patent application filed on August 2, 2021, bearing application number CN202110882817.6, and a PCT patent application filed on November 2, 2021, bearing application number PCT / CN2021 / 128089, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of biomedicine, and in particular to small molecule inhibitors of 3CL protease and their use for the treatment or prevention of coronavirus infections. [Background technology]

[0003] The novel coronavirus (SARS-CoV-2) is a positive-strand RNA virus with the largest genome of any currently known RNA virus. Research has shown that the virus primarily infects cells through the mucosal system of the human respiratory tract. After entering the cell, viral genes are cleaved by proteases, initiating necessary protein translation and replication. The 3CL protease recognizes specific enzyme cleavage sites and cleaves the polyprotein precursor into multiple nonstructural proteins, which is crucial for the viral life cycle and is an excellent target for antiviral drugs. Many commercially available antiviral drugs target the 3CL protease of HIV, HCV, and other viruses. While the HIV 3CL protease inhibitors lopinavir and ritonavir have shown some interaction with the 3CL protease of the novel coronavirus in vitro, clinical trials have shown no significant effect on patients infected with the novel coronavirus. Therefore, potent 3CL protease inhibitors that specifically target the novel coronavirus are particularly important. Summary of the Invention

[0004] In a first aspect, the present invention provides a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a precursor drug thereof, or a metabolite thereof, [ka] Formula (I) where: P1 is selected from 5-10 membered heteroaryl groups unsubstituted or optionally substituted with a group R1, wherein said heteroaryl contains at least one heteroatom selected from N, O or S; P2 together with two adjacent carbon atoms form a 3-6 membered cycloalkyl or heterocycloalkyl group that is unsubstituted or optionally substituted with a C1-C3 alkyl group or halogen, wherein the heterocycloalkyl group contains at least one heteroatom selected from N, O, or S; P3 is [ka] or [ka] is selected from Furthermore, here, R1 is selected from hydrogen, deuterium, halogen, cyano group, oxo group, nitro group, C1-C5 alkyl group, C1-C3 haloalkyl group, C1-C4 alkoxy group, C5-C10 aryl group, or 5-10 membered heteroaryl group; R2 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, or a C5-C10 aryl group; R3 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, a C5-C10 aryl group, or a 5-10 membered heteroaryl group; Ring A is selected from unsubstituted or optionally halogen-substituted C5-C10 aryl groups or 5-10 membered heteroaryl groups, wherein said heteroaryl contains at least one heteroatom selected from N, O or S; X is [ka] or [ka] is selected from.

[0005] In one embodiment of the present invention, the compound of formula (I) may more specifically have the following formula (II): [ka] (II)

[0006] In one embodiment of the present invention, the compound of formula (I) may more specifically have the following formula (III): [ka] (III)

[0007] In another embodiment of the present invention, P1 may be selected from unsubstituted or optionally substituted by a group R1, 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl, wherein said heteroaryl contains 1 to 3 heteroatoms selected from N, O or S; P2 together with two adjacent carbon atoms can form an unsubstituted or optionally substituted with methyl, ethyl, fluorine or chlorine, 3-6 membered cycloalkyl or heterocycloalkyl group, wherein the heterocycloalkyl group contains 1-2 heteroatoms selected from N, O or S; P3 is [ka] or [ka] may be selected from Furthermore, here, R1 may be selected from hydrogen, deuterium, halogen, cyano, oxo, nitro, C1-C5 alkyl, C1-C3 haloalkyl, C1-C4 alkoxy, C5-C10 aryl, or 5-10 membered heteroaryl; R2 may be selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group or a C5-C10 aryl group; R3 may be selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, a C5-C10 aryl group, or a 5-10 membered heteroaryl group; Ring A may be selected from unsubstituted or optionally halogen-substituted phenyl, pyridyl, pyrimidinyl, pyrrole, furyl or thienyl groups; X is [ka] or [ka] may be selected from:

[0008] In another embodiment of the present invention, P1 is [ka] or [ka] may be selected from P2 is [ka] [ka] or [ka] which together with the two adjacent carbon atoms form a cyclopropyl group substituted with two methyls, a cyclopropyl group substituted with two fluorines, or a cyclopentyl group; P3 is [ka] or [ka] may be selected from Furthermore, here, R1 may be selected from hydrogen, deuterium, halogen, cyano group, nitro group, C1-C5 alkyl group, C1-C3 haloalkyl group or C1-C4 alkoxy group, C5-C10 aryl group or 5-10 membered heteroaryl group; R2 may be selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group or a C5-C10 aryl group; R3 may be selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, a C5-C10 aryl group, or a 5-10 membered heteroaryl group; Ring A may be selected from unsubstituted or optionally substituted with fluorine, chlorine or bromine, phenyl; X is [ka] or [ka] may be selected from:

[0009] In a preferred embodiment of the present invention, R1 may be selected from hydrogen, deuterium, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl or pyridyl; R2 may be selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl or halophenyl; R3 may be selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl, or pyridyl. In one preferred embodiment of the present invention, R1 may be selected from hydrogen, bromine, cyano, methyl, phenyl, benzyl, pyridyl or pyrazole; R2 may be selected from an isopropyl group, a tert-butyl group, a phenyl group or a chlorophenyl group; R3 may be selected from a methyl group, a trifluoromethyl group, a cyclopropyl group, a tert-butoxy group, a tolyl group, a chlorophenyl group, an aminophenyl group, or an amidophenyl group.

[0010] In a preferred embodiment of the invention, the compound of formula (I) may in particular have the following formula: [ka]

[0011] For simplicity, the term "compound of formula (I)" or "compound of the present invention" hereinafter may include any isotopically labeled compound of formula (I), or its optical isomers, geometric isomers, tautomers or isomeric mixtures, or a pharmaceutically acceptable salt thereof, or a precursor drug thereof, or a metabolite thereof.

[0012] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center may have an R or S configuration, and the various isomers formed thereby are optical isomers. Optical isomers include all diastereomers, enantiomers, mesomers, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral columns or chiral synthesis.

[0013] The term "geometric isomer" means that when a double bond is present in a compound, the compound may have cis-, trans-, E- and Z-isomers. Geometric isomers include cis-, trans-, E-, Z-isomers or mixtures thereof. The term "tautomer" refers to an isomer resulting from the rapid displacement of an atom in a molecule between two positions. Those skilled in the art will recognize that tautomers can be converted into each other and may coexist in equilibrium under certain conditions.

[0014] Unless otherwise specified, reference herein to "compounds of formula (I)" or "compounds of the invention" also includes isotopically labeled compounds obtained by replacing any atom of the compound with its isotopic atom. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compound of formula (I), in which one or more atoms are replaced with an atom having the same atomic number as the atom generally found in nature, but a different atomic mass or mass number.

[0015] Examples of isotopes that may be included in the compounds of the present invention include hydrogen isotopes such as 2H(D) and 3H(T), carbon isotopes such as 11C, 13C, and 14C, chlorine isotopes such as 36Cl, fluorine isotopes such as 18F, iodine isotopes such as 123I and 125I, nitrogen isotopes such as 13N and 15N, oxygen isotopes such as 15O, 17O, and 18O, and sulfur isotopes such as 35S.

[0016] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or in analogy to the methods described in the examples and preparations appended hereto, by substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0017] The compounds of formula (I) can exist in the form of pharmaceutically acceptable salts, such as acid addition salts and / or base addition salts of the compounds of formula (I). Unless otherwise specified, "pharmaceutically acceptable salts" as used herein includes acid addition salts or base addition salts that can occur in the compounds of formula (I).

[0018] Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexylaminesulfonate, ethylenedisulfonate, formate, fumarate, glucoheptanoate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydrogen iodide / iodide, 2-hydrogen iodide, 2-hydroxybenzoate ... Examples of suitable base addition salts include, but are not limited to, ethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, whey, oxalate, hexadecanoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, trizma, and zinc salts. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0019] Certain compounds of the present invention may exist in unsolvated and solvated forms, including hydrated forms. In general, compounds of formula (I) are within the scope of the present invention whether they exist in solvated or unsolvated form.

[0020] Certain compounds of the present invention may exist in different crystalline or amorphous forms and the compounds of formula (I) in all such forms are included within the scope of the present invention.

[0021] To avoid ambiguity, the following definitions are provided for terms used herein. Unless otherwise specified, the following terms have the following meanings:

[0022] The term "pharmaceutically acceptable" means that the corresponding compound, carrier, or molecule is suitable for administration to humans. Preferably, the term means that it has been approved for use in mammals, preferably humans, by a regulatory agency of any country, such as CFDA (China), EMEA (Europe), or FDA (USA).

[0023] The term "precursor drug" refers to a derivative that is converted into the compound of the present invention under physiological conditions in vivo by reaction with enzymes, gastric acid, etc., for example, by a reaction such as oxidation, reduction, or hydrolysis catalyzed by the respective enzymes.

[0024] By "metabolite" is meant any molecule derived in a cell or organism, preferably human, from any compound of the invention.

[0025] The term "cyano" means -CN.

[0026] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in a group are independently replaced with a corresponding number of substituents.

[0027] As used herein, the term "independently" means that when the number of substituents is more than one, the substituents may be the same or different.

[0028] As used herein, the terms "optional" or "optionally" mean that the described event may or may not occur. For example, when a group is "optionally substituted," it means that the group may or may not be substituted.

[0029] As used herein, the term "heteroatom" refers to oxygen (O), nitrogen (N), or S(O)m, where m can be 0, 1, or 2, i.e., a sulfur atom S, or a sulfoxide group SO, or a sulfonyl group S(O)2.

[0030] As used herein, the term "alkyl group" refers to a saturated aliphatic hydrocarbon, including straight-chain and branched-chain groups. In some embodiments, alkyl groups have 1 to 8, or 1 to 6, or 1 to 3 carbon atoms. For example, the term "C alkyl group" refers to a straight-chain or branched-chain group having 1 to 8 carbon atoms. The term "C alkyl group" includes within its definition the terms "C alkyl group," "C-C alkyl group," and "C-C alkyl group." Examples 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 (eg, 1 to 5) suitable substituents.

[0031] As used herein, the term "n-membered heterocycloalkyl group" refers to a cycloalkyl group having m ring-forming carbon atoms and (nm) ring-forming heteroatoms, wherein the heteroatoms are selected from O, S, and N. For example, 3- to 7-membered heterocycloalkyl groups include, but are not limited to, oxetane, thiooxetane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine, oxacycloheptane, hexahydrothiepine, hexamethyleneimine, and the like. Heterocycloalkyl groups may be optionally substituted with one or more suitable substituents.

[0032] As used herein, the term "C5-7 aryl group" refers to an aryl group having an aromatic ring containing from 5 to 7 carbon atoms, preferably a phenyl group.

[0033] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming the aromatic ring, wherein the heteroatoms are selected from O, S, and N. For example, 5- to 7-membered heteroaryls include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine, etc. The heteroaryl may be optionally substituted with one or more suitable substituents.

[0034] As used herein, the term "C7-11 bicyclic aryl group" 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 with one or more suitable substituents.

[0035] As used herein, the term "n-membered bicyclic heteroaryl group" refers to a bicyclic heteroaryl group having m carbon atoms forming an aromatic bicyclo and (nm) heteroatoms forming the aromatic bicyclo, wherein the heteroatoms are selected from O, S, and N. For example, 7- to 11-membered bicyclic heteroaryl groups include, but are not limited to, quinoline, isoquinoline, benzothiazole, etc. The bicyclic heteroaryl may be optionally substituted with one or more suitable substituents.

[0036] As used herein, the term "haloalkyl group" refers to an alkyl group having one or more halogen substituents (at most a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). For example, the term "C1-6 haloalkyl group" refers to a C1-6 alkyl group having one or more halogen substituents (at most a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). As another example, the term "C1-4 haloalkyl group" refers to a C1-4 alkyl group having one or more halogen substituents (at most perhaloalkyl groups, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom), the term "C1-3 haloalkyl group" refers to a C1-3 alkyl group having one or more halogen substituents (at most perhaloalkyl groups, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom), and the term "C1-2 haloalkyl group" refers to a C1-2 alkyl group (i.e., methyl or ethyl groups) having one or more halogen substituents (at most perhaloalkyl groups, i.e., each hydrogen atom of the alkyl group is replaced with a halogen atom). As yet another example, the term "C1 haloalkyl group" refers to a methyl group having one, two, or three halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, and the like.

[0037] As used herein, numerical ranges for the number of substituents, carbon atoms, and ring atoms represent a point-by-point recitation of all integers within the range, and the ranges are used only as a shorthand notation. For example, "1 to 4 substituents" represents 1, 2, 3, or 4 substituents, and "3 to 8 ring atoms" represents 3, 4, 5, 6, 7, or 8 ring atoms. Thus, numerical ranges for the number of substituents, carbon atoms, and ring atoms also include any subranges therein, and each subrange is also considered to be disclosed herein.

[0038] The compounds of the present invention can be prepared by various methods known to those skilled in the art of organic synthesis. Those skilled in the art can obtain methods for synthesizing other compounds by referring to the synthetic routes of the specific compounds in the specific examples of the present invention and by appropriately adjusting the reaction materials and reaction conditions.

[0039] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a precursor drug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

[0040] The pharmaceutically acceptable carrier may be an organic or inorganic inert carrier material, and suitable carriers include, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, mannitol, cellulose, cellulose derivatives, sodium saccharin, glucose, sucrose, magnesium carbonate, saline, glycerin, ethanol, etc. Furthermore, the pharmaceutical composition may contain other pharmaceutical additives, such as seasonings, preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, disintegrating agents, lubricants, glidants, etc.

[0041] The pharmaceutical composition of the present invention may be in the form of a liquid, solid, or semisolid dosage form. Liquid dosage forms include solutions (including true solutions and colloidal solutions), emulsions (including oil-in-water, water-in-oil, and complex emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments. Solid dosage forms include tablets (including regular tablets, enteric-coated tablets, troches, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, pills, suppositories, films, patches, aerosols, and sprays. Semisolid dosage forms include ointments, gelling agents, and pastes. The pharmaceutical composition of the present invention may be in the form of conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0042] In some embodiments, the dosage form of the pharmaceutical composition is selected from tablets, granules, powders, syrups, inhalants, and injections.

[0043] 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 contain (a) a filler or filler (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) a binder (e.g., carboxymethylcellulose, alginate esters, gel, polyvinylpyrrolidone, sucrose, and gum arabic), (c) a humectant (e.g., glycerin), (d) a disintegrant (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicic acid esters, sodium carbonate), (e) a solution barrier (e.g., paraffin), (f) an absorption promoter (e.g., a quaternary ammonium compound), (g) a wetting agent (e.g., cetyl alcohol and stearic acid monoglyceride), (h) a humectant (e.g., cetethyl alcohol and stearic acid monoglyceride), (i) a humectant (e.g., cetethyl alcohol and stearic acid monoglyceride), (j) a humectant (e.g., cetethyl alcohol and stearic acid monoglyceride), (k ... It may further comprise mixing with an adsorbent (e.g., kaolin and bentonite) and (i) a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

[0044] Formulations suitable for parenteral administration, such as injections, may include aqueous and non-aqueous isotonic sterile solutions suitable for injection, and aqueous and non-aqueous sterile suspensions. The parenteral formulations provided herein may optionally be contained in unit-dose or multi-dose sealed containers (e.g., ampoules) and stored under freeze-dried (lyophilized) conditions requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately prior to use. Examples of suitable diluents for reconstituting the pharmaceutical composition (e.g., prior to injection) include bacteriostatic water for injection, 5% aqueous glucose solution, phosphate-buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.

[0045] Sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may also contain conventional propellants such as chlorofluorocarbons, volatile unsubstituted hydrocarbons, butane, propane, etc. Inhalants may contain excipients such as lactose, or aqueous solutions containing polyethylene oxide-9-lauryl ether, glycocholate, and deoxycholate, or oily solutions administered in the form of nasal drops or sprays or gels.

[0046] The content of the compound of the present invention in the pharmaceutical composition can be adjusted according to actual needs (dosage form, administration method, administration target, etc.), and is, for example, 0.1 to 95% by weight, 1 to 95% by weight, 5 to 90% by weight, 10 to 80% by weight, etc.

[0047] Specifically, the pharmaceutical composition of the present invention may contain, inter alia, 0.01 to 10 g (such as 0.05 g, 0.1 g, 0.5 g, 1 g, or 5 g) of the compound of the present invention.

[0048] In a third aspect, the present invention provides the use of a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a precursor drug thereof, or a metabolite thereof, in the preparation of a medicament for treating or preventing a coronavirus infection or a coronavirus disease or symptom in a subject in need thereof. The compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a precursor drug thereof, or a metabolite thereof may be used to treat or prevent a coronavirus infection or a coronavirus disease or symptom in a subject in need thereof.

[0049] The term "subject" as used herein refers to any human or non-human organism that may benefit from treatment with a compound of Formula (I). Exemplary subjects include humans or mammals of any age. Preferably, the subject is a human.

[0050] The term "treating" as used herein includes the treatment of a disease or condition in a mammal, particularly a human, and includes (a) inhibiting the infection, disease or condition, i.e., inhibiting or slowing the progression of the infection, disease or condition; (b) alleviating the infection, disease or condition, i.e., causing the disease or condition to resolve; and / or (c) curing the infection, disease or condition.

[0051] As used herein, the term "preventing" includes prophylactic therapy in mammals, particularly humans, aimed at reducing the likelihood of an infection, disease, or condition occurring. Patients receiving prophylactic therapy may be selected based on their increased risk of contracting the infection or disease or condition compared to the general population. "Preventing" may include treating subjects who have not yet developed an infection or clinical condition, as well as preventing secondary outbreaks of the same or similar infection or clinical condition.

[0052] The inventors of the present invention have discovered that the compounds of the present invention can inhibit coronavirus infection, for example, by acting as reversible covalent small molecule inhibitors of the 3CL protease of the novel coronavirus (i.e., 3CL protease inhibitors), thereby inhibiting coronavirus viral replication. Therefore, the compounds of the present invention may be used to prevent or treat coronavirus infection or coronavirus-related diseases or symptoms.

[0053] 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 having greater than 85% homology to any of the foregoing coronaviruses and having viral activity. In some embodiments, the coronavirus is novel coronavirus (SARS-CoV-2).

[0054] In some embodiments, the coronavirus disease or symptoms include respiratory infection caused by the virus, severe acute respiratory syndrome (SARS), pneumonia (including severe pneumonia), gastroenteritis (including acute gastroenteritis), cough, fever, chills, vomiting, headache, chills, shortness of breath, cytokine storm, and the like. In a fourth aspect, the present invention provides a method for treating or preventing a coronavirus infection or a coronavirus disease or symptom, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a precursor drug thereof, or a metabolite thereof.

[0055] In some embodiments, the compounds of the present invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, buccal mucosa, ophthalmically, pulmonary, respiratory tract, vaginally, rectally, intraperitoneally, intralesionally, perilesional, and the like.

[0056] A "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered alone or in combination, is effective in treating or preventing a coronavirus infection or a disease or symptom caused by a coronavirus. 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 an attending physician would normally consider when determining the optimal individual regimen and dosage level for a particular patient. For example, the daily dosage of the compound of the present invention can be, inter alia, 0.001 to 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).

[0057] The specific administration frequency can be determined by one skilled in the art, and includes, 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, and the like.

[0058] In a fifth aspect, the present invention provides a method for preparing a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, the specific content of which is as follows: [ka]

[0059] Here, a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, is prepared by condensation reaction of a compound of formula (I-1) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (I-2), wherein P1, P2 and P3 are defined as in formula (I).

[0060] In one preferred embodiment of the present invention, the condensation reaction is carried out in the presence of a condensing agent and a base reagent. In one preferred embodiment of the present invention, the condensing agent is selected from one or more of a carbodiimide-based condensing agent, an onium salt-based condensing agent, and an organophosphorus-based condensing agent.

[0061] In one preferred embodiment of the 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.

[0062] In one preferred embodiment of the present invention, the basic reagent is selected from an organic base or an inorganic base. In one preferred embodiment of the invention, the basic reagent is selected from one or more of DIEA, NMM and triethylamine.

[0063] In one preferred embodiment of the present invention, a compound of formula (II) and an isotopically labeled compound of formula (III), or a mixture of optical isomers, geometric isomers, tautomers or isomers thereof, or a pharmaceutically acceptable salt thereof, can be obtained by resolving a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer thereof, or a pharmaceutically acceptable salt thereof, [ka] .

[0064] Those skilled in the art can understand that the definitions and preferred terms described in one aspect of the present invention can be applied to other aspects as well. Those skilled in the art can understand that the embodiments of each aspect of the present invention can be combined in various ways without departing from the subject and spirit of the present invention, and these combinations are also included within the scope of the present invention. [Brief explanation of the drawings]

[0065] The drawings are included to provide a further understanding of the invention, constitute a part of the specification, and together with the following specific embodiments are included to explain, but not to limit, the invention. [Figure 1] Pharmacokinetic (PK) data of the compound GDI-001 (15 mg / kg) administered orally to rats is shown. [Figure 2] Pharmacokinetic (PK) data of the oral compound GDI-006 (15 mg / kg) in rats is shown. [Figure 3] Pharmacokinetic (PK) data of the oral compound GDI-011 (15 mg / kg) in rats is shown. [Figure 4] Pharmacokinetic (PK) data of the compound GDI-012 (15 mg / kg) administered orally to rats is shown. [Figure 5] Pharmacokinetic (PK) data of the oral compound GDI-014 (15 mg / kg) in rats is shown. DETAILED DESCRIPTION OF THE INVENTION

[0066] The compounds of formula (I) of the present invention can be synthesized by various methods well known to those skilled in the art of organic synthesis. The following specific examples illustrate some exemplary synthetic methods for compounds of formula (I), which are well known in the field of synthetic chemistry. Obviously, by referring to the exemplary schemes in this patent, those skilled in the art can easily design synthetic routes for other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0067] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention. Unless otherwise specified, all reactants used in each example are commercially available, and instruments and devices used in synthesis experiments and analytical tests of products are conventional instruments and devices commonly used in organic synthesis.

[0068] 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]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate) [ka] 1) Synthesis steps of compound GDI-001 [ka]

[0069] Step 1: At 0 °C, DIEA (701 mg, 5.43 mmol, 945 μL, 4 eq), HOBt (275 mg, 2.04 mmol, 1.5 eq), and BOP (900 mg, 2.04 mmol, 1.5 eq) were added to a solution of Cpd.4 (0.50 g, 1.36 mmol, 1 eq) and Cpd.6 (288 mg, 1.36 mmol, 1 eq) in DMF (2 mL). Step 2: Continue stirring for 2 hours. Step 3, LC-MS shows the appearance of the target product. Step 4: Filter the reaction mixture and spin-dry the filtrate. Step 5: Purify directly by prep-HPLC (neutral conditions). Step 6, obtain white solid GDI-001 (320 mg, 553 μmol, 40.8% yield, 97.2% purity). 1H NMR (400 MHz, DMSO-d6) δ 9.63-9.37 (m, 1H), 8.76 (d, J = 3.1 Hz, 1H), 8.66 (d, J = 7.7 Hz, 1H), 8.09 (s, 1H), 6.68 (t, J = 8.1 Hz, 1H), 6.46-6.17 (m, 1H), 4.24 (s, 1H), 4.00 (d, J = 9.1 Hz, 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).

[0070] Example 2 Preparation of Compound GDI-002 ((1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutyryl)-N-((5-bromopyridin-3-yl)(cyano)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide formate) [ka] 1) The operation of step 1 is the same as in Example 1. 2) Synthesis steps of compound GDI-002 [ka]

[0071] Step 1: Dissolve GDI-001 (280 mg, 498 μmol, 1 eq) in HCOOH (5.6 mL) at room temperature. Step 2: React at 40°C for 1 hour. Step 3, LC-MS shows that GDI-001 is completely consumed and the main peak is the target product MS. Step 4: Direct spin drying to obtain crude solid. Step 5: Dilute the solid crude with MeCN (10 mL) and HO (50 mL) and then lyophilize to remove excess HCOOH to obtain 0.26 g of GDI-002 as crude product. Step 6: Direct separation and purification by prep-HPLC (FA conditions). Step 7, obtain white solid GDI-002 (0.23 g, 452 μmol, 90.9% yield, 100% purity, FA salt). 1H NMR (400 MHz, DMSO-d6) δ 9.65-9.45 (m, 1H), 8.76 (s, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 8.11 (d, J = 10.2 Hz, 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).

[0072] Example 3 Preparation of Compound 3 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-((5-bromopyridin-3-yl)(cyano)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) [ka]

[0073] 1) The operations in steps 1 and 2 are the same as those in Example 2. 2) Synthesis steps of compound GDI-003 Step 1: At 0 °C, add AcO (32.1 mg, 315 μmol, 29.5 μL, 1 eq) to a solution of GDI-002 (160 mg, 315 μmol, 1 eq, FA) and TEA (63.7 mg, 629 μmol, 87.6 μL, 2 eq) in DCM (3.2 mL). Step 2: Continue stirring at 0°C for 2 hours. Step 3, LC-MS shows that GDI-002 is completely consumed and the target product MS appears. Step 4: Spin-dry the reaction mixture. Step 5: Purify directly by prep-HPLC (neutral conditions). Step 6, obtain a pale yellow solid GDI-003 (87 mg, 172 μmol, 54.8% yield, 100% purity). 1H NMR (400 MHz, DMSO-d6) δ 9.64-9.42 (m, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.08 (s, 1H), 7.95-7.81 (m, 1H), 6.48-6.21 (m, 1H), 4.28 (d, J = 8.5 Hz, 1H), 4.21 (d, J = 3.1 Hz, 1H), 3.94-3.73 (m, 2H), 1.84 (s, 3H), 1.60-1.48 (m, 1H), 1.40-1.24 (m, 1H), 1.06-0.98 (m, 3H), 0.98-0.88 (m, 9H), 0.88-0.82 (m, 3H).

[0074] 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]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate) Compound GDI-004 was obtained in the same manner as in Example 3. [ka]

[0075] 1H NMR (400 MHz, DMSO-d6) δ 9.71-9.50 (m, 1H), 9.08-9.00 (m, 1H), 8.98 (d, J = 10.3 Hz, 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 = 9.4 Hz, 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).

[0076] Example 5 Preparation of Compound GDI-005 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(5-methylpyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide)

[0077] 1) Synthesis steps of Cpd.8 [ka]

[0078] Step 1: At 0 °C, dissolve (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (174 mg, 616.20 μmol, 1 eq) in DCM (3.48 mL). Step 2, then add TEA (124.70 mg, 1.23 mmol, 171.53 uL, 2 eq). Step 3: Add Ac2O (75.49 mg, 739.44 μmol, 69.26 μL, 1.2 eq) in portions to the reaction mixture. Step 4: Continue stirring at 0°C for 2 hours. Step 5, LC-MS shows the target product. Step 6: Add saturated NH4Cl (300 mL) solution dropwise. Step 7: Extract the reaction mixture with EtOAc (300 mL). Step 8, combine the organic phases and spin dry. Step 9, colorless oil (1R,2S,5S)-3-[(2S)-2-acetylamino-3,3-dimethyl-butanoyl]-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.

[0079] 2) Synthesis steps of Cpd.9 [ka]

[0080] Step 1: At 0 °C, Cpd.8 (0.18 g, 554.85 μmol, 1 eq) was added to a mixture of MeOH (1.8 mL) and HO (0.54 mL), followed by LiOH.HO (46.57 mg, 1.11 mmol, 2 eq). Step 2: Continue stirring at 0°C for 2 hours. Step 3, LC-MS shows the appearance of the target product. Step 4: Quench the reaction with saturated NH4Cl (100 mL) at 0 °C. Step 5: Adjust the pH to 5-6 with 2M citric acid solution under low temperature. Step 6: Extract the aqueous phase with EtOAc (20 mL*3). Step 7, combine the organic phases and spin dry. Step 8, colorless liquid (1R,2S,5S)-3-[(2S)-2-acetylamino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (130 mg, 418.83 μmol, 75.49% yield) was obtained.

[0081] 3) Synthesis steps of compound GDI-005 [ka]

[0082] Step 1: At 0 °C, add DIEA (108.26 mg, 837.66 μmol, 145.91 μL, 4 eq), HOBt (42.45 mg, 314.12 μmol, 1.5 eq), and BOP (138.93 mg, 314.12 μmol, 1.5 eq) to a solution of (1R,2S,5S)-3-[(2S)-2-acetylamino-3,3-dimethyl-butanoyl]-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). Step 2: Continue stirring for 2 hours. Step 3, LC-MS shows the appearance of the target product. Step 4: Filter the reaction mixture and spin-dry the filtrate. Step 5: Purify directly by prep-HPLC (neutral conditions). Step 6: Obtained a gray-yellow solid GDI-005 (27.1 mg, 61.65 μmol, 29.44% yield).

[0083] 1H NMR (400 MHz, DMSO-d6) δ 9.57-9.33 (m, 1H), 8.55-8.37 (m, 2H), 7.87 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 6.38-6.15 (m, 1H), 4.29 (d, J = 8.7 Hz, 1H), 4.23 (s, 1H), 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).

[0084] Example 6 Preparation of Compound GDI-006 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(isoquinolin-4-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-006 was obtained in the same manner as in Example 5. [ka]

[0085] 1H NMR (400 MHz, DMSO-d6) δ 9.59-9.44 (m, 1H), 9.42 (s, 1H), 8.72 (d, J = 7.0 Hz, 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 = 14.6 Hz, 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).

[0086] Example 7 Preparation of Compound GDI-007 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanol)-N-(cyano(5-(trifluoromethyl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide) Compound GDI-007 was obtained in the same manner as in Example 5. [ka]

[0087] 1H NMR (400 MHz, DMSO-d6) δ 9.36-9.17 (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, 8.7 Hz, 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).

[0088] Example 8 Preparation of Compound GDI-008 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(5-methoxypyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-008 was obtained in the same manner as in Example 5. [ka] 1H NMR (400 MHz, DMSO-d6) δ 9.56-9.38 (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 = 8.6 Hz, 1H), 4.26-4.18 (m, 1H), 3.86 (s, 3H), 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).

[0089] Example 9 Preparation of Compound GDI-009 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-((5-bromo-4-methylpyridin-3-yl)(cyano)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-009 was obtained in the same manner as in Example 5. [ka]

[0090] 1H NMR (400 MHz, DMSO-d6) δ 9.44-9.15 (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 = 10.1 Hz, 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).

[0091] Example 10 Preparation of Compound GDI-010 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(5-cyanopyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-010 was obtained in the same manner as in Example 5. [ka]

[0092] 1H NMR (400 MHz, DMSO-d6) δ 9.68-9.48 (m, 1H), 9.07 (d, J = 5.0 Hz, 1H), 8.94 (d, J = 9.7 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 6.53-6.25 (m, 1H), 4.27 (d, J = 8.5 Hz, 1H), 4.21 (d, J = 4.4 Hz, 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).

[0093] 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-trifluoroacetamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-011 was obtained in the same manner as in Example 5. [ka]

[0094] 1H NMR (400 MHz, DMSO-d6) δ 9.66-9.46 (m, 1H), 8.76 (s, 1H), 8.67 (d, J = 5.3 Hz, 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).

[0095] 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-trifluoroacetamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-012 was obtained in the same manner as in Example 5. [ka]

[0096] 1H NMR (400 MHz, DMSO-d6) δ 9.72-9.51 (m, 1H), 9.48-9.32 (m, 1H), 9.04 (s, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 6.59-6.33 (m, 1H), 4.37 (d, J = 7.3 Hz, 1H), 4.25 (s, 1H), 3.99-3.80 (m, 1H), 3.68 (t, J = 12.0 Hz, 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).

[0097] 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) Compound GDI-013 was obtained in the same manner as in Example 5. [ka]

[0098] 1H NMR (400 MHz, DMSO-d6) δ 9.68-9.46 (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 = 22.8 Hz, 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).

[0099] 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-trifluoroacetamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-014 was obtained in the same manner as in Example 5. [ka]

[0100] 1H NMR (400 MHz, DMSO-d6) δ 9.74-9.52 (m, 1H), 9.50-9.32 (m, 1H), 9.11-9.03 (m, 1H), 8.94 (d, J = 6.0 Hz, 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 = 12.3 Hz, 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).

[0101] Example 15 Preparation of Compound GDI-015 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-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-formamide) Compound GDI-015 was obtained in the same manner as in Example 5. [ka]

[0102] 1H NMR (400 MHz, DMSO-d6) δ 9.72-9.51 (m, 1H), 9.32-9.24 (m, 1H), 8.93 (d, J = 6.8 Hz, 1H), 8.52 (s, 1H), 7.99-7.80 (m, 1H), 6.59-6.39 (m, 1H), 4.26 (d, J = 8.8 Hz, 1H), 4.22 (d, J = 6.9 Hz, 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).

[0103] 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-formamide) Compound GDI-016 was obtained in the same manner as in Example 5. [ka]

[0104] 1H NMR (400 MHz, DMSO-d6) δ 9.68-9.55 (m, 1H), 9.02-8.91 (m, 2H), 8.18 (d, J = 7.6 Hz, 1H), 7.80-7.70 (m, 1H), 7.67-7.55 (m, 2H), 7.30 (d, J = 7.9 Hz, 2H), 6.50-6.27 (m, 1H), 4.07 (d, J = 5.8 Hz, 1H), 3.77 (td, J = 10.5, 5.6 Hz, 1H), 3.58 (s, 1H), 3.43 (dd, J = 17.4, 10.1 Hz, 1H), 2.32 (s, 3H), 0.95 (d, J = 17.3 Hz, 3H), 0.75 (d, J = 2.8 Hz, 9H), 0.57 (d, J = 22.5 Hz, 3H).

[0105] 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-trifluoroacetamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-017 was obtained in the same manner as in Example 5. [ka]

[0106] 1H NMR (400 MHz, DMSO-d6) δ 9.67-9.62 (m, 1H), 9.40-9.32 (m, 1H), 9.23 (dd, J = 3.4, 2.0 Hz, 1H), 8.89 (t, J = 2.6 Hz, 1H), 8.49 (dt, J = 4.8, 2.2 Hz, 1H), 6.53-6.38 (m, 1H), 4.33 (t, J = 6.7 Hz, 1H), 4.21 (d, J = 5.1 Hz, 1H), 3.91-3.83 (m, 1H), 3.68-3.60 (m, 1H), 2.43 (s, 3H), 1.53 (dd, J = 14.9, 6.7 Hz, 1H), 1.39-1.27 (m, 1H), 0.99 (d, J = 13.9 Hz, 3H), 0.89 (d, J = 13.8 Hz, 9H), 0.82 (d, J = 5.7 Hz, 3H).

[0107] Example 18 Preparation of Compound GDI-018 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(5-(methylcarbamoyl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-018 was obtained in the same manner as in Example 5. [ka]

[0108] 1H NMR (400 MHz, DMSO-d6) δ 9.56-9.45 (m, 1H), 9.00 (t, J = 2.4 Hz, 1H), 8.76 (dt, J = 6.2, 3.2 Hz, 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 = 4.2 Hz, 3H), 1.85 (s, 3H), 1.59-1.49 (m, 1H), 1.38-1.23 (m, 1H), 1.02 (d, J = 16.1 Hz, 3H), 0.92 (d, J = 5.8 Hz, 9H), 0.87 (d, J = 12.0 Hz, 3H).

[0109] 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-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-019 was obtained in the same manner as in Example 5. [ka]

[0110] 1H NMR (400 MHz, DMSO-d6) δ 9.70-9.54 (m, 1H), 9.00 (d, J = 8 Hz, 1H), 8.93 (d, J = 8 Hz, 1H), 8.21-8.15 (m, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.22 (dd, J = 16.1, 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.51-6.27 (m, 1H), 4.10 (d, J = 2.5 Hz, 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 = 16.4 Hz, 3H), 0.74 (s, 9H), 0.67 (d, J = 17.4 Hz, 3H).

[0111] Example 20 Preparation of Compound GDI-020 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(1H-pyrrole[2,3-b]pyridin-5-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-020 was obtained in the same manner as in Example 5. [ka]

[0112] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.38 (t, J = 7.5 Hz, 1H), 8.31 (dd, J = 4.6, 2.2 Hz, 1H), 8.08 (dd, J = 6.8, 2.2 Hz, 1H), 7.88 (t, J = 9.6 Hz, 1H), 7.56 (s, 1H), 6.50 (ddd, J = 8.7, 3.4, 1.8 Hz, 1H), 6.34-6.24 (m, 1H), 4.31 (d, J = 8.7 Hz, 1H), 4.25 (s, 1H), 3.91-3.74 (m, 2H), 1.84 (d, J = 5.3 Hz, 3H), 1.58-1.46 (m, 1H), 1.36-1.15 (m, 2H), 1.00 (d, J = 27.2 Hz, 3H), 0.94 (d, J = 2.9 Hz, 9H), 0.85 (d, J = 8.3 Hz, 3H).

[0113] 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-formamide) Compound GDI-021 was obtained in the same manner as in Example 5. [ka]

[0114] 1H NMR (400 MHz, DMSO-d6) δ 9.66-9.50 (m, 1H), 8.80-8.62 (m, 2H), 8.09 (dt, J = 4.6, 2.2 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.71-7.58 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.45-6.21 (m, 1H), 4.11 (d, J = 4.3 Hz, 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 = 15.4 Hz, 3H), 0.92-0.71 (m, 9H), 0.61 (d, J = 17.7 Hz, 3H).

[0115] 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-trifluoroacetamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-022 was obtained in the same manner as in Example 5. [ka]

[0116] 1H NMR (400 MHz, DMSO-d6) δ 9.62-9.46 (m, 1H), 9.44-9.30 (m, 2H), 8.73 (d, J = 5.9 Hz, 1H), 8.29-8.20 (m, 1H), 8.03-7.88 (m, 1H), 7.80 (td, J = 6.7, 3.5 Hz, 2H), 6.92-6.83 (m, 1H), 4.40 (t, J = 7.6 Hz, 1H), 4.24 (d, J = 14.3 Hz, 1H), 3.98-3.91 (m, 1H), 3.75-3.66 (m, 1H), 1.65-1.50 (m, 1H), 1.35 (d, J = 7.6 Hz, 1H), 1.08-0.90 (m, 12H), 0.81 (d, J = 7.0 Hz, 3H).

[0117] 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)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-023 was obtained in the same manner as in Example 5. [ka] 1H NMR (400 MHz, DMSO-d6) δ 9.62-9.51 (m, 1H), 9.42 (d, J = 3.0 Hz, 1H), 8.71 (d, J = 6.4 Hz, 1H), 8.25 (dd, J = 8.9, 4.1 Hz, 1H), 8.03-7.72 (m, 4H), 7.66 (dd, J = 12.6, 8.1 Hz, 2H), 7.31 (t, J = 8.8 Hz, 2H), 6.90-6.80 (m, 1H), 4.08 (d, J = 9.0 Hz, 1H), 3.84 (dt, J = 13.1, 6.7 Hz, 1H), 3.65 (d, J = 8.4 Hz, 1H), 3.53-3.40 (m, 1H), 2.34 (d, J = 3.8 Hz, 3H), 1.58-1.48 (m, 1H), 1.35-1.18 (m, 1H), 1.06-0.80 (m, 12H), 0.54 (d, J = 11.5 Hz, 3H).

[0118] 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-formamide) Compound GDI-024 was obtained in the same manner as in Example 5. [ka]

[0119] 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.17 (dd, J = 13.6, 7.5 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 6.1, 2.5 Hz, 1H), 7.39 (dd, J = 8.2, 4.3 Hz, 1H), 7.12 (tdd, J = 7.0, 3.2, 1.2 Hz, 1H), 7.06-6.95 (m, 1H), 6.25 (dd, J = 7.6, 1.8 Hz, 1H), 4.29 (dd, J = 8.7, 1.7 Hz, 1H), 4.24 (d, J = 2.6 Hz, 1H), 3.86-3.76 (m, 2H), 1.80 (d, J = 6.6 Hz, 3H), 1.53-1.41 (m, 1H), 1.29-1.07 (m, 1H), 0.99 (d, 44 Hz, 3H), 0.93 (s, 9H), 0.79 (d, 8 Hz, 3H).

[0120] 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-formamide) Compound GDI-025 was obtained in the same manner as in Example 5. [ka]

[0121] 1H NMR (400 MHz, DMSO-d6) δ 9.81-9.50 (m, 2H), 8.89-8.60 (m, 2H), 8.10 (dt, J = 12.6, 2.2 Hz, 1H), 6.46-6.23 (m, 1H), 4.28 (d, J = 4.3 Hz, 1H), 3.89 (d, J = 8.0 Hz, 2H), 3.63-3.47 (m, 1H), 1.64-1.54 (m, 1H), 1.45-1.31 (m, 1H), 1.04 (d, J = 12.8 Hz, 3H), 1.0-0.96 (m, 9H), 0.90 (d, J = 5.6 Hz, 3H).

[0122] 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-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-026 was obtained in the same manner as in Example 5. [ka]

[0123] 1H NMR (400 MHz, DMSO-d6) δ 9.66-9.52 (m, 1H), 8.76 (dd, J = 8.0, 4.0 Hz, 1H), 8.66 (dd, J = 8.0, 4.0 Hz, 1H), 8.10 (q, J = 2.3 Hz, 1H), 7.68-7.47 (m, 2H), 7.27 (dd, J = 11.5, 8.9 Hz, 1H), 6.78-6.65 (m, 2H), 6.45-6.22 (m, 1H), 4.15 (d, J = 2.1 Hz, 1H), 3.85-3.77 (m, 1H), 3.62-3.40 (m, 2H), 2.99 (s, 6H), 1.59-1.49 (m, 1H), 1.37-1.22 (m, 1H), 1.00 (d, J = 15.0 Hz, 3H), 0.82 (d, J = 3.1 Hz, 9H), 0.70 (d, J = 14.5 Hz, 3H).

[0124] Example 27 Preparation of Compound GDI-027 ((1R,2S,5S)—N-(cyano(isoquinolin-4-yl)methyl)-3-((S)-2-((4-(dimethylamino)phenyl)sulfonamine)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-027 was obtained in the same manner as in Example 5. [ka]

[0125] 1H NMR (400 MHz, DMSO-d6) δ 9.62-9.50 (m, 1H), 9.42 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 5.9 Hz, 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, 7.8 Hz, 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, 3.4 Hz, 1H), 3.46 (dd, J = 10.1, 6.5 Hz, 1H), 2.97 (s, 6H), 1.60-1.48 (m, 1H), 1.28 (d, J = 7.7 Hz, 1H), 1.01 (d, J = 2.7 Hz, 2H), 0.96-0.72 (m, 10H), 0.64 (d, J = 10.6 Hz, 3H).

[0126] 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-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-028 was obtained in the same manner as in Example 5. [ka]

[0127] 1H NMR (400 MHz, DMSO-d6) δ 9.60-9.50 (m, 1H), 9.17-9.14 (m, 1H), 8.73-8.65 (m, 1H), 8.62-8.59 (m, 1H), 8.34 (q, J = 2.6 Hz, 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 = 17.3 Hz, 3H), 0.94-0.83 (m, 12H).

[0128] Example 29 Preparation of Compound GDI-029 ((1R,2S,5S)—N-(cyano(isoquinolin-4-yl)methyl)-3-((S)-3,3-dimethyl-2-((trifluoromethyl)sulfonamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-029 was obtained in the same manner as in Example 5. [ka]

[0129] 1H NMR (400 MHz, DMSO-d6) δ 9.76-9.52 (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 = 14.5 Hz, 1H), 4.08 (d, J = 218.1 Hz, 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).

[0130] Example 30 Preparation of Compound GDI-030 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-030 was obtained in the same manner as in Example 5. [ka]

[0131] 1H NMR (400 MHz, DMSO-d6) δ 9.54-9.38 (m, 1H), 8.86 (d, J = 2.7 Hz, 1H), 8.49 (d, J = 6.5 Hz, 1H), 8.33 (d, J = 20.3 Hz, 1H), 8.06-7.95 (m, 2H), 7.86 (t, J = 8.4 Hz, 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).

[0132] Example 31 Preparation of Compound GDI-031 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-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-formamide) Compound GDI-031 was obtained in the same manner as in Example 5. [ka]

[0133] 1H NMR (400 MHz, DMSO-d6) δ 9.64-9.52 (m, 1H), 9.26 (s, 1H), 8.93 (d, J = 7.7 Hz, 1H), 8.63-8.45 (m, 1H), 7.84 (t, J = 9.0 Hz, 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 = 14.0 Hz, 3H), 0.98-0.72 (m, 12H).

[0134] 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-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-032 was obtained in the same manner as in Example 5. [ka]

[0135] 1H NMR (400 MHz, DMSO-d6) δ 13.13 (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).

[0136] Example 33 Preparation of Compound GDI-033 ((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutyryl)-N-(cyano(8-fluoroisoquinolin-4-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-033 was obtained in the same manner as in Example 5. [ka]

[0137] 1H NMR (400 MHz, DMSO-d6) δ 9.72-9.33 (m, 2H), 8.83 (d, J = 8.1 Hz, 1H), 8.06-7.73 (m, 3H), 7.61 (t, J = 9.1 Hz, 1H), 6.89 (dd, J = 11.0, 8.1 Hz, 1H), 4.27 (t, J = 8.2 Hz, 1H), 4.19 (d, J = 13.4 Hz, 1H), 3.93-3.79 (m, 2H), 1.82 (d, J = 9.8 Hz, 3H), 1.60-1.48 (m, 1H), 1.34-1.07 (m, 1H), 1.06-0.76 (m, 15H).

[0138] Example 34: Preparation of compound GDI-034 (5-((1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamido)(cyano)methyl)methyl nicotinate) Compound GDI-034 was obtained in the same manner as in Example 5. [ka]

[0139] 1H NMR (400 MHz, DMSO-d6) δ 9.59-9.48 (m, 1H), 9.09 (s, 1H), 8.89 (dd, J = 6.0, 2.8 Hz, 1H), 8.38 (s, 1H), 7.85 (t, J = 8.0 Hz, 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 = 13.6 Hz, 3H), 0.88 (m, 12H).

[0140] 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-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-formamide) Compound GDI-035 was obtained in the same manner as in Example 5. [ka]

[0141] 1H NMR (400 MHz, DMSO-d6) δ 13.15 (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 = 8.0 Hz, 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).

[0142] Example 36 and Example 37: Preparation of Compound GDI-036 and Compound GDI-037 Compound 6 was subjected to chiral resolution to give compounds GDI-036 and GDI-037. The chiral column was YMC Cellulose-SC (10 μm 50*250 mm ) and the mobile phase was hexane and ethanol in a ratio of 7:3. The separation amount was 300 mg, and the retention times were 2 and 7.5 minutes, respectively.

[0143] 1H NMR (400 MHz, DMSO-d6) δ = 9.44 (d, J = 7.9 Hz, 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), 7.94-7.89 (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).

[0144] 1H 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).

[0145] Test Example 1: Activity measurement of compounds SARS-CoV-2 / Hela-ACE Study The compounds were transferred to a 384-well plate (Greiner, Part. No. 781090-2B), followed by the addition of Hela-ACE cells (cell density: 5000 cells / 20 μL, MEM medium containing 2% FBS). The plate containing the cells was then transferred to a BSL3 laboratory. SARS-CoV-2 (USA-WA1 / 2020, grown in Vero E6 cells) was diluted to an MOI of 0.75–1 to achieve 30–60% cell infection. The test plate was incubated at 37°C and 5% CO2 for 48 hours, after which formaldehyde was added to achieve a final concentration of 4% fixed cells. A human polyclonal serum antibody was used as the primary antibody, and goat anti-human H+L conjugated Alexa 488 (Thermo Fisher Scientific A11013) was used as the secondary antibody. DNA was stained with DAPI (Thermo Fisher Scientific D1306).

[0146] Uninfected cytotoxicity test The compounds were transferred to a 1536-well plate (Corning No. 9006BC), and then Hela-ACE cells (cell density: 600 cells / 5 μL, MEM culture medium containing 2% FBS) were added. The test plate was incubated at 37°C and 5% CO2 for 48 hours, after which the cell activity test was performed. 2 μL of 50% Cell-Titer Glo (Promega No. G7573) was diluted with water and added to the cell test plate, and the values ​​were then read using an EnVision Plate Reader (Perkin Elmer).

[0147] Enzyme activity test Inhibition tests were performed using 200 nM recombinant SARS-CoV-2 main protease and 15 μM fluorescent substrate (Dabcyl-TSAVL QSGFRK-Glu(EDANS), Genscript). The assay buffer consisted of 50 mM Tris-HCl, pH 7.3, and 1 mM EDTA. SARS-CoV-2 3CLpro was dissolved in 25 μL of assay buffer and mixed with different concentrations of compounds. The mixture was incubated at 37°C for 30 minutes. The reaction was then initiated by adding 25 μL of substrate dissolved in assay buffer. The fluorescence signal was immediately measured at 350 nm (excitation) / 490 nm (emission) every minute at 37°C for 10 minutes using a SpectraMax® M5 multimode microplate reader. The RFU at 6 minutes after reactions with different concentrations of compounds, compared to the reaction with the lowest concentration, was used to generate IC50 curves. For each compound, the IC50 value against SARS-CoV-2 3CLpro was measured at 12 concentrations. Experimental data were analyzed using GraphPad Prism software. Activity results for exemplary compounds are shown in Table 1 below. Table 1: Activity results for exemplary compounds

[0148] [Table 1] JPEG0007810788000064.jpg190144JPEG0007810788000065.jpg184144JPEG0007810788000066.jpg19014 4JPEG0007810788000067.jpg190144JPEG0007810788000068.jpg202144JPEG0007810788000069.jpg75144

[0149] Test Example 2: Oral pharmacokinetics measurement in rats Male SD rats were orally administered 15 mg / kg of the compounds in the examples of the present invention, and blood samples were taken at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours. The samples were centrifuged with the anticoagulant EDTA-K2 and acetonitrile, and then analyzed for drug concentration by LC / MS / MS. The test results are shown in Table 1 and Figures 1-5. Figure 1 shows the PK diagram for oral compound GDI-001 in rats, Figure 2 shows the PK diagram for oral compound GDI-006 in rats, Figure 3 shows the PK diagram for oral compound GDI-011 in rats, Figure 4 shows the PK diagram for oral compound GDI-012 in rats, and Figure 5 shows the PK diagram for oral compound GDI-014 in rats.

[0150] [Table 2]

Claims

1. In the compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of these isomers, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Formula (I) In formula (I), P1 is selected from 5-10 membered heteroaryl groups unsubstituted or optionally substituted with a group R1, wherein said heteroaryl contains at least one heteroatom selected from N, O or S; P2 together with the two adjacent carbon atoms form a cyclopropyl group that is unsubstituted or optionally substituted with a C1-C3 alkyl group or halogen; P3 is 【Chemistry 2】 or 【Transformation 3】 is selected from Furthermore, here, R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, C1-C5 alkyl, C1-C3 haloalkyl, C1-C4 alkoxy, C5-C10 aryl, or 5- to 10-membered heteroaryl; R2 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, or a C5-C10 aryl group; R3 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, a C5-C10 aryl group, or a 5- to 10-membered heteroaryl group; Ring A is selected from unsubstituted or optionally halogen-substituted C5-C10 aryl groups or 5- to 10-membered heteroaryl groups, wherein said heteroaryl contains at least one heteroatom selected from N, O, or S; X is 【Chemistry 4】 or 【Transformation 5】 Selected from: A compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) has the formula (II): 【Transformation 6】 (II) 10. A compound of formula (I) according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) has the formula (III): 【Transformation 7】 (III) 10. A compound of formula (I) according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

4. P1 is selected from 5- to 6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl unsubstituted or optionally substituted with a group R1, wherein said heteroaryl contains 1 to 3 heteroatoms selected from N, O or S; P2 together with two adjacent carbon atoms form a 3-6 membered cycloalkyl or heterocycloalkyl group that is unsubstituted or optionally substituted with methyl, ethyl, fluorine or chlorine, wherein the heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O or S; P3 is 【Transformation 8】 or 【Chemistry 9】 and further selected from R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, C1-C5 alkyl, C1-C3 haloalkyl, C1-C4 alkoxy, C5-C10 aryl, or 5- to 10-membered heteroaryl; R2 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, or a C5-C10 aryl group; R3 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, a C5-C10 aryl group, or a 5- to 10-membered heteroaryl group; Ring A is selected from unsubstituted or optionally halogen-substituted phenyl, pyridyl, pyrimidinyl, pyrrole, furyl or thienyl groups; X is 【Chemistry 10】 or 【Chemistry 11】 Selected from: A compound of formula (I) according to any one of claims 1 to 3, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

5. P1 is 【Chemistry 12】 or 【Chemistry 13】 is selected from P2 is 【Chemistry 14】 or 【Chemistry 15】 and each together with the two adjacent carbon atoms forms a cyclopropyl group substituted with two methyls, a cyclopropyl group substituted with two fluorines, or a cyclopentyl group; P3 is 【Chemistry 17】 or [Chemistry 18] and further selected from R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, C1-C5 alkyl, C1-C3 haloalkyl, C1-C4 alkoxy, C5-C10 aryl, or 5- to 10-membered heteroaryl; R2 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, or a C5-C10 aryl group; R3 is selected from a C1-C5 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a C1-C4 alkoxy group, a C5-C10 aryl group, or a 5- to 10-membered heteroaryl group; Ring A is selected from unsubstituted or optionally substituted phenyl groups with fluorine, chlorine or bromine; X is 【Chemistry 19】 or 【Chemistry 20】 Selected from: A compound of formula (I) according to any one of claims 1 to 3, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

6. R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl, and pyridyl; R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, and halophenyl groups; R3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, tert-butoxy, phenyl, halophenyl, and pyridyl; A compound of formula (I) according to any one of claims 1 to 3, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

7. R1 is selected from hydrogen, bromine, cyano, methyl, fluoromethyl, methoxy, phenyl, benzyl, pyridyl, and pyrazole; R2 is selected from an isopropyl group, a tert-butyl group, a phenyl group, or a chlorophenyl group; R3 is selected from a methyl group, a trifluoromethyl group, a cyclopropyl group, a tert-butoxy group, a tolyl group, a chlorophenyl group, an aminophenyl group, or an amidophenyl group; A compound of formula (I) according to any one of claims 1 to 3, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

8. The compound of formula (I) 【Chemistry 21】 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof,

9. A pharmaceutical composition comprising the compound of formula (I) according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

11. 1. A medicament for use in treating or preventing a coronavirus infection or a disease or symptom caused by a coronavirus in a subject in need thereof, comprising a compound of formula (I) as defined in claim 1 or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of these isomers thereof, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical according to claim 11, wherein 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 having greater than 85% homology to any of the above coronaviruses and having viral activity.

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

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