Ketoamide derivatives and their uses

Abstract

The present invention discloses a group of ketoamide derivatives and uses thereof, and specifically discloses a compound represented by formula (IV) and its pharma- ceutically acceptable salts. TIFF2024527057000072.tif43170

Description

[Technical Field]

[0001] The present invention relates to a group of ketoamide derivatives and uses thereof, and specifically to a compound represented by formula (IV) and a pharmaceutically acceptable salt thereof: [Background technology]

[0002] The type 2 atypical pneumonia caused by the novel coronavirus (SARS-Cov-2), which emerged in December 2019, has rapidly spread around the world, posing unprecedented challenges to human health and social development.

[0003] Coronavirus 3CL protease, also known as the major protease, is a key protein in viral replication. Its main function is to hydrolyze two polyproteins expressed by the virus. Sequence analysis suggests that 3CL protease may be an important target for drug design. Development of inhibitors to inhibit the coronavirus replication process would be highly valuable and significant for the prevention and treatment of coronavirus infections.

[0004] PF-07321332 is a potent, orally active SARS-CoV 3CL PRO inhibitor and its structure is as follows: TIFF0007735531000001.tif40170 Summary of the Invention

[0005] The present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof: TIFF0007735531000002.tif43170 where, R3 is the formula TIFF0007735531000003.tif21170 and R4, R1 is independently F, Cl, Br, I, or OR 11 , CN, CH3S(O) m - and NHR 12, and C 1~3 alkyl, and 1~3 alkyl is optionally substituted with 1, 2 or 3 F; R 11 is H, C 1~3 Alkyl, CH3(OCH2CH2) p - and H(OCH2CH2) q -C selected from above 1~3 alkyl is optionally substituted with 1, 2 or 3 F; R 12 is C 1~3 alkyl, CH3CO- and CH3SO2-, and 1~3 alkyl, CH3CO- and CH3SO2- are optionally and independently substituted with 1, 2 or 3 F; m is selected from 0, 1 and 2; p and q are selected from 1, 2, 3, 4, 5 and 6; n is selected from 0, 1, 2, 3 and 4; R2 is C 1~4 Alkyl, C 3~6 cycloalkyl and benzyl, 1~4 Alkyl, C 3~6 cycloalkyl and benzyl are optionally substituted with 1, 2 or 3 F; R4 is C optionally substituted with 1, 2 or 3 F 1~8 alkyl, Ring A is C 3~10 selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, and phenyl; Ring B is C 3~8 cycloalkyl and 5-membered heterocycloalkyl; 3~8 Cycloalkyl and 5-membered heterocycloalkyl may have one or two R a optionally substituted with R a are each independently H and C 1~3 alkyl, The above "5-membered heterocycloalkyl" contains 1, 2 or 3 heteroatoms or atomic groups independently selected from O, S, SO2, N, P and Se.

[0006] In some embodiments of the present invention, R1 above is selected from F and methyl, and other variables are as defined herein.

[0007] In some embodiments of the present invention, ring A above is represented by the formula TIFF0007735531000004.tif16170, and other variables are as defined herein.

[0008] In some embodiments of the present invention, the above formula The structural unit shown in TIFF0007735531000005.tif21170 is TIFF0007735531000006.tif16170, and other variables are as defined herein.

[0009] In some embodiments of the present invention, R4 above is selected from tert-butyl, and the other variables are as defined herein.

[0010] In some embodiments of the present invention, the above R a is selected from H and methyl, and other variables are as defined herein.

[0011] In some embodiments of the present invention, ring B above is represented by the formula TIFF0007735531000007.tif18170, and other variables are as defined herein.

[0012] In some embodiments of the present invention, the above formula The structural unit shown in TIFF0007735531000008.tif18170 is TIFF0007735531000009.tif23170, and other variables are as defined herein.

[0013] The present invention provides a compound represented by the formula: or a pharmaceutically acceptable salt thereof: TIFF0007735531000010.tif43170 where, R1 is independently F, Cl, Br, I, or OR 11 , CN, CH3S(O) m - and NHR 12 , and C 1~3 alkyl, and 1~3 alkyl is optionally substituted with 1, 2 or 3 F; R 11 is H, C 1~3 Alkyl, CH3(OCH2CH2) p - and H(OCH2CH2) q -C selected from above 1~3 alkyl is optionally substituted with 1, 2 or 3 F; R 12 is C 1~3 alkyl, CH3CO- and CH3SO2-, and 1~3 alkyl is optionally substituted with 1, 2 or 3 F; m is selected from 0, 1 and 2; p and q are selected from 1, 2, 3, 4, 5 and 6; n is selected from 0, 1, 2, 3 and 4; R2 is C 1~4 Alkyl, C 3~6 cycloalkyl and benzyl, 1~4 Alkyl, C 3~6 cycloalkyl and benzyl are optionally substituted with 1, 2 or 3 F; Ring A is C 3~10 selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, and phenyl; Ring B is C 3~6cycloalkyl and 5-membered heterocycloalkyl; 3~6 Cycloalkyl and 5-membered heterocycloalkyl may have one or two R a optionally substituted with R a are each independently H and C 1~3 alkyl, The above "5-membered heterocycloalkyl" contains 1, 2 or 3 heteroatoms or atomic groups independently selected from O, S, SO2, N, P and Se.

[0014] In some embodiments of the present invention, R1 above is selected from F and methyl, and other variables are as defined herein.

[0015] In some embodiments of the present invention, ring A above is represented by the formula TIFF0007735531000011.tif16170, and other variables are as defined herein.

[0016] In some embodiments of the present invention, the above formula The structural unit shown in TIFF0007735531000012.tif21170 is TIFF0007735531000013.tif16170, and other variables are as defined herein.

[0017] In some embodiments of the present invention, the above R a is selected from H and methyl, and other variables are as defined herein.

[0018] In some embodiments of the present invention, the above formula The structural unit shown in TIFF0007735531000014.tif18170 is TIFF0007735531000015.tif23170, and other variables are as defined herein.

[0019] In some embodiments of the present invention, the compound is selected from the structures shown in formulas (I-1), (IV-1) and (IV-2). TIFF0007735531000016.tif137170 wherein R1, R2, R3, n and ring A are as defined in the present invention.

[0020] In some embodiments of the present invention, the compound is selected from the structures shown in formulas (I-1a), (IV-1a), and (IV-2a). TIFF0007735531000017.tif137170 wherein R1, R2, R3, n and ring A are as defined in the present invention.

[0021] Further embodiments of the present invention result from any combination of the above variables.

[0022] The present invention provides a compound represented by the formula: or a pharmaceutically acceptable salt thereof: TIFF0007735531000018.tif175170

[0023] The present invention provides a compound represented by the formula: or a pharmaceutically acceptable salt thereof: TIFF0007735531000019.tif174170

[0024] The present invention provides a method of combination administration, comprising administering a therapeutically effective amount of a compound according to any one of the technical solutions of the present invention or a pharmaceutically acceptable salt thereof, and a therapeutically acceptable dose of another antiviral drug to a subject in need of said treatment.

[0025] The present invention further provides a method for treating coronavirus infection, comprising administering a therapeutically effective amount of a compound according to any one of the technical solutions of the present invention or a pharmaceutically acceptable salt thereof, and a therapeutically acceptable dose of another antiviral agent to a subject in need of said treatment.

[0026] In some embodiments of the present invention, the other antiviral drug is ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, or lopinavir. In the method for treating coronavirus infection, the compound or a pharmaceutically acceptable salt thereof according to any one of the technical solutions of the present invention is used in a mass ratio of 1:1 to 5:1 with respect to ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, or lopinavir, specifically 1:1, 2:1, 3:1, 4:1, or 5:1. Surprisingly, experiments have shown that using two therapeutic components in this ratio range helps achieve a synergistic effect and achieve a better integrated therapeutic effect. Furthermore, the method can be used to administer therapeutic components contained in the same unit dosage form, i.e., a combined dosage form, or to administer formulations containing different therapeutic components separately, i.e., clinical combination dosing.

[0027] In some embodiments of the invention, the coronavirus infection is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2 and variants thereof.

[0028] In some embodiments of the present invention, the coronavirus infection is SARS-CoV-2 and variants thereof.

[0029] The present invention also provides the following synthetic route: TIFF0007735531000020.tif154170 Technical Effects

[0030] The compounds of the present invention have excellent in vitro inhibitory activity against the novel coronavirus Mpro protease, excellent in vitro anti-coronavirus activity at the cellular level, and no cytotoxicity.In pharmacokinetic studies, the compounds of the present invention have significantly higher plasma exposure, slower clearance rate, longer half-life, and better pharmacokinetic properties than the reference molecule PF-07321332. Definitions and Explanations

[0031] Unless otherwise specified, the following terms and phrases used herein shall have the following meanings: A particular term or phrase, unless specifically defined, should not be considered unclear or ambiguous and should be understood in its general sense. Where a trade name is mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0032] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, other problem or complication and commensurate with a reasonable benefit / risk ratio.

[0033] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents found in the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent.

[0034] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid or base using conventional chemical methods. Generally, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof.

[0035] The term "pharmaceutical composition" refers to a composition containing one or more of the compounds described in the present application, their isomers, or pharmaceutically acceptable salts thereof, and other ingredients such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and facilitate absorption of the active ingredient to exert its biological activity.

[0036] The term "therapeutically effective amount" is intended to include an amount of a compound sufficient, when administered, to prevent or slow to some extent the progression of one or more symptoms of a disease or therapeutic condition. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit a detectable biological or pharmacological response in a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human. Such a response is desired by a researcher, veterinarian, physician, or clinician.

[0037] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0038] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all of these compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomer- or diastereomer-enriched mixtures, and all of these mixtures are within the scope of the present invention. Substituents such as alkyl may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0039] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0040] Unless otherwise specified, the term "cis-trans isomers" or "geometric isomers" refers to isomers resulting from the inability to freely rotate about a double bond or a single bond of a ring-forming carbon atom.

[0041] Unless otherwise specified, the term "diastereomer" means a stereoisomer whose molecules have two or more centers of chirality and which are not mirror-image related to one another.

[0042] Unless otherwise specified, "(+)" denotes dextrorotatory, "(-)" denotes levorotatory, and "(±)" denotes racemic.

[0043] Unless otherwise noted, solid wedge bonds ( TIFF0007735531000021.tif4170) and wedge-dashed bond ( TIFF0007735531000022.tif5170) which shows the absolute configuration of one stereocenter and is represented by a linear solid bond ( TIFF0007735531000023.tif4170) and straight dashed bond ( TIFF0007735531000024.tif5170), which shows the relative configuration of the stereocenters, and the wavy lines ( TIFF0007735531000025.tif4170) with solid wedge-shaped connections ( TIFF0007735531000026.tif4170) or wedge-dashed bond ( TIFF0007735531000027.tif5170) or wavy line ( TIFF0007735531000028.tif4170) with straight solid line join ( TIFF0007735531000029.tif4170) or straight dashed bond ( TIFF0007735531000030.tif5170).

[0044] Unless otherwise specified, the terms "enriched in one isomer," "enriched isomer," "enriched in one enantiomer," or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100% and is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0045] Unless otherwise specified, the terms "isomeric excess" or "enantiomeric excess" refer to the relative percentage difference between two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, the isomeric or enantiomeric excess (ee) is 80%.

[0046] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared using chiral synthesis, chiral reagents, or other conventional techniques. Single enantiomers of certain compounds of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the desired pure enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, followed by separation and recovery of the diastereomers by conventional methods known in the art to provide the pure enantiomers. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic methods using chiral stationary phases, optionally in combination with chemical derivatization (e.g., carbamate formation from an amine).

[0047] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioactive isotopes such as C). For example, hydrogen can be replaced with deuterium to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxicity and side effects, increased drug stability, enhanced therapeutic efficacy, and extended biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0048] The term "optionally" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description encompasses cases where the event or circumstance occurs as well as cases where the event or circumstance does not occur.

[0049] The term "substituted" means that any one or more hydrogen atoms at a particular atom are replaced with a substituent, and the substituent may include deuterium and hydrogen variants, provided that the particular valence state is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur in aromatic groups. The term "optionally substituted" means substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any based on chemically achievable criteria.

[0050] When any variable (e.g., R) occurs more than one time in a constituent or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with zero to two R, then such group may also be optionally substituted with up to two R, and each occurrence of R is independent. Further, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0051] When the number of one linking group is 0, for example, -(CRR)0-, this means that the linking group is a single bond.

[0052] When the number of substituents is 0, it means that the substituent is not present, and -A-(R)0 means that the structure is actually -A.

[0053] When a substituent is vacant, it means that the substituent is not present; for example, when X is vacant in AX, it means that the structure is actually A.

[0054] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked, for example, ALZ means that when L represents a single bond, the structure is actually AZ.

[0055] If the bond of a substituent can bridge more than one atom in a ring, then such a substituent can be attached to any atom in this ring, e.g., the structural unit TIFF0007735531000031.tif11170 means that the substituent R can be substituted at any position of the cyclohexyl or cyclohexadiene. When a recited substituent does not indicate which atom is bonded to the substituted group, such substituent may be bonded to any of the atoms; for example, a pyridyl group may be bonded to the substituted group as a substituent through any of the carbon atoms in the pyridine ring.

[0056] When the linking direction of the listed linking groups is not indicated, the linking direction is arbitrary, for example, When the linking group L in TIFF0007735531000032.tif13170 is -MW-, -MW- links ring A and ring B in the same direction as the reading order from left to right. TIFF0007735531000033.tif15170 may be constructed by concatenating ring A and ring B in the opposite reading order from left to right. TIFF0007735531000034.tif15170 Combinations of the above linking groups, substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0057] Unless otherwise specified, when a group has one or more linkable sites, any one or more of the sites of the group can be linked to other groups via a chemical bond. If the linking mode of the chemical bond is non-directional and there is an H atom at the linkable site, when the chemical bond is linked, the number of H atoms at the site decreases according to the number of linked chemical bonds to form a group with the corresponding valence. The chemical bond between the above site and other groups is represented by a straight solid bond ( TIFF0007735531000035.tif5170), straight dashed bond ( TIFF0007735531000036.tif6170), or wavy line ( For example, the linear solid bond in -OCH3 indicates that the group is connected to another group via its oxygen atom. The straight dashed bond in TIFF0007735531000038.tif7170 represents a bond between the nitrogen atoms of the group and other groups at both ends of the group. The wavy lines in TIFF0007735531000039.tif13170 indicate that the phenyl group is linked to another group via the carbon atoms at positions 1 and 2 of the phenyl group.

[0058] Unless otherwise specified, the number of atoms in a ring is usually defined as the number of members in the ring, for example, a "5- to 7-membered ring" refers to a "ring" having 5 to 7 atoms arranged around it.

[0059] Unless otherwise stated, C n~n+m or C n~ C n+m includes any specific example of n to n+m carbons, for example, C 1~12 Includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 and further includes any range of n to n+m, for example, C 1~12 C 1~3 , C 1~6 , C 1~9 , C 3~6 , C 3~9 , C 3~12 , C 6~9 , C 6~12 , and C 9~12 Similarly, n- to n+m-membered rings indicate that the number of atoms in the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered ring, and further includes any range of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0060] Unless otherwise stated, "C 1~8 The term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 8 carbon atoms. 1~8 C for alkyl 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~4 , C8, C7, C6 and C5 alkyl, and the like, and may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). 1~8 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, and the like.

[0061] Unless otherwise stated, "C 1~4 The term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 4 carbon atoms. 1~4 C for alkyl 1~2 , C 1~3 and C 2~3 alkyl, etc., and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1~4 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0062] Unless otherwise stated, "C 1~3 The term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1~3 C for alkyl 1~2 and C 2~3alkyl, etc., and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1~3 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0063] Unless otherwise stated, "C 3~10 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 3 to 10 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spirocyclic, parallel ring, and bridged rings. 3~10 Cycloalkyl has C 3~8 , C 3~6 , C 3~5 , C 4~10 , C 4~8 , C 4~6 , C 4~5 , C 5~8 or C 5~6 and the like, which may be monovalent, divalent or multivalent. 3~10 Illustrative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]dicyclodecane, and the like.

[0064] Unless otherwise stated, "C 3~8 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 3 to 8 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spirocyclic, parallel ring, and bridged rings. 3~8 Cycloalkyl has C 3~8 , C 3~6 , C 3~5 , C 4~8 , C 4~6 , C 4~5 , C 5~8 or C 5~6 and the like, which may be monovalent, divalent or multivalent. 3~8Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.4]cyclohexane, and the like.

[0065] Unless otherwise stated, "C 3~6 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spirocyclic, parallel ring, and bridged rings. 3~6 Cycloalkyl has C 3~4 , C 3~5 , C 4~5 , C 5~8 or C 5~6 and the like, which may be monovalent, divalent or multivalent. 3~6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0066] Unless otherwise stated, the term "3 to 10-membered heterocycloalkyl," by itself or in combination with other terms, respectively, means a saturated cyclic group consisting of 3 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, N, P, and Se, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms can optionally be oxidized (i.e., NO, S(O)). p and P(O) p, p is 1 or 2). The heterocycloalkyl includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spirocyclic, parallel ring, and bridged ring. Furthermore, for the "3- to 10-membered heterocycloalkyl," a heteroatom can occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. The 3- to 10-membered heterocycloalkyl includes 3- to 9-membered, 3- to 8-membered, 3- to 6-membered, 5- to 9-membered, 5-membered, 6-membered, 7-membered, 8-membered, and 9-membered heterocycloalkyl, etc. Illustrative examples of 3- to 10-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxepanyl, etc.

[0067] Unless otherwise stated, the term "5-membered heterocycloalkyl," by itself or in combination with other terms, means a saturated cyclic group consisting of 5 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms independently selected from O, S, N, P, and Se, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms can optionally be oxidized (i.e., NO, S(O)). p and P(O) p, p is 1 or 2. Illustrative examples of 5-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, and the like.

[0068] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0069] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the diffraction intensity data is collected from the cultivated single crystal using a Bruker D8 venture diffractometer, with a CuKα radiation source and a φ / ω scan mode, and after collecting relevant data, the crystal structure can be further analyzed by a direct method (Shelxs97) to confirm the absolute configuration.

[0070] The solvents used in the present invention can be obtained commercially.

[0071] In the present invention, the following abbreviations have been used: ACN is acetonitrile, Boc is tert-butoxycarbonyl, Bn is benzyl, DCM is dichloromethane, DMSO is dimethyl sulfoxide, °C is degrees Celsius, hr is hours, LiBH4 is sodium borohydride, THF is tetrahydrofuran, Ts is p-toluenesulfonyl, Ac is acetyl, Me is methyl, and Et is ethyl.

[0072] Compounds are named according to conventional naming conventions in the art or by using ChemDraw® software; commercially available compounds use the supplier's catalog name. DETAILED DESCRIPTION OF THE INVENTION

[0073] The present invention will be described in more detail below with reference to examples, but is not intended to limit the present invention in any way. Although the present invention has been described in detail in this specification, specific embodiments thereof have also been disclosed, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0074] Example 1 TIFF0007735531000040.tif36170Synthetic route: TIFF0007735531000041.tif139170

[0075] Step 1: Synthesis of the hydrochloride salt of compound 1-2 Compound 1-1 (500 mg, 1.75 mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (10 mL, 4N) was added, followed by reaction with stirring for 2 hours at 20° C. The mixture was concentrated under reduced pressure without purification to give the hydrochloride salt of compound 1-2. 1 HNMR(400MHz,CD3OD)δ=4.28-4.20(m,1H),3.91-3.81(m,3H),3.45-3.35(m,2H),2.86-2 .74(m,1H),2.48-2.36(m,1H),2.29-2.19(m,1H),2.02-1.94(m,1H),1.93-1.80(m,1H).

[0076] Step 2: Synthesis of Compounds 1-4 Compound Boc-L-cyclohexylglycine (1 g, 3.89 mmol) was added to N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.77 g, 4.66 mmol) was added. The mixture was stirred for 0.5 hours. Diisopropylethylamine (1.26 g, 9.72 mmol) and the hydrochloride salt of compound 1-3 (1.02 g, 4.66 mmol) were added, and the mixture was stirred at 20 °C for 16 hours. Methyl tert-butyl ether (50 mL) was added to the reaction mixture, and the mixture was washed with water (20 mL), 3% citric acid (20 mL × 2), and saturated aqueous sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 1-4. 1 HNMR(400MHz,CDCl3)δ=5.22-5.11(m,1H),4.36(d,J=3.9Hz,1H),4.27(dd,J=6.9,9.3Hz,1H),4.21-4.12(m,2H),3.83(dd,J=7.8,10.4Hz,1H),3.70(br dd,J=3.6,10.4Hz,1H),2.81-2.61(m,2H),1.82-1.70(m,6H),1.68-1.61(m,4H ),1.56-1.48(m,2H),1.46-1.38(m,9H),1.29-1.22(m,4H),1.21-0.98(m,4H).

[0077] Step 3: Synthesis of Compounds 1-5 Compound 1-4 (1.41 g, 3.34 mmol) was added to tetrahydrofuran (14 mL), and a solution of lithium hydroxide monohydrate LiOH.HO (280.03 mg, 6.67 mmol) in water (5 mL) was added, followed by stirring at 20° C. for 16 hours. The crude product was neutralized with 3% citric acid solution (50 mL), extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-5 without further purification. 1HNMR(400MHz,DMSO-d6)δ=12.58-12.23(m,1H),6.92-6.82(m,1H),4.11-3.94(m,2H),3.82-3.76(m,1H),3.72-3.62(m, 1H),2.73-2.64(m,1H),2.62-2.55(m,1H),1.92-1.42(m,12H),1.40-1.32(m,9H),1.18-1.06(m,3H),1.00-0.81(m,2H).

[0078] Step 4: Synthesis of Compounds 1-6 Compound 1-5 (650 mg, 1.65 mmol) was added to 2-butanone (7 mL), followed by the addition of 1-hydroxybenzotriazole (222.63 mg, 1.65 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (379.03 mg, 1.98 mmol), and diisopropylethylamine (638.84 mg, 4.94 mmol). The mixture was stirred at 20 ° C for 0.5 hours, and then the hydrochloride salt of compound 1-2 (366.88 mg, 1.65 mmol) was added. The mixture was stirred at 20 ° C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane:methanol (30 mL × 2, 10:1). The combined organic phases were washed with 3% citric acid (20 mL × 2) and saturated aqueous sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain compound 1-6. 1 HNMR(400MHz,CDCl3)δ=7.49-7.42(m,1H),6.23-6.05(m,1H),5.28-5.17 (m,1H),4.64-4.51(m,1H),4.43-4.24(m,2H),3.92-3.81(m,1H),3.78-3 .70(m,3H),3.39-3.27(m,2H),2.94-2.75(m,2H),2.57-2.36(m,2H),2.2 4-2.07(m,1H),1.94-1.50(m,14H),1.49-1.41(m,9H),1.27-0.95(m,6H).

[0079] Step 5: Synthesis of Compounds 1-7 Compound 1-6 (3.10 g, 5.51 mmol) was dissolved in tetrahydrofuran (31 mL), and lithium borohydride (240.02 mg, 11.02 mmol) was added at 0 °C. The mixture was then slowly heated to 20 °C and reacted for 2 h. Water (10 mL) and ethyl acetate (20 mL) were added to the reaction mixture and stirred for 10 min. A white solid precipitated and was filtered to give the crude product 1-7 as a filter cake. [M+1]+ = 535.4.

[0080] Step 6: Synthesis of Compounds 1-8 Compound 1-7 (0.5 g, 935.13 μmol) was dissolved in dichloromethane (10 mL). Dess-Martin reagent (594.94 mg, 1.40 mmol) was then added to the reaction mixture and stirred at 25 °C for 16 h. Saturated sodium thiosulfate (15 mL) and saturated sodium bicarbonate solution (15 mL) were added to the reaction mixture and stirred for 10 min. The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 1-8. [M+1]+ = 533.4.

[0081] Step 7: Synthesis of Compounds 1-9 Compound 1-8 (436 mg, 818.52 μmol) was dissolved in dichloromethane (5 mL), and glacial acetic acid (58.98 mg, 982.22 mmol) and cyclopentyl isocyanide (94.44 mg, 982.22 μmol) were added to the reaction mixture. The mixture was stirred at 25°C for 2 h. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture and stirred for 10 min. The mixture was extracted with dichloromethane (20 mL). The organic phase was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-9 was obtained by silica gel column chromatography (dichloromethane:methanol = 10:1). [M+1]+ = 688.4.

[0082] Step 8: Synthesis of Compounds 1-10 Compound 1-9 (190 mg, 276.22 μmol) was dissolved in methanol (3 mL), followed by the addition of a solution of potassium carbonate (95.44 mg, 690.54 μmol) in water (2 mL). The mixture was stirred at 20°C for 16 hours. 3% citric acid (20 mL) was added to the reaction mixture, which was then extracted three times with dichloromethane (40 mL). The organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1-10. [M+1] + =646.5.

[0083] Step 9: Synthesis of Compounds 1-11 Compound 1-10 (238.00 mg, 368.52 μmol) was dissolved in dichloromethane (24 mL), and then Dess-Martin reagent (203.19 mg, 479.08 μmol) was added. The reaction was stirred at 20°C for 18 h. Sodium thiosulfate (15 mL) and sodium bicarbonate solution (15 mL) were added to the reaction mixture, and the mixture was stirred for 10 min. The mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The product 1-11 was obtained by silica gel column chromatography (dichloromethane:methanol = 20:1). [M+1] + =644.5.

[0084] Step 10: Synthesis of Compounds 1-12 Compound 1-11 (125 mg, 194.16 μmol) was dissolved in tetrahydrofuran (3 mL), and then hydrogen chloride-ethyl acetate (4 M, 2.91 mL) was added. The reaction was stirred at 20 °C for 1 h. The reaction solution was directly rotary evaporated on an oil pump, and the rotary evaporation was repeated with a small amount of dichloromethane to give compound 1-12. [M+1] + =544.4.

[0085] Step 11: Synthesis of Compound 1 Compound 1-12 (125 mg, 229.91 μmol) was dissolved in tetrahydrofuran (2.5 mL) and trifluoroacetic anhydride (193.15 mg, 919.63 μmol) and pyridine (127.30 mg, 1.61 mmol) were added at 0°C. The mixture was stirred at 20°C for 16 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (40 mL x 2). The organic phase was washed sequentially with 3% citric acid (40 mL) and saturated aqueous sodium chloride (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC to obtain compound 1. [M+1] + =640.0; 1 HNMR(400MHz,CD3OD)δ ppm 0.94-1.10(m,2H),1.13-1.32(m,3H)1.32-1.46(m,1H),1.47-1.57(m,3H),1.59-1.68(m,4H),1.69-1.8 1(m,6H),1.83-2.00(m,5H),2.01-2.17(m,1H),2.19-2.38(m,1H),2.49-2.57(m,1H),2.58-2.70(m,1H), 2.73-2.89(m,1H),3.20-3.26(m,1H),3.37-3.45(m,1H),3.73-3.86(m,1H),3.88-3.97(m,1H),4.03-4.1 0(m,1H),4.11-4.18(m,1H),4.19-4.29(m,1H),4.29-4.37(m,1H),4.39-4.47(m,1H),4.57-4.60(m,2H).

[0086] Example 2 TIFF0007735531000042.tif41170Synthetic route: TIFF0007735531000043.tif71170

[0087] Step 1: Synthesis of Compound 2-1 Compound 1-8 (630 mg, 1.18 mmol) was dissolved in dichloromethane (7 mL), and glacial acetic acid (85.23 mg, 1.42 mmol) and benzyl isocyanide (166.26 mg, 1.42 mmol) were added to the reaction mixture. The mixture was stirred at 20 °C for 16 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with dichloromethane (40 mL × 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 2-1 was obtained by silica gel column chromatography (dichloromethane:methanol = 20:1). [M+1] + =710.4.

[0088] Step 2: Synthesis of compound 2-2 Compound 2-1 (519 mg, 731.12 μmol) was dissolved in anhydrous methanol (7.8 mL). Then, a solution of potassium carbonate (252.61 mg, 1.83 mmol) in water (5.2 mL) was added to the reaction mixture and stirred at 20°C for 16 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (20 mL). The organic phase was washed with 3% citric acid (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 2-2 was obtained without further purification. [M+1]+ = 668.3.

[0089] Step 3: Synthesis of Compound 2-3 Compound 2-2 (420 mg, 628.90 μmol) was dissolved in dichloromethane (4.2 mL), and Dess-Martin reagent (346.76 mg, 817.57 μmol) was added to the reaction mixture. The mixture was stirred at 20°C for 16 hours. Sodium thiosulfate (15 mL) and saturated sodium bicarbonate solution (20 mL) were added to the reaction mixture, and the mixture was extracted twice with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 2-3 was obtained by silica gel column chromatography (dichloromethane:methanol = 20:1). [M+1] + =666.4.

[0090] Step 4: Synthesis of the hydrochloride salt of compound 2-4 Compound 2-3 (50 mg, 75.10 μmol) was dissolved in tetrahydrofuran (0.5 mL), and a 4 M solution of hydrogen chloride in ethyl acetate (1.13 mL) was added to the reaction mixture. The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure and rotary evaporated with a small amount of dichloromethane until a white foam formed. The hydrochloride salt of compound 2-4 was obtained. [M+1] + =566.4.

[0091] Step 5: Synthesis of Compound 2 The hydrochloride salt of compound 2-4 (42.98 mg, 75.98 μmol) was dissolved in tetrahydrofuran (0.5 mL) and cooled to 0°C. Pyridine (42.07 mg, 531.83 μmol) and trifluoroacetic anhydride (63.83 mg, 303.91 μmol) were added. The reaction mixture was warmed to room temperature (20°C) and stirred for 16 h. Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with 3% citric acid (10 mL), then saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC to give compound 2. [M+1] + =662.0.

[0092] Example 3 TIFF0007735531000044.tif42170Synthetic route: TIFF0007735531000045.tif64170

[0093] Step 1: Synthesis of Compound 3-1 Compound 1-8 (223 mg, 418.65 μmol) was dissolved in dichloromethane (2.5 mL), and glacial acetic acid (30.17 mg, 502.37 μmol) and tert-butyl isocyanide (41.76 mg, 502.37 μmol) were added to the reaction mixture. The mixture was stirred at 25°C for 2 h. Saturated ammonium chloride solution (5 mL) was added to the reaction mixture and stirred for 10 min. Dichloromethane (10 mL) was added for extraction. The organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 3-1. [M+1] + =676.4.

[0094] Step 2: Synthesis of compound 3-2 Compound 3-1 (122 mg, 180.51 μmol) was dissolved in methanol (2.5 mL), and then a solution of potassium carbonate (62.37 mg, 451.28 μmol) in water (1.5 mL) was added. The mixture was stirred at 20°C for 16 hours. 3% citric acid (10 mL) was added to the reaction mixture, which was then extracted three times with dichloromethane (20 mL). The organic phase was washed with saturated aqueous sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 3-2. [M+1] + =634.4.

[0095] Step 3: Synthesis of compound 3-3 Compound 3-2 (1.2 g, 1.89 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of Dess-Martin reagent (1.04 g, 2.46 mmol). The reaction was allowed to proceed with stirring at 20 °C for 18 h. Sodium thiosulfate (60 mL) and sodium bicarbonate solution (60 mL) were added to the reaction mixture, which was then stirred for 10 min. The mixture was then extracted with dichloromethane (120 mL x 2). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 3-3. [M+1] + =632.5.

[0096] Step 4: Synthesis of Compound 3-4 Compound 3-3 (380 mg, 601.46 μmol) was dissolved in tetrahydrofuran (10 mL), and then hydrogen chloride-ethyl acetate (4 M, 9.02 mL) was added. The reaction was stirred at 20 °C for 1 h. The reaction solution was dried directly on an oil pump and concentrated under reduced pressure with a small amount of dichloromethane until the mixture became white particles, yielding compound 3-4. [M+1]+ = 532.4.

[0097] Step 5: Synthesis of Compound 3 Compound 3-4 (380 mg, 714.71 μmol) was dissolved in tetrahydrofuran (10 mL), and then trifluoroacetic anhydride (395.73 mg, 5 mmol) and pyridine (600.44 mg, 2.86 mmol) were added at 0 °C. The reaction was stirred at 20 °C for 16 h. Water (60 mL) and dichloromethane (120 mL × 2) were added to the reaction mixture for extraction. The organic phase was washed sequentially with 3% citric acid (120 mL) and saturated aqueous sodium chloride (120 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC to obtain compound 3. 1 HNMR(400MHz,CD3OD)δ ppm 0.88-1.33(m,6H)1.34-1.45(m,9H)1.47-2.01(m,15H)2.19-2.44(m,1H)2.51-2.90(m,3H)3. 18-3.28(m,1H)3.69-4.03(m,2H)4.16-4.31(m,1H)4.37-4.48(m,1H)4.53-4.67(m,1H).[M+1] + =628.4.

[0098] Example 4 TIFF0007735531000046.tif38170Synthetic route: TIFF0007735531000047.tif86170

[0099] Step 1: Synthesis of compound 4-2 Compound 4-1 was dissolved in N,N-dimethylformamide (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium (1.24 g, 3.27 mmol) was added, and the mixture was stirred for 0.5 h. Diisopropylethylamine (1.41 g, 10.90 mmol, 1.90 mL) and the hydrochloride salt of compound 1-3 (527.06 mg, 2.40 mmol) were added, and the mixture was incubated at 20 °C for 2 h. The reaction mixture was extracted with ethyl acetate (200 mL) and 3% citric acid solution (100 mL). The organic phase was separated and washed with half-saturated brine (100 mL) until neutral, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to give compound 4-2. 1 HNMR(400MHz,CDCl3)δ=5.44-5.24(m,1H),4.44(dd,J=6.6,8.8Hz,1H),4.36(d,J=3.8Hz,1H),4.20-4.14(m,2H),3.85(dd,J= 7.9,10.3Hz,1H),3.66(dd,J=3.5,10.3Hz,1H),2.75-2.64(m,2H),1.98-1.59(m,13H),1.50-1.43(m,9H),1.27-1.25(m,3H).

[0100] Step 2: Synthesis of compound 4-3 4-2 (0.8 g, 2.03 mmol) was dissolved in tetrahydrofuran (10 mL) and water (6 mL), and lithium hydroxide monohydrate (170.19 mg, 4.06 mmol) was added and stirred at 20 °C for 16 h. The reaction mixture was extracted with dichloromethane (200 mL) and 3% citric acid (100 mL). The organic phase was separated and washed with saturated brine (100 mL) until neutral, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4-3. 1HNMR(400MHz,CD3OD)δ=4.36(br d,J=8.3Hz,1H),4.29-4.23(m,1H),3.95-3.77(m,2H),3.73(br t,J=6.2Hz,1H),2.76-2.61(m,2H),2.02-1.57(m,13H),1.44(s,9H).

[0101] Step 3: Synthesis of compound 4-4 4-3 (0.7 g, 1.91 mmol) was dissolved in 2-butanone (15 mL), 1-hydroxybenzotriazole (258.11 mg, 1.91 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (439.43 mg, 2.29 mmol) were added, and the mixture was stirred for 0.5 h. Diisopropylethylamine (1.23 g, 9.55 mmol, 1.66 mL) and the hydrochloride salt of compound 1-2 (467.88 mg, 2.10 mmol) were added, and the mixture was reacted at 20 °C for 16 h. The reaction mixture was extracted with 3% citric acid (100 mL) and dichloromethane (200 mL). The organic phase was separated and further extracted with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0 to 10:1) to obtain compound 4-4. 1 HNMR(400MHz, CD3OD)δ=8.65(br d,J=8.4Hz,1H),7.99-7.69(m,1H),7.61-7.44(m,1H),4.58-4.44(m,1H),4.34 (d,J=8.0Hz,1H),4.22(d,J=4.0Hz,1H),3.92(dd,J=7.9,10.3Hz,1H),3.78(br dd,J=3.6,10.3Hz,1H),3.72(s,3H),3.30-3.26(m,2H),2.89-2.77(m,1H),2.75-2.50 (m,3H),2.36-2.25(m,1H),2.21-2.08(m,1H),2.05-1.52(m,14H),1.49-1.39(m,9H).

[0102] Step 4: Synthesis of Compounds 4-5 Compound 4-4 (0.75 g, 1.40 mmol) was dissolved in tetrahydrofuran (7.5 mL), cooled to 0 °C, and lithium borohydride (91.66 mg, 4.21 mmol) was added. The mixture was slowly heated to 20 °C and reacted for 1 h. Semi-saturated NH4Cl (30 mL) was added to the reaction mixture and stirred for 30 min to quench the reaction. Dichloromethane (60 mL × 2) was then added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4-5. 1 HNMR(400MHz,CD3OD)δ=4.35(br d,J=7.9Hz,1H),4.22-4.14(m,1H),4.04-3.89(m,2H),3.85-3.66(m,2H),3.50(br t,J=5.2Hz,2H),3.29-3.25(m,1H),2.91-2.78(m,1H),2.74-2.56(m,3H),2.44(br d,J=7.6Hz,1H),2.36-2.25(m,1H),2.00-1.74(m,14H),1.44(s,9H).

[0103] Step 5: Synthesis of Compounds 4-6 4-5 (0.55 g, 1.09 mmol) was dissolved in dichloromethane (20 mL), Dess-Martin reagent (506.49 mg, 1.19 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with saturated sodium thiosulfate solution (30 mL × 2), saturated sodium bicarbonate solution (30 mL × 2), and dichloromethane (60 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4-6. 1 HNMR(400MHz,CDCl3)δ=9.56-9.44(m,1H),8.01(br d,J=6.0Hz,1H),6.14-5.97(m,1H),5.50-5.35(m,1H),4.55-4.29(m,3H),3.94-3.83(m,1H),3.65(br d,J=7.3Hz,1H),3.42-3.29(m,2H),2.94-2.76(m,2H),2.74-2.68(m,1H),2.6 0-2.49(m,1H),2.39(td,J=3.2,5.9Hz,1H),1.97-1.60(m,15H),1.44(s,8H).

[0104] Step 6: Synthesis of Compounds 4-7 Compound 4-6 (0.75 g, 1.49 mmol) was dissolved in dichloromethane (7.5 mL), and glacial acetic acid (107.10 mg, 1.78 mmol) and tert-butyl isocyanide (148.27 mg, 1.78 mmol) were added. The mixture was stirred at 20 °C for 2 h. Saturated ammonium chloride solution (30 mL) and dichloromethane (60 mL) were added to the reaction mixture for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4-7. [M+1] + =648.2.

[0105] Step 7: Synthesis of Compounds 4-8 Compound 4-7 (0.8 g, 1.23 mmol) was dissolved in methanol (6.5 mL) and water (4 mL), and potassium carbonate (426.69 mg, 3.09 mmol) was added. The mixture was stirred at 20 °C for 2 h. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture and stirred for 10 min. Dichloromethane (60 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4-8 was obtained by purification using silica gel column chromatography (dichloromethane:methanol = 1:0 to 10:1). 1 HNMR(400MHz,CDCl3)δ=7.08(br d,J=8.3Hz,1H),6.87-6.62(m,1H),6.07-5.94(m,1H),5.98(br s,1H),5.35(br d,J=8.6Hz,1H),4.52-4.30(m,2H),4.28-3.98(m,3H),3.74-3.57(m,1H),3.33(br d,J=8.3Hz,2H),2.81-2.65(m,3H),2.54(td,J=8.0,15.5Hz,1H),2.41-2.31(m,1 H),2.03-1.69(m,13H),1.63-1.52(m,2H),1.46-1.41(m,9H),1.38-1.32(m,9H).

[0106] Step 8: Synthesis of Compounds 4-9 Compound 4-8 (0.65 g, 1.07 mmol) was dissolved in dichloromethane (12 mL), Dess-Martin reagent (682.67 mg, 1.61 mmol) was added, and the mixture was allowed to react at 20 °C for 16 h. The reaction mixture was extracted with saturated sodium thiosulfate solution (30 mL x 2), saturated sodium bicarbonate solution (30 mL x 2), and dichloromethane (60 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4-9 was obtained by silica gel column chromatography (dichloromethane:methanol = 1:0 to 10:1). [M+1] + =604.5.

[0107] Step 9: Synthesis of trifluoroacetates of compounds 4-10 Compound 4-9 (450 mg, 745.34 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was reacted for 1 hour at 20° C. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate of the target compound 4-10. 1 HNMR(400MHz,DMSO-d6)δ=8.51(d,J=8.4Hz,1H),8.04(br s,3H),7.64(s,1H),5.75(s,1H),5.23-5.05(m,1H),4.29-4.22(m,1H),4.20- 4.10(m,1H),3.79-3.65(m,1H),3.63-3.55(m,1H),3.15-3.04(m,1H),2.69(br d,J=7.4Hz,3H),2.44-2.34(m,1H),2.25-2.17(m,1H),1.85-1.51(m,13H),1.48-1.33(m,2H),1.30(s,9H).

[0108] Step 10: Synthesis of Compound 4 The trifluoroacetate of 4-10 (275 mg, 546.03 μmol) was dissolved in dichloromethane (2.7 mL), and pyridine (431.91 mg, 5.46 mmol) and trifluoroacetic anhydride (286.71 mg, 1.37 mmol) were added at 0 °C. The mixture was then allowed to react at 20 °C for 2 h. The reaction mixture was extracted with 3% citric acid solution (30 mL) and dichloromethane (60 mL * 2). The organic phase was separated and washed with saturated brine (60 mL) until neutral, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4 was obtained by silica gel column chromatography (dichloromethane:methanol = 10:1). 1 HNMR(400MHz,CDCl3)δ=8.09(br d,J=5.9Hz,1H),7.40(br d,J=8.6Hz,1H),6.89-6.71(m,1H),5.92-5.79(m,1H),5.41-5.20(m,1H),4.90-4.68(m,1H) ),4.28(d,J=3.5Hz,1H),4.01-3.82(m,1H),3.61-3.46(m,1H),3.40-3.29(m,2H),2.86(br d,J=11.0Hz,1H),2.81-2.74(m,1H),2.55-2.42(m,1H),2.00-1.62(m,17H),1.40-1.37(m,9H).

[0109] Example 5 TIFF0007735531000048.tif42170Synthetic route: TIFF0007735531000049.tif123170

[0110] Step 1: Synthesis of compound 5-2 Compound 5-1 (0.65 g, 2.67 mmol) was dissolved in N,N-dimethylformamide (20 mL). O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium (1.22 g, 3.21 mmol) was then added to the reaction mixture, which was stirred at 20 °C for 0.5 h. Diisopropylethylamine (863.20 mg, 6.68 mmol) and the hydrochloride salt of compound 1-3 (704.37 mg, 3.21 mmol) were then added to the reaction mixture, which was stirred at 20 °C for 5 h. The reaction mixture was directly diluted with 3% citric acid (30 mL), extracted with ethyl acetate (60 mL), and washed with saturated brine (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography, and the fraction was directly concentrated under reduced pressure to obtain compound 5-2. [M+1] += 409.2.

[0111] Step 2: Synthesis of compound 5-3 Compound 5-2 (1 g, 2.11 mmol) was dissolved in tetrahydrofuran (18 mL) and water (6 mL), and lithium hydroxide monohydrate (176.83 mg, 4.21 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with 3% citric acid (30 mL) and extracted with ethyl acetate (60 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The product was obtained without further purification. Compound 5-3 was obtained. [M+1] + =381.2.

[0112] Step 3: Synthesis of compound 5-4 Compound 5-3 (1 g, 2.63 mmol) was dissolved in 2-butanone (40 mL). 1-Hydroxybenzotriazole (355.13 mg, 2.63 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (604.61 mg, 3.15 mmol) were then added to the reaction mixture. The mixture was stirred at 25 °C for 0.5 h. Diisopropylethylamine (1.36 g, 10.51 mmol) and the hydrochloride salt of compound 1-2 (702.28 mg, 3.15 mmol) were then added to the reaction mixture. The mixture was stirred for 16 h. The reaction mixture was extracted with dichloromethane (30 mL). The organic phase was washed with 3% citric acid (30 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography afforded compound 5-4. [M+1] + =549.3.

[0113] Step 4: Synthesis of compound 5-5 Compound 5-4 (1.24 g, 2.26 mmol) was dissolved in tetrahydrofuran (30 mL), and then lithium borohydride (147.67 mg, 6.78 mmol) was added to the reaction mixture. The mixture was stirred at 25 °C for 3 h. The reaction mixture was extracted with dichloromethane (30 mL), and the organic phase was quenched with saturated ammonium chloride (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-5. [M+1] + =521.3.

[0114] Step 5: Synthesis of Compound 5-6 Compound 5-5 (0.5 g, 960.32 μmol) was dissolved in dichloromethane (20 mL), and then Dess-Martin reagent (448.04 mg, 1.06 mmol) was added to the reaction mixture. The mixture was stirred at 25° C. for 16 h. The reaction was quenched with saturated sodium bicarbonate solution (20 mL) and sodium thiosulfate solution (20 mL) and extracted with dichloromethane (60 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-6. [M+1] + =519.3.

[0115] Step 6: Synthesis of Compounds 5-7 Compound 5-6 (0.6 g, 1.16 mmol) and glacial acetic acid (83.36 mg, 1.39 mmol) were dissolved in dichloromethane (20 mL). tert-Butyl isocyanide (115.40 mg, 1.39 mmol) was then added to the reaction mixture, and the mixture was stirred at 25 °C for 3 h. The reaction mixture was directly diluted with water (20 mL) and extracted with dichloromethane (60 mL). The combined organic phases were dried, concentrated, and purified by column chromatography to give compound 5-7. [M+1] += 662.4.

[0116] Step 7: Synthesis of Compounds 5-8 Compound 5-7 (0.4 g, 604.39 μmol) was dissolved in methanol (12 mL). Then, an aqueous solution (6 mL) of potassium carbonate (208.83 mg, 1.51 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mL). The combined organic phase was washed with 3% citric acid (15 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-8. [M+1] + =620.4.

[0117] Step 8: Synthesis of Compounds 5-9 Compound 5-8 (0.35 g, 564.71 μmol) was dissolved in dichloromethane (10 mL), and then Dess-Martin reagent (359.27 mg, 847.06 μmol) was added to the reaction mixture. The mixture was stirred at 25 °C for 12 h. The reaction was quenched with saturated sodium bicarbonate solution (20 mL) and sodium thiosulfate solution (20 mL), extracted with dichloromethane (20 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-9. [M+1] + =618.4.

[0118] Step 9: Synthesis of Compounds 5-10 Compound 5-9 (240 mg, 388.49 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was reacted at 20° C. for 1 hour. The reaction mixture was concentrated to give compound 5-10. [M+1] + =518.4.

[0119] Step 10: Synthesis of Compound 5 Compound 5-10 (180 mg, 347.72 μmol) was dissolved in dichloromethane (3 mL), and pyridine (275.05 mg, 3.48 mmol) and trifluoroacetic anhydride (182.58 mg, 869.30 μmol) were added at 0 °C. The mixture was allowed to react for 2 h at 20 °C. The reaction mixture was extracted with dichloromethane (60 mL) and 3% citric acid solution (30 mL). The organic phase was separated and extracted with saturated brine (30 mL). The organic phase was separated and dried over anhydrous sodium sulfate, then concentrated. Compound 5 was obtained by column chromatography. 1 HNMR(400MHz,DMSO-d6)δ ppm 9.79-9.92(m,1H)8.46(d,J=8.13Hz,1H)7.12-7.99(m,2H)5.95-6.29(m,1H)4.89-5.14(m,1H)4.02-4.38(m,2H)3.57-3 .86(m,2H)2.87-3.30(m,3H)2.63-2.76(m,1H)2.01-2.42(m,3H)1.36-1.99(m,15H)1.26-1.33(m,9H)1.15-1.26(m,2H).

[0120] Example 6 TIFF0007735531000050.tif36170Synthetic route: TIFF0007735531000051.tif163170

[0121] Step 1: Synthesis of compound 6-2 Sodium borohydride (10.42 g, 275.44 mmol) was dissolved in tetrahydrofuran (300 mL), purged with nitrogen three times, and cooled to 0 °C. Compound 6-1 (20 g, 140.65 mmol) was dissolved in tetrahydrofuran (100 mL) and slowly added dropwise to the reaction system. Next, boron trifluoride ethyl etherate (281.30 mmol, 34.72 mL) was slowly added dropwise. The reaction mixture was warmed to 20 °C and stirred for 2 h. Ethanol (1 L) was added, and after stirring for 15 min, the reaction mixture was concentrated and extracted with water (100 mL) and dichloromethane (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6-2. 1 HNMR(400MHz,CDCl3)δ ppm 3.6(s,2H),1.40-1.56(m,5H),1.23-1.37(m,5H),0.93(s,3H).

[0122] Step 2: Synthesis of compound 6-3 Compound 6-2 (17.99 g, 140.32 mmol) was dissolved in dichloromethane (180 mL), and pyridinium chlorochromate (45.37 g, 210.47 mmol) and silica gel (45 g, 748.59 mmol) were added. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure at 20 °C to obtain crude product 6-3, which was used directly in the next reaction. 1 HNMR(400MHz,CDCl3)δ ppm 9.37(s,1H),1.16-1.54(m,10H),0.93(s,3H).

[0123] Step 3: Synthesis of compound 6-4 Compound 6-3 (17 g, 134.71 mmol) was dissolved in chloroform (150 mL), R-phenylglycinol (18.48 g, 134.71 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 h. The mixture was then cooled to 0 °C, and trimethylsilyl cyanide (26.73 g, 269.42 mmol, 33.71 mL) was added. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 6-4. 1 HNMR(400MHz,CDCl3)δ ppm 7.13-7.27(m,5H),3.89-3.96(m,1H),3.61-3.69(m,1H),3.37-3.47(m,1H),2.92 - 3.02(m,1H),1.03-1.41(m,10H),0.93(s,3H). [M+1] + =273.2.

[0124] Step 4: Synthesis of compound 6-5 Compound 6-4 (10 g, 36.71 mmol) was dissolved in methanol (100 mL) and dichloromethane (100 mL), cooled to 0 °C, and lead tetraacetate (13.56 g, 27.53 mmol) was added. The mixture was purged with nitrogen three times and stirred at 0 °C for 2 h. Saturated sodium bicarbonate solution (200 mL) and dichloromethane (45 mL × 3) were added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 6-5. [M+1] + =241.0.

[0125] Step 5: Synthesis of compound 6-6 Compound 6-5 (5.4 g, 22.47 mmol) was dissolved in hydrochloric acid (6 M, 490 mL), and the reaction mixture was heated to 100° C. and stirred for 24 h. The reaction mixture was cooled to room temperature and extracted with chloroform (300 mL × 3). The aqueous phase was concentrated under reduced pressure to give compound 6-6. 1 HNMR(400MHz,CD3OD)δ ppm 4.46(s,1H),1.41-1.74(m,10H),1.20(s,3H).

[0126] Step 6: Synthesis of Compounds 6-7 Compound 6-6 (3.6 g, 17.33 mmol) was dissolved in methanol (36 mL), triethylamine (52.00 mmol, 7.24 mL) and di-tert-butyl dicarbonate (26.00 mmol, 5.97 mL) were added, and the reaction mixture was stirred at 20° C. for 4 h. The reaction mixture was adjusted to pH 3 with aqueous citric acid (3%) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6-7.

[0127] Step 7: Synthesis of Compounds 6-8 Compound 6-7 (1.5 g, 5.53 mmol) and the hydrochloride salt of compound 1-3 (1.46 g, 6.63 mmol) were dissolved in ethyl acetate (15 mL). N,N-diisopropylethylamine (2.86 g, 22.11 mmol, 3.85 mL) and n-propylphosphoric acid anhydride (5.28 g, 8.29 mmol, 4.93 mL, 50% ethyl acetate solution) were added, and the reaction mixture was stirred at 55 °C for 16 h. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:0 to 10:1) to give compound 6-8. [M+1] + =437.1.

[0128] Step 8: Synthesis of Compounds 6-9 Compound 6-8 (1.52 g, 3.48 mmol) was dissolved in methanol (15 mL) and water (5 mL), and lithium hydroxide monohydrate (166.77 mg, 6.96 mmol) was added. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was adjusted to pH 3 with 3% aqueous citric acid and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6-9. [M-56+H] + =353.2.

[0129] Step 9: Synthesis of Compounds 6-10 Compound 6-9 (1.42 g, 3.48 mmol) and compound 1-1 (1.50 g, 4.18 mmol, TsOH) were dissolved in ethyl acetate (15 mL), N,N-diisopropylethylamine (1.80 g, 13.92 mmol, 2.42 mL) and n-propylphosphoric acid anhydride (5.28 g, 8.29 mmol, 4.93 mL, 50% ethyl acetate solution) were added, and the mixture was stirred at 55 °C for 16 h. 30 mL of water was added to the reaction mixture, which was then extracted three times with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (dichloromethane:methanol = 100:0-10:1) afforded compound 6-10. [M+1] + =577.4.

[0130] Step 10: Synthesis of Compounds 6-11 Compound 6-10 (605 mg, 1.05 mmol) was dissolved in THF (12 mL), LiBH4 (45 mg, 2.1 mmol) was slowly added at 0 °C, and the mixture was slowly heated to 20 °C and allowed to react for 2 h. Saturated ammonium chloride solution (10 mL) was slowly added to the reaction mixture, followed by extraction with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6-11. [M+1] + =549.1.

[0131] Step 11: Synthesis of Compounds 6-12 Compound 6-11 (575 mg, 1.05 mmol) was dissolved in dichloromethane (10 mL), Dess-Martin reagent (533.35 mg, 1.26 mmol) was added, and the reaction mixture was stirred at 20 °C for 16 h. Saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) were added to the reaction mixture, followed by extraction with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:0-10:1) to give compound 6-12. [M+1]+ =547.1.

[0132] Step 12: Synthesis of Compounds 6-13 Compound 6-12 (330 mg, 603.63 μmol) was dissolved in dichloromethane (3 mL), acetic acid (72.50 mg, 1.21 mmol, 69.04 μL) and cyclopentyl isocyanide (68.92 mg, 724.35 μmol, 80.14 μL) were added, and the reaction mixture was stirred at 20 °C for 2 h. Saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:0 to 10:1) to give compound 6-13. [M+1] + =702.4.

[0133] Step 13: Synthesis of Compounds 6-14 Compound 6-13 (304 mg, 433.12 μmol) was dissolved in methanol (3 mL) and water (2 mL), potassium carbonate (149.65 mg, 1.08 mmol) was added, and the reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was adjusted to pH 3 with 3% aqueous citric acid solution and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product compound 6-14, which was used directly in the next reaction. [M+1] + =660.2.

[0134] Step 14: Synthesis of Compounds 6-15 Compound 6-14 (285.7 mg, 432.97 μmol) was dissolved in dichloromethane (6 mL), Dess-Martin reagent (220.37 mg, 519.57 μmol) was added, and the reaction mixture was stirred at 20 °C for 16 h. Saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) were added to the reaction mixture, followed by extraction with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:0 to 10:1) to give 6-15. [M+1] + =658.4.

[0135] Step 15: Synthesis of trifluoroacetates of compounds 6-16 Compound 6-15 (265.8 mg, 404.05 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (921.40 mg, 8.08 mmol, 598.31 μL) was added, and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate of compound 6-16, which was used directly in the next reaction. [M+1] + =558.3.

[0136] Step 16: Synthesis of Compound 6 The trifluoroacetate of compound 6-16 (271 mg, 403.43 μmol) was dissolved in dichloromethane (3 mL), and pyridine (223.38 mg, 2.82 mmol, 227.94 μL) and trifluoroacetic anhydride (127.10 mg, 605.14 μmol, 84.17 μL) were added at 0°C. The reaction mixture was slowly heated to 20°C and stirred for 2 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with 3% citric acid (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative HPLC (chromatography column: Xtimate C18 100*30mm*3μm; mobile phase: [A: water (formic acid)-B: acetonitrile]:acetonitrile%: 40%-80%, 8min) to obtain compound 6.1 HNMR(400MHz,CDCl3)δ ppm 7.01-7.27(m,1H),6.76-6.99(m,1H),6.05-6.46(m,1H),5.02-5.43(m,1H),4.59-4.75(m,1H),4.25-4.49(m,1H),4.09-4.23(m,1H), 3.75-4.08(m,1H),3.59-3.73(m,1H),3.25-3.54(m,2H),2.42-2.92(m,3H),1.82-2.37(m,8H),1.25-1.80(m,20H),0.90-1.20(m,4H). [M+1] + =654.4.

[0137] Example 7 TIFF0007735531000052.tif42170Synthetic route: TIFF0007735531000053.tif176170

[0138] Step 1: Synthesis of compound 7-2 7-1 (90 g, 348.41 mmol) was dissolved in dichloromethane (900 mL), and Dess-Martin reagent (162.55 g, 383.26 mmol) was added. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate (900 mL), and the pH was adjusted to 7-8 with aqueous sodium carbonate. The mixture was separated, and the aqueous phase was extracted with dichloromethane (900 mL). The combined organic phase was concentrated under reduced pressure to give compound 7-2. The crude product was used directly in the next reaction.

[0139] Step 2: Synthesis of compound 7-3 N-Cyclopentylformamide (2.79 g, 24.68 mmol) was dissolved in dichloromethane (55 mL). Burgess reagent (7.67 g, 32.19 mmol) was added at 20 °C, and the reaction mixture was stirred at 20 °C for 1 hour. Water (1.93 mL) was added and the mixture was stirred for 30 minutes. Next, 7-2 (5.5 g, 21.46 mmol) and acetic acid (2.45 mL) were added, and the reaction mixture was stirred at 20 °C for 12 hours. 2.5% aqueous sodium chlorite solution (105.62 mL) was added to the reaction mixture and the mixture was stirred for 30 minutes. The reaction mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product 7-3 was used directly in the next step.

[0140] Step 3: Synthesis of compound 7-4 7-3 (2 g, 5.41 mmol) was dissolved in methanol (60 mL) and water (30 mL), potassium carbonate (5.04 g, 36.45 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was adjusted to pH 5-6 with saturated citric acid solution, extracted with dichloromethane (100 mL), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was added to ethyl acetate (50 mL), and n-heptane (50 mL) was added dropwise with stirring for 2 h. The solid was filtered, and the filter cake was dried in vacuo to obtain compound 7-4. [M-100+1] + =269.9.

[0141] Step 4: Synthesis of the hydrochloride salt of compound 7-5 7-4 (10 g, 24.30 mmol) was dissolved in ethyl acetate (20 mL), and a hydrogen chloride-ethyl acetate solution (4 M, 5.41 mL) was added. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was dried in vacuo to give the hydrochloride salt of compound 7-5. [M+1] + =270.0.

[0142] Step 5: Synthesis of compound 7-7 Compound 7-6 (2.00 g, 6.04 mmol) was dissolved in tetrahydrofuran (30 mL), zinc powder (3.25 g, 49.70 mmol), zirconocene dichloride (2.19 g, 7.24 mmol), and dibromomethane (1.15 g, 6.64 mmol) were added, and the reaction mixture was heated to 80 °C and stirred for 5 h. After completion of the reaction, the mixture was cooled to room temperature, water (5 mL) was added, and the mixture was filtered. The filtrate was collected and extracted with methyl tert-butyl ether (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by high-performance silica gel chromatography (ISCO®; 12 g SepaFlash® high-performance silica gel column, eluent 0-20% ethyl acetate / petroleum ether, flow rate 30 mL / min) to give compound 7-7. [M+1] + =330.1.

[0143] Step 6: Synthesis of Compounds 7-8 Under nitrogen protection, diethylzinc (1M, THF, 37.95 mL) was added to dichloromethane (45 mL) and the reaction mixture was stirred at 0 °C. Then, trifluoroacetic acid (4.33 g, 37.95 mmol) was added and stirred for 30 min. A dichloromethane solution (70 mL) of compound 7-7 (2.50 g, 7.59 mmol) was added, and the reaction mixture was slowly heated to 25 °C and stirred for 16 h. Saturated aqueous ammonium chloride (100 mL) was added and the mixture was separated. The aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phase was concentrated under reduced pressure. The resulting crude product was purified by high-performance silica gel chromatography (ISCO®; 12 g SepaFlash® high-performance silica gel column, eluent 0-20% ethyl acetate / petroleum ether, flow rate 30 mL / min) to give compound 7-8. [M+1] + =344.1.

[0144] Step 7: Synthesis of Compounds 7-9 Compound 7-8 (600.00 mg, 1.75 mmol) was dissolved in ethanol (30 mL), and dioxane hydrochloride solution (4 M, 500.00 μL) and dry palladium on carbon (200 mg, 10% content) were added. The reaction mixture was stirred under a hydrogen atmosphere (15 Psi) at 25° C. for 12 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 7-9. The crude product was used directly in the next step.

[0145] Step 8: Synthesis of Compounds 7-10 Compounds 7-9A (852.41 mg, 3.69 mmol) and 7-9 (735.00 mg, 3.51 mmol) were dissolved in N,N-dimethylformamide (30 mL) and dichloromethane (40 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.81 g, 4.77 mmol) and N,N-diisopropylethylamine (1.36 g, 10.53 mmol) were added, and the reaction mixture was stirred at 25°C for 16 hours under nitrogen protection. The reaction mixture was poured into 200 mL of 4 M aqueous citric acid solution, extracted with dichloromethane (100 mL x 3), and the combined organic phase was concentrated under reduced pressure. The resulting crude product was purified by high-performance silica gel chromatography (ISCO®; 12 g SepaFlash® high-performance silica gel column, eluent 0-20% ethyl acetate / petroleum ether, flow rate 30 mL / min) to give compounds 7-10. [M+Na] + =445.2.

[0146] Step 9: Synthesis of Compounds 7-11 Compound 7-10 (1.30 g, 3.08 mmol) was dissolved in tetrahydrofuran (6 mL), water (6 mL), and methanol (6 mL). Lithium hydroxide monohydrate (387.30 mg, 9.23 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into 100 mL of dichloromethane, diluted, and then 50 mL of 1N aqueous hydrochloric acid was added to separate the layers. The organic phase was extracted, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 7-11. The crude product was used directly in the next step. [M-tBu+1] + =339.1.

[0147] Step 10: Synthesis of the hydrochloride salts of compounds 7-12 Compound 7-11 (1.20 g, 3.04 mmol) was dissolved in tert-butyl methyl ether (10 mL), and hydrogen chloride-ethyl acetate (4 M, 760.45 μL) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give the hydrochloride salt of compound 7-12. The crude product was used directly in the next step. [M+1] + =295.1.

[0148] Step 11: Synthesis of Compounds 7-13 The hydrochloride salt of compound 7-12 (1.20 g, 3.63 mmol) was dissolved in methanol (10 mL), triethylamine (1.84 g, 18.14 mmol) and ethyl trifluoroacetate (1.03 g, 7.25 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane (100 mL) was added. The mixture was washed with 100 mL of 5% aqueous citric acid, separated, and extracted. The aqueous phase was extracted with dichloromethane (200 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness. The crude product was stirred in a mixture of methyl tert-butyl ether and petroleum ether (1:6, 10 mL) at 25 °C for 1 hour and filtered to obtain crude product 7-13, which was directly used in the next step. [M+1] + =390.9.

[0149] Step 12: Synthesis of Compounds 7-13A and 7-13B Compound 7-13 (100 mg, 256.15 μmol) was purified by preparative HPLC (chromatography column: Xtimate C18 150*40 mm*5 μm; mobile phase: [A: water (hydrochloric acid) - B: acetonitrile]; acetonitrile%: 43%-63%, 10 min) to give 7-13A (pre-peak, retention time: 4.198 min, [M+1] + =391.2) and 7-13B (later peak, retention time: 4.377 min, [M+1] + =391.2). Analysis method: Chromatography column: ChromCore 120 C18 3 μm, 3.0*30 mm; Mobile phase: [A: water (trifluoroacetic acid) - B: acetonitrile]; Acetonitrile %: 10% - 80% in 6 minutes, then 80% held for 0.5 minutes, flow rate 0.8 mL / min.

[0150] Step 13: Synthesis of Compounds 7-14A Compound 7-13A (35 mg, 89.65 μmol) and the hydrochloride salt of 7-5 (41.12 mg) were dissolved in DCM (0.5 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.62 mg, 107.58 μmol), 2-hydroxypyridine-1-oxide (2.49 mg, 22.41 μmol), and N,N-diisopropylethylamine (34.76 mg, 268.96 μmol) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with dichloromethane (5 mL), washed with saturated aqueous citric acid (1 mL) and saturated brine (1 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness to give crude product 7-14A, which was used directly in the next step. [M+1] + =642.2.

[0151] Step 14: Synthesis of Compound 7-14B Compound 7-13B (25.00 mg, 64.04 μmol) and the hydrochloride salt of 7-5 (29.37 mg) were dissolved in DCM (0.5 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.73 mg, 76.84 μmol), 2-hydroxypyridine-1-oxide (1.78 mg, 16.01 μmol), and N,N-diisopropylethylamine (24.83 mg, 192.11 μmol) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with dichloromethane (5 mL), washed with saturated aqueous citric acid (1 mL) and saturated brine (1 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness to give crude product 7-14B, which was used directly in the next step. [M+1] + =642.2.

[0152] Step 15: Synthesis of Compound 7A Compound 7-14A (50 mg, 77.92 μmol) was dissolved in DCM (0.5 mL), Dess-Martin reagent (39.66 mg, 93.50 μmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium thiosulfate (2 mL), saturated aqueous sodium bicarbonate (2 mL), and saturated brine (2 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 1:1 to 0:1) to obtain compound 7A. [M+1] + =640.2.

[0153] Step 16: Synthesis of Compound 7B Compound 7-14B (35 mg, 54.54 μmol) was dissolved in DCM (0.5 mL), Dess-Martin reagent (27.76 mg, 65.45 μmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium thiosulfate (2 mL), saturated aqueous sodium bicarbonate (2 mL), and saturated brine (2 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 1:1 to 0:1) to obtain compound 7B. 1 HNMR(400MHz,CDCl3)δ ppm 8.95(br d,J=4.02Hz,1H),7.31(br d,J=9.29Hz,1H),6.76(br d,J=7.78Hz,1H),5.56(s,1H),5.00-5.10(m,1H),4.71(d,J=9.03Hz,1H),4.44(s,1H),4.10-4.19(m,1H) ),4.05(t,J=9.91Hz,1H),3.66(dd,J=6.40,10.67Hz,1H),3.28-3.37(m,2H),3.02(q,J=7.11Hz,1H),2. 37-2.53(m,3H),1.95-2.25(m,5H),1.81-1.92(m,2H),1.64-1.76(m,1H),1.63-1.78(m,4H),1.39-1.51 (m,3H),1.20-1.35(m,3H),1.06-1.08(m,1H),1.08(s,9H),0.56-0.59(m,3H),0.45-0.48(m,1H).[M+1] + =640.2.

[0154] Biological Testing

[0155] Experimental Example 1: Evaluation of the in vitro inhibitory activity of test compounds against the novel coronavirus Mpro protease 1. Experimental materials: 1.1 Reagents, consumables, and sources: Tris:Sigma; EDTA: Sigma; NaCl: Sigma; 384 well Plate: Perkin Elmer; Dimethyl sulfoxide(DMSO):Sigma; Substrate(Dabcyl-KTSAVLQSGFRKM-(Edans)):GenScript; SARS-CoV-2 Mpro:WuXi AppTec; GC376:TargetMol. 1.2 Equipment, Source: SpectraMax M2e microplate reader: Molecular Devices; Echo 655 Liquid Handler: Labcyte; Tabletop high-speed centrifuge: Eppendorf. 2. Experimental Method: Compounds were dissolved in DMSO and diluted three-fold using an Echo 655 according to the test concentration requirements. Ten concentration points were placed in two duplicate wells per concentration in a 384-well plate. Mpro protein and substrate were diluted in test buffer (100 mM NaCl, 20 mM Tris-HCl, 1 mM EDTA). Mpro protein was added to the 384-well test plate and incubated with the compound at room temperature for 30 min. Substrate was then added, with test concentrations of 25 nM Mpro protein and 25 μM substrate. The plates were then incubated at 30°C in a constant temperature incubator for 60 min. The fluorescence signal was then measured using a microplate reader at Ex / Em = 340 nm / 490 nm. Simultaneously, background wells containing both substrate and compound but no Mpro protein were used as controls. 3. Data Analysis: 1) The inhibition rate was calculated using the following formula: Inhibition rate % = [(compound - BG 化合物 )-(ZPE-BG ZPE )] / [(HPE-BG HPE )-(ZPE-BG ZPE )] * 100% #HPE: 100% inhibition control, containing 25 nM Mpro protein + 25 μM substrate + 1 μM GC376 ZPE: no inhibition control, containing 25 nM Mpro protein + 25 μM substrate but no compound Compound: Test compound well. Contains 25 nM Mpro protein + 25 μM substrate + compound BG: Background control wells containing 25 μM substrate + compound but no Mpro protein 2) The compound inhibition rate data (% inhibition) was analyzed using GraphPad Prism software by log(agonist) vs. response--variable slope nonlinear fitting to obtain the IC of the compound. 50 The values ​​were obtained and the experimental results are listed in Table 1. TIFF0007735531000054.tif53170Conclusion: The compounds of the present invention have excellent in vitro inhibitory activity against the novel coronavirus Mpro protease.

[0156] Experimental Example 2: Application of a cytopathic model to evaluate the in vitro anti-coronavirus activity of compounds 1. Experimental Materials 1.1. Reagents, Consumables, and Sources MEM medium: Sigma; L-Glutamine: Gibco; Non-essential amino acids: Gibco; Double antibody (Penicillin-Streptomycin Solution): HyClone; Fetal bovine serum (FBS): ExCell; Phosphate buffer solution (DPBS): Corning; 0.25% Trypsin: Gibco CellTiter Glo Cell Viability Assay Kit: Promega; Remdesivir: MCE; 96-well plates: Grenier. 1.2. Devices and Sources Microplate reader: BioTek; Cell counter: Beckman; CO2 incubator: Thermo. 1.3. Cells and viruses MRC5 cells and coronavirus HCoV OC43 were purchased from ATCC. MRC5 cells were cultured in MEM (Sigma) medium supplemented with 10% fetal bovine serum (Excell), 1% double antibody (Hyclone), 1% L-glutamine (Gibco), and 1% non-essential amino acids (Gibco). Experimental medium was MEM (Sigma) medium supplemented with 5% fetal bovine serum (Excell), 1% double antibody (Hyclone), 1% L-glutamine (Gibco), and 1% non-essential amino acids (Gibco). 2. Experimental Method TIFF0007735531000055.tif39170 cells were seeded at a certain density (Table 2) into a 96-well microplate and cultured overnight in a 5% CO2, 37°C incubator. The next day, 50 μL of diluted compounds (8 concentrations, 2 duplicate wells) were added per well. The diluted virus was then added at 100 TCID per well. 50 , and added to the cells at 50 μL per well. A cell control (cells without compound treatment or virus infection), a virus control (cells infected with virus without compound treatment), and a medium control (medium only) were set up. The final volume of the medium in the experiment was 200 μL, and the final concentration of DMSO in the medium was 0.5%. The cells were cultured in a 5% CO2, 33°C incubator for 5 days. Cell viability was detected using the cell viability assay kit CellTiter Glo (Promega). The cytotoxicity assay was performed under the same conditions as the antiviral assay, but without virus infection. 3. Data Analysis The antiviral activity and cytotoxicity of the compounds were expressed as the inhibition rate (%) of virus-induced cytopathic effect and cell viability (%) of the compounds at different concentrations, respectively. The calculation formula was as follows: Inhibition rate (%) = (test well reading - mean value of virus control) / (mean value of cell control - mean value of virus control) x 100 Cell viability (%) = (test well reading - mean of medium control) / (mean of cell control - mean of medium control) x 100 The inhibition rate and cell viability of the compounds were analyzed by nonlinear fitting using GraphPad Prism, and the half effective concentration (EC50) and half cytotoxic concentration (CC50) values ​​of the compounds were calculated. The experimental results are listed in Table 3. TIFF0007735531000056.tif43170 Conclusion: The compounds of the present invention have excellent in vitro anti-coronavirus activity at the cellular level and no cytotoxicity.

[0157] Experimental Example 3: Pharmacokinetic study in mice In this study, C57BL / 6J male mice were used as test animals, and an LC / MS / MS method was applied to quantitatively measure the plasma concentrations of the test compound at different time points in mice after intravenous injection and oral gavage administration, and to evaluate the pharmacokinetic profile of the test drug in mice. Test compound solutions were administered orally and by gavage to mice (6-8 weeks old, overnight fasted). After intravenous administration, 40 μL of blood was collected from the saphenous vein of each mouse at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, and 24.0 h. The blood was then placed in anticoagulant tubes containing EDTA-K2 and centrifuged at 3200 g for 10 min at 4°C to collect plasma. Plasma samples were then processed and analyzed for drug concentrations by LC-MS / MS. After oral gavage, 40 μL of blood was collected from the saphenous vein of each mouse at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h. The blood was then placed in anticoagulant tubes containing EDTA-K2 and centrifuged at 3200 g for 10 min at 4°C to collect plasma. After processing the plasma samples, the drug concentrations in the blood were measured by LC-MS / MS. The experimental results are shown in Tables 4 and 5. TIFF0007735531000057.tif92170TIFF0007735531000058.tif88170ND indicates not detected, and NA indicates not determined. Conclusion: The compounds of the present invention have significantly higher plasma exposure, slower clearance rates, longer half-lives and better pharmacokinetic properties than the reference molecule PF-07321332.

Claims

1. A compound of formula (IV) or a pharmaceutically acceptable salt thereof: (where, R ３ is the expression is a group represented by R １ are each independently F, Cl, Br, I, OR １１ , C.N., C.H. ３ S (O) ｍ - and NHR １２ , and C １～３ alkyl, wherein C １～３ alkyl is optionally substituted with 1, 2 or 3 F; R １１ is H, C １～３ Alkyl, CH ３ (OCH ２ CH ２ ) ｐ - and H(OCH ２ CH ２ ) ｑ -, wherein C １～３ alkyl is optionally substituted with 1, 2 or 3 F; R １２ is C １～３ Alkyl, CH ３ CO- and CH ３ SO ２ -, wherein C １～３ Alkyl, CH ３ CO- and CH ３ SO ２ - is optionally and independently substituted with 1, 2 or 3 F; m is selected from 0, 1 and 2; p and q are selected from 1, 2, 3, 4, 5 and 6; n is selected from 0, 1, 2, 3 and 4; R ２ is C １～４ Alkyl, C ３～６ cycloalkyl and benzyl, １～４ Alkyl, C ３～６ cycloalkyl and benzyl are optionally substituted with 1, 2 or 3 F; Ring A is C ３～１０ selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, and phenyl; Ring B is C ３～８ cycloalkyl and 5-membered heterocycloalkyl, ３～８ Cycloalkyl and 5-membered heterocycloalkyl are each independently one or two R ａ optionally substituted with R ａ are each independently H and C １～３ alkyl.)

2. R １ is selected from F and methyl 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. Ring A is C ３～１０ selected from cycloalkyl 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. Ring A is of the formula is selected from the group consisting of groups represented by 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

5. formula The structural unit represented by the formula is selected from the group consisting of groups represented by 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. R ａ is selected from H and methyl 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. Ring B is a group represented by the formula is selected from the group consisting of groups represented by 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. formula The structural unit represented by the formula is selected from the group consisting of groups represented by 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. The compound is selected from the structures represented by formulas (I-1), (IV-1) and (IV-2): Here, R １ , R ２ , R ３ , n and ring A are as defined in any one of claims 1 to 5.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

10. The compound is selected from the structures represented by formulas (I-1a), (IV-1a) and (IV-2a): Here, R １ , R ２ , R ３ , n and ring A are as defined in claim 9 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof.

11. A compound selected from the compounds represented by the following formulae or a pharmaceutically acceptable salt thereof:

12. 12. The compound of claim 11, selected from the group consisting of compounds of the following formulae: or a pharmaceutically acceptable salt thereof.

13. 10. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and another antiviral agent, in the manufacture of a medicament for treating coronavirus infection.

14. The coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2, or a mutant thereof.

14. The use according to claim 13.

15. The other antiviral drug is ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, or lopinavir.

14. The use according to claim 13.

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