Protease inhibitors and methods of making and using the same

Abstract

Disclosed are protease inhibitors and methods of making and using the same, which can be used as PLpro inhibitors in combination with one or more pharmaceutically acceptable excipients or with one or more other active ingredients for treating diseases or conditions caused by or associated with viral infection. The excipients can be carriers, diluents, binders, lubricants, wetting agents, etc. The protease inhibitors have high inhibitory activity and can be used for broad-spectrum antiviral, especially against coronaviruses.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and in particular to a PLPro protease inhibitor, its preparation method, and its application. Background Technology

[0002] Coronaviruses primarily affect the respiratory, gastrointestinal, and nervous systems, often causing respiratory and intestinal diseases, neurological symptoms, and myocarditis. Infection with these viruses can seriously impact human health. While some progress has been made in the development of vaccines and antibody drugs against coronaviruses, the development of antiviral drugs will provide new means of combating coronaviruses. Summary of the Invention

[0003] This invention provides a protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, said protease inhibitor having the structure of formula (I):

[0004]

[0005] in,

[0006] M is independently selected from: C, N, O, S;

[0007] n is an integer independently selected from 1 to 5 (e.g., 1, 2, 3, 4, 5);

[0008] L1 is absent or selected from: C1-C6 alkylene groups, -CO-, -SO2-;

[0009] L2 is absent or selected from: C1-C6 alkylene or C1-C6 heteroalkylene; any one of A1-A5 is CR1, and the other groups are independently selected from CR1' or N;

[0010] R1 is selected from: substituted or unsubstituted nitrogen-containing heterocycles, -R L -OR';

[0011] R A It is a C1-C6 alkyl group;

[0012] R1' is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, halogen, -Si(C1-C6 alkyl), -NO2-R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH=NR', -R L -CN、-R L -OR'、-RL -OC(O)R'、-R L -S(O) t -NR'R”, -R L -S(O) t -R'、-R L -NR'R”, -R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”, -R L -NO2, -R L -N = CR'R", which can be arbitrarily replaced;

[0013] t is 1 or 2;

[0014] R L Selected from: single bond, C1-C6 alkylene, C3-C6 heteroalkylene, C3-C6 cycloalkylene, C3-C6 heterocyclic, -NR4C(O)-, -NR4S(O) t -, -C(O)-, -C(O)O-, -NR4-, -C(O)NR4-, -S(O) t NR4-, which may be optionally replaced;

[0015] R' and R" are independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, halogen, which may optionally be substituted.

[0016] In this implementation, M is C.

[0017] In the implementation, n is independently selected from an integer from 1 to 3.

[0018] In this implementation, n is 1.

[0019] In this implementation, n is 2.

[0020] In the implementation, L1 is absent or selected from: C1-C6 alkylene groups, -CO-.

[0021] In the embodiments, L2 is absent or selected from C1-C6 alkylene groups.

[0022] In the implementation, R1 is a substituted or unsubstituted nitrogen-containing heterocycle.

[0023] In this implementation, R1 is selected from: -R L -OR'、

[0024] Preferably, the Selected from the following structure:

[0025]

[0026] In the implementation method, the R A It is a methyl group.

[0027] In the implementation method, the R A It is tert-butyl.

[0028] In the embodiments, R1' is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, -R L -OR', which can be arbitrarily replaced.

[0029] In the implementation method, R1' is selected from: H, -CH3, -OH.

[0030] In the implementation method, A1 is N in A1-A5;

[0031] In the implementation method, A2 is N in A1-A5;

[0032] In the implementation method, A3 in A1-A5 is N;

[0033] In the implementation method, A4 is N in A1-A5;

[0034] In the implementation method, A5 is N in A1-A5;

[0035] In the implementation, any one of the groups A1-A5 is CR1, and the other groups are CR1'.

[0036] In this embodiment, the protease inhibitor is selected from structures having formulas (I-1), (I-2), (I-3), and (I-4), as follows:

[0037]

[0038] In this embodiment, the protease inhibitor is selected from structures having formula (I-1), as follows:

[0039]

[0040] in,

[0041] Any one of the groups in A1-A5 is CR1, and the other groups are independently selected from CR1' or N;

[0042] R1 is a substituted or unsubstituted nitrogen-containing heterocycle;

[0043] R1' is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, halogen, -N3, -B(OH)2, -Si(C1-C6 alkyl), -NO2-R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH=NR', -R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”, -R L -S(O) t -R'、-R L -NR'R”, -R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”, -R L -NO2, -R L -N = CR'R", which can be arbitrarily replaced;

[0044] t is 1 or 2;

[0045] R L Selected from: single bond, C1-C6 alkylene, C3-C6 heteroalkylene, C3-C6 cycloalkylene, C3-C6 heterocyclic, -NR4C(O)-, -NR4S(O) t -, -C(O)-, -C(O)O-, -NR4-, -C(O)NR4-, -S(O) t NR4-, which may be optionally replaced;

[0046] R' and R" are independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, halogen, which may optionally be substituted;

[0047] R4 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, hydroxyl, alkoxy.

[0048] In this embodiment, the protease inhibitor is selected from structures having formulas (II-1), (II-2), (II-3), (II-4), (II-5), and (II-6), as follows:

[0049]

[0050] In an embodiment, the protease inhibitor has the structure of formula (II-1):

[0051]

[0052] In this embodiment, the protease inhibitor is selected from structures having formulas (III-1), (III-2), (III-3), (III-4), (III-5), and (III-6), as follows:

[0053]

[0054] In an embodiment, the protease inhibitor has the structure of formula (III-1):

[0055]

[0056] In this implementation, R1 is selected from: -OH、

[0057] Among them, R2, R2', and R4 are independently selected from H, (=O), C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, halogen, -N3, -B(OH)2, and -R. L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、 -R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”, -R L -S(O) t -R'、-R L -NR'R”, -R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”, -R L -NO2, -R L -N=CR'R”;

[0058] Z1 is selected from NR3' or O;

[0059] m1 is 1 or 2;

[0060] R3 and R3' are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and -R. L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、 -R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”, -R L -S(O) t -R'、-R L -NR'R”, -R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”, -R L -NO2, -R L -N=CR'R。

[0061] In the embodiments, R4 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, hydroxyl, alkoxy.

[0062] In this embodiment, R1 is selected from: -OH,

[0063] In this embodiment, R1 is -OH.

[0064] In this implementation, R1 is selected from:

[0065] In this implementation, R1 is selected from:

[0066] Where Z2 is 0 or

[0067] m is 1, 2, or 3;

[0068] R 45 R 46 Independently selected from H, (=O), C1-C6 alkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, halogen, -N3, -B(OH)2, -R L -COR'、-R L-C(O)OR'、-R L -C(O)NR'R”、 -R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”, -R L -S(O) t -R'、-R L -NR'R”, -R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”, -R L -NO2, -R L -N=CR'R。

[0069] R 41 R 42 Independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、 -R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”, -R L -S(O) t -R'、-R L -NR'R”, -R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”, -R L -NO2, -R L -N=CR'R。

[0070] In the implementation method, R3, R3', R 41 R 42 Independently selected from H, -C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOH, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-CONH2.

[0071] In the implementation method, R2, R2', R4, R41 R 42 Independently selected from: -H, (=O), F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF3, -OH, -N3, -B(OH)2

[0072] -CN、

[0073] In this embodiment, the protease inhibitor has the following structure:

[0074]

[0075]

[0076] In this embodiment, the protease inhibitor has the following structure:

[0077]

[0078]

[0079] The present invention also provides a pharmaceutical composition comprising the above-mentioned protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0080] The pharmaceutical composition may also include one or more other active ingredients used in combination.

[0081] For example, the excipients may be carriers, diluents, adhesives, lubricants, wetting agents, etc.

[0082] The pharmaceutical compositions of the present invention can be formulated in the following forms: syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, solutions, creams, ointments, lotions, gels, emulsions, etc.

[0083] The present invention also provides the use of the above-mentioned protease inhibitors and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the above-mentioned pharmaceutical compositions as PLpro inhibitors, for example as antiviral drugs.

[0084] The present invention also provides the use of the above-mentioned protease inhibitors and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the above-mentioned pharmaceutical compositions in medicaments for reducing and / or inhibiting coronavirus replication.

[0085] The present invention also provides the use of the above-mentioned protease inhibitors and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the above-mentioned pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases or conditions caused by or related to viral infections.

[0086] In one embodiment of the present invention, the virus is a coronavirus, such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, MERS-CoV, etc.

[0087] Specifically, the aforementioned diseases or conditions are those caused by or related to coronavirus infection, such as COVID-19, SARS, MERS, etc.

[0088] The present invention also provides a method for preventing and / or treating diseases or conditions caused by or related to viral infection, comprising the step of administering to a subject an effective amount of the above-described protease inhibitor of the present invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound of the present invention, or the above-described pharmaceutical composition of the present invention.

[0089] In particular, the aforementioned diseases or conditions are caused by or related to coronavirus infection, such as MERS.

[0090] Specifically, the subjects mentioned above are animals; in one embodiment of the present invention, the subjects mentioned above are mammals, such as humans, monkeys, cats, dogs, rats, bats, etc. Attached Figure Description

[0091] Figure 1 The figure shows the inhibition rate curve of compound C1.

[0092] Figure 2 The figure shows the inhibition rate curve of compound C2.

[0093] Figure 3 The figure shows the inhibition rate curve of compound C3.

[0094] Figure 4 The figure shows the inhibition rate curve of compound C5.

[0095] Figure 5 The figure shows the inhibition rate curve of compound C8.

[0096] Figure 6 The figure shows the inhibition rate curve of compound C12.

[0097] Figure 7 The figure shows the inhibition rate curve of compound C13. Detailed Implementation

[0098] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0099] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by single bonds. Typical alkyl groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is replaced by a cycloalkyl group, the corresponding radical is a "cycloalkylalkyl" radical, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is replaced by an aryl group, the corresponding radical is an "aralkyl" radical, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is replaced by a heterocyclic group, the corresponding radical is a "heterocyclicalkyl" radical. "Alkylene" usually refers to an alkyl group with two free valence bonds. Typical alkylene groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene, ethylene, propylene, butylene, etc.

[0100] The term "alkoxy" refers to a substituent formed when a hydrogen atom in a hydroxyl group is replaced by an alkyl group. Typical alkoxy groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0101] The term "cycloalkyl" refers to a saturated or partially saturated (especially saturated) monocyclic or polycyclic group that may contain 1 to 4 monocyclic and / or fused rings and 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

[0102] The term "aryl" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing a monoaryl group and / or a fused aryl group, such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. Typical aryl groups are those containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, and indenyl. "Arylidene" refers to a divalent group derived from aromatic hydrocarbons by removing two hydrogen atoms.

[0103] The term "heterocyclic group" includes heteroaromatic and heterocyclic groups containing 1 to 3 monocyclic and / or fused rings and 3 to 18 ring atoms. Preferred heteroaromatic and heterocyclic groups contain 5 to 10 ring atoms. Suitable heteroaryl groups in the compounds of the present invention contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms. Examples of heteroaryl groups, such as, but not limited to, coumarins, including 8-coumarins; quinolinyl groups, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indoleyl, isoindoleyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl, cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc. Suitable heterocyclic groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. Examples of heterocyclic groups, such as, but not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiocyclohexyl, piperazine, aziridine, oxocyclobutyl, thiocyclobutyl, high-piperidinyl, oxocyclopropane, thiocyclopropane, acrylonitrile, oxoaziridine, diacylonitrile, triacylonitrile, 1,2,3,6-tetracyclyl Hydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiopentyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinazinyl, etc.

[0104] The above-mentioned groups can be replaced by one or more suitable groups at one or more available positions, such as: OR', =O, SR', SOR', SO2R', OSO2R', OSO3R', NO2, NHR', N(R')2, =N-R', N(R')COR', N(COR')2, N(R')SO2R', N(R')C(=NR')N(R')R', N3, CN, halogen, COR', COOR', OCOR', OCOOR', OCONHR', OCON(R')2, CONHR', CON(R')2, CON(R')OR', CON(R')SO2R', PO(OR')2, PO(OR')R', PO(OR')(N(R')R'), Cl-C 12 Alkyl, C3-C 10cycloalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, aryl, and heterocyclic groups, wherein each R' group is independently selected from: hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, COalkyl, COOH, C1-C 12 Alkyl, C3-C 10 cycloalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, aryl, and heterocyclic groups. These groups are themselves substituted, and the substituents can be selected from the aforementioned list.

[0105] "Halogen" refers to bromine, chlorine, iodine, or fluorine.

[0106] "Halogenated alkyl" refers to a group in which the hydrogen atom on the alkyl group is replaced by a halogen atom (F, Cl, Br, I), such as -CH2Rh, -CHRh2, -CRh3, where Rh is F, Cl, Br or I; such as -CF3.

[0107] The term "pharmaceutically acceptable salt" refers to an acidic or basic salt that is theoretically non-toxic, non-irritating, and non-allergenic, and that can achieve or provide clinically acceptable pharmacokinetic, absorption, distribution, and metabolic properties of a drug molecule to achieve its intended purpose. The salts described in this invention include pharmaceutically acceptable acidic or basic salts of compounds with acidic, basic, or amphoteric groups. A list of suitable salts can be found in SM Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0108] The pharmaceutically acceptable salts described in this invention include acid addition salts and base addition salts.

[0109] The acid addition salts include, but are not limited to, salts from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, as well as salts from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanic acids, hydroxyalkanic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, and galacturonic acids. Acid addition salts can be prepared by contacting a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base, and the free base can be separated in a conventional manner.

[0110] The base addition salts described in this invention refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting a sufficient amount of the desired base in a conventional manner to form a salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be separated in a conventional manner.

[0111] The term "solvent" should be understood to refer to any form of the compounds of the present invention, wherein the compounds are linked to another molecule (usually a polar solvent) by a non-covalent bond, particularly including hydrates and alcohols, such as methanols. Hydrates are preferred solvates.

[0112] The term "prodrug" is used in its broad sense and encompasses derivatives that can be converted into the compounds of the present invention in vivo. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable acylureas, and biohydrolyzable phosphate ester analogs. Preferably, the prodrug having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is readily obtained by esterification of any carboxylic acid moiety present in the molecule.

[0113] Any compound referred to herein is intended to represent such a particular compound and certain variations or forms thereof. In particular, the compounds referred to herein may have an asymmetric center and therefore exist in different enantiomers or diastereomers. Thus, any given compound referred to herein represents any racemic compound, one or more enantiomers, one or more diastereomers, or mixtures thereof. Similarly, stereoisomers or geometric isomers of the double bonds may also exist, thus in some cases the molecule may exist as (E)-isomers or (Z)-isomers (trans and cis isomers). If the molecule contains multiple double bonds, then each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds of the molecule. Furthermore, the compounds referred to herein may exist as ator isomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers, and ator isomers, and mixtures thereof, are within the scope of this invention.

[0114] Example 1:

[0115]

[0116] C1: 1 H NMR (600MHz, DMSO-d6) δ9.16(s,1H),9.05(s,1H),8.67(d,J=8.5Hz,1H),7.94(d,J=8.1Hz,1H),7.82(dd,J=15 .5,7.6Hz,2H),7.61–7.55(m,1H),7.53(dd,J=8.1,6.7Hz,1H),7.50–7.44(m,1H),6.98(d,J=8.4Hz,1H),6.81 (dd,J=8.2,2.7Hz,1H),6.56(d,J=2.9Hz,1H),4.09(d,J=4.8Hz,2H),3.48(s,2H),2.97(d,J=12.3Hz,2H),1.9 5(dd,J=8.8,4.6Hz,2H),1.91(s,3H),1.87(q,J=7.0,6.1Hz,2H),1.36(d,J=5.1Hz,2H),1.19(d,J=5.6Hz,2H). 13C NMR(151MHz,DMSO-d6)δ170.01,147.94,138.32,138.01,132.25,131.28,128.94,128.87,128.11,126.14,125.88,1 25.62,125.53,115.79,113.61,54.22,51.11,34.58,25.82,18.31,14.55.MS(ESI,m / z):C27H29N3O,[M+H]+412.239.

[0117] Figure 1 The figure shows the inhibition rate curve of compound C1.

[0118] Example 2

[0119]

[0120] C2: 1 H NMR (600MHz, DMSO-d6) δ11.08(d,J=10.1Hz,1H),9.08(s,1H),8.67(d,J=8.4Hz,1H),7.93(d,J=8.0Hz,1H),7.82(dd,J =13.5,7.6Hz,2H),7.60–7.55(m,1H),7.52(dd,J=8.0,6.6Hz,1H),7.47(t,J=7.6Hz,1H),6.98(d,J=8.3Hz,1H),6.80( dd,J=8.5,2.7Hz,1H),6.56(d,J=2.7Hz,1H),4.02–3.97(m,2H),3.53(dd,J=12.9,2.7Hz,2H),3.24(d,J=12.3Hz,2H), 2.70(d,J=4.9Hz,3H), 2.15(tt,J=8.2,5.4Hz,2H), 1.89(d,J=7.5Hz,5H), 1.36(q,J=4.3Hz,2H), 1.18(q,J=4.6Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ170.04,147.64,138.38,138.03,133.94,132.26,131.25,128.93,128.86,128.10,126.13,125.87,1 25.64,125.51,115.72,113.53,62.33,51.50,38.59,34.57,23.89,18.27,14.55.MS(ESI,m / z):C28H31N3O,[M+H]+426.254.

[0121] Figure 2 The figure shows the inhibition rate curve of compound C2.

[0122]

[0123] Example 3

[0124] C3: 1 H NMR (600MHz, DMSO-d6) δ9.08(d,J=2.4Hz,1H),8.66(d,J=8.4Hz,1H),7.94(d,J=8.1Hz,1H),7.82 (dd,J=13.0,7.6Hz,2H),7.60–7.55(m,1H),7.52(dd,J=8.1,6.7Hz,1H),7.47(t,J=7.6Hz,1H),6. 99(d,J=8.3Hz,1H),6.80(dd,J=8.4,2.6Hz,1H),6.56(d,J=2.6Hz,1H),4.29–4.25(m,2H),2.99– 2.88(m,4H),2.01(ddt,J=16.9,8.1,4.6Hz,4H),1.90(s,3H),1.37(s,2H),1.18(t,J=3.6Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ169.96,143.25,139.04,138.05,133.94,132.26,131.90,128.93,128.88,128.12,126.13,125.89,1 25.63,125.54,124.53,116.60,114.31,52.55,43.70,34.59,26.13,18.36,14.58.MS(ESI,m / z):C27H29N3O,[M+H]+412.238.

[0125] Figure 3 The figure shows the inhibition rate curve of compound C3.

[0126] Example 4

[0127]

[0128] C4: 11H NMR (600 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 8.1, 2.8 Hz, 1H), 7.83 (dd, J = 8.5, 2.8 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.55–7.49 (m, 1H), 7.46 (td, J = 7.7, 2.4 Hz, 1H), 6.90 (dd, J = 8.5, 2.6 Hz, 1H), 6.70 (dd, J = 8.4, 2.9 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.06 (d, J = 4.6 Hz, 2H), 3.33 (t, J = 1.7 Hz, 2H), 2.38 (dd, J = 10.9, 3.0 Hz, 2H), 2.16 (d, J = 10.7 Hz, 2H), 2.02 (d, J = 2.9 Hz, 3H), 1.90 (s, 3H), 1.86–1.81 (m, 2H), 1.74 (dd, J = 8.0, 4.3 Hz, 2H), 1.36 (s, 2H), 1.17 (d, J = 4.9 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 144.94, 138.09, 133.96, 132.26, 131.63, 128.91, 128.79, 128.07, 126.06, 125.84, 125.65, 125.49, 122.93, 116.51, 114.23, 56.86, 55.01, 45.63, 34.61, 28.13, 18.40, 14.47. MS (ESI, m / z): C28H31N3O, [M+H]+ 426.254.

[0129] Example 5

[0130]

[0131] C5: 1H NMR (600MHz, DMSO-d6) δ9.05(d,J=3.0Hz,1H),8.66(d,J=8.4Hz,1H),7.94(d,J=8.1Hz,1H),7.83(dd,J =10.9,7.6Hz,2H),7.58(dd,J=8.4,6.8Hz,1H),7.53(t,J=7.4Hz,1H),7.47(t,J=7.6Hz,1H),6.98(d,J =8.2Hz,1H),6.41(dd,J=8.2,2.6Hz,1H),6.19(d,J=2.5Hz,1H),4.14(s,1H),3.99(t,J=8.0Hz,2H),3. 82(dd,J=8.8,5.2Hz,2H),2.82–2.66(m,6H),1.92(s,3H),1.36(t,J=5.6Hz,2H),1.19(t,J=5.4Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ169.91,148.96,138.36,138.00,133.93,132.26,131.21,128.93,128.12,126.16,125.89,12 5.62,125.54,124.44,113.13,110.85,55.58,54.45,34.50,18.45,14.64.MS(ESI,m / z):C26H29N3O,[M+H]+400.237.

[0132] Figure 4 The figure shows the inhibition rate curve of compound C5.

[0133] Example 6:

[0134]

[0135] C6: 11H NMR (600 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.82 (dd, J = 17.7, 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.46 (p, J = 6.8, 6.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.33 (dd, J = 8.2, 2.5 Hz, 1H), 6.11 (d, J = 2.6 Hz, 1H), 5.56 (d, J = 6.4 Hz, 1H), 4.50 (h, J = 5.9 Hz, 1H), 3.95 (t, J = 7.0 Hz, 2H), 3.36 (dd, J = 7.6, 5.1 Hz, 2H), 1.90 (s, 3H), 1.37–1.32 (m, 2H), 1.17 (d, J = 5.7 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 170.11, 150.17, 138.09, 133.95, 132.26, 131.10, 128.91, 128.81, 128.09, 126.10, 125.87, 125.63, 125.50, 123.24, 112.95, 110.71, 62.24, 61.24, 34.54, 18.43, 14.50. MS (ESI, m / z): C24H24N2O2, [M+H]+ 373.191.

[0136] Example 7:

[0137]

[0138] C7: 1 1H NMR (600 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 8.2, 1.4 Hz, 1H), 7.85–7.78 (m, 2H), 7.57 (ddd, J = 8.4, 6.7, 1.4 Hz, 1H), 7.54–7.43 (m, 3H), 6.91 (d, J = 8.2 Hz, 1H), 6.33 (dd, J = 8.2, 2.5 Hz, 1H), 6.11 (d, J = 2.6 Hz, 1H), 4.35 (h, J = 6.9 Hz, 1H), 3.95 (t, J = 7.3 Hz, 2H), 3.42 (t, J = 6.8 Hz, 2H), 1.89 (s, 3H), 1.39 (s, 9H), 1.37–1.32 (m, 2H), 1.16 (q, J = 4.6 Hz, 2H). 13C NMR(151MHz,DMSO-d6)δ170.06,155.25,149.92,138.12,138.05,133.94,132.26,131.10,128.91,128.81,128.09,126.10,125.87,1 25.63,125.50,123.48,112.96,110.68,78.59,59.37,41.24,34.54,28.66,18.44,14.51.MS(ESI,m / z):C29H33N3O3,[M+H]+472.259.

[0139] Example 8:

[0140]

[0141] C8: 1 H NMR (600MHz, DMSO-d6) δ9.00 (s, 1H), 8.66 (d, J = 8.4Hz, 1H), 7.93 (dd, J = 8.2, 1.4Hz, 1H), 7.83 (d, J = 8 .2Hz,1H),7.80(dd,J=7.1,1.3Hz,1H),7.55(dddd,J=27.6,8.0,6.7,1.3Hz,2H),7.46(dd,J=8.2,7.1 Hz,1H),6.90(d,J=8.2Hz,1H),6.32(dd,J=8.1,2.5Hz,1H),6.10(d,J=2.5Hz,1H),3.92(t,J=7.0Hz, 2H),3.73(p,J=6.6Hz,1H),3.24–3.19(m,2H),1.90(s,3H),1.37–1.29(m,2H),1.16(q,J=4.7Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ170.14,150.36,138.06,133.94,132.26,131.05,128.91,128.80,128.08,126.09,125.87,125.6 4,125.50,123.06,112.94,110.67,62.63,43.84,40.53,34.54,18.44,14.50.MS(ESI,m / z):C24H25N3O,[M+H]+372.207.

[0142] Figure 5 The figure shows the inhibition rate curve of compound C8. Example 9:

[0143]

[0144] C9: 1 H NMR (600MHz, DMSO-d6) δ9.03(s,1H),8.66(d,J=8.4Hz,1H),7.93(d,J=8.1Hz,1H),7.85–7.79(m,2H),7. 77(d,J=8.5Hz,1H),7.57(ddd,J=8.4,6.8,1.4Hz,1H),7.52(ddd,J=8.0,6.8,1.3Hz,1H),7.48–7.44(m, 1H),6.93(d,J=8.2Hz,1H),6.36(dd,J=8.2,2.5Hz,1H),6.14(d,J=2.5Hz,1H),4.28–4.19(m,1H),4.06( t,J=7.3Hz,2H),3.55–3.45(m,2H),2.91(s,3H),1.90(s,3H),1.42–1.32(m,2H),1.17(q,J=4.6Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ170.00,149.80,138.15,138.04,133.94,131.15,128.92,128.10,126.12,125.62,125.51,12 3.80,113.08,110.84,59.92,43.34,40.74,40.53,34.55,18.45,14.52.MS(ESI,m / z):C25H27N3O3S,[M+H]+450.184.

[0145] Example 10:

[0146]

[0147] C10: 11H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 8.43 (d, J = 6.9 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.85–7.78 (m, 2H), 7.60–7.44 (m, 3H), 6.92 (d, J = 8.1 Hz, 1H), 6.35 (d, J = 7.3 Hz, 1H), 6.14 (s, 1H), 4.52 (dd, J = 12.9, 6.4 Hz, 1H), 3.98 (t, J = 7.3 Hz, 2H), 3.45 (t, J = 6.5 Hz, 2H), 1.91 (s, 3H), 1.81 (s, 3H), 1.38–1.32 (m, 2H), 1.21–1.13 (m, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.02, 169.43, 149.81, 138.10, 138.04, 133.94, 132.25, 131.12, 128.89, 128.80, 128.07, 126.08, 125.85, 125.61, 125.48, 123.56, 112.90, 110.63, 59.38, 34.56, 22.96, 18.44, 14.52. MS (ESI, m / z): C26H27N3O2, [M+H]+ 414.213.

[0148] Example 11:

[0149]

[0150] C11: 1 1H NMR (600 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.85–7.78 (m, 2H), 7.57 (ddd, J = 8.4, 6.7, 1.5 Hz, 1H), 7.55–7.51 (m, 1H), 7.51–7.44 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.34 (dd, J = 8.1, 2.5 Hz, 1H), 6.12 (d, J = 2.5 Hz, 1H), 3.80 (t, J = 7.1 Hz, 2H), 3.57 (t, J = 4.7 Hz, 4H), 3.49–3.44 (m, 2H), 3.23–3.18 (m, 1H), 2.30 (s, 4H), 1.90 (s, 3H), 1.34 (q, J = 4.4 Hz, 2H), 1.17 (q, J = 4.7 Hz, 2H). 13C NMR(151MHz,DMSO-d6)δ170.10,149.99,138.07,133.94,132.25,131.10,128.91,128.85,128.08,126.11,125.86,125.64,1 25.51,112.68,110.46,66.40,56.11,55.02,49.99,40.53,34.53,18.42,14.54.MS(ESI,m / z):C25H27N3O3S,[M+H]+442.249.

[0151] Example 12:

[0152]

[0153] C12: 1 H NMR (400MHz, Methanol-d4) δ8.61(d,J=8.5Hz,1H),7.91(d,J=7.6Hz,2H),7.82(d,J=8 .3Hz,1H),7.58(t,J=7.6Hz,1H),7.51(t,J=7.5Hz,1H),7.46(t,J=7.7Hz,1H),6.99(d, J=8.2Hz,1H),6.46(dd,J=8.3,2.5Hz,1H),6.25(d,J=2.6Hz,1H),3.73(q,J=8.0Hz,4H ), 2.60 (s, 6H), 1.97 (s, 3H), 1.58 (s, 3H), 1.46 (d, J = 7.3Hz, 2H), 1.32 (d, J = 6.0Hz, 2H). 13 C NMR(101MHz,Methanol-d4)δ172.36,148.61,137.33,136.79,134.16,132.10,130.78,128.37,127.85,125.58,125.09,124.70 ,124.49,124.44,112.86,110.00,60.56,59.51,36.64,34.15,16.81,14.65,13.54.MS(ESI,m / z):C27H31N3O,[M+H]+414.258.

[0154] Figure 6 The inhibition rate curve of compound C12 is shown. Example 13:

[0155]

[0156] C13: 1H NMR (400MHz, Methanol-d4) δ8.61(d,J=8.5Hz,1H),7.96–7.86(m,2H),7.82(d,J=8.3Hz,1H),7.58(t,J=7. 6Hz,1H),7.51(t,J=7.6Hz,1H),7.45(t,J=7.6Hz,1H),6.94(d,J=8.2Hz,1H),6.41(dd,J=8.2,2.5Hz,1H),6 .20(d,J=2.5Hz,1H),3.97(t,J=7.1Hz,2H),3.62(p,J=6.1Hz,1H),3.46(t,J=6.4Hz,2H),2.35(d,J=1.5Hz ,3H),1.96(s,3H),1.45(d,J=5.6Hz,2H),1.32(d,J=6.7Hz,2H).MS(ESI,m / z):C25H27N3O,[M+H]+386.223.

[0157] Figure 7 The figure shows the inhibition rate curve of compound C13.

[0158] Example 14:

[0159]

[0160] C14: 1 H NMR(400MHz, DMSO-d6)δ9.10(s,1H),8.29–8.18(m,1H),7.93(dt,J=6.8,3.4Hz,1H),7.80(d,J=8.2Hz,1 H),7.72(dd,J=7.3,1.2Hz,1H),7.53–7.43(m,3H),6.92(d,J=8.2Hz,1H),6.34(dd,J=8.2,2.6Hz,1H),6. 10(d,J=2.5Hz,1H),3.80(t,J=7.0Hz,2H),3.40(dd,J=7.3,5.7Hz,2H),3.12(p,J=6.1Hz,1H),2.92(q,J =9.2,6.3Hz,2H),2.75(d,J=9.6Hz,2H),2.25–2.12(m,1H),2.08(s,6H),1.94(s,3H),1.89–1.75(m,1H). 13C NMR(101MHz,DMSO-d6)δ168.96,149.96,140.79,138.44,134.58,131.01,130.26,129.37,127.69,126.17,125.98,125.46,125.43,1 25.09,123.29,112.51,110.77,60.56,56.73,56.31,41.98,34.09,31.41,18.38,16.77.MS(ESI,m / z):C27H31N3O,[M+H]+414.2540.

[0161] Example 15

[0162]

[0163] C15: 1 H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.87(s,1H),8.70(d,J=8.3Hz,1H),8.12(s,1H),7 .93(d,J=7.9Hz,1H),7.82(d,J=7.6Hz,2H),7.63–7.56(m,1H),7.53(d,J=7.5Hz,1H),7 .51–7.42(m,3H),7.00(t,J=7.8Hz,3H),6.72(s,1H),6.70(s,1H),2.09(s,3H),2.00(s ,3H),1.38–1.32(m,2H),1.19–1.13(m,2H).MS(ESI,m / z):C29H27N3O2,[M+H]+450.210.

[0164] Example 16

[0165]

[0166] C16: 1H NMR (400MHz, DMSO-d6) δ9.82(s,1H),8.92(s,1H),8.70(d,J=8.4Hz,1H),8.28(s,1H),7.93(d,J =8.0Hz,1H),7.83(d,J=7.6Hz,2H),7.62–7.57(m,1H),7.57–7.43(m,3H),7.12(t,J=8.0Hz,1H), 7.03(d,J=8.0Hz,1H),6.98(d,1H),6.81(s,1H),6.79(s,1H),6.70(d,J=7.8Hz,1H),2.10(s,3H) ,2.02(s,3H),1.39–1.33(m,2H),1.19–1.13(m,2H).MS(ESI,m / z):C29H27N3O2,[M+H]+450.210.

[0167] Example 17

[0168]

[0169] C17: 1 H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 9.07 (s, 1H), 8.64 (d, J = 8.3Hz, 1H), 7.96 –7.89(m,2H),7.81(t,J=7.2Hz,2H),7.59–7.50(m,2H),7.50–7.44(m,1H),7.4 4–7.38(m,2H),7.00–6.84(m,4H),6.68(s,1H),2.02(s,3H),1.95(s,3H),1.3 6–1.31(m,2H),1.19–1.14(m,2H).MS(ESI,m / z):C29H27N3O2,[M+H]+450.210.

[0170] Example 18

[0171]

[0172] C18: 1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),9.01(s,1H),8.69–8.61(m,1H),8.04(s,1H), 7.95–7.91(m,1H),7.86–7.80(m,2H),7.55–7.48(m,3H),7.12–7.05(m,2H),7.01–6 .98(m,1H),6.80(s,1H),6.68–6.61(m,1H),2.51(s,6H),1.99(s,3H),1.39–1.34( m,2H),1.23(s,9H),1.20–1.15(m,2H).MS(ESI,m / z):C32H33N3O2,[M+H]+492.257.

[0173] Example 19

[0174]

[0175] C19: 1 H NMR (400MHz, CDCl3) δ8.13–8.06(m,1H),7.90–7.86(m,1H),7.85–7.81(m,1H),7.77(d,J=8.2Hz ,1H),7.52–7.46(m,2H),7.46–7.40(m,1H),6.84(d,J=8.1Hz,1H),6.26(dd,J=8.1,2.4Hz,1H),6 .19(d,J=2.1Hz,1H),6.07(s,1H),4.02–3.97(m,2H),3.70–3.64(m,2H),3.29(s,2H),2.26(s,6H ),1.74(s,3H),1.29–1.26(m,2H),1.26–1.23(m,2H).MS(ESI,m / z):C27H31N3O,[M+H]+414.247.

[0176] Example 20

[0177]

[0178] C20: 1H NMR (400MHz, CDCl3) δ8.14–8.08(m,1H),7.91–7.86(m,1H),7.86–7.82(m,1H),7.80–7.7 5(m,1H),7.52–7.41(m,3H),6.88(d,J=8.1Hz,1H),6.36–6.31(m,1H),6.19–6.11(m,2H), 3.90–3.84(m,2H),3.61–3.55(m,2H),3.32(s,2H),3.26–3.18(m,1H),2.23(s,6H),1.68 (s,3H),1.33–1.29(m,2H),1.27–1.23(m,2H).MS(ESI,m / z):C27H31N3O,[M+H]+414.247.

[0179] Example 21

[0180]

[0181] C21: 1 H NMR (400MHz, CDCl3) δ8.43(d,J=8.1Hz,1H),7.91(d,J=7.7Hz,1H),7.80(d,J=8.1Hz,1H),7.59–7.48(m,3H),7.47–7.41(m,1H),6.94 (d,J=8.4Hz,2H),6.60(d,J=8.4Hz,2H),3.51(s,2H),1.28–1.20(m,2H),1.06–0.97(m,2H).MS(ESI,m / z):C20H19NO,[M+H]+290.147.

[0182] Example 22

[0183]

[0184] C22: 1H NMR (400MHz, CDCl3) δ8.39(d,J=8.2Hz,1H),7.91(d,J=7.8Hz,1H),7.79(d,J=8.1 Hz,1H),7.58–7.53(m,1H),7.53–7.46(m,2H),7.44–7.39(m,1H),6.68(d,J=8.1Hz ,1H),5.96(d,J=2.0Hz,1H),5.80(dd,J=8.1,2.1Hz,1H),3.47(s,2H),3.06(s,3H) ,1.40–1.27(m,2H),1.06–0.97(m,2H).MS(ESI,m / z):C21H21NO2,[M+H]+320.157.

[0185] Compound preparation:

[0186] (1) Preparation of cyclopropylamine intermediate (1-(naphth-1-yl)cyclopropylamine): The synthetic route is as follows:

[0187]

[0188] The specific steps are as follows:

[0189] 1-Naphthonitrile (1.5 mmol, 1.0 eq) was placed in a round-bottom flask, and 10 mL of dry tetrahydrofuran was added as a solvent. Then, tetraisopropyl titanate (5.5 mmol, 1.0 eq) was added, and the reaction mixture was cooled to -78 °C. Ethyl Grignard reagent (11 mmol, 2.2 eq) was then slowly added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and reacted for 1.5 hours. Subsequently, boron trifluoride diethyl ether (10 mmol, 2.0 eq) was added dropwise, and the mixture was stirred at room temperature for three hours after the addition was complete. After the reaction was complete, 20 mL of 2N hydrochloric acid was added dropwise, and the mixture was stirred and quenched for 20 minutes. Then, excess saturated sodium hydroxide solution was added. The mixture was extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and separated by silica gel column chromatography to obtain cyclopropylamine intermediate 2.

[0190] (2) Preparation of the compounds in Examples 1-4, the synthetic routes are as follows:

[0191]

[0192] 2-Methyl-5-bromobenzoate (3, 2 mmol, 1.0 eq) was placed in a 50 mL sealed tube, and nitrogen-containing amine compound 4 (3 mmol, 1.5 eq), tris(dibenzylacetone)dipalladium (0.04 mmol, 0.02 eq), X-PHOS ligand (0.08 mmol, 0.04 eq), and cesium carbonate (4 mmol, 2.0 eq) were added. Toluene solvent (10 mL) was then added, and the reaction system was protected with argon gas, sealed, and heated to 110 °C with stirring overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated and purified by column chromatography to obtain intermediate 5.

[0193] Intermediate 5 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then lithium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the reaction system was acidified with 2N hydrochloric acid. After adding ethyl acetate, a white solid precipitated. The solid was filtered out and dried to obtain intermediate 6.

[0194] Add DMF solvent to 6 and the previously obtained three-membered cyclic amine intermediate 2 in a 1:1 ratio, add HATU (1.5 eq) and DIPEA (2.0 eq), react at 70 °C for 12 h, extract the reaction solution with ethyl acetate, wash three times with saturated ammonium chloride solution, evaporate the organic phase to dryness, and purify by silica gel column chromatography to obtain product 7.

[0195] When amine compound 6 is protected by Boc (tert-butyloxycarbonyl), the final product is obtained by removing the tert-butyloxycarbonyl group from compound 7 with hydrochloric acid.

[0196]

[0197]

[0198] 2-Methyl-5-bromobenzoate (3, 2 mmol, 1.0 eq) was placed in a 50 mL sealed tube, and nitrogen-containing amine compound 4 (3 mmol, 1.5 eq), tris(dibenzylacetone)dipalladium (0.04 mmol, 0.02 eq), X-PHOS ligand (0.08 mmol, 0.04 eq), and cesium carbonate (4 mmol, 2.0 eq) were added. Toluene solvent (10 mL) was then added, and the reaction system was protected with argon gas, sealed, and heated to 110 °C with stirring overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated and purified by column chromatography to obtain intermediate 5.

[0199] Intermediate 5 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then lithium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the reaction system was acidified with 2N hydrochloric acid. After adding ethyl acetate, a white solid precipitated. The solid was filtered out and dried to obtain intermediate 6.

[0200] Add DMF solvent to 6 and the previously obtained three-membered cyclic amine intermediate 2 in a 1:1 ratio, add HATU (1.5 eq) and DIPEA (2.0 eq), react at 70 °C for 12 h, extract the reaction solution with ethyl acetate, wash three times with saturated ammonium chloride solution, evaporate the organic phase to dryness, and purify by silica gel column chromatography to obtain product 7.

[0201] When amine compound 6 is protected by Boc (tert-butyloxycarbonyl), the final product is obtained by removing the tert-butyloxycarbonyl group from compound 7 with hydrochloric acid.

[0202] (3) Preparation of the compound in Example 5, the synthetic route is as follows:

[0203]

[0204] 2-Methyl-5-bromobenzoate (3, 10 mmol, 1.0 eq) was placed in a 350 mL sealed tube, and 3-dimethylaminoacridine (19, 15 mmol, 1.5 eq), tris(dibenzylacetone)dipalladium (0.2 mmol, 0.02 eq), X-PHOS ligand (0.4 mmol, 0.04 eq), and cesium carbonate (50 mmol, 5.0 eq) were added. Toluene solvent (60 mL) was then added, and the reaction mixture was protected with argon gas, sealed, and heated to 110 °C with stirring overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated, and the mixture was purified by column chromatography to obtain intermediate 20.

[0205] Intermediate 20 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then potassium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the organic solvent was evaporated to dryness. Then, 2N hydrochloric acid was added to the remaining aqueous solution to acidify it and adjust the pH to 1. The aqueous solution was then evaporated to dryness, and methanol solution was added to extract the organic matter. The mixture was filtered and the residue was removed. The filtrate was collected and evaporated to dryness to obtain a white solid, which is intermediate 21.

[0206] Product 21 was added to DMF solvent in a 1:1 equivalent ratio with the previously obtained three-membered cyclic amine intermediate 2, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was evaporated to dryness. The product was then purified by silica gel column chromatography to obtain product 22. The final product 22 is C5.

[0207] (4) Preparation of the compound in Example 6, the synthetic route is as follows:

[0208]

[0209] 2-Methyl-5-bromobenzoate (3, 10 mmol, 1.0 eq) was placed in a 350 mL sealed tube, and aziridine-3-ol (47, 15 mmol, 1.5 eq), tris(dibenzylacetone)dipalladium (0.2 mmol, 0.02 eq), X-PHOS ligand (0.4 mmol, 0.04 eq), and cesium carbonate (50 mmol, 5.0 eq) were added. Toluene solvent (60 mL) was then added, and the reaction mixture was protected with argon gas, sealed, and heated to 110 °C with stirring overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated, and the mixture was purified by column chromatography to obtain intermediate 48.

[0210] Intermediate 48 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then potassium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the organic solvent was evaporated to dryness. Then, 2N hydrochloric acid was added to the remaining aqueous solution to acidify it and adjust the pH to 1. The aqueous solution was then evaporated to dryness, and methanol solution was added to extract the organic matter. The mixture was filtered and the residue was removed. The filtrate was collected and evaporated to dryness to obtain a white solid, which was intermediate 49.

[0211] 49 was added to DMF solvent in a 1:1 equivalent ratio with the previously obtained three-membered cyclic amine intermediate 2, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was evaporated to dryness. The product 50 was then purified by silica gel column chromatography. The final product 50 is C6.

[0212] (5) Preparation of compounds in Examples 7, 8, 9, and 10, the synthetic routes are as follows:

[0213]

[0214] 2-Methyl-5-bromobenzoate (3, 10 mmol, 1.0 eq) was placed in a 350 mL sealed tube, and 3-N-tert-butoxycarbonylaminocyclobutylamine (51, 15 mmol, 1.5 eq), tris(dibenzylacetone)dipalladium (0.2 mmol, 0.02 eq), X-PHOS ligand (0.4 mmol, 0.04 eq), and cesium carbonate (50 mmol, 5.0 eq) were added. Toluene solvent (60 mL) was then added, and the reaction mixture was protected with argon gas, sealed, and heated to 110 °C with stirring overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated, and the mixture was purified by column chromatography to obtain intermediate 52.

[0215] Intermediate 52 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then potassium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the organic solvent was evaporated to dryness, and the mixture was extracted once with ethyl acetate. The organic phase was discarded, and then 2N hydrochloric acid was added to the remaining aqueous solution to acidify it to pH = 1. The mixture was extracted once with ethyl acetate, and the organic phase was collected. After evaporation to dryness, a white solid was obtained, which was intermediate 53.

[0216] Product 53 was added to DMF solvent in a 1:1 equivalent ratio with the previously obtained three-membered cyclic amine intermediate 2, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was evaporated to dryness. The product was then purified by silica gel column chromatography to obtain product 54. The final product 54 is C7.

[0217] Intermediate 54 (4 mmol, 1.0 eq) was dissolved in 20 mL of dichloromethane solvent, and 2 mL of 4N hydrochloric acid-dioxane solution was added. The mixture was stirred at room temperature for 2 hours, and a white solid precipitated. The solid was filtered off and dried to obtain final product 55. Final product 55 is Example C8.

[0218] Intermediate 55 (1 mmol, 1.0 eq) was dissolved in 5 mL of dichloromethane, and triethylamine (2 mmol, 2.0 eq) was added, followed by dropwise addition of methanesulfonic anhydride (1.5 mmol, 1.5 eq). After stirring at room temperature for 4 hours, the organic solvent was evaporated and purified by column chromatography to obtain final product 56. Final product 56 is Example C9.

[0219] Intermediate 55 (1 mmol, 1.0 eq) was dissolved in 5 mL of dichloromethane, and triethylamine (2 mmol, 2.0 eq) was added, followed by dropwise addition of acetyl chloride (1.5 mmol, 1.5 eq). After stirring at room temperature for 4 hours, the organic solvent was evaporated and purified by column chromatography to obtain final product 57. Final product 57 is Example C10.

[0220] (6) Preparation of the compound in Example 11, the synthetic route is as follows:

[0221]

[0222] 2-Methyl-5-bromobenzoate (3, 10 mmol, 1.0 eq) was placed in a 350 mL sealed tube, and 4-(azacyclobut-3-yl)morpholine (58, 15 mmol, 1.5 eq), tris(dibenzylacetone)palladium (0.2 mmol, 0.02 eq), X-PHOS ligand (0.4 mmol, 0.04 eq), and cesium carbonate (50 mmol, 5.0 eq) were added. Toluene solvent (60 mL) was then added, and the reaction mixture was protected with argon gas, sealed, heated to 110 °C, and stirred overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated, and the mixture was purified by column chromatography to obtain intermediate 59.

[0223] Intermediate 59 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then potassium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the organic solvent was evaporated to dryness. Then, 2N hydrochloric acid was added to the remaining aqueous solution to acidify it and adjust the pH to 1. The aqueous solution was then evaporated to dryness, and methanol solution was added to extract the organic matter. The mixture was filtered and the residue was removed. The filtrate was collected and evaporated to dryness to obtain a white solid, which is intermediate 60.

[0224] 60 was added to DMF solvent in a 1:1 equivalent ratio with the previously obtained three-membered cyclic amine intermediate 2, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was evaporated to dryness. The product 61 was then purified by silica gel column chromatography. The final product 61 is C11.

[0225] (7) Preparation of the compound in Example 12, the synthetic route is as follows:

[0226]

[0227] 2-Methyl-5-bromobenzoate (3, 10 mmol, 1.0 eq) was placed in a 350 mL sealed tube, and N,N,3-trimethylazine-3-amine (62, 15 mmol, 1.5 eq), tris(dibenzylacetone)dipalladium (0.2 mmol, 0.02 eq), X-PHOS ligand (0.4 mmol, 0.04 eq), and cesium carbonate (50 mmol, 5.0 eq) were added. Toluene solvent (60 mL) was then added, and the reaction mixture was protected with argon gas, sealed, and heated to 110 °C with stirring overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated, and the mixture was purified by column chromatography to obtain intermediate 63.

[0228] Intermediate 63 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then potassium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the organic solvent was evaporated to dryness. Then, 2N hydrochloric acid was added to the remaining aqueous solution to acidify it and adjust the pH to 1. The aqueous solution was then evaporated to dryness, and methanol solution was added to extract the organic matter. The mixture was filtered and the residue was removed. The filtrate was collected and evaporated to dryness to obtain a white solid, which was intermediate 64.

[0229] Product 64 was added to DMF solvent in a 1:1 equivalent ratio with the previously obtained three-membered cyclic amine intermediate 2, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was evaporated to dryness. The product was then purified by silica gel column chromatography to obtain product 65. The final product 65 is C12.

[0230] (8) Preparation of the compound in Example 13, the synthetic route is as follows:

[0231]

[0232] 3 methyl-5-bromobenzoate (10 mmol, 1.0 eq) was placed in a 350 mL sealed tube, and tert-butyl azacyclobutane (66 mmol, 1.5 eq), tris(dibenzylacetone)palladium (0.2 mmol, 0.02 eq), X-PHOS ligand (0.4 mmol, 0.04 eq), and cesium carbonate (50 mmol, 5.0 eq) were added. Toluene solvent (60 mL) was then added, and the reaction mixture was protected with argon gas, sealed, and heated to 110 °C with stirring overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated, and the mixture was purified by column chromatography to obtain intermediate 67.

[0233] Intermediate 67 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then potassium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the organic solvent was evaporated to dryness, and the mixture was extracted once with ethyl acetate. The organic phase was discarded, and then 2N hydrochloric acid was added to the remaining aqueous solution to acidify it to pH = 1. The mixture was extracted once with ethyl acetate, and the organic phase was collected. After evaporation to dryness, a white solid was obtained, which was intermediate 68.

[0234] 68 was added to DMF solvent in a 1:1 ratio with the previously obtained three-membered cyclic amine intermediate 2, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was dried by rotary evaporation. The product 69 was then purified by silica gel column chromatography.

[0235] Intermediate 54 (4 mmol, 1.0 eq) was dissolved in 20 mL of dichloromethane, and trifluoroacetic acid (8 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 2 hours. After the organic solution was evaporated to dryness, excess saturated sodium bicarbonate solution was added. The organic phase was extracted with ethyl acetate and purified by silica gel column chromatography to obtain final product 70. Final product 70 is C13.

[0236] (9) Preparation of the compound in Example 14, the synthetic route is as follows:

[0237]

[0238] 1-Naphthaleneacetic acid methyl ester 31 (10 mmol, 1.0 eq) and 1,3-dibromopropane (10 mmol, 1.0 eq) were placed in a round-bottom flask and dissolved in 50 mL of DMF. Sodium hydride (60% dispersion in mineral oil, 40 mmol, 4.0 eq) was added fractionally with stirring in an ice bath. The ice bath was then removed, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed once with saturated ammonium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Column chromatography was used to purify the product intermediate 32.

[0239] Intermediate 32 (6.25 mmol, 1.0 eq) was dissolved in a tetrahydrofuran / methanol / water mixture (3:1:1, 50 mL), and potassium hydroxide (25 mmol, 4.0 eq) was added. The reaction was carried out at 50 °C for 8 h. After confirming that the reactants had been completely converted, the solvent was evaporated to dryness, the pH was adjusted to 1 with 2N HCl solution, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, collected, and evaporated to dryness to give a white solid product 33.

[0240] Intermediate 33 (6.25 mmol, 1.0 eq) was dissolved in 25 mL of ultra-dry toluene, and triethylamine (13.75 mmol, 2.2 eq) was added. DPPA (7.5 mmol, 1.2 eq) was added under argon protection. The mixture was stirred at room temperature for 30 min until all carboxylic acid precursors were converted to acyl azides. The mixture was then heated to 75 °C and reacted for 4 h until most of the acyl azides were converted to isocyanates. Excess hydrochloric acid (2 M aqueous solution, >4.0 eq) was added, and the mixture was cooled to 60 °C and reacted overnight. The pH was adjusted to alkaline with sodium bicarbonate solution, and ethyl acetate was added for extraction. The organic phase was collected, evaporated to dryness, and separated by silica gel column chromatography to obtain intermediate 34.

[0241] Intermediate 34 and the previously obtained carboxylic acid intermediate 6 were added to DMF solvent in a 1:1 equivalent ratio, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 50°C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was evaporated to dryness. The product 35 was then purified by silica gel column chromatography. The final product 35 is the compound of Example 14.

[0242] (10) Preparation of compounds in Examples 15, 16, 17, 18, 19 and 20, the synthetic routes are as follows:

[0243]

[0244] (11) The preparation method for step 1 of the route is as follows:

[0245]

[0246] 1-Naphthonitrile (1.5 mmol, 1.0 eq) was placed in a round-bottom flask, and 10 mL of dry tetrahydrofuran was added as a solvent. Then, tetraisopropyl titanate (5.5 mmol, 1.0 eq) was added, and the reaction mixture was cooled to -78 °C. Ethyl Grignard reagent (11 mmol, 2.2 eq) was then slowly added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and reacted for 1.5 hours. Subsequently, boron trifluoride diethyl ether (10 mmol, 2.0 eq) was added dropwise, and the mixture was stirred at room temperature for three hours after the addition was complete. After the reaction was complete, 20 mL of 2N hydrochloric acid was added dropwise, and the mixture was stirred and quenched for 20 minutes. Then, excess saturated sodium hydroxide solution was added. The mixture was extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and separated by silica gel column chromatography to obtain cyclopropylamine intermediate 2.

[0247] (12) The preparation method for step 2 of the route is as follows:

[0248]

[0249] 2-Methyl-5-bromobenzoic acid (3a) and the previously obtained ternary cyclic amine intermediate 2 were added to DMF solvent in a 1:1 ratio, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 25 °C for 3 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was dried by rotary evaporation. The solution was then purified by silica gel column chromatography to obtain intermediate 4a.

[0250] (13) The preparation method for step 3 of the route is as follows:

[0251]

[0252] Example 17: Preparation of the compound, the synthetic route is as follows:

[0253]

[0254] 380 mg of intermediate 4 (1 mmol, 1.0 eq) was placed in a 50 mL sealed tube, and 225 mg of amine compound 5a (1.5 mmol, 1.5 eq), 18 mg of tris(dibenzylacetone)dipalladium (0.02 mmol, 0.02 eq), 19 mg of X-PHOS ligand (0.04 mmol, 0.04 eq), and 651 mg of cesium carbonate (2 mmol, 2.0 eq) were added. Then, 5 mL of toluene solvent was added, and the reaction system was protected with argon gas, sealed, heated to 110 °C, and stirred overnight. After substrate conversion was confirmed by TLC, the organic solvent was evaporated, and the product was purified by column chromatography to obtain the final product XCH-65, the compound of Example 17.

[0255] Example 15 Preparation of Compounds

[0256]

[0257] The preparation of the compound in Example 15 was the same as that in Example 17, except that 2-methyl-5-bromobenzoic acid (3a) was replaced with 2-methyl-4-bromobenzoic acid (3b).

[0258] Example 16 Preparation of Compounds

[0259]

[0260] The preparation of the compound in Example 16 was the same as that in Example 15, except that amine compound 5a was replaced with 5b.

[0261] Example 18 Preparation of Compound

[0262]

[0263] The preparation of the compound in Example 16 was the same as that in Example 17, except that amine compound 5a was replaced with 5c.

[0264] Example 19 Preparation of Compounds

[0265]

[0266] The preparation of the compound in Example 19 was the same as that in Example 17, except that 2-methyl-5-bromobenzoic acid (3a) was changed to 3d and amine compound 5a was changed to 5d.

[0267] Example 19 Preparation of Compounds

[0268]

[0269] The preparation of the compound in Example 20 was the same as that in Example 17, except that 2-methyl-5-bromobenzoic acid (3a) was changed to 3c and amine compound 5a was changed to 5d.

[0270] Preparation of the compound in Example 22: The synthetic route is as follows:

[0271]

[0272] Weigh 183 mg of 1a (1 mmol, 1.0 eq), 122 mg of 2d (1 mmol, 1.0 eq), 33 μL (1 mmol, 1 eq) of AcOH, and 635 mg of NaBH(OAc)3 (3 mmol, 3.0 eq), dissolve in 10 mL of THF, place in a flask, and stir overnight under Ar protection. Wash with saturated sodium bicarbonate aqueous solution and ethyl acetate, retaining the organic phase. Column chromatography yields the final product XCH-190, which is the compound of Example 22.

[0273] Experimental Example 1: Detection of PLpro inhibitory activity of the compounds prepared in the above examples

[0274] Biological testing conditions:

[0275] 1. Reaction buffer: 20mM HEPEs, pH 7.5, 100mM NaCl, 1mM TCEP

[0276] 2. Preparation of mother liquor:

[0277] (1) 20μM Ub-AMC (Ub-AMC dry powder is dissolved directly with reaction buffer, and the precipitate is removed by centrifugation before use);

[0278] (2) 400 nM PLpro (purified by molecular sieve and frozen at -80°C, thawed on ice before use and diluted with reaction buffer);

[0279] (3) 40 μM test compound (the dry powder of the test compound was dissolved in DMSO to 40 mM; diluted with 50% DMSO to 400 μM; and then diluted with reaction buffer to 40 μM);

[0280] 3. For the single-point inhibition test reaction system: 10 μM Ub-AMC, 100 nM PLpro, 1 μM test compound, total volume 20 μL, reaction in 384 wells;

[0281] Add 5 μL of PLpro stock solution and 5 μL of test compound stock solution to a 384-well plate and incubate at 4°C for 30 min.

[0282] Add 10 μL of Ub-AMC stock solution to a 384-well plate, react at 37 °C for 30 min, and then measure the AMC fluorescence intensity (excitation: 360 nm; emission: 460 nm).

[0283] 4. Control group (+Control): DMSO at the corresponding dilution factor replaces the test compound;

[0284] Blank group: Reaction buffer replaces PLpro;

[0285] 5. Data processing: Subtract the Blank value from the measured value and normalize it based on the DMSO value;

[0286] 6. IC 50 Measurement:

[0287] Concentration gradient of test compounds (nM): 10000, 5000, 1000, 500, 250, 125, 62.5, 31.25, 15.625, 10, 5, 2, 1, 0.5, 0.1, 0.01

[0288] Measure fluorescence value after 15 min of reaction (the enzyme reaction rate is in the linear range at around 15 min, and in the non-linear range at 30 min);

[0289] 7. Data Fitting: After normalization, the data is processed using Sigmaplot (fitting equation: Logistic, 3Parameter).

[0290] The results are shown in the table below.

[0291] Table 1 Experimental Results

[0292]

[0293]

[0294]

[0295] GRL0617 was a positive control (Ghosh et al., 2009; Ghosh et al., 2010; Ratia et al., 2008).

Claims

1. A protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, said protease inhibitor having the structure of formula (I-1): Formula (I-1) in, Any one of A1-A5 is CR1, and the others are CR1 ’ ; R1is selected from: , ; R2 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, halogen; R5 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -R L -OR'、-R L -NR'R''; R3 is selected from: H, C1-C6 alkyl groups; R1 ’ Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl; R L is a single bond; R' and R'' are independently selected from: H, C1-C6 alkyl, and C1-C6 haloalkyl.

2. The protease inhibitor according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein the protease inhibitor has the structure of formula (II-1): (I-1).

3. The protease inhibitor according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein the protease inhibitor has the structure of formula (III-1): (III-1).

4. A protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, said protease inhibitor having the structure of formula (I-1): Formula (I-1) in, Any one of A1-A5 is CR1, and the others are CR1 ’ ; R1 is: ; Among them, R 41 R 42 Independently selected from: H, C1-C6 alkyl, -R L -COR'、-R L -S(O) t -R'; R5 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, halogen; R1 ’ is selected from the group consisting of H, Ci-C6-alkyl, Ci-C6-haloalkyl; t is 2; R L is a single bond; R' is independently selected from: C1-C6 alkyl, C1-C6 haloalkyl.

5. A protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, said protease inhibitor having the structure of formula (I-1): Formula (I-1) in, Any one of A1-A5 is CR1, and the others are CR1 ’ ; R1is: wherein Z2is O or ; m2 is 1 or 2; R 45 R 46 Independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, halogen; R5 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, halogen; R1 ’ Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl.

6. The protease inhibitor according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein R... 41 R 42 Independently selected from: H, -C1-C6 alkyl.

7. The protease inhibitor according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein R... 41 R 42 Independently selected from: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, .

8. A protease inhibitor or a pharmaceutically acceptable salt, stereoisomer, or deuterated compound thereof, wherein the protease inhibitor has the following structure: 。

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