Coronavirus papain-like protease inhibitors comprising acenaphthenyl groups and uses thereof

Abstract

The present application relates to the field of medicinal chemistry, in particular to a coronavirus papain-like protease inhibitor containing acenaphthenyl shown in formula (I) and uses thereof,

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and specifically relates to a coronavirus papain-like protease inhibitor containing acenaphthenyl shown in formula (I) and uses thereof. BACKGROUND

[0002] Coronaviruses are a large family of viruses that are widespread in nature. Currently, there are seven known coronaviruses that can infect humans, including HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (which causes severe acute respiratory syndrome, SARS), MERS-CoV (which causes Middle East respiratory syndrome, MERS), and 2019 novel coronavirus (2019-nCoV or SARS-CoV-2, simply referred to as new coronavirus).

[0003] Papain-like protease (PLpro) is one of the two cysteine proteases residing in the viral polyprotein, responsible for processing the polyprotein into its functional units. These functional units in turn assemble into complexes to perform viral RNA synthesis. PLpro is conserved in many coronaviruses, including SARS-CoV-1, MERS CoV and SARS-CoV-2, with high homology between species / strains. If PLPro can be selectively inhibited, viral replication can be prevented and used to treat viral infections caused by these species and strains. SUMMARY

[0004] The first aspect of the present application provides a compound shown in formula (I), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof,

[0005]

[0006] (I).

[0007] Embodiment 1-1:

[0008] The compound shown in formula (I), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] (I)

[0011] wherein,

[0012] R1and R2are each independently selected from C 1-6 alkyl and C 1-6haloalkyl, or R1and R2together with the carbon atoms to which they are commonly attached form a C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl;

[0013] R3is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N-(C 1-6 alkyl)2, -S(=O)2-C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, -S(=O)2NH2, C 1-6 alkyl and C 1-6 haloalkyl;

[0014] R4is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N-(C 1-6 alkyl)2, -S(=O)2-C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, -S(=O)2NH2, C 1-6 alkyl and C 1-6 haloalkyl;

[0015] L1is selected from -C 1-6 alkylene-, -NH-C 1-6 alkylene-, 4-10 membered heterocyclalkylene, 4-10 membered heterocyclalkenylene, 6-12 membered arylene;

[0016] R5is each independently selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N-(C 1-6 alkyl)2, -S(=O)2-C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, -S(=O)2NH2, C 1-6 alkyl and C 1-6 haloalkyl, or two R5form =O, or two R5together with the atoms to which they are attached form a C3-8 cycloalkyl or 4-10 membered heterocycloalkyl, said C 3-8 cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted with one or more groups selected from halogen, nitro, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl or ethyl;

[0017] L2is selected from a bond, -NH-, -O-, -S-, -C 1-6 alkylene-, -NH-C 1-6 alkylene-, -O-C 1-6 alkylene-, -S-C 1-6 alkylene- and 4-10 membered heterocycloalkylene;

[0018] R6is each independently selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N-(C 1-6 alkyl)2, -S(=O)2-C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-6 alkyl and 4-7 membered heterocycloalkyl;

[0019] or, R5and -L2-(R6) p are connected to form a 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl is optionally substituted with one or more groups selected from OH and C 1-4 alkyl;

[0020] m is 0, 1, 2 or 3;

[0021] n is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0022] p is 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0023] Embodiment 1-2: The compound of Embodiment 1-1, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected from C 1-4 alkyl and C 1-4 haloalkyl, or R1and R2, together with the carbon atoms to which they are commonly attached, form a C 3-5 cycloalkyl or 4-5 membered heterocycloalkyl;

[0024] Preferably, R1and R2are each independently selected from methyl, ethyl and propyl, or R1and R2together with the carbon atom to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetanyl, oxetanyl or azetanyl group;

[0025] Preferably, R1and R2are each independently methyl, or R1and R2together with the carbon atom to which they are both attached form a cyclopropyl or oxetanyl group;

[0026] Preferably, the structural unit is .

[0027] Embodiment 1-3: The compound according to Embodiment 1-1 or 1-2, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R3is selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl; 1-4 alkyl, -NH-C 1-4 alkyl, -N-(C 1-4 alkyl)2, C 1-4 alkyl and C 1-4 haloalkyl;

[0028] Preferably, R3is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl;

[0029] Preferably, R3is selected from chlorine, -O-methyl, methyl, ethyl and trifluoromethyl;

[0030] Preferably, R3is selected from chlorine and methyl;

[0031] Preferably, R3is methyl.

[0032] Embodiment 1-4: The compound according to any one of Embodiments 1-1 to 1-3, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -O-C 1-4 alkyl, -NH-C 1-4 alkyl, -N-(C 1-4 alkyl)2, C 1-6 alkyl and C 1-6 haloalkyl;

[0033] Preferably, R4is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl;

[0034] Preferably, R4 is hydrogen.

[0035] Embodiment 1-5: The compound according to any one of embodiments 1-1 to 1-4, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0036] L1is selected from -C 1-4 alkylene-, -NH-C 1-4 alkylene-, 4-7 membered heterocycloalkylene, 4-7 membered heterocycloalkenylene, 6-10 membered arylene, preferably said 4-7 membered heterocycloalkylene or 4-7 membered heterocycloalkenylene contains 1 or 2 N atoms, preferably, L1is selected from methylene, ethylene, propylene, -NH-methylene-, -NH-ethylene-, -NH-propylene-, azetidinylene, pyrrolidinylene, tetrahydroimidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, homopiperazinylene, morpholinylene, tetrahydropyridinylene and phenylene;

[0037] R5is each independently selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -O-C 1-4 alkyl, -NH-C 1-4 alkyl, -N-(C 1-4 alkyl)2, C 1-4 alkyl and C 1-4 haloalkyl, preferably, R5is each independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halomethyl and haloethyl, preferably, R5is each independently selected from hydrogen, fluorine, -COOH, -NH2and methyl;

[0038] or, two R5form =O;

[0039] or, two R5form a C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, said C 3-6The cycloalkyl or 4-7-membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2, or methyl. Preferably, the two R5 groups and the attached atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, tetrahydroimidazolyl, piperidinyl, piperazine, homopiperidinyl, or homopiperidinyl. The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, tetrahydroimidazolyl, piperidinyl, piperazine, homopiperidinyl, or homopiperidinyl group is optionally substituted with 1, 2, or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2, or methyl. Preferably, the two R5 groups and the attached atom form cyclopropyl, aziridine, pyrrolidine, or piperidinyl. The cyclopropyl, aziridine, pyrrolidine, or piperidinyl group is optionally substituted with 1 -OH or methyl group.

[0040] Structural unit Selected from , , , , , , , , , , and R5 is defined as described above, where n is 0, 1, 2, 3, or 4.

[0041] Preferably, structural unit Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 and , if not otherwise specified, the right side of the structural unit is connected to L2, and the *-end indicates the connection to L2.

[0042] Embodiment 1-6: The compound according to any one of embodiments 1-1 to 1-5, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein L2is selected from the group consisting of a bond, -C 1-4 alkylene-, and 4-7-membered heterocycloalkylene, preferably L2is selected from the group consisting of a bond, methylene, ethylene, propylene, azetidinylene, pyrrolidinylene, and piperidinylene;

[0043] R6is each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -COOH, -NH2, -NH-C 1-4 alkyl, -N-(C 1-4 alkyl)2, -S(=O)2-C 1-4 alkyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, C 1-4 alkyl, and morpholinyl, preferably R6is each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, methyl, ethyl, propyl, butyl, and morpholinyl, preferably R6is each independently selected from the group consisting of hydrogen, fluorine, -OH, -CN, -COOH, -CH3, -CH2CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH2CH2CH3, 、 、 and ;

[0044] the structural unit is selected from 、 , 、 、 、 、 and , R6is as defined above, and p is 1, 2, 3 or 4,

[0045] Preferably, the structural unit is selected from -CN, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and ;

[0046] Preferably, the structural unit is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0047] Implementation Scheme 1-7: The compound, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, as described in any one of Implementation Schemes 1-1 to 1-6, wherein the compound is selected from the compound represented by Formula (I-1).

[0048]

[0049] (I-1)

[0050] in,

[0051] The definitions of L1, L2, R3, R5, R6, n, and p are as described in any one of the implementation schemes 1-1 to 1-6;

[0052] 1 ) Preferably, the compound is selected from the group consisting of compounds of formula (I-1 -A)

[0053]

[0054] (I-1 -A)

[0055] wherein

[0056] R3, R5, L2, R6, n and p are defined as in any one of embodiments 1 -1 to 1 -6,

[0057] Preferably, R3 is methyl,

[0058] Preferably, R5 is hydrogen, or two R5 together with the atoms to which they are attached form a pyrrolidinyl group, which is optionally substituted with 1 methyl group,

[0059] Preferably, L2 is selected from the group consisting of a bond, azetidinylene, pyrrolidinylene and piperidinylene,

[0060] Preferably, R6 is each independently selected from the group consisting of hydrogen, fluorine, -OH and methyl,

[0061] Preferably, R5 and -L2-(R6) p together form a pyrrolidinyl group, which is optionally substituted with 1 methyl group,

[0062] Preferably, n is 0, 1 or 2,

[0063] Preferably, p is 1, 2 or 3;

[0064] Further preferably, the compound is selected from the group consisting of compounds of formula (I-1 -A1 )

[0065]

[0066] (I-1 -A1 )

[0067] wherein

[0068] R3, R6 and p are defined as in any one of embodiments 1 -1 to 1 -6, and ring A is selected from the group consisting of 4-7 heterocycloalkyl,

[0069] Preferably, R3 is methyl,

[0070] Preferably, ring A is selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl,

[0071] Preferably, R6 is each independently selected from the group consisting of hydrogen, fluorine, -OH and methyl,

[0072] Preferably, p is 1 or 2;

[0073] 2) or preferably, the compound is selected from the group consisting of compounds of formula (I-1-B)

[0074]

[0075] (I-1-B)

[0076] wherein,

[0077] T1is C, CH or N, is a single or double bond, R3, R5, L2, R6, n and p are defined as in any one of embodiments 1-1 to 1-6,

[0078] preferably, R3is methyl,

[0079] preferably, R5is each independently selected from the group consisting of hydrogen, -COOH and methyl, or two R5form =0, or two R5and the atoms to which they are attached form a cyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl, said azetidinyl, pyrrolidinyl, piperidinyl or homopiperidinyl being optionally substituted with 1 -OH,

[0080] preferably, L2is selected from the group consisting of a bond, methylene, ethylene and propylene,

[0081] preferably, R6is each independently selected from the group consisting of hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=0)2OH, -S(=0)2CH3, -S(=0)2NH2, -NH2, -NHCH3, -N(CH3)2, , , ,

[0082] preferably, R5and -L2-(R6) p are attached to form a pyrrolidinyl, said pyrrolidinyl being optionally substituted with 1 hydroxyl,

[0083] preferably, n is 0, 1 or 2,

[0084] preferably, p is 1, 2 or 3;

[0085] preferably, the compound is selected from the group consisting of compounds of formula (I-1-B1)

[0086]

[0087] (I-1-B1)

[0088] wherein,

[0089] R3, R5, L2and R6are defined as in any one of embodiments 1-1 to 1-6,

[0090] Preferably, said R3 is methyl,

[0091] Preferably, said R5 is each independently selected from the group consisting of -COOH and methyl,

[0092] Preferably, said L2 is selected from the group consisting of a bond, methylene, ethylene and propylene,

[0093] Preferably, said R6 is each independently selected from the group consisting of hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=0)2OH, -S(=0)2CH3, -S(=0)2NH2, -NH2, -NHCH3, -N(CH3)2, , , ,

[0094] Preferably, p is 1 or 2;

[0095] Preferably, said compound is selected from the group consisting of compounds of formula (I-1-B2)

[0096]

[0097] (I-1-B2)

[0098] wherein,

[0099] R3, L2, R6 and p are as defined in any one of embodiments 1-1 to 1-6,

[0100] Preferably, said R3 is methyl,

[0101] Preferably, said L2 is selected from the group consisting of a bond and methylene,

[0102] Preferably, said R6 is each independently selected from the group consisting of hydrogen and methyl,

[0103] Preferably, p is 1 or 2;

[0104] Preferably, said compound is selected from the group consisting of compounds of formula (I-1-B3)

[0105]

[0106] (I-1-B3)

[0107] wherein,

[0108] R3, L2, R6 and p are as defined in any one of embodiments 1-1 to 1-6,

[0109] Preferably, said R3 is methyl,

[0110] Preferably, said L2 is selected from the group consisting of a bond and methylene,

[0111] each R6is independently selected from hydrogen and methyl,

[0112] Preferably, p is 1 or 2.

[0113] Preferably, the compound is selected from a compound of formula (I-1-B4)

[0114]

[0115] (I-1-B4)

[0116] wherein,

[0117] R3, L2, R6and p are as defined in any one of embodiments 1-1 to 1-6,

[0118] Preferably, R3is methyl,

[0119] Preferably, L2is selected from a bond and methylene,

[0120] each R6is independently selected from hydrogen and methyl,

[0121] Preferably, p is 1 or 2.

[0122] 3) or preferably, the compound is selected from a compound of formula (I-1-C)

[0123]

[0124] (I-1-C)

[0125] wherein,

[0126] R3, R5, L2, R6, n and p are as defined above,

[0127] Preferably, R3is methyl,

[0128] Preferably, R5is hydrogen, or two R5together with the atoms to which they are attached form a pyrrolidinyl or piperidinyl group, which is optionally substituted with 1 methyl group,

[0129] Preferably, L2is selected from a bond, a pyrrolidinylene and a piperidinylene group,

[0130] each R6is independently selected from hydrogen, -NH2, -NHCH3, -N(CH3)2and ,

[0131] Preferably, n is 0, 1 or 2.

[0132] Preferably, p is 1, 2 or 3.

[0133] 4) or preferably, the compound is selected from the group consisting of compounds of formula (I-1-D)

[0134]

[0135] (I-1-D)

[0136] wherein,

[0137] R3, L2and R6are as defined above,

[0138] Preferably, R3is methyl,

[0139] Preferably, L2is a bond,

[0140] Preferably, R6is methyl.

[0141] Embodiment 1-8:

[0142] (I-2) wherein the compound is selected from the group consisting of compounds of formula (I-2)

[0143]

[0144] (I-2)

[0145] wherein,

[0146] R1and R2are each independently selected from the group consisting of C 1-4 alkyl and C 1-4 haloalkyl, or R1and R2, together with the carbon atom to which they are both attached, form a C 3-5 cycloalkyl or 4-5 membered heterocycloalkyl;

[0147] R3is selected from the group consisting of hydrogen, halogen, -OH, -CN, -COOH, -NH2, -O-C 1-4 alkyl, -NH-C 1-4 alkyl, -N-(C 1-4 alkyl)2, C 1-4 alkyl and C 1-4 haloalkyl;

[0148] L1is selected from the group consisting of C 1-4 alkylene, -NH-C 1-4 alkylene, 4-7 membered heterocycloalkylene, 4-7 membered heterocycloalkenylene, 6-10 membered arylene;

[0149] R5is each independently selected from the group consisting of hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -O-C 1-4 alkyl, -NH-C 1-4alkyl, -N-(C 1-4 alkyl, -N-(C 1-4 alkyl, -N-(C 1-4 haloalkyl, or two R5form =0, or two R5and the attached atoms form a C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, said C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 groups selected from fluoro, chloro, -OH, -CN, -COOH, -NH2, or methyl;

[0150] L2is selected from a bond, -C 1-4 alkylene-, and 4-7 membered heterocycloalkylene;

[0151] R6is each independently selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -O- 1-6 alkyl, -NH-C 1-6 alkyl, -N-(C 1-6 alkyl, -S(=O)2-C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-NH-C 1-6 alkyl, -NH-C(=O)-C 1-6 alkyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-6 alkyl, and 4-7 membered heterocycloalkyl;

[0152] m is 0, 1, 2, or 3;

[0153] n is 0, 1, 2, 3, or 4;

[0154] p is 0, 1, 2, 3, or 4.

[0155] Embodiments 1-9: The compound according to embodiments 1-1 or 1-8, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected from methyl, ethyl, and propyl, or R1and R2and the common attached carbon atom form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxetanyl, or azetidinyl;

[0156] Preferably, R1and R2are each independently methyl, or R1and R2and the common attached carbon atom form a cyclopropyl or oxetanyl;

[0157] Preferably, structural unit is .

[0158] Embodiment 1-10: The compound according to any one of embodiments 1-1, 1-8 or 1-9, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halogenated methyl and halogenated ethyl;

[0159] Preferably, R3is selected from the group consisting of chlorine, -O-methyl, methyl, ethyl and trifluoromethyl;

[0160] Preferably, R3is selected from the group consisting of chlorine and methyl;

[0161] Preferably, R3is methyl.

[0162] Embodiment 1-11 : The compound according to any one of embodiments 1-1, 1-8 to 1-10, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0163] L1is selected from the group consisting of -NH-ethylene-, -NH-propylene-, azetidinylene, pyrrolidinylene, tetrahydroimidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, homopiperazinylene, morpholinylene and tetrahydropyridinylene;

[0164] R5is each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halogenated methyl and halogenated ethyl, preferably R5is each independently selected from the group consisting of hydrogen, fluorine, -COOH and methyl;

[0165] or two R5form =0;

[0166] or two R5form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydroimidazolyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl group with the attached atoms, optionally substituted with 1, 2, 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2or methyl, preferably two R5form a cyclopropyl, azetidinyl, pyrrolidinyl or piperidinyl group with the attached atoms, optionally substituted with 1 -OH or methyl;

[0167] Structural unit selected from , , , , 、 、 and , R5is as defined above, n is 0, 1 or 2,

[0168] Preferably, the structural unit is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and ;

[0169] Preferably, the structural unit is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and Unless otherwise specified, the right side of the structural unit is connected to L2, and the * end indicates that it is connected to L2.

[0170] Implementation Scheme 1-12: The compound described in any one of Implementation Schemes 1-1, 1-8 to 1-11, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, wherein L2 is selected from the group consisting of methyl, ethyl, propyl, aziridine, pyrrolidine, and piperidinyl;

[0171] R6 is independently selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl groups, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-4 Alkyl and morpholinyl groups, preferably, R6 is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl, S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, methyl, ethyl, propyl, butyl, and morpholinyl groups, preferably, R6 is independently selected from hydrogen, fluorine, -OH, -CN, -COOH, -CH3, -S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2. , , and ;

[0172] Structural unit Selected from , , , , , , and R6 is defined as described above, where p is 1 or 2.

[0173] Preferably, structural unit Selected from -CN , , , ,

[0174] Preferably, the structural unit is selected from ,​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ , , , , , , , , , , , , , , , , , , , and .

[0175] Implementation Scheme 1-13: The compound, or its stereoisomer, or its tautomer, or its solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, as described in any one of Implementation Schemes 1-1 to 1-12, wherein the compound is selected from:

[0176] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0177] The second aspect of the present application provides a pharmaceutical composition comprising at least one compound of the first aspect described above, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

[0178] The third aspect of the present application provides the use of a compound of the first aspect described above, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the second aspect described above, in the manufacture of a medicament for treating and / or preventing a disease or condition, or reducing the severity of a disease or condition, wherein the disease or condition is caused by a coronavirus, wherein the medicament comprises a human medicament and a veterinary medicament;

[0179] Preferably, the disease or condition is selected from respiratory diseases (e.g. simple infections such as fever, cough and sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxemic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock and feline infectious peritonitis.

[0180] The fourth aspect of the present application provides the compound of the first aspect described above, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect described above, for use in the treatment and / or prevention of a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is caused by a coronavirus, wherein the medicament includes human medicine and veterinary medicine;

[0181] Preferably, the disease or condition is selected from respiratory diseases (e.g. simple infections such as fever, cough and sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxemic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock and feline infectious peritonitis.

[0182] The fifth aspect of the present application provides a method for the treatment and / or prevention of a disease or condition or alleviating the severity of the disease or condition, which comprises administering to an individual in need an effective amount of the compound of the first aspect described above, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect described above, wherein the disease or condition is caused by a coronavirus, wherein the medicament includes human medicine and veterinary medicine;

[0183] Preferably, the disease or condition is selected from respiratory diseases (e.g. simple infections such as fever, cough and sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxemic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock and feline infectious peritonitis.

[0184] Definitions of terms

[0185] In the present application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by a person of ordinary skill in the art. Meanwhile, in order to better understand the present application, the definitions and explanations of the relevant terms are provided as follows.

[0186] As used herein, the chemical structure is controlling in the event of a discrepancy between the chemical structure and the compound name.

[0187] Unless otherwise defined, bivalent radicals are not directionally restricted, e.g., A-L-B, when L is -C(=O)-NH-, A-L-B is A-C(=O)-NH-B or A-NH-C(=O)-B.

[0188] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the present application which is pharmaceutically acceptable and which possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts, formed with inorganic acids, e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids; or organic acids, e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids; or by using other methods such as ion exchange.

[0189] Pharmaceutically acceptable salts of the compounds of the present application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like.

[0190] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and

[0191] Pharmaceutically acceptable salts also are intended to encompass half-salts wherein the ratio of compound:acid is 2:1, respectively. Exemplary half-salts are those derived from acids containing two carboxylate groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary half-salts are those derived from diprotic mineral acids, such as sulfuric acid. Preferred exemplary half-salts include, but are not limited to, half-maleate, half-fumarate, and half-succinate.

[0192] As used herein, the term "isotopically-labeled compound" refers to a compound in which one or more atoms are replaced by the same atom having an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, hydrogen isotopes such as 2 H, 3 H; carbon isotopes such as 11 C, 13 C and 14 C; chlorine isotopes such as 36 Cl; fluorine isotopes such as 18 F; iodine isotopes such as 123 I and 125 I; nitrogen isotopes such as 13 N and 15 N; oxygen isotopes such as 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0193] As used herein, the term "stereoisomer" denotes isomers formed by the presence of at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can give rise to racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Particular individual molecules can also exist as geometric isomers (cis / trans).

[0194] Similarly, the compounds of the present application can exist in mixtures of two or more structurally distinct forms in rapid equilibrium, often referred to as tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0195] Unless otherwise indicated, the compounds of the present application can exist in stereoisomeric forms (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present application can exhibit more than one type of isomerism, and consist of mixtures (e.g., racemic mixtures and diastereomeric pairs) of isomers.

[0196] The compounds of the present application can exist in the form of solvates (e.g., hydrates) in which a compound of the present application contains a solvent, e.g., water, methanol or ethanol, as an integral part of the crystal lattice of the compound. The amount of the solvent can be present in stoichiometric or non-stoichiometric amounts.

[0197] As used herein, the term "optionally substituted" means that the group can be unsubstituted or substituted with a substituent, e.g., "C 1-6 "alkyl optionally substituted with halo" means that the C 1-6 alkyl group can be unsubstituted or substituted with halo, resulting in haloalkyl. It is understood that -N-(C 1-6 alkyl)2 means that the nitrogen atom is attached to two C 1-6 alkyl groups, which can be the same or different.

[0198] As used herein, the phrase "each independently selected from" is used throughout this document to mean that the specific options expressed between the same or different symbols in different groups are independent of each other, unless explicitly indicated otherwise.

[0199] As used herein, the term "halogen" means fluorine, chlorine, bromine, iodine.

[0200] As used herein, the term "alkyl" means a straight or branched chain monovalent saturated hydrocarbon group, e.g., C 1-6 alkyl means having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms; C 1-4 alkyl means having 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, and the like.

[0201] As used herein, the term "alkylene" means a straight or branched chain divalent saturated hydrocarbon group, e.g., C 1-4 alkylene means having 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

[0202] As used herein, the term "halo" means that the group it modifies is substituted with one or more halogens, for example, 1, 2, 3, 4, 5, or 6 halogens. For example, "Ci-6haloalkyl" means a Ci-6alkyl group as previously defined that is substituted with one or more halogens, examples including but not limited to CF3, CHF2, or CF2CF3, and the like.

[0203] As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group consisting of carbon atoms. For example, a C3-6cycloalkyl group means a cycloalkyl group having 3, 4, 5, or 6 carbon atoms, such as a C3cycloalkyl group, a C4cycloalkyl group, a C5cycloalkyl group, a C6cycloalkyl group, and the like. 3-6 Cycloalkyl groups have 3 to 6 carbon atoms, such as 3, 4, 5, or 6 carbon atoms, such as a C3-6cycloalkyl group, and the like. 3-6 Cycloalkyl groups include C3-6cycloalkyl groups, such as a C3cycloalkyl group, a C4cycloalkyl group, a C5cycloalkyl group, a C6cycloalkyl group, and the like. 4-6 Cycloalkyl groups include C3-6cycloalkyl groups, such as a C3cycloalkyl group, a C4cycloalkyl group, a C5cycloalkyl group, a C6cycloalkyl group, and the like. 4-5 Cycloalkyl groups include C3-6cycloalkyl groups, such as a C3cycloalkyl group, a C4cycloalkyl group, a C5cycloalkyl group, a C6cycloalkyl group, and the like. 3-5 Cycloalkyl groups include C3-6cycloalkyl groups, such as a C3cycloalkyl group, a C4cycloalkyl group, a C5cycloalkyl group, a C6cycloalkyl group, and the like.

[0204] As used herein, the term "heterocycloalkyl" means a saturated monovalent cyclic group consisting of ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms, the remainder being carbon atoms; preferably the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a 4-6 membered heterocycloalkyl group means a heterocycloalkyl group consisting of 4-6 ring atoms, such as a 4-5 membered heterocycloalkyl group, and the like. Examples include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and the like.

[0205] As used herein, the term "heterocycloalkyl" means a saturated monovalent cyclic group consisting of ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms, the remainder being carbon atoms; preferably the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a 4-6 membered heterocycloalkyl group means a heterocycloalkyl group consisting of 4-6 ring atoms, such as a 4-5 membered heterocycloalkyl group, and the like. Examples include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and the like.

[0206] As used herein, the term "heterocycloalkyl" means a saturated monovalent cyclic group consisting of ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms, the remainder being carbon atoms; preferably the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a 4-6 membered heterocycloalkyl group means a heterocycloalkyl group consisting of 4-6 ring atoms, such as a 4-5 membered heterocycloalkyl group, and the like. Examples include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and the like.

[0207] As used herein, the term "partially unsaturated" refers to a ring system that is neither fully unsaturated (i.e., contains the maximum number of double bonds possible) nor fully saturated (i.e., contains no double bonds). In other words, a partially unsaturated ring system contains at least one double bond, but not the maximum number of double bonds possible.

[0208] As used herein, the term "arylene" refers to an unsaturated group consisting of carbon atoms having a conjugated pi electron system. For example, a 6-12 membered arylene group consists of 6 to 12 (e.g., 6, 7, 8, 9, or 10) ring atoms, including 6-10 membered arylene groups, and the like. Examples include, but are not limited to, phenylene, naphthylene, and the like.

[0209] As used herein, the term "pharmaceutically acceptable carrier and / or excipient" refers to a carrier and / or excipient that is compatible, physiologically and / or pharmacologically, with the subject and the active ingredient, and is well-tolerated by the subject (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutically acceptable carriers and / or excipients include, but are not limited to, pH adjusting agents, surfactants, ionic strength enhancers, diluents, agents to maintain osmotic pressure, agents to retard absorption, preservatives, stabilizers. For example, pH adjusting agents include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic or non-ionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents to maintain osmotic pressure include, but are not limited to, sugars, NaCl, and the like. Agents to retard absorption include, but are not limited to, monostearate and gelatin. Diluents include, but are not limited to, water, aqueous buffers (e.g., buffered saline), alcohols, and polyols (e.g., glycerin), and the like. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thiomersal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like. Stabilizers have the meaning commonly understood by those skilled in the art, and are capable of stabilizing the desired activity of the active ingredient in the pharmaceutical, including, but not limited to, sodium glutamate, gelatin, SPGA, sugars (e.g., sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (e.g., glutamic acid, glycine), proteins (e.g., dried lactose, albumin, or casein) or degradation products thereof (e.g., lactalbumin hydrolysate), and the like.

[0210] As used herein, the term "effective amount" means an amount that is sufficient to achieve or at least partially achieve a desired effect. For example, an effective prophylactic amount is an amount that is sufficient to prevent, retard, or delay the onset of a disease; an effective therapeutic amount is an amount that is sufficient to cure or at least partially arrest the disease and its complications in an already afflicted patient. Determining such effective amounts is well within the capability of those skilled in the art, e.g., given the severity of the disease to be treated, the general state of the patient's own immune system, the patient's general condition such as age, body weight, and sex, the mode of administration of a drug, and other therapies being administered concurrently, etc.

[0211] As used herein, the term "treatment" is intended to mean alleviating, reducing, ameliorating or eliminating the disease state or condition in question. A subject is successfully "treated" if, after receiving a therapeutic amount of the antibody conjugate drug or racemate, enantiomeric, diastereomeric, pharmaceutically acceptable salt, or mixture of the foregoing, of the present application according to the methods described herein, the subject exhibits an observable and / or detectable reduction in or improvement in one or more indicia and symptoms. It will also be appreciated that the treatment of the disease state or condition in question includes not only the complete treatment of the disease state or condition, but also the partial treatment thereof, wherein some biological or medically relevant result is achieved.

[0212] As used herein, the term "prevention" is intended to mean avoiding, reducing, retarding or delaying the onset of a disease or disease-related symptoms, and where such disease or disease-related symptoms have not yet arisen prior to the administration of the relevant drug. "Prevention" does not require complete prevention of the onset of a disease or disease-related symptoms, e.g., a subject can be "prevented" from developing a particular disease or disease-related symptoms if the risk of developing such disease or disease-related symptoms is reduced, or the severity of the symptoms that do develop is attenuated, following the administration of the relevant drug.

[0213] Beneficial effects

[0214] The present application provides a novel papain-like protease inhibitor, the inhibitor of the present application has good antiviral activity, inhibits the infection of the new coronavirus on cells, has good liver stability and oral pharmacokinetic properties. DETAILED DESCRIPTION

[0215] Embodiments of the present application will be described in detail with reference to the following examples, but those skilled in the art will appreciate that the following examples are intended to be illustrative only and should not be viewed as limiting the scope of the present application. Where specific conditions are not specified in the examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. Where the manufacturer of the reagent or instrument is not specified, it is a conventional product that can be obtained on the market.

[0216] Compound preparation:

[0217] Preparation of intermediate 4, 5-bromo-N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)- 2-methylbenzamide, synthesis route as follows

[0218]

[0219] (1) Preparation of intermediate 2, l,2-dihydroacenaphthylene-5-carbonitrile

[0220]

[0221] 350 mL sealed tube, charge with starting material 5-bromoacenaphthylene (23.3 g, 0.1 mol, 1 eq), CuCN (17.9 g, 0.2 mol, 2 eq), NMP (100 mL), 170 0 C stir overnight. Cool, TLC spot plate, check for disappearance of starting material. Filter, wash filter cake with NMP, slowly add water to filtrate, solid precipitates, filter to give light yellow solid (14.5 g, 81%). 1 H NMR (600 MHz, Chloroform-d) δ 7.87 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.65 (dd, J = 8.3, 6.9 Hz, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 3.45 (s, 4H).

[0222] (2) Preparation of intermediate 3, l-(l,2-dihydroacenaphthyl-5-yl)cyclopropane-l-amine

[0223]

[0224] 500 mL single neck flask, charge with l,2-dihydroacenaphthylene-5-carbonitrile (9 g, 50.22 mmol, 1 eq), THF (90 mL), add tetraisopropyl titanate (16.35 mL, 55.24 mmol, 1.1 eq), cool to -78 0C, ethylmagnesium bromide (36.83 mL, 110.48 mmol, 2.2 eq) was added dropwise, and the mixture was stirred at ambient temperature for 2 h. Boron trifluoride etherate (12.4 mL, 100.44 mmol, 2 eq) was added, and the mixture was stirred at ambient temperature for 4 h. TLC spot check showed that the starting material was consumed. The reaction was quenched with 2 N dilute hydrochloric acid, and the pH was adjusted to 9 with NaOH solution. The mixture was extracted with EtOAc (300 mL*3) / H2O (300 mL) at ambient temperature. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (DCM:MeOH = 100:0-100:10) gave a black-brown oil (5 g, 47%). LC-MS (ESI, m / z): C 15 H 15 N, [M+H] + =209.90.

[0225] (3) Preparation of intermediate 4: 5-bromo-N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methylbenzamide

[0226]

[0227] 250 mL single-necked flask was charged with 1-(1,2-dihydroacenaphthyl-5-yl)cyclopropane-1-amine (5 g, 23.89 mmol, 1 eq), 2-methyl-5-bromobenzoic acid (4.62 g, 21.5 mmol, 0.9 eq), DMF (50 mL), DIEA (8.32 mL, 47.78 mmol, 2 eq), HATU (10.9 g, 28.67 mmol, 1.2 eq), 50 0 C was stirred overnight. TLC spot check showed that the starting material was consumed. The mixture was cooled, and solid was precipitated by slow addition of H2O. The mixture was stirred for 30 min and filtered. The filter cake was dissolved in EtOAc, concentrated, and purified by column chromatography (PE:EtOAc = 100:5-100:50). Concentration gave a white solid (3.6 g, 41%). LC-MS (ESI, m / z): C 15 H 15 N, [M+H] + =406.96.

[0228] Example 1 (P1): Preparation of N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methyl-5-(piperidin-4-yl)benzamide hydrochloride, according to the following synthetic route

[0229]

[0230] (1) Preparation of Intermediate 5: tert-butyl 4-(3-((l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)-3,6-dihydropyridine-l(2H)-carboxylate

[0231]

[0232] 25 mL vial, 5-bromo-N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methylbenzamide (200 mg, 0.5 mmol, 1 eq), N-Boc-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (185 mg, 0.6 mmol, 1.2 eq), Cs2CO3(488 mg, 1.5 mmol, 3 eq), X-phos (47 mg, 0.1 mmol, 0.2 eq), Pd2(dba)3(12 mg, 0.05 mmol, 0.1 eq), 1,4-dioxane (6 mL), 110 0 C overnight. Cool, TLC spot plate, check starting material consumed. Add EtOAc (20 mL*3) / H2O (20 mL), extract, combine organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate to dryness. Column chromatography (PE:EtOAc = 100:5-100:50), get pale yellow oil 5 (220 mg, 87%).

[0233] (2) Preparation of Intermediate 6: N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methyl-5-(l,2,3,6-tetrahydropyridin-4-yl)benzamide hydrochloride

[0234]

[0235] 25 mL vial, 5-bromo-N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methylbenzamide (200 mg, 0.5 mmol, 1 eq), N-Boc-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (185 mg, 0.6 mmol, 1.2 eq), Cs2CO3(488 mg, 1.5 mmol, 3 eq), X-phos (47 mg, 0.1 mmol, 0.2 eq), Pd2(dba)3(12 mg, 0.05 mmol, 0.1 eq), 1,4-dioxane (6 mL), 110

[0236] (3) Preparation of Compound P1: N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methyl-5-(piperidin-4-yl)benzamide

[0237]

[0238] In a 25 mL single-necked flask, N-(1-(1,2-dihydroacenaphthene-5-yl)cyclopropyl)-2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide hydrochloride (90 mg, 0.22 mmol), methanol (3 mL), and Pd / C (20 mg) were added. The mixture was stirred overnight at ambient temperature under hydrogen atmosphere. The mixture was filtered and concentrated to dryness. MTBE (4 mL) was added, and a solid precipitated. The precipitate was filtered to give an off-white solid (20 mg, 22%). LC-MS (ESI, m / z): C 28 H 30 N₂O, [M+H] + =410.96.

[0239] Example 4 (P4): Preparation of 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(1-(1,2-dihydroacenaphthene-5-yl)cyclopropyl)-2-methylbenzamide, the synthetic route is as follows.

[0240]

[0241] (1) Preparation of intermediate 5: 3-(3-((1-(1,2-dihydroacenaphthene-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0242]

[0243] Seal the tube with 15 mL of the solution and add 5-bromo-N-(1-(1,2-dihydroacenaphthene-5-yl)cyclopropyl)-2-methylbenzamide (100 mg, 0.25 mmol, 1 eq), 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (59 mg, 0.3 mmol, 1.2 eq), Cs₂CO₃ (244 mg, 0.75 mmol, 3 eq), Ru-phos (22 mg, 0.05 mmol, 0.2 eq), Pd(OAc)₂ (6 mg, 0.025 mmol, 0.1 eq), 1,4-dioxane (3 mL), 110 0 Stirred overnight at C. Cool, TLC spotted, the starting material disappeared. Filter, concentrate to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) gave a pale yellow solid (78 mg, 60%). LC-MS (ESI, m / z): [M+H] + =523.96

[0244] (2) Preparation of compound P4: 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-(1-(1,2- dihydroacenaphthyl-5-yl)cyclopropyl)-2-methylbenzamide

[0245]

[0246] 25 mL single-necked flask, 3-(3-((1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl) carbamoyl)-4-methylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (78 mg, 0.15 mmol), DCM (4 mL), HCl / 1,4-dioxane (2 mL, 3 M) were added, and the mixture was stirred at ambient temperature for 2 h. TLC spotting showed that the starting material was consumed. The mixture was concentrated, saturated NaHCO3 solution was added to adjust the pH to 9, and EtOAc (20 mL*3) / H2O (20 mL) was added for extraction. The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. Column chromatography (DCM:MeOH=100:0-100:10) gave a white solid (9 mg). LC-MS (ESI, m / z): C28H29N3O, [M+H]+=423.90.

[0247] Example 30 (P30): Preparation of N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- chloro-5-(4-methylpiperazin-1-yl)benzamide, the synthetic route is as follows

[0248]

[0249] (1) Preparation of intermediate A3: 2-(1,2-dihydroacenaphthyl-5-yl)phenylacetonitrile

[0250]

[0251] A1 (1000 mg, 4.30 mmol) and A2 (1008 mg, 5.18 mmol) were placed in a sealed tube, DMSO (30 mL) and H2O (12 mL) were added, KF (750 mg, 12.90 mmol) was added, and Pd(dppf)Cl2 was added. N2 was bubbled for 30 s, and the temperature was raised to 130 o C, and the mixture was stirred overnight. After the reaction was completed, the reaction solution was cooled to room temperature, EtOAc was added to the reaction solution, and the mixture was filtered through diatomite. The filter cake was washed with EtOAc, the obtained filtrate was separated, the aqueous phase was extracted twice with EtOAc, the combined organic phase was concentrated under reduced pressure, and column chromatography (PE:EtOAc=50:1-30:1-15:1) was performed to give yellow solid A3 (498 mg, 60%).

[0252] 1 H NMR (600 MHz, Chloroform-d) δ 7.60 – 7.54 (m, 2H), 7.50 (d, J =7.0 Hz, 1H), 7.36 (d, J = 7.1 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 4.06 (s,2H), 3.45 – 3.38 (m, 4H).

[0253] (2) Preparation of intermediate A4: 1-(1,2-dihydroacenaphthyl-5-yl)phenylacetonitrile cyclopropyl-1-carbonitrile

[0254]

[0255] A3 (498 mg, 2.58 mmol) was placed in a single-necked flask, DMF (6 mL) was added, and the temperature was lowered to 0 o C, NaH (237 mg, 5.93 mmol, added in 3 portions with 5 min intervals) was added portionwise, the reaction was stirred for 0.5 h, then 1,2-dibromoethane was added dropwise, the temperature was raised to room temperature, and the reaction was stirred overnight until the starting material was completely consumed. After the reaction was completed, water was added to the reaction solution, EtOAc was added for extraction three times, the organic phases were combined, and concentrated under reduced pressure. After being dissolved, column chromatography purification (PE:EtOAc=50:1) was performed to obtain yellow solid A4 (106 mg, 21%), which was directly used in the next reaction.

[0256] (3) Preparation of intermediate A5: 1-(1,2-dihydroacenaphthyl-5-yl)phenylacetonitrile cyclopropyl-1-carboxamide

[0257]

[0258] A4 (106 mg, 0.48 mmol) was placed in a single-necked flask, i-PrOH (2 mL) and NaOH (58 mg, 1.44 mmol) were added, and the temperature was raised to 90 o C, the reaction was stirred for 7 h until the starting material was completely consumed, and a solid was precipitated, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, a solid was precipitated, and the reaction was stirred at room temperature for 1.0 h. Filtration was performed, the filter cake was washed with water, and suction was performed to obtain yellow solid A5 (73 mg, 64%) which was directly used in the next reaction. LC-MS (ESI, m / z): [M+H]+= 238.56.

[0259] (4) Preparation of intermediate A6: 1-(1,2-dihydroacenaphthyl-5-yl)phenylacetonitrile cyclopropyl-1-amine

[0260]

[0261] Place A5 (73 mg, 0.31 mmol) in a single-necked flask, add t-BuOH (2 mL), and cool to 0°C. o C. Add NaClO (0.87 mmol, 0.36 mL) solution and NaOH (3 N, 0.87 mmol, 0.29 mL) solution, stir and react overnight until the reactants are completely reacted, then stop the reaction. After the reaction is complete, add water to the reaction solution, extract three times with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, wash the filter cake with DCM, concentrate the filtrate under reduced pressure and dry to obtain a yellow oily substance A6 (58 mg, 89%), which is directly used in the next reaction. LC-MS (ESI, m / z): [M+H]+ = 210.43.

[0262] (5) Preparation of intermediate A9: methyl 2-chloro-5-(4-methylpiperazin-1-yl)benzoate

[0263]

[0264] Place A7 (500 mg, 2.01 mmol) and A8 (242 mg, 2.41 mmol) in a sealed tube, add toluene (10 mL), X-Phos (37 mg, 0.078 mmol), Cs₂CO₃ (1310 mg, 4.02 mmol), and Pd₂(dba)₃ (37 mg, 0.040 mmol), bubble with N₂ for 30 s, and heat to 110 °C. o C. Stir the reaction overnight until the reactants are completely reacted, then stop the reaction. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure to remove solvent, and then purify by column chromatography (PE:EtOAc=10:1-2:1, to DCM:MeOH=20:1) to obtain a yellow oily substance, namely yellow oily substance A9 (433 mg, 80%). LC-MS (ESI, m / z): [M+H]+= 269.25.

[0265] (6) Preparation of intermediate A10: 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid

[0266]

[0267] Place A9 (433 mg, 1.62 mmol) in a single-necked flask, add THF (2 mL) and EtOH (2 mL), then add a NaOH (324 mg, 8.10) H2O (2 mL) solution, and heat to 60°C. oC, stirring for 2 h, the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, the pH was adjusted to 4-5 with a saturated citric acid solution, and the solvent was concentrated under reduced pressure. The resulting mixture was dissolved in DCM (300 mL), dried over anhydrous sodium sulfate, filtered, the filter cake was washed with DCM (30 mL), and the resulting filtrate was concentrated under reduced pressure to obtain a yellow solid A10 (412 mg, 100%). LC-MS (ESI, m / z): [M+H]+= 255.38.

[0268] (7) Preparation of compound P30: N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- chloro-5-(4-methylpiperazin-1-yl)benzamide

[0269]

[0270] A6 (33 mg, 0.16 mmol) and A10 (43 mg, 0.17 mmol) were placed in a single-necked flask, DMF (1.5 mL), DIPEA (68 mg, 0.52 mmol), and HATU (77 mg, 0.20 mmol) were added, and the temperature was raised to 50 o C, stirring for 1.0 h, the starting material was completely reacted, and the reaction was stopped. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, a yellow solid was precipitated, it was extracted with DCM three times, the organic phases were combined, concentrated under reduced pressure, and column chromatography purification (DCM:MeOH=20:1) was performed to obtain a white solid P30 (8.4 mg). LC-MS (ESI, m / z): C27H28ClN3O, [M+H]+ = 446.29.

[0271] Example 31 (P31): Preparation of N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- ethyl-5-(4-methylpiperazin-1-yl)benzamide, the synthetic route is as follows

[0272]

[0273] (1) Preparation of intermediate A9: methyl 2-ethyl-5-(4-methylpiperazin-1-yl)benzoate

[0274]

[0275] A7 (1000 mg, 4.11 mmol) and A8 (618 mg, 6.17 mmol) were placed in a sealed tube, toluene (20 mL), X-Phos (78 mg, 0.16 mmol), Cs2CO3 (2678 mg, 8.22 mmol) and Pd2(dba)3 (75 mg, 0.082 mmol) were added, N2 was bubbled for 30 s, and the temperature was raised to 110 o C, the reaction was stirred overnight, and the starting material was completely consumed. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and purified by column chromatography (PE:EtOAc = 1:1) to obtain yellow oil A9 (1000 mg, 93%). LC-MS (ESI, m / z): [M+H]+= 262.35.

[0276] (2) Preparation of intermediate A10: 2-ethyl-5-(4-methylpiperazin-1-yl)benzoic acid

[0277]

[0278] A9 (712 mg, 2.72 mmol) was placed in a single-necked flask, THF (3 mL) and EtOH (3 mL) were added, followed by a solution of NaOH (544 mg, 13.60) in H2O (3 mL), and the temperature was raised to 60 o C, the reaction was stirred for 2 h, and the starting material was completely consumed. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove THF and EtOH, the pH was adjusted to 4-5 with a saturated citric acid solution, concentrated under reduced pressure to remove the solvent, and the resulting mixture was dissolved in DCM (500 mL), dried over anhydrous sodium sulfate, filtered, the filter cake was washed with DCM (50 mL), and the resulting filtrate was concentrated under reduced pressure to obtain yellow solid A10 (675 mg, 100%). LC-MS (ESI, m / z): [M+H]+= 249.45.

[0279] (3) Preparation of compound P31: N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-ethyl-5-(4-methylpiperazin-1-yl)benzamide

[0280]

[0281] A6 (24 mg, 0.11 mmol) and A10 (30 mg, 0.12 mmol) were placed in a single-necked flask, DMF (1.5 mL), DIPEA (47 mg, 0.36 mmol) and HATU (54 mg, 0.14 mmol) were added, and the temperature was raised to 50 oC, stirring the reaction for 1.0 h until the starting material was completely reacted, and stopping the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, water was added, and a yellow solid was precipitated, which was extracted with DCM three times, the organic phases were combined, concentrated under reduced pressure, and then purified by column chromatography (DCM:MeOH=20:1) to obtain white solid P31 (11.2 mg, 23%). LC-MS (ESI, m / z): C29H33N3O, [M+H]+ =440.37.

[0282] Example 32 (P32): Preparation of N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- methoxy-5-(4-methylpiperazin-1-yl)benzamide, synthesis route as follows

[0283]

[0284] (1) Preparation of intermediate 2: 2-methoxy-5-(4-methylpiperazin-1-yl)benzoate

[0285]

[0286] 100 mL single-necked flask, 5-bromo-2-methoxybenzoic acid methyl ester (500 mg, 2.04 mmol, 1.0 eq.), 1-methylpiperazine (204 mg, 2.04 mmol, 1.0 eq.), Pd2(dba)3 (37 mg, 0.04 mmol, 0.02 eq.), X-phos (39 mg, 0.08 mmol, 0.04 eq.), Cs2CO3 (1.3 g. 4.08 mmol, 2.0 eq.), 1,4-dioxane (10 mL), N2 protection, stirring at 110°C overnight. Cool, TLC spot plate, detect complete reaction of starting material. Dilute with water (20 mL) and EtOAc (20 mL), separate. The aqueous phase is extracted with EtOAc (20 mL*3). Combine all organic phases, dry with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the crude product by column chromatography to obtain 2-methoxy-5-(4-methylpiperazin-1-yl)benzoate (530 mg, 98% yield). LC-MS (ESI, m / z): [M+H]+= 265.48.

[0287] (2) Preparation of intermediate 3: 2-methoxy-5-(4-methylpiperazin-1-yl)benzoic acid

[0288]

[0289] 100 mL single neck flask, add 2-methoxy-5-(4-methylpiperazin-1-yl)benzoic acid (20 mg, 0.08 mmol, 1.0 eq.), 1-(1,2-dihydroacenaphthyl-5-yl)cyclopropane-1- amine (17 mg, 0.08 mmol, 1.0 eq.), HATU (46 mg, 0.12 mmol, 1.5 eq.), DIPEA (21 mg, 0.16 mmol, 2.0 eq.), DMF (3 mL), stir at 50 °C overnight. Cool down, TLC spot plate, check the starting material is consumed. Add water (10 mL) and dilute with EtOAc (10 mL), separate. The aqueous phase is extracted with EtOAc (15 mL * 3). Combine all the organic phase, dry over anhydrous sodium sulfate, filter, concentrate to dryness. The crude product is separated by prep-HPLC to give N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methoxy-5-(4- methylpiperazin-1-yl)benzamide (1.6 mg). LC-MS (ESI, m / z): [M+H]+= 442.18.

[0290] (3) Preparation of compound P32: N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- methoxy-5-(4-methylpiperazin-1-yl)benzamide

[0291]

[0292] 100 mL single neck flask, add 2-methoxy-5-(4-methylpiperazin-1-yl)benzoic acid (20 mg, 0.08 mmol, 1.0 eq.), 1-(1,2-dihydroacenaphthyl-5-yl)cyclopropane-1- amine (17 mg, 0.08 mmol, 1.0 eq.), HATU (46 mg, 0.12 mmol, 1.5 eq.), DIPEA (21 mg, 0.16 mmol, 2.0 eq.), DMF (3 mL), stir at 50 °C overnight. Cool down, TLC spot plate, check the starting material is consumed. Add water (10 mL) and dilute with EtOAc (10 mL), separate. The aqueous phase is extracted with EtOAc (15 mL * 3). Combine all the organic phase, dry over anhydrous sodium sulfate, filter, concentrate to dryness. The crude product is separated by prep-HPLC to give N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methoxy-5-(4- methylpiperazin-1-yl)benzamide (1.6 mg). LC-MS (ESI, m / z): [M+H]+= 442.18.

[0293] Example 33 (P33): Preparation of N-(3-(1,2-dihydroacenaphthyl-5-yl)oxetan-3-yl)-5-(4- methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide, the synthetic route is as follows

[0294]

[0295] (1) Preparation of intermediate 1: N-(3-(1,2-dihydroacenaphthyl-5-yl)oxetan-3-yl)-2- methylpropane-2-sulfonamide

[0296]

[0297] Dissolve 5-bromoacenaphthene (500 mg, 2.14 mmol) in anhydrous THF (30 mL), cool to -78 °C, then add 2.5M n-butyllithium (1.7 mL, 4.28 mmol). After the addition is complete, react at this temperature for 30 min, then add compound 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfonamide (375 mg, 2.14 mmol), and continue to react for 5 h. After the reaction is complete, quench the reaction by dropwise addition of saturated ammonium chloride solution, add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and purify by column chromatography (DCM:MeOH = 30:1) to obtain intermediate 1 (373 mg, 53%). LC-MS (ESI, m / z): C 19 H 23 NO2S, [M+H] + = 330.23.

[0298] (2) Preparation of intermediate 2: 3-(1,2-dihydroacenaphthyl-5-yl)oxetan-3-amine hydrochloride

[0299]

[0300] Dissolve intermediate 1 (373 mg, 1.13 mmol) in DCM (10 mL), add HCl / 1,4-dioxane (5 mL), and react at room temperature for 2 h. After the reaction is complete, remove the solvent by concentration under reduced pressure to obtain intermediate 2. LC-MS (ESI, m / z): C 15 H 15 NO, [M+H] + = 226.48.

[0301] (3) Preparation of intermediate 5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoic acid methyl ester

[0302]

[0303] Methyl 5-bromo-2-(trifluoromethyl)benzoate (300 mg, 1.06 mmol), 1- methylpiperazine (159 mg, 1.59 mmol), Pd2(dba)3(97 mg, 0.11 mmol), X-Phos (50 mg, 0.11 mmol) and Cs2CO3(1.04 g, 3.18 mmol) were dissolved in toluene (20 mL) and heated to 110 °C for 12 h under nitrogen. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was removed by concentration under reduced pressure, extracted with dichloromethane, washed with water three times, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 30:1) to obtain intermediate 3 (256 mg, 80 %). LC-MS (ESI, m / z): C 14 H 17 F3N2O2, [M+H] + = 303.17.

[0304] (4) Preparation of intermediate 5-(4-methylpiperazin-1-yl)-2- (trifluoromethyl)benzoic acid

[0305]

[0306] Intermediate 3 (256 mg, 0.85 mmol) was dissolved in a mixture of EtOH\H2O (1:1, 10 mL), and sodium hydroxide (102 mg, 2.55 mmol) was added. The reaction mixture was heated to 60 °C for 1 h. After the reaction was completed, the reaction mixture was cooled to 0 °C, 1N hydrochloric acid was slowly added to adjust the pH to 5, and the solvent was removed by concentration under reduced pressure. The residue was dissolved in a mixture of DCM:MeOH = 10:1, filtered, and concentrated under reduced pressure to obtain intermediate 4 (240 mg, 98 %). LC-MS (ESI, m / z): C 13 H 15 F3N2O2, [M+H] + = 289.08.

[0307] (5) Preparation of compound P33: N-(3-(1,2-dihydroacenaphthyl-5-yl)oxetan-3-yl)-5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide

[0308]

[0309] Intermediate 2 (100 mg, 0.38 mmol), intermediate 4 (165 mg, 0.57 mmol) were dissolved in DMF (5 mL), DIPEA (0.33 mL, 1.9 mmol), HATU (216 mg, 0.57 mmol) were added, and the reaction was warmed to 50 °C for 2 h. After the reaction was completed, it was cooled to room temperature, and water was added. After stirring vigorously, a white solid precipitated, which was filtered, dissolved, and purified by column chromatography (DCM:MeOH=20:1) to give compound P33 (116 mg, 62 %). LC-MS (ESI, m / z): C 28 H 28 F3N3O2, [M+H] + = 495.81.

[0310] Example 34 (P34): Preparation of N-(2-(1,2-dihydroacenaphthyl-5-yl)propan-2-yl)-5-(4- methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide, the synthetic route is as follows

[0311]

[0312] (1) Preparation of intermediate 1: 2-(1,2-dihydroacenaphthyl-5-yl)propan-2-amine

[0313]

[0314] Anhydrous cerium trichloride (821 mg, 3.33 mmol) was added to 30 mL of dry tetrahydrofuran at 0 °C, and stirred at room temperature for 2 h under argon protection. The reaction system was cooled to -78 °C, and 2.5 M methyl lithium (1.3 mL, 3.33 mmol) was slowly added. After stirring for 30 min, 1,2-dihydroacenaphthylene-5-nitrile (200 mg, 1.11 mmol) was added, and the reaction system was stirred at room temperature for 2 h. It was cooled to -78 °C again, and excess ammonia water was added dropwise. Ethyl acetate was used for extraction, and the organic phase was collected and separated by column chromatography (DCM:MeOH=20:1) to give intermediate 1 (150 mg, 64 %). LC-MS (ESI, m / z): C 15 H 17 N, [M+H] + = 212.06.

[0315] (2) Preparation of compound P34: N-(2-(1,2-dihydroacenaphthyl-5-yl)propan-2-yl)-5-(4- methylpiperazin-1-yl)-2-(trifluoromethyl)benzamide

[0316]

[0317] Intermediate 1 (50 mg, 0.24 mmol), 5-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)benzoic acid (103 mg, 0.36 mmol) were dissolved in DMF (3 mL), DIPEA (0.13 mL, 0.72 mmol), HATU (137 mg, 0.36 mmol) were added, and the reaction was warmed to 50 °C for 2 h. After the reaction was completed, it was cooled to room temperature, and water was added. After stirring vigorously, a white solid was precipitated, which was filtered, dissolved, and purified by column chromatography (DCM:MeOH=20:1) to obtain compound P34 (87 mg, 76 %). LC-MS (ESI, m / z): C 28 H 30 F3N3O, [M+H] + = 481.98.

[0318] Example 38 (P38): N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methyl-5-(1,7- diazaspiro[4.4]non-7-yl)benzamide, was synthesized according to the following scheme

[0319]

[0320] (1) Preparation of Intermediate 5: 5-(1-benzyl-1,7-diazaspiro[4.4]non-7-yl)-N-(1-(1,2- dihydroacenaphthyl-5-yl)cyclopropyl)-2-methylbenzamide

[0321]

[0322] 15 mL sealed tube, 5-bromo-N-(1-(1,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- methylbenzamide (100 mg, 0.25 mmol, 1 eq), 1-benzyl-1,7-diazaspiro[4.4]nonane (65 mg, 0.3 mmol, 1.2 eq), Cs2CO3 (244 mg, 0.75 mmol, 3 eq), Ru-phos (22 mg, 0.05 mmol, 0.2 eq), Pd(OAc)2 (6 mg, 0.025 mmol, 0.1 eq), 1,4-dioxane (3 mL) were stirred at 110 0 C overnight. After cooling, TLC was spotted, and the disappearance of the starting material was detected. After filtration, it was concentrated to dryness and purified by column chromatography (DCM:MeOH=100:0-100:10) to obtain a white solid (105 mg). LC-MS (ESI, m / z): C29H31N3O [M+H]+ = 542.12.

[0323] (2) Compound P38: N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methyl-5-(l,7- diazaspiro[4.4]non-7-yl)benzamide

[0324]

[0325] 25 mL single necked flask was charged with intermediate 5 (105 mg), MeOH (3 mL), Pd(OH)2(11 mg), replaced with hydrogen gas for 3 times, hydrogen gas condition, stirred at ambient temperature overnight. TLC spot plate, checked for starting material disappearance. Filtered, concentrated to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) to give off-white solid (25 mg). LC-MS (ESI, m / z): C30H33N3O [M+H]+ = 452.12.

[0326] Example 41 (P41): 5-(piperazine-4-carboximidamide)-N-(l-(l,2-dihydroacenaphthyl-5- yl)cyclopropyl)-2-methylbenzamide, was synthesized according to the following scheme:

[0327]

[0328] (1) Preparation of intermediate 5: tert-butyl 4-(3-((l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)carbamoyl)-4-methylphenyl)piperazine-l-carboxylate

[0329]

[0330] 250 mL sealed tube was charged with 5-bromo-N-(l-(l,2-dihydroacenaphthyl-5- yl)cyclopropyl)-2-methylbenzamide (1 g, 2.5 mmol, 1 eq), tert-butyl piperazine-l-carboxylate acetate (730 mg, 3 mmol, 1.2 eq), Cs2CO3(2.44 g, 7.5 mmol, 3 eq), Ru-phos (220 mg, 0.5 mmol, 0.2 eq), Pd(OAc)2(60 mg, 0.25 mmol, 0.1 eq), 1,4-dioxane (30 mL), 110 0 C overnight. Cooled, TLC spot plate, checked for starting material disappearance. Filtered, concentrated to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) to give off-white solid (820 mg, 65%). LC-MS (ESI, m / z): [M+H] + = 511.96.

[0331] (2) Preparation of intermediate 6: N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- methyl-5-(piperazin-l-yl)benzamide hydrochloride

[0332]

[0333] 50 mL single neck flask was charged with 4-(3-((l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl) carbamoyl)-4-methylphenyl)piperazine-l-carboxylic acid tert-butyl ester (820 mg, 1.6 mmol), DCM (6 mL), HCl / 1,4-dioxane (3 mL, 3 M), and the reaction was stirred at ambient temperature for 2 h. TLC spot check indicated the starting material was consumed. The reaction was filtered and concentrated to dryness to give a light yellow solid (900 mg).

[0334] Preparation of compound P41: 5-(piperazine-4-carboximidamide)-N-(l-(l,2- dihydroacenaphthyl-5-yl)cyclopropyl)-2-methylbenzamide

[0335]

[0336] 25 mL single neck flask was charged with N-(l-(l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2- methyl-5-(piperazin-l-yl)benzamide hydrochloride (134 mg, 0.3 mmol, 1 eq), 1H- pyrazole-l-carboximidamide hydrochloride (33 mg, 0.36 mmol, 1.2 eq), DIEA (193 mg, 1.5 mmol, 5 eq), DMF (3 mL), and the reaction was stirred at 50 °C overnight. The reaction was cooled, and a TLC spot check indicated the starting material was consumed. The reaction was filtered and concentrated to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) gave a white solid (30 mg). LC-MS (ESI, m / z): C29H31N3O [M+H]+ = 454.12. 0 C overnight. The reaction was cooled, and a TLC spot check indicated the starting material was consumed. The reaction was filtered and concentrated to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) gave a white solid (30 mg). LC-MS (ESI, m / z): C29H31N3O [M+H]+ = 454.12.

[0337] Example 42 (P42): Preparation of 5-(4-(N-formimidoylcarboximidamido)piperazin-l-yl)-N-(l- (l,2-dihydroacenaphthyl-5-yl)cyclopropyl)-2-methylbenzamide, according to the following scheme

[0338]

[0339] 25 mL single neck flask was charged with intermediate 6 (134 mg, 0.3 mmol, 1 eq), intermediate 7 (30 mg, 0.36 mmol, 1.2 eq), trimethylsilyl chloride (98 mg, 0.9 mmol, 3 eq), 1,4-dioxane (1 mL), and acetonitrile (1 mL), and the reaction was stirred at 50 °C overnight. The reaction was cooled, and a TLC spot check indicated the starting material was consumed. The reaction was filtered and concentrated to dryness. Column chromatography (DCM:MeOH = 100:0-100:10) gave a white solid (30 mg). LC-MS (ESI, m / z): C29H31N3O [M+H]+ = 454.12.0 Stirred overnight at C. Cool, TLC spotted, the starting material disappeared. Filter, concentrate to dryness. Column chromatography (DCM:MeOH = 100:0-100:10), yielding an off-white solid (35 mg). LC-MS (ESI, m / z): C29H31N3O [M+H]+ = 496.12.

[0340] The synthetic routes for compounds in other embodiments are as follows:

[0341]

[0342] Referring to Examples 1, 4, 38, 41, and 42, the corresponding products were obtained by replacing the starting materials. Specifically, for example, in a 15 mL sealed tube, 5-bromo-N-(1-(1,2-dihydroacenaphthene-5-yl)cyclopropyl)-2-methylbenzamide (100 mg, 0.25 mmol, 1 eq), the starting material corresponding to R (containing N-heterocyclic hydrochloride) (1.2 eq), Cs2CO3 (244 mg, 0.75 mmol, 3 eq), Ru-phos (22 mg, 0.05 mmol, 0.2 eq), Pd(OAc)2 (6 mg, 0.025 mmol, 0.1 eq), 1,4-dioxane (2 mL), 110 0 Stir overnight at C. Cool, spot by TLC, and check for disappearance of the starting material. Filter and concentrate to dryness. Perform column chromatography (e.g., DCM:MeOH = 100:0-100:10), and if protecting groups are present, perform deprotection to obtain the corresponding compound.

[0343] The raw material structure and source of the R group are shown in Table 1 below.

[0344] Table 1

[0345]

[0346]

[0347]

[0348]

[0349]

[0350] The structure and identification results of the embodiments of the present invention are summarized in Table 2 below.

[0351] Table 2

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368] Test Example 1. Enzyme activity test at protein level

[0369] 1. Recombinantly express SARS-CoV-2 PLpro catalytic domain to obtain reaction protein.

[0370] 2. Substrate: Z-Arg-Leu-Arg-Gly-Gly-AMC (GLPBIO, Cat. No. GA23715).

[0371] 3. Buffer: 50 mM HEPES, 10 mM DTT, 0.1 mM EDTA, pH 7.2.

[0372] 4. 384-well plate: greiner, Cat. No. 784076.

[0373] 5. Inhibitor compound.

[0374] 6. Prepare a single concentration or a certain concentration gradient of the compound dissolved in DMSO.

[0375] 7. Incubate the protein with the compound for 10 minutes.

[0376] 8. Add 15 μL of protein and compound mixture solution to each well in a 384-well plate.

[0377] 9. Prepare 80 μM substrate working solution.

[0378] 10. Add 5 μL of 80 μM substrate working solution to each well and incubate for 10 minutes.

[0379] 11. Detection: BioTek synergy NEO2, Ex: 360 nM / Em: 460 nm.

[0380] 12. Data analysis: Use Prism to perform nonlinear regression fitting of the data to calculate IC 50 values, the results of which are shown in Table 3.

[0381] Table 3. Chymotrypsin inhibitory activity

[0382]

[0383] Note: +: 0.5 uM < IC50 <= 1 μM; ++: 0.1 μM < IC50 <= 0.5 μM; +++: 0.03 μM < IC50 <= 0.1 μM; ++++: IC50 < 0.03 μM

[0384] Test Example 2. Inhibition of activity of SARS-CoV-2 infection of Vero E6 cells

[0385] 1. Cell line: African green monkey kidney cells Vero E6 (ATCC, CRL-1586).

[0386] 2. Virus strain: SARS-Cov-2 WT (WT-IQTC02-16#-P2-YQ), XBB.1 (XBB.1-P3-YQ), Omicron BA.5 (GDPCC-303-Omicron-BA.5-P3-YQ) (Guangzhou Customs Technology Center).

[0387] 3. Positive control: Ensitrelvir (product number HY-143216, MedChemExpress LLC).

[0388] 4. Infection dose: MOI (multiplicity of infection) = 0.01.

[0389] 5. The day before, add 250 μL of cells to each well of a 48-well plate, so that the number of cells per well is about 5 x 10 4 .

[0390] 6. Gradient dilution (1:3) was performed at the highest concentration of 10 μM, with three replicate wells for each concentration.

[0391] 7. Virus strain (MOI = 0.01) was added to each well to infect cells for 48 hours.

[0392] 8. RNA was extracted from supernatant 48 hours later using a kit (QIAamp Viral RNA Mini Kit, Qiagen) and then the viral copy number was detected by qRT-PCR, and the half-maximal effective concentration (EC 50 ) was calculated based on the absolute copy number. The results are shown in Table 4.

[0393] Table 4 Inhibition activity of VeroE6 cells infected with virus strains

[0394]

[0395] Test Example 3. Liver microsomal stability test

[0396] 1. Pre-warm PBS (pH 7.4).

[0397] 2. Preparation of intermediate solutions of test and positive reference compounds

[0398] 2.1 500 µM intermediate solution: Add 5 µL of 10 mM compound stock solution and positive reference compounds to 95 µL DMSO;

[0399] 2.2 1.5 µM intermediate solution in liver microsomes (0.75 mg / mL): Add 1.5 µL of 500 µM intermediate solution and 18.75 µL of 20 mg / mL liver microsomes to 479.75 µL of PBS.

[0400] 3. Prepare NADPH stock solution (6 mM, 5 mg / mL) by dissolving NADPH into PBS.

[0401] 4. Distribute 30 µL of 1.5 µM intermediate solution containing 0.75 mg / mL microsomal solution into the assay plate designated for different time points (0, 5, 15, 30, 45 minutes).

[0402] 5. Pre-incubate the plate at 37°C for 5 minutes.

[0403] 6. For 0 minutes, add 150 µL of termination solution containing internal standard of acetonitrile:methanol (1 : 1) to the well before adding 15 µL of NADPH stock solution (6 mM).

[0404] 7. For other time points, 15 μΐ^of NADPH stock solution (6 mM) was added to the wells to start the reaction and timing.

[0405] 8. At 5, 15, 30, 45 min, 150 μΐ^of internal standard acetonitrile:methanol (1 : 1) stop solution was added to the wells of the corresponding plate to stop the reaction.

[0406] 9. After stopping, the plates were shaken for 10 min (600 rpm) and then centrifuged at 4000 rpm for 15 min.

[0407] 10. 80 μΐ^of supernatant from each well was transferred to a 96-well sample plate containing 140 μΐ^of pure water for LC / MS analysis.

[0408] Table 5. Results of liver microsomal stability test

[0409]

[0410] Note: Rat means: rat; Human means: human; t 1 / 2 means: half-life; Clint means: clearance rate; Eh means: clearance ratio.

[0411] Test Example 4. Pharmacokinetic test

[0412] Rat routine PK test:

[0413] 1. The experimental design is shown in the following table:

[0414]

[0415] Note: **: Blood samples of 3 rats were collected at each time point. *: The animals of the oral administration group were fasted overnight (10-14 hours) before administration, and fed 4 hours after administration.

[0416] 2. Preparation of the administration preparation:

[0417] Solvent formula: 10% DMSO, 5% ethanol, 5% Cremophor EL and 80% deionized water. 6.68 mg of the test product was weighed into a suitable container, 1.316 mL of DMSO was measured, vortexed for 1 min, and ultrasonicated for 10 min to obtain a 5 mg / mL clear DMSO stock solution.

[0418] Take 1 mL of 5 mg / mL DMSO stock solution, add 0.5 mL of ethanol, vortex for 1 min, add 0.5 mL of Cremophor EL, vortex for 1 min, and finally add 8 mL of deionized water, vortex for 1 min, to obtain a clear administration preparation with a concentration of 0.5 mg / mL. Prepare immediately before use, and store at room temperature after preparation.

[0419] 3. Animal selection:

[0420] All animals suitable for the experiment are weighed before the start of the study, and after the removal of a certain number of animals with a high and / or low body weight, the animals used in the test have a body weight within ± 20% of the average body weight.

[0421] 4. Animal housing:

[0422] The test animals are housed in rat cages (2-5 animals / cage), and approximately 12 hours / 12 hours of light-dark alternation lighting is provided daily. The dark period can be interrupted intermittently as required for study-related activities. The animal room environmental temperature and relative humidity are monitored daily and controlled within the ranges of 20-26°C and 40-70%, respectively.

[0423] 5. Route of administration:

[0424] Oral gavage administration is used, and the route of administration is consistent with the intended route of administration in the clinic.

[0425] 6. Cage-side observations:

[0426] All animals are observed at least twice daily at the cage side (observations can be accompanied by sampling) during the experiment, and the observations include morbidity, mortality, injury, and feeding and watering, etc. Animals in poor health are marked for further observation, and euthanasia is performed if necessary.

[0427] 7. Collection of biological samples:

[0428] Oral sampling: There are a total of 8 collection time points, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration.

[0429] Plasma: After the animals are euthanized, blood is taken by puncture. The sample is placed in a tube containing K2-EDTA and stored on ice until centrifugation. The blood sample is centrifuged at 6800 g for 6 minutes within 1 hour after collection at 2-8°C, and the plasma sample is stored at about -80°C.

[0430] 8. Analysis of biological samples

[0431] The compounds were analyzed. The samples were analyzed with the quality control samples to evaluate the intra-day accuracy of the analysis batch. Acceptance criteria: At least 50% of the quality control samples for each quality control concentration level and at least >66.7% of the quality control samples for all quality control concentration levels should be accurate between 80 - 120% (organized as 75%-125%).

[0432] When calculating the pharmacokinetic parameters, the BLQ concentration data before the peak time (Tmax) after oral administration of the group was calculated as "0", and the BLQ concentration data after Tmax did not participate in the calculation.

[0433] The following main pharmacokinetic parameters were calculated by non-compartment model statistical moment method of Phoenix WinNonlin® 7.0 software: Tmax, Cmax, AUC(0-t), T1 / 2, etc.

[0434] 9. Final disposal of animals

[0435] All surviving experimental animals were euthanized after the end of the experiment (carbon dioxide euthanasia using a dedicated euthanasia box).

[0436] 10. Analysis method

[0437] Analysis instrument: LC-MS / MS-12 (TQ5500, Triple quad);

[0438] Pipette: Eppendorf

[0439] Shaker: 5810R, Eppendorf

[0440] Centrifuge: 420R, 220R, Eppendorf

[0441] (If necessary, other suppliers or other models of equipment can be used)

[0442] Sample processing:

[0443] 1), Take 30 μL of mixed standard curve sample, quality control sample, blank sample, zero concentration sample and test sample.

[0444] 2), For standard curve samples, quality control samples, zero concentration samples and test samples, add 300 μL of internal standard working solution (containing 100 ng / mL IS), and for blank samples, ULOQ without IS sample (if necessary) Add the same volume of acetonitrile.

[0445] 3), vortex for 1 min

[0446] 4), centrifuge at 4°C for 7 minutes (18000g)

[0447] 5) Take 200 μΐ, of supernatant and add to corresponding 96 well injection plate

[0448] 6) Inject 4 μΐ, and perform LC-MS / MS analysis.

[0449] Table 6. In vivo oral pharmacokinetic data for compounds

[0450]

[0451] It should be noted finally that the above examples are merely intended to illustrate the technical solutions of the present application and not to limit it; although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the specific embodiments of the present application can be modified or some technical features can be replaced by equivalent ones; without departing from the spirit of the technical solutions of the present application, they should be covered in the technical solution range of the present application claimed.

Claims

1. The compound represented by formula (I), or its stereoisomer, or its pharmaceutically acceptable salt, （I） in, R1 and R2 form a cyclopropyl group with the carbon atom they are bonded to; R3 is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R4 is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; m can be 0, 1, 2, or 3; Structural unit Selected from ; Or, structural unit The definition is as follows: L1 is selected from 4-7-membered heterocyclic alkyl and 4-7-membered heterocyclic alkenyl groups, wherein the 4-7-membered heterocyclic alkyl or 4-7-membered heterocyclic alkenyl group contains one or two N atoms; R5 is independently selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, either two R5 atoms forming an =O group, or two R5 atoms forming a C group with the attached atom. 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, wherein C 3-6 The cycloalkyl or 4-7 membered heterocycloalkyl group may be optionally substituted with 1, 2, or 3 groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2, or methyl; L2 is selected from the key, -C 1-4 Alkylene and 4-7 membered heterocyclic alkylene; R6 is independently selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl groups, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-4 Alkyl and morpholino groups; Alternatively, R5 and -L2-(R6) p Linked to form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally coupled with one or more elements selected from OH and C. 1-4 Alkyl group substitution; n is 0, 1, 2, 3 or 4; p can be 1, 2, 3 or 4.

2. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, R3 is selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

3. The compound of claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, R3 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl.

4. The compound of claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, R3 is selected from chlorine, -O-methyl, methyl, ethyl, and trifluoromethyl.

5. The compound of claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, R3 is selected from chlorine and methyl.

6. The compound of claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R3 is a methyl group.

7. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, R4 is selected from hydrogen, halogen, -OH, -CN, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

8. The compound of claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl.

9. The compound of claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R4 is hydrogen.

10. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L1 is selected from aziridine, pyridine, tetrahydroimidazolyl, piperidinyl, piperazine, hexahydropyrimidinyl, homopiperazine, morpholinyl, and tetrahydropyridinyl. R5 is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halomethyl and haloethyl; Alternatively, two R5s can form a = 0; Alternatively, the two R5 groups may form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydroimidazolyl, piperidinyl, piperazine, homopiperidinyl, or homopiperidinyl groups with the attached atom, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydroimidazolyl, piperidinyl, piperazine, homopiperidinyl, or homopiperidinyl groups may be optionally substituted by one, two, or three groups selected from fluorine, chlorine, -OH, -CN, -COOH, -NH2, or methyl.

11. The compound of claim 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R5 is independently selected from hydrogen, fluorine, -COOH, -NH2 and methyl; Alternatively, two R5s can form a = 0; Alternatively, the two R5 atoms may form a cyclopropyl, aziridine, pyrrolidinyl, or piperidinyl group with the attached atom, wherein the cyclopropyl, aziridine, pyrrolidinyl, or piperidinyl group may optionally be substituted with one -OH or a methyl group.

12. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, Structural unit Selected from , , , , , , , and R5 is defined as described in claim 1, where n is 0, 1, 2, 3, or 4.

13. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Unless otherwise specified, the right side of the structural unit is connected to L2, and the * end indicates that it is connected to L2.

14. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L2 is selected from the group consisting of methyl, ethyl, propylene, azeticyclic butyl, pyridine, and piperidinyl. R6 is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, methyl, ethyl, propyl, butyl, and morpholino.

15. The compound of claim 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R6 are each independently selected from hydrogen, fluorine, -OH, -CN, -COOH, -CH3, -CH2CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH2CH2CH3, , , and .

16. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , and R6 is defined as described in claim 1, where p is 1, 2, 3, or 4.

17. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from -CN , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

18. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

19. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the compound shown in formula (I-1). （I-1） in, The definition of L1 is as described in claim 1; The definition of L2 is as described in claim 1; R3 is defined as described in claim 1; R5 is defined as described in claim 1; R6 is defined as described in claim 1; The definitions of n and p are as described in claim 1.

20. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, The compound is selected from the compound shown in formula (I-1-A). (I-1-A) in, R3 is defined as described in claim 1; R5 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1; The definitions of n and p are as described in claim 1.

21. The compound of claim 20, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. n is 0, 1, or 2. p is 1, 2, or 3.

22. The compound of claim 20 or 21, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: The R5 is hydrogen, or two R5s form a pyrrolidinyl group with the attached atom, wherein the pyrrolidinyl group is optionally substituted with one methyl group. The L2 is selected from alkyl, nitride, pyridine, and piperidinyl groups. Each of the R6 groups is independently selected from hydrogen, fluorine, -OH, and methyl.

23. The compound of claim 20 or 21, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R5 and -L2-(R6) p They are linked to form a pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted with one methyl group.

24. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, The compound is selected from the compound shown in formula (I-1-A1). (I-1-A1) in, R3 is defined as described in claim 1; R6 is defined as described in claim 1; p is defined as described in claim 1; Ring A is selected from 4-7 heterocyclic alkyl groups.

25. The compound of claim 24, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. The ring A is selected from aziridine, pyrrolidinyl, and piperidinyl, and each of the R6 groups is independently selected from hydrogen, fluorine, -OH, and methyl. p is 1 or 2.

26. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, The compound is selected from the compound shown in formula (I-1-B). (I-1-B) in, T1 is C, CH, or N; It can be a single bond or a double bond; R3 is defined as described in claim 1; R5 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1; The definitions of n and p are as described in claim 1.

27. The compound of claim 26, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. n is 0, 1, or 2. p is 1, 2, or 3.

28. The compound of claim 26 or 27, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: Each of the R5 atoms is independently selected from hydrogen, -COOH, and methyl, or two R5 atoms form =O, or two R5 atoms form cyclopropyl, aziridine, pyrrolidinyl, piperidinyl, or homopiperidinyl groups with the attached atom, wherein the aziridine, pyrrolidinyl, piperidinyl, or homopiperidinyl group is optionally substituted with one -OH atom. The L2 is selected from the group consisting of methyl, ethyl, and propylidene. Each of the R6 groups is independently selected from hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2. , and .

29. The compound of claim 26 or 27, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R5 and -L2-(R6) p They are linked to form a pyrrolidinyl group, wherein the pyrrolidinyl group is optionally substituted with one hydroxyl group.

30. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the compound shown in formula (I-1-B1). (I-1-B1) in, R3 is defined as described in claim 1; R5 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1; The definition of p is as described in claim 1.

31. The compound of claim 30, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. Each of the R5s is independently selected from -COOH and methyl groups. The L2 is selected from the group consisting of methyl, ethyl, and propylidene. Each of the R6 groups is independently selected from hydrogen, -OH, -COOH, -CN, -CH3, -CH(CH3)2, -S(=O)2OH, -S(=O)2CH3, -S(=O)2NH2, -NH2, -NHCH3, -N(CH3)2. , , , p is 1 or 2.

32. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, The compound is selected from the compound shown in formula (I-1-B2). (I-1-B2) in, R3 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1; The definition of p is as described in claim 1.

33. The compound of claim 32, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. The L2 is selected from the bond and methylene group. Each of the R6 molecules is independently selected from hydrogen and methyl. p is 1 or 2.

34. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the compound shown in formula (I-1-B3). (I-1-B3) in, R3 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1; The definition of p is as described in claim 1.

35. The compound of claim 34, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. The L2 is selected from the bond and methylene group. Each of the R6 molecules is independently selected from hydrogen and methyl. p is 1 or 2.

36. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, The compound is selected from the compound shown in formula (I-1-B4). (I-1-B4) in, R3 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1; The definition of p is as described in claim 1.

37. The compound of claim 36, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. The L2 is selected from the bond and methylene group. Each of the R6 molecules is independently selected from hydrogen and methyl. p is 1 or 2.

38. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, The compound is selected from the compound shown in formula (I-1-C). (I-1-C) in, R3 is defined as described in claim 1; R5 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1; The definitions of n and p are as described in claim 1.

39. The compound of claim 38, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. n is 0, 1, or 2. p is 1, 2, or 3.

40. The compound of claim 38 or 39, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: The R5 is hydrogen, or two R5s form a pyrroloalkyl or piperidinyl group with the attached atom, wherein the pyrroloalkyl or piperidinyl group is optionally substituted with one methyl group. The L2 is selected from alkyl, pyridine, and piperidinyl groups. Each of the R6 groups is independently selected from hydrogen, -NH2, -NHCH3, -N(CH3)2, and... .

41. The compound of claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, The compound is selected from the compound shown in formula (I-1-D). (I-1-D) in, R3 is defined as described in claim 1; The definition of L2 is as described in claim 1; R6 is defined as described in claim 1.

42. The compound of claim 41, or its stereoisomer, or its pharmaceutically acceptable salt, having one or more of the following characteristics: R3 is a methyl group. L2 is a bond. R6 is a methyl group.

43. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 44. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 43, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers.

45. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 43, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and one or more excipients.

46. ​​Use of any compound of claims 1 to 43, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claims 44 or 45, in the preparation of a medicament for treating and / or preventing a disease or condition or for reducing the severity of said disease or condition, wherein said disease or condition is caused by a coronavirus, and wherein said medicament comprises human and veterinary medicines.

47. The use as described in claim 46, wherein, The disease or condition mentioned is selected from respiratory diseases and feline infectious peritonitis.

48. The use as described in claim 47, wherein, The respiratory illness is a simple infection.

49. The use as described in claim 48, wherein, The uncomplicated infection is selected from fever, cough, and sore throat.

50. The use as described in claim 47, wherein, The respiratory illness is pneumonia.

51. The use as described in claim 47, wherein, The respiratory illness is an acute respiratory infection.

52. The use as described in claim 47, wherein, The respiratory disease is severe acute respiratory infection (SARI).

53. The use as described in claim 47, wherein, The respiratory diseases mentioned are selected from hypoxic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

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