Papain-like protease inhibitors and uses thereof

Abstract

The present application relates to the field of medicinal chemistry, in particular to papain-like protease inhibitors and uses thereof.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to papain inhibitors and their uses. Background Technology

[0002] Viruses cause a variety of infectious diseases in humans, such as rabies, poliomyelitis, hepatitis, pneumonia, encephalitis, COVID-19, SARS, and MERS. Most of them are highly contagious, can cause acute discomfort, and can even be fatal.

[0003] Papain-like protease (PLPro) is a hydrolase expressed on the nsp3 region of the 5' end of the coronavirus genome. It is a key protein in coronavirus replication, primarily functioning to cleave specific tetrapeptide structures on polymers to yield the mature functional protein. Furthermore, PLPro can cleave ubiquitin units of key host cell immune proteins, protecting the coronavirus from host cell immune attacks. Therefore, inhibiting PLPro not only suppresses coronavirus replication but also enhances the host cell's immune system's surveillance of the coronavirus. Summary of the Invention

[0004] The first aspect of the present invention provides a compound of 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] Implementation Plan 1-1:

[0007] The compound represented by formula (I), or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt,

[0008]

[0009] in,

[0010] R1 is selected from C 5-12 cycloalkyl, C 5-12 Cycloalkenyl and 5-12 heteroaryl groups, wherein each of R1 is independently optionally surrounded by one or more R a replace;

[0011] R a Each is independently selected from hydrogen, oxo, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6Alkyl)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;

[0012] R2 is selected from -NH2, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 1-6 Alkyl, 4-14 membered heterocyclic, 4-10 membered heterocyclic-4-10 membered heterocyclic, 4-10 membered heterocyclic-C 1-6 Alkylene-4-10-membered heterocyclic group, 4-10-membered heterocyclic-NH-4-10-membered heterocyclic group, C 6-12 Aryl and 5-12 heteroaryl groups, wherein each of the R2s is independently optionally surrounded by one or more R groups. b replace;

[0013] R b Each is independently selected from hydrogen, oxo, 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 groups, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH and C 1-6 Alkyl, the C 1-6 Each alkyl group may be independently and optionally substituted with one or more R groups;

[0014] R is independently selected from hydrogen, oxo, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl group 2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl groups and -NH-C(=O)-C 1-6 alkyl;

[0015] 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;

[0016] 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;

[0017] m can be 0, 1, 2, or 3.

[0018] Implementation Scheme 1-2. The compound described in Implementation Scheme 1-1, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, wherein R1 is selected from C 6-12 cycloalkyl, C 6-12 Cycloalkenyl and 5-10 heteroaryl groups, wherein each of R1 is independently optionally surrounded by one or more R a Replace, R a Each is independently selected from hydrogen, oxo, 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;

[0019] Preferably, R aEach is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -O-ethyl, methyl, ethyl, propyl, halomethyl, haloethyl and halopropyl;

[0020] Preferably, R a Each is independently selected from hydrogen, fluorine, chlorine, -OH, -O-methyl, methyl, ethyl, CH3F, CHF2, and CF3;

[0021] Preferably, R a Each is independently selected from hydrogen, chlorine, -OH, -O-methyl, and methyl;

[0022] Preferably, R1 is selected from C 6-10 cycloalkyl, C 6-10 Cycloalkenyl and 9-10 heteroaryl groups, wherein each R1 is independently optionally surrounded by 1, 2, 3, 4, 5, 6 or 7 R groups. a Replace, R a As defined in this implementation plan;

[0023] Preferably, R1 is selected from adamantyl, tetrahydronaphthyl, indanyl, benzofuranyl, benzothiopheneyl, indolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, and isoquinolinyl, and each R1 is independently optionally divided by 1, 2, 3, 4, or 5 Rs. a Replace, R a As defined in this implementation plan;

[0024] Preferably, R1 is selected from

[0025] More preferably, R1 is selected from Each R1 is independently controlled by 1, 2, 3, 4, or 5 Rs. a Replace, R a As defined in this implementation plan;

[0026] More preferably, R1 is selected from

[0027] More preferably, R1 is selected from

[0028] More preferably, R1 is

[0029] Implementation Scheme 1-3. The compound described in Implementation Scheme 1-1 or Implementation Scheme 1-2, or its stereoisomer, or its tautomer, or its solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein,

[0030] R2 is selected from -NH2, -NH-C1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, 4-10 membered heterocyclic, 4-8 membered heterocyclic-4-8 membered heterocyclic, 4-8 membered heterocyclic-C 1-4 Alkylene-4-8-membered heterocyclic group, 4-8-membered heterocyclic-NH-4-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups, wherein each R2 is independently selected by 1, 2, 3, 4, 5, 6 or 7 R groups. b Replace, R b Selected from hydrogen, oxo, halogen, nitro, -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)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH and C 1-4 Alkyl, the C 1-4 Each alkyl group is independently and optionally substituted with 1, 2, 3, 4, or 5 R groups, where R is selected from hydrogen, oxo, fluorine, chlorine, bromine, nitro, -OH, -CN, -COOH, -NH2, and -NH-C. 1-4 Alkyl, -N-(C 1-4 Alkyl)2, -S(=O)2OH, -S(=O)2-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl group, -C(=O)-NH-C 1-4 Alkyl groups and -NH-C(=O)-C 1-4 alkyl;

[0031] Preferably, R b Each of the following is independently selected from hydrogen, oxo, 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)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, methyl, ethyl, propyl, and butyl, wherein each of the methyl, ethyl, propyl, and butyl groups is independently optionally substituted by 1, 2, 3, 4, or 5 Rs, as defined in this embodiment;

[0032] Preferably, R bEach is independently selected from hydrogen, =O, -F, -OH, -CN, -COOH, -NH2, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -N(CH3)-CH(CH3)2, -S(=O)2CH3, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH2, -CH3, -CH2CN, -CH2COOH, -CH2NHCH 2CH2CH2CH3, -CH2CH3, -CH2CH2NH2, -CH2CH2OH, -CH2CH2COOH, -CH2CH2S(=O)OH, -CH2C(CH3)2OH, -CH2CH2N(CH3)2, -CH2CH(OH)CH3, -CH2CH2CH2NH2, -CH2CH2CH2N(CH3)2 and -CH2CH2CH2S(=O)2CH3;

[0033] Preferably, R is independently selected from hydrogen, oxo, fluorine, chlorine, bromine, nitro, -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)2OH, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-propyl and -S(=O)2NH2;

[0034] Preferably, R is independently selected from hydrogen, -OH, -CN, -COOH, -NH2, -N(CH3)2, -NHCH2CH2CH2CH3, -S(=O)2OH and -S(=O)2CH3;

[0035] Preferably, R2 is selected from -NH2, C 1-4 Alkyl, 4-7 member nitrogen-containing monocyclic heterocyclic group, 7-10 member nitrogen-containing bridged ring heterocyclic group, 7-10 member nitrogen-containing fused ring heterocyclic group, 7-10 member nitrogen-containing spirocyclic heterocyclic group, 4-6 member nitrogen-containing monocyclic heterocyclic group-4-6 member nitrogen-containing monocyclic heterocyclic group, 4-6 member nitrogen-containing monocyclic heterocyclic group-CH2-4-6 member nitrogen-containing monocyclic heterocyclic group, 4-6 member nitrogen-containing monocyclic heterocyclic group-NH-4-6 member nitrogen-containing monocyclic heterocyclic group, and phenyl, wherein each of the R2 is independently optionally separated by 1, 2, 3, 4, or 5 R b Replace, R b As defined in this implementation plan;

[0036] Preferably, R2 is selected from Each of the R2s can be independently selected by 1, 2, 3, 4 or 5 Rs.b Replace, R b As defined in this implementation plan;

[0037] Preferably, R2 is selected from

[0038] Implementation Scheme 1-4. 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 Scheme 1-1 to Implementation Scheme 1-3, wherein R3 is selected from hydrogen, fluorine, chlorine, bromine, -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;

[0039] Preferably, R3 is selected from hydrogen, fluorine, chlorine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl;

[0040] Preferably, R3 is a methyl group.

[0041] Implementation Scheme 1-5. 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 Scheme 1-1 to Implementation Scheme 1-4, 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 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0042] Preferably, R4 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl;

[0043] Preferably, R4 is hydrogen.

[0044] Implementation Scheme 1-6. 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 Scheme 1-1 to Implementation Scheme 1-5, wherein the compound is selected from...

[0045] 1) The compound shown in formula (IA)

[0046]

[0047] Wherein, R1 and R2 are as defined in any of the implementation schemes 1-1 to 1-3;

[0048] Preferably, R1 is selected from Each R1 is independently controlled by 1, 2, 3, 4, or 5 Rs. a Replace, R a As defined in Implementation Scheme 1-1 or Implementation Scheme 1-2,

[0049] Preferably, R1 is selected from

[0050] Preferably, R1 is

[0051] More preferably, the compound is selected from compounds of formula (I-A1), (I-A2), and (I-A3).

[0052]

[0053] Among them, R a R2 is as defined in any of the implementation schemes 1-1 to 1-3;

[0054] Alternatively, the compound shown in formula (I-B1) 2)

[0055]

[0056] in,

[0057] R1, R3, R4, and m are defined as in any of the implementation schemes 1-1 to 1-5.

[0058] R5 is 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,

[0059] R6 is selected from -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -NH-4-8-membered heterocyclic alkyl and 4-8-membered heterocyclic alkyl, wherein R6 is optionally selected from one or more halogens, =O, -OH, -CN, -COOH, -NH2, C 1-4 Alkyl and C 1-4 Substitution of alkyl groups, or

[0060] R5 and R6 form a 4-8 membered heterocyclic alkyl group with the attached atom, wherein the 4-8 membered heterocyclic alkyl group is optionally bonded by one or more atoms selected from halogen, =O, -OH, -CN, -COOH, -NH2, C 1-4 Alkyl and C 1-4 Substitution of alkyl groups;

[0061] Preferably, R1 is selected from Each R1 is independently controlled by 1, 2, 3, 4, or 5 Rs. a Replace, R a As defined in Implementation Scheme 1-1 or Implementation Scheme 1-2;

[0062] Preferably, R1 is

[0063] Preferably, R5 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl; preferably, R5 is hydrogen.

[0064] Preferably, R6 is selected from -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, -NH-4-6-membered heterocyclic alkyl and 4-6-membered heterocyclic alkyl, wherein R6 is optionally substituted by 1, 2, 3 or 4 groups selected from halogen, =O, -OH, -CN, -COOH, -NH2, methyl, ethyl, halomethyl and haloethyl.

[0065] Preferably, R6 is selected from -NH-ethyl, -NH-propyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(ethyl)-ethyl, -NH-tetrahydrofuranyl, and The ring A is a 4-6 membered heterocyclic alkyl group, and the R6 is optionally substituted with one or two groups selected from fluorine, =O, -OH, -NH2, methyl, and halomethyl groups.

[0066] Preferably, R6 is selected from or,

[0067] Preferably, R5 and R6 form a 5-6 membered heterocyclic alkyl group with the attached atom, wherein the 5-6 membered heterocyclic alkyl group is optionally substituted by 1, 2 or 3 groups selected from fluorine, =O, -OH, -NH2, methyl and halomethyl, and preferably the 5-6 membered heterocyclic alkyl group is a pyrrolidinyl group;

[0068] Preferably, when R5 and R6 form a pyrroloalkyl group with the attached atoms, the structural unit... Selected from

[0069] Alternatively, the compound shown in formula (I-B2) 3)

[0070]

[0071] in,

[0072] R1, R3, R4, and m are as defined in any of the implementation schemes 1-1 to 1-5.

[0073] T1 is C, CH, or N.

[0074] It can be a single bond or a double bond.

[0075] R7 is 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 Alkylene-CN, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, or,

[0076] Two R7s form = 0, or,

[0077] Two R7 atoms form C with the adjacent atoms. 3-6 Cycloalkyl, 4-8 membered heterocyclic alkyl,

[0078] R8 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 groups, -S(=O)2OH, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH, C 1-6 Alkyl and C 1-6 Halogenated alkyl, the C 1-6 The alkyl group is optionally surrounded by one or more elements selected from halogens, =O, -OH, -CN, -COOH, -NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2CH3, C 1-4 Alkyl, C 1-4 Haloalkyl, -NH-C1-4 Alkyl and -N-(C 1-4 Substitution of alkyl groups, or

[0079] R8 and R7 form a 4-8 membered heterocyclic alkyl group with the attached atom, wherein the 4-8 membered heterocyclic alkyl group is optionally bonded by one or more atoms selected from halogens, =O, -OH, -CN, -COOH, -NH2, C 1-4 Alkyl and C 1-4 Substitution of alkyl groups,

[0080] n is 0, 1, 2, 3, 4, 5, or 6;

[0081] Preferably, R7 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, -N(methyl)-methyl, methyl, ethyl, halomethyl, haloethyl, and -CH2CN. More preferably, R7 is selected from hydrogen, -COOH, methyl, and -CH2CN, or...

[0082] Preferably, the two R7s form = 0, or,

[0083] Preferably, the two R7 atoms form a cyclopropyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, piperidinyl, or homopiperidinyl group with the attached atom.

[0084] Preferably, the structural unit is formed when two R7 atoms form a cyclopropyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, piperidinyl, or homopiperidinyl group with the adjacent atoms. Selected from

[0085] Preferably, R8 is selected from hydrogen, fluorine, chlorine, nitro, -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 C 1-4 Halogenated alkyl, the C 1-4 The alkyl group may be optionally substituted with one, two, or three groups selected from fluorine, chlorine, =O, -OH, -CN, -COOH, -NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2CH3, methyl, halomethyl, -NH-methyl, -NH-ethyl, -N(methyl)-methyl, and -N(ethyl)-ethyl.

[0086] Preferably, R8 is selected from hydrogen, -CN, -NH2, -CH3, or,

[0087] Preferably, R8 and R7 form a 5-6 membered heterocyclic alkyl group with the attached atom, wherein the 5-6 membered heterocyclic alkyl group is optionally substituted by 1, 2 or 3 groups selected from -OH, -CN, -COOH, -NH2, methyl and halomethyl, and preferably the 5-6 membered heterocyclic alkyl group is a pyrrolidinyl group;

[0088] Preferably, when R8 and R7 form a 5-6 membered heterocyclic alkyl group with the attached atoms, the structural unit... Selected from

[0089] Alternatively, the compound shown in formula (I-B3) 4)

[0090]

[0091] R1, R3, R4, R9 and R 10 As defined in any of Implementation Scheme 1-1 to Implementation Scheme 1-5

[0092] R9 is 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,

[0093] R 10 Selected from -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-8 membered heterocyclic alkyl, wherein R 10 The atom is optionally selected from one or more halogens, =O, -OH, -CN, -COOH, -NH2, C 1-4 Alkyl and C 1-4 Substitution of alkyl groups, or

[0094] R9 and R 10 It forms a 4-8 membered heterocyclic alkyl group with the attached atom, wherein the 4-8 membered heterocyclic alkyl group is optionally bonded by one or more atoms selected from halogen, =O, -OH, -CN, -COOH, -NH2, C 1-4 Alkyl and C 1-4 Substitution of alkyl groups;

[0095] Preferably, R1 is

[0096] Preferably, R9 is selected from hydrogen, fluorine, chlorine, bromine, -OH, -CN, -COOH, -NH2, -O-methyl, -NH-methyl, methyl, ethyl, halomethyl and haloethyl; preferably, R9 is hydrogen.

[0097] Preferably, R 10 The R group is selected from -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, aziridine, pyrrolidinyl, and piperidinyl. 10 It may be optionally substituted with one, two, or three groups selected from halogens, -OH, -CN, -COOH, -NH2, and methyl.

[0098] Preferably, R 10 Selected from -NH(CH3), -N(CH3)2, -N(CH3)-CH(CH3)2, or,

[0099] Preferably, R9 and R 10 The atoms connected to it form a 5-6 membered heterocyclic alkyl group, wherein the 5-6 membered heterocyclic alkyl group is optionally substituted with 1, 2 or 3 groups selected from fluorine, =O, -OH, -NH2, methyl and halomethyl, and preferably the 5-6 membered heterocyclic alkyl group is selected from pyrrolidinyl and piperidinyl;

[0100] Preferably, when R9 and R 10 The structural unit forms pyrrolidinyl or piperidinyl groups with the attached atoms. Selected from

[0101] Implementation Plans 1-7:

[0102] The compound described in Scheme 1-1, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds shown in Formula (II),

[0103]

[0104] in,

[0105] R1 is selected from C 5-12 cycloalkyl, C 5-12 Cycloalkenyl and 5-12 heteroaryl groups, wherein each of R1 is independently optionally surrounded by one or more R a replace;

[0106] R a Each is independently selected from hydrogen, oxo, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0107] R2 is selected from 4-14 membered heterocyclic groups, 4-10 membered heterocyclic-4-10 membered heterocyclic groups, and 4-10 membered heterocyclic-C heterocyclic groups. 1-4 Alkyl-4-10-membered heterocyclic groups, wherein each of the R2 groups is independently optionally surrounded by one or more R groups. b replace;

[0108] R b Each is independently selected from hydrogen, oxo, 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 groups, -S(=O)2NH2, -C(=NH)NH2, -C(=NH)NHC(=NH)NH and C 1-6 Alkyl, the C 1-6 Each alkyl group may be independently and optionally substituted with one or more R groups;

[0109] R is independently selected from hydrogen, oxo, halogen, nitro, -OH, -CN, -COOH, -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl groups, -S(=O)2OH, -S(=O)2NH2 and -S(=O)2-C 1-6 alkyl;

[0110] 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, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0111] Implementation Scheme 1-8. The compound described in Implementation Scheme 1-1 or Implementation Scheme 1-7, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, wherein R1 is selected from C 6-12 cycloalkyl, C 6-12 Cycloalkenyl and 5-10 heteroaryl groups, wherein each R1 is independently optionally surrounded by 1, 2 or 3 R groups. a Replace, Ra Each is independently selected from hydrogen, oxo, 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;

[0112] Preferably, R a Each is independently selected from hydrogen, halogen, -OH, -OC. 1-4 Alkyl and C 1-4 alkyl;

[0113] Preferably, R a Each is independently selected from hydrogen, chlorine, -OH, -O-methyl, and methyl;

[0114] Preferably, R1 is selected from C 9-10 cycloalkyl, C 9-10 Cycloalkenyl and 9-10 heteroaryl groups, wherein each R1 is independently optionally surrounded by 1, 2 or 3 R groups. a Replace, R a As defined in this implementation plan;

[0115] Preferably, R1 is selected from adamantyl, tetrahydronaphthyl, indanyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, and isoquinolinyl, and each R1 is independently optionally divided by 1, 2, or 3 R... a Replace, R a As defined in this implementation plan;

[0116] Preferably, R1 is selected from

[0117] More preferably, R1 is selected from Each of R1 is independently controlled by 1, 2, or 3 R1s. a Replace, R a As defined in this implementation plan;

[0118] More preferably, R1 is selected from

[0119] More preferably, R1 is selected from

[0120] More preferably, R1 is selected from

[0121] Implementation Scheme 1-9. The compound described in Implementation Scheme 1-1, 1-7 or 1-8, or its stereoisomer, tautomer, or solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein,

[0122] R2 is selected from 4-10 membered heterocyclic groups, 4-8 membered heterocyclic-4-8 membered heterocyclic groups, and 4-8 membered heterocyclic-C group. 1-2 Alkyl-4-8-membered heterocyclic groups, wherein each of the R2 groups is independently optionally surrounded by 1, 2, or 3 R groups. b Replace, R b Selected from hydrogen, oxo, halogen, nitro, -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)2NH2 and C 1-4 Alkyl, the C 1-4 Each alkyl group is independently and optionally substituted with one, two, or three R groups, where R is selected from hydrogen, oxo, halogen, nitro, -OH, -CN, -COOH, -NH2, and -NH-C. 1-4 Alkyl, -N-(C 1-4 alkyl)2 and -S(=O)2-C 1-4 alkyl;

[0123] Preferably, R b Each is independently selected from hydrogen, oxo, halogen, -OH, -NH2, -NH-C 1-4 Alkyl, -S(=O)2-methyl and C 1-4 Alkyl, the C 1-4 Each alkyl group may be independently substituted by one, two, or three Rs, as defined in this embodiment;

[0124] Preferably, R b Each of the following is independently selected from hydrogen, oxo, fluorine, -OH, -NH2, -NH-methyl, -N(methyl)-methyl, -N(methyl)-ethyl, -S(=O)2-methyl, methyl, ethyl, propyl, and butyl, wherein each of the methyl, ethyl, propyl, and butyl groups is independently optionally substituted by 1, 2, or 3 Rs, as defined in this embodiment;

[0125] Preferably, R bEach is independently selected from hydrogen, =O, -F, -OH, -NH2, -NH(CH3), -N(CH3)2, -N(CH3)-CH(CH3)2, -S(=O)2CH3, -CH3, -CH2CH3, -CH2CH2OH, -CH2C(CH3)2OH, -CH2CH2N(CH3)2, -CH2CH(OH)CH3, -CH2CH2CH2N(CH3)2 and -CH2CH2CH2S(=O)2CH3;

[0126] Preferably, R is independently selected from hydrogen, -OH, and -NH-C. 1-4 Alkyl, -N-(C 1-4 alkyl)2 and -S(=O)2-C 1-4 alkyl;

[0127] Preferably, R is independently selected from hydrogen, -OH, -N(CH3)2 and -S(=O)2CH3;

[0128] Preferably, R2 is selected from 5-10-membered heterocyclic groups, 4-6-membered hypocyclic groups-4-6-membered heterocyclic groups, and 4-6-membered hypocyclic groups-CH2-4-6-membered heterocyclic groups. The 5-10-membered heterocyclic group contains one or two heteroatoms selected from N and O, and includes monocyclic, bicyclic, and tricyclic forms. The 4-6-membered hypocyclic group contains one or two heteroatoms selected from N and O, and is a monocyclic group. Each R2 is independently selected by one, two, or three R atoms. b replace;

[0129] Preferably, R2 is selected from 4-7 member nitrogen-containing monocyclic heterocyclic groups, 7-10 member nitrogen-containing bridged ring heterocyclic groups, 7-10 member nitrogen-containing fused ring heterocyclic groups, 7-10 member nitrogen-containing spirocyclic heterocyclic groups, 4-6 member nitrogen-containing monocyclic sub-heterocyclic groups-4-6 member nitrogen-containing monocyclic heterocyclic groups, and 4-6 member nitrogen-containing monocyclic sub-heterocyclic groups-CH2-4-6 member nitrogen-containing monocyclic heterocyclic groups, wherein each R2 is independently selected by 1, 2, or 3 R groups. b Replace, R b As defined in this implementation plan;

[0130] Preferably, R2 is selected from

[0131] Each of R2 is independently selected by 1, 2 or 3 R... b Replace, R b As defined in this implementation plan;

[0132] Preferably, R2 is selected from

[0133] Implementation Scheme 1-10. 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 Scheme 1-1, Implementation Scheme 1-7-Implementation Scheme 1-9, wherein R3 is selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0134] Preferably, R3 is selected from methyl, ethyl, and halomethyl;

[0135] Preferably, R3 is a methyl group.

[0136] Implementation Scheme 1-11. 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 Scheme 1-1, Implementation Scheme 1-7-Implementation Scheme 1-10, wherein the compound is selected from the compounds shown in formula (II-A).

[0137]

[0138] R1 and R2 are as defined in any of the following implementation schemes: 1-1, 1-7, and 1-9.

[0139] Preferably, R1 is selected from quinolinyl and indaneyl, and each R1 is independently bounded by 1, 2 or 3 R groups. a Replace, R a As defined in embodiments 1-1, 1-7, or 1-8, preferably, R a Selected from hydrogen and -O-methyl,

[0140] Preferably, R1 is selected from

[0141] Preferably, R1 is selected from

[0142] Preferably, R2 is selected from 5-8 membered heterocyclic groups and 4-6 membered heterocyclic groups, wherein the 5-8 membered heterocyclic group contains one or two N heteroatoms and includes monocyclic and bridged rings, and the 4-6 membered heterocyclic group contains one N atom and is monocyclic. Each R2 is independently selected by one or two R atoms. b Replace, R b Each is independently selected from hydrogen, halogen, -OH, -NH2, and C. 1-4 Alkyl, preferably R b Each is independently selected from hydrogen, -OH, and methyl.

[0143] Preferably, R2 is selected from piperazine, 3,6-diazabicyclo[3.1.1]heptyl, and aziridine-4-6 heterocyclic groups, each of which is independently optionally divided by one or two R groups. b Replace, R b Each is independently selected from hydrogen, -OH, and methyl.

[0144] Preferably, R2 is selected from Each of R2 is independently selected by one or two R... b Replace, R b Each is independently selected from hydrogen, -OH, and methyl.

[0145] Preferably, R2 is selected from

[0146] More preferably, the compound is selected from compounds of formula (II-A1) and (II-A2).

[0147]

[0148] Among them, R a R2 is as defined in any of Implementation Scheme 1-1, Implementation Scheme 1-7-Implementation Scheme 1-9, or as defined in this Implementation Scheme;

[0149] Alternatively, the compound shown in formula (II-B1) 2)

[0150]

[0151] in,

[0152] R1 is as defined in implementation schemes 1-1, 1-7, or 1-8.

[0153] R5 is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, and methyl.

[0154] R6 is selected from 4-6-membered heterocyclic alkyl groups, wherein the 4-6-membered heterocyclic alkyl group is optionally composed of 1, 2, or 3 elements selected from halogen, =O, -OH, -CN, -COOH, -NH2, and C. 1-4 Alkyl group substitution, or

[0155] R5 and R6 form a 4-6 membered heterocyclic alkyl group with the attached atom, wherein the 4-6 membered heterocyclic alkyl group is optionally surrounded by one, two, or three atoms selected from halogens, -OH, and C. 1-4 Alkyl group substitution;

[0156] Preferably, R1 is a 9-10 member heteroaryl group, wherein the 9-10 member heteroaryl group is optionally surrounded by 1, 2, or 3 R groups. a Replace, R a As defined in implementation scheme 2-1 or implementation scheme 2-2, R1 is preferably quinolinyl.

[0157] Preferably, R1 is

[0158] Preferably, R5 is selected from hydrogen, fluorine, chlorine, -OH and -COOH, and preferably R5 is hydrogen;

[0159] Preferably, R6 is selected from 4-6-membered heterocyclic alkyl groups, wherein the 4-6-membered heterocyclic alkyl group contains one or two N heteroatoms, and the 4-6-membered heterocyclic alkyl group is optionally substituted with one or two groups selected from fluorine, =O, -OH and methyl.

[0160] Preferably, R6 is selected from aziridine, pyrrolidinyl, piperidinyl, and piperazine, wherein the aziridine, pyrrolidinyl, piperidinyl, and piperazine are optionally substituted with one or two groups selected from fluorine, =O, -OH, and methyl.

[0161] Preferably, R6 is selected from or,

[0162] Preferably, R5 and R6 form a 5-6 membered heterocyclic alkyl group with the attached atom, wherein the 5-6 membered heterocyclic alkyl group is optionally substituted with one methyl group, and preferably the 5-6 membered heterocyclic alkyl group is a pyrrolidinyl group;

[0163] Preferably, when R5 and R6 form a pyrroloalkyl group with the attached atoms, the structural unit... Selected from

[0164] Alternatively, the compound shown in formula (II-B2) 3)

[0165]

[0166] in,

[0167] R1 is as defined in implementation schemes 1-1, 1-7, or 1-8.

[0168] T1 is C, CH, or N.

[0169] It can be a single bond or a double bond.

[0170] R7 is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, and C. 1-4 Alkyl, or,

[0171] Two R7 atoms form C with the adjacent atoms. 3-6 Cycloalkyl, 4-7 membered heterocyclic alkyl,

[0172] R8 is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, -NH-C 1-6Alkyl, -N-(C 1-6 Alkyl)2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2NH2, C 1-6 Alkyl and C 1-6 Halogenated alkyl, the C 1-6 The alkyl group is optionally surrounded by one, two, or three elements selected from halogens, =O, -OH, -CN, -COOH, -NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)2CH3, C 1-4 Alkyl, -NH-C 1-4 Alkyl and -N-(C 1-4 Substitution of alkyl groups, or

[0173] R8 and R7 form a 4-8 membered heterocyclic alkyl group with the attached atom, wherein the 4-8 membered heterocyclic alkyl group is optionally surrounded by one, two, or three atoms selected from halogens, =O, -OH, -CN, -COOH, -NH2, and C. 1-4 Alkyl group substitution,

[0174] n is 0, 1, 2, 3 or 4;

[0175] Preferably, R7 is selected from hydrogen and C. 1-4 Alkyl group, preferably R7 is selected from hydrogen and methyl, or,

[0176] Preferably, the two R7 atoms form a cyclopropyl, aziridine, pyrrolidinyl, piperidinyl, or homopiperidinyl group with the attached atom.

[0177] Preferably, the structural unit is formed when two R7 atoms form a cyclopropyl, aziridine, pyrrolidinyl, piperidinyl, or homopiperidinyl group with the attached atoms. Selected from

[0178] Preferably, R8 is selected from hydrogen, -NH2, -S(=O)2-C 1-4 Alkyl and C 1-4 Alkyl, the C 1-4 The alkyl group may be optionally substituted with one, two, or three groups selected from fluorine, -OH, -S(=O)2CH3, methyl, and -N(methyl)-methyl.

[0179] Preferably, R8 is selected from hydrogen, -NH2, -CH3, or,

[0180] Preferably, R8 and R7 form a 5-6 membered heterocyclic alkyl group with the attached atom, wherein the 5-6 membered heterocyclic alkyl group is optionally substituted with one -OH group, and preferably the 5-6 membered heterocyclic alkyl group is a pyrrolidinyl group;

[0181] Preferably, the structural unit is formed when R8 and R7 form a pyrroloalkyl group with the attached atoms. Selected from

[0182] Alternatively, the compound shown in formula (II-B3) 4)

[0183]

[0184] R1 is as defined in implementation schemes 1-1, 1-7, or 1-8.

[0185] R9 is selected from hydrogen, halogen, nitro, -OH, -CN, -COOH, -NH2, and methyl.

[0186] R 10 Selected from -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2 and 4-6 membered heterocyclic alkyl, wherein R 10 The element can be selected from 1, 2, or 3 of the following: halogen, -OH, -CN, -COOH, and C. 1-4 Alkyl group substitution, or

[0187] R9 and R 10 It forms a 4-6 membered heterocyclic alkyl group with the attached atom, wherein the 4-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2 or 3 atoms selected from halogen, -OH, -CN, -COOH and C. 1-4 Alkyl group substitution;

[0188] Preferably, R1 is

[0189] Preferably, R9 is selected from hydrogen, fluorine, chlorine, -OH and -COOH, and preferably, R9 is hydrogen;

[0190] Preferably, R 10 The R group is selected from -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, aziridine, pyrrolidinyl, and piperidinyl. 10 It may be optionally substituted with one group selected from halogen, -OH, -CN, -COOH, -NH2, and methyl.

[0191] Preferably, R 10 Selected from -NH(CH3), -N(CH3)2, -N(CH3)-CH(CH3)2, or,

[0192] Preferably, R9 and R 10It forms a 5-6 membered heterocyclic alkyl group with the attached atom, wherein the 5-6 membered heterocyclic alkyl group is optionally substituted with a group selected from -OH and methyl, and preferably the 5-6 membered heterocyclic alkyl group is selected from pyrrolidinyl and piperidinyl;

[0193] Preferably, when R9 and R 10 The structural unit forms pyrrolidinyl or piperidinyl groups with the attached atoms. Selected from

[0194] Implementation Scheme 1-12. 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 Scheme 1-11, wherein the compound is selected from:

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] 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 1-12, wherein the compound is selected from: compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70.

[0203] A second aspect of the invention provides a pharmaceutical composition comprising at least one compound described in the first aspect above, or a stereoisomer thereof, a tautomer thereof, a solvate thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

[0204] The third aspect of the invention provides the use of the compounds described in the first aspect above, or their stereoisomers, tautomers, or solvates, or their isotopically labeled compounds, or their pharmaceutically acceptable salts, or the pharmaceutical compositions described in the second aspect above, in the preparation of a medicament for treating and / or preventing a disease or condition or reducing the severity of said disease or condition, wherein said disease or condition is caused by a coronavirus, and wherein said medicament includes human and veterinary medicines.

[0205] Preferably, the disease or condition is selected from respiratory diseases (e.g., uncomplicated infections such as fever, cough and sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (ARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock and feline infectious peritonitis.

[0206] The fourth aspect of the present invention provides the compounds described in the first aspect above, or their stereoisomers, tautomers, or solvates, or their isotopically labeled compounds, or their pharmaceutically acceptable salts, or the pharmaceutical compositions described in the second aspect above, for treating and / or preventing diseases or conditions or reducing the severity of said diseases or conditions, said diseases or conditions being caused by coronaviruses, said pharmaceuticals including human pharmaceuticals and veterinary pharmaceuticals.

[0207] Preferably, the disease or condition is selected from respiratory diseases (e.g., uncomplicated infections such as fever, cough and sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (ARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock and feline infectious peritonitis.

[0208] The fifth aspect of the invention provides a method for treating and / or preventing a disease or condition or reducing the severity of said disease or condition, comprising administering to an individual in need an effective amount of the compound described in the first aspect 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 described in the second aspect above, wherein said disease or condition is caused by a coronavirus, and wherein said pharmaceuticals include human pharmaceuticals and veterinary pharmaceuticals.

[0209] Preferably, the disease or condition is selected from respiratory diseases (e.g., uncomplicated infections such as fever, cough and sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, COVID-19, severe acute respiratory syndrome (ARS), Middle East respiratory syndrome (MERS)), sepsis, septic shock and feline infectious peritonitis.

[0210] Terminology Definition

[0211] In this application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, to better understand this application, definitions and explanations of relevant terms are provided below.

[0212] In the event that the compound name used in this application is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0213] As used in this application, the term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0214] Similarly, the compounds of this application may exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0215] Unless otherwise stated, the compounds of this application may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of this application may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0216] The compounds of this invention may exist as solvates (such as hydrates), wherein the compounds of this application contain a solvent, such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the solvent may be stoichiometric or non-stoichiometric.

[0217] As used herein, the term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms of the same number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in compounds of this application include, but are not limited to, hydrogen isotopes such as... 2 H, 3 H; carbon isotopes, for example 11 C, 13 C and 14 C; Chlorine isotopes, for example 36 Cl; fluorine isotopes, for example 18 F; Iodine isotopes, for example 123 I and 125 I; nitrogen isotopes, for example 13 N and 15 N; oxygen isotopes, for example 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0218] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic acids or acids formed with organic acids, or salts containing acidic protons on the parent compound but surrounded by metal ions, or coordination compounds formed with organic bases.

[0219] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and similar salts.

[0220] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using the relative ions of halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0221] Pharmaceutically acceptable salts are also intended to include hemisalts, wherein the ratio of compound to acid is 2:1. Exemplary hemisalts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemisalts are those derived from diprotic mineral acids (e.g., sulfuric acid). Preferred exemplary hemisalts include (but are not limited to) hemi-maleic acid salts, hemi-fumaric acid salts, and hemi-succinic acid salts.

[0222] As used in this application, the term "optionally substituted" means that the group may be unsubstituted or substituted, for example, "C..." 1-6 "Alkyl optional halogen substitution" indicates C 1-6 Alkyl groups can be unsubstituted or substituted with halogens to yield haloalkyl groups. It should be understood that when stating "R is selected from C...", the expression "R is selected from C..." is considered appropriate. 1-6Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 Alkyl, the C 1-6 When "alkyl groups are optionally substituted with halogens", it indicates that C 1-6 Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 C in alkyl 1-6 Alkyl groups are optionally substituted with halogens. It should be understood that -N-(C 1-6 Alkyl)2 indicates that two carbon atoms are attached to the nitrogen atom. 1-6 Alkyl groups, which can be the same or different.

[0223] As used herein, unless otherwise expressly indicated, the descriptive phrase “...each independently selected” used throughout may mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0224] As used in this application, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0225] As used in this application, the term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group, such as C10. 1-6 Alkyl groups refer to those having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms; C 1-4 Alkyl refers to a compound 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, etc.

[0226] As used in this application, the term "alkylene" refers to a straight-chain or branched divalent saturated hydrocarbon group, such as C 1-4 Alkylenes refer to compounds having 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Examples of alkylenes include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0227] As used in this application, the term "halogenated" refers to a modified group being substituted with one or more halogens, for example, substituted with 1, 2, 3, 4, 5, or 6 halogens. For example, "C 1-6 "Halogenated alkyl" refers to C as defined above. 1-6 The alkyl group is substituted with one or more halogens, including but not limited to CF3, CHF2, or CF2CF3.

[0228] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 5-12 The cycloalkyl group has 5 to 12 carbon atoms, such as 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, wherein the C5-12 Cycloalkyl groups include C 6-12 cycloalkyl, C 6-10 cycloalkyl, C 6-8 Cycloalkyl groups, etc. The cycloalkyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, cyclohexyl, cycloheptyl, adamantyl, etc.

[0229] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 5-12 The cycloalkenyl group has 5 to 12 carbon atoms, such as 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the C 5-12 Cycloalkenyl groups include C 6-12 Cycloalkenyl, C 6-10 Cycloalkenyl, C 6-8 Cycloalkenyl groups, etc. The cycloalkenyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, cyclohexenyl and hexahydronaphthyl.

[0230] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic group composed of ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are 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 may optionally be oxidized. For example, a 5-12 membered heterocyclic group refers to a group composed of 5-12 ring atoms, including 5-10 membered heterocyclic groups, 5-7 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-6 membered heterocyclic groups, etc. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, oxo-heterobutyl, azirrobutyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. The term "nitrogen-containing monocyclic heterocyclic group" means that at least one heteroatom in the heterocyclic group is a nitrogen atom, and the heterocyclic group is monocyclic; examples include, but are not limited to, piperidinyl. The term "nitrogen-bridged heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is a bridged ring. Examples include, but are not limited to, those containing nitrogen atoms. The term "nitrogen-containing fused heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is fused ring, examples of which include, but are not limited to, nitrogen-containing fused rings. The term "nitrogen-containing spirocyclic heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is a fused ring, examples of which include, but are not limited to, nitrogen-containing spirocyclic heterocyclic groups. wait.

[0231] As used herein, the term "hybrid subcyclic group" refers to a saturated or partially unsaturated divalent cyclic group composed of ring atoms, wherein one, two, three, or four ring atoms are heteroatoms, and the remainder are 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 may optionally be oxidized. For example, a 4-8 membered heterocyclic group refers to a group composed of 4-8 ring atoms, including 4-6 membered heterocyclic groups, 5 membered heterocyclic groups, etc. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, oxocyclic butyl, azacyclic butyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl. The term "nitrogen-containing monocyclic heterocyclic group" refers to a heterocyclic group in which at least one heteroatom is a nitrogen atom, and the heterocyclic group is monocyclic; examples include, but are not limited to, oxocyclic butyl.

[0232] As used in this application, the term "partially unsaturated" refers to a ring system that is neither saturated (i.e., does not contain double bonds) nor completely unsaturated (i.e., contains the maximum possible number of double bonds). In other words, a partially unsaturated ring system contains at least one double bond, but not the maximum possible number of double bonds.

[0233] As used herein, the term "heteroaryl" refers to an unsaturated group consisting of ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are 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 may optionally be oxidized. For example, 5-10-membered heteroaryls consist of 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, including 5-9-membered, 9-10-membered, and 5-6-membered heteroaryls, etc. The heteroaryls include monocyclic and polycyclic compounds, examples of which include, but are not limited to, imidazolyl, pyridinyl, quinolinyl, or isoquinolinyl compounds.

[0234] As used herein, the term "pharmaceutical carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, as is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutical carriers and / or excipients include, but are not limited to: pH adjusters, surfactants, ionic strength enhancers, diluents, agents for maintaining osmotic pressure, agents for delaying absorption, preservatives, and stabilizers. For example, pH adjusters include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic 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, etc. Agents for maintaining osmotic pressure include, but are not limited to, sugars, NaCl, and their analogues. Agents for delaying absorption include, but are not limited to, monostearates and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols, and polyols (such as glycerol). Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meaning commonly understood by those skilled in the art for stabilizing the desired activity of the active ingredient in a pharmaceutical product, including, but not limited to, monosodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin, or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0235] As used herein, the term "effective amount" means an amount sufficient to achieve, or at least partially achieve, the desired effect. For example, an effective amount for disease prevention means an amount sufficient to prevent, stop, or delay the onset of a disease; an effective amount for disease treatment means an amount sufficient to cure or at least partially stop the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is entirely within the capabilities of those skilled in the art. For example, an effective amount for therapeutic purposes will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general characteristics such as age, weight, and sex, the method of administration of the drug, and other concurrent treatments, etc.

[0236] As used herein, the term "treatment" aims to alleviate, reduce, improve, or eliminate a targeted disease state or symptom. A subject is successfully "treated" if, in accordance with the methods described herein, a therapeutic amount of the antibody-drug conjugate or its racemic, enantiomer, diastereomer, pharmaceutically acceptable salt, or mixture of the foregoing forms is received, and one or more indications and symptoms exhibit an observable and / or detectable reduction or improvement. It should also be understood that treatment of the disease state or symptom includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[0237] As used in this application, the term "prevention" aims to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms before the onset of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, reducing the risk of a subject developing a specific disease or disease-related symptoms after the administration of the relevant drug, or lessening the severity of subsequently occurring related symptoms, can be considered as "prevention" of the onset or development of the disease.

[0238] Beneficial effects:

[0239] This invention provides a novel papain inhibitor that exhibits good antiviral activity, hepatic stability, and oral pharmacokinetic properties. Detailed Implementation

[0240] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0241] Example:

[0242] Preparation of Intermediate 1: Methyl 2-methyl-5-(4-methylpiperazin-1-yl)benzoate

[0243]

[0244] Under nitrogen protection, methyl 5-bromo-2-methylbenzoate (2.98 g, 13 mmol, 1 eq.), 1-methylpiperazine (1.30 g, 13 mmol, 1 eq.), Pd2(dba)3 (238.1 mg, 0.26 mmol, 0.02 eq.), XPhos (247.9 mg, 0.52 mmol, 0.04 eq.), CsCO3 (8.47 g, 26 mmol, 2 eq.), and 1,4-dioxane (40 mL) were added sequentially to a round-bottom flask. The mixture was stirred at 110 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain 2.5 g of the target compound as a yellow solid. MS m / z (ESI): 249.01 [M+H] + .

[0245] Preparation of Intermediate 2: 2-Methyl-5-(4-methylpiperazin-1-yl)benzoic acid

[0246]

[0247] Intermediate 1 (4.69 g, 20 mmol, 1 eq.), NaOH (4.1 g, 10 mmol, 5 eq.), and THF / MeOH / H₂O (48 mL:16 mL:16 mL) were added sequentially to a flask, and the reaction was carried out at 50 °C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature, and dilute hydrochloric acid was added dropwise at 0 °C to adjust the pH to 5-6. After standing for 10 minutes, a white solid precipitated, which was filtered to obtain 3.3 g of the target product as a white solid. MS m / z (ESI): 235.19 [M+H] + .

[0248] Preparation of intermediate 3: 7-methylbenzo[b]thiophene

[0249]

[0250] 7-Bromobenzo[b]thiophene (1 g, 4.69 mmol, 1.0 eq.) and methylboronic acid (561 mg, 9.38 mmol, 2.0 eq.) were dissolved in 1,4-dioxane (20 mL). SPhos (41 mg, 0.10 mmol, 0.02 eq.), Pd(AcO)₂ (11 mg, 0.05 mmol, 0.01 eq.), and K₃PO₄·3H₂O (2.5 g, 9.38 mmol, 2.0 eq.) were added sequentially to the reaction solution. The reaction was carried out at 100 °C for 16 hours under N₂ protection. TLC (PE) showed complete reaction of the compounds. The reaction solution was cooled to room temperature. The reaction was quenched with water (40 mL), and the aqueous phase was extracted with EtOAc (30 mL x 3). All organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 7-methylbenzo[b]thiophene (531 mg).

[0251] Preparation of intermediate 4: 3-bromo-7-methylbenzo[b]thiophene

[0252]

[0253] Intermediate 3 (531 mg, 3.5 mmol, 1.0 eq.) was dissolved in DMF (8 mL) and AcOH (1 mL), cooled to 0 °C, and NBS (748 mg, 4.2 mmol, 1.2 eq.) was slowly added. The reaction was stirred at room temperature for 16 hours. HPLC detection showed the disappearance of the starting peak and the appearance of a new peak. The reaction was quenched with water (15 mL), and the aqueous phase was extracted with EtOAc (20 mL * 3). All organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give 3-bromo-7-methylbenzo[b]thiophene (677 mg).

[0254] Preparation of intermediate 5: 7-methylbenzo[b]thiophene-3-carboxynitrile

[0255]

[0256] Intermediate 4 (677 mg, 2.98 mmol, 1.0 eq.) was dissolved in DMF (15 mL), and CuCN (534 mg, 5.96 mmol, 2.0 eq.) was added. The reaction was stirred at 150 °C for 24 hours. TLC showed that the starting material reacted completely. The reaction was cooled to room temperature, quenched with water (30 mL), and the aqueous phase was extracted with EtOAc (20 mL * 3). All organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give 7-methylbenzo[b]thiophene-3-onitrile (297 mg).

[0257] Preparation of Intermediate 6: 1-(quinolin-4-yl)cyclopropane-1-carboxynitrile

[0258]

[0259] Under nitrogen protection, Pd₂(dba)₃ (582 mg, 0.625 mmol, 0.05 eq.) and NiXantphos (696 mg, 1.25 mmol, 0.1 eq.) were dissolved in THF (36 mL) and stirred at room temperature for 5 minutes. Then, cyclopentyl methyl ether (36 mL) solution, 4-bromoquinoline (2.6 g, 12.5 mmol, 1 eq.), and cyclopropaneformonitrile (1.29 g, 18.75 mmol, 1.5 eq.) were added dropwise, followed by LiHMDS (25.8 mL, 1 M in THF, 2 eq.). After the addition was complete, the reaction mixture was reacted at 60 °C for 1 h. After the reaction was complete, the reaction mixture was extracted with dichloromethane and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by column chromatography to obtain 1.8 g of the title compound as a yellow solid. MS m / z(ESI): 194.98 [M+H] + .

[0260] Preparation of Intermediate 7: 1-(quinolin-4-yl)cyclopropane-1-carboxamide

[0261]

[0262] Intermediate 6 (194.3 mg, 1 mmol, 1 eq.) was dissolved in isopropanol (4 mL), and NaOH (200 mg, 5 mmol, 5 eq.) was added. The mixture was stirred at 90 °C for 6 h. After the reaction was complete, the reaction mixture was extracted with DCM / water and concentrated under reduced pressure to give 181 mg of the brown solid title product. MS m / z (ESI): 213.15 [M+H] + .

[0263] Preparation of intermediate 8: 1-(quinolin-4-yl)cyclopropane-1-amine

[0264]

[0265] Intermediate 7 (106.2 mg, 0.5 mmol, 1 eq.) was dissolved in tert-butanol (2 mL), and 3M NaOH (1.3 mL) and NaClO (1.6 mL) were added at 0 °C. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 45 mg of the target product. MS m / z (ESI): 185.18 [M+H] + .

[0266] Preparation of Intermediate 9: 5-Bromo-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide

[0267]

[0268] Intermediate 8 (2.00 g, 10.86 mmol, 1 eq.), 5-bromo-2-methylbenzoic acid (2.80 g, 13.03 mmol, 1.2 eq.), DIPEA (4.21 g, 32.57 mmol, 3 eq.), HATU (4.96 g, 13.03 mmol, 1.2 eq.), and DMF (15 mL) were added sequentially to a flask, and the reaction was carried out at 50 °C for 3 h. After the reaction was complete, the product was purified by column chromatography to obtain 2.1 g of solid product. MS m / z (ESI): 380.71 [M+H] + .

[0269] Example 1

[0270] This embodiment provides compound 1: N-(1-(1-hydro-indole-3-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0271]

[0272] The synthetic route of Example 1 is as follows:

[0273]

[0274] (1) Preparation of intermediate 10: tert-butyl 3-cyano-1H-indole-1-carboxylic acid

[0275]

[0276] 1H-indole-3-carboxynitrile (0.71 g, 5 mmol, 1 eq.), Boc₂O (1.4 mL, 6 mmol, 1.2 eq.), DMAP (61.1 mg, 0.5 mmol, 0.1 eq.), triethylamine (1.39 mL, 10 mmol, 2 eq.), and dichloromethane (15 mL) were added sequentially to a flask, and the reaction was carried out overnight at room temperature. After the reaction was complete, the organic solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 0.98 g of the target compound as a yellow solid, MS m / z (ESI): 242.99 [M+H]. + .

[0277] (2) Preparation of intermediate 11: 3-(1-aminocyclopropyl)-1H-indole-1-carboxylic acid tert-butyl ester

[0278]

[0279] Under nitrogen protection and at -78°C, Ti(OEt)4 (501.8 mg, 2.2 mmol, 1.1 eq.) was added to a 15 mL solution of intermediate 10 (484.6 mg, 2 mmol, 1 eq.) in tetrahydrofuran, followed by the slow dropwise addition of ethyl magnesium bromide (1.47 mL, 3 M in Et2O, 4.4 mmol, 2.2 eq.). After the addition was complete, the mixture was stirred at room temperature for 1 h. Then, boron trifluoride diethyl ether (4 mmol, 567.5 mg, 2 eq.) was added dropwise, and the reaction was allowed to proceed for 1 h at room temperature. After the reaction was complete, the reaction was quenched at 0°C with a saturated ammonium chloride solution (5 mL). The reaction mixture was extracted with dichloromethane and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was purified by preparative liquid chromatography to obtain 56 mg of the title compound as a yellow solid. MS m / z(ESI): 273.14 [M+H] + .

[0280] (3) Preparation of intermediate 12: tert-butyl 3-(1-(2-methyl-5-(4-methylpiperazin-1-yl)benzoylamino)cyclopropyl)-1H-indole-1-carboxylic acid

[0281]

[0282] Intermediate 11 (50.0 mg, 0.184 mmol, 1 eq.), intermediate 2 (51.6 mg, 0.22 mmol, 1.2 eq.), DIPEA (71.2 mg, 0.551 mmol, 3 eq.), HATU (83.8 mg, 0.22 mmol, 1.2 eq.), and DMF (3 mL) were added sequentially to a flask, and the mixture was reacted at 50 °C for 3 h. After the reaction was complete, the reaction mixture was extracted three times with DCM and saturated brine. The organic layer was separated and concentrated under reduced pressure to obtain 92 mg of crude product. MS m / z (ESI): 489.49 [M+H] + .

[0283] (4) Preparation of compound 1: N-(1-(1-H-indol-3-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0284]

[0285] Intermediate 12 (92 mg) was dissolved in 3 mL of DCM, and 1.5 mL of TFA was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the crude product was dissolved in DMSO, and the compound was purified by preparative liquid chromatography. The purified compound was then lyophilized to obtain 2.1 mg of a pale yellow solid. MS m / z (ESI): 389.37 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ10.79(s,1H),8.88(s,1H),7.89(d,J=8.0Hz,1H),7.32(d,J= 8.1Hz,1H),7.21(d,J=2.4Hz,1H),7.06(t,J=7.5Hz,1H),7.02-6.92(m,2H),6.85(dd ,J=8.4,2.6Hz,1H),6.73(d,J=2.6Hz,1H),3.05(s,3H),2.44(s,3H),2.22(s,2H),2. 07(s,2H),1.99(dt,J=18.6,7.2Hz,1H),1.33-1.26(m,1H),1.23(s,4H),1.13(s,2H).

[0286] Example 2

[0287] This embodiment provides compound 2: N-(1-(1H-indol-4-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0288]

[0289] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 389.40 [M+H] + .

[0290] Example 3

[0291] This embodiment provides compound 3: N-(1-(1H-benzo[d]imidazol-4-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0292]

[0293] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 390.34 [M+H] + .

[0294] Example 4

[0295] This embodiment provides compound 4: N-(1-(1,2,3,4,4a,8a-tetrahydronaphthyl-1-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0296]

[0297] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 406.40 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.52-7.46(m,1H),7.12-7.06(m,2H),7.05(d,J=5.4Hz,1H),6.97(d,J=8.4Hz,1H ),6.83(dd,J=8.4,2.6Hz,1H),6.54(d,J=2.7Hz,1H),3.03(t,J=5.1Hz,4H),2.89(t,J=6.5Hz,1H),2.70( q,J=5.7,5.2Hz,2H),2.52(s,3H),2.28(s,3H),2.07-1.95(m,5H),1.90(td,J=8.8,8.2,4.9Hz,1H),1.60 -1.52(m,1H),1.24(d,J=5.1Hz,2H),0.96(dt,J=10.7,5.2Hz,1H),0.88-0.76(m,1H),0.75-0.59(m,2H).

[0298] Example 5

[0299] This embodiment provides compound 5: N-(1-(isoquinoline-4-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0300]

[0301] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 401.46 [M+H] + .

[0302] Example 6

[0303] This embodiment provides compound 6: N-(1-(benzo[b]thiophen-3-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0304]

[0305] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 406.37 [M+H] + .

[0306] Example 7

[0307] This embodiment provides compound 7: N-(1-(isoquinoline-8-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0308]

[0309] The synthetic route of Example 7 is as follows:

[0310]

[0311] (1) Preparation of intermediate 13: 2-(isoquinoline-8-yl)acetonitrile

[0312]

[0313] Under nitrogen protection, 8-bromoisoquinoline (1.04 g, 5 mmol, 1.1 eq.), 4-isooxazoloboric acid (1.17 g, 6 mmol, 1.2 eq., CAS: 928664-98-6), KF (870 mg, 15 mmol, 3 eq.), Pd(dppf)Cl2 (365.5 mg, 0.5 mmol, 0.1 eq.), DMSO (6 mL), and H2O (2 mL) were added sequentially to a 40 mL sealed tube. The reaction was carried out at 130 °C for 16 h under nitrogen protection. After the reaction was complete, the reaction mixture was extracted with ethyl acetate and water, and the organic phase was collected and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain 0.6 g of the yellow solid title compound. MS m / z (ESI): 168.99 [M+H] + .

[0314] (2) Preparation of intermediate 14: 1-(isoquinolin-8-yl)cyclopropane-1-carboxynitrile

[0315]

[0316] Intermediate 13 (504 mg, 3 mmol, 1 eq.) was dissolved in DMF. NaH (306 mg, 3 mmol, 60% purity, 2.55 eq.) was added in three batches (5 min apart) at 0 °C, with stirring at 0 °C for 30 min. Then, 1,2-dibromoethane (0.23 mL, 3 mmol, 1 eq.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 6 h. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was extracted three times with ethyl acetate, and the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to give 210 mg of a yellowish-white product. MS m / z (ESI): 195.17 [M+H] + .

[0317] (3) Preparation of intermediate 15: 1-(isoquinolin-8-yl)cyclopropane-1-carboxamide

[0318]

[0319] Intermediate 14 (194.3 mg, 1 mmol, 1 eq.) was dissolved in isopropanol (4 mL), and NaOH (200 mg, 5 mmol, 5 eq.) was added. The mixture was stirred at 90 °C for 6 h. After the reaction was complete, the reaction mixture was extracted with DCM / water and concentrated under reduced pressure to give 189 mg of the brown solid title product. MS m / z (ESI): 213.14 [M+H] + .

[0320] (4) Preparation of intermediate 16: 1-(isoquinolin-8-yl)cyclopropyl-1-amine

[0321]

[0322] Intermediate 15 (106.2 mg, 0.5 mmol, 1 eq.) was dissolved in tert-butanol (2 mL), and 3M NaOH (1.3 mL) and NaClO (1.6 mL) were added at 0 °C. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the crude product was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 22 mg of the target product. MS m / z (ESI): 185.19 [M+H] + .

[0323] (5) Preparation of compound 7: N-(1-(isoquinolin-8-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide

[0324]

[0325] Intermediate 16 (33.9 mg, 0.184 mmol, 1 eq.), intermediate 2 (51.6 mg, 0.22 mmol, 1.2 eq.), DIPEA (71.2 mg, 0.551 mmol, 3 eq.), HATU (83.8 mg, 0.22 mmol, 1.2 eq.), and DMF (3 mL) were added sequentially to a flask, and the mixture was reacted at 50 °C for 3 h. After the reaction was complete, the reaction solution was extracted three times with DCM and saturated brine. The organic layer was collected, concentrated under reduced pressure, and purified by column chromatography to obtain 23 mg of solid product. MS m / z (ESI): 401.43 [M+H] + .

[0326] Example 8

[0327] This embodiment provides compound 8: 2-methyl-5-(4-methylpiperazin-1-yl)-N-(1-(quinolin-8-yl)cyclopropyl)benzamide

[0328]

[0329] use The above compound was prepared according to the method in Example 7. MS m / z (ESI): 401.49 [M+H] + .

[0330] Example 9:

[0331] This embodiment provides compound 9: 2-methyl-5-(4-methylpiperazin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0332]

[0333] The synthetic route of Example 9 is as follows:

[0334]

[0335] Preparation of Compound 9: 2-Methyl-5-(4-methylpiperazin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide

[0336]

[0337] Intermediate 8 (33.9 mg, 0.184 mmol, 1 eq.), intermediate 2 (51.6 mg, 0.22 mmol, 1.2 eq.), DIPEA (71.2 mg, 0.551 mmol, 3 eq.), HATU (83.8 mg, 0.22 mmol, 1.2 eq.), and DMF (3 mL) were added sequentially to a flask, and the mixture was reacted at 50 °C for 3 h. After the reaction was complete, the reaction solution was extracted three times with DCM and saturated brine. The organic layer was separated, concentrated under reduced pressure, and purified by column chromatography to obtain 51 mg of solid product. MS m / z (ESI): 401.42 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.16 (s, 1H), 8.87 (d, J = 4.4Hz, 1H), 8.67 (dd, J = 8.5, 1.4Hz, 1H), 8.04 (dd,J=8.4,1.2Hz,1H),7.76(ddd,J=8.4,6.8,1.4Hz,1H),7.69(d,J=4.4Hz,1H),7.65(ddd,J =8.3,6.8,1.3Hz,1H),6.96(d,J=8.4Hz,1H),6.84(dd,J=8.4,2.7Hz,1H),6.60(d,J=2.7Hz,1 H),3.30(s,4H),3.03(s,4H),2.27(s,3H),1.89(s,3H),1.40-1.34(m,2H),1.26-1.24(m,2H).

[0338] Example 10:

[0339] This embodiment provides compound 10: N-(benzofuran-2-yl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0340] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 400.10 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ9.04(s,1H),7.56-7.51(m,1H),7.48-7.44(m,1H),7.2 3-7.18(m,2H),7.10(d,J=8.3Hz,1H),6.98(d,J=2.6Hz,1H),6.95(dd,J=8.3,2. 7Hz,1H),6.66(s,1H),3.23(s,4H),2.83(s,4H),2.25(s,3H),2.00(dt,J=12.3, 6.9Hz, 1H), 1.47 (q, J = 5.0Hz, 2H), 1.30 ( q, J = 5.0Hz, 2H), 1.24 ( d, J = 5.0Hz, 2H).

[0341] Example 11:

[0342] This embodiment provides compound 11: N-(1-(adamantane-1-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0343]

[0344] use (600MHz, DMSO-d6) δ8.16(s,1H),7.04(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.76(d,J=2.7Hz,1H),3.16(s,3H),2.75(s,3H),2.43(s,2H ),2.20(s,3H),2.00(dt,J=12.2,6.9Hz,1H),1.94(s,3H),1.72-1.55(m,6H),1.52(s,5H),1.24(d,J=4.7Hz,3H),0.82(s,2H),0.58(s,2H).

[0345] Example 12:

[0346] This embodiment provides compound 12: 2-methyl-N-(1-(1-methyl-1H-indol-4-yl)cyclopropyl)-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0347]

[0348] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 402.02 [M+H] + .

[0349] Example 13:

[0350] This embodiment provides compound 13: N-(1-(8-chloroquinoline-4-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0351]

[0352] use The above compound was prepared according to the method in Example 9. MS m / z (ESI): 436.97 [M+H] + .

[0353] Example 14:

[0354] This embodiment provides compound 14: 2-methyl-N-(1-(7-methylbenzo[b]thiophen-3-yl)cyclopropyl)-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0355]

[0356] The sample was prepared using intermediate 5 according to the method described in Example 1. MS m / z (ESI): 419.15 [M+H] + .

[0357] Example 15:

[0358] This embodiment provides compound 15: 2-methyl-5-(4-methylpiperazin-1-yl)-N-(1-(8-methylquinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0359]

[0360] use The above compound was prepared according to the method in Example 9. MS m / z (ESI): 415.16 [M+H] + .

[0361] Example 16:

[0362] This embodiment provides compound 16: 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0363]

[0364] The synthetic route of Example 16 is as follows:

[0365]

[0366] (1) Preparation of intermediate 17: 3-(4-methyl-3-((1-(quinolin-4-yl)cyclopropyl)carbamoyl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester

[0367]

[0368] Intermediate 9 (38.1 mg, 0.1 mmol, 1 eq.), 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (39.7 mg, 0.2 mmol, 2 eq.), Cs₂CO₃ (97.8 mg, 0.3 mmol, 3 eq.), Pd(OAc)₂ (2.3 mg, 0.01 mmol, 0.1 eq.), RuPhos (9.3 mg, 0.02 mmol, 0.2 eq.), and 1,4-dioxane (1.5 mL) were added sequentially to a sealed tube. The reaction was carried out at 110 °C for 16 h under nitrogen protection. After the reaction was complete, the product was evaporated to dryness under reduced pressure to obtain 48 mg of crude solid product. MS m / z (ESI): 498.92 [M+H] + .

[0369] (2) Preparation of compound 16: 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide

[0370]

[0371] Intermediate 17 (48 mg, crude product), a 1,4-dioxane hydrochloric acid solution (4 M, 2 mL), and DCM (2 mL) were added sequentially to a flask, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the product was purified by preparative liquid chromatography and lyophilized to obtain 9.2 mg of solid product. MS m / z (ESI): 399.04 [M+H] + .

[0372] Example 17:

[0373] This embodiment provides compound 17: 2-methyl-5-(4-(methylsulfonyl)piperazin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0374]

[0375] Preparation of Compound 17: 2-Methyl-5-(4-(methylsulfonyl)piperazin-1-yl)-N-(1-(quinoline-4-yl)cyclopropyl)benzamide

[0376]

[0377] Intermediate 9 (38.1 mg, 0.1 mmol, 1 eq.), 1-(methanesulfonyl)piperazine (32.8 mg, 0.2 mmol, 2 eq.), Cs₂CO₃ (97.8 mg, 0.3 mmol, 3 eq.), Pd(OAc)₂ (2.3 mg, 0.01 mmol, 0.1 eq.), RuPhos (9.3 mg, 0.02 mmol, 0.2 eq.), and 1,4-dioxane (1.5 mL) were added sequentially to a sealed tube. The reaction was carried out at 110 °C for 16 h under nitrogen protection. After the reaction was complete, the product was purified by preparative liquid chromatography and lyophilized to obtain 13.8 mg of solid product. MS m / z (ESI): 465.17 [M+H] + .

[0378] Example 18:

[0379] This embodiment provides compound 18: 2-methyl-5-(piperazin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0380]

[0381] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 387.15 [M+H] + .

[0382] Example 19:

[0383] This embodiment provides compound 19: 2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)-5-(1,7-diazaspiro[4.4]non-7-yl)benzamide, with the following structure:

[0384]

[0385] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 427.03 [M+H] + .

[0386] Example 20:

[0387] This embodiment provides compound 21: 5-(1,4-diaza-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0388]

[0389] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 401.13 [M+H] + .

[0390] Example 21:

[0391] This embodiment provides compound 21: 5-(4-aminopiperidin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0392]

[0393] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 401.14 [M+H] + .

[0394] Example 22:

[0395] This embodiment provides compound 22: 5-(3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0396]

[0397] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 411.05 [M+H] + .

[0398] Example 23:

[0399] This embodiment provides compound 23: 5-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0400]

[0401] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 412.98 [M+H] + .

[0402] Example 24:

[0403] This embodiment provides compound 24: 2-methyl-5-(3-methylpiperazin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0404]

[0405] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 401.23 [M+H] + .

[0406] Example 25:

[0407] This embodiment provides compound 25: 5-((1S)-1,5-diazabicyclo[4.2.1]nonan-5-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0408]

[0409] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 427.10 [M+H] + .

[0410] Example 26:

[0411] This embodiment provides compound 26: 5-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-2-methyl-N-(1-(quinoline-4-yl)cyclopropyl)benzamide, with the following structure:

[0412]

[0413] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 472.18 [M+H] + .

[0414] Example 27:

[0415] This embodiment provides compound 27: 5-(3-aminopyrrolidone-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0416]

[0417] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 387.10 [M+H] + .

[0418] Example 28:

[0419] This embodiment provides compound 28: 2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)-5-(4,7-diazaspiro[2.5]oct-7-yl)benzamide, with the following structure:

[0420]

[0421] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 413.09 [M+H] + .

[0422] Example 29:

[0423] This embodiment provides compound 29: 5-(4-(dimethylamino)piperidin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0424]

[0425] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 429.07 [M+H] + .

[0426] Example 30:

[0427] This embodiment provides compound 30: 2-methyl-5-(3-(methylamino)pyrrolidone-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0428]

[0429] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 401.07 [M+H] + .

[0430] Example 31:

[0431] This embodiment provides compound 31: 2-methyl-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0432]

[0433] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 413.11 [M+H] + .

[0434] Example 32:

[0435] This embodiment provides compound 32: 5-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0436]

[0437] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 430.99 [M+H] + .

[0438] Example 33:

[0439] This embodiment provides compound 33: 5-(3-(dimethylamino)pyrrolidone-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0440]

[0441] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 415.10 [M+H] + .

[0442] Example 34:

[0443] This embodiment provides compound 34: (R)-5-(3-(dimethylamino)pyrrolidin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0444]

[0445] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 415.11 [M+H] + .

[0446] Example 35:

[0447] This embodiment provides compound 35: 2-methyl-5-(4-methyl-1,4-diazacyclohept-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0448]

[0449] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 415.03 [M+H] + .

[0450] Example 36:

[0451] This embodiment provides compound 36: 2-methyl-5-(2-methylpiperazin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0452]

[0453] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 400.98 [M+H] + .

[0454] Example 37:

[0455] This embodiment provides compound 37: 5-(4-aminopiperazin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0456]

[0457] use The above compound was prepared according to the method described in Example 16. MS m / z (ESI): 402.21 [M+H] + .

[0458] Example 38:

[0459] This embodiment provides compound 38: (S)-5-(4-ethyl-3-methylpiperazin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0460]

[0461] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 429.10 [M+H] + .

[0462] Example 39:

[0463] This embodiment provides compound 39: (R)-5-(3-(isopropyl(methyl)amino)pyrrolidin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0464]

[0465] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 443.27 [M+H] + .

[0466] Example 40:

[0467] This embodiment provides compound 40: 5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0468]

[0469] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 427.08 [M+H] + .

[0470] Example 41:

[0471] This embodiment provides compound 41: 2-methyl-5-(3-methyl-3,6-diazabicyclo[3.2.0]hept-6-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0472]

[0473] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 413.13 [M+H] + .

[0474] Example 42:

[0475] This embodiment provides compound 42: 5-(3-(4-hydroxy-4-methylpiperidin-1-yl)azacyclobutan-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0476]

[0477] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 470.99 [M+H] + .

[0478] Example 43:

[0479] This embodiment provides compound 43: 5-(3-hydroxy-3-methyl-[1,3'-azinocyclobutane]-1'-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0480]

[0481] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 443.06 [M+H] + .

[0482] Example 44:

[0483] This embodiment provides compound 44: 2-methyl-5-(3-(piperidin-1-yl)pyrrolidin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0484]

[0485] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 455.08 [M+H] + .

[0486] Example 45:

[0487] This embodiment provides compound 45: 5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0488]

[0489] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 459.19 [M+H] + .

[0490] Example 46:

[0491] This embodiment provides compound 46: 5-(3-(3-hydroxypyrrolidin-1-yl)azacyclobutan-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0492]

[0493] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 443.24 [M+H]+ .

[0494] Example 47:

[0495] This embodiment provides compound 47: 5-([1,3'-bipyrrolidine]-1'-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0496]

[0497] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 441.25 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.12(s,1H),8.86(d,J=4.4Hz,1H),8.68(d,J=8.4Hz,1H),8.05(d,J=8.4Hz,1H),7.75(ddd,J=8.4,6.8,1.4Hz,1H),7.6 8(d,J=4.4Hz,1H),7.64(ddd,J=8.2,6.7,1.3Hz,1H),6.90(d,J=8.3Hz,1H),6.43(dd,J=8.3,2.6Hz,1H),6.20(d,J=2.6Hz,1H),3.29(d,J=9.1Hz ,4H),3.22(td,J=8.8,3.0Hz,1H),3.13(td,J=9.0,6.9Hz,1H),2.96(dd,J=9.1,7.3Hz,1H),2.79(p,J=7.0Hz,1H),2.11(dtd,J=12.8,6.7,3.0Hz ,1H),1.99(dq,J=12.8,7.0,6.5Hz,1H),1.88(s,3H),1.83(dq,J=12.0, 8.7Hz,1H),1.74-1.65(m,4H),1.36(t,J=3.5Hz,2H),1.25-1.24(m,2H).

[0498] Example 48:

[0499] This embodiment provides compound 48: 5-(3,3-difluoro-4-(pyrrolidin-1-yl)piperidin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0500]

[0501] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 491.12 [M+H] + .

[0502] Example 49:

[0503] This embodiment provides compound 49: 5-(3-(3-fluoropyrrolidone-1-yl)azacyclobutan-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0504]

[0505] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 445.14 [M+H] + .

[0506] Example 50:

[0507] This embodiment provides compound 50: 5-((7S,8aR)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0508]

[0509] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 443.12 [M+H] + .

[0510] Example 51:

[0511] This embodiment provides compound 51: 5-(3-(3-hydroxypiperidin-1-yl)azacyclobutan-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0512]

[0513] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 457.20 [M+H] + .

[0514] Example 52:

[0515] This embodiment provides compound 52: 5-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0516]

[0517] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 445.13 [M+H] + .

[0518] Example 53:

[0519] This embodiment provides compound 53: 2-methyl-5-(4-(3-(methanesulfonyl)propyl)piperazin-1-yl)-N-(1-(quinoline-4-yl)cyclopropyl)benzamide, with the following structure:

[0520]

[0521] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 506.11 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.16 (s, 1H), 8.87 (d, J = 4.4Hz, 1H), 8.67 (dd, J = 8.4, 1.4Hz, 1H), 8.04 (dd, J = 8.5, 1.3 Hz,1H),7.76(ddd,J=8.3,6.8,1.4Hz,1H),7.69(d,J=4.4Hz,1H),7.66-7.62(m,1H),6.96(d,J=8.4Hz,1H),6. 84(dd,J=8.4,2.7Hz,1H),6.60(d,J=2.6Hz,1H),3.30(s,4H),3.15-3.09(m,2H),3.01(t,J=5.0Hz,3H),2.98( s,3H),2.47(t,J=5.0Hz,3H),2.41(t,J=7.0Hz,1H),1.90-1.84(m,4H),1.39-1.34(m,2H),1.26-1.24(m,2H).

[0522] Example 54:

[0523] This embodiment provides compound 54: 5-(3-(3,3-difluoropyrrolidin-1-yl)azacyclobutan-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0524]

[0525] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 463.04 [M+H] + .

[0526] Example 55:

[0527] This embodiment provides compound 55: 2-methyl-5-(1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0528]

[0529] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 441.15 [M+H] + .

[0530] Example 56:

[0531] This embodiment provides compound 56: 5-(4-(3-hydroxypyrrolidin-1-yl)piperidin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0532]

[0533] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 471.18 [M+H] + .

[0534] Example 57:

[0535] This embodiment provides compound 57: 2-methyl-5-(6-methyl-2,6-diazaspiro[3.4]oct-2-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0536]

[0537] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 427.19 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ9.13(s,1H),8.86(d,J=4.4Hz,1H),8.65(dd,J=8.5,1.4Hz,1H),8.04(dd,J=8.5,1 .3Hz,1H),7.76(ddd,J=8.3,6.8,1.4Hz,1H),7.68(d,J=4.4Hz,1H),7.65(ddd,J=8.3,6.8,1.3Hz,1H),6.91 (d,J=8.2Hz,1H),6.33(dd,J=8.2,2.5Hz,1H),6.12(d,J=2.5Hz,1H),3.66(d,J=7.1Hz,2H),3.59(d,J=7.1H z,2H),2.68(s,2H),2.27(s,3H),2.01(t,J=7.1Hz,2H),1.87(s,3H),1.42-1.32(m,2H),1.26-1.22(m,4H).

[0538] Example 58:

[0539] This embodiment provides compound 58: 2-methyl-5-(4-(morpholinomethyl)piperidin-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0540]

[0541] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 485.01 [M+H] + .

[0542] Example 59:

[0543] This embodiment provides compound 59: 5-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0544]

[0545] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 458.22 [M+H] + .

[0546] Example 60:

[0547] This embodiment provides compound 60: 2-methyl-5-((3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0548]

[0549] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 427.15 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.13(s,1H),8.87(d,J=4.4Hz,1H),8.68(dd,J=8.5,1.4Hz,1H),8.05(dd,J=8.4,1.3Hz,1H),7.76(ddd, J=8.3,6.8,1.4Hz,1H),7.69(d,J=4.4Hz,1H),7.64(ddd,J=8.3,6.8,1.3Hz,1H),6.90(d,J=8.3Hz,1H),6.49(dd,J=8.3,2.6Hz, 1H),6.27(d,J=2.6Hz,1H),3.21(d,J=10.1Hz,1H),3.16(t,J=8.8Hz,1H),3.02-2.93(m,3H),2.89-2.77(m,2H),2.27(s,3H),2. 26-2.20(m,1H),2.03-1.98(m,1H),1.88(s,3H),1.56(dddd,J=12.6,9.9,7.4,5.4Hz,1H),1.40-1.33(m,2H),1.26-1.24(m,2H).

[0550] Example 61:

[0551] This embodiment provides compound 61: 5-(3-(4-fluoropiperidin-1-yl)azacyclobutan-1-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0552]

[0553] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 459.13 [M+H] + .

[0554] Example 62:

[0555] This embodiment provides compound 62: 5-([1,3'-adiazonylbutane]-1'-yl)-2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0556]

[0557] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 413.21 [M+H] + .

[0558] Example 63:

[0559] This embodiment provides compound 63: 2-methyl-5-(3-(4-methylpiperazin-1-yl)azacyclobutane-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0560]

[0561] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 456.25 [M+H] + .

[0562] Example 64:

[0563] This embodiment provides compound 64: 2-methyl-5-(3-(piperidin-1-yl)azacyclobutane-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0564]

[0565] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 441.17 [M+H] + .

[0566] Example 65:

[0567] This embodiment provides compound 65: 2-methyl-5-(3-(3-oxopiperazin-1-yl)azacyclobutane-1-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0568]

[0569] use The above compound was prepared according to the method described in Example 17. MS m / z (ESI): 455.04 [M+H] + .

[0570] Example 66:

[0571] This embodiment provides compound 66: 2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide, with the following structure:

[0572]

[0573] The synthetic route of Example 66 is as follows:

[0574]

[0575] (1) Preparation of intermediate 18: tert-butyl 4-(4-methyl-3-((1-(quinolin-4-yl)cyclopropyl)carbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0576]

[0577] Intermediate 9 (38.1 mg, 0.1 mmol, 1 eq.), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (37.1 mg, 0.12 mmol, 1.2 eq., CAS: 286961-14-6), Cs₂CO₃ (65.2 mg, 0.2 mmol, 2 eq.), Pd₂(dba)₃ (9.1 mg, 0.01 mmol, 0.1 eq.), XPhos (9.5 mg, 0.02 mmol, 0.2 eq.), and 1,4-dioxane (1.5 mL) were added sequentially to a sealed tube. The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was complete, the product was evaporated to dryness under reduced pressure to obtain 52 mg of crude solid product. MS m / z (ESI): 484.05 [M+H] + .

[0578] (2) Preparation of compound 66: 2-methyl-N-(1-(quinolin-4-yl)cyclopropyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide

[0579]

[0580] Intermediate 18 (52 mg, crude product), a 1,4-dioxane hydrochloric acid solution (4 M, 2 mL), and DCM (2 mL) were added sequentially to a flask, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the product was purified by preparative liquid chromatography and lyophilized to obtain 11.3 mg of solid product. MS m / z (ESI): 384.06 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ9.27(s,1H),8.87(d,J=4.4Hz,1H),8.66(d,J=8.3Hz,1H),8.05 (d,J=8.4Hz,1H),7.77(ddd,J=8.4,6.7,1.4Hz,1H),7.70(d,J=4.4Hz,1H),7.67-7.63(m ,1H),7.32(dd,J=8.0,2.1Hz,1H),7.13-7.08(m,2H),6.10(d,J=3.5Hz,1H),3.45(s,2H) ,3.00(t,J=5.7Hz,2H),2.34(s,2H),1.99(s,3H),1.42-1.34(m,2H),1.27-1.25(m,2H).

[0581] Example 67:

[0582] This embodiment provides compound 67: 2-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(1-(quinolin-4-yl)cyclopropyl)benzamide, with the following structure:

[0583]

[0584] use The above compound was prepared according to the method described in Example 66. MS m / z (ESI): 398.17 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.26 (s, 1H), 8.87 (d, J = 4.4Hz, 1H), 8.66 (dd, J = 8.4, 1.4Hz, 1H), 8.05 (dd, J = 8 .5,1.3Hz,1H),7.77(ddd,J=8.3,6.8,1.4Hz,1H),7.70(d,J=4.4Hz,1H),7.66(ddd,J=8.3,6.8,1.3Hz, 1H),7.32(dd,J=7.9,2.1Hz,1H),7.14-7.06(m,2H),6.07(s,1H),3.01(d,J=3.1Hz,2H),2.56(t,J=5. 7Hz,2H),2.39(tt,J=3.7,2.1Hz,2H),2.28(s,3H),1.99(s,3H),1.42-1.35(m,2H),1.27-1.25(m,2H).

[0585] Example 68:

[0586] This embodiment provides compound 68: N-(1-(1H-indazol-7-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0587]

[0588] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 390.12 [M+H] + .

[0589] Example 69:

[0590] This embodiment provides compound 69: N-(1-(7-methoxy-2,3-dihydro-1H-inden-4-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0591]

[0592] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 420.19 [M+H] + .

[0593] Example 70:

[0594] This embodiment provides compound 70: N-(1-(7-hydroxy-2,3-dihydro-1H-inden-4-yl)cyclopropyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide, with the following structure:

[0595]

[0596] use The above compound was prepared according to the method in Example 1. MS m / z (ESI): 406.17 [M+H] + .

[0597] Test Example 1. Protein Level Enzyme Activity Test

[0598] 1. The SARS-CoV-2PLpro catalytic domain was recombinantly expressed to obtain the reactive protein.

[0599] 2. Substrate: Z-Arg-Leu-Arg-Gly-Gly-AMC (GLPBIO, part number GA23715).

[0600] 3. Buffer solution: 50mM HEPES, 10mM DTT, 0.1mM EDTA, pH 7.2.

[0601] 4.384 orifice plate: Greiner, part number 784076.

[0602] 5. Inhibitor compounds.

[0603] 6. Prepare stock solutions of compounds with a single concentration or a certain concentration gradient dissolved in DMSO.

[0604] 7. Mix the protein and compound and incubate for 10 minutes.

[0605] 8. Add 15 μL of the protein and compound mixture to each well of a 384-well plate.

[0606] 9. Prepare an 80 μM substrate working solution.

[0607] 10. Add 5 μL of 80 μM substrate working solution to each well and incubate for 10 minutes.

[0608] 11. Detection: BioTek synergy NEO2, Ex: 360nM / Em: 460nm.

[0609] 12. Data Analysis: Use Prism to perform nonlinear regression fitting on the data and calculate IC. 50 The values ​​are shown in Table 1.

[0610] Table 1. Inhibitory activity against papain

[0611]

[0612]

[0613] Note: +: 0.1μM <IC50≤1μM;++:0.04μM<IC50≤0.1μM;+++:IC50≤0.04μM

[0614] Test Example 2. Inhibition of SARS-CoV-2 infection activity in Vero E6 cells

[0615] 1. Cell line: African green monkey kidney cells Vero E6 (ATCC, CRL-1586).

[0616] 2. Virus strains: 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).

[0617] 3. Positive control: Ensitrelvir (trade code HY-143216, MedChemExpress LLC).

[0618] 4. Infection dose: MOI (multiple of infection) = 0.01.

[0619] 5. The day before, add 250 μL of cells to each well of a 48-well plate, so that the cell count in each well is approximately 5 × 10⁻⁶. 4 .

[0620] 6. Perform serial dilutions (1:3) at the highest concentration of 10 μM, with three replicates for each concentration.

[0621] 7. Add the virus strain (MOI=0.01) to each well to infect the cells for 48 hours.

[0622] 8. After 48 hours, supernatant RNA was extracted using the QIAamp Viral RNA Mini Kit (Qiagen), and viral copy number was detected by qRT-PCR. The half-maximal effective concentration (EC50) was calculated based on the absolute copy number. 50 The results are shown in Table 2.

[0623] Table 2. Inhibitory activity of the virus strain in VeroE6 cells.

[0624]

[0625] Note: +: 0.1μM <IC50≤1μM;++:0.04μM<IC50≤0.1μM;+++:IC50≤0.04μM

[0626] Test Example 3. Liver Microsomal Stability Test

[0627] 1. Preheat PBS (pH 7.4).

[0628] 2. Preparation of intermediate solutions for test and positive reference compounds

[0629] 2.1 500 μM intermediate solution: Add 5 μL of 10 mM compound stock solution and positive reference compound to 95 μL LDMSO;

[0630] 2.2 1.5 μM intermediate solution in liver microsomes (0.75 mg / mL): 1.5 μL of 500 μM intermediate solution and 18.75 μL of 20 mg / mL liver microsomes were added to 479.75 μL of PBS.

[0631] 3. Prepare a NADPH stock solution (6 mM, 5 mg / mL) by dissolving NADPH in PBS.

[0632] 4. Dispense 30 μL of 1.5 μM intermediate solution containing 0.75 mg / mL microsome solution into assay plates designated for different time points (0, 5, 15, 30, 45 minutes).

[0633] 5. Incubate the plate at 37°C for 5 minutes.

[0634] 6. For 0 minutes, before adding 15 μL of NADPH stock solution (6 mM), add 150 μL of stop solution containing internal standard acetonitrile:methanol (1:1) to the well.

[0635] 7. For other time points, add 15 μL of NADPH stock solution (6 mM) to the well to start the reaction and begin timing.

[0636] 8. At 5, 15, 30, and 45 minutes, add 150 μL of the internal standard acetonitrile:methanol (1:1) stop solution to the wells of the corresponding plates to stop the reaction.

[0637] 9. After termination, shake the plate for 10 minutes (600 rpm), then centrifuge at 4000 rpm for 15 minutes.

[0638] 10. Transfer 80 μL of supernatant from each well to a 96-well plate containing 140 μL of pure water for LC / MS analysis.

[0639] Table 3 Results of Liver Microsome Stability Test

[0640]

[0641]

[0642] Note: Rat means rat; Human means human; t 1 / 2 Clint indicates half-life; Clint indicates the elimination rate; Eh indicates the elimination ratio.

[0643] Test Example 4. Pharmacokinetic Study

[0644] Rats routine PK test:

[0645] 1. The experimental design is shown in the table below:

[0646]

[0647] Notes: **: Blood samples were collected from 3 rats at each time point. *: Animals in the oral administration group were fasted overnight (10-14 hours) before administration and fed 4 hours after administration.

[0648] 2. Preparation of drug delivery formulations:

[0649] Solvent formulation: 10% DMSO, 5% ethanol, 5% Cremophor EL and 80% deionized water. Weigh 6.68 mg of the test sample into a suitable container, measure 1.316 mL of DMSO, vortex for 1 min, sonicate for 10 min to obtain a 5 mg / mL clear DMSO stock solution.

[0650] Take 1 mL of 5 mg / mL DMSO stock solution, add 0.5 mL of ethanol, vortex for 1 min, then 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 drug formulation with a concentration of 0.5 mg / mL. Prepare immediately before use and store at room temperature after preparation.

[0651] 3. Animal selection:

[0652] Before the study began, all animals suitable for the experiment were weighed. After removing a certain number of animals that were too large and / or too small, the animals used for the experiment were weighed within ±20% of their average weight.

[0653] 4. Animal husbandry:

[0654] The test animals will be housed in rat cages (2–5 animals / cage), with approximately 12 hours / 12 hours of alternating light and dark lighting per day. The dark period may be interrupted intermittently as needed for the research activities. The ambient temperature and relative humidity of the animal room will be monitored daily and maintained within the range of 20–26°C and 40–70% RH.

[0655] 5. Route of administration:

[0656] The medication was administered orally via gavage, following the route of administration as intended for clinical use.

[0657] 6. Observe from the cage side:

[0658] During the experiment, all animals should be observed at least twice daily at their cages (observation may be conducted during sampling). Observations should include morbidity, mortality, damage, and the availability of food and water. Animals in poor health should be marked and observed further; euthanasia may be necessary in some cases.

[0659] 7. Biological sample collection:

[0660] Oral sampling: A total of 8 sampling time points were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.

[0661] Plasma: Blood was collected by puncture after euthanasia of the animal. The sample was placed in a tube containing K2-EDTA and stored on ice until centrifugation. Within 1 hour of blood sample collection, the sample was centrifuged at 6800g for 6 minutes at 2-8°C until plasma samples were obtained, which were then frozen at approximately -80°C.

[0662] 8. Biological sample analysis

[0663] Analyze the compounds. Simultaneously evaluate the intra-day accuracy of the analytical batch using quality control samples. Acceptance criteria: The accuracy of at least 50% of the quality control samples at each quality control concentration level, and at least 66.7% of the quality control samples at all quality control concentration levels, should be between 80% and 120% (75% to 125% for tissues).

[0664] When calculating pharmacokinetic parameters, BLQ concentration data before the time to peak concentration (Tmax) after oral administration are calculated as "0", and BLQ concentration data after Tmax are not included in the calculation.

[0665] Using Phoenix The non-compartmental model statistical moment method of software 7.0 calculates the following main pharmacokinetic parameters: Tmax, Cmax, AUC(0-t), T1 / 2, etc.

[0666] 9. Final disposal of animals

[0667] All surviving laboratory animals were euthanized at the end of the experiment (using a special euthanasia box for carbon dioxide euthanasia).

[0668] 10. Analytical Methods

[0669] Analytical instrument: LC-MS / MS-12 (TQ5500, Triple quad);

[0670] Eppendorf pipette

[0671] Oscillator: 5810R, Eppendorf

[0672] Centrifuges: 420R, 220R, Eppendorf

[0673] (If necessary, other suppliers or other models of equipment may be used)

[0674] Sample processing:

[0675] 1) Take 30 μL of the mixed standard curve sample, quality control sample, blank sample, zero concentration sample and test sample.

[0676] 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). For blank samples and ULOQ without IS samples (if necessary), add the same volume of acetonitrile.

[0677] 3) Vortex mix for 1 minute

[0678] 4) Centrifuge at 4℃ for 7 minutes (18000g)

[0679] 5) Take 200 μL of supernatant and add it to the corresponding 96-well sample plate.

[0680] 6) Inject 4 μL of sample and perform LC-MS / MS analysis.

[0681] Table 4. In vivo oral drug metabolism kinetics data of the compounds

[0682]

[0683] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. The compounds described below, or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, 2. The compounds described below, or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, 3. A pharmaceutical composition comprising at least one compound of claim 1 or 2, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

4. Use of the compound of claim 1 or 2, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 3, 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.

5. The use as described in claim 4, wherein, The disease or condition mentioned is selected from respiratory diseases, sepsis, septic shock, and feline infectious peritonitis.

6. The use as described in claim 5, wherein, The respiratory illness is a simple infection.

7. The use as described in claim 6, wherein, The uncomplicated infection is selected from fever, cough, and sore throat.

8. The use as described in claim 5, wherein, The respiratory disease mentioned is pneumonia.

9. The use as described in claim 5, wherein, The respiratory illness is an acute respiratory infection.

10. The use as described in claim 5, wherein, The respiratory disease is severe acute respiratory infection (SARI).

11. The use as described in claim 5, 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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