Novel PLpro protein inhibitor and application thereof

Abstract

The invention discloses a novel PLpro protein inhibitor and application thereof. The inhibitor has the following structure, has better inhibitory activity, can be used for reducing and / or inhibiting coronavirus replication and preventing and / or treating diseases or symptoms caused by virus infection or related to virus infection, and has very good application prospects and values in the field of medicines. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and particularly relates to a novel PLpro protein inhibitor and its application. Background Art

[0002] Coronaviruses mainly invade the respiratory tract, gastrointestinal tract, and nervous system, etc., often causing respiratory and intestinal diseases, nervous system symptoms, and myocarditis. The novel coronavirus (SARS-CoV-2) is a new strain of coronavirus, which has caused the novel coronavirus disease (COVID-19). The infections of the above viruses have seriously affected human health.

[0003] Coronaviruses achieve virus replication through the coordinated work of key proteins such as its main protease (Main Protease, abbreviated as Mpro or 3CLpro), RNA-dependent RNA polymerase (abbreviated as RdRp), and papain-like protease (abbreviated as PLpro). Drug research on these key proteins helps to better cope with the challenge of coronaviruses repeatedly invading human society. Due to the uniqueness of the PLpro structure, there are very few reports on candidate drugs for it. Summary of the Invention

[0004] To overcome the deficiencies of the prior art, the present invention provides a novel PLpro protein inhibitor and its application.

[0005] In the first aspect of the present invention, a compound is provided, which has the following structure:

[0006]

[0007] Wherein,

[0008] Ring A is a carbocyclic ring or a heterocyclic ring;

[0009] Ring B is a bicyclic or tricyclic carbocyclic ring or a heterocyclic ring;

[0010] L1 is -(C 0-6 alkylene)-Q1-(C 0-6 alkylene)-, and Q1 is selected from: a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C 3-6 cycloalkylene, C 6-10Arylene, 3- to 10-membered heteroarylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(O)2-, -N(R6)-, -N(R6)CO-, -CON(R6)-, -S(O)2-, -SO-, -N(R6)S(O)2-, -N=C(R6)-, -N(R6)-C(=NR7)-; R6 and R7 are independently selected from: -H, C 1-10 alkyl, -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, alkyl, cycloalkyl, aryl, heterocyclic group are optionally substituted by a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); R x and R y are independently selected from: -H, C1-C 10 alkyl;

[0011] L2 is -(C 0-6 alkylene)-Q2-(C 0-6 alkylene)-, and Q2 is selected from: a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C 3-6 cycloalkylene, C 6-10 arylene, 3- to 10-membered heteroarylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(O)2-, -N(R8)-, -N(R8)CO-, -CON(R8)-, -S(O)2-, -SO-, -N(R8)S(O)2-, -N═C(R8)-, -N(R8)-C(═NR9)-; R8 and R9 are independently selected from: -H, C 1-10 alkyl, -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, alkyl, cycloalkyl, aryl, and heterocyclic group are optionally substituted with a group selected from: ═O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); R x and R y are independently selected from: -H, C1-C 10 alkyl;

[0012] L3 is -(C 0-6 alkylene)-Q3-(C 0-6 alkylene)-, and Q3 is selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C 3-6 cycloalkylene, C 6-10 arylene, 3- to 10-membered heteroarylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(O)2-, -N(R 10 )-, -N(R 10 )CO-, -CON(R 10 )-, -S(O)2-, -SO-, -N(R 10 )S(O)2-, -N=C(R 10 )-, -N(R 10 )-C(=NR 11 )-; R 10 and R 11 are independently selected from: -H, C 1-10 alkyl, -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, alkyl, cycloalkyl, aryl, heterocyclic group are optionally substituted with a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4 - 10 - membered heterocyclic group); R x and R y are independently selected from: -H, C1 - C 10 alkyl;

[0013] R1 is one or more independent substituents on the A ring, selected from: -H, =O, halogen, -CN, -NO2, -CF3, -OCF3, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, and heterocyclic group are optionally substituted with a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group);

[0014] R2 is one or more independent substituents on the B ring, selected from: -H, =O, halogen, -CN, -NO2, -CF3, -OCF3, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, heterocyclic group are optionally substituted with a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group);

[0015] R3, R4, R5 are independently selected from: -H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -(C 0-10 alkylene)-(C3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, and heterocyclic group are optionally substituted with a group selected from the following: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group).

[0016] In some embodiments of the present invention, Q1 is C 3-6 subcycloalkyl or 3- to 6-membered subheterocyclic group; wherein one or more H in the subcycloalkyl and subheterocyclic group are optionally substituted with a group selected from the following: =O, halogen, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10(alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4 - 10 - membered heterocyclic group).

[0017] More specifically, Q1 has the following structure: wherein, W1 is selected from: -C(R W1 R W1 ')-, -O-, -S-, -C(O)-, -C(S)-, -N(R W1 ), -, -S(O)2-, -C(=CR W1 ), C 1-3 alkylene; R W1 , R W1 ' are independently selected from: -H, halogen, C 1-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl);

[0018] W2 is selected from: -C(R W2 R W2 ')-, -O-, -S-, -C(O)-, -C(S)-, -N(R W2 )-, -S(O)2-, -C(=CR W2 )-, C 1-3 alkylene; R W2 , R W2 ' are independently selected from: -H, halogen, C 1-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl).

[0019] In some embodiments of the present invention, the moiety has the following structure:

[0020] More specifically, R W1 , R W2 are independently selected from: -H, halogen, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 haloalkyl.

[0021] In some embodiments of the present invention, the moiety has the following structure: In particular

[0022] In some embodiments of the present invention, L1 is

[0023] In some embodiments of the present invention, L1 is wherein, RW1 , R W2 is independently selected from: -H, -CN, C 1-10 alkyl, C 1-10 haloalkyl; for example, L1 is

[0024] In some embodiments of the present invention, L1 is

[0025] In some embodiments of the present invention, L3 is a single bond.

[0026] In some embodiments of the present invention, the compound has the following structure:

[0027]

[0028] In some embodiments of the present invention, Q2 is selected from: -N(R8)-, -N(R8)CO-, -CON(R8)-, -C(O)-, -N(R8)S(O)2-, -N(R8)-C(=NR9)-.

[0029] Specifically, R8 and R9 are independently selected from: -H, C 1-6 alkyl.

[0030] In some embodiments of the present invention, L2 is -N(R8)CO-, such as -N(H)CO-.

[0031] In some embodiments of the present invention, the compound has the following structure:

[0032]

[0033] Specifically, ring A is a 5- to 14-membered at least partially unsaturated carbocyclic or heterocyclic ring; in some embodiments of the present invention, ring A is an aromatic ring, such as In some embodiments of the present invention, ring A is a partially unsaturated bicyclic carbocyclic ring, such as In some embodiments of the present invention, ring A is a monocyclic heterocyclic ring, such as In some embodiments of the present invention, ring A is a bicyclic heterocyclic ring, such as

[0034] In some embodiments of the present invention, ring A is a tricyclic ring, such as

[0035] Preferably, ring A is a benzene ring, a naphthalene ring or a bicyclic heteroaromatic ring.

[0036] In some embodiments of the present invention, ring A is a naphthalene ring or a 6,6-fused bicyclic nitrogen-containing heteroaromatic ring; more specifically, The moiety has the following structure: wherein X1, X2, X3, X4, X5, X6, X7, and X8 are independently selected from: CH or N; more specifically, The moiety can be For example In particular

[0037] In some embodiments of the present invention, the compound has the following structure:

[0038]

[0039] Specifically, R1 can be selected from: -H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl), -CON(C 0-6 alkyl)(C 0-6 alkyl), -N(H)SO2(C 1-6 alkyl), -SO2N(C 0-6 alkyl)(C 0-6 alkyl); wherein one or more H in the alkyl are optionally substituted with a group selected from the following: halogen, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl).

[0040] More specifically, R1 can be selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2,

[0041] In some embodiments of the present invention, R1 is -H.

[0042] Specifically, ring B is a bicyclic or tricyclic at least partially unsaturated carbocyclic or heterocyclic ring; in some embodiments of the present invention, ring B is an aromatic ring, such as In some embodiments of the present invention, Ring B is a partially unsaturated bicyclic carbocyclic ring, such as In some embodiments of the present invention, Ring B is a bicyclic heterocyclic ring, such as

[0043] In some embodiments of the present invention, Ring B is a tricyclic heterocyclic ring, such as

[0044] Preferably, Ring B is a naphthalene ring, a bicyclic heterocyclic ring (such as a 6,6-fused bicyclic heterocyclic ring, a 5,6-fused bicyclic heterocyclic ring, a 6,7-fused bicyclic heterocyclic ring), or a bicyclic partially unsaturated carbocyclic ring.

[0045] In some embodiments of the present invention, part has the following structure: wherein, Y1, Y2, Y3, and Y4 are independently selected from: CH, N; Ring J is a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring.

[0046] In some embodiments of the present invention, Y1 is N, and Y2, Y3, and Y4 are all CH.

[0047] In some embodiments of the present invention, Y2 is N, and Y1, Y3, and Y4 are all CH.

[0048] In some embodiments of the present invention, Y1 and Y3 are N, and Y2 and Y4 are all CH.

[0049] In some embodiments of the present invention, Y1 and Y4 are N, and Y2 and Y3 are all CH.

[0050] Specifically, Ring J has the following structure:

[0051] Specifically, part has the following structure:

[0052] In some embodiments of the present invention, part has the following structure:

[0053]

[0054]

[0055]

[0056] Specifically, the part is identical in structure to the part (as described above), with the connection sites swapped left and right.

[0057] Specifically, R2 can be selected from: -H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl), -CON(C 0-6 alkyl)(C 0-6 alkyl), -N(H)SO2(C 1-6 alkyl), -SO2N(C 0-6 alkyl)(C 0-6 alkyl); wherein one or more H in the alkyl are optionally substituted with a group selected from: halogen, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl).

[0058] More specifically, R2 can be selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2,

[0059] In some embodiments of the present invention, R2 is -H.

[0060] In some embodiments of the present invention, the compound has the following structure:

[0061]

[0062] Specifically, R3 can be selected from: -H, C 1-6 alkyl; in some embodiments of the present invention, R3 is -H.

[0063] Specifically, R4 can be selected from: -H, C 1-6 alkyl; in some embodiments of the present invention, R4 is -H.

[0064] In some embodiments of the present invention, the compound has the following structure:

[0065]

[0066] Specifically, R5 can be selected from: -H, C 1-6 alkyl; in some embodiments of the present invention, R5 is C 1-3 alkyl, such as methyl, ethyl.

[0067] In some embodiments of the present invention, the compound has the following structure:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] In the second aspect of the present invention, there are provided pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the compound described in the first aspect.

[0081] In the third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0082] Specifically, in this pharmaceutical composition, the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof can be used alone or in combination with other types of active ingredients.

[0083] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of the following: fillers, binders, lubricants, disintegrants, antioxidants, buffers, bacteriostatic agents, suspending agents, solubilizers, thickeners, stabilizers, preservatives, etc.

[0084] Specifically, the pharmaceutical composition may be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory administration, etc.).

[0085] In some embodiments of the present invention, the pharmaceutical composition is an oral preparation, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, oral tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled release preparations (e.g., immediate release preparations, sustained release preparations, sustained release microcapsules).

[0086] In some embodiments of the present invention, the pharmaceutical composition is an injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection).

[0087] In other embodiments of the present invention, the pharmaceutical composition is an intravenous drip preparation, a transdermal absorption preparation, a lotion, a suppository (e.g., rectal suppository, vaginal suppository), a nasal preparation, a pulmonary preparation (inhalant), an eye drop, etc.

[0088] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is further divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a capsule, a tablet or any dosage form; alternatively, the unit dosage form may also be a packaged preparation, such as tablets, capsules and powders packaged in vials or ampoules.

[0089] Specifically, the amount of the active ingredient in the unit dosage preparation may vary or be adjusted between 0.1 mg and 1000 mg (e.g., 0.1, 1, 5, 10, 20, 40, 50, 100, 200, 400, 500, 1000 mg), depending on the specific application and potency of the active ingredient. If necessary, the composition may further contain other suitable therapeutic agents.

[0090] In the fourth aspect of the present invention, there is provided the use of the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound as a PLpro inhibitor, such as in the preparation of an antiviral drug.

[0091] In some embodiments of the present invention, the virus is a coronavirus, such as, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2, etc., especially SARS-CoV, MERS-CoV, SARS-CoV-2.

[0092] In the fifth aspect of the present invention, there is provided the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof in the preparation of a medicament for preventing and / or treating a disease or disorder caused by or associated with a viral infection.

[0093] In some embodiments of the present invention, the virus is a coronavirus, such as, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2, etc., especially SARS-CoV, MERS-CoV, SARS-CoV-2.

[0094] Specifically, the disease or disorder is a disease or disorder caused by or associated with a coronavirus infection, such as a respiratory disease, a digestive disease, a cardiovascular disease, a neurological disease, an eye disease, etc., especially a respiratory disease.

[0095] Specifically, the disease or disorder is a respiratory disease, such as pneumonia.

[0096] Specifically, the disease or disorder is a digestive disease, such as infectious gastroenteritis, and patients may present symptoms such as abdominal pain, diarrhea, nausea, vomiting, etc.

[0097] Specifically, the disease or disorder is a cardiovascular disease, such as acute coronary syndrome, myocarditis, stress (takotsubo) cardiomyopathy, arrhythmia and thromboembolic diseases, etc.

[0098] Specifically, the disease or disorder is a neurological disease, such as encephalitis, acute myelitis and acute disseminated encephalomyelitis, parainfectious encephalopathy, central nervous system demyelinating diseases, peripheral neuropathy, etc.

[0099] Specifically, the disease or disorder is an eye disease, such as conjunctivitis, scleritis, uveitis, lacrimal gland inflammation, retinal vascular occlusion, optic neuritis, orbital neuropathy, etc.

[0100] Preferably, the disease or disorder is Coronavirus Disease 2019 (COVID-19), Severe Acute Respiratory Syndromes (SARS), Middle East respiratory syndrome (MERS), etc.

[0101] In a sixth aspect of the present invention, there is provided a method for killing a virus, which comprises the step of administering an effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or the pharmaceutical composition described in the third aspect.

[0102] In some embodiments of the present invention, the method is carried out in vivo.

[0103] In some embodiments of the present invention, the method is carried out in vitro.

[0104] Specifically, the virus is a coronavirus, as described above.

[0105] In a seventh aspect of the present invention, there is provided a method for preventing and / or treating a disease caused by a viral infection, which comprises the step of administering an effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or the pharmaceutical composition described in the third aspect to a subject in need thereof.

[0106] Specifically, the virus is a coronavirus, as described above.

[0107] Specifically, the disease or disorder is a disease or disorder caused by or associated with a coronavirus infection, such as COVID-19, SARS, MERS, etc.

[0108] Specifically, the subject is an animal; in some embodiments of the present invention, the subject is a mammal, such as a human, a monkey, a cat, a dog, a mouse, a bat, etc.; in some embodiments of the present invention, the subject is a bird.

[0109] The present invention provides a novel PLpro protein inhibitor, which has good inhibitory activity, can be used to reduce and / or inhibit coronavirus replication, prevent and / or treat diseases or disorders caused by or associated with viral infections, can fill the gap in antiviral drugs, and has very good application prospects and value in the pharmaceutical field. Detailed embodiments

[0110] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as those commonly understood by those skilled in the technical field to which the present invention pertains.

[0111] In the present invention, the term "aliphatic group" refers to a straight-chain or branched hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a cycloalkyl group (also referred to herein as "alicyclic", "cycloalkyl") that is completely saturated or contains one or more unsaturated units, which is connected to other parts of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0112] The term "carbocyclic ring" is composed entirely of carbon atoms and can be divided into alicyclic rings and aromatic rings.

[0113] The term "alkyl" refers to a straight-chain or branched hydrocarbon chain radical that does not contain unsaturated bonds, and this hydrocarbon chain radical is connected to other parts of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. In the present invention, C0 alkyl refers to H, that is, C 0-10 alkyl (or C0-C 10 alkyl) includes H and C 1-10 alkyl (or C1-C 10 alkyl).

[0114] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by removing two hydrogen atoms from an alkane molecule, which can be straight-chain or branched and is connected to other parts of the molecule by a single bond. In this article, typical alkylene contains 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, C0 alkylene refers to a single bond, that is, C 0-10 alkylene (or C0-C 10 alkylene) includes a single bond and C 1-10 alkylene (or C1-C 10 alkylene).

[0115] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and / or fused rings, having 3 - 18 carbon atoms, preferably 3 - 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl, etc.

[0116] The term "alkoxy" refers to a substituent formed by replacing the hydrogen in a hydroxyl group with an alkyl group, such as an alkoxy group containing 1 - 10 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, etc.

[0117] The term "alkylamino" refers to a substituent formed by replacing one or two hydrogens in an amino group (-NH2) with an alkyl group, such as an alkylamino group containing 1 - 10 carbon atoms, for example

[0118] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0119] The term "haloalkyl" refers to a group formed by replacing one or more hydrogens in an alkyl group with a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), such as -CHF2, -CH2F, -CF3, -CH2 - CF3, -CH2CH2 - CF3, -CH2CH2CH2 - CF3.

[0120] The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing monoaryl groups and / or fused aryl groups, such as those containing 1 - 3 monocyclic or fused rings and 6 - 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. The C6 - C 12 aryl in the present invention refers to an aryl group containing 6 - 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0121] The term "heterocyclic group" refers to a 3- to 18-membered non-aromatic ring group that contains 2 to 17 carbon atoms and 1 to 10 heteroatoms. The heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, spiro, or bridged ring systems. The heterocyclic group can be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryls in the compounds of the present invention contain 1, 2, or 3 heteroatoms selected from N, O, S, and P atoms. The heteroaryls include, for example, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indazinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furanopyridyl. Suitable heterocycloalkyls in the compounds of the present invention contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms. The heterocycloalkyls include, for example, pyrrolidinyl, tetrahydrofuryl, dihydrofuran, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thiiranyl, azepinyl, oxazepinyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinuclidinyl. In the present invention, for an optionally substituted heterocyclic group, the position of substitution can be any suitable carbon atom or heteroatom. For example, for where the position of substitution of R can be any suitable carbon atom or nitrogen atom, and it can be, for example

[0122] In the present invention, "D" refers to deuterium; "substituted with deuterium" means replacing one or more hydrogen atoms with the corresponding number of deuterium atoms.

[0123] It should be recognized that depending on the source of the chemical materials used in the synthesis, there may be some variation in the natural isotope abundances in the synthesized compounds. Accordingly, the compounds of the present invention will inherently contain minor amounts of deuterated isotopologues. Despite such variation, the concentrations of the stable hydrogen and carbon isotopes at natural abundance are low and insignificant compared to the degree of stable isotope substitution in the compounds of the present invention. See, e.g., Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0124] In the compounds of the present invention, any atom not specified as deuterium is present at its natural isotope abundance. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen with its isotopic composition at natural abundance. Similarly, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium", that position is understood to have deuterium with an abundance that is at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0125] As used herein, the term "isotope enrichment factor" refers to the ratio of the isotopic abundance of a particular isotope to its natural abundance.

[0126] In other embodiments, the compounds of the present invention have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) for each specified deuterium atom.

[0127] The term "isotopologue" refers to a substance in which the chemical structure is identical to a particular compound of the present invention except for its isotopic composition.

[0128] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts.

[0129] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromides, iodides, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates, and also include salts of amino acids such as arginates, glucuronates, galacturonates, etc. Acid addition salts can be prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to form the salt. The free base form can be regenerated by contacting the salt form with a base and the free base can be isolated in a conventional manner.

[0130] The term "base addition salt" refers to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and the free acid can be isolated in a conventional manner.

[0131] The term "stereoisomers" includes enantiomers, diastereomers, and geometric isomers. Some compounds of the present invention have cycloalkyl groups which can be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

[0132] The term "solvate" refers to the physical association of a compound of the present invention with one or more solvent molecules. This physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, etc.

[0133] The term "prodrug" refers to a form of a compound of formula I that is suitable for administration to a patient, has no excessive toxicity, irritation, allergic reaction, etc., and is effective for its intended purpose, including acetal, ester, and zwitterionic forms. The prodrug is converted in vivo, such as by hydrolysis in the blood, to give the parent compound.

[0134] The terms "patient" or "subject", etc. are used interchangeably herein and refer to any animal or its cells treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys, or humans, especially humans.

[0135] The term "treatment" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, arresting, and / or stopping one or more clinical symptoms of a disease after the onset of the disease.

[0136] The term "prevention" refers to avoiding, minimizing, or making it difficult for a disease to occur or develop by treatment before the onset of the disease.

[0137] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated herein by reference in their entirety.

[0138] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention.

[0139] Synthesis Examples:

[0140] 1. The synthesis route is as follows:

[0141]

[0142] The B-ring structure includes:

[0143] (1) Route step 1 is as follows:

[0144]

[0145] Weigh 1.64 g (25 mmol, 2.5 eq.) of zinc powder. Wash it three times with 2 M hydrochloric acid or stir and wash it with 0.5 M hydrochloric acid for 5 min, then wash it three times with anhydrous ethanol and anhydrous diethyl ether respectively. Dry it by stirring in an oil bath at 140 °C with a vacuum pump for 2 h. Place the activated zinc powder in a three-necked flask, add ultra-dry tetrahydrofuran (5 mL) under Ar protection, and add 173 μL (2 mmol, 0.2 eq.) of 1,2-dibromoethane. Reflux and heat to 75 °C, continue the reaction for 30 min after observing a large number of bubbles; cool naturally to room temperature, slowly add 255 μL (2 mmol, 0.2 eq.) of trimethylchlorosilane and continue the reaction for 15 min after observing a large number of bubbles. Heat to 65 °C, dissolve 1.04 mL of methyl 1-bromocyclopropanecarboxylate (10 mmol, 1.0 eq) in 15 mL of ultra-dry tetrahydrofuran, and slowly add it dropwise to the reaction system. Keep the reaction at 65 °C for 4 h (when a large amount is added, the reaction can be carried out overnight to ensure complete reaction), to obtain intermediate 2, which can be directly used in step 2 without post-treatment.

[0146] Route step 2 is as follows:

[0147]

[0148] Weigh 2070 mg (10 mmol, 1.0 eq.) of 1-bromonaphthalene (3), add 91.5 mg (0.1 mmol, 0.01 eq) of Pd2(dba)3 and 71 mg (0.1 mmol, 0.01 eq) of Qphos, and dissolve them in 20 mL of anhydrous tetrahydrofuran. Under Ar protection, add the Reformatsky reagent of intermediate 2 (20 mmol, 1 N, 2.0 eq) dissolved in 20 mL of tetrahydrofuran. Stir at room temperature for 30 min. After detecting that the reaction has been completely converted, spin-dry the solvent, dissolve it in ethyl acetate, wash it three times with water and once with saturated brine, and retain the organic phase and dry it with anhydrous sodium sulfate. Purify by column chromatography to obtain intermediate 4.

[0149] (3) Route step 3:

[0150]

[0151] Weigh 2518 mg (11.09 mmol, 1.0 eq) of intermediate 4, dissolve it in a mixed solvent of tetrahydrofuran / methanol / water (3:1:1, 65 mL), and add 2484 mg of potassium hydroxide (44.37 mmol, 4.0 eq). React at 50 °C for 8 h. After detecting that the reactant has been completely converted, add 2 N HCl solution to adjust the pH to 3, spin off all the solvent, add 25 mL of methanol, filter and retain the filtrate, spin-dry the filtrate to obtain a gray solid, and finally wash the gray solid repeatedly with DCM / PE to obtain the white solid product 5.

[0152] (4) Route step 4:

[0153]

[0154] Weigh 426 mg (2 mmol, 1.0 eq) of intermediate 5 and dissolve it in 25 mL of ultradry toluene. Add 0.611 mL of triethylamine (4.4 mmol, 2.2 eq), and under Ar protection, add 0.516 mL of DPPA (2.4 mmol, 1.2 eq). Stir at room temperature for 30 min until all carboxylic acid raw materials are converted to acyl azide, then heat to 75 °C and react for 4 h until most of the acyl azide is converted to isocyanate. Add an excess of hydrochloric acid (2 M aqueous solution, > 4.0 eq), cool down to 60 °C, and react overnight. Add sodium bicarbonate solution to adjust the pH to alkaline, then extract with ethyl acetate, and perform column chromatography to obtain the white powder product 6.

[0155] (5) Route step 5:

[0156]

[0157] Weigh 600 mg (3.27 mmol, 1.0 eq) of intermediate 6, an appropriate amount of bis-bicyclic dicarboxylic acid monomethyl ester intermediate (1 mmol, 1.0 eq), and 1690 μL of DIPEA (3 mmol, 3.0 eq), and dissolve them in 40 mL of THF. Stir until completely dissolved. Add 1370 mg of HATU (1.1 mmol, 1.1 eq) and react at room temperature for 3 h. After the reaction raw materials are completely converted, wash the reaction solution with water and ethyl acetate to remove THF, retain the organic phase, spin-dry to obtain the crude product, and purify it by column chromatography to obtain intermediate 7.

[0158] (6) Route step 6:

[0159]

[0160] Weigh 500 mg (1.26 mmol, 1.0 eq) of intermediate 7 and 316 μL of 80% hydrazine hydrate (5 mmol, 5.0 eq), and dissolve them in 10 mL of EtOH. Stir until completely dissolved. React at 80 °C for 12 h. After the reaction raw materials are completely converted, wash the reaction solution with water and ethyl acetate to remove EtOH, retain the organic phase, spin-dry to obtain the crude product, and purify it by column chromatography to obtain intermediate 8.

[0161] (7) Route step 7:

[0162]

[0163] Weigh 100 mg (0.25 mmol, 1.0 eq) of intermediate 8, 88 μL of DIPEA (0.5 mmol, 2.0 eq) and 45 mg of monomethyl fumaroyl chloride (0.3 mmol, 1.5 eq), dissolve them in 10 mL of DCM, and stir until completely dissolved. React at room temperature for 2 h. After the reaction raw materials are completely converted, wash the reaction solution with water and ethyl acetate to remove salts, retain the organic phase, spin-dry to obtain the crude product, and purify by column chromatography to obtain the final product 9.

[0164] Example of Activity Detection

[0165] The experimental results are shown in the following table.

[0166] Table 1 Test Results

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

[0191] The foregoing embodiments and methods described in the present invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0192] The mere listing of the steps of the method in a certain order in the present invention does not constitute any limitation on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, the compound having the following structure: Wherein, Ring A is a carbocyclic or heterocyclic ring; Ring B is a bicyclic or tricyclic carbocyclic or heterocyclic ring; L1 is -(C 0-6 alkylene)-Q1-(C 0-6 alkylene)-, where Q1 is selected from: a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C 3-6 cycloalkylene, C 6-10 arylene, 3-10 membered heteroarylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(O)2-, -N(R6)-, -N(R6)CO-, -CON(R6)-, -S(O)2-, -SO-, -N(R6)S(O)2-, -N=C(R6)-, -N(R6)-C(=NR7)-; R6 and R7 are independently selected from: -H, C 1-10 alkyl, -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4-10 membered heterocyclic group); wherein one or more H in the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, alkyl, cycloalkyl, aryl, heterocyclic group are optionally substituted by a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); R x and R y are independently selected from: -H, C1-C 10 alkyl; L2 is -(C 0-6 alkylene)-Q2-(C 0-6 alkylene)-, where Q2 is selected from: a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C 3-6 cycloalkylene, C 6-10 arylene, 3-10 membered heteroarylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(O)2-, -N(R8)-, -N(R8)CO-, -CON(R8)-, -S(O)2-, -SO-, -N(R8)S(O)2-, -N=C(R8)-, -N(R8)-C(=NR9)-; R8 and R9 are independently selected from: -H, C 1-10 alkyl, -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4-10 membered heterocyclic group); wherein one or more H in the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, alkyl, cycloalkyl, aryl, heterocyclic group are optionally substituted by a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); R x and R y independently selected from: -H, C1-C 10 alkyl; L3 is -(C 0-6 alkylene)-Q3-(C 0-6 alkylene)-, where Q3 is selected from: a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C 3-6 cycloalkylene, C 6-10 arylene, 3-10 membered heteroarylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(O)2-, -N(R 10 )-, -N(R 10 )CO-, -CON(R 10 )-, -S(O)2-, -SO-, -N(R 10 )S(O)2-, -N=C(R 10 )-, -N(R 10 )-C(=NR 11 )-; R 10 and R 11 are independently selected from: -H, C 1-10 alkyl, -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4-10 membered heterocyclic group); wherein one or more H in the alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, alkyl, cycloalkyl, aryl, heterocyclic group are optionally substituted by a group selected from the following: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 (alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4 - 10 membered heterocyclic group); R x and R y are independently selected from: -H, C1 - C 10 alkyl; R1 is one or more independent substituents on the A ring, selected from: -H, =O, halogen, -CN, -NO2, -CF3, -OCF3, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, and heterocyclic group are optionally substituted with a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); R2 is one or more independent substituents on the B ring, selected from: -H, =O, halogen, -CN, -NO2, -CF3, -OCF3, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, and heterocyclic group are optionally substituted with a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4 - 10 membered heterocyclic group); R3, R4, and R5 are independently selected from: -H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group); wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, or heterocyclic group are optionally substituted with a group selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, C 0-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -(C 0-10 alkylene)-(C 3-6 cycloalkyl), -(C 0-10 alkylene)-(C 6-10 aryl), -(C 0-10 alkylene)-(4- to 10-membered heterocyclic group).

2. The compound according to claim 1, wherein, Q1 has the following structure: wherein, W1 is selected from: -C(R W1 R W1 ')-, -O-, -S-, -C(O)-, -C(S)-, -N(R W1 )-, -S(O)2-, -C(=CR W1 )-, C 1-3 alkylene; R W1 , R W1 ' are independently selected from: -H, halogen, C 1-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl); W2 is selected from: -C(R W2 R W2 )-, -O-, -S-, -C(O)-, -C(S)-, -N(R W2 )-, -S(O)2-, -C(=CR W2 )-, C 1-3 alkylene Group; R W2 and R W2 ' are independently selected from: -H, halogen, C 1-10 alkyl, -O(C 0-10 alkyl), -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C 0-10 alkyl)CO(C 0-10 alkyl), -N(C 0-10 alkyl)CON(C 0-10 alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -SC 0-10 alkyl, -SO(C 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 alkyl)(C 0-10 alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl); Preferably, the part has the following structure: More preferably, is selected in part from the following structures: More preferably, L1 is 3. The compound according to claim 2, wherein, Q2 is selected from: -N(R8)-, -N(R8)CO-, -CON(R8)-, -C(O)-, -N(R8)S(O)2-, -N(R8)-C(=NR9)-; Preferably, L2 is -N(R8)CO-; More preferably, R8 is selected from: -H, C 1-6 alkyl group.

4. The compound according to any one of claims 1 - 3, wherein, The compound has the following structure:

5. The compound according to any one of claims 1 - 4, wherein, Ring A is a 5- to 14-membered at least partially unsaturated carbocyclic or heterocyclic ring, preferably a naphthalene ring or a 6,6-fused bicyclic nitrogen-containing heteroaromatic ring; Preferably, the part has the following structure: wherein, X1, X2, X3, X4, X5, X6, X7, X8 are independently selected from: CH or N; More preferably, selected in part from: In particular 6. The compound according to claim 5, wherein, R1 is selected from: -H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl), -CON(C 0-6 alkyl)(C 0-6 alkyl), -N(H)SO2(C 1-6 alkyl), -SO2N(C 0-6 alkyl)(C 0-6 alkyl); wherein one or more H in the alkyl are optionally substituted with a group selected from: halogen, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl); Preferably, R1 is selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2, More preferably, R1 is -H.

7. The compound according to any one of claims 1 - 6, wherein, Ring B is a naphthalene ring, a bicyclic heterocyclic ring or a bicyclic partially unsaturated carbocyclic ring; Preferably, ring B is selected from: More preferably, the moiety has the following structure: wherein Y1, Y2, Y3, and Y4 are independently selected from: CH, N; and the J ring is a 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring; More preferably, the J ring is selected from:

8. The compound according to claim 7, wherein Partially selected from the following structure: Preferably, is selected from the following structures:

9. The compound according to any one of claims 1-8, wherein R2 is selected from: -H, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl), -CON(C 0-6 alkyl)(C 0-6 alkyl), -N(H)SO2(C 1-6 alkyl), -SO2N(C 0-6 alkyl)(C 0-6 alkyl); wherein one or more H in the alkyl are optionally substituted by a group selected from: halogen, -O(C 0-6 alkyl), -N(C 0-6 alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl); Preferably, R2 is selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, More preferably, R2 is -H.

10. The compound according to any one of claims 1-9, wherein R3 and R4 are independently selected from: -H, C 1-6 alkyl; Preferably, R3 is -H; Preferably, R4 is -H.

11. The compound according to any one of claims 1-10, wherein R5 is selected from: -H, C 1-6 alkyl; Preferably, R5 is C 1-3 alkyl group.

12. The compound according to claim 1, wherein The compound is selected from the following structures:

13. A pharmaceutical composition comprising the compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

14. Use of the compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, in the preparation of a medicament for preventing and / or treating a disease or disorder caused by or associated with a viral infection.

15. The use according to claim 14, wherein The virus is a coronavirus, preferably selected from: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2.

16. The use according to claim 14, wherein The disease or disorder is selected from: respiratory diseases, digestive system diseases, cardiovascular diseases, nervous system diseases, eye diseases, especially respiratory diseases; Preferably, the disease or disorder is selected from: COVID-19, SARS, MERS.

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