Antiviral heterocyclic scaffold derivative, preparation method therefor, pharmaceutical combination comprising same, and use thereof

Abstract

The present invention relates to the field of pharmacological research, and specifically relates to a compound as shown in general formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor or prodrug thereof, a preparation method therefor, a pharmaceutical combination comprising same, and a use of the compound in the prevention and / or treatment of respiratory diseases caused by viruses (such as SARS-CoV2, SARS-CoV, and MERS-CoV) and in the inhibition of nonstructural proteins of the related viruses, such as a papain-like protease protein.

Description

A class of antiviral heterocyclic skeleton derivatives, preparation methods, drug combinations and uses thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical research, and specifically relates to a class of antiviral heterocyclic backbone derivatives and their preparation methods and uses, wherein the virus targets coronaviruses containing papain-like proteases or catalytic domains similar thereto. In particular, it is a novel coronavirus SARS-CoV2 PL pro Inhibitors have significant inhibitory activity at the molecular level. Background Art

[0002] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the 2019 novel coronavirus pneumonia (COVID-19), is the seventh known coronavirus to have jumped to humans from other reservoirs, such as bats and rodents. Since its discovery in December 2019, SARS-CoV-2 has caused over 7 million deaths worldwide, making it one of the deadliest viruses in human history. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus in the family Coronaviridae. The SARS-CoV-2 genome is approximately 29.9 kb in length, one of the largest genomes among RNA viruses, encoding 16 nonstructural proteins (Nsp1 to Nsp16), four structural proteins, and nine accessory proteins. Virus-targeted inhibitors are being developed to block different stages of the SARS-CoV-2 life cycle, including entry, proteolytic processing (Mpro, PLpro), RNA synthesis (Nsp12 to Nsp16), and assembly.

[0003] Among them, papain (PLpro) is a cysteine ​​protease that not only cleaves pp1a and pp1ab polyproteins to release viral proteins NSP1, NSP2, and NSP3, but also removes host ubiquitin and ubiquitin-like interferon-stimulated gene 15 (ISG15) from signaling proteins to suppress innate immune responses. pro The catalytic site contains a classic catalytic triad (Cys111-His272-Asp286), which preferentially cleaves the tetrapeptide motif LXGG↓XX in adjacent viral proteins (NSP1-NSP2, NSP2-NSP3, NSP3-NSP4) and the C-terminal tails of cellular ubiquitin and ISG15. There is a flexible loop called blocking loop 2 (BL2) that controls the entry of the substrate into the catalytic site. Therefore, the inhibitor can interact with the amino acid residues on the loop (such as hydrogen bonds), which has an important influence on the improvement of its activity.

[0004] There are drugs on the market for other COVID-19 targets (such as RdRp and 3CLpro), but there are currently no reports of SCoV2PLpro target inhibitors on the market. Therefore, the development of inhibitors against this target is of great significance for overcoming the immune escape of the virus in host cells and developing safer and more effective inhibitors. Summary of the Invention

[0005] The object of the present invention is to provide an antiviral heterocyclic skeleton derivative, and a preparation method, a pharmaceutical composition and use thereof.

[0006] In the first aspect of the present invention, a heterocyclic skeleton derivative, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor, prodrug or deuterated compound thereof is provided, wherein the structure is shown in formula (I):

[0007] in,

[0008] is a C6-C12 aryl group or a 3-12 membered heteroaryl group, and the hydrogen atoms on the aryl or heteroaryl group may be optionally replaced by R a1 replace;

[0009] is a 3-12 membered heteroaryl or a 3-12 membered heterocyclic group, and the hydrogen atoms on the heteroaryl or heterocyclic group may be optionally replaced by R b1 replace;

[0010] X1 and X2 are independently selected from: NH, O, S;

[0011] R1 and R2 are each independently selected from H, halogen, substituted or unsubstituted C1-C6 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, -C(=O)R 4 、-OC(=O)R 4 、-C(=O)OR 4 、-OR 4 、-SR 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)2N(R 4 )2、-N(R 4 )2、-C(=O)N(R 4 )2、-NR 4 -C(=O)R 4 、-NR 4 -C(=O)OR 4 、-NR 4 -S(=O)2-R 4、C(=O)-N(R 4 )2, -C1-C6 alkylene-N(R 4 )2, -C1-C6 alkylene-OR 4 、-C1-C6 alkenylene-OR 4 and -O-C1-C6 alkylene-N(R 4 )2; wherein, any of the above R 4 R1 and R2 are independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group; or, R1 and R2, to which they are attached, form a 3-6 membered cycloalkyl or 3-6 membered heterocyclic group, which may be optionally substituted;

[0012] R3 represents one or more independent substituents on the ring, each R3 is independently selected from H, halogen, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, -N(R 5 )2、-OR 5 、-SR 5 、-C(=O)N(R 5 )2, -C(=O)OR 5 、-OC(=O)R 5 、-NR 5 -C(=O)R 5 、-NR 5 -C(=O)OR 5 、-NR 5 -S(=O)2-R 5 、-C1-C6 alkylene-N(R 5 )2, -C1-C6 alkylene-OR 5 、-C1-C6 alkenylene-OR 5 、-O-C1-C6 alkylene-N(R 5 )2 and -NR 5 -C1-C6 alkylene-OR 5 ; Among them, any of the above R 5 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl;

[0013] R a1 represents one or more independent substituents on the ring, each R a1 independently selected from H, halogen, substituted or unsubstituted saturated or partially unsaturated C1-C6 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, -C(=O)R 6 、-OC(=O)R 6 、-C(=O)OR6 、-OR 6 、-SR 6 、-S(=O)R 6 、-S(=O)2R 6 、-S(=O)2N(R 6 )2、-N(R 6 )2、-C(=O)N(R 6 )2、-NR 6 -C(=O)R 6 、-NR 6 -C(=O)OR 6 、-NR 6 -S=OR 6 、-NR 6 -S(=O)2-R 6 、C(=O)-N(R 6 )2, -C1-C6 alkylene-N(R 6 )2, -C1-C6 alkylene-OR 6 、-C1-C6 alkenylene-OR 6 and -O-C1-C6 alkylene-N(R 6 )2; wherein, any of the above R 6 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl;

[0014] R b1 represents one or more independent substituents on the ring, each R b1 independently selected from H, (=O), halogen, nitro, cyano, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, C1-C6 haloalkyl, C3-C8 cycloalkyl, -N(R 9 )2、-OR 9 、-SR 9 、-C(=O)N(R 9 )2, -C(=O)OR 9 、-S(=O)2-R 9 、-NR 9 -C(=O)R 9 、-NR 9 -C(=O)OR 9 、-NR 9 -S(=O)2-R 9 、-C1-C6 alkylene-R 9 、-C1-C6 alkylene-N(R 9 )2, -C1-C6 alkylene-OR 9 、-C1-C6 alkenylene-OR9 、-O-C1-C6 alkylene-N(R 9 )2、-NR 9 -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-COOH, or forming a substituted or unsubstituted fused ring, spiro ring or bridged ring structure with the B ring structure; wherein any of the above R 9 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl;

[0015] The above substitution means that one or more H in the group is replaced by a group selected from halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or that two H in -CH2- in the group are replaced by oxo=O;

[0016] Provided that, when R1 is methyl and R2 is H, or R2 is methyl and R1 is H, the B ring is R b1 substituted or unsubstituted 3-12 membered heteroaryl and the B ring is not a 6-membered unsubstituted heteroaryl.

[0017] As used herein, the "aliphatic hydrocarbon group" means a linear or branched aliphatic hydrocarbon group, which does not contain an aromatic structure. The "aliphatic hydrocarbon group" can be saturated or unsaturated, wherein a saturated aliphatic hydrocarbon group is an alkyl group, and an unsaturated aliphatic hydrocarbon group can include "alkenyl", "alkynyl" and "dienyl". In this article, "C1-C6 aliphatic hydrocarbon group" can include C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 dienyl (including independent dienyl and conjugated dienyl). It is optionally substituted with one or more (such as one to three) suitable substituents.

[0018] As used herein, described " cycloalkyl " means the cyclic group that is made up of carbon atoms of non-aromatic, and it can be saturated or partially unsaturated.Wherein saturated cycloalkyl is cycloalkyl, and partially unsaturated cycloalkyl can comprise cycloalkenyl, cycloalkynyl.Herein, " C3-C6 cycloalkyl " can comprise C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 cycloalkynyl.It is optionally substituted by 1 or more (such as 1 to 3) applicable substituents.

[0019] In a preferred embodiment of the present invention, is a C10 aryl group or a 10-membered heteroaryl group, preferably a naphthyl group.

[0020] In a preferred embodiment of the present invention, Has the following structure:

[0021] Among them, X a1 、X a2 、X a3 、X a4 、X a5 、X a6 、X a7 Independently selected from: CH, N;

[0022] R a1 represents one or more independent substituents on the ring, each R a1 independently selected from H, C1-C6 alkyl, halogen, substituted or unsubstituted saturated or partially unsaturated C1-C6 aliphatic hydrocarbon, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, -C(=O)R 6 、-OC(=O)R 6 、-C(=O)OR 6 、-OR 6 、-SR 6 、-S(=O)R 6 、-S(=O)2R 6 、-S(=O)2N(R 6 )2、-N(R 6 )2、-C(=O)N(R 6 )2、-NR 6 -C(=O)R 6 、-NR 6 -C(=O)OR 6 、-NR 6 -S=OR 6 、-NR 6 -S(=O)2-R 6 、C(=O)-N(R 6 )2, -C1-C6 alkylene-N(R 6 )2, -C1-C6 alkylene-OR 6 、-C1-C6 alkenylene-OR 6 and -O-C1-C6 alkylene-N(R 6 )2; wherein, any of the above R 6 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl group.

[0023] Specifically, R a1 represents one or more independent substituents on the ring, each R a1 independently independently selected from H, C1-C6 alkyl, halogen, 3-8 membered heterocyclyl, -NH-C1-C6 alkyl, -O-C1-C6 alkyl.

[0024] More specifically, R a1 For H.

[0025] In a preferred embodiment of the present invention, X a1 -X a7 All are CH, that is The structure is 1-naphthyl, which has the following structure:

[0026] Specifically, X a1 -X a7 At least one (for example, one, two, three, four) of them is N.

[0027] Specifically, X a1 -X a7 There is only one N in It may be a quinolyl group (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl) or an isoquinolyl group (2-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl).

[0028] In another preferred embodiment of the present invention, Has the following structure:

[0029] Specifically, R1 and R2 are independently selected from H, substituted or unsubstituted C1-C6 alkyl.

[0030] Specifically, R1 and R2 are independently selected from H, C1-C3 alkyl.

[0031] Specifically, when R1 and R2 are different substituents (such as R1 is H and R2 is a C1-C3 alkyl, or R1 is a C1-C3 alkyl and R2 is H), the carbon atom to which the two are connected can be in R configuration or S configuration.

[0032] Specifically, The structure is as follows:

[0033] In a preferred embodiment of the present invention, R1 and R2 form a 3-5 membered cyclic structure with the carbon atom to which they are connected, preferably a 3-5 membered cycloalkyl group or a 3-5 membered heterocyclic group.

[0034] Specifically, R1 and R2 form a cyclopropyl, cyclobutyl, cyclopentyl, oxirane, oxetane or azetidine group with the carbon atom to which they are attached.

[0035] Specifically, The structure is as follows:

[0036] More preferably, The structure is as follows:

[0037] In a preferred embodiment of the present invention, X1 and X2 are independently selected from the following heteroatoms: NH and O.

[0038] Specifically, X1 is selected from NH, X2 is selected from NH or O; or X1 is selected from NH, X2 is selected from O; or X1 is selected from O, X2 is selected from O.

[0039] In a preferred embodiment of the present invention, Formula I may have the following structure:

[0040] Preferably, R3 is selected from H, halogen, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, -N(R 5 )2、-OR 5 、-NR 5 -C(=O)R 5 、-OC(=O)R 5 、-NR 5 -S(=O)2-R 5 ; Among them, any of the above R 5 All can be independently selected from H, C1~C6 alkyl;

[0041] R a1 , Ring B is as described herein.

[0042] More preferably, R3 is selected from H.

[0043] Further preferably, R3 represents an independent substituent on the benzene ring and the substitution position is as follows:

[0044] In a preferred embodiment of the present invention, It is a 4-10 membered heteroaryl group or a 4-10 membered heterocyclic group, preferably a 5-6 membered heteroaryl group, a 4-6 membered heterocyclic group or an 8-10 membered condensed-ring heterocyclic group.

[0045] In a preferred embodiment of the present invention, Contains at least one nitrogen atom.

[0046] In a preferred embodiment of the present invention, Has the following structure:

[0047] Wherein, m and n are independently 0 or 1;

[0048] Y1, Y2, Y3, Y4, Y5, and Y6 are independently selected from C, N, O, and S, and not all are C;

[0049] R 10 、R 11 represents one or more independent substituents on the ring, each R 10 、R 11 independently selected from H, (=O), halogen, nitro, cyano, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, C3-C8 cycloalkyl, -N(R 9 )2、-OR 9 、-SR 9 、-C(=O)N(R 9 )2, -C(=O)OR 9 、-S(=O)2-R 9 、-NR 9 -C(=O)R 9 、-NR 9 -C(=O)OR 9 、-NR 9 -S(=O)2-R 9 、-C1-C6 alkylene-R 9 、-C1-C6 alkylene-N(R 9 )2, -C1-C6 alkylene-OR 9 、-C1-C6 alkenylene-OR 9 、-O-C1-C6 alkylene-N(R 9 )2、-NR 9 -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-COOH, or forming a substituted or unsubstituted fused ring, spiro ring or bridged ring structure with the above cyclic structure; wherein any of the above R 9 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl group.

[0050] Specifically, R b1 Same as R 10 or R 11 .

[0051] More specifically, the It is a chemically stable structure. When the valence state is missing, it is supplemented by H.

[0052] when In the case of structure VI-1, Y1, Y2, Y3, Y4, Y5, and Y6 are selected from CH (which can be replaced by C), N, O, and S, wherein H can be optionally replaced by R 10 replace.

[0053] when In the case of structure VI-2, Y1, Y2, Y3, Y4, Y5, and Y6 are selected from CH2 (which may be replaced by C), NH (which may be replaced by N), O, and S, wherein H may be optionally replaced by R 11 replace.

[0054] Specifically, Formula I may have the following structure:

[0055] Specifically, m is 0, and at least one of Y1, Y2, Y3, Y4, and Y6 is selected from N, O, and S.

[0056] Specifically, m is 1, at least one of Y1-Y5 is selected from N, and Y6 is C; for example, Y1 is N; or, Y2 is N; or, Y3 is N; or, Y4 is N; or, Y5 is N.

[0057] Specifically, Formula I may have the following structure:

[0058] Specifically, m is 0, n is 0, and the structure composed of Y1-Y6 is represents a four-membered ring structure, and at least one of Y1, Y3, Y4, and Y6 is selected from N, O, and S.

[0059] Specifically, m is 0, n is 1, and the structure composed of Y1-Y6 is represents a five-membered ring structure, and at least one of Y1, Y2, Y3, Y4, and Y6 is selected from N, O, and S.

[0060] Specifically, m is 1, n is 0, and the structure composed of Y1-Y6 is represents a five-membered ring structure, and at least one of Y1, Y3, Y4, Y5, and Y6 is selected from N, O, and S.

[0061] Specifically, m is 1, n is 1, and the structure composed of Y1-Y6 is represents a six-membered ring structure, and at least one of Y1, Y2, Y3, Y4, Y5, and Y6 is selected from N, O, and S.

[0062] More specifically, one or two of Y1, Y2, Y3, Y4, Y5, and Y6 are heteroatoms selected from N, O, and S.

[0063] More specifically, R 10 、R 11 represents one or more independent substituents on the ring, each R 10 、R 11independently selected from H, (=O), halogen, nitro, cyano, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, C3-C6 cycloalkyl, -N(R 9 )2、-OR 9 、-SR 9 、-C1-C6 alkylene-R 9 、-C1-C6 alkylene-N(R 9 )2, -C1-C6 alkylene-OR 9 、-C1-C6 alkenylene-OR 9 , -C1-C6 alkylene-COOH; wherein any of the above R 9 Each of them can be independently selected from H, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-6 membered heterocyclic group or C6-C10 aryl group.

[0064] More specifically, R 10 、R 11 represents one or more independent substituents on the ring, each R 10 、R 11 independently selected from H, (=O), halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, amino, C1-C6 alkoxy, -C1-C4 alkylene-R 9 、-C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2, -C1-C6 alkylene-COOH; wherein any of the above R 9 Each of them can be independently selected from H, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-6 membered heterocyclic group or C6-C10 aryl group.

[0065] More specifically, R 10 、R 11 represents one or more independent substituents on the ring, each R 10 、R 11 Independently selected from H, (=O), halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, amino, C1-C6 alkoxy, -C1-C6 alkylene-OH, -C1-C6 alkylene-O-(C1-C6 alkyl), -C1-C6 alkylene-NH2, -C1-C6 alkylene-NH-(C1-C6 alkyl), -C1-C6 alkylene-C3-C6 cycloalkyl, -C1-C6 alkylene-C6-C10 aryl, -C1-C6 alkylene-COOH.

[0066] More specifically, R 10 、R 11represents one or more independent substituents on the ring, each R 10 、R 11 Independently selected from H, (=O), halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, amino, C1-C6 alkoxy, -C1-C3 alkylene-OH, -C1-C3 alkylene-O-(C1-C6 alkyl), -C1-C3 alkylene-NH2, -C1-C3 alkylene-NH-(C1-C6 alkyl), -C1-C3 alkylene-C3-C6 cycloalkyl, -C1-C3 alkylene-C6-C10 aryl, -C1-C3 alkylene-COOH.

[0067] Specifically, in Formula VI-2 and Formula VII-2, two R 11 The atoms connected thereto may together form a C3-C6 cycloalkane ring or a 3-6 membered heterocycle, so that ring B is a spiro ring structure.

[0068] Specifically, in Formula VI-2 and Formula VII-2, two R on adjacent ring atoms 11 The atoms connected thereto may together form a C4-C8 cycloalkane ring, a 4-8 membered heterocyclic ring, a C6-C10 aryl group, or a 4-8 membered heteroaryl group, so that ring B is a condensed ring structure.

[0069] Specifically, in Formula VI-1 and Formula VII-1, two R on adjacent ring atoms 10 The atoms connected thereto may together form a C4-C8 cycloalkane ring, a 4-8 membered heterocyclic ring, a C6-C10 aryl group, or a 4-8 membered heteroaryl group, so that ring B is a condensed ring structure.

[0070] More specifically, in Formula VI-1 and Formula VII-1, two R on adjacent ring atoms 10 The atoms connected thereto may together form a phenyl group, so that the B ring is a benzo-fused ring structure.

[0071] In some preferred embodiments of the present invention, when R1 is methyl and R2 is H, or R2 is methyl and R1 is H, the B ring is R b1 Substituted 3-12 membered heteroaryl.

[0072] In some preferred embodiments of the present invention, when R1 is C1-C6 alkyl and R2 is H, or R2 is C1-C6 alkyl and R1 is H, the B ring is R b1 a substituted or unsubstituted 3-12-membered heteroaryl group, and the B ring is not a 6-membered unsubstituted heteroaryl group.

[0073] In some preferred embodiments of the present invention, when R1 is C1-C6 alkyl and R2 is H, or R2 is C1-C6 alkyl and R1 is H, the B ring is R b1a substituted 5- to 6-membered heteroaryl group or an unsubstituted 5-membered heteroaryl group.

[0074] In some preferred embodiments of the present invention, the compound of formula I has the following structure:

[0075] in, As described in this article.

[0076] More specifically, It can have the following structure:

[0077] Specifically, R 12 and R 14 Independently selected from the following structures: absent, H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C1-C4 alkylene-R 9 、-C1-C6 alkylene-OR 9 、-C1-C6 alkylene-N(R 9 )2; wherein, any of the above R 9 Each of them can be independently selected from H, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cycloalkyl, saturated or partially unsaturated 3-6 membered heterocyclic group or C6-C10 aryl;

[0078] R 13 represents one or more independent substituents on the ring, each R 13 Independently selected from H, (=O), halogen, nitro, -OH, -NH2, C1-C6 alkoxy or C1-C6 alkyl.

[0079] Specifically, R 12 、R 13 、R 14 Each is independently selected from H, (=O), halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, amino, C1-C6 alkoxy, -C1-C6 alkylene-OH, -C1-C6 alkylene-O-(C1-C6 alkyl), -C1-C6 alkylene-NH2, -C1-C6 alkylene-NH-(C1-C6 alkyl), -C1-C4 alkylene-C3-C6 cycloalkyl, -C1-C4 alkylene-C6-C10 aryl.

[0080] in particular, It can have the following structure:

[0081] More specifically, R 13 represents one or more independent substituents on the ring, each R 13Independently selected from H, (=O), halogen, nitro, -OH, -NH2, C1-C6 alkoxy or C1-C6 alkyl.

[0082] More specifically, R 12 and R 14 Independently selected from the following structures: C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkylene-OH, -C1-C4 alkylene-O-(C1-C6 alkyl), -C1-C4 alkylene-NH2, -C1-C4 alkylene-NH-(C1-C6 alkyl), -C1-C4 alkylene-C3-C6 cycloalkyl, -C1-C4 alkylene-C6-C10 aryl.

[0083] More specifically, R 12 and R 14 Independently selected from the following structures: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF3, -OH and the following groups:

[0084] More specifically, when one of the R 13 When it is oxo (=O), the nitrogen atom in the heteroaromatic ring can be replaced by R 12 or R 14 replace.

[0085] More specifically, when R in the B ring 13 When neither is oxo (=O), the N atom in the heteroaromatic ring cannot be replaced by R 12 or R 14 replace.

[0086] In some preferred embodiments of the present invention, X1, X2, R1, R2, and R3 are each independently a group corresponding to those in the examples.

[0087] The compounds in the prior art have never disclosed or suggested that R1R2 can form a cyclic structure, and among the compounds where R1R2 can form a cyclic structure, there is no disclosure of a structure that can form a CO-NH-ring B.

[0088] After analyzing the crystal structure, the researchers unexpectedly discovered that the CONH moiety can generate additional hydrogen bonds and that the naphthalene ring of Ring A is flipped compared to the known structure (GRL0617, PDB: 7CJM). These findings are not reported in the prior art.

[0089] In some preferred embodiments of the present invention, the above compound has the following structure:

[0090] In the second aspect of the present invention, there is provided a use of a compound of formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor, prodrug or deuterated compound thereof, characterized in that it is used to prepare (a) SARS-CoV2 PL pro inhibitors, and / or (b) for preventing and / or treating SARS-CoV2 PL pro Pharmaceutical compositions for treating inflammatory diseases.

[0091] In another preferred embodiment, the SARS-CoV2 PL pro Mediated diseases are diseases caused by viral infection.

[0092] In another preferred embodiment, the disease is an infection caused by a virus selected from the group consisting of coronavirus, calicivirus or picornavirus.

[0093] In another preferred embodiment, the disease is an infection caused by a virus selected from the group consisting of SARS-CoV-2 virus, SARS-CoV virus, and MERS-CoV virus.

[0094] In the third aspect of the present invention, a pharmaceutical composition is provided, comprising a compound of formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor, prodrug or deuterated compound thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0095] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] FIG1 shows the inhibitory effect of compound SIMM11 at different concentrations.

[0097] FIG2 shows the inhibitory effect of compound SIMM12 at different concentrations.

[0098] FIG3 shows the inhibitory effect of compound SIMM13 at different concentrations.

[0099] FIG4 shows the inhibitory effect of compound SIMM14 at different concentrations.

[0100] FIG5 shows the inhibitory effect of compound SIMM15 at different concentrations.

[0101] FIG6 shows the inhibitory effect of compound SIMM16 at different concentrations.

[0102] FIG7 shows the inhibitory effect of compound SIMM17 at different concentrations.

[0103] FIG8 shows the inhibitory effect of compound SIMM18 at different concentrations.

[0104] FIG9 shows the inhibitory effect of compound SIMM19 at different concentrations. DETAILED DESCRIPTION

[0105] After extensive and in-depth research, the inventors have discovered for the first time a compound with a completely new structure, which has excellent inhibitory effect on SARS-CoV2 PL pro The compounds in the prior art only report the case where one of the R1R2 groups is a methyl group, and never disclose or suggest that R1R2 can form a ring structure. However, the present invention unexpectedly found that the compound with R1R2 forming a ring structure has excellent inhibitory effect on SARS-CoV2 PL pro The effect can be used as SARS-CoV2 PL pro The inhibitor has broad application prospects. On this basis, the present invention was completed.

[0106] The other elements of the present invention are described below in more detail.

[0107] definition

[0108] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0109] The words "include," "comprising," "having," "containing," or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0110] As used herein, described " alkyl " is defined as linear or branched saturated aliphatic hydrocarbon.In some embodiments, alkyl has 1 to 12, for example 1 to 6 carbon atom.For example, as used herein, described " C1-C6 alkyl " refers to the linear or branched group (for example methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) of 1 to 6 carbon atom, it is optionally replaced (this moment this group is referred to as " haloalkyl ") (for example CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or-CH2CH2CF3 etc.) by 1 or more (such as 1 to 3) applicable substituents such as halogen. The "C1-C4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0111] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C2-C6 alkenyl"). Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When a compound of the present invention contains an alkenyl group, the compound may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0112] As used herein, the "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. For example, the "C3-C6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring carbon atoms, which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl-substituted cyclopropyl.

[0113] As used herein, the "heterocyclyl" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. Among them, a saturated heterocyclyl is a heterocycloalkyl, and a partially unsaturated heterocyclyl can be a heterocycloalkenyl or a heterocycloalkynyl. For example, a "3-10 membered (sub)heterocyclyl" is a saturated or partially unsaturated (sub)heterocyclyl having 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (such as 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene and heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. The group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0114] As used herein, the "aryl" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the "C6-C10 (sub)aryl" and "C6-C10 aromatic ring" refer to an aromatic group containing 6 to 10 carbon atoms, such as (sub)phenyl (phenyl ring) or (sub)naphthyl (naphthalene ring). The (sub)aryl and aromatic ring are optionally substituted with one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C1-C6 alkyl, etc.).

[0115] As used herein, "heteroaryl", "heteroaromatic ring" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0116] As a more specific terminology explanation is as follows:

[0117] "Alkyl" refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be optionally substituted or unsubstituted.

[0118] "Alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one C—C is an sp2 double bond, wherein the alkenyl group may be independently optionally substituted with one or more substituents described herein, specific examples of which include, but are not limited to, vinyl, allyl, and butylene. The alkenyl group may be optionally substituted or unsubstituted.

[0119] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls may be optionally substituted or unsubstituted.

[0120] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl is divided into single spiro, double spiro or multiple spiroalkyl according to the number of shared spiro atoms between the rings, preferably single spiro and double spiroalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to:

[0121] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to:

[0122] "Bridged cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

[0123] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0124] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic non-aromatic heterocyclic group containing 3 to 12 ring atoms, wherein at least one ring atom is a heteroatom, such as an oxygen, nitrogen, or sulfur atom. Preferably, the heterocyclic group has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl group may be optionally substituted or unsubstituted.

[0125] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O)m heteroatoms, and the remaining ring atoms are carbon, m=1 or 2. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to:

[0126] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be fused together. The "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, the aryl is a C6-C10 aryl, more preferably phenyl and naphthyl, and most preferably phenyl. The aryl group may be substituted or unsubstituted. The "aryl" may be fused with a heteroaryl, heterocyclyl, or cycloalkyl group, wherein the aryl ring is attached to the parent structure. Non-limiting examples include, but are not limited to:

[0127] "Heteroaryl" refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. The embodiment of "heteroaryl" includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl can be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0128] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0129] "Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as defined herein. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

[0130] "Hydroxy" refers to an -OH group.

[0131] "Halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0132] "Amino" refers to -NH2.

[0133] "Cyano" refers to -CN.

[0134] "Nitro" refers to -NO2.

[0135] "Benzyl" refers to -CH2-phenyl.

[0136] "Carboxyl" refers to -C(O)OH.

[0137] "Acyl" refers to a group of the type acetyl -C(O)CH3.

[0138] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Diastereomers can be separated into their individual diastereomers based on their physical chemical differences by methods such as chromatography, crystallization, distillation, or sublimation. Enantiomers can be separated by converting a chiral isomeric mixture into a diastereomeric mixture by reacting the diastereomers with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers. The intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are encompassed by the scope of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to name the sign of rotation of plane polarized light of the compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. These stereoisomers have the same order of attachment of atoms or groups of atoms to each other, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The "racemic mixture" and "racemate" mentioned above refer to a mixture of two enantiomers in equal moles, lacking optical activity.

[0139] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons. Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers are within the scope of the present invention.

[0140] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective for use in humans or animals. Salts of the compounds can be prepared by using a sufficient amount of a base or acid in a pure solution or a suitable inert solvent to form the corresponding addition salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, and pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, such as hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid.

[0141] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0142] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0143] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0144] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.

[0145] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0146] Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0147] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0148] The present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity but are converted, for example by hydrolytic cleavage, into compounds of the invention having the desired activity when administered to or on the body. Typically such prodrugs will be functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compound.

[0149] The prodrugs of the present invention can be esters formed by hydroxyl compounds (such as formates and acetates), esters, amides, anhydrides, etc. formed by carboxyl compounds, or amides formed by amino compounds (such as formamide and acetamide).

[0150] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0151] Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition can also optionally contain a small amount of wetting agent, emulsifier or pH buffer. Oral formulations can contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.

[0152] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0153] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0154] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0155] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0156] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0157] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0158] The content or dosage of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, for example 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0159] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0160] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0161] In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0162] Preparation of antiviral heterocyclic skeleton derivatives, i.e. compounds of formula (I)

[0163] Once the structures of the compounds of the present invention are known, the compounds of the present invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art.

[0164] Several feasible schemes for the synthesis of the compound are briefly described below:

[0165] Option 1:

[0166] In the first step, the compound of formula (I-1) reacts with (R)-(+)-tert-butylsulfenamide in the presence of a Lewis acid and a reducing agent at low temperature to obtain a compound of formula (I-2);

[0167] In the second step, the compound of general formula (I-2) is subjected to acidic conditions to remove the tert-butylsulfinyl group to obtain a compound of general formula (I-3);

[0168] In the third step, the compound of general formula (I-3) undergoes a condensation reaction with a substituted benzoic acid in the presence of a condensing agent to obtain a compound of general formula (I-4);

[0169] In the fourth step, the compound of the general formula (I-4) reacts with an acid-substituted heterocycle or a nitrile-substituted heterocycle under alkaline conditions or in the presence of a Lewis acid to obtain a compound of the general formula (I-5);

[0170] Option 2:

[0171] In the first step, the compound of formula (II-1) reacts with an ethyl Grignard reagent in the presence of a Lewis acid in the presence of a reducing agent to obtain a compound of formula (I-2);

[0172] In the second step, the compound of general formula (II-2) undergoes a condensation reaction with a substituted benzoic acid in the presence of a condensing agent to obtain a compound of general formula (II-3);

[0173] In the third step, the compound of general formula (II-3) reacts with an acid-substituted heterocycle or a nitrile-substituted heterocycle under alkaline conditions or in the presence of a Lewis acid to obtain a compound of general formula (II-4);

[0174] In the above preparation method, the reagent providing alkaline conditions is selected from organic bases or inorganic bases, the organic bases are triethylamine, N,N-diisopropylethylamine, lithium diisopropylamide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide, butyl lithium. One or more;

[0175] The reagent providing protonic acid conditions is one or more of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, and phosphoric acid; Lewis acids include but are not limited to one or more of aluminum trichloride, trimethylaluminum, boron trifluoride etherate, titanium tetrachloride, tin tetrachloride, tetraisopropyl titanate, and tetraethyl titanate;

[0176] The condensing agent includes, but is not limited to, one or more of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 2-(1H-benzotriazol L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1-hydroxybenzotriazole (HOBt) and 1-propylphosphoric anhydride (T3P);

[0177] The reducing agent includes, but is not limited to, one or more of diborane, sodium borohydride, and sodium cyanoborohydride.

[0178] The above reaction is preferably carried out in a solvent, and the solvent used is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.

[0179] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0180] Example

[0181] The method of the present invention is described below by means of specific examples to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are in Hz.

[0182] Mass spectra were obtained using LC / MS instrumentation, using ESI as the ionization method.

[0183] HPLC model: Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150 mm, 3.5 μm); mobile phase: A:ACN, B:Water (0.1% H3PO4); flow rate: 1.0 mL / min; gradient: 5%A for 1 min, increase to 20%A within 4 min, increase to 80%A within 8 min, 80%A for 2 min, back to 5%A ​​within 0.1 min; wavelength: 220 nm; column oven: 35°C.

[0184] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0185] Preparation of the key intermediate 5-amino-2-methyl-N-(naphthalen-1-ylcyclopropyl)benzamide (M-3) in the above example:

[0186] Step 1: 1-(Naphthalen-1-yl)cyclopropane-1-amine (M-1)

[0187] Naphthalene-1-carbonitrile (10 g, 65 mmol) was dissolved in 200 mL of 1,4-dioxane solution, followed by the addition of Ti(i-PrO)₄ (20.4 g, 71.7 mmol). The mixture was stirred and cooled to -78°C under a nitrogen atmosphere. EtMgBr (130 mmol) was slowly added dropwise to the reaction system, and the mixture was stirred at room temperature for 2 h. BF₃·Et₂O (18.5 g, 130.7 mmol) was then slowly added to the system, and stirring was continued for 3 h. The reaction was completed by TLC. After completion, 4 M HCl was added to quench the reaction, and excess sodium hydroxide solution was added to adjust the pH to 8-10. The reaction solution was extracted with ethyl acetate, purified by flash chromatography, and dried to obtain product M-1 as a reddish-brown oil.

[0188] LC-MS: m / z = 184.0 [M+H] +

[0189] 1H NMR(400MHz,MeOD)δ8.45(dq,J=8.5,1.0Hz,1H),7.92-7.84(m,1H),7.76(dt,J=8.3,1.1Hz ,1H),7.61-7.47(m,3H),7.40(dd,J=8.2,7.0Hz,1H),1.22-1.14(m,2H),1.04-0.95(m,2H). 13 C NMR(101MHz,MeOD)δ140.89,134.32,131.63,128.53,127.51,125.77,125.61,125.32, 125.19,123.97,48.26,48.05,47.91,47.84,47.62,47.41,47.20,46.99,35.54,13.60.

[0190] Step 2: [(4-methyl-3-{[(naphthalen-1-ylcyclopropyl)amino]carbonyl}phenyl)amino]methanoic acid-2-methylprop-2-yl ester (M-2)

[0191] Compound M-1 (2 g, 10.9 mmol) and 2-methyl-5-({[(2-methylprop-2-yl)oxy]carbonyl}amino)benzoic acid (2.7 g, 10.9 mmol) were dissolved in 15 mL of DMF, and HATU (6.2 g, 16.4 mmol) and DIPEA (4.2 g, 32.7 mmol) were added with stirring. The reaction was stirred at room temperature for 4 h, and 700 mL of water was added to quench the reaction. The organic phases were extracted with ethyl acetate (100 mL*3) and then combined and dried over anhydrous sodium sulfate. The product M-2 was then purified by flash chromatography and dried to dryness.

[0192] LC-MS: m / z = 417.0 [M+H] +

[0193] 1 H NMR (400MHz, CDCl3) δ8.50 (d, J=8.4Hz, 1H), 7.93 (ddd, J=17.2, 7.6, 1.3Hz, 2 H),7.81(d,J=8.2Hz,1H),7.58(ddd,J=8.4,6.8,1.4Hz,1H),7.55-7.44(m,2 H),7.21(d,J=7.9Hz,1H),7.17(s,1H),7.00(d,J=8.2Hz,1H),6.64(s,1H),6 .42(s,1H),2.10(s,3H),1.60-1.56(m,2H),1.50(s,9H),1.42-1.37(m,2H). 13C NMR (101MHz, CDCl3) δ169.49,152.77,136.92,136.83,135.88,134.01,131.96,131.39,130.51,128.97,128. 77,128.31,126.20,125.47,124.21,120.15,117.11,80.64,77.36,77.04,76.73,34.80,28.31,18.78,14.82.

[0194] Step 3: 1-(5-amino-2-methylphenyl)-2-(naphthalen-1-ylcyclopropyl)ethan-1-one (M-3)

[0195] Dissolve compound M-2 (2 g, 4.8 mmol) in 10 mL of 1,4-dioxane solution. Add 10 mL of 4M HCl / 1,4-dioxane solution dropwise with stirring. Allow to react at room temperature for 4 h. Monitor the reaction by LC-MS. Filter the resulting hydrochloride solid and use it directly in subsequent reactions without further treatment.

[0196] LC-MS: m / z = 317.2 [M+H] +

[0197] Preparation of the key intermediate 5-amino-2-methyl-N-(naphthalen-1-ylcyclopropyl)benzamide (N-3) in the above example:

[0198] Step 1: (1R)-1-(naphthalen-1-yl)ethan-1-amine (N-1)

[0199] 1-(Naphthalen-1-yl)ethan-1-one (2 g, 11.8 mmol) and Ti(OEt)4 (4 g, 17.7 mmol) were dissolved in 20 mL of THF and stirred under a nitrogen atmosphere. (R)-(+)-tert-butylsulfenamide (1.7 g, 14.16 mmol) was then added and the temperature was raised to 60°C and stirred for 4-6 hours. After the reaction was complete as monitored by LC-MS, the temperature was lowered to 0°C and sodium borohydride (1.3 g, 35.4 mmol) was slowly added. The reaction was continued in an ice bath for 3 hours, and the reaction was complete as monitored by LC-MS. After completion of the reaction, the reaction solution was filtered through celite and concentrated. 10 mL of a 4M HCl / 1,4-dioxane solution was added to the concentrated solid. After completion of the reaction as monitored by LC-MS, the product N-1 was purified by flash chromatography.

[0200] LC-MS: m / z = 172.1 [M+H] +

[0201] Step 2: 2-methylpropane-2-yl {[3-({[(1R)-1-(naphthalen-1-yl)ethyl]amino}carbonyl)-4-methylphenyl]amino}methane ester (N-2)

[0202] Compound N-1 (2 g, 11.7 mmol) and 2-methyl-5-({[(2-methylprop-2-yl)oxy]carbonyl}amino)benzoic acid (2.9 g, 11.7 mmol) were dissolved in 15 mL of DMF, and HATU (6.7 g, 17.6 mmol) and DIPEA (4.5 g, 35.1 mmol) were added with stirring. The reaction was stirred at room temperature for 4 h, and quenched by adding 700 mL of water. The organic phases were extracted with ethyl acetate (100 mL*3), combined, and dried over anhydrous sodium sulfate. The product N-2 was then purified by flash chromatography and dried to dryness.

[0203] LC-MS: m / z = 405.2 [M+H] +

[0204] Step 3: 5-amino-2-methyl-N-[(1R)-1-(naphthalen-1-yl)ethyl]benzamide (N-3)

[0205] Compound M-2 (2 g, 4.8 mmol) was dissolved in 10 mL of 1,4-dioxane solution. 10 mL of 4M HCl / 1,4-dioxane solution was added dropwise with stirring. The mixture was allowed to react at room temperature for 4 h. LC-MS monitored the reaction completion. The hydrochloride solid was filtered to obtain a small amount of ethyl acetate, stirred for 30 min, and filtered to obtain the white solid product N-3.

[0206] LC-MS: m / z = 305.2 [M+H] +

[0207] 1 H NMR (400MHz, CDCl3) δ8.20 (d, 1H, J = 8.4Hz), 7.85 (d, 1H, J = 8.0Hz), 7.78 (d, 1H, J = 8.0Hz), 7.57-7.40 (m, 4H), 6. 89(d,1H,J=8.0Hz),6.70(m,2H,J=13.5Hz),6.10-6.07(m,2H),3.25(s,2H),2.27(s,3H),1.73(d,3H,J=6.0Hz). 13C NMR (101MHz, CDCl3) δ169.0,143.9,138.0,136.9,133.8,131.7,131.1,128.7,1 28.3,127.2,126.5,125.8,125.1,123.5,122.5,116.6,113.3,44.7,20.5,18.6.

[0208] Example 1:

[0209] The above intermediate N-3 (40 mg, 0.13 mmol), 5-bromo-2-chloropyridine-3-carboxylic acid (31 mg, 0.13 mmol), and Hatu (74 mg, 0.2 mmol) were dissolved in DMF, and DIPEA (50 mg, 0.40 mmol) was added at room temperature. The mixture was stirred at room temperature for 4 h. After TLC detection, the reaction was complete and purified by HPLC to obtain 61 mg of a white solid product (yield 90%).

[0210] SIMM1: 1 H NMR (400MHz, DMSO) δ10.72(s,1H),8.97(d,J=8.0Hz,1H),8.72(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),8.26(d,J=8.4Hz,1H),7.96(d,J= 8.0Hz,n1H),7.85(d,J=8.2Hz,1H),7.73-7.47(m,7H),7.24(d,J=8.3Hz,1H),5.95(q,J=7.3Hz,1H),2.26(s,3H),1.59(d,J=6.8Hz,3H). 13 C NMR (101MHz, DMSO) δ168.31,162.40,151.55,140.79,140.65,138.31,136.49,133.85,131.20,130.91,129.15,127.76,126.67,126.12, 125.92,123.66,122.94,120.56,119.48,118.54,44.75,40.59,40.38,40.17,39.96,39.76,39.55,39.34,21.95,19.15.HRMS(ESI)calcd for C 26 H 22 BrClN3O2[M+H] + 522.0578,found 522.0579.

[0211] Example 2:

[0212] The reaction steps were the same as those in Example 1. Starting from the intermediate N-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0213] SIMM2: 1 H NMR (400MHz, DMSO) δ10.61(s,1H),8.98(d,J=8.1Hz,1H),8.26(d,J=8.5Hz,1H),8.19(d,J=9.0Hz,1H),7.96(d,J=8.0Hz,1H),7.84(d,J=8.2 Hz,1H),7.71(d,J=8.3Hz,1H),7.67-7.47(m,6H),7.27-7.19(m,3H),5.95(q,J=7.3Hz,1H),3.94(s,3H),2.26(s,3H),1.59(d,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO)δ168.44,164.45,163.96,140.72,139.13,138.28,136.96, 136.01,133.85,131.09,130.91,130.55,129.14,127.74,127.49,126.66,126 .11,125.92,123.67,122.94,120.46,118.46,115.79,114.68,57.03,44.75,4 0.59,40.38,40.17,39.96,39.75,39.55,39.34,21.99,19.12.HRMS(ESI)calcd for C 28 H 26 N3O5[M+H] + 484.1867, found 484.1867.

[0214] Example 3:

[0215] The reaction steps were the same as those in Example 1. Starting from the intermediate N-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0216] SIMM3: 1H NMR (400MHz, DMSO) δ11.90 (s, 1H), 10.40 (s, 1H), 8.93 (d, J = 8.0Hz, 1H), 8.26 ( d,J=8.4Hz,1H),7.96(d,J=8.1Hz,1H),7.85(d,J=8.2Hz,1H),7.75(d,J=8.4H z,1H),7.71(s,1H),7.66-7.50(m,5H),7.21(d,J=8.2Hz,1H),6.86(s,1H),6. 55(d,J=6.7Hz,1H),5.94(t,J=7.5Hz,1H),2.25(s,3H),1.59(d,J=6.8Hz,3H). 13 CNMR(101MHz,DMSO)δ168.41,164.23,162.87,146.82,140.70,138.03,136 .63,136.52,133.86,131.03,130.98,130.91,129.15,127.75,126.66,126 .12,125.94,123.68,122.94,121.41,119.42,119.06,103.64,44.77,40.5 7,40.36,40.15,39.94,39.73,39.53,39.32,22.00,19.16.HRMS(ESI)calcd for C 26 H 24 N3O3[M+H] + 426.1812, found 426.1815

[0217] Example 4:

[0218] The reaction steps were the same as those in Example 1. Starting from the intermediate N-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0219] SIMM4: 1H NMR (400MHz, DMSO) δ10.34(s,1H),8.93(d,J=8.0Hz,1H),8.27(d,J=8.5Hz,1H),7.97(d,J=8.0Hz,1H),7.91(d,J=3.9Hz,1H),7.85(d,J=8.2Hz,1 H),7.76-7.69(m,1H),7.65-7.50(m,5H),7.27(d,J=3.6Hz,1H),7.21(d, J=8.4Hz,1H),5.95(t,J=7.4Hz,1H),2.26(s,3H),1.59(d,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO)δ168.35,159.24,140.63,139.52,138.09,136.35,13 4.44,133.86,131.07,130.92,130.85,129.55,129.15,128.79,127.76, 126.66,126.12,125.93,123.68,122.98,121.38,119.32,44.75,40.59, 40.38,40.17,39.97,39.76,39.55,39.34,21.97,19.16.HRMS(ESI)calcd for C 25 H 22 ClN2O2S[M+H] + 449.1085, found 449.1089.

[0220] Example 5:

[0221] The reaction steps were the same as those in Example 1. Starting from the intermediate N-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0222] SIMM5: 1 H NMR (400MHz, DMSO) δ12.02(s,1H),8.96(d,J=8.0Hz,1H),8.41(s,1H),8.26(d,J=8.5Hz,1H),8.10(s,1H),7.96(d,J=8.1Hz,1H),7.85 (d,J=8.3Hz,1H),7.69-7.49(m,7H),7.22(d,J=8.1Hz,1H),5.97-5.90(m,1H),2.31-2.24(m,3H),1.60(d,J=6.9Hz,3H),1.22(s,1H). 13C NMR(101MHz,DMSO)δ168.23,161.80,160.79,146.60,141.01,140.68,138 .15,136.05,133.86,131.43,131.15,130.91,129.15,127.75,126.64,126 .11,125.94,123.68,122.98,121.82,120.91,118.83,98.51,44.87,40.59 ,40.38,40.17,39.97,39.76,39.55,39.34,21.95,19.24.HRMS(ESI)calcd for C 26 H 23 BrN3O3[M+H] + 504.0917,found 504.0918.

[0223] Example 6:

[0224] The reaction steps were the same as those in Example 1. Starting from the intermediate N-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0225] SIMM6: 1 H NMR (400MHz, DMSO) δ12.76(s,1H),12.19(s,1H),8.95(d,J=7.9Hz,1H),8.47(d,J =7.2Hz,1H),8.26(d,J=8.4Hz,1H),7.96(d,J=8.0Hz,1H),7.82(dd,J=14.4,7.1H z,2H),7.64(dd,J=15.6,9.3Hz,4H),7.53(d,J=9.7Hz,2H),7.21(d,J=8.1Hz,1H) ,6.58(t,J=6.7Hz,1H),5.94(p,J=7.2Hz,1H),2.25(s,3H),1.60(d,J=6.8Hz,3H). 13C NMR (101MHz, DMSO) δ168.32,163.02,162.01,145.07,140.71,140.61,138. 13,136.38,133.87,131.40,130.92,130.81,129.16,127.75,126.64,126. 11,125.95,123.69,122.99,120.83,120.43,118.75,107.44,44.88,40.59 ,40.38,40.17,39.96,39.75,39.54,39.33,21.95,19.23.HRMS(ESI)calcd for C 26 H 24 N3O3[M+H] + 426.1812,found426.1813.

[0226] Example 7:

[0227] The reaction steps were the same as those in Example 1. Starting from the intermediate N-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0228] SIMM7: 1 H NMR (400MHz, DMSO) δ10.27(s,1H),8.93(d,J=8.0Hz,1H),8.27(d,J=8.4Hz,1H),8.02(d,J=3.6Hz,1H),7.97(d,J=8.1Hz,1H),7.88-7.82 (m,2H),7.75(d,J=8.0Hz,1H),7.68-7.51(m,5H),7.22(dt,J=8.0,4.9Hz,2H),5.94(q,J=7.2Hz,1H),2.26(s,3H),1.59(d,J=6.9Hz,3H). 13 C NMR (101MHz, DMSO) δ168.44,160.31,140.42,138.05,136.72,133.86,132.37,130.99,130.53,129.53,129.15,128.57,127.75,126.66, 126.12,125.94,123.70,122.97,121.36,119.30,44.75,40.59,40.38,40.17,39.96,39.75,39.55,39.34,22.00,19.15.HRMS(ESI)calcd for C 25 H 23N2O2S[M+H] + 415.1475, found 415.1471.

[0229] Example 8:

[0230] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0231] SIMM8: 1 H NMR (400MHz, DMSO) δ11.88(s,1H),10.30(s,1H),9.16(s,1H),8.67(d,J=8.4Hz ,1H),7.94(dd,J=8.0,1.5Hz,1H),7.85(dd,J=7.6,6.1Hz,2H),7.69(dd,J=8.3, 2.3Hz,1H),7.61-7.44(m,5H),7.12(d,J=8.4Hz,1H),6.82(d,J=1.8Hz,1H),6.5 1(dd,J=6.7,1.8Hz,1H),2.01(s,3H),1.38(q,J=4.7Hz,2H),1.24-1.17(m,2H). 13 C NMR (101MHz, DMSO) δ169.60,164.09,162.84,146.70,138.24,137.93,136.59,136.43,133.94,132.28,130.87,130.72,129.00,128.91, 128.17,126.27,125.91,125.59,125.52,121.27,119.05,103.56,40 .60,40.39,40.18,39.97,39.76,39.55,39.34,34.46,18.79,14.71.

[0232] Example 9:

[0233] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0234] SIMM9: 1H NMR (400MHz, DMSO) δ11.23(s,1H),10.19(s,1H),9.17(s,1H),8.67(d,J=8.4Hz,1H),7.95(d,J=8.0Hz,1H),7.86(t,J=6.7Hz,2H),7.78-7.68(m,2H ),7.62-7.46(m,4H),7.37(d,J=7.2Hz,1H),7.14(d,J=8.3Hz,1H),6.80(d ,J=8.6Hz,1H),2.01(s,3H),1.38(d,J=5.7Hz,2H),1.21(d,J=5.5Hz,2H). 13 C NMR (101MHz, DMSO) δ169.54,162.81,141.03,138.33,137.94,136.05,133.94,132.27,131.06,130.65,129.02,128.92,128. 18,126.27,125.92,125.58,125.54,120.80,118.64,40.62,40.40,40.20,39.99,39.78,39.57,39.36,34.48,18.79,14.72.

[0235] Example 10:

[0236] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0237] SIMM10: 1 H NMR (400MHz, DMSO) δ10.17 (s, 1H), 9.18 (s, 1H), 8.69 (dd, J = 8.5, 1.3Hz, 1H) ,8.00-7.91(m,2H),7.91-7.80(m,3H),7.72(dd,J=8.3,2.3Hz,1H),7.63-7 .45(m,3H),7.40(d,J=2.3Hz,1H),7.20(dd,J=5.0,3.7Hz,1H),7.12(d,J=8 .4Hz,1H),2.02(s,3H),1.39(q,J=4.8Hz,2H),1.20(td,J=4.9,2.4Hz,2H). 13C NMR (101MHz, DMSO) δ169.63,160.20,140.41,138.28,137.95,136.66,133.95,132.34,132.29,130.89,130.19,129.45,129.04,128.92, 128.56,128.18,126.27,125.92,125.62,125.54,121.16,118.93,40 .62,40.41,40.20,40.00,39.79,39.58,39.37,34.45,18.74,14.73.

[0238] Example 11:

[0239] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0240] SIMM11: 1 H NMR (400MHz, DMSO) δ9.95(s,1H),9.15(s,1H),8.67(d,J=8.3Hz,1H),7.94(dd,J=8.1,1.5Hz,1H ),7.85(dt,J=8.3,2.4Hz,2H),7.61-7.45(m,5H),7.30(d,J=2.3Hz,1H),7.06(d,J=8.4Hz,1H), 3.15(dddd,J=17.2,12.1,6.8,3.2Hz,2H),2.79(dtd,J=10.2,7.7,3.3Hz,1H),2.28(dd,J=7.8, 2.5Hz,2H),1.97(s,3H),1.94-1.65(m,2H),1.36(q,J=4.4Hz,2H),1.18(dq,J=7.2,3.5Hz,2H). 13 C NMR (101MHz, DMSO) δ172.45,169.84,169.68,138.24,137.94,137.04,133.92,132.26,130.90,129.64,129.00,128.91,128.17,126.27,12 5.91,125.60,125.52,120.06,117.81,40.58,40.37,40.22,40.16,3 9.96,39.74,39.68,39.54,39.33,34.43,33.99,26.10,18.72,14.70.

[0241] Example 12:

[0242] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0243] SIMM12: 1 H NMR (400MHz, DMSO) δ10.06(s,1H),9.17(s,1H),8.67(d,J=8.3Hz,1H),7.94(d,J=8.0H z,1H),7.88-7.81(m,2H),7.76(d,J=2.5Hz,1H),7.61-7.46(m,4H),7.30(d,J=2.3Hz, 1H),7.07(d,J=8.3Hz,1H),3.25(t,J=7.6Hz,1H),3.21-3.10(m,2H),1.98(s,3H),1.9 2(dd,J=7.9,4.5Hz,2H),1.87-1.55(m,2H),1.36(d,J=4.6Hz,2H),1.22-1.16(m,2H). 13 C NMR (101MHz, DMSO) δ169.69,169.35,168.21,138.21,137.94,136.98,133.92,132.27,130.91,129.67,128.99,128.91,128.16,126.27,12 5.90,125.59,125.52,119.95,117.71,49.78,41.77,40.59,40.38,4 0.17,39.96,39.75,39.54,39.34,34.44,25.00,21.03,18.75,14.69.

[0244] Example 13:

[0245] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0246] SIMM13: 1H NMR (400MHz, DMSO) δ10.14(s,1H),9.19(s,1H),8.68(d,J=8.3Hz,1H),7.98-7.89(m,2H),7.86(dd,J=7.4,5.8Hz,2H),7.72(dd,J=8.3,2.3Hz,1H),7. 61-7.44(m,4H),7.30(d,J=3.5Hz,1H),7.11(d,J=8.4Hz,1H),6.68(dd,J= 3.5,1.7Hz,1H),2.01(s,3H),1.37(q,J=4.6Hz,2H),1.20(q,J=5.7Hz,2H). 13 C NMR (101MHz, DMSO) δ169.67,156.55,147.82,146.22,138.24,137.94,136.47,133.94,132.28,130.84,130.19,129.02,128.92,128.18, 126.28,125.92,125.61,125.54,121.16,118.93,115.08,112.58,40 .59,40.38,40.17,39.96,39.75,39.54,39.33,34.44,18.75,14.71.

[0247] Example 14:

[0248] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0249] SIMM14: 1 H NMR (400MHz, DMSO) δ11.29(s,1H),10.21(s,1H),9.20(s,1H),8.67(d,J=8.4Hz ,1H),7.95(dd,J=7.8,1.4Hz,1H),7.89-7.81(m,2H),7.80-7.68(m,2H),7.62- 7.47(m,4H),7.36(d,J=7.3Hz,1H),7.14(d,J=8.4Hz,1H),6.80(d,J=8.5Hz,1H ),3.54-3.31(m,1H),2.01(s,3H),1.38(q,J=4.6Hz,2H),1.20(q,J=4.9Hz,2H). 13C NMR (101MHz, DMSO) δ169.55,162.86,161.78,141.03,138.31,137.93,136.07,133.94,132.27,131.06,130.64,129.03,128.93, 128.19,126.29,125.93,125.58,125.55,120.80,118.62,40.58,40.37,40.16,39.95,39.75,39.54,39.33,34.47,18.81,14.72.

[0250] Example 15:

[0251] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0252] SIMM15: 1 H NMR (400MHz, DMSO) δ10.62(s,1H),9.18(s,1H),8.74-8.65(m,2H),8.12(dt,J=7.8,1.2 Hz,1H),8.05(td,J=7.7,1.7Hz,1H),7.97-7.92(m,1H),7.89-7.84(m,2H),7.80(dd,J= 8.2,2.3Hz,1H),7.71(d,J=2.3Hz,1H),7.65(ddd,J=7.5,4.8,1.3Hz,1H),7.61-7.47(m ,3H),7.13(d,J=8.3Hz,1H),2.01(s,3H),1.39(q,J=4.7Hz,2H),1.20(t,J=3.4Hz,2H). 13 C NMR (101MHz, DMSO) δ169.69,162.89,150.28,148.87,138.57,138.16,137.98,136.28,133.94,132.31,130.87,130.53,129.01,128.92,128. 17,127.37,126.26,125.91,125.63,125.54,122.80,121.20,119.03, 40.59,40.39,40.18,39.97,39.76,39.55,39.34,34.48,18.83,14.74.

[0253] Example 16:

[0254] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0255] SIMM16: 1 H NMR (400MHz, DMSO) δ11.61(d,J=3.5Hz,1H),9.70(s,1H),9.19(s,1H),8.68(d,J=8.3Hz,1H),7. 94(dd,J=8.0,1.5Hz,1H),7.89-7.83(m,2H),7.74(dd,J=8.3,2.3Hz,1H),7.61-7.46(m,3H),7.4 1(d,J=2.3Hz,1H),7.09(d,J=8.4Hz,1H),7.02(ddd,J=3.8,2.4,1.4Hz,1H),6.94(td,J=2.7,1. 4Hz,1H),6.14(dt,J=3.7,2.4Hz,1H),2.00(s,3H),1.37(q,J=4.6Hz,2H),1.19(q,J=4.8Hz,2H). 13 C NMR (101MHz, DMSO) δ169.82,159.48,138.18,137.96,137.28,133.93,132.28,130.78,129.28,129.03,128.90,128.16,126.38,126.28, 125.93,125.62,125.54,123.02,120.66,118.41,111.68,109.40,40 .55,40.34,40.13,39.93,39.72,39.51,39.30,34.42,18.70,14.73.

[0256] Example 17:

[0257] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0258] SIMM17: 1H NMR (400MHz, DMSO) δ9.91 (s, 1H), 9.16 (s, 1H), 8.66 (dd, J = 8.4, 1.3Hz, 1H), 7. 94(dd,J=8.0,1.5Hz,1H),7.88-7.81(m,2H),7.60-7.46(m,5H),7.27(d,J=2.3 Hz,1H),7.08(d,J=8.4Hz,1H),4.00(td,J=5.7,2.4Hz,1H),2.14(t,J=6.4Hz, 2H),1.98(s,3H),1.96-1.55(m,4H),1.38-1.34(m,2H),1.19(t,J=3.4Hz,2H). 13 C NMR (101MHz, DMSO) δ171.11,171.03,169.64,138.32,137.92,136.79,133.93,132.26,130.91,129.81,129.00,128.92,128.17,126.26,12 5.91,125.58,125.53,120.22,118.02,55.90,40.59,40.38,40.17,3 9.96,39.75,39.54,39.34,34.43,31.61,26.37,18.89,18.70,14.68.

[0259] Example 18:

[0260] The reaction steps were the same as those in Example 1, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0261] SIMM18: 1H NMR (400MHz, DMSO) δ10.53(s,1H),9.25-9.09(m,2H),8.78(d,J=10.8Hz,1H),8.65(dd,J=8.4,1. 3Hz,1H),7.94(dd,J=8.0,1.5Hz,1H),7.85(d,J=7.6Hz,2H),7.63-7.44(m,4H),7.27(d,J=2.3Hz, 1H),7.13(d,J=8.3Hz,1H),4.36(s,1H),3.87(t,J=10.5Hz,1H),3.32-2.89(m,2H),2.19-2.11(m, 1H),2.00(s,3H),1.86-1.76(m,1H),1.75-1.46(m,4H),1.36(q,J=3.9Hz,2H),1.24-1.14(m,2H). 13 C NMR (101MHz, DMSO) δ169.50,167.62,138.46,137.88,135.95,133.92,132.24,131.18,130.69,128.99,128.92,128.18,126.27,125.9 2,125.53,120.32,118.11,58.06,43.75,40.58,40.37,40.16,39.95,39.74,39.53,39.32,34.45,27.48,22.10,21.66,18.73,14.68.

[0262] Example 19:

[0263] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0264] SIMM19: 1H NMR (400MHz, DMSO) δ10.58(s,1H),9.69(s,1H),9.19(s,1H),8.71-8.57(m,2H),7.94( dd,J=8.0,1.5Hz,1H),7.85(d,J=7.6Hz,2H),7.61-7.46(m,4H),7.29(d,J=2.3Hz,1H), 7.13(d,J=8.3Hz,1H),4.32(d,J=9.1Hz,1H),3.26(d,J=7.8Hz,2H),2.41-2.29(m,1H), 2.00(s,3H),1.90(qd,J=7.9,4.3Hz,3H),1.36(q,J=4.7Hz,2H),1.19(q,J=4.2Hz,2H). 13 C NMR (101MHz, DMSO) δ169.46,167.20,138.45,137.88,135.97,133.92,132.24,131.17,130.73,129.00,128.92,128.18,126.27,125.92,12 5.55,125.53,120.38,118.24,60.07,46.20,40.57,40.36,40.16,39 .95,39.74,39.63,39.53,39.32,34.44,30.05,24.03,18.74,14.68.s

[0265] Example 20:

[0266] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0267] SIMM20: 1 H NMR (500MHz, DMSO) δ10.39(s,1H),9.20(s,1H),9.07(d,J=2.4Hz,1H),8.75(dd,J=4.9,1.7Hz,1H),8.68(d,J=8.5 Hz,1H),8.25(dt,J=8.0,2.0Hz,1H),7.14(d,J=8.3Hz,1H),2.03(s,3H),1.38(q,J=4.9Hz,2H),1.23-1.18(m,2H). 13C NMR (126MHz, DMSO) δ169.63,164.29,152.60,149.08,138.29,137.93,136 .72,135.82,133.94,132.28,130.90,130.80,130.49,129.03,128.92,128 .18,126.28,125.92,125.60,125.54,123.96,121.24,119.02,40.47,40. 30,40.22,40.14,40.06,39.97,39.80,39.64,39.47,34.45,18.80,14.72.

[0268] Example 21:

[0269] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0270] SIMM21: 1 H NMR (500MHz, DMSO) δ10.45(s,1H),9.20(s,1H),8.81-8.74(m,2H),8.68(d,J=8.4Hz,1H),7.94(d,J=8.1Hz,1H),7.89-7.81(m,4H),7.74(dd,J=8.3 ,2.3Hz,1H),7.59(ddd,J=8.4,6.8,1.5Hz,1H),7.55-7.45(m,3H),7.15(d ,J=8.3Hz,1H),2.03(s,3H),1.38(q,J=4.7Hz,2H),1.21(t,J=3.3Hz,2H). 13 C NMR (126MHz, DMSO) δ169.58,164.19,150.75,142.12,138.30,137.92,136.49,133.94,132.28,130.93,130.75,129.03,128.92,128.18,126 .28,125.92,125.59,125.54,121.94,121.34,119.14,40.47,40.30,4 0.22,40.14,40.06,39.97,39.80,39.63,39.47,34.45,18.81,14.71.

[0271] Example 22:

[0272] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0273] SIMM22: 1 H NMR (500MHz, DMSO) δ10.72(s,1H),9.18(s,1H),9.00(s,2H),8.68(s,1H),7.98-7.44(m,9H),7.14(s,1H),2.01(s,3H),1.38(s,2H),1.20(s,2H). 13 CNMR(126MHz,DMSO)δ169.65,161.45,158.68,158.29,138.21,137.94,136.30,133.93,132.30,130.91,130.74,128.91,128 .17,126.27,125.91,125.56,123.63,121.17,118.98,40.47,40.30,40.13,39.97,39.80,39.63,39.47,34.48,18.83,14.71.

[0274] Example 23:

[0275] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0276] SIMM25: 1 H NMR(400MHz,DMSO)δ10.38(s,1H),9.15(s,1H),8.74-8.63(m,1H),7.98- 7.91(m,1H),7.89-7.82(m,3H),7.73-7.63(m,2H),7.62-7.45(m,3H),7.3 0(dd,J=8.5,4.1Hz,1H),7.21(dd,J=8.4,1.4Hz,1H),7.10(d,J=8.3Hz,1H ),6.90(s,1H),2.00(s,3H),1.38(q,J=4.6Hz,2H),1.19(q,J=4.8Hz,2H). 13C NMR (101MHz, DMSO) δ169.72,166.26,147.34,138.08,137.99,136.35,136.03,133.94,132.30,130.85,129.97,128.99,128.92,128.42,128. 26,128.16,126.25,125.89,125.63,125.54,125.39,120.87,118.67, 40.60,40.39,40.18,39.97,39.76,39.55,39.35,34.47,18.80,14.72.

[0277] Example 24:

[0278] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0279] SIMM26: 1 H NMR (500MHz, DMSO) δ9.63 (s, 1H), 9.13 (s, 1H), 8.67 (d, J = 8.4Hz, 1H), 7.94 (d, J = 8.1Hz, 1H),7.87-7.82(m,2H),7.61-7.55(m,2H),7.53(t,J=7.3Hz,1H),7.48(t,J=7.6Hz,1H) ,7.41-7.36(m,1H),7.05(d,J=8.2Hz,1H),2.86(d,J=12.2Hz,1H),2.10(s,3H),1.96(s ,4H),1.69(d,J=11.3Hz,2H),1.59-1.49(m,3H),1.38-1.35(m,2H),1.25-1.17(m,4H). 13 C NMR (126MHz, DMSO) δ172.19,169.73,138.21,137.96,136.87,133.93,13 2.28,130.73,129.64,129.00,128.90,128.15,126.24,125.90,125.62, 125.52,120.35,118.13,70.42,55.42,44.40,40.48,40.31,40.24,40.1 5,39.98,39.81,39.64,39.48,34.42,29.86,25.28,23.42,18.68,14.70.

[0280] Example 25:

[0281] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0282] SIMM27: 1 H NMR (400MHz, DMSO) δ9.60 (s, 1H), 9.13 (s, 1H), 8.66 (d, J = 8.3Hz, 1H), 7.94 (d, J=8.0Hz,1H),7.84(d,J=7.6Hz,2H),7.59-7.44(m,4H),7.35(d,J=2.3Hz,1H), 7.04(d,J=8.3Hz,1H),3.09-2.71(m,2H),2.23-2.12(m,1H),1.95(s,3H),1.72 -1.44(m,6H),1.36(d,J=4.4Hz,2H),1.27-1.16(m,4H),0.97(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO)δ172.58,169.71,138.24,137.95,136.83,133.93,13 2.27,130.74,129.59,128.97,128.90,128.15,126.23,125.89,125.60, 125.51,120.30,118.07,67.99,50.58,49.85,40.60,40.39,40.18,39.9 7,39.77,39.56,39.35,34.43,29.86,25.15,23.48,18.66,14.67,12.08.

[0283] Example 26:

[0284] SIMM18 (40 mg, 0.09 mmol), bromomethylbenzene (16 mg, 0.09 mmol) and potassium carbonate (39 mg, 0.28 mmol) were dissolved in DMF and stirred at 60°C for 8 h. The reaction was complete when detected by TLC, and then purified by HPLC to obtain the target product.

[0285] SIMM28: 1H NMR (400MHz, DMSO) δ9.77(s,1H),9.15(s,1H),8.67(d,J=8.2Hz,1H),7.95(d,J=7.9Hz ,1H),7.85(dd,J=7.7,3.4Hz,2H),7.64-7.44(m,4H),7.44-7.38(m,1H),7.37-7.14(m, 5H),7.06(d,J=8.3Hz,1H),3.70(d,J=13.3Hz,1H),3.15(d,J=13.3Hz,1H),2.98-2.71( m,2H),1.97(s,3H),1.77(d,J=10.0Hz,1H),1.67(d,J=11.0Hz,2H),1.56-1.09(m,8H). 13 C NMR (101MHz, DMSO) δ172.55,169.74,138.72,138.31,137.96,136.86,133.94, 132.29,130.77,129.64,129.24,128.99,128.91,128.57,128.17,127.40,126. 24,125.90,125.61,125.53,120.36,118.10,68.01,60.06,51.15,40.60,40.40,40.19,39.98,39.77,39.56,39.35,34.43,29.77,24.99,23.43,18.66,14.69.

[0286] Example 27:

[0287] The compound 5-hydroxy-2-methyl-N-(naphthalen-1-ylcyclopropyl)benzamide (100 mg, 0.32 mmol) and 1-(((2-methylprop-2-yl)oxy)carbonyl)piperidine-2-carboxylic acid (65.7 mg, 0.32 mmol) were dissolved in DMF, and EDCI (60.4 mg, 0.35 mmol) and DMAP (18 mg, 0.16 mmol) were added sequentially with stirring at room temperature. After reacting at room temperature for 4 h, the mixture was purified by flsah, and then Boc was removed by hydrochloric acid (4 M in Dioxane). Purification by HPLC gave a white solid product.

[0288] SIMM29: 1H NMR (500MHz, DMSO) δ9.46 (s, 1H), 9.26 (s, 1H), 9.18 (s, 1H), 8.64 (dd, J = 8.4, 1.2Hz, 1H), 7.96-7.92 (m, 1H) ,7.86-7.82(m,2H),7.60-7.50(m,2H),7.47(dd,J=8.1,7.1Hz,1H),7.24(d,J=8.4Hz,1H),7.09(dd,J=8.2 ,2.6Hz,1H),6.89(d,J=2.6Hz,1H),4.34(d,J=9.4Hz,1H),3.32(d,J=12.4Hz,1H),2.95(d,J=10.4Hz,1H), 2.25-2.17(m,1H),1.85-1.71(m,3H),1.62(qd,J=11.5,3.2Hz,2H),1.43-1.32(m,2H),1.22-1.15(m,2H). 13 C NMR (126MHz, DMSO) δ168.64,168.18,147.58,139.20,137.76,133.94,133 .56,132.21,131.98,128.99,128.94,128.22,126.24,125.91,125.54,125 .49,122.31,119.98,56.28,43.97,40.48,40.40,40.31,40.24,40.15,40. 07,39.98,39.81,39.65,39.48,34.51,25.97,21.71,21.60,18.69,14.59.

[0289] Example 28:

[0290] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0291] SIMM30: 1H NMR (400MHz, DMSO) δ9.83(s,1H),9.14(s,1H),8.67(d,J=8.3Hz,1H),7.94(d,J=8.0Hz,1H),7.84(d,J=7.6Hz,2H),7.61-7.45(m,4H),7.3 7(s,1H),7.05(d,J=8.3Hz,1H),2.81-2.69(m,4H),2.63(d,J=10.0Hz,1H),2.15(d,J=16.4Hz,8H),1.96(s,3H),1.36(s,2H),1.18(s,2H). 13 C NMR (101MHz, DMSO) δ169.91,169.69,138.21,137.95,136.62,133.93,132.27,130.76,129.86,128.99,128.90,128.15,126.24,125.90,125. 62,125.51,120.47,118.26,68.75,57.66,54.41,53.87,45.79,43.61, 40.61,40.40,40.19,39.98,39.77,39.56,39.35,34.43,18.70,14.69.

[0292] Example 29:

[0293] The reaction steps were the same as those in Example 1. Starting from the intermediate M-3, a one-step amide condensation reaction was performed and the target product was purified by HPLC.

[0294] SIMM31:1H NMR (400MHz, DMSO) δ10.80 (s, 1H), 9.21 (s, 1H), 8.67 (dd, J = 8.4, 1.3Hz, 1H) ,7.98-7.91(m,1H),7.85(d,J=7.6Hz,2H),7.63-7.45(m,5H),7.41(d,J=2. 3Hz, 1H), 7.15 (d, J = 8.3Hz, 1H), 6.54 (dd, J = 9.2, 1.3Hz, 1H), 6.43 (dd, J = 6. 8,1.4Hz,1H),2.02(s,3H),1.38(p,J=4.6Hz,2H),1.20(t,J=3.4Hz,2H).13C NMR (101MHz, DMSO) δ169.48,161.92,161.49,144.69,139.42,138.43,137.88,135.98,133.93,132.26,131.17,131.08,128.98,128.92,128 .20,126.29,125.92,125.54,121.32,120.92,118.68,105.87,40.59, 40.38,40.17,39.96,39.75,39.54,39.33,34.48,33.14,18.81,14.67.

[0295] Example 30:

[0296] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0297] SIMM33: 1H NMR(500MHz,DMSO)δ10.52(d,J=2.2Hz,1H),9.19(s,1H),8.78(q,J=10.7Hz,1H),8.66(d,J=8.4Hz,1H), 7.97-7.90(m,1H),7.88-7.80(m,2H),7.62-7.44(m,4H),7.28(d,J=2.3Hz,1H),7.12(d,J=8.4Hz,1H),3. 87(t,J=10.6Hz,1H),3.28(d,J=12.3Hz,1H),2.95(td,J=13.5,10.3Hz,1H),2.19-2.12(m,1H),2.00(s, 3H), 1.80 (dt, J=12.8, 3.3Hz, 1H), 1.75-1.47 (m, 4H), 1.37 (q, J=3.5Hz, 2H), 1.19 (dd, J=5.6, 2.9Hz, 2H). 13 C NMR (126MHz, DMSO) δ169.51,167.62,138.47,137.91,135.95,133.93,132.2 6,131.16,130.71,128.99,128.90,128.17,126.26,125.90,125.55,125.52, 120.34,118.15,117.76,115.43,58.08,43.77,40.44,40.27,40.19,40.10,40.03,39.94,39.77,39.60,39.44,34.46,27.47,22.09,21.65,18.71,14.67.

[0298] Example 31:

[0299] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0300] SIMM34: 1H NMR (500MHz, DMSO) δ10.52(s,1H),9.18(s,2H),8.77(q,J=11.0Hz,1H),8.66(dd,J=8.4,1.2Hz,1H),7.94(dd, J=8.2,1.4Hz,1H),7.85(d,J=7.3Hz,2H),7.62-7.44(m,4H),7.27(d,J=2.3Hz,1H),7.12(d,J=8.4Hz,1H),3.9 1-3.85(m,1H),3.28(d,J=12.3Hz,1H),2.95(q,J=11.7Hz,1H),2.19-2.12(m,1H),2.00(s,3H),1.80(dt,J=12 .4,3.2Hz,1H),1.72(dt,J=14.3,3.4Hz,1H),1.68-1.46(m,3H),1.36(q,J=3.6Hz,2H),1.19(t,J=4.0Hz,2H). 13 C NMR (126MHz, DMSO) δ169.52,167.62,138.46,137.89,135.95,133.93,13 2.25,131.17,130.70,128.99,128.91,128.18,126.27,125.91,125.53, 120.34,118.14,58.07,43.77,40.45,40.38,40.29,40.21,40.12,40.04 ,39.95,39.79,39.62,39.45,34.46,27.48,22.09,21.65,18.72,14.68.

[0301] Example 32:

[0302] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0303] SIMM35: 1H NMR(500MHz,DMSO)δ11.05(s,1H),9.99(s,1H),9.41(s,1H),9.19(s,1H),8.64( dd,J=8.5,1.3Hz,1H),7.96-7.90(m,1H),7.84(d,J=7.6Hz,2H),7.60-7.44(m,4H ),7.38-7.25(m,5H),7.15(d,J=8.4Hz,1H),5.21(s,1H),3.76-3.42(m,2H),3.18 -2.94(m,2H),1.99(s,3H),1.40-1.30(m,2H),1.19(ddd,J=8.4,5.9,3.6Hz,2H). 13 C NMR (126MHz, DMSO) δ169.40,165.92,158.70,138.59,137.87,135.68,133.93, 133.22,132.23,131.25,129.87,128.98,128.92,128.43,128.19,127.50,126. 25,126.12,125.90,125.53,120.58,118.39,57.01,40.48,40.40,40.31,40.23,40.14,40.07,39.98,39.89,39.81,39.64,39.48,34.48,24.95,18.74,14.65.

[0304] Example 33:

[0305] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0306] SIMM36: 1H NMR (500MHz, DMSO) δ10.57(s,1H),9.17(s,1H),8.65(dd,J=8.4,1.2Hz,1H),7.94(dd,J=8.1,1.5Hz ,1H),7.87-7.80(m,2H),7.58(ddd,J=8.4,6.7,1.5Hz,1H),7.53(ddd,J=8.0,6.8,1.3Hz,1H),7.51- 7.45(m,2H),7.24(d,J=2.3Hz,1H),7.13(d,J=8.3Hz,1H),4.24-4.15(m,2H),3.90(dt,J=12.4,3.2H z,1H),3.74-3.60(m,2H),3.31-3.12(m,2H),1.99(s,3H),1.38-1.31(m,2H),1.18(q,J=5.1Hz,2H). 13 C NMR (126MHz, DMSO) δ169.41,164.13,138.49,137.87,135.61,133.93,13 2.24,131.21,131.01,128.99,128.92,128.19,126.27,125.91,125.53, 120.48,118.29,66.23,63.43,56.64,42.58,40.47,40.40,40.31,40.23 ,40.14,40.06,39.97,39.89,39.81,39.64,39.47,34.46,18.74,14.67.

[0307] Example 34:

[0308] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0309] SIMM37: 1H NMR(500MHz,DMSO)δ10.71(s,1H),9.18(s,1H),8.65(d,J=8.4Hz,1H),7.94(dd,J=8.2,1.4Hz,1H), 7.84(d,J=7.6Hz,2H),7.58(ddd,J=8.4,6.7,1.5Hz,1H),7.55-7.50(m,2H),7.47(t,J=7.6Hz,1H),7 .25(d,J=2.2Hz,1H),7.14(d,J=8.3Hz,1H),4.31(dd,J=11.6,3.6Hz,1H),3.82(dd,J=13.4,3.6Hz,1 H),3.55-3.42(m,2H),3.33-3.14(m,3H),2.00(s,3H),1.36(q,J=4.4Hz,2H),1.19(t,J=3.3Hz,2H). 13 C NMR (126MHz, DMSO) δ169.39,163.68,138.48,137.88,135.53,133.93,13 2.24,131.16,131.13,128.99,128.92,128.18,126.26,125.91,125.54,1 20.74,118.58,118.46,116.10,54.33,42.68,40.46,40.38,40.29,40.2 1,40.12,40.04,39.95,39.87,39.79,39.62,39.45,34.45,18.74,14.66.

[0310] Example 35:

[0311] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0312] SIMM38: 1H NMR(500MHz,DMSO)δ10.49(s,1H),9.53(s,1H),9.18(s,1H),8.87(s,1H),8.66(dd,J=8.4,1.2Hz,1 H),7.58(ddd,J=8.4,6.8,1.5Hz,1H),7.55-7.50(m,2H),7.48(dd,J=8.2,7.1Hz,1H),7.30(d,J=2.3 Hz,1H),7.13(d,J=8.3Hz,1H),5.05(t,J=8.6Hz,1H),4.03-3.76(m,2H),2.69(dtd,J=11.8,9.4,6. 1Hz,1H),2.45(ddt,J=11.8,9.7,7.8Hz,1H),2.00(s,3H),1.39-1.33(m,2H),1.19(q,J=4.8Hz,2H). 13 CNMR(126MHz,DMSO)δ169.47,138.47,137.90,135.91,133.93,132.25,131.18,130.75,129.00,128.91,128.18,126.28,125.91,125.56,125 .53,120.38,118.25,58.69,43.56,40.46,40.29,40.21,40.12,40.04, 39.96,39.88,39.79,39.72,39.62,39.46,34.45,23.79,18.74,14.68.

[0313] Example 36:

[0314] The reaction steps were the same as those in Example 18, starting from the intermediate M-3, after a one-step amide condensation reaction, flash purification, and then Boc removal in HCl / dioxane solution, followed by HPLC purification to obtain the target product.

[0315] SIMM39: 1H NMR(500MHz,DMSO)δ10.62(s,1H),9.82(s,1H),9.57(s,1H),9.19(s,1H),8.66(dd,J= 8.4,1.2Hz,1H),7.97-7.91(m,1H),7.89-7.81(m,2H),7.61-7.45(m,4H),7.31(d,J=2 .3Hz,1H),7.29-7.24(m,4H),7.15(d,J=8.4Hz,1H),4.39(d,J=7.7Hz,2H),4.33-4.26 (m,1H),3.45-3.02(m,2H),2.00(s,3H),1.37(q,J=3.7Hz,2H),1.19(t,J=4.2Hz,2H). 13 C NMR (126MHz, DMSO) δ169.47,166.94,138.55,137.89,135.84,133.94,132.25 ,131.22,130.86,129.09,129.00,128.93,128.89,128.19,128.05,127.46,1 27.07,126.27,125.92,125.54,120.48,118.28,55.23,44.40,40.47,40.30,40.23,40.14,40.06,39.97,39.80,39.64,39.47,34.48,29.83,18.75,14.68.

[0316] Pharmacological activity test compound inhibitory effect on novel coronavirus PL proteolytic enzyme

[0317] The volume of the entire enzymatic reaction system was 120 μL, with a final concentration of 50 nM PL protease and 20 μM substrate (RLRGG-AMC) at the reaction buffer. The reaction system buffer consisted of 50 mM TRIS pH 7.5 and 0.1 mg / mL BSA. PL protease and the above compounds were added to a 96-well plate, with duplicate wells at each concentration incubated at room temperature for 20 minutes. The substrate was then added and the plate was quickly placed in a microplate reader for reading. Excitation and emission wavelengths were 360 ​​nm and 460 nm, respectively. The assay lasted 5 minutes, with fluorescence readings taken every 1 minute. The reaction rate was fitted based on the readings and compared with the control group (DMSO) to calculate the inhibition rate. The calculation formula was: Inhibition rate = 1 - (reaction rate of the test group / reaction rate of the control group).

[0318] The above conventional reagents were purchased from Sigma-Aldrich, the substrates were synthesized by GenScript Biotech, and the microplate reader model was Bio-tek Synergy H1.

[0319] The activity test results are shown in Table 1 below:

[0320] Table 1 Inhibitory effect of the compounds of the present invention on the novel coronavirus PL proteolytic enzyme Note: “ / ” means not tested.

[0321] The activity of the compounds in the prior art is around 1 μM, while the compounds of the present invention all have very excellent inhibitory activity, with inhibition rates exceeding 50% at the 320 nM level.

[0322] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0323] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor, prodrug or deuterated compound thereof; in, is a C6-C12 aryl group or a 3-12 membered heteroaryl group, and the hydrogen atoms on the aryl or heteroaryl group may be optionally replaced by R a1 replace; is a 3-12 membered heteroaryl or a 3-12 membered heterocyclic group, and the hydrogen atoms on the heteroaryl or heterocyclic group may be optionally replaced by R b1 replace; X1 and X2 are independently selected from: NH, O, S; R1 and R2 are each independently selected from H, halogen, substituted or unsubstituted C1-C6 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, -C(=O)R 4 、-OC(=O)R 4 、-C(=O)OR 4 、-OR 4 、-SR 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)2N(R 4 )2、-N(R 4 )2、-C(=O)N(R 4 )2、-NR 4 -C(=O)R 4 、-NR 4 -C(=O)OR 4 、-NR 4 -S(=O)2-R 4 、C(=O)-N(R 4 )2, -C1-C6 alkylene-N(R 4 )2, -C1-C6 alkylene-OR 4 、-C1-C6 alkenylene-OR 4 and -O-C1-C6 alkylene-N(R 4 )2; wherein, any of the above R 4 R1 and R2 are independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group; or, R1 and R2, to which they are attached, form a 3-6 membered cycloalkyl or 3-6 membered heterocyclic group, which may be optionally substituted; R3 represents one or more independent substituents on the ring, each R3 is independently selected from H, halogen, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, -N(R 5 )2、-OR 5 、-SR 5 、-C(=O)N(R 5 )2, -C(=O)OR 5 、-OC(=O)R 5 、-NR 5 -C(=O)R 5 、-NR 5 -C(=O)OR 5 、-NR 5 -S(=O)2-R 5 、-C1-C6 alkylene-N(R 5 )2, -C1-C6 alkylene-OR 5 、-C1-C6 alkenylene-OR 5 、-O-C1-C6 alkylene-N(R 5 )2 and -NR 5 -C1-C6 alkylene-OR 5 ; Among them, any of the above R 5 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl; R a1 represents one or more independent substituents on the ring, each R a1 independently selected from H, halogen, substituted or unsubstituted saturated or partially unsaturated C1-C6 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, -C(=O)R 6 、-OC(=O)R 6 、-C(=O)OR 6 、-OR 6 、-SR 6 、-S(=O)R 6 、-S(=O)2R 6 、-S(=O)2N(R 6 )2、-N(R 6 )2、-C(=O)N(R 6 )2、-NR 6 -C(=O)R 6 、-NR 6 -C(=O)OR 6 、-NR 6 -S=OR 6 、-NR 6 -S(=O)2-R 6 、C(=O)-N(R 6 )2, -C1-C6 alkylene-N(R 6 )2, -C1-C6 alkylene-OR 6 、-C1-C6 alkenylene-OR 6 and -O-C1-C6 alkylene-N(R 6 )2; wherein, any of the above R 6 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl; R b1 represents one or more independent substituents on the ring, each R b1 independently selected from H, (=O), halogen, nitro, cyano, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, C1-C6 haloalkyl, C3-C8 cycloalkyl, -N(R 9 )2、-OR 9 、-SR 9 、-C(=O)N(R 9 )2, -C(=O)OR 9 、-S(=O)2-R 9 、-NR 9 -C(=O)R 9 、-NR 9 -C(=O)OR 9 、-NR 9 -S(=O)2-R 9 、-C1-C6 alkylene-R 9 、-C1-C6 alkylene-N(R 9 )2, -C1-C6 alkylene-OR 9 、-C1-C6 alkenylene-OR 9 、-O-C1-C6 alkylene-N(R 9 )2、-NR 9 -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-COOH, or forming a substituted or unsubstituted fused ring, spiro ring or bridged ring structure with the B ring structure; wherein any of the above R 9 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl; The above substitution means that one or more H in the group is replaced by a group selected from halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, or that two H in -CH2- in the group are replaced by oxo=O; Provided that, when R1 is methyl and R2 is H, or R2 is methyl and R1 is H, the B ring is R b1 substituted or unsubstituted 3-12 membered heteroaryl and the B ring is not a 6-membered unsubstituted heteroaryl.

2. The compound according to claim 1, wherein Has the following structure: Among them, X a1 、X a2 、X a3 、X a4 、X a5 、X a6 、X a7 Independently selected from: CH, N; R a1 represents one or more independent substituents on the ring, each R a1 independently selected from H, C1-C6 alkyl, halogen, substituted or unsubstituted saturated or partially unsaturated C1-C6 aliphatic hydrocarbon, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, -C(=O)R 6 、-OC(=O)R 6 、-C(=O)OR 6 、-OR 6 、-SR 6 、-S(=O)R 6 、-S(=O)2R 6 、-S(=O)2N(R 6 )2、-N(R 6 )2、-C(=O)N(R 6 )2、-NR 6 -C(=O)R 6 、-NR 6 -C(=O)OR 6 、-NR 6 -S=OR 6 、-NR 6 -S(=O)2-R 6 、C(=O)-N(R 6 )2, -C1-C6 alkylene-N(R 6 )2, -C1-C6 alkylene-OR 6 、-C1-C6 alkenylene-OR 6 and -O-C1-C6 alkylene-N(R 6 )2; wherein, any of the above R 6 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl; Preferably, Has the following structure: More preferably, Has the following structure: Among them, R a1 As described in claim 1.

3. The compound according to claim 1, wherein R1 and R2 are independently selected from H, C1-C3 alkyl, or R1 and R2 together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl or a 3-5 membered heterocyclic group; Preferably, The structure is as follows: More preferably, The structure is as follows:

4. The compound according to claim 1, wherein X1, X2 are independently selected from the following heteroatoms: NH, O; More preferably, X1 is selected from NH, X2 is selected from NH or O; or X1 is selected from O, X2 is selected from O.

5. The compound according to claim 1, wherein The compound has the following structure: Among them, R a1 、R3、 As stated in claim 1, Preferably, R3 is selected from H, halogen, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, -N(R 5 )2、-OR 5 、-NR 5 -C(=O)R 5 、-OC(=O)R 5 、-NR 5 -S(=O)2-R 5 ; Among them, any of the above R 5 All can be independently selected from H, C1~C6 alkyl; Further preferably, R3 represents an independent substituent on the benzene ring and the substitution position is as follows:

6. The compound according to claim 1, wherein Has the following structure: Wherein, m and n are independently 0 or 1; Y1, Y2, Y3, Y4, Y5, and Y6 are independently selected from C, N, O, and S, and not all are C; R 10 、R 11 represents one or more independent substituents on the ring, each R 10 、R 11 independently selected from H, (=O), halogen, nitro, cyano, substituted or unsubstituted C1-C6 aliphatic hydrocarbon, C3-C8 cycloalkyl, -N(R 9 )2、-OR 9 、-SR 9 、-C(=O)N(R 9 )2, -C(=O)OR 9 、-S(=O)2-R 9 、-NR 9 -C(=O)R 9 、-NR 9 -C(=O)OR 9 、-NR 9 -S(=O)2-R 9 、-C1-C6 alkylene-R 9 、-C1-C6 alkylene-N(R 9 )2, -C1-C6 alkylene-OR 9 、-C1-C6 alkenylene-OR 9 、-O-C1-C6 alkylene-N(R 9 )2、-NR 9 -C1-C6 alkylene-OR 9 , -C1-C6 alkylene-COOH, or forming a substituted or unsubstituted fused ring, spiro ring or bridged ring structure with the above cyclic structure; wherein any of the above R 9 Each of them can be independently selected from H, guanidino, C1-C6 alkyl, saturated or partially unsaturated C3-C6 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-C10 aryl group.

7. The compound according to claim 1, wherein Has the following structure: Preferably, Has the following structure: Among them, R 13 represents one or more independent substituents on the ring, each R 13 Independently selected from H, (=O), halogen, nitro, -OH, -NH2, C1-C6 alkoxy or C1-C6 alkyl; R 12 and R 14 Independently selected from the following structures: absent, -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF3, -OH, 8. The compound according to claim 1, wherein The compound has the following structure:

9. Use of a compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor, prodrug or deuterated compound thereof, characterized in that: For the preparation of (a) SARS-CoV2 PL pro inhibitors, and / or (b) for preventing and / or treating SARS-CoV2 PL pro Pharmaceutical compositions for treating inflammatory diseases.

10. A pharmaceutical composition, characterized in that The invention comprises a compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer, racemate, hydrate, ester, solvate, metabolic precursor, prodrug or deuterated compound thereof, and a pharmaceutically acceptable carrier and / or excipient.

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