Amide compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention provides a compound containing a general formula I as well as a preparation method, a pharmaceutical composition and application thereof, and particularly provides a compound with a structure as shown in the general formula I as well as a racemate, an isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture of the racemate, the isomer, the S-isomer and the pharmaceutically acceptable salt. The compound has good inhibitory activity on PL protease, so that the compound can be used for treating, preventing and relieving diseases related to the PL protease, and particularly can be used for treating viral diseases with the PL protease, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV and the like. # imgabs0 #

Description

A class of amide compounds and their preparation methods, pharmaceutical compositions and uses Technical Field

[0001] The present invention relates to the fields of pharmaceutical chemistry and pharmacotherapy, and in particular to a class of compounds containing the general formula I as coronavirus papain-like protease inhibitors, a preparation method thereof, a pharmaceutical composition containing such compounds, and a class of compounds containing papain-like protease inhibitors (also known as PL pro , or PL protease) inhibitors, particularly for the treatment of viral diseases in which PL protease is present, such as those caused by SARS-CoV-2, SARS-CoV and MERS-CoV. Background Art

[0002] The novel coronavirus is a medium-sized, spherical, enveloped, single-stranded positive-strand RNA virus with a diameter of approximately 80 to 160 nm and a genome length of approximately 30 kb, making it the largest known RNA virus. The SARS-CoV-2 genome contains 14 open reading frames (ORFs) encoding 27 proteins. The 3′-terminal third of the genome encodes the viral structural and accessory proteins. These structural proteins include the spike (S), nucleocapsid (N), membrane (M), and envelope (E). The S protein primarily mediates viral entry by binding to host cell receptors; the N protein encapsidates the viral genome to form a nucleoprotein complex; and the M and E proteins are primarily involved in viral replication, assembly, and budding. The 5′-end 2 / 3 of the genome contains two large overlapping ORFs: ORF1a and ORF1b, which encode replicase polyprotein 1ab (pp1ab) and replicase polyprotein 1a (pp1a), respectively. These two replicase polyproteins are cleaved into non-structural proteins (NSPs) by two proteases and participate in viral replication and transcription.

[0003] PL protease is one of the important proteolytic enzymes that can cleave the replicase polyprotein from three conserved sites to form NSP1, NSP2 and NSP3. It is an indispensable hydrolase for SARS-CoV-2 replication and transcription. After the outbreak of the new coronavirus pneumonia, Cui Sheng's team reported the crystal structure of PL protease without ligand (PDB ID7CJD) on July 10, 2020, with a resolution of The study found that SARS-CoV-2PL pro It is difficult to crystallize in the absence of ligands, and PLpro C111S can generate measurable crystals, and although the active site C111S prevents the screening of cysteine-active inhibitors and fragments, it does not affect the targeting of non-covalent inhibitors to the substrate pocket. pro The crystal structure of C111S resembles an open right hand, consisting of four subdomains: an N-terminal ubiquitin-like domain (Ubl, β1-β3), an α-helical thumb domain (α2-α7), a palm domain (β8-β13), and a β-pleated zinc finger domain (β4-β7). The blocking loop region (BL2) in the palm domain is located between β11-β12 and covers residues 267-271. BL2 is a flexible loop that adopts a corresponding conformation based on the size of the substrate. In the absence of ligand, the BL2 loop is located between β11 and β12 and is located between β11 and β12. pro In the BL2Loop, the BL2Loop adopts a relatively closed conformation. The junction of the thumb domain and the palm domain is PL pro The catalytic active site of PL is composed of a catalytic triad of Cys-His-Asp residues. pro The zinc finger domain consists of a Zn-terminal tetrahedrally coordinated by four cysteines. 2+ , to maintain PL pro The structural integrity and catalytic effect of

[0004] PL protease is a multifunctional viral protease that can not only hydrolyze viral polyproteins to form non-structural proteins and participate in viral replication and transcription, but also has deubiquitination and de-ISG activity, which can help coronaviruses evade the host's innate immune response. pro It can not only inhibit the replication process of the virus, but also inhibit the coronavirus from escaping the host's natural immune response. pro It is an ideal anti-coronavirus drug target, but the research progress of PL protease inhibitors is slow. At present, the research on this target is still in its initial stage and there is a lack of inhibitors with good activity. Therefore, the development of SARS-CoV-2PL pro Small molecule inhibitors are particularly important.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a SARS-CoV-2PL pro Small molecule inhibitors.

[0007] The first aspect of the present invention provides a compound of the structure represented by general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:

[0008] in,

[0009] X can be selected from the following group: NH, O, S, C=O, S=O or SO2;

[0010] Y may be independently selected from the group consisting of NH, O, or S;

[0011] The ring is a substituted or unsubstituted 6-20 membered heteroaromatic condensed ring; and the A ring is not

[0012] Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, substituted or unsubstituted 6-20 membered heteroaromatic fused ring, wherein the substituent is 1, 2, 3 or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, cyano, nitro, amino, amine (preferably C1-C6 amine), hydroxyl, hydroxymethyl, carboxyl, thiol, sulfonyl, C6-C10 aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclic group, wherein the aromatic heterocycle, aromatic fused ring or heterocyclic group independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0013] R 1 Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein one or more hydrogen atoms on the substituent group are substituted by a substituent selected from the group consisting of: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl;

[0014] R 2 and R 3 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl;

[0015] R 4 For 1, 2, 3 or 4 substituents on the ring may be selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, sulfhydryl, -S(O)2OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, aryl or heteroaromatic ring-substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon-substituted C1-C6 alkyl, C1-C6 alkylamino, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclyl, substituted or unsubstituted C1-C6 alkyl and (CH2) p NH(CH2) p COOR 6 NR 7 (CH2) p -;

[0016] in, The ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a 3-12 membered heterocyclic ring, a 5-12 membered heteroaromatic ring, or a 7-20 membered heteropolycyclic ring (including fused rings, bridged rings, or spiro rings);

[0017] Z can be selected from the following group: -O-, -NR 7 -、-(CH2) p NR 7 -、-NR 7 CO-、-NR 7 SO2- and NR 7 (CH2) p ; Among them, R 5 For 1, 2, 3 or 4 substituents on the ring are selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl; R 6 R is hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl; 7 is H or C1-C4 alkyl;

[0018] The m, n, p and q are each independently 0, 1, 2, 3 or 4;

[0019] Unless otherwise specified, the heteroaromatic ring, heterocondensed ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the heterocyclic group includes a saturated or partially unsaturated ring;

[0020] The alkyl, alkoxy, alkenyl, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclic group, aryl, and heteroaryl groups are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, sulfhydryl, C1-C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group;

[0021] The halogen is F, Cl, Br or I.

[0022] In another preferred embodiment, the The ring is selected from the group consisting of:

[0023] In another preferred embodiment, the The ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring, a substituted or unsubstituted 4-7 membered heterocyclic ring (including saturated or partially unsaturated rings), or a 7-20 membered heteropolycyclic ring (including fused, bridged, or spiro rings).

[0024] In another preferred embodiment, the The ring is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted pyrimidine ring, a substituted or unsubstituted triazine ring, a substituted or unsubstituted pyrrole ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted imidazole ring, a substituted or unsubstituted thiazole ring, and a substituted or unsubstituted tetrahydrofuran ring.

[0025] In another preferred embodiment, the R 4 1 or 2 substituents located on ring B are selected from the group consisting of halogen, cyano, amino, amine, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl NR(CH2) p -、(CH2) p NH(CH2) p COOR 6 and in, The ring is preferably a 3-7 membered heterocyclic ring, a 7-20 membered heteropolycyclic ring (including a fused ring, a bridged ring or a spiro ring); Z can be selected from the following groups: -O-, -NH-, -NHCO- and NH(CH2) p 、-(CH2) p NR 7 -.

[0026] In another preferred embodiment, the The ring is selected from the group consisting of:

[0027] The The ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted 4-7 membered heteroaromatic ring;

[0028] The R 4 For 1, 2 or 3 substituents on the ring are each independently selected from the group consisting of deuterium, halogen, cyano, amino, amine, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl NR 7 (CH2) p -,and in, The ring is preferably a 3- to 7-membered heterocyclic ring.

[0029] In another preferred embodiment, the compound is the compound described in each embodiment.

[0030] The second aspect of the present invention provides a pharmaceutical composition comprising: one or more of the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0031] In a third aspect, the present invention provides a compound of formula I as described in the first aspect of the present invention, and its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, or mixture thereof, for use in preparing a pharmaceutical composition for treating or preventing diseases associated with PL protease activity.

[0032] In another preferred embodiment, the disease is a disease caused by a virus that contains PL protease. Preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, or a combination thereof.

[0033] 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. DETAILED DESCRIPTION

[0034] After extensive and in-depth research, the inventors have designed and synthesized a novel class of quinolinoneamide compounds. These compounds exhibit excellent inhibitory activity against PL proteases and are therefore useful for treating, preventing, and alleviating diseases associated with PL proteases, particularly viral diseases involving PL proteases, such as those caused by SARS-CoV-2, SARS-CoV, and MERS-CoV. Based on these findings, the inventors completed the present invention.

[0035] the term

[0036] In the present invention, the halogen is F, Cl, Br or I.

[0037] In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art. In the present invention, unless otherwise specified, all chemical formulae are intended to encompass any possible optical or geometric isomers (e.g., R-type, S-type or racemate, or cis-trans isomers of olefins, etc.).

[0038] In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0039] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0040] In the present invention, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0041] In the present invention, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0042] In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. The terms "C3-C8 cycloalkyl," "C3-C7 cycloalkyl," and "C3-C6 cycloalkyl" have similar meanings.

[0043] In the present invention, the term "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecyl. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0044] In the present invention, the term "C1-C12 alkoxycarbonyl" refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

[0045] In the present invention, the term "C1-C12 alkylaminocarbonyl" refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl and the like.

[0046] In the present invention, the term "C1-C6 amino group" refers to a structure such as "-NH-R" or "-NR2" (R is a C1-C6 alkyl group), or a similar structure.

[0047] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning. Preferably, "aryl group" is "C6-C12 aryl group" or "C6-C10 aryl group". The term "C6-C12 aryl group" refers to an aromatic ring group having 6 to 12 carbon atoms (including 6, 7, 8, 9, or 10 carbon atoms) without heteroatoms in the ring, such as phenyl and naphthyl. The term "C6-C10 aryl group" has a similar meaning.

[0048] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to heteroaromatic groups containing one to multiple heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted. In the present invention, preferred aromatic heterocycles or heteroaryl groups are 5-12 members, preferably 5-7 members, such as 5-membered, 6-membered, 9-membered or 10-membered.

[0049] In the present invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxolanyl. The term "3-7 membered heterocyclic group" has a similar meaning. Preferably, the heterocyclic group includes a fully saturated or partially unsaturated ring, and may also include a monocyclic, polycyclic, fused, spirocyclic or bridged ring, but preferably does not have aromaticity. In a preferred embodiment, the 3-12 membered heterocyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic group.

[0050] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, the two rings having a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, etc.

[0051] Compounds of formula I as PL protease inhibitors

[0052] The present invention provides a compound of the structure represented by general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:

[0053] in,

[0054] X can be selected from the following group: NH, O, S, C=O, S=O or SO2;

[0055] Y may be independently selected from the group consisting of NH, O, or S;

[0056] The ring is a substituted or unsubstituted 6-20 membered heteroaromatic fused ring;

[0057] Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, substituted or unsubstituted 6-20 membered heteroaromatic fused ring, wherein the substituent is 1, 2, 3 or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, cyano, nitro, amino, amine (preferably C1-C6 amine), hydroxyl, hydroxymethyl, carboxyl, thiol, sulfonyl, C6-C10 aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclic group, wherein the aromatic heterocycle, aromatic fused ring or heterocyclic group independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0058] The m, n, p and q are each independently 0, 1, 2, 3 or 4;

[0059] R 1 Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein one or more hydrogen atoms on the substituent group are substituted by a substituent selected from the group consisting of: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl;

[0060] R 2 and R 3 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl;

[0061] R 4 For 1, 2, 3 or 4 substituents on the ring may be selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O)2OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, aryl or heteroaromatic ring-substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon-substituted C1-C6 alkyl, C1-C6 alkylamino, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclyl, substituted or unsubstituted C1-C6 alkyl and (CH2) p NH(CH2) p COOR 6 NR 7 (CH2) p -;

[0062] in, The ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a 3-12 membered heterocyclic ring, a 5-12 membered heteroaromatic ring, or a 7-20 membered heteropolycyclic ring (including fused rings, bridged rings, or spiro rings);

[0063] Z can be selected from the following group: -O-, -NR 7 -、-(CH2) p NR 7 -、-NR 7 CO-、-NR 7 SO2- and NR 7 (CH2) p ; Among them, R 5 For 1, 2, 3 or 4 substituents on the ring are selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl; R 6 R is hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl; 7 is H or C1-C4 alkyl;

[0064] Unless otherwise specified, the heteroaromatic ring, heterocondensed ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the heterocyclic group includes a saturated or partially unsaturated ring;

[0065] The alkyl, alkoxy, alkenyl, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclic group, aryl, and heteroaryl groups are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, sulfhydryl, C1-C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group;

[0066] The halogen is F, Cl, Br or I.

[0067] The preferred compounds of the present invention are the compounds in the examples, as shown in the following table:

[0068] Preparation of compounds of formula I

[0069] The present invention also provides a method for preparing the compound represented by general formula I, which is carried out according to the following scheme (example):

[0070] Step a: Compound 1 is dissolved in a solvent, potassium hydroxide and carbon disulfide are added, and the mixture is reacted under heating for 24 hours to obtain Compound 2; the solvent is tetrahydrofuran, diethyl ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane, water or a mixture thereof; the heating temperature range is 50-80°C;

[0071] Step b: Compound 2 is dissolved in an organic solvent, triethylamine and p-fluorobenzyl bromide are added, and the mixture is heated and stirred until the reaction is complete to obtain Compound 3; the organic solvent is tetrahydrofuran, diethyl ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; the heating temperature range is 50-80°C;

[0072] Step c: Compound 3 is dissolved in an organic solvent, ethyl 2-bromobutyrate and potassium carbonate are added, and the mixture is heated and stirred until the reaction is complete to obtain Compound 4; the organic solvent is tetrahydrofuran, diethyl ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; the heating temperature range is 50-80°C;

[0073] Step d: Compound 4 was dissolved in a mixed solvent of tetrahydrofuran, methanol, and water, followed by addition of potassium hydroxide and heating under reflux for 1 hour. After completion of the reaction, the organic solvent was removed by rotary evaporation under reduced pressure, the pH was adjusted to acidic with 1M dilute hydrochloric acid, and then diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5.

[0074] Step e: Compound 5 is dissolved in an organic solvent, followed by the addition of HATU, DIPEA, and o-toluidine, and the mixture is reacted at room temperature for 10 hours to obtain Compound 6. The organic solvent is tetrahydrofuran, diethyl ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane, or a mixture thereof;

[0075] Pharmaceutical compositions and methods of administration

[0076] Because the compounds of the present invention have excellent PL protease inhibitory activity, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat viral diseases caused by PL protease, such as diseases caused by SARS-CoV-2, SARS-CoV, and MERS-CoV.

[0077] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg / kg) of the compound of the present invention per dose, more preferably 10-2000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0078] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0079] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0080] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0081] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0082] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0083] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0084] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0085] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0086] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0087] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0088] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 6 to 600 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0089] 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 only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0090] Example 1 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (1)

[0091] 1.1 1H-Imidazolo[4,5-b]pyridine-2-thiol

[0092] 2,3-Diaminopyridine (10 g, 91.6 mmol) was dissolved in 88 mL of ethanol and 18 mL of water. Potassium hydroxide (10.28 g, 183.26 mmol) was added, followed by carbon disulfide (13.95 g, 183.26 mmol). The mixture was refluxed at 80°C for 24 hours. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure to obtain a brown solid. The crude product was directly used in the next reaction without further purification.

[0093] 1.2 2-((4-Fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridine

[0094] 1H-Imidazolo[4,5-b]pyridine-2-thiol (5 g, 33.07 mmol) was dissolved in ethanol, and triethylamine (3.35 g, 33.07 mmol) and p-fluorobenzyl bromide (6.25 g, 33.07 mmol) were added. The mixture was refluxed at 60°C for 1 hour. After completion of the reaction, the mixture was evaporated under reduced pressure, filtered, and the filter cake was washed with anhydrous ethanol (10 mL x 3) and dried to obtain 6.1 g of a white solid, with a two-step yield of 71%.

[0095] 1.3 Ethyl 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanoate

[0096] 2-((4-Fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridine (2 g, 7.71 mmol) and ethyl 2-bromobutyrate (3.01 g, 15.43 mmol) were dissolved in N,N-dimethylformamide, followed by the addition of potassium carbonate (3.2 g, 23.14 mmol). The reaction was refluxed at 60°C for 12 hours. After completion of the reaction, the mixture was diluted with a large amount of water and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography using petroleum ether / ethyl acetate = 1.5 / 1 (volume ratio) as the eluent to obtain a yellow oil in a yield of 43%.

[0097] 1.4 2-(2-((4-Fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanoic acid

[0098] The intermediate ethyl 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-1-yl)butanoate (300 mg, 0.8 mmol) was dissolved in 10 mL of tetrahydrofuran, 5 mL of methanol, and 5 mL of water. Potassium hydroxide (225 mg, 4.0 mmol) was then added and refluxed at 60°C for 1 hour. After the reaction, the organic solvent was removed by rotary evaporation under reduced pressure. The pH was adjusted to acidic with 1 M dilute hydrochloric acid, and then diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction without further separation or purification.

[0099] Synthesis of final product 1

[0100] The intermediate 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanoic acid (200 mg, 0.58 mmol) was dissolved in dichloromethane, followed by the addition of HATU (331 mg, 0.87 mmol) and DIPEA (150 mg, 1.16 mmol). The mixture was stirred at room temperature for 10 minutes, and then 2-methylaniline (68.25 mg, 0.64 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Column chromatography was performed using petroleum ether / ethyl acetate = 3 / 1-1 / 1 (volume ratio) as the eluent to obtain 95 mg of a white solid in a yield of 38%. 1 H NMR(500MHz,Chloroform-d)δ9.02(s,1H),7.98(d,J=7.5Hz,1H),7.82(d,J=6.6Hz,1H),7.77(d,J=8.0Hz,1H),7.46–7.42(m,2H),7.16–7.02(m,4 H),7.00–6.94(m,2H),5.82(t,J=7.8Hz,1H),4.60(s,2H),2.67–2.57(m, 1H),2.32–2.25(m,1H),2.08(s,3H),1.07(t,J=7.4Hz,3H).LRMS(ESI)m / z 435(M+).

[0101] Example 2 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)propionamide (2)

[0102] Ethyl 2-bromobutyrate was replaced with ethyl 2-bromopropionate. The remaining raw materials, reagents, and preparation methods were the same as in Example 1 to obtain product 2. LRMS (ESI) m / z 421 (M+).

[0103] Example 3 2-Cyclopropyl-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)acetamide (3)

[0104] Ethyl 2-bromobutyrate was replaced with ethyl 2-bromo-2-cyclopropylacetate, and the remaining raw materials, reagents, and preparation methods were the same as in Example 1 to obtain product 3. LRMS (ESI) m / z 447 (M+)

[0105] Example 4 2-Cyclopropyl-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-phenylacetamide (4)

[0106] Product 4 was obtained by replacing ethyl 2-bromobutyrate with ethyl 2-bromo-2-cyclopropylacetate and 2-methylaniline with aniline, and using the remaining raw materials, reagents and preparation method as in Example 1. 1 H NMR(500MHz,Chloroform-d)δ9.9(s,1H),8.2(dd,J=8.4,1.3Hz,1H),7.6–7.5 (m,3H),7.4(ddt,J=7.4,5.0,1.1Hz,2H),7.4–7.3(m,2H),7.1(tt,J=7.5,1.6 Hz,1H),7.0–7.0(m,2H),6.9–6.8(m,1H),4.6(dd,J=7.0,1.8Hz,1H),4.5–4.4 (m,2H),2.4(h,J=7.0Hz,1H),1.6–1.5(m,2H),1.5–1.3(m,2H).LRMS(ESI)m / z 433(M+)

[0107] Example 5 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-phenylbutanamide (5)

[0108] The product 5 was obtained by replacing ethyl 2-bromobutyrate with ethyl 2-bromopropionate and 2-methylaniline with aniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1. LRMS (ESI) m / z 407 (M+)

[0109] Example 6 (S)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (6)

[0110] Substituting ethyl 2-bromobutyrate with (S)-ethyl 2-bromobutyrate, the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain product 6. LRMS (ESI) m / z 435 (M+).

[0111] Example 7 (R)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (7)

[0112] The product 7 was obtained by replacing ethyl 2-bromobutyrate with (R)-ethyl 2-bromobutyrate and using the same raw materials, reagents and preparation method as in Example 1. LRMS (ESI) m / z 435 (M+)

[0113] Example 8 2-(2-(4-Fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-phenylpentanamide (8)

[0114] The product 8 was obtained by replacing ethyl 2-bromobutyrate with ethyl 2-bromovalerate and 2-methylaniline with aniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1. LRMS (ESI) m / z 435 (M+)

[0115] Example 9 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-phenylbutylamine (9)

[0116] Substituting 2-methylaniline with aniline, the remaining raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 9. LRMS (ESI) m / z 421 (M+)

[0117] Example 10 N-(2-ethylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (10)

[0118] 2-Methylaniline was replaced by 2-ethylaniline, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 10. LRMS (ESI) m / z 449 (M+)

[0119] Example 11 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methoxyphenyl)butanamide (11)

[0120] 2-Methylaniline was replaced by 2-methoxyaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 11. LRMS (ESI) m / z 451 (M+)

[0121] Example 12 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-cyanophenyl)butanamide (12)

[0122] 2-Methylaniline was replaced by 2-cyanoaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 12. LRMS (ESI) m / z 446 (M+)

[0123] Example 13 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-fluorophenyl)butanamide (13)

[0124] 2-Methylaniline was replaced by 2-fluoroaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 13. LRMS (ESI) m / z 439 (M+)

[0125] Example 14 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-chlorophenyl)butanamide (14)

[0126] 2-Methylaniline was replaced by 2-chloroaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 14. LRMS (ESI) m / z 455 (M+)

[0127] Example 15 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-bromophenyl)butanamide (15)

[0128] 2-Methylaniline was replaced by 2-bromoaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 15. LRMS (ESI) m / z 499 (M+)

[0129] Example 16 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(3-methylphenyl)butanamide (16)

[0130] The remaining raw materials, reagents and preparation methods were the same as those in Example 1, except that 2-methylaniline was replaced by 3-methylaniline to obtain product 16. LRMS (ESI) m / z 435 (M+)

[0131] Example 17 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(3-fluorophenyl)butanamide (17)

[0132] 2-Methylaniline was replaced by 3-fluoroaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 17. LRMS (ESI) m / z 439 (M+)

[0133] Example 18 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(4-methylphenyl)butanamide (18)

[0134] 2-methylaniline was replaced by 4-methylaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 18. LRMS (ESI) m / z 435 (M+)

[0135] Example 19 N-(5-amino-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (19)

[0136] 2-Methylaniline was replaced by 5-amino-2-methylaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 19. LRMS (ESI) m / z 450 (M+)

[0137] Example 20 N-(5-chloro-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (20)

[0138] 2-Methylaniline was replaced by 5-chloro-2-methylaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 20. LRMS (ESI) m / z 469 (M+)

[0139] Example 21 N-(5-ethyl-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (21)

[0140] 2-Methylaniline was replaced by 5-ethyl-2-methylaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 21. LRMS (ESI) m / z 463 (M+)

[0141] Example 22 N-(5-propyl-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (22)

[0142] 2-Methylaniline was replaced by 5-propyl-2-methylaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 22. LRMS (ESI) m / z 477 (M+)

[0143] Example 23 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(5-(2-hydroxyethyl)-2-methylphenyl)butanamide (23)

[0144] The remaining raw materials, reagents and preparation methods are the same as those in the previous step except that 2-methylaniline is replaced by 5-(2-hydroxyethyl)-2-methylaniline.

[0145] Example 1, to obtain product 23. LRMS (ESI) m / z 479 (M+)

[0146] Example 24 2-(6-Fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(5-(2-hydroxyethyl)-2-methylphenyl)butanamide (24)

[0147] 2,3-diaminopyridine was replaced by 2,3-diamino-5-fluoro-pyridine, 2-methylaniline was replaced by 5-(2-hydroxyethyl)-2-methylaniline, and the remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain product 24. LRMS (ESI) m / z 497 (M+)

[0148] Example 25 tert-Butyl (3-(2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamido)-4-methylphenyl)carbamate (25)

[0149] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-fluoro-pyridine, and 2-methylaniline was replaced by (3-amino-4-methylphenyl)-carbamic acid tert-butyl ester. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain product 25. LRMS (ESI) m / z 568 (M+)

[0150] Example 26 N-(5-amino-2-methylphenyl)-2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (26)

[0151] 2,3-diaminopyridine was replaced by 2,3-diamino-5-fluoro-pyridine, and 2-methylaniline was replaced by 2,4-diaminotoluene. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 26. LRMS (ESI) m / z 468 (M+)

[0152] Example 27 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(pyridin-2-yl)butanamide (27)

[0153] 2-Methylaniline was replaced by 2-aminopyridine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 27. LRMS (ESI) m / z 422 (M+)

[0154] Example 28 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(1H-pyrrol-1-yl)butanamide (28)

[0155] 2-Methylaniline was replaced by 1-aminopyrrole. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 28. LRMS (ESI) m / z 410 (M+)

[0156] Example 29 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(1-methyl-1H-pyrazol-4-yl)butanamide (29)

[0157] 2-Methylaniline was replaced by 1-methyl-4-aminopyrazole. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 29. LRMS (ESI) m / z 425 (M+)

[0158] Example 30 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(tetrahydrofuran-3-yl)butanamide (30)

[0159] 2-Methylaniline was replaced by 3-aminotetrahydrofuran. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 30. LRMS (ESI) m / z 415 (M+)

[0160] Example 31 2-(2-((4-methoxybenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (31)

[0161] 4-Fluorobenzyl bromide was replaced by 4-methoxybenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 31. LRMS (ESI) m / z 447 (M+)

[0162] Example 32 N-(o-tolyl)-2-(2-((4-(trifluoromethoxy)benzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide

[0163] 4-Fluorobenzyl bromide was replaced by 4-trifluoromethoxybenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 32. LRMS (ESI) m / z 501 (M+)

[0164] Example 33 2-(2-((2-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (33)

[0165] 4-Fluorobenzyl bromide was replaced by 2-Fluorobenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 33. LRMS (ESI) m / z 435 (M+)

[0166] Example 34 2-(2-((3-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (34)

[0167] 4-Fluorobenzyl bromide was replaced by 3-Fluorobenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 34. LRMS (ESI) m / z 435 (M+)

[0168] Example 35 2-(2-((3-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-ethylphenyl)butanamide (35)

[0169] 2-Methylaniline was replaced by 2-ethylaniline, 4-fluorobenzyl bromide was replaced by 3-fluorobenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 35. LRMS (ESI) m / z 449 (M+)

[0170] Example 36 2-(2-((4-fluorobenzyl)sulfoxide)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (36)

[0171] Compound 1 (50 mg, 0.12 mmol) was dissolved in dichloromethane, followed by the addition of m-chloroperbenzoic acid (21.8 mg, 0.13 mmol) at 0°C. The mixture was refluxed at 0°C for 5 hours. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution, diluted with water, and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. Column chromatography using dichloromethane / methanol = 50 / 1 (volume ratio) as the eluent afforded 19 mg of product 36 in a 37% yield. 1 H NMR(500MHz,Chloroform-d)δ9.24(d,1H),8.39–8.33(m,2H),7.58–7.51(m,1H),7.37–7.31(m,1H),7.22–7.03(m,5H),6.94–6.84(m,2H) ,6.20(q,J=8.0Hz,1H),4.52(m,1H),4.41(m,1H),2.64–2.52(m,1H),2.26–2.18(m,1H),2.14(d,J=9.4Hz,3H),1.04(m,3H).LRMS(ESI)m / z 451(M+)

[0172] Example 37 2-(2-((4-fluorobenzyl)sulfonyl)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (37)

[0173] The raw materials, reagents and preparation method required for the synthesis of compound 37 were the same as those in Example 36 to obtain product 37. LRMS (ESI) m / z 467 (M+)

[0174] Example 38 2-(6-Fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (38)

[0175] 2,3-diaminopyridine was replaced with 2,3-diamino-5-fluoropyridine, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 38. LRMS (ESI) m / z 453 (M+)

[0176] Example 39 2-(5,6-difluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (39)

[0177] 2,3-diaminopyridine was replaced with 2,3-diamino-5,6-difluoropyridine, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 39. LRMS (ESI) m / z 471 (M+)

[0178] Example 40 2-(2-((4-fluorobenzyl)thio)-6-(trifluoromethyl)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (40)

[0179] 2,3-diaminopyridine was replaced with 2,3-diamino-5-trifluoromethylpyridine, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 40. LRMS (ESI) m / z 503 (M+)

[0180] Example 41 2-(6-Fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(1H-pyrrol-1-yl)butanamide (41)

[0181] 2,3-diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine, and 2-methylaniline was replaced by 1-aminopyrrole. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 41. LRMS (ESI) m / z 428 (M+)

[0182] Example 42 2-(2-(4-fluorobenzyl)thio)-6-(trifluoromethyl)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(1H-pyrrol-1-yl)butanamide (42)

[0183] 2,3-diaminopyridine was replaced by 2,3-diamino-5-trifluoromethylpyridine, and 2-methylaniline was replaced by 1-aminopyrrole. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 42. LRMS (ESI) m / z 478 (M+)

[0184] Example 43 2-(5,6-difluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(1H-pyrrol-1-yl)butanamide (43)

[0185] 2,3-diaminopyridine was replaced by 2,3-diamino-5,6-difluoropyridine, and 2-methylaniline was replaced by 1-aminopyrrole. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 43. LRMS (ESI) m / z 446 (M+)

[0186] Example 44 2-Cyclopropyl-2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(1H-pyrrol-1-yl)acetamide (44)

[0187] Ethyl 2-bromobutyrate was replaced by ethyl 2-bromo-2-cyclopropylacetate, 2,3-diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine, and 2-methylaniline was replaced by 1-aminopyrrole. The remaining raw materials, reagents, and preparation methods were the same as those in Example 1 to obtain product 44. LRMS (ESI) m / z 440 (M+)

[0188] Example 45 2-Cyclopropyl-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(1H-pyrrol-1-yl)acetamide (45)

[0189] Ethyl 2-bromobutyrate was replaced by ethyl 2-bromo-2-cyclopropylacetate, and 2-methylaniline was replaced by 1-aminopyrrole. The remaining raw materials, reagents, and preparation methods were the same as those in Example 1 to obtain product 45. LRMS (ESI) m / z 422 (M+)

[0190] Example 46 N-(2,5-dimethylphenyl)-2-(2-(4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (46)

[0191] 2-Methylaniline was replaced by 2,5-dimethylaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 46. LRMS (ESI) m / z 449 (M+)

[0192] Example 47 N-(2,5-dimethylphenyl)-2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (47)

[0193] 2,3-diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine, and 2-methylaniline was replaced by 2,5-dimethylaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 47. LRMS (ESI) m / z 467 (M+)

[0194] Example 48 2-(2-((5-fluoropyridin-2-yl)methyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (48)

[0195] The remaining raw materials, reagents and preparation methods are the same as those in the previous step except that 4-fluorobenzyl bromide is replaced by 2-(bromomethyl)-5-fluoropyridine hydrobromide.

[0196] Example 1, yielding product 48. LRMS (ESI) m / z 436 (M+)

[0197] Example 49 2-(2-((3-(Thien-2-yl)benzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)butanamide (49)

[0198] 4-Fluorobenzyl bromide was replaced by 2-[3-(bromomethyl)phenyl]thiophene. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 49. LRMS (ESI) m / z 499 (M+)

[0199] Example 50 2-(2-((3-(Thien-2-yl)benzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)pentanamide (50)

[0200] 4-Fluorobenzyl bromide was replaced by 2-[3-(bromomethyl)phenyl]thiophene, ethyl 2-bromobutyrate was replaced by ethyl 2-bromovalerate, and the remaining raw materials, reagents, and preparation methods were the same as in Example 1 to obtain product 50. LRMS (ESI) m / z 513 (M+)

[0201] Example 51 3-Cyclopropyl-2-(2-((3-(thiophen-2-yl)benzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)propanamide (51)

[0202] 4-Fluorobenzyl bromide was replaced by 2-[3-(bromomethyl)phenyl]thiophene, ethyl 2-bromobutyrate was replaced by ethyl 2-bromo-3-cyclopropylpropionate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product 51. LRMS (ESI) m / z 525 (M+)

[0203] Example 52: tert-Butyl 3-((3-(2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamido)-4-methylphenyl)amino)azetidine-1-carboxylate (52)

[0204] The intermediate 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanoic acid (1.4) was prepared in the same manner as in Example 1. The other intermediate tert-butyl 3-((3-amino-4-methylphenyl)amino)azetidine-1-carboxylate (1.5) was prepared as follows.

[0205] Commercially available 4-methyl-3-nitroaniline was used as the starting material to undergo reductive amination with 1-Boc-3-azetidinone, and further palladium-carbon hydrogen reduction reaction was performed to give intermediate 1.5.

[0206] The intermediate 1.4 (400 mg, 1.16 mmol) was dissolved in ultra-dry dichloromethane, and oxalyl chloride (367.5 mg, 2.9 mmol) was slowly added dropwise under ice bath, and the mixture was allowed to react at room temperature. A catalytic amount of DMF was then added and the mixture was allowed to react at room temperature for 2.5 hours. The reaction solution was spin-dried and then dissolved in ultra-dry dichloromethane at room temperature.

[0207] Add intermediate 1.5 (385.5 mg, 1.39 mmol) and triethylamine (468.8 mg, 4.63 mmol) and react at room temperature.

[0208] After 12 hours, the reaction was completed, water was added to dilute and extracted with dichloromethane, the organic phases were combined, and saturated chlorine was added.

[0209] The residue was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography using petroleum ether / ethyl acetate = 1 / 1 (volume ratio) as eluent to obtain 150 mg of a yellow oil, which was the product 52. LRMS (ESI) m / z 605 (M+)

[0210] Example 53 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)propanamide (53)

[0211] Ethyl 2-bromobutyrate was replaced with ethyl 2-bromopropionate. The remaining raw materials, reagents, and preparation methods were the same as in Example 52. Finally, 2 mL of a 4 M hydrochloric acid-dioxane solution was added and the mixture was allowed to react at room temperature for 2 hours. After the reaction, sodium hydroxide solution was added to adjust the pH to neutral, the mixture was diluted with water, and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Column chromatography was performed using dichloromethane / methanol = 5 / 1 (volume ratio) as the eluent to obtain product 53. LRMS (ESI) m / z 491 (M+)

[0212] Example 54 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (54)

[0213] Ethyl 2-bromopropionate was replaced with ethyl 2-bromobutyrate, and the remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 54. LRMS (ESI) m / z 505 (M+)

[0214] Example 55 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-cyclopropyl-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)acetamide (55)

[0215] Ethyl 2-bromopropionate was replaced with ethyl 2-bromo-2-cyclopropylacetate. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 55. LRMS (ESI) m / z 517 (M+)

[0216] Example 56 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)pentanamide (56)

[0217] Ethyl 2-bromopropionate was replaced with ethyl 2-bromovalerate, and the remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 56. LRMS (ESI) m / z 519 (M+)

[0218] Example 57 Tert-butyl 3-((3-(2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamido)-4-methylphenyl)amino)pyrrolidine-1-carboxylate (57)

[0219] 1-Boc-3-azetidinone was replaced with 1-Boc-3-azacyclopentanone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 57. LRMS (ESI) m / z 619 (M+)

[0220] Example 58 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)butanamide (58)

[0221] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 1-Boc-3-azetidinone with 1-Boc-3-azacyclopentanone. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 58. LRMS (ESI) m / z 519 (M+)

[0222] Example 59 tert-Butyl 4-(3-(2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamido)-4-methylphenyl)amino)piperidine-1-carboxylate (59)

[0223] 1-Boc-3-azetidinone was replaced with 1-Boc-4-azacyclohexanone. The remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 59. LRMS (ESI) m / z 633 (M+)

[0224] Example 60 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(piperidin-4-ylamino)phenyl)butanamide (60)

[0225] The product 60 was obtained by replacing ethyl 2-bromopropionate with ethyl 2-bromobutyrate and 1-Boc-3-azetidinone with 1-Boc-4-azacyclohexanone. The remaining raw materials, reagents and preparation methods were the same as those in Example 53. LRMS (ESI) m / z 533 (M+)

[0226] Example 61 N-(5-((azetidin-3-ylamino)methyl)-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (61)

[0227] Ethyl 2-bromopropionate was replaced by ethyl 2-bromobutyrate, and 4-methyl-3-nitroaniline was replaced by 4-methyl-3-nitrobenzylamine. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 61. LRMS (ESI) m / z 519 (M+)

[0228] Example 62 (3-(2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamido)-4-methylbenzyl)glycine (62)

[0229] 4-Methyl-3-nitroaniline was replaced by 4-methyl-3-nitrobenzaldehyde, 1-Boc-3-azetidinone was replaced by glycine, and the remaining raw materials, reagents, and preparation methods were the same as those for Intermediate 1.5 to obtain (3-amino-4-methylbenzyl)glycine. The remaining raw materials, reagents, and preparation methods were the same as those for Example 1 to obtain product 62. LRMS (ESI) m / z 522 (M+)

[0230] Example 63 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((1-methylazetidin-3-yl)amino)phenyl)butanamide (63)

[0231] 1-Boc-3-azetidinone was replaced with 1-methyl-3-azetidinone, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 63. LRMS (ESI) m / z 519 (M+)

[0232] Example 64 Tert-butyl 3-((3-(2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamido)-4-methylphenyl(methyl)amino)azetidine-1-carboxylate (64)

[0233] 4-Methyl-3-nitroaniline was replaced by N,4-dimethyl-3-nitroaniline. The remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 64. LRMS (ESI) m / z 619 (M+)

[0234] Example 65 N-(5-(azetidin-3-yl(methyl)amino)-2-methylphenyl)-2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (65)

[0235] Ethyl 2-bromopropionate was replaced by ethyl 2-bromobutyrate, 4-methyl-3-nitroaniline was replaced by N,4-dimethyl-3-nitroaniline, and the remaining raw materials, reagents and preparation methods were the same as those in Example 53 to obtain product 65. LRMS (ESI) m / z 519 (M+)

[0236] Example 66 2-(2-(4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(1-methylazetidin-3-yl)amino)phenyl)pentanamide (66)

[0237] Ethyl 2-bromopropionate was replaced by ethyl 2-bromovalerate, and 1-Boc-3-azetidinone was replaced by 1-methyl-3-azetidinone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 52 to obtain product 66. LRMS (ESI) m / z 533 (M+)

[0238] Example 67 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (67)

[0239] Ethyl 2-bromopropionate was replaced by ethyl 2-bromobutyrate, and 2,3-diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 67. LRMS (ESI) m / z 537 (M+)

[0240] Example 68 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(5,6-difluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (68)

[0241] Ethyl 2-bromopropionate was replaced by ethyl 2-bromobutyrate, and 2,3-diaminopyridine was replaced by 2,3-diamino-5,6-difluoropyridine. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 68. LRMS (ESI) m / z 541 (M+)

[0242] Example 69 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((5-fluoropyrazin-2-yl)methyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (69)

[0243] Ethyl 2-bromopropionate was replaced by ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide was replaced by 2-(bromomethyl)-5-fluoropyrazine. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 69. LRMS (ESI) m / z 507 (M+)

[0244] Example 70 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(6-fluoro-2-((5-fluoropyrazin-2-yl)methyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (70)

[0245] Replace ethyl 2-bromopropionate with ethyl 2-bromobutyrate, 4-fluorobenzyl bromide with 2-(bromomethyl)-5-fluoropyrazine, and 2,3-diaminopyridine with 2,3-diamino-5-fluoropyridine. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 70. LRMS (ESI) m / z 525 (M+)

[0246] Example 71 N-(5-(azetidin-3-ylamino)-2-(2-(3-(thiophen-2-yl)benzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (71)

[0247] Ethyl 2-bromopropionate was replaced by ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide was replaced by 2-[3-(bromomethyl)phenyl]thiophene. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 71. LRMS (ESI) m / z 569 (M+)

[0248] Example 72 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-methylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (72)

[0249] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-methylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 72. LRMS (ESI) m / z 501 (M+)

[0250] Example 73 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-ethylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (73)

[0251] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-ethylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 73. LRMS (ESI) m / z 515 (M+)

[0252] Example 74 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-chlorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (74)

[0253] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-chlorobenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 74. LRMS (ESI) m / z 521 (M+)

[0254] Example 75 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-bromobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (75)

[0255] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-bromobenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 75. LRMS (ESI) m / z 565 (M+)

[0256] Example 76 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-cyanobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (76)

[0257] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-cyanobenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 76. LRMS (ESI) m / z 512 (M+)

[0258] Example 77 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-nitrobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (77)

[0259] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-nitrobenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 77. LRMS (ESI) m / z 532 (M+)

[0260] Example 78 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-trifluoromethylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (78)

[0261] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-trifluoromethylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 78. LRMS (ESI) m / z 555 (M+)

[0262] Example 79 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-methoxybenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (79)

[0263] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-methoxybenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 79. LRMS (ESI) m / z 517 (M+)

[0264] Example 80 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-hydroxybenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (80)

[0265] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-hydroxybenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 80. LRMS (ESI) m / z 503 (M+)

[0266] Example 81 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-methoxymethylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (81)

[0267] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-methoxymethylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 81. LRMS (ESI) m / z 531 (M+)

[0268] Example 82 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-isopropylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (82)

[0269] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-isopropylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 82. LRMS (ESI) m / z 529 (M+)

[0270] Example 83 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-propylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (83)

[0271] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-propylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 83. LRMS (ESI) m / z 529 (M+)

[0272] Example 84 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((4-isobutylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (84)

[0273] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 4-isobutylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 84. LRMS (ESI) m / z 543 (M+)

[0274] Example 85 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((3,5-dimethylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (85)

[0275] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 3,5-dimethylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 85. LRMS (ESI) m / z 515 (M+)

[0276] Example 86 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((3,5-difluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (86)

[0277] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 3,5-difluorobenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 86. LRMS (ESI) m / z 523 (M+)

[0278] Example 87 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((3,5-dihydroxybenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (87)

[0279] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 3,5-dihydroxybenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 87. LRMS (ESI) m / z 519 (M+)

[0280] Example 88 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((3,5-dimethoxybenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (88)

[0281] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 3,5-dimethoxybenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 88. LRMS (ESI) m / z 547 (M+)

[0282] Example 89 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((3,5-diethylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (89)

[0283] Substitute ethyl 2-bromopropionate with ethyl 2-bromobutyrate, and 4-fluorobenzyl bromide with 3,5-diethylbenzyl bromide. The remaining raw materials, reagents, and preparation methods are the same as those in Example 53 to obtain product 89. LRMS (ESI) m / z 543 (M+)

[0284] Example 90 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((3,4,5-trimethylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (90)

[0285] The product 90 was obtained by replacing ethyl 2-bromopropionate with ethyl 2-bromobutyrate and 4-fluorobenzyl bromide with 3,4,5-trimethylbenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 53. LRMS (ESI) m / z 529 (M+)

[0286] Example 91 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(2-((3,4,5-trimethoxybenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (91)

[0287] The product 91 was obtained by replacing ethyl 2-bromopropionate with ethyl 2-bromobutyrate and 4-fluorobenzyl bromide with 3,4,5-trimethoxybenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 53. LRMS (ESI) m / z 577 (M+)

[0288] Example 92 N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)-2-(2-(4-methylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (92)

[0289] 4-Fluorobenzyl bromide was replaced by 4-methylbenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 58 to obtain product 92. LRMS (ESI) m / z 515 (M+)

[0290] Example 93 N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)-2-(2-(4-ethylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (93)

[0291] 4-Fluorobenzyl bromide was replaced by 4-ethylbenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 58 to obtain product 93. LRMS (ESI) m / z 529 (M+)

[0292] Example 94 N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)-2-(2-(4-isopropylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (94)

[0293] 4-Fluorobenzyl bromide was replaced by 4-isopropylbenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 58 to obtain product 94. LRMS (ESI) m / z 543 (M+)

[0294] Example 95 N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)-2-(2-(4-isobutylbenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (95)

[0295] 4-Fluorobenzyl bromide was replaced by 4-isobutylbenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 58 to obtain product 95. LRMS (ESI) m / z 557 (M+)

[0296] Example 96 N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)-2-(2-(4-methoxybenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide (96)

[0297] 4-Fluorobenzyl bromide was replaced by 4-methoxybenzyl bromide. The remaining raw materials, reagents and preparation methods were the same as those in Example 58 to obtain product 96. LRMS (ESI) m / z 531 (M+)

[0298] Example 97 3-Chloro-2-(2-(4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(o-tolyl)propylamine (97)

[0299] Ethyl 2-bromobutyrate was replaced with ethyl 2-bromo-3-chloropropionate, and the remaining raw materials, reagents, and preparation methods were the same as in Example 1 to obtain product 97. LRMS (ESI) m / z 455 (M+)

[0300] Example 98 2-(2-(4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-3-phenyl-N-(o-tolyl)propylamine (98)

[0301] The product 98 was obtained by replacing ethyl 2-bromobutyrate with ethyl 2-bromo-3-phenylpropionate and using the same raw materials, reagents and preparation method as in Example 1. LRMS (ESI) m / z 497 (M+)

[0302] Example 99 2-(2-(4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-3-(thiophen-2-yl)-N-(o-tolyl)propylamine (99)

[0303] Ethyl 2-bromobutyrate was replaced with ethyl 2-bromo-3-(thiophen-2-yl)propionate, and the remaining raw materials, reagents, and preparation methods were the same as in Example 1 to obtain product 99. LRMS (ESI) m / z 503 (M+)

[0304] 1.5 Intermediate 2-(2-((4-fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)butanoic acid ethyl ester

[0305] Intermediate 1.5 was prepared in the same manner as Intermediate 1.3 by column chromatography using petroleum ether / ethyl acetate = 2 / 1 (volume ratio) as eluent to obtain a yellow oil in a yield of 22%.

[0306] 1.6 Intermediate 2-(2-((4-fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)butanoic acid

[0307] The preparation method of intermediate 1.6 is the same as that of intermediate 1.4.

[0308] Example 100 2-(2-(4-fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(p-tolyl)butanamide (100)

[0309] The remaining raw materials, reagents and preparation methods were the same as those in Example 1, except that 2-methylaniline was replaced by 4-methylaniline to obtain product 100. LRMS (ESI) m / z 435 (M+)

[0310] Example 101 2-(2-(4-fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(o-tolyl)butanamide (101)

[0311] Substituting 4-methylaniline with 2-methylaniline, the remaining raw materials, reagents and preparation method were the same as those in Example 100 to obtain product 101. 1H NMR(500MHz,Chloroform-d)δ8.48(d,J=4.9Hz,1H),7.77(d,J=8.1Hz,1H),7.64 (d,J=8.1Hz,1H),7.45(dd,J=8.4,5.3Hz,2H),7.17–7.11(m,2H),7.09–7.02(m, 3H),6.96–6.91(m,2H),4.93(dd,J=10.1,5.4Hz,1H),4.75–4.64(m,2H),2.56–2 .46(m,1H),2.28–2.21(m,1H),1.76(s,3H),0.81(t,J=7.4Hz,3H).LRMS(ESI)m / z 435(M+)

[0312] Example 102 2-(2-(4-fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(o-methoxyphenyl)butanamide (102)

[0313] Substituting 4-methylaniline with 2-methoxyaniline, the remaining raw materials, reagents and preparation method were the same as those in Example 100 to obtain product 102. 1 H NMR(600MHz,Chloroform-d)δ8.47(dd,J=4.8,1.5Hz,1H),8.21(dd,J=8.0,1.6Hz,1H),7.82 –7.72(m,2H),7.49–7.45(m,2H),7.11(dd,J=8.1,4.9Hz,1H),7.03(td,J=7.8,1.6Hz,1H),6 .97–6.91(m,3H),6.76(dd,J=8.2,1.3Hz,1H),4.91(dd,J=10.3,5.4Hz,1H),4.76–4.71(m,2 H),3.54(s,3H),2.52–2.44(m,1H),2.29–2.21(m,1H),0.79(t,J=7.4Hz,3H).LRMS(ESI)m / z 451(M+)

[0314] Example 103 2-(2-(4-Fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(o-fluorophenyl)butanamide (103)

[0315] Substituting 4-methylaniline with 2-fluoroaniline, the remaining raw materials, reagents and preparation method were the same as those in Example 100 to obtain product 103. 1H NMR(500MHz,Chloroform-d)δ8.48–8.43(m,1H),8.07–7.82(m,2H),7.44–7.39(m,2H),7.16–6.87(m,6H),5.00(d d,J=10.0,5.6Hz,1H),4.68–4.63(m,2H),2.53–2.39(m,1H),2.37–2.13(m,2H),0.80–0.75(m,3H).LRMS(ESI)m / z 439(M+)

[0316] Example 104 2-(2-(4-Fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(m-fluorophenyl)butanamide (104)

[0317] Substituting 4-methylaniline with 3-fluoroaniline, the remaining raw materials, reagents, and preparation methods were the same as those in Example 100 to obtain product 104. 1 H NMR(500MHz,DMSO-d6)δ10.45(s,1H),8.34(dd,J=4.7,1.5Hz,1H),8.02(dd,J=8 .1,1.5Hz,1H),7.54–7.50(m,3H),7.38–7.32(m,1H),7.30–7.26(m,1H),7.19(d d,J=8.1,4.7Hz,1H),7.14–7.09(m,2H),6.94–6.89(m,1H),5.16(t,J=7.9Hz,1H ),4.67(d,J=4.9Hz,2H),2.32–2.25(m,2H),0.61(t,J=7.2Hz,3H).LRMS(ESI)m / z 439(M+)

[0318] Example 105 2-(2-(4-Fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(p-fluorophenyl)butanamide (105)

[0319] Substituting 4-methylaniline with 4-fluoroaniline, the remaining raw materials, reagents and preparation method were the same as those in Example 100 to obtain product 105. 1H NMR (600MHz, DMSO-d6) δ10.32(s,1H),8.33(dd,J=4.8,1.5Hz,1H),8.02(dd,J=8.1,1.5Hz,1H),7.59–7.50(m,4H),7.2 1–7.09(m,5H),5.14(dd,J=8.7,7.0Hz,1H),4.71–4.63(m,2H),2.31–2.23(m,2H),0.60(t,J=7.3Hz,3H).LRMS(ESI)m / z 439(M+)

[0320] Example 106 2-(2-(4-Fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(1H-pyrrol-1-yl)butanamide (106)

[0321] Substituting 4-methylaniline with 1-aminopyrrole, the remaining raw materials, reagents, and preparation methods were the same as those in Example 100 to obtain product 106. 1 H NMR(500MHz,DMSO-d6)δ11.50(s,1H),8.35(dd,J=4.9,1.5Hz,1H),7.96(dd,J=8.2 ,1.5Hz,1H),7.60–7.53(m,2H),7.20(dd,J=8.1,4.8Hz,1H),7.18–7.13(m,2H),6.6 3(t,J=2.3Hz,2H),6.01(t,J=2.3Hz,2H),5.18(dd,J=10.4,5.2Hz,1H),4.74–4.66 (m,2H),2.32–2.24(m,1H),2.22–2.12(m,1H),0.60(t,J=7.3Hz,3H).LRMS(ESI)m / z 410(M+)

[0322] Example 107 2-(6-Fluoro-2-(4-fluorobenzyl)thio)-1H-imidazo[4,5-b]pyridin-1-yl)-N-(o-tolyl)butanamide (107)

[0323] 2,3-diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine, 4-methylaniline was replaced by 2-methylaniline, and the remaining raw materials, reagents and preparation methods were the same as those in Example 100 to obtain product 107. 1H NMR(500MHz,Chloroform-d)δ8.38–8.31(m,1H),7.71–7.56(m,2H),7.49–7.36(m,2H),7.24–7.13(m,2H),7.12–7.04(m,2H),6.99–6.91(m, 2H),4.89(dd,J=9.9,5.7Hz,1H),4.75–4.61(m,2H),2.51–2.41(m,1H),2.26–2.18(m,1H),1.87(s,3H),0.83(t,J=7.3Hz,3H).LRMS(ESI)m / z 453(M+)

[0324] Example 108 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)pentanamide

[0325] Ethyl 2-bromopropionate was replaced with ethyl 2-bromovalerate, and 1-Boc-3-azetidinone was replaced with 1-Boc-3-azacyclopentanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 108. LRMS (ESI) m / z 533 (M+)

[0326] Example 109 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(piperidin-4-ylamino)phenyl)pentanamide

[0327] Ethyl 2-bromopropionate was replaced by ethyl 2-bromovalerate, and 1-Boc-3-azetidinone was replaced by 1-Boc-4-azacyclohexanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 109. LRMS (ESI) m / z 547 (M+)

[0328] Example 110 2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)butanamide

[0329] 2,3-diaminopyridine was replaced with 2,3-diamino-5-fluoropyridine, ethyl 2-bromopropionate was replaced with ethyl 2-bromobutyrate, and 1-Boc-3-azetidinone was replaced with 1-Boc-3-azacyclopentanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 110. LRMS (ESI) m / z 537 (M+)

[0330] Example 111 2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(piperidin-4-ylamino)phenyl)butanamide

[0331] 2,3-diaminopyridine was replaced with 2,3-diamino-5-fluoropyridine, ethyl 2-bromopropionate was replaced with ethyl 2-bromobutyrate, and 1-Boc-3-azetidinone was replaced with 1-Boc-4-azacyclohexanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 111. LRMS (ESI) m / z 551 (M+)

[0332] Example 112 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(6-chloro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide

[0333] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-chloropyridine, 2-bromopropionic acid ethyl ester was replaced by 2-bromobutyric acid ethyl ester, and the remaining raw materials, reagents and preparation methods were the same as those in Example 53 to obtain product 112. LRMS (ESI) m / z 540 (M+)

[0334] Example 113 2-(6-chloro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)butanamide

[0335] 2,3-diaminopyridine was replaced with 2,3-diamino-5-chloropyridine, ethyl 2-bromopropionate was replaced with ethyl 2-bromobutyrate, and 1-Boc-3-azetidinone was replaced with 1-Boc-4-azacyclopentanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 113. LRMS (ESI) m / z 554 (M+)

[0336] Example 114 2-(6-chloro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(piperidin-4-ylamino)phenyl)butanamide

[0337] 2,3-diaminopyridine was replaced with 2,3-diamino-5-chloropyridine, ethyl 2-bromopropionate was replaced with ethyl 2-bromobutyrate, and 1-Boc-3-azetidinone was replaced with 1-Boc-4-azacyclohexanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 114. LRMS (ESI) m / z 568 (M+)

[0338] Example 115 N-(5-(azetidin-3-ylamino)-2-methylphenyl)-2-(6-bromo-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)butanamide

[0339] 2,3-diaminopyridine was replaced by 2,3-diamino-5-bromopyridine, ethyl 2-bromopropionate was replaced by ethyl 2-bromobutyrate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 53 to obtain product 115. LRMS (ESI) m / z 584 (M+)

[0340] Example 116 2-(6-bromo-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(pyrrolidin-3-ylamino)phenyl)butanamide

[0341] 2,3-diaminopyridine was replaced with 2,3-diamino-5-bromopyridine, ethyl 2-bromopropionate was replaced with ethyl 2-bromobutyrate, and 1-Boc-3-azetidinone was replaced with 1-Boc-4-azacyclopentanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 116. LRMS (ESI) m / z 598 (M+)

[0342] Example 117 2-(6-bromo-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(piperidin-4-ylamino)phenyl)butanamide

[0343] 2,3-diaminopyridine was replaced with 2,3-diamino-5-bromopyridine, ethyl 2-bromopropionate was replaced with ethyl 2-bromobutyrate, and 1-Boc-3-azetidinone was replaced with 1-Boc-4-azacyclohexanone. The remaining raw materials, reagents, and preparation methods were the same as those in Example 53 to obtain product 116. LRMS (ESI) m / z 612 (M+)

[0344] Example 118 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(oxetan-3-ylamino)phenyl)butanamide

[0345] 1-Boc-3-azetidinone was replaced with oxetane-3-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 118. LRMS (ESI) m / z 506 (M+)

[0346] Example 119 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydrofuran-3-yl)amino)phenyl)butanamide

[0347] 1-Boc-3-azetidinone was replaced with dihydrofuran-3(2H)-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 119. LRMS (ESI) m / z 520 (M+)

[0348] Example 120 2-(2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)amino)phenyl)butanamide

[0349] 1-Boc-3-azetidinone was replaced with tetrahydro-4H-pyran-4-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 120. LRMS (ESI) m / z 534 (M+)

[0350] Example 121 2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(oxetan-3-ylamino)phenyl)butanamide

[0351] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine, 1-Boc-3-azetidinone was replaced by oxetane-3-one, and the remaining raw materials, reagents, and preparation methods were the same as those in Example 52 to obtain product 121. LRMS (ESI) m / z 524 (M+)

[0352] Example 122 2-(6-fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydrofuran-3-yl)amino)phenyl)butanamide

[0353] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine, 1-Boc-3-azetidinone was replaced by dihydrofuran-3(2H)-one, and the remaining raw materials, reagents and preparation method were the same as those in Example 52 to obtain product 122. LRMS (ESI) m / z 538 (M+)

[0354] Example 123 2-(6-Fluoro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)amino)phenyl)butanamide

[0355] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-fluoropyridine, 1-Boc-3-azetidinone was replaced by tetrahydro-4H-pyran-4-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 123. LRMS (ESI) m / z 552 (M+)

[0356] Example 124 2-(6-chloro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(oxetan-3-ylamino)phenyl)butanamide

[0357] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-chloropyridine, 1-Boc-3-azetidinone was replaced by oxetane-3-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 124. LRMS (ESI) m / z 541 (M+)

[0358] Example 125 2-(6-chloro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydrofuran-3-yl)amino)phenyl)butanamide

[0359] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-chloropyridine, 1-Boc-3-azetidinone was replaced by dihydrofuran-3(2H)-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 125. LRMS (ESI) m / z 555 (M+)

[0360] Example 126 2-(6-chloro-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)amino)phenyl)butanamide

[0361] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-chloropyridine, 1-Boc-3-azetidinone was replaced by tetrahydro-4H-pyran-4-one, and the remaining raw materials, reagents and preparation method were the same as those in Example 52 to obtain product 126. LRMS (ESI) m / z 569 (M+)

[0362] Example 127 2-(6-bromo-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-(oxetan-3-ylamino)phenyl)butanamide

[0363] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-bromopyridine, 1-Boc-3-azetidinone was replaced by oxetane-3-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 127. LRMS (ESI) m / z 585 (M+)

[0364] Example 128 2-(6-bromo-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydrofuran-3-yl)amino)phenyl)butanamide

[0365] 2,3-Diaminopyridine was replaced by 2,3-diamino-5-bromopyridine, 1-Boc-3-azetidinone was replaced by dihydrofuran-3(2H)-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 128. LRMS (ESI) m / z 599 (M+)

[0366] Example 129 2-(6-bromo-2-((4-fluorobenzyl)thio)-4H-imidazo[4,5-b]pyridin-4-yl)-N-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)amino)phenyl)butanamide

[0367] 2,3-diaminopyridine was replaced by 2,3-diamino-5-bromopyridine, 1-Boc-3-azetidinone was replaced by tetrahydro-4H-pyran-4-one, and the remaining raw materials, reagents and preparation methods were the same as those in Example 52 to obtain product 129. LRMS (ESI) m / z 613 (M+)

[0368] Synthesis of 4 comparative compounds

[0369] Intermediate 1.7: Ethyl 2-(2-((4-fluorobenzyl)thio)-3H-imidazo[4,5-b]pyridin-3-yl)butanoate

[0370] Intermediate 1.7 was prepared in the same manner as Intermediate 1.3 by column chromatography using petroleum ether / ethyl acetate = 10 / 1 (volume ratio) as eluent to obtain a yellow oil in a yield of 22%.

[0371] Intermediate 1.8: 2-(2-((4-Fluorobenzyl)thio)-3H-imidazo[4,5-b]pyridin-3-yl)butanoic acid

[0372] The preparation method of intermediate 1.8 is the same as that of intermediate 1.4.

[0373] Compound D1: 2-(2-(4-fluorobenzyl)thio)-3H-imidazo[4,5-b]pyridin-3-yl)-N-(o-tolyl)butanamide (D1)

[0374] The preparation method of compound D1 is the same as that of Example 1 to obtain product D1. 1 H NMR(500MHz,Chloroform-d)δ9.43(s,1H),8.27(dd,J=5.0,1.4Hz,1H),8.02(dd,J=7.9,1.5Hz,1H) ,7.83(dd,J=8.1,1.2Hz,1H),7.48–7.40(m,2H),7.28(d,J=2.5Hz,1H),7.18(td,J=7.8,1.6Hz,1H), 7.14(dd,J=7.6,1.7Hz,1H),7.05(td,J=7.4,1.3Hz,1H),7.03–6.96(m,2H),5.12(dd,J=10.1,6.0Hz,1H), 4.64(q,J=13.1Hz,2H),2.68(m,1H),2.60–2.51(m,1H),2.13(s,3H),0.83(t,J=7.4Hz,3H).LRMS(ESI)m / z 435(M+)

[0375] Compound D2: 2-(2-(4-fluorobenzyl)thio)-3H-imidazo[4,5-b]pyridin-3-yl)-N-(o-tolyl)propionamide (D2)

[0376] Product D2 was obtained by replacing ethyl 2-bromobutyrate with ethyl 2-bromopropionate and using the same raw materials, reagents and preparation method as in Example D1. 1 H NMR(500MHz,Chloroform-d)δ8.81(s,1H),8.27(dd,J=4.9,1.4Hz,1H),7.99(dd,J=8.0 ,1.4Hz,1H),7.79(d,J=8.1Hz,1H),7.44–7.39(m,2H),7.26–7.23(m,1H),7.19–7.14(m ,1H),7.11(dd,J=7.7,1.6Hz,1H),7.03(td,J=7.4,1.3Hz,1H),6.98–6.94(m,2H),5.40 (q,J=7.2Hz,1H),4.65–4.58(m,2H),2.02(s,3H),2.00(d,J=7.3Hz,3H).LRMS(ESI)m / z 421(M+)

[0377] Compound D3: 2-(2-(4-fluorobenzyl)thio)-3H-imidazo[4,5-b]pyridin-3-yl)-N-(o-tolyl)pentanamide (D3)

[0378] Product D3 was obtained by replacing ethyl 2-bromobutyrate with ethyl 2-bromovalerate and using the same raw materials, reagents and preparation method as in Example D1. 1 H NMR (600MHz, Chloroform-d) δ9.40 (s, 1H), 8.26 (dd, J = 5.0, 1.4Hz, 1H), 8.06–7.95 (m, 1H), 7.86–7. 74(m,1H),7.49–7.37(m,2H),7.28–7.26(m,1H),7.20–7.14(m,1H),7.12(d,J=7.5Hz,1H),7.03(td ,J=7.4,1.3Hz,1H),7.01–6.92(m,2H),5.21(s,1H),4.69–4.55(m,2H),2.70–2.62(m,1H),2.45–2. 38(m,1H),2.11(s,3H),1.23–1.17(m,1H),1.12–1.05(m,1H),0.88(t,J=7.4Hz,3H).LRMS(ESI)m / z 449(M+)

[0379] Compound D4: 2-(2-(3-fluorobenzyl)thio)-3H-imidazo[4,5-b]pyridin-3-yl)-N-(o-tolyl)butanamide (D4)

[0380] Substituting 4-fluorobenzyl bromide with 3-fluorobenzyl bromide, the remaining raw materials, reagents and preparation methods were the same as those in Example D1 to obtain product D4. 1 H NMR(500MHz,Chloroform-d)δ9.44(s,1H),8.25(dd,J=5.0,1.4Hz,1H),7.99(dd,J=8.0,1 .4Hz,1H),7.87–7.77(m,1H),7.26–7.20(m,3H),7.20–7.15(m,2H),7.14–7.10(m,1H),7.0 3(td,J=7.4,1.3Hz,1H),6.97–6.92(m,1H),5.06(dd,J=10.1,6.0Hz,1H),4.68–4.59(m,2H ),2.72–2.62(m,1H),2.58–2.50(m,1H),2.11(s,3H),0.81(t,J=7.4Hz,3H).LRMS(ESI)m / z 435(M+).

[0381] Pharmacological activity test examples

[0382] Pharmacological Example 1. Molecular level inhibitory activity test of compounds against PL protease

[0383] Experimental principle: Based on SARS-CoV-1 / 2PL pro Protein is a basic characteristic of proteolytic enzymes. The fluorescence method for detecting PL pro Screening system for protein activity. PL pro The protein can specifically recognize and cleave the double-glycine peptide. The activity detection can use the fluorescent peptide as a substrate, and the generation of fluorescent signals can be used to reflect the activity of the proteolytic enzyme.

[0384] Table 1: Inhibition rate and IC of some compounds 50 data

[0385] Experimental conclusion: The above compounds have no effect on SARS-CoV-1 / 2PL pro All of them have good inhibitory effects, among which 24 and 20 compounds have good inhibitory effects on SARS-CoV-1 / 2PL pro Inhibitory effect IC 50 <1μM, compounds 114-117, these four compounds are effective against SARS-CoV-1 / 2PL pro Inhibitory effect IC 50 The compounds described in the above table all have better inhibitory activity against PL protease of SARS-CoV-1 / 2 than the comparative compounds D1-D4.

[0386] Pharmacological Example 2. Test of the inhibitory activity of the compound on SARS-CoV-2 virus cell level

[0387] Vero E6 cells were cultured in DMEM supplemented with 10% FBS at 37°C and humidified with 5% CO2. Before infection, 100,000 Vero E6 cells were seeded in a 48-well plate in DMES (10% FBS) and incubated at 37°C with 5% CO2 humidification. After 12 h, the culture medium was replaced with 200 μL DMEM (2% FBS) per well, cultured at 50 μM (for primary screening) for 2 h, and then SARS-CoV-2 was added at an MOI of 0.01, and then the culture dish was incubated at 37°C with humidification of 5% CO2. 24 hours after infection, the supernatant was collected, the viral RNA in the supernatant was extracted, and then reverse transcribed using the PrimeScript RT reagent kit and gDNA eraser (TaKaRa). To determine the viral copy number, TB was used. Premix Ex Taq TMAbsolute quantitative RT-PCR was performed using a TaKaRa II. The primers used for qRT-PCR were RBD-qF1: 5′-caatggttaaggcacagg-3′ and RBD-qR1: 5′-ctcaagtgttagatcacg-3′. All experiments involving SARS-CoV-2 were performed in a BSL3 laboratory at the Wuhan Institute of Virology, Chinese Academy of Sciences.

[0388] Experimental results:

[0389] The preferred compounds had a certain inhibitory effect on the SARS-CoV-2 delta mutant strain. The results are shown in Table 2.

[0390] The results of the virus proliferation inhibition experiment showed that the tested compounds could effectively inhibit the replication of the SARS-CoV-2 viral genome in the infection supernatant, among which compounds 114 and 127 had the best inhibitory effect, EC 50 4.39±0.79 μM and 5.82±0.92 μM, respectively.

[0391] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of the structure represented by general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof: in, X can be selected from the following group: NH, O, S, C=O, S=O or SO2; Y may be independently selected from the group consisting of NH, O, or S; The ring is a substituted or unsubstituted 6-20 membered heteroaromatic condensed ring; and the Huan Buwei Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, substituted or unsubstituted 6-20 membered heteroaromatic fused ring, wherein the substituents are 1, 2, 3 or 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, cyano, nitro, amino, amine (preferably C1-C6 alkyl-NH-, or (C1-C6 alkyl)2-N-), hydroxyl, hydroxymethyl, carboxyl, thiol, sulfonyl, C6-C10 aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclic group, wherein the aromatic heterocycle, aromatic fused ring or heterocyclic group independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; R 1 Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein one or more hydrogen atoms on the substituent group are substituted by a substituent selected from the group consisting of: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl; R 2 and R 3 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, C6-C10 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl; R 4 For 1, 2, 3 or 4 substituents on the ring may be selected from the following groups: hydrogen, deuterium, halogen, cyano, nitro, amino, amine, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O)2OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, aryl or heteroaromatic ring-substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon-substituted C1-C6 alkyl, C1-C6 alkylamino, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclyl, substituted or unsubstituted C1-C6 alkyl Motokazu -(CH2) p NH(CH2) p COOR 6 、-(CH2) p NHR 7 ; in, The ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a 3-12 membered heterocyclic ring, a 5-12 membered heteroaromatic ring, or a 7-20 membered heteropolycyclic ring (including fused rings, bridged rings, or spiro rings); Z can be selected from the following group: -O-, -NR 7 -、-(CH2) p -、-(CH2) p NR 7 -、-NR 7 CO-、-NR 7 SO2- and NR 7 (CH2) p ; Among them, R 5 For 1, 2, 3 or 4 substituents on the ring are selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl; R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, C6-C10 aryl, and 3-12 membered heterocyclyl; R 7 is H or C1-C4 alkyl; The m, n, p and q are each independently 0, 1, 2, 3 or 4; Unless otherwise specified, the heteroaromatic ring, heterocondensed ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the heterocyclic group includes a saturated or partially unsaturated ring; The alkyl, alkoxy, alkenyl, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, and heteroaryl groups are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, sulfhydryl, Boc, C1-C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl; The halogen is F, Cl, Br or I.

2. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The The ring is selected from the group consisting of:

3. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The The ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring, a substituted or unsubstituted 4-7 membered heterocyclic ring (including saturated or partially unsaturated rings), or a 7-20 membered heteropolycyclic ring (including fused, bridged, or spiro rings).

4. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The The ring is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted pyrimidine ring, a substituted or unsubstituted triazine ring, a substituted or unsubstituted pyrrole ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted imidazole ring, a substituted or unsubstituted thiazole ring, and a substituted or unsubstituted tetrahydrofuran ring.

5. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The R 4 1 or 2 substituents located on the B ring are selected from the following groups: halogen, cyano, amino, amine, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl NR(CH2) p -、(CH2) p NH(CH2) p COOR 6 and in, The ring is preferably a 3-7 membered heterocyclic ring, a 7-20 membered heteropolycyclic ring (including a fused ring, a bridged ring or a spiro ring); Z can be selected from the following groups: -O-, -NH-, -NHCO- and NH(CH2) p 、-(CH2) p NR 7 -.

6. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The The ring is selected from the group consisting of: The The ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted 4-7 membered heteroaromatic ring; The R 4 For 1, 2 or 3 substituents on the ring are each independently selected from the group consisting of deuterium, halogen, cyano, amino, amine, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl NR 7 (CH2) p -,and in, The ring is preferably a 3- to 7-membered heterocyclic ring.

7. The compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The compounds are as shown in the following table.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: one or more of the compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

9. The use of the compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: Used for preparing a pharmaceutical composition for treating or preventing diseases related to PL protease activity.

10. The use according to claim 8, characterized in that The disease is a disease caused by a virus that contains PL protease. Preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, or a combination thereof.

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