Antiviral compounds, methods of making and using the same

Abstract

The application discloses an antiviral compound and a preparation method and application thereof, in particular, an anti-coronavirus compound capable of serving as a PLPro inhibitor and a preparation method and application thereof. The compound has a structure shown in general formula I, has high inhibitory activity, can be used for broad-spectrum antiviral, in particular, coronavirus (for example, SARS-CoV, MERS-CoV, SARS-CoV-2), and has a very good potential application prospect in the field of drugs.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to an antiviral compound, its preparation method and application, and particularly to an anticoronavirus compound that can be used as a PLPro inhibitor, its preparation method and application. Background Technology

[0002] Many important infectious diseases affecting humans are caused by viruses. These diseases include rabies, smallpox, polio, hepatitis, pneumonia, yellow fever, immunodeficiency, and various encephalitis. Many of them are highly contagious, cause acute discomfort, and are often fatal. Others, such as rubella and cytomegalovirus, can cause birth defects. Coronaviruses are a large family of viruses, with the largest genomes known among positive-sense RNA viruses. Based on differences in host, serotype gene sequence, and structure, coronaviruses can be divided into four classes: alpha, beta, gamma, and delta. Of these four categories, α and β coronaviruses only infect mammals, while γ and δ coronaviruses mainly infect birds. α coronaviruses include human coronaviruses (HCoV-229E, HCoV-NL63), long-winged bat coronaviruses (HKU1, HKU8), canine coronaviruses (CCoV), and feline coronaviruses (FCoV). β coronaviruses include human coronaviruses (HCoV-OC43, HCoV-HKU1), novel coronavirus (SARS-CoV-2), SARS coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), mouse coronavirus, and fruit bat coronavirus HKU9. γ coronaviruses mainly include avian coronaviruses such as infectious bronchitis virus (IBV). δ coronaviruses include nightingale coronavirus (BuCoV HKU11), white-eye coronavirus (WECoV), wild duck coronavirus (WiCoV), and moorhen coronavirus (CMCoV).

[0003] Papain-like protease (PLPro) is a hydrolase expressed on the 5' end of the coronavirus genome, specifically on nsp3. Its main function is to cleave the LXGG tetrapeptide structure between nsp1-2, nsp2-3, and nsp3-4 of the polyprotein pp1a. This polyprotein needs to be hydrolyzed to become the mature functional protein, thus it is a key protein for coronavirus replication. Equally important, PLPro can cleave ubiquitin units of key host cell immune proteins, thereby protecting the coronavirus from host cell immune attack. Therefore, inhibiting PLPro not only inhibits coronavirus replication but also enhances the host cell's immune system's surveillance of the coronavirus, thereby reducing cytokine storms. PLPro is crucial for the viral life cycle and can serve as a potential target for anti-coronavirus drug design and screening. PLPro inhibitors with different chemical structures have been developed, but their inhibitory activity still needs further improvement. Summary of the Invention

[0004] This invention provides a compound having the following structure:

[0005]

[0006] in,

[0007] Ar is selected from: naphthyl, quinolinyl, isoquinolinyl or quinazolinyl, wherein the hydrogen atom in naphthyl, quinolinyl, isoquinolinyl or quinazolinyl may optionally be replaced by C1-C6 alkyl, -NH2, -OH, -OC1-C6 alkyl, -CH2X, -CHX2, -CX3;

[0008] L1 is selected from: C1-C6 alkylene groups, -CO-, -SO2-;

[0009] A1, A2, A3, A4, and A5 are independently selected from C or N, and when A1, A2, A3, A4, or A5 is an N atom, the connected R1, R2, R3, R4, or R5 does not exist;

[0010] R1, R2, R3, R4, and R5 are independently selected from: H, C1-C6 alkyl, -L2-NR9R 10 -L2-OH, -L2-OC1-C6 alkyl, -CN, -X, -CH2X, -CHX2, -CX3; or, two of R1, R2, R3, R4 and R5 together with the atoms they are attached to form a heterocyclic group;

[0011] L2 is selected from: single bond, C1-C6 alkylene group, -CO-, -SO2-, -NHCO-, -NH-SO2-;

[0012] R9 and R10 Independently selected from: H, C1-C6 alkyl, -CH2X, -CHX2, -SO2 (C1-C6 alkyl), -CX3, -L3-NR 11 R 12 Nitrogen-containing heterocyclic groups;

[0013] L3 is selected from: C1-C6 alkylene, -CO-, -SO2-, -NHCO-, -NH-SO2-, phenylene,

[0014] R 11 and R 12 Independently selected from: H, C1-C6 alkyl, -CH2X, -CHX2, -SO2 (C1-C6 alkyl), -CX3, -CO (C1-C6 alkyl);

[0015] X is selected from: F, Cl, Br, I;

[0016] R6 is selected from: H, C1-C6 alkyl groups;

[0017] W1 and W2 are independently selected from: C, N, O; and when W1 or W2 is O, the corresponding R7 or R8 does not exist;

[0018] R7 and R8 are independently selected from: H, (=O), C1-C6 alkyl, -X, -CH2X, -CHX2, -CX3, hydroxyl, -OC1-C6 alkyl.

[0019] In embodiments of the present invention, the above-mentioned compounds for

[0020] Specifically, the naphthyl group can be 1-naphthyl or 2-naphthyl.

[0021] Specifically, the quinolinyl group can be 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, or 8-quinolinyl.

[0022] Specifically, the aforementioned isoquinolinyl group can be 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, or 8-isoquinolinyl.

[0023] Specifically, the aforementioned quinoxalinyl group can be 2-quinoxalinyl, 4-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, or 8-quinoxalinyl.

[0024] In one embodiment of the present invention, Ar in Formula I above is naphthyl, such as 1-naphthyl or 2-naphthyl, especially 1-naphthyl.

[0025] Specifically, R6 is selected from: H, -CH3, -CH2CH3; in one embodiment of the present invention, R6 is H.

[0026] Specifically, W1 is C, W2 is C; or, W1 is C, W2 is N; or, W1 is C, W2 is O.

[0027] Specifically, R7 and R8 are independently selected from: H, (=O), C1-3 alkyl, -CF3, hydroxyl; in one embodiment of the present invention, both R7 and R8 are H.

[0028] Specifically, the above compounds can have the following structures:

[0029]

[0030] Specifically, in Formula I above, the number of N atoms in A1, A2, A3, A4, and A5 is 0-2 (e.g., 0, 1, 2).

[0031] In one embodiment of the present invention, A1, A2, A3, A4 and A5 are all C.

[0032] In another embodiment of the present invention, A1 is N, and A2, A3, A4 and A5 are C.

[0033] In another embodiment of the present invention, A2 is N, and A1, A3, A4 and A5 are C.

[0034] In another embodiment of the present invention, A3 is N, and A1, A2, A4 and A5 are C.

[0035] In another embodiment of the present invention, A4 is N, and A1, A2, A3 and A5 are C.

[0036] In another embodiment of the present invention, A5 is N, and A1, A2, A3 and A4 are C.

[0037] In another embodiment of the present invention, A1 and A2 are N, and A3, A4 and A5 are C.

[0038] In another embodiment of the present invention, A1 and A3 are N, and A2, A4 and A5 are C.

[0039] In another embodiment of the present invention, A1 and A4 are N, and A2, A3 and A5 are C.

[0040] In another embodiment of the present invention, A1 and A5 are N, and A2, A3 and A4 are C.

[0041] In another embodiment of the present invention, A2 and A3 are N, and A1, A4 and A5 are C.

[0042] In another embodiment of the present invention, A2 and A4 are N, and A1, A3 and A5 are C.

[0043] In another embodiment of the present invention, A2 and A5 are N, and A1, A3 and A4 are C.

[0044] In another embodiment of the present invention, A3 and A4 are N, and A1, A2 and A5 are C.

[0045] In another embodiment of the present invention, A3 and A5 are N, and A1, A2 and A4 are C.

[0046] In another embodiment of the present invention, A4 and A5 are N, and A1, A2 and A3 are C.

[0047] Specifically, the above compounds can have the following structures:

[0048]

[0049] In one embodiment of the present invention, L1 is -CO- or -SO2-.

[0050] Specifically, L2 is selected from: single bond, -CH2-, -SO2-, -NHCO-, -NH-SO2-.

[0051] Specifically, R9 and R 10 Independently selected from H, -CH3, -CH2CH3, -C(CH3)3, -SO2CH3, -L3-NR9R 10 Three to five saturated nitrogen-containing heterocyclic groups (e.g.) Among them, R 13 Selected from: H, C1-C6 alkyl groups.

[0052] Specifically, L3 is selected from: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CO-, -SO2-,

[0053] Specifically, R 11 and R 12 Independently selected from: H, -CH3, -CH2CH3, -COCH3, -COCH2CH3.

[0054] Specifically, at least one of R1, R2, R3, R4 and R5 is -L2-NR7R8.

[0055] In one embodiment of the present invention, R1, R2, R3, R4, and R5 are independently selected from: H, -CH3, -OCH3, -CF3, and -L2-NR7R8; more specifically, -L2-NR7R8 is selected from:

[0056] In another embodiment of the invention, two adjacent atoms of R1, R2, R3, R4, and R5 together with the atom connecting them in the middle form a heterocyclic group, such as a five- to seven-membered heteroaryl group (e.g., a five- or six-membered nitrogen-containing heteroaryl group), which, together with... The ring forms a fused ring. In one embodiment of the invention, the heteroaryl group is... Parts can be, for example R1, R2, and R5 have the corresponding definitions of the present invention.

[0057] In one embodiment of the present invention, the above compound has the following structure: Wherein, R1, R3, and R4 have the corresponding definitions of the present invention, and at least one of R1, R3, and R4 is -L2-NR7R8.

[0058] Specifically, in Formula III, R1 is selected from: H, C1-C6 alkyl, -CF3, and R3 and R4 are independently -L2-NR7R8; more specifically, in Formula III, R1 is selected from: H, -CH3, -CF3, and R3 and R4 are independently selected from: in particular

[0059] In another embodiment of the present invention, the above compound has the following structure: Where R2 is -L2-NR7R8.

[0060] Specifically, in Equation IV, R2 is selected from: in particular

[0061] In another embodiment of the present invention, the above compound has the following structure: Wherein, R2 and R5 have the corresponding definitions of the present invention, and at least one of R2 and R5 is -L2-NR7R8.

[0062] Specifically, in formula V, R5 is selected from: H, C1-C6 alkyl, -CF3, and R2 is -L2-NR7R8; more specifically, in formula V, R5 is selected from: H, -CH3, -CF3, and R2 is selected from: in particular In some embodiments of the present invention, the above-mentioned compounds have the following structures:

[0063]

[0064]

[0065] in particular

[0066]

[0067] The present invention also provides pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds of the above-mentioned compounds.

[0068] The present invention also provides a method for producing the above-mentioned compound, which may include the following process route:

[0069]

[0070] Specifically, in step (1) above, the ethyl Grignard reagent can be ethyl magnesium bromide.

[0071] Specifically, step (1) above is carried out in an organic solvent (such as tetrahydrofuran).

[0072] Specifically, the reaction temperature in step (1) above is room temperature.

[0073] The present invention also provides a pharmaceutical composition comprising the above-described compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and one or more pharmaceutically acceptable excipients.

[0074] Specifically, in the above-mentioned pharmaceutical composition, the compound of the present invention can be used as the sole active ingredient, or it can be used in combination with one or more other active ingredients for the same or different indications. The compound of the present invention and the other active ingredients can be formulated for simultaneous, separate or sequential administration.

[0075] Specifically, the pharmaceutically acceptable excipients mentioned above may include sweeteners (such as sucrose, xylitol, fructooligosaccharides, cyclamate, stevia, aspartame, etc.), flavoring agents (such as fragrances, flavorings, etc.), gelling agents (such as sodium alginate, gum arabic, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), clarifying agents (such as chitosan, gelatin, etc.), preservatives (such as benzoic acid and its salts, sorbic acid and its salts, parabens, etc.), disintegrants (such as low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxyacetic acid starch, croscarmellose sodium, starch, etc.), and binders (such as hydroxypropyl cellulose, hydroxypropyl methylcellulose). The ingredients include: povidone, copovidone, pregelatinized starch, etc.; lubricants (such as stearic acid, magnesium stearate, sodium fumarate stearate, etc.); wetting agents (such as polyoxyethylene sorbitan fatty acid ester, poloxamer, polyoxyethylene castor oil derivatives, etc.); suspending agents (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, copovidone, sodium carboxymethyl cellulose, methylcellulose, etc.); stabilizers (such as citric acid, fumaric acid, succinic acid, etc.); fillers (such as starch, sucrose, lactose, microcrystalline cellulose, etc.); and binders (such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone, etc.).

[0076] Specifically, the above-mentioned pharmaceutical compositions can be in any dosage form or administration method, which can be selected by those skilled in the art as appropriate, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, oral tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled-release formulations (e.g., instantaneous-release formulations, sustained-release formulations, sustained-release microcapsules), aerosols, and films (e.g., oral). Disintegrating film preparations, oral mucosa-adhesive film preparations, injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), intravenous infusions, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories (e.g., rectal suppositories, vaginal suppositories), pills, nasal preparations, pulmonary preparations (inhalation), eye drops, etc.; forms of administration, such as oral administration or parenteral administration (e.g., intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, infusion, intracerebral, rectal, etc.).

[0077] The present invention also provides the use of the above-mentioned compounds and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the above-mentioned pharmaceutical compositions as PLpro inhibitors, for example as antiviral drugs.

[0078] The present invention also provides the use of the above-mentioned compounds and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the above-mentioned pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases or conditions caused by or related to viral infections.

[0079] Specifically, in the above applications, the compounds and pharmaceutical compositions have the corresponding definitions of the present invention.

[0080] In one embodiment of the present invention, the virus is a coronavirus, such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2, etc., especially SARS-CoV, MERS-CoV, and SARS-CoV-2.

[0081] Specifically, the aforementioned diseases or conditions are those caused by or related to coronavirus infection, such as COVID-19, SARS, MERS, etc.

[0082] The present invention also provides a method for preventing and / or treating diseases or conditions caused by or related to viral infection, comprising the step of administering to a subject an effective amount of the above-described compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound of the present invention, or the above-described pharmaceutical composition of the present invention.

[0083] Specifically, in the above methods, the compounds, pharmaceutical compositions, diseases, or symptoms have the corresponding definitions of the present invention.

[0084] In particular, the aforementioned diseases or conditions are caused by or related to coronavirus infection, such as COVID-19, SARS, MERS, etc.

[0085] Specifically, the subjects mentioned above are animals; in one embodiment of the present invention, the subjects are mammals, such as humans, monkeys, cats, dogs, rats, bats, etc.; in another embodiment of the present invention, the subjects are birds.

[0086] This invention provides a novel compound that can be used as a PLPro inhibitor. It has high activity and can be used for broad-spectrum antiviral activity, especially against coronaviruses (such as SARS-CoV, MERS-CoV, and SARS-CoV-2). It has very good application prospects and value in the pharmaceutical field. Attached Figure Description

[0087] Figure 1 The figure shows the inhibition rate curve of the compound prepared in Example 2.

[0088] Figure 2 The figure shows the inhibition rate curve of the compound prepared in Example 35.

[0089] Figure 3 The figure shows the inhibition rate curve of the positive control compound GRL0617. Detailed Implementation

[0090] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0091] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by single bonds. Typical alkyl groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is replaced by a cycloalkyl group, the corresponding radical is a "cycloalkylalkyl" radical, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is replaced by an aryl group, the corresponding radical is an "aralkyl" radical, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is replaced by a heterocyclic group, the corresponding radical is a "heterocyclicalkyl" radical. "Alkylene" usually refers to an alkyl group with two free valence bonds. Typical alkylene groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene, ethylene, propylene, butylene, etc.

[0092] The term "alkoxy" refers to a substituent formed when a hydrogen atom in a hydroxyl group is replaced by an alkyl group. Typical alkoxy groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0093] The term "cycloalkyl" refers to a saturated or partially saturated (especially saturated) monocyclic or polycyclic group that may contain 1 to 4 monocyclic and / or fused rings and 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

[0094] The term "aryl" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing a monoaryl group and / or a fused aryl group, such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. Typical aryl groups are those containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, and indenyl. "Arylidene" refers to a divalent group derived from aromatic hydrocarbons by removing two hydrogen atoms.

[0095] The term "heterocyclic group" includes heteroaromatic and heterocyclic groups containing 1 to 3 monocyclic and / or fused rings and 3 to 18 ring atoms. Preferred heteroaromatic and heterocyclic groups contain 5 to 10 ring atoms. Suitable heteroaryl groups in the compounds of the present invention contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms. Examples of heteroaryl groups, such as, but not limited to, coumarins, including 8-coumarins; quinolinyl groups, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indoleyl, isoindoleyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl, cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc. Suitable heterocyclic groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. Examples of heterocyclic groups, such as, but not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiocyclohexyl, piperazine, aziridine, oxocyclobutyl, thiocyclobutyl, high-piperidinyl, oxocyclopropane, thiocyclopropane, acrylonitrile, oxoaziridine, diacylonitrile, triacylonitrile, 1,2,3,6-tetracyclyl Hydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiopentyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinazinyl, etc.

[0096] The above-mentioned groups can be replaced by one or more suitable groups at one or more available positions, such as: OR', =O, SR', SOR', SO2R', OSO2R', OSO3R', NO2, NHR', N(R')2, =N-R', N(R')COR', N(COR')2, N(R')SO2R', N(R')C(=NR')N(R')R', N3, CN, halogen, COR', COOR', OCOR', OCOOR', OCONHR', OCON(R')2, CONHR', CON(R')2, CON(R')OR', CON(R')SO2R', PO(OR')2, PO(OR')R', PO(OR')(N(R')R'), Cl-C 12 Alkyl, C3-C 10 cycloalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, aryl, and heterocyclic groups, wherein each R' group is independently selected from: hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, COalkyl, COOH, C1-C 12 Alkyl, C3-C 10 cycloalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, aryl, and heterocyclic groups. These groups are themselves substituted, and the substituents can be selected from the aforementioned list.

[0097] "Halogen" refers to bromine, chlorine, iodine, or fluorine. Haloalkyl refers to a group in which the hydrogen atom on the alkyl group is replaced by a halogen atom (F, Cl, Br, I), such as -CH2Rh, -CHRh2, -CRh3, where Rh is F, Cl, Br, or I; such as -CF3.

[0098] The term "pharmaceutically acceptable salt" refers to an acidic or basic salt that is theoretically non-toxic, non-irritating, and non-allergenic, and that can achieve or provide clinically acceptable pharmacokinetic, absorption, distribution, and metabolic properties of a drug molecule to achieve its intended purpose. The salts described in this invention include pharmaceutically acceptable acidic or basic salts of compounds with acidic, basic, or amphoteric groups. A list of suitable salts can be found in SM Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0099] The pharmaceutically acceptable salts described in this invention include acid addition salts and base addition salts.

[0100] The acid addition salts include, but are not limited to, salts from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, as well as salts from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanic acids, hydroxyalkanic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, and galacturonic acids. Acid addition salts can be prepared by contacting a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base, and the free base can be separated in a conventional manner.

[0101] The base addition salts described in this invention refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting a sufficient amount of the desired base in a conventional manner to form a salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be separated in a conventional manner.

[0102] The term "solvent" should be understood to refer to any form of the compounds of the present invention, wherein the compounds are linked to another molecule (usually a polar solvent) by a non-covalent bond, particularly including hydrates and alcohols, such as methanols. Hydrates are preferred solvates.

[0103] The term "prodrug" is used in its broad sense and encompasses derivatives that can be converted into the compounds of this invention in vivo. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable acylureas, and biohydrolyzable phosphate ester analogs. Preferably, prodrugs having a carboxyl functional group are lower alkyl esters of carboxylic acids. The carboxylic acid esters are readily obtained by esterification of any carboxylic acid moiety present in the molecule. Prodrugs can generally be prepared by known methods, such as those described in Burger's "Medicinal Chemistry and Drug Discovery, 6th Edition" (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers).

[0104] Any compound referred to herein is intended to represent such a particular compound and certain variations or forms thereof. In particular, the compounds referred to herein may have an asymmetric center and therefore exist in different enantiomers or diastereomers. Thus, any given compound referred to herein represents any racemic compound, one or more enantiomers, one or more diastereomers, or mixtures thereof. Similarly, stereoisomers or geometric isomers of the double bonds may also exist, thus in some cases the molecule may exist as (E)-isomers or (Z)-isomers (trans and cis isomers). If the molecule contains multiple double bonds, then each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds of the molecule. Furthermore, the compounds referred to herein may exist as ator isomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers, and ator isomers, and mixtures thereof, are within the scope of this invention.

[0105] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0106] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0107] Example 1:

[0108]

[0109] THU101: 1 H NMR(400 MHz, Methanol-d4) δ 8.65 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.46 (dt, J = 15.3, 7.6 Hz, 2H), 7.17 (d, J = 2.8 Hz, 1H), 6.52 (dd, J = 6.2, 2.8 Hz, 1H), 2.92 (s, 6H), 1.51 (t, J = 3.5 Hz, 2H), 1.33 (t, J = 3.5 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 146.50, 138.04, 133.97, 132.27, 131.56, 128.95, 128.81, 128.10, 126.15, 125.88, 125.59, 125.51, 123.06, 113.39, 111.21, 56.85, 55.72, 47.13, 44.40, 43.92, 34.64, 24.35, 18.30, 14.51. MS(ESI, m / z): C21H21N3O, [M + H]+ 332.17.

[0110] Example 2:

[0111]

[0112] THU102: 1 H NMR(400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.52 (ddt, J = 29.4, 15.2, 7.4 Hz, 3H), 6.76 (d, J = 8.1 Hz, 1H), 6.45 (dd, J = 8.0, 2.5 Hz, 1H), 6.29 (d, J = 2.5 Hz, 1H), 4.91 (s, 2H), 1.87 (s, 3H), 1.33 (d, J = 5.4 Hz, 2H), 1.16 (d, J = 5.3 Hz, 2H). 13C NMR(101MHz,DMSO-d6)δ170.49,146.47,138.34,138.16,133.91,132.31,131.03,128.92,128.85,128.03,126.19 ,125.84,125.69,125.49,121.49,115.00,112.79,34.34,18.37,14.68.MS(ESI,m / z):C21H20N2O,[M+H]+317.16.

[0113] Example 3:

[0114]

[0115] THU103: 1 H NMR(400MHz,Chloroform-d)δ9.00(s,1H),8.61(d,J=8.5Hz,1H),8.31(dd,J=4.6,1.6Hz ,1H),8.01(dd,J=7.1,1.3Hz,1H),7.89(d,J=8.2Hz,1H),7.80(d,J=8.2Hz,1H),7.64(ddd ,J=8.4,6.8,1.4Hz,1H),7.50(dt,J=8.0,6.5Hz,3H),7.22(dd,J=7.8,4.6Hz,1H),2.68(s ,3H),1.57(t,J=3.4Hz,2H),1.44–1.39(m,2H).MS(ESI,m / z):C20H18N2O,[M+H]+303.27.

[0116] Example 4:

[0117]

[0118] THU104: 1 H NMR(400MHz,Chloroform-d)δ8.47(d,J=8.3Hz,1H),8.40–8.32(m,2H),7.94(dd,J=7.7,4.4Hz,2H),7.84(d,J=8.2Hz,1H),7 .64–7.45(m,3H),7.29(s,1H),6.99(d,J=4.9Hz,1H),6.75(s,1H),2.16(s,3H),1.60(t,J=3.6Hz,2H),1.45(t,J=3.6Hz,2H). 1313C NMR (101 MHz, Chloroform-d) δ 151.82, 147.44, 129.04, 128.69, 128.48, 126.21, 125.50, 123.77, 120.23, 34.93, 16.15, 14.80, 14.71. MS (ESI, m / z): C20H18N2O, [M+H]+ 303.25.

[0119] Example 5:

[0120]

[0121] THU105: 1 1H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.49–8.38 (m, 2H), 7.96–7.75 (m, 4H), 6.98 (s, 1H), 2.42 (s, 3H), 1.59 (t, J = 4.9 Hz, 2H), 1.45 (t, J = 4.9 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 158.98, 158.87, 154.47, 154.37, 136.27, 129.87, 129.44, 129.34, 129.21, 129.06, 128.96, 128.85, 128.73, 126.65, 126.43, 125.70, 125.48, 124.01, 35.32, 15.02, 14.93, 14.79. MS (ESI, m / z): C19H17N3O, [M+H]+ 304.34.

[0122] Example 6:

[0123]

[0124] THU106: 1 1H NMR (400 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.62 (dd, J = 8.6, 6.8 Hz, 1H), 7.48 (dt, J = 11.7, 7.5 Hz, 2H), 7.36 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 5.8, 2.4 Hz, 1H), 1.60 (t, J = 5.6 Hz, 2H), 1.40 (t, J = 5.6 Hz, 2H).13 C NMR(101MHz,Chloroform-d)δ153.84,137.16,133.96,132.13,128.78,128.67,128.22,126.18,125.45 ,125.38,124.53,111.00,107.99,53.43,34.17,29.33,14.68.MS(ESI,m / z):C19H17N3O,[M+H]+304.21.

[0125] Example 7:

[0126]

[0127] THU107: 1 H NMR(400MHz,Chloroform-d)δ8.49(d,J=8.4Hz,1H),8.45–8.28(m,2H),8.00-7.85(m,2H),7.83(d,J=8.3Hz,1H),7.65-7.40(m,3H),7.07( d,J=5.1Hz,1H),6.92(s,1H),2.26(d,J=1.9Hz,3H),1.61(t,J=4.5Hz,2H),1.44(t,J=4.5Hz,2H).MS(ESI,m / z):C20H18N2O,[M+H]+303.25.

[0128] Example 8:

[0129]

[0130] THU108: 1 H NMR (400MHz, Methanol-d4) δ8.67(d,J=8.5Hz,1H),7.90(dd,J=11.4,8.0Hz,2H),7.80(d,J=8.3Hz,1H),7.61(t,J=7.8Hz,1 H),7.47(dt,J=15.8,8.0Hz,3H),7.19(d,J=7.4Hz,1H),6.63(d,J=8.3Hz,1H),1.54(t,J=7.4Hz,2H),1.33(t,J=7.4Hz,2H). 13C NMR(101MHz,Methanol-d4)δ166.25,158.73,137.91,136.91,134.12,132.08,128.36,128.21,127.91,1 25.74,125.14,124.72,124.28,111.66,110.35,33.83,13.76.MS(ESI,m / z):C19H17N3O,[M+H]+304.39.

[0131] Example 9:

[0132]

[0133] THU109: 1 H NMR (400MHz, Methanol-d4) δ8.62–8.55(m,1H),8.00-7.90(m,2H),7.87–7.79(m,2H),7.58(ddd,J=8.4,6.8,1.4Hz,1H ),7.54–7.47(m,1H),7.47–7.41(m,1H),6.81(d,J=2.8Hz,1H),2.09(s,3H),1.45(t,J=3.5Hz,2H),1.34–1.28(m,2H). 13 C NMR (101MHz, Methanol-d4) δ170.50,142.54,141.95,136.53,135.59,134.14,132.68,132.06,128.40,127. 94,125.72,125.16,124.71,124.34,120.35,34.15,19.00,13.53.MS(ESI,m / z):C20H19N3O,[M+H]+318.18.

[0134] Example 10:

[0135]

[0136] THU110: 1 H NMR (400MHz, Methanol-d4) δ8.66(d,J=8.5Hz,1H),7.93–7.83(m,3H),7.77(d,J=8.2Hz,1H),7.58(t,J=7.7Hz,1 H),7.48(t,J=7.5Hz,1H),7.42(t,J=7.7Hz,1H),6.72(d,J=4.2Hz,2H),1.44(t,J=4.4Hz,2H),1.32–1.26(m,2H).13 C NMR (101MHz, Methanol-d4) δ168.08,159.77,147.04,144.46,136.53,134.11,132.10,128.61,128.39,127. 94,125.71,125.12,124.68,124.32,109.64,106.77,34.25,13.66.MS(ESI,m / z):C19H17N3O,[M+H]+304.26.

[0137] Example 11:

[0138]

[0139] THU111: 1 H NMR (400MHz, Methanol-d4) δ8.70(dd,J=8.5,1.2Hz,1H),7.89(ddd,J=16.0,7.7,1.3Hz,2H),7.79(d,J=8.3Hz,1H),7.60(ddd,J=8.4,6.8,1 .4Hz,1H),7.53–7.37(m,2H),7.13–7.02(m,1H),6.99–6.88(m,2H),6.78(ddd,J=7.9,2.3,1.2Hz,1H),1.49–1.43(m,2H),1.33–1.26(m,2H). 13 C NMR(101MHz,Methanol-d4)δ170.28,147.75,136.96,135.62,134.11,132.17,128.64,128.48,128.32,127.76,1 25.63,125.05,124.64,124.47,117.77,116.04,113.34,34.22,13.68.MS(ESI,m / z):C20H18N2O,[M+H]+304.17.

[0140] Example 12:

[0141]

[0142] THU112: 11H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.90 (dd, J = 15.6, 7.6 Hz, 2H), 7.80 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.47 (d, J = 19.8 Hz, 2H), 6.83 (s, 1H), 6.74 (d, J = 5.3 Hz, 1H), 3.04 (s, 6H), 1.48 (s, 2H), 1.33 (s, 2H). 13 13C NMR (101 MHz, Methanol-d4) δ 168.37, 159.32, 147.29, 143.71, 136.58, 134.13, 132.11, 128.64, 128.38, 127.92, 125.65, 125.11, 124.66, 124.34, 108.33, 104.15, 37.06, 34.32, 13.65. MS (ESI, m / z): C21H21N3O, [M+H]+ 332.37.[[ID=​​​​​​​​​​​​​​​

[0147]

[0148] THU114: 1 H NMR(400 MHz, Methanol-d4) δ 8.60 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 7.8, 3.4 Hz, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.77 (dd, J = 8.0, 2.0 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.54 - 7.44 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 2.10 (s, 3H), 1.49 (t, J = 5.8 Hz, 2H), 1.34 (t, J = 3.6 Hz, 2H). 13 C NMR(100 MHz, Methanol-d4) δ 168.25, 141.87, 140.12, 134.40, 133.27, 132.91, 132.02, 130.37, 128.90, 127.79, 127.72, 127.00, 126.30, 125.96, 125.14, 124.85, 124.50, 35.89, 20.76, 18.80. MS(ESI, m / z): C21H20N2O3S, [M + H]+ 381.12.

[0149] Example 15:

[0150]

[0151] THU115: 1 H NMR(400 MHz, Methanol-d4) δ 8.70 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 7.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 9.4 Hz, 2H), 7.66 - 7.55 (m, 2H), 7.43 - 7.53 (m, 3H), 4.12 (s, 2H), 1.49 (d, J = 6.3 Hz, 2H), 1.36 (d, J = 5.5 Hz, 2H). 13C NMR (100MHz, Methanol-d4) δ169.32,142.50,134.32,133.94,133.27,132.91,130.29,128.76,128.57,127.79,127. 72,127.31,126.30,125.96,125.14,124.85,124.50,46.33,35.96,18.80.MS(ESI,m / z):C21H20N2O,[M+H]+317.16.

[0152] Example 16:

[0153]

[0154] THU116: 1 H NMR(400MHz, DMSO-d6)δ9.07(s,1H),8.65(d,J=8.2Hz,1H),8.43(s,1H),7.94(d,J=7.9Hz,1H),7.88-7.75(m,2H),7.63-7.50(m,2H), 7.48(d,J=8.0Hz,1H),7.30(d,J=8.2Hz,1H),7.06(s,1H),6.96(d,J=8.3Hz,1H),5.77(s,2H),1.94(s,3H),1.34(s,2H),1.17(s,2H). 13 C NMR(100MHz,Methanol-d4)δ168.61,156.09,137.72,135.48,135.39,134.40,133.27,132.91,130.48,127.79,127.72,1 26.30,125.96,125.14,124.85,124.50,121.11,117.46,35.89,20.80,18.80.MS(ESI,m / z):C22H21N3O2,[M+H]+360.16.

[0155] Example 17:

[0156]

[0157] THU117: 11H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.65 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.84 (t, J = 7.4 Hz, 2H), 7.63–7.43 (m, 3H), 7.40 (dt, J = 8.1, 2.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 3.50 (d, J = 1.7 Hz, 6H), 2.04 (d, J = 1.7 Hz, 3H), 1.41 (d, J = 5.6 Hz, 2H), 1.24–1.19 (m, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.45, 138.98, 137.78, 137.74, 133.95, 132.21, 131.93, 131.80, 131.61, 129.37, 128.98, 128.92, 128.25, 126.20, 125.93, 125.54, 125.43, 43.41, 34.64, 19.00, 14.56, 14.52. MS (ESI, m / z): C23H24N2O5S2, [M+H]+ 473.12.

[0158] Example 18:

[0159]

[0160] THU118: 1 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 8.20 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.4 Hz, 2H), 7.51 (ddd, J = 27.0, 15.4, 7.1 Hz, 3H), 7.02 (t, J = 8.9 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.80 (s, 1H), 1.86 (d, J = 2.3 Hz, 3H), 1.34 (s, 2H), 1.19–1.13 (m, 2H). 13C NMR(100MHz,DMSO-d6)δ167.29,138.75,135.89,134.47,133.00,132.69,132.23,129.92,127.69,127.62,126.10, 125.79,124.91,124.63,124.31,121.34,117.71,35.89,20.64,18.60.MS(ESI,m / z):C21H21N3O3S,[M+H]+396.13.

[0161] Example 19:

[0162]

[0163] THU119: 1 H NMR(400MHz, DMSO-d6)δ9.14(s,1H),8.63(d,J=8.2Hz,1H),7.95–7.89(m,1H),7.86–7.78(m,2H),7.59–7.42(m,3H),6.86(t,J=7.7Hz,1H),6.41( d,J=8.0Hz,1H),6.28(d,J=7.4Hz,1H),4.54(s,2H),1.74(s,3H),1.38–1 .32(m,2H).1.17-1.14(m,2H).MS(ESI,m / z):C21H20N2O,[M+H]+317.16.

[0164] Example 20:

[0165]

[0166] THU120: 1H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.63 (d, J = 8.3Hz, 1H), 7.92 (dd, J = 8.0, 1.5Hz, 1H), 7.85–7. 73(m,2H),7.57(ddd,J=8.4,6.7,1.6Hz,1H),7.51(ddd,J=8.0,6.8,1.3Hz,1H),7.44(dd,J=8.2, 7.1Hz,1H),6.85(d,J=8.3Hz,1H),6.80(d,J=2.2Hz,1H),6.63(dd,J=8.3,2.3Hz,1H),5.75(s,2H ),1.29(q,J=4.7,4.3Hz,2H),1.13(q,J=4.8Hz,2H).MS(ESI,m / z):C21H17F3N2O,[M+H]+371.13.

[0167] Example 21:

[0168]

[0169] THU121: 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.64(d,J=8.2Hz,1H),7.92(dd,J=7.9,1.6H z,1H),7.86–7.76(m,2H),7.61–7.40(m,3H),6.79(t,J=7.7Hz,1H),6.57(dd,J=8 .0,1.3Hz,1H),6.21(dd,J=7.5,1.3Hz,1H),4.87(s,2H),1.69(s,3H),1.32(q,J= 4.6,4.1Hz,2H),1.14(q,J=4.7Hz,2H).MS(ESI,m / z):C21H20N2O,[M+H]+317.16.

[0170] Example 22:

[0171]

[0172] THU122: 11H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 9.1 Hz, 2H), 7.91 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 6.94–6.85 (m, 1H), 6.26 (d, J = 7.4 Hz, 2H), 5.25 (s, 2H), 2.05 (s, 3H), 1.30 (d, J = 6.0 Hz, 2H), 1.12 (s, 2H). MS (ESI, m / z): C21H20N2O, [M+H]+ 317.16.

[0173] Example 23:

[0174]

[0175] THU123: 1 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.62 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 12.6, 7.9 Hz, 2H), 7.65–7.49 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 6.56 (d, J = 8.6 Hz, 1H), 6.22 (s, 1H), 5.85 (s, 2H), 1.29 (s, 3H), 1.13 (s, 2H). MS (ESI, m / z): C21H17F3N2O, [M+H]+ 371.13.

[0176] Example 24:

[0177]

[0178] THU124: 1 1H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.64–7.53 (m, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.18–7.01 (m, 3H), 6.45 (d, J = 2.1 Hz, 2H), 5.57 (s, 1H), 3.57 (s, 2H), 1.79 (d, J = 1.9 Hz, 3H), 1.69 (s, 2H), 1.20 (s, 2H). 13CNMR(101MHz,Chloroform-d)δ144.07,138.46,134.30,133.72,132.54,131.28,129.04,128.30,127.50,126. 45,125.59,125.57,124.56,123.09,118.52,116.19,36.85,18.27.MS(ESI,m / z):C20H20N2O2S,[M+H]+353.13.

[0179] Example 25:

[0180]

[0181] THU125: 1 H NMR(400MHz, DMSO-d6)δ9.07(s,1H),8.69(d,J=8.0Hz,1H),8.23–7.96(m,3H),7.93(d,J=7.6Hz,1H),7.81(t,J=7.9Hz,2H),7.62–7.42(m,3H), 6.96(d,J=7.9Hz,1H),6.75(d,J=7.9Hz,1H),6.52(s,1H),3.50–3.41(m ,2H),2.86(s,2H),2.80(s,3H),1.90(s,3H),1.37(s,2H),1.17(s,2H). 13 C NMR(101MHz,DMSO-d6)δ170.12,138.35,138.08,133.93,132.28,131.44,128.90,128.85,128.09,126.1 3,125.89,125.70,125.51,50.08,36.15,34.58,18.36,14.57.MS(ESI,m / z):C24H27N3O,[M+H]+374.22.

[0182] Example 26:

[0183]

[0184] THU126: 11H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.69 (d, J = 8.4 Hz, 3H), 7.98–7.90 (m, 1H), 7.82 (t, J = 8.3 Hz, 2H), 7.64–7.43 (m, 3H), 6.96 (d, J = 8.5 Hz, 1H), 6.74 (dd, J = 8.5, 2.8 Hz, 1H), 6.49 (d, J = 2.8 Hz, 1H), 3.49 (t, J = 6.9 Hz, 2H), 2.96 (q, J = 6.6 Hz, 2H), 2.79 (s, 3H), 2.54 (d, J = 5.3 Hz, 3H), 1.92 (s, 3H), 1.37 (q, J = 4.4 Hz, 2H), 1.18 (t, J = 3.3 Hz, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.18, 138.08, 133.93, 132.28, 131.43, 128.91, 128.10, 126.15, 125.89, 125.68, 125.52, 48.85, 45.51, 34.58, 33.09, 18.36, 14.57. MS (ESI, m / z): C25H29N3O, [M+H]+ 424.20.

[0185] Example 27:

[0186]

[0187] THU127: 1 1H NMR (400 MHz, Methanol-d4) δ 8.61 (d, J = 8.4 Hz, 1H), 7.91 (dd, J = 7.2, 1.4 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.61–7.55 (m, 1H), 7.51 (td, J = 7.4, 6.7, 1.2 Hz, 1H), 7.46 (dd, J = 8.3, 7.1 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.69 (dd, J = 8.6, 2.8 Hz, 1H), 6.40 (d, J = 2.8 Hz, 1H), 3.40 (t, J = 6.9 Hz, 4H), 2.54 (s, 4H), 2.32 (s, 12H), 2.00 (s, 3H), 1.46 (t, J = 3.5 Hz, 2H), 1.32 (q, J = 4.7 Hz, 2H). MS (ESI, m / z): C29H38N4O, [M+H]+ 459.31.

[0188] Example 28:

[0189]

[0190] THU128: 1 H NMR(400MHz, Methanol-d4) δ 8.64 (d, J = 8.5 Hz, 1H), 8.33 (d, J = 21.6 Hz, 1H), 7.96–7.87 (m, 2H), 7.82 (dd, J = 7.9, 4.5 Hz, 1H), 7.60 (dddd, J = 8.4, 6.8, 2.9, 1.4 Hz, 1H), 7.55–7.45 (m, 2H), 7.38 (d, J = 1.8 Hz, 1H), 2.20 (d, J = 17.9 Hz, 3H), 1.49 (td, J = 7.8, 7.3, 2.9 Hz, 2H), 1.33 (dt, J = 11.6, 5.6 Hz, 2H). 13 C NMR(101MHz, Methanol-d4) δ 172.29, 141.94, 136.76, 134.18, 132.​​​​​​​​​​​​C NMR(101MHz,Methanol-d4)δ171.86,139.27,137.44,136.49,134.16,132.07,131.62,129.01,128.42,128.00,125.81 ,125.22,124.70,124.43,117.64,114.42,51.80,47.30,34.38,16.97,13.54.MS(ESI,m / z):C24H25N3O,[M+H]+372.46.

[0194] Example 30:

[0195]

[0196] THU130: 1 H NMR (400MHz, Methanol-d4) δ8.60(d,J=8.4Hz,1H),7.90(d,J=7.6Hz,2H),7.81(d,J=8.2Hz,1H),7.59(t,J =7.7Hz,1H),7.51(t,J=7.5Hz,1H),7.44(t,J=7.7Hz,1H),6.89(d,J=8.3Hz,1H),6.59(d,J=8.3Hz,1H),6.3 8(s,1H),3.41(d,J=18.7Hz,3H),3.15–3.06(m,1H),2.83(s,3H),2.10(d,J=13.8Hz,2H),1.94(s,3H),1.5 7(d,J=21.0Hz,2H),1.46(d,J=5.6Hz,2H),1.30(d,J=5.4Hz,2H).MS(ESI,m / z):C27H31N3O,[M+H]+414.36.

[0197] Example 31:

[0198]

[0199] THU131: 11H NMR (400 MHz, MeOD) δ 8.61 (d, J = 8.5 Hz, 1H), 7.94–7.86 (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.48–7.41 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.58 (dd, J = 8.2, 2.6 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 3.35–3.31 (m, 2H), 3.26 (d, J = 10.9 Hz, 1H), 3.11 (d, J = 12.8 Hz, 2H), 2.71 (t, J = 12.2 Hz, 2H), 1.96 (d, J = 2.1 Hz, 5H), 1.44 (d, J = 5.7 Hz, 2H), 1.30 (s, 2H). 13 13C NMR (101 MHz, MeOD) δ 172.88, 145.07, 137.40, 136.86, 134.16, 132.12, 130.80, 128.37, 128.27, 127.81, 125.60, 125.09, 124.71, 124.52, 114.76, 111.47, 48.91, 46.97, 43.91, 34.11, 31.18, 16.72, 13.49. MS (ESI, m / z): C26H29N3O, [M+H]+ 400.23.

[0200] Example 32:

[0201]

[0202] THU132: 1 1H NMR (400 MHz, MeOD) δ 8.61 (d, J = 8.5 Hz, 1H), 7.95–7.89 (m, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.60 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.49 (ddd, J = 21.5, 8.0, 6.8 Hz, 2H), 7.24 (s, 2H), 7.01 (s, 1H), 4.41–4.31 (m, 1H), 3.59 (ddd, J = 27.7, 12.4, 7.3 Hz, 2H), 3.48–3.36 (m, 2H), 2.38 (dq, J = 14.6, 7.4 Hz, 1H), 2.21 (dq, J = 13.7, 7.1 Hz, 1H), 2.06 (s, 3H), 1.50 (q, J = 4.8 Hz, 2H), 1.36–1.31 (m, 2H). 13C NMR(101MHz,MeOD)δ170.80,138.39,136.57,134.16,132.07,131.91,128.44,128.40,127.96,125.76,125.17,12 4.71,124.41,120.56,117.66,57.00,44.37,34.25,28.18,17.17,13.57.MS(ESI,m / z):C25H27N3O,[M+H]+386.22.

[0203] Example 33:

[0204]

[0205] THU133: 1 H NMR (400MHz, MeOD) δ8.60(d,J=8.4Hz,1H),7.94–7.89(m,2H),7.83(d,J=8.3Hz,1H),7.58(t,J=7.6Hz,1H),7.47(ddd,J=25.3,12.5,5 .0Hz,3H),7.25(d,J=2.4Hz,1H),7.12(d,J=8.3Hz,1H),2.05(s,3H),1.66(d,J=7.2Hz,2H),1.50–1.40(m,4H),1.33(d,J=5.8Hz,2H). 13 C NMR(101MHz,MeOD)δ171.60,167.98,137.12,136.68,134.84,134.13,132.08,131.53,130.51,128.38(d,J=5.5Hz),127.90,1 25.69,125.14,124.70,124.43,122.30,119.54,35.50,34.15,17.21,13.64,12.05.MS(ESI,m / z):C25H25N3O2,[M+H]+400.19.

[0206] Example 34:

[0207]

[0208] THU134: 11H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 6.5 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.59–7.43 (m, 3H), 7.08–6.93 (m, 3H), 6.83 (s, 1H), 6.54 (s, 1H), 6.34 (d, J = 7.4 Hz, 1H), 6.29–6.20 (m, 2H), 2.12 (s, 3H), 1.60–1.51 (m, 2H), 1.43–1.35 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.77, 147.52, 144.20, 140.67, 137.30, 136.86, 133.99, 131.91, 131.68, 130.22, 129.01, 128.74, 128.33, 128.09, 126.19, 125.51, 125.49, 124.08, 119.83, 116.88, 108.06, 107.92, 103.66, 34.81, 18.69, 14.83. MS (ESI, m / z): C27H25N3O, [M + H]+ 408.20.

[0209] Example 35:

[0210]

[0211] THU135: 1 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.01 (s, 1H), 8.65 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.57–7.37 (m, 4H), 7.07 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.78 (s, 1H), 6.64 (d, J = 8.0 Hz, 1H), 2.02 (s, 3H), 1.98 (s, 3H), 1.40–1.29 (m, 2H), 1.20–1.14 (m, 2H). 13C NMR (101MHz, CDCl3) δ170.09,168.50,144.07,139.60,138.59,137.19,136.41,133.96,132.04,129.90,129.74,128.88,128.77,128.04,125 .69,125.38,125.25,124.65,120.82,117.74,112.87,110.75,107.47, 34.83,24.82,19.10,14.58.MS(ESI,m / z):C29H27N3O2,[M+H]+450.21.

[0212] Preparation of the compounds in the above examples:

[0213] (1) Preparation of cyclopropylamine intermediate (1-(naphth-1-yl)cyclopropylamine): The synthetic route is as follows:

[0214]

[0215] The specific steps are as follows:

[0216] 1-Naphthonitrile (1.5 mmol, 1.0 eq) was placed in a round-bottom flask, and 10 mL of dry tetrahydrofuran was added as a solvent. Then, tetraisopropyl titanate (5.5 mmol, 1.0 eq) was added, and the reaction mixture was cooled to -78 °C. Ethyl Grignard reagent (11 mmol, 2.2 eq) was then slowly added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and reacted for 1.5 hours. Subsequently, boron trifluoride diethyl ether (10 mmol, 2.0 eq) was added dropwise, and the mixture was stirred at room temperature for three hours after the addition was complete. After the reaction was complete, 20 mL of 2N hydrochloric acid was added dropwise, and the mixture was stirred and quenched for 20 minutes. Then, excess saturated sodium hydroxide solution was added. The mixture was extracted with ethyl acetate, and the organic phase was collected, evaporated to dryness, and separated by silica gel column chromatography to obtain cyclopropylamine intermediate 2.

[0217] (2) The preparation of the compound in Example 24 was carried out via the following synthetic route:

[0218]

[0219] The specific procedure was as follows: Compound 2 (1.0 mmol, 1.0 eq) was placed in a round-bottom flask, 10 mL of THF was added as solvent, and triethylamine (4.0 eq) was added. Compound 3 (1.0 mmol, 1.0 eq) in THF solution was then added dropwise at 0 °C. After the addition was complete, the ice bath was removed, and the mixture was stirred at 50 °C for 12 h. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with ethyl acetate and water. The mixture was washed once with saturated ammonium chloride solution and once with saturated brine. The organic phase was evaporated to dryness, and purified by silica gel column chromatography to obtain product THU124.

[0220] (3) The preparation of the compound in Example 28 was carried out via the following synthetic route:

[0221]

[0222] Intermediate 4 and the previously obtained three-membered cyclic amine intermediate 2 were added to DMF solvent in a 1:1 ratio, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was dried by rotary evaporation. The product THU128 was then purified by silica gel column chromatography.

[0223] (4) Preparation of compounds from other examples, the synthetic routes are as follows:

[0224]

[0225] The specific steps are as follows:

[0226] Intermediate M1 (1.0 eq) was placed in a round-bottom flask, and tetrahydrofuran:water = 2:1 was added as a solvent. Then lithium hydroxide (4.0 eq) was added to the reaction system. After stirring at 60°C for 6 hours, the reaction system was acidified with 2N hydrochloric acid. After adding ethyl acetate, a white solid precipitated. The solid was filtered out and dried to obtain intermediate M2.

[0227] Intermediate M2 and the previously obtained three-membered cyclic amine intermediate 2 were added to DMF solvent in a 1:1 equivalent ratio, along with HATU (1.5 eq) and DIPEA (2.0 eq). The mixture was reacted at 70 °C for 12 h. The reaction solution was extracted with ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was dried by rotary evaporation. The product P was then purified by silica gel column chromatography.

[0228] Upper Middle R 1 R is one or more independent substituents on the ring. 1 Y1, Y2, Y3, and Y4 are selected based on the specific compound structure.

[0229] For example, for compounds THU116, THU117, THU118, THU125, THU126, THU127, THU129, THU130, THU131, THU132, THU134, and THU135, intermediate M1 is... Its synthetic route is as follows:

[0230]

[0231] Among them, R 2 =H, -CH3, -SO2CH3 or -CH2CH2N(CH3)2;

[0232] R 3 =-CH3, -CONH2, -SO2CH3, -SO2NH2, -CH2CH2NH2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2,

[0233]

[0234] The specific procedure was as follows: methyl 2-methyl-5-bromobenzoate (5, 10.0 mmol, 1.0 eq), an amine compound (6, 10.0 mmol, 1.0 eq), tris(dibenzylacetone)palladium (0.2 mmol, 0.02 eq), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (0.8 mmol, 0.08 eq), and cesium carbonate (20.0 mmol, 2.0 eq) were placed in a sealed tube, and 50 mL of toluene was added as a solvent. The mixture was stirred continuously at 110 °C for 24 h under argon protection. After the reaction was completed, the reaction solution was transferred to a round-bottom flask, the solvent was evaporated, and the mixture was extracted with ethyl acetate and water. The organic phase was washed once with saturated ammonium chloride solution and once with saturated brine. The organic phase was evaporated and purified by silica gel column chromatography to obtain intermediate M1.

[0235] Experimental Example 1: Detection of PLpro inhibitory activity of the compounds prepared in the above examples

[0236] Biological testing conditions:

[0237] 1. Reaction buffer: 20mM HEPEs, pH 7.5, 100mM NaCl, 1mM TCEP

[0238] 2. Preparation of mother liquor:

[0239] (1) 20μM Ub-AMC (Ub-AMC dry powder is dissolved directly with reaction buffer, and the precipitate is removed by centrifugation before use);

[0240] (2) 400 nM PLpro (purified by molecular sieve and frozen to -80°C, thawed on ice before use and diluted with reaction buffer);

[0241] (3) 40 μM test compound (the dry powder of the test compound was dissolved in DMSO to 40 mM; diluted to 400 μM with 50% DMSO; and then diluted to 40 μM with reaction buffer);

[0242] 3. For the single-point inhibition test reaction system: 10 μM Ub-AMC, 100 nM PLpro, 1 μM test compound, total volume 20 μL, reaction in 384 wells;

[0243] Add 5 μL of PLpro stock solution and 5 μL of test compound stock solution to a 384-well plate and incubate at 4°C for 30 min.

[0244] Add 10 μL of Ub-AMC stock solution to a 384-well plate, react at 37 °C for 30 min, and then measure the AMC fluorescence intensity (excitation: 360 nm; emission: 460 nm).

[0245] 4. +Control: Replace the test compound with DMSO at the corresponding dilution factor;

[0246] Blank: Reaction buffer replaces PLpro;

[0247] 5. Data processing: Subtract the Blank value from the measured value and normalize it based on the DMSO value;

[0248] 6. IC 50 Measurement:

[0249] Concentration gradient of test compounds (nM): 10000, 5000, 1000, 500, 250, 125, 62.5, 31.25, 15.625, 10, 5, 2, 1, 0.5, 0.1, 0.01

[0250] Measure fluorescence value after 15 min of reaction (the enzyme reaction rate is in the linear range at around 15 min, and in the non-linear range at 30 min);

[0251] 7. Data fitting: After normalization, the data is processed using Sigmaplot (fitting equation: Logistic, 3Parameter).

[0252] The results are shown in the table below.

[0253] Table 1 Experimental Results

[0254]

[0255]

[0256]

[0257]

[0258] GRL0617 served as a positive control and represents one of the most potent inhibitory molecules against PLpro reported in the literature (Ghosh et al., 2009; Ghosh et al., 2010; Ratia et al., 2008).

[0259] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0260] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0261] Listing the steps of the method in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure: （Ⅰ） in, Ar is a naphthyl group, wherein the hydrogen atom in the naphthyl group is optionally replaced by C1-C6 alkyl, -NH2, -OH, -OC1-C6 alkyl, -CH2X, -CHX2, or -CX3; L1 is -CO- or -SO2-; A1, A2, A3, A4, and A5 are independently selected from C or N, and when A1, A2, A3, A4, or A5 is an N atom, there are no connected R1, R2, R3, R4, or R5; and the number of N atoms in A1, A2, A3, A4, and A5 is 0-2. R1, R2, R3, R4and R5are independently selected from the group consisting of: H, C1-C6alkyl, -L2-NR9R 10 -OH, -OC1-C6alkyl, -CN, -X, -CH2X, -CHX2, -CX3; L2 is selected from: single bond, C1-C6 alkylene group, -CO-, -SO2-, -NHCO-, -NH-SO2-; R9and R 10 independently selected from the group consisting of: H, C1-C6alkyl, -CH2X, -CHX2, -SO2(C1-C6alkyl), -CX3, -L3-NR 11 R 12 , , , wherein R 13 is selected from the group consisting of: H, C1-C6alkyl; L3is selected from: C1-C6alkylene, -CO-, -SO2-, -NHCO-, -NH-SO2-, phenylene, , ; R 11 and R 12 are independently selected from the group consisting of H, C1-C6 alkyl, -CO(C1-C6 alkyl); X is selected from: F, Cl, Br, I; R6 is selected from: H, C1-C6 alkyl groups; W1 is C, W2 is C; R7 and R8 are independently selected from: H, (=O), C1-3 alkyl, -CF3, hydroxyl.

2. The compound of claim 1, wherein Ar represents 1-naphthyl.

3. The compound of claim 1, wherein A1, A2, A3, A4, and A5 are all C; or, A1 is N, A2, A3, A4, and A5 are C; or, A2 is N, A1, A3, A4, and A5 are C; or, A3 is N, A1, A2, A4, and A5 are C; or, A4 is N, A1, A2, A3, and A5 are C; or, A5 is N, A1, A2, A3, and A4 are C; or, A1 and A2 are N, A3, A4 and A5 are C; or, A1 and A3 are N, A2, A4 and A5 are C; or, A1 and A4 are N, A2, A3 and A5 are C; or, A1 and A5 are N, A2, A3 and A4 are C; or, A2 and A3 are N, A1, A4 and A5 are C; or, A2 and A4 are N, A1, A3 and A5 are C; or, A2 and A5 are N, A1, A3 and A4 are C; or, A3 and A4 are N, A1, A2 and A5 are C; or, A3 and A5 are N, A1, A2 and A4 are C; or, A4 and A5 are N, and A1, A2 and A3 are C.

4. The compound of claim 1, wherein Both R7 and R8 are H.

5. The compound of claim 1, wherein The compound has the following structure: or .

6. The compound of claim 1, wherein R6 is selected from: H, -CH3, -CH2CH3.

7. The compound of any one of claims 1-6, wherein L2 is selected from: single bond, -CH2-, -SO2-, -NHCO-, -NH-SO2-; and / or, R9and R 10 are independently selected from H, -CH3, -CH2CH3, -C(CH3)3, -SO2CH3, -L3-NR 11 R 12 , , , .

8. The compound of claim 1, wherein L3is selected from: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CO-, -SO2-, , , ; and / or, R 11 and R 12 are independently selected from the group consisting of: H, -CH3, -CH2CH3, -COCH3, -COCH2CH3.

9. The compound of claim 1, wherein R1, R2, R3, R4, and R5are independently selected from the group consisting of: H, -CH3, -OCH3, -CF3, -L2-NR9R 10 .

10. The compound of claim 1, wherein -L2-NR9R 10 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , .

11. The compound of claim 1, wherein The compound has the following structure: or .

12. A pharmaceutical composition comprising a compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

13. The use of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12, in the preparation of a medicament for the prevention and / or treatment of diseases or conditions caused by or related to a viral infection, wherein the virus is a coronavirus.

14. Use according to claim 13, wherein the compound is ###00010### or a pharmaceutically acceptable salt thereof. The viruses were selected from: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, and SARS-CoV-2.

15. The use according to claim 13, wherein the compound is ###00010### 13 The disease or condition is COVID-19, SARS, or MERS. The disease or condition is COVID-19, SARS, or MERS. The disease or condition is COVID

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