Benzothiazole compounds, preparation methods thereof and applications

Abstract

The present invention discloses a benzothiazole compound, a preparation method thereof and an application. This kind of compound has a highly efficient inhibitory effect on SARS-CoV-2 and can be used for anti-SARS-CoV-2.

Description

Technical Field

[0001] The present invention relates to a benzothiazole compound, a preparation method thereof and an application thereof. Background Art

[0002] Benzothiazole is a bicyclic system formed by the fusion of a benzene ring and a thiazole ring. Hofmann first synthesized 2-phenylbenzothiazole compounds containing this structural fragment in 1879. As early as the 1950s, there were reports on the use of 2-aminobenzothiazole as a central muscle relaxant. However, this type of structure did not attract the wide attention of medicinal chemists at that time. It was not until Riluzole et al. reported that the compound PK-26124 (6-trifluoromethoxy-2-aminobenzothiazole) could interfere with glutamatergic neurotransmission in biochemical, electrophysiological and behavioral experiments that medicinal chemists became interested in the biological activities of benzothiazole derivatives and began to conduct extensive research on them. Moreover, it was gradually found that some bioactive natural products also contain benzothiazole structural fragments. After that, benzothiazole derivatives or their bioisosteres have been applied in many fields such as medicine and pesticides due to their extensive biological activities. For example, in medicine, they are used for antiviral, anticonvulsant, antibacterial, anti-inflammatory, antitumor, and medical imaging agents, etc.; in agriculture, they are used as herbicides and insecticides.

[0003] The following compounds are antiviral compounds of benzothiazole reported in recent years. Among them, compound a, compound b, and compound c all have the effect of anti-hepatitis C virus; compound d is an inhibitor of HSV-1 virus; compound e has a strong inhibitory effect on CVB5, ADV7, and EV71 viruses; compound f has an obvious inhibitory effect on Zika virus and dengue virus.

[0004]

[0005] The development of small molecule anti-SARS-CoV-2 is particularly important. Benzothiazole compounds, as an advantageous backbone with pharmacological activity, especially have important applications in antiviral aspects. However, so far, there have been no reports on the anti-SARS-CoV-2 of benzothiazole small molecule compounds. Summary of the Invention

[0006] The technical problem to be solved by the present invention is that there is currently no benzothiazole small molecule drug for anti-SARS-CoV-2. Therefore, the present invention provides a benzothiazole compound, a preparation method thereof and an application thereof. This type of compound has a high inhibitory effect on SARS-CoV-2 and can be used for anti-SARS-CoV-2.

[0007] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0008]

[0009] Wherein,

[0010] Ring A is a saturated or partially unsaturated 4- to 10-membered heterocyclic ring;

[0011] Ring B is a 6- to 10-membered aromatic ring, a 5- to 10-membered heteroaromatic ring, or a saturated or partially unsaturated 4- to 10-membered heterocyclic ring;

[0012] Ring C is a 6- to 10-membered aromatic ring;

[0013] R 1 Each independently is halogen, =O, C 1-4 alkyl, halo C 1-4 alkyl, 3- to 10-membered cycloalkyl or -C(=O)(CH2) 1-3 -R 1-1 ;

[0014] R 1-1 is OH or -OC(O)CH3;

[0015] R 2 and R 3 Each independently is halogen, nitro, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, halo C 1-4 alkyl, halo C 1-4 alkoxy or halo C 1-4 alkylthio;

[0016] m1, m2 and m3 each independently are 0, 1, 2 or 3;

[0017] X is -(CR b R c )n1-, -C(O)-, -C(O)-NR a (CR b R c )n1- or -S(O)-NR a (CR b R c )n1-;

[0018] R a 、R b and R c Each independently is H or C 1-4 alkyl;

[0019] n1 each independently is 0, 1, 2, 3 or 4;

[0020] The number of heteroatoms in the 4- to 10-membered heterocyclic ring and 5- to 10-membered heteroaromatic ring is 1, 2, or 3, and each heteroatom is independently N, O, or S.

[0021] In some embodiments,

[0022] Ring A is a saturated or partially unsaturated 4- to 10-membered heterocyclic ring;

[0023] Ring B is a 6- to 10-membered aromatic ring, a 5- to 10-membered heteroaromatic ring, or a saturated or partially unsaturated 4- to 10-membered heterocyclic ring;

[0024] Ring C is a 6- to 10-membered aromatic ring;

[0025] R 1 are each independently halogen, ═O, C 1-4 alkyl, halo-C 1-4 alkyl, 3- to 10-membered cycloalkyl, or -C(═O)(CH2) 1-3 -R 1-1 ;

[0026] R 1-1 is OH or -OC(O)CH3;

[0027] R 2 and R 3 are each independently halogen, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, or halo-C 1-4 alkylthio;

[0028] m1, m2, and m3 are each independently 0, 1, 2, or 3;

[0029] X is -(CR b R c )n1-, -C(O)-, -C(O)-NR a (CR b R c )n1-, or -S(O)-NR a (CR b R c )n1-;

[0030] R a 、R b and R c are each independently H or C 1-4 alkyl;

[0031] n1 is each independently 0, 1, or 2;

[0032] The number of heteroatoms in the 4- to 10-membered heterocyclic ring and the 5- to 10-membered heteroaromatic ring is 1, 2, or 3, and each heteroatom is independently N, O, or S.

[0033] In certain preferred embodiments of the present invention (hereinafter referred to as "in some embodiments"), some groups in the compound represented by Formula I are defined as follows (the undefined groups are the same as those described in any aspect of the present application).

[0034] In some embodiments, in the definition of Ring A, at least one heteroatom in the 4- to 10-membered heterocyclic ring is N. Ring A is preferably linked to benzothiazole through the N atom.

[0035] In some embodiments, in the definition of Ring B, the 6- to 10-membered aromatic ring is a benzene ring.

[0036] In some embodiments, in the definition of Ring B, the number of heteroatoms in the 5- to 10-membered heteroaromatic ring is 1 or 2.

[0037] In some embodiments, in the definition of Ring B, the heteroatom in the 4- to 10-membered heterocyclic ring is O.

[0038] In some embodiments, in the definition of Ring C, the 6- to 10-membered aromatic ring is a benzene ring.

[0039] In some embodiments, R 1 In the definition of, the halogen is F.

[0040] In some embodiments, R 1 In the definition of, the C 1-4 alkyl is methyl, ethyl, or isopropyl.

[0041] In some embodiments, R 1 In the definition of, the 3- to 10-membered cycloalkyl is cyclopropyl.

[0042] In some embodiments, R 1 In the definition of, the halo-C 1-4 alkyl is fluoro-C 1-4 alkyl.

[0043] In some embodiments, R 2 and R 3 In the definition of, the halogens are each independently F or Cl.

[0044] In some embodiments, R 2 and R 3 In the definition of, the C 1-4 alkyls are each independently methyl.

[0045] In some embodiments, R 2 and R3 In the definition of, said C 1-4 alkoxy groups are each independently methoxy.

[0046] In some embodiments, R 2 and R 3 In the definition of, said C 1-4 alkylthio groups are each independently methylthio.

[0047] In some embodiments, R 2 and R 3 In the definition of, said halo C 1-4 alkyl, halo C 1-4 alkoxy and halo C 1-4 alkylthio groups are each independently fluoro.

[0048] In some embodiments, ring A is preferably

[0049] In some embodiments, ring A is ( represents the position where ring A is connected to benzothiazole).

[0050] In some embodiments, ring B is

[0051] In some embodiments, ring B is ( represents the position where ring B is connected to X).

[0052] In some embodiments, ring C is

[0053] In some embodiments, R 1 are each independently F, ═O, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2F,

[0054] In some embodiments, R 2 are each independently halogen, nitro, C 1-4 alkyl, C 1-4 alkoxy or halo C 1-4 alkoxy, preferably F, Cl, nitro, -CH3, -OCH3 or -OCF3.

[0055] In some embodiments, R 3 are each independently halogen, C 1-4 alkyl, C 1-4 alkylthio or halo C1-4 Alkyl, preferably F, Cl, -CH3, -SCH3 or -CF3.

[0056] In some embodiments, is

[0057] Preferably

[0058] In some embodiments, is

[0059] For example

[0060] In some embodiments, is Preferably

[0061] In some embodiments, R a , R b and R c are each independently H.

[0062] In some embodiments, n1 is each independently 1 or 2.

[0063] In some embodiments, n1 is each independently 3 or 4.

[0064] In some embodiments, X is -CH2-, -C(O)-, -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-CH2CH2- or -S(O)-NH-, preferably -CH2- or -C(O)-NH-CH2-.

[0065] In some embodiments, X is -CH2-, -C(O)-, -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-CH2CH2-, -C(O)-NH-CH2CH2CH2-, -C(O)-NH-CH2CH2CH2CH2- or -S(O)-NH-.

[0066] In some embodiments, is

[0067] For example

[0068] In some embodiments, the compound of formula I is as shown in formula I-a:

[0069]

[0070] Wherein, the definitions of each group are the same as described above.

[0071] In some embodiments, the compound of formula I is as shown in formula I-b:

[0072]

[0073] Wherein, the definitions of each group are the same as described above.

[0074] In some embodiments, the compound of formula I is as shown in formula I-c:

[0075]

[0076] Wherein, the definitions of each group are the same as described above.

[0077] In some embodiments, the compound of formula I is as shown in formula I-d:

[0078]

[0079] Wherein, the definitions of each group are the same as described above.

[0080] In some embodiments, the compound of formula I is as shown in formula I-e:

[0081]

[0082] Wherein, the definitions of each group are the same as described above, and m4 is 2 or 3.

[0083] In some embodiments, the pharmaceutically acceptable salt of the compound of formula I can be hydrochloride or mesylate. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt is selected from any of the following structures:

[0084]

[0085]

[0086]

[0087] In some embodiments, the compound of formula I is selected from any of the following structures:

[0088]

[0089]

[0090]

[0091] The present invention also provides a method for preparing the compound represented by the above formula I, which includes Method 1 and Method 2. Among them,

[0092] Method 1 includes the following steps: In a solvent (such as a halogenated hydrocarbon solvent, and for example, dichloromethane), reacting the compound represented by formula II with the compound represented by formula III as shown below to obtain the compound represented by formula I.

[0093]

[0094] Among them, X is -CH2-, and the definitions of the remaining groups are the same as those described above;

[0095] Method 2 includes the following steps: In a solvent (such as a halogenated hydrocarbon solvent, and for example, dichloromethane), reacting the compound represented by formula II with triphosgene in the presence of a base (such as triethylamine) to obtain an isocyanate product, and reacting the isocyanate product with the compound represented by formula III'' in the presence of a base (such as triethylamine) to obtain the compound represented by formula I.

[0096]

[0097] Among them, X is -C(O)-NR a (CR b R c )n1-, and the definitions of the remaining groups are the same as those described above.

[0098] In the method for preparing the compound represented by formula I, the reaction conditions can be the conventional conditions for such reactions in the art.

[0099] The present invention also provides a pharmaceutical composition, which comprises the compound represented by formula I described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compound represented by formula I or a pharmaceutically acceptable salt thereof can be in a therapeutically effective amount.

[0100] The present invention also provides the use of the compound represented by formula I described herein or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating patients infected with the SARS-CoV-2 virus.

[0101] Definition description

[0102] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to the corresponding commodity or its active ingredient.

[0103] In the present invention, the term "substituted" or "substituent" means that a hydrogen atom in a group is replaced by a specified group. When the substitution position is not specified, the substitution can occur at any position, but only a stable or chemically feasible compound is allowed. Examples are as follows: The structure represents that the hydrogen atoms on ring A are substituted by m1 R 1 groups.

[0104] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted by 0 - 2 R groups, the group can optionally be substituted by at most two R groups, and each R in each case has independent options. In addition, combinations of substituents and / or their variants are only allowed if such combinations result in a stable compound.

[0105] When the number of a linking group is absent, it means that the linking group is a single bond. For example, when L is absent in A - L - Z, the structure formed is A - Z.

[0106] In the present invention, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group. C 1-4 alkyl refers to an alkyl group having 1 - 4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0107] In the present invention, the term "alkoxy" refers to -O-alkyl, where the alkyl is defined as described above. C 1-4 alkoxy refers to -O-(C 1-4 alkyl), where C 1-4 alkyl is defined as described above.

[0108] In the present invention, the term "alkylthio" refers to -S-alkyl, where the alkyl is defined as described above. C 1-4 alkylthio refers to -O-(C 1-4 alkyl), where C 1-4 alkyl is defined as described above.

[0109] In the present invention, the term "haloalkyl" refers to a group formed by replacing one or more (such as 2, 3, 4, 5 or 6) hydrogen atoms in an alkyl group with a halogen, where each halogen is independently F, Cl, Br or I. Halo C1-4 An alkyl group refers to a C that is substituted with one or more halogens 1-4 alkyl group, wherein C 1-4 The definition of the alkyl group is as described above. In some embodiments, the halo C 1-4 alkyl group is a fluoro C 1-4 alkyl group.

[0110] In the present invention, the term "haloalkoxy" refers to a group formed by substituting one or more (e.g., 2, 3, 4, 5, or 6) hydrogen atoms in an alkoxy group with halogens, wherein each halogen is independently F, Cl, Br, or I. The halo C 1-4 alkoxy group refers to a C 1-4 alkoxy group that is substituted with one or more halogens, wherein C 1-4 The definition of the alkoxy group is as described above. In some embodiments, the halo C 1-4 alkoxy group is a fluoro C1-4 alkoxy group. The definition of the alkoxy group is as described above.

[0111] In the present invention, the term "haloalkylthio" refers to a group formed by substituting one or more (e.g., 2, 3, 4, 5, or 6) hydrogen atoms in an alkylthio group with halogens, wherein each halogen is independently F, Cl, Br, or I. The halo C 1-4 alkylthio group refers to a C 1-4 alkylthio group that is substituted with one or more halogens, wherein C 1-4 The definition of the alkylthio group is as described above. In some embodiments, the halo C 1-4 alkylthio group is a fluoro C1-4 alkylthio group. The definition of the alkylthio group is as described above.

[0112] In the present invention, the term "heterocycle" refers to a saturated, partially unsaturated, or aromatic monocyclic or polycyclic (e.g., fused ring, spiro ring, or bridged ring) cyclic group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently selected from N, O, and S. In a saturated heterocycle, the carbon atoms and heteroatoms on the ring are all saturated. Examples of saturated heterocycles include, but are not limited to In an aromatic heterocycle, each ring is aromatic. Examples of aromatic heterocycles include, but are not limited to In a partially unsaturated heterocycle, at least one atom on the ring is saturated and at least one atom is unsaturated. Examples of partially unsaturated heterocycles include, but are not limited to The 4-10 membered heterocycle can specifically be a 4, 5, 6, 7, 8, 9, or 10 membered heterocycle. The 5-10 membered heterocycle can specifically be a 5, 6, 7, 8, 9, or 10 membered heterocycle.

[0113] In the present invention, the term "aryl ring" refers to an aromatic carbocyclic ring, each ring of which is aromatic. The 6-10 membered aryl ring may specifically be a benzene ring or a naphthalene ring.

[0114] In the present invention, the term "heteroaryl ring" refers to an aromatic heterocyclic ring, each ring of which is aromatic. Examples of the heteroaryl ring include, but are not limited to The 5-10 membered heteroaryl ring may specifically be a 5, 6, 7, 8, 9 or 10 membered heteroaryl ring.

[0115] In the present invention, the term "cycloalkyl" refers to a monocyclic or polycyclic (such as fused ring, spiro ring or bridged ring) monovalent hydrocarbon group, each carbon atom of which is saturated. The 3-10 membered cycloalkyl may specifically be a 3, 4, 5, 6, 7, 8, 9 or 10 membered cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0116] In the present invention, the term "heterocycloalkyl" refers to a group formed by replacing at least one carbon atom in the cycloalkyl with a heteroatom selected from N, O and S. The 3-10 membered heterocycloalkyl may specifically be a 3, 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl. Examples of the heterocycloalkyl include, but are not limited to

[0117] The compounds of the present invention and their structures also represent all isomeric forms (including stereoisomers and tautomers, where stereoisomers such as enantiomers, diastereoisomers, geometric isomers (such as cis-trans isomers) and conformational isomers). They can be defined as (R)- / (S)- or (D)- / (L)- or (R,R)- / (R,S)- / (S,S)- according to the absolute stereochemistry of amino acids. The present invention includes all these possible isomers, as well as their racemic, enantiomerically enriched and optionally pure forms. The optically active (+) and (-), (R)- and (S)- and (R,R)- / (R,S)- / (S,S)- or (D)- and (L)- isomers can be synthesized using chiral starting materials, prepared by chiral resolution, or can be resolved by conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using a chiral column. When the compounds described herein contain an alkenyl double bond or other geometrically asymmetric center, unless otherwise specified, the compounds include both E and Z geometric isomers. In the chemical structure, the bond does not specify the configuration, that is, if there is configurational isomerism in the chemical structure, the bond can be or simultaneously contain and both configurations. Similarly, all tautomeric forms are also included.

[0118] In the present invention, the term "tautomer" refers to the movement of a proton from one atom of a molecule to another position within the same molecule. The present invention encompasses tautomers of any of the said compounds.

[0119] In the present invention, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any of the components contained in the composition.

[0120] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention with relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. The acid addition salt is obtained by contacting the acid with the neutral form of such a compound.

[0121] In the present invention, the term "patient" includes any animal, preferably a mammal, more preferably a human.

[0122] On the basis of conforming to common general knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0123] The reagents and raw materials used in the present invention are all commercially available.

[0124] The positive and progressive effects of the present invention are as follows: The compounds of the present invention have a highly efficient inhibitory effect on SARS-CoV-2, have a significant effect on inhibiting the novel coronavirus, and at the same time have multiple advantages such as high efficiency, low toxicity, strong selectivity, and strong specificity. Detailed Description of the Invention

[0125] The present invention will be further illustrated by way of examples below, but the present invention is not thereby limited to the scope of the said examples. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0126] Preparation of Intermediate D

[0127]

[0128] Dissolve compound A (10 mmol, 2 g) in 50 mL of tetrahydrofuran. Sequentially add methylpiperazine (10 mmol) and DIPEA (10 mmol), and react at room temperature for 30 min to obtain a tetrahydrofuran solution of crude product B, which can be used for the next reaction. At 40 °C, dissolve Na2S·9H2O (30 mmol) in 40 mL of water, add NaHCO3 (30 mmol), and after all the solids are dissolved, add 40 mL of methanol. Raise the temperature of the reaction solution to 70 °C. Dropwise add the above-mentioned tetrahydrofuran solution of crude product B into the reaction solution and continue to react for 2 h to obtain a solution of crude product C. When the temperature of the above reaction solution drops to 50 °C, sequentially add Na2S2O4 (100 mmol) and K2CO3 (100 mmol) thereto. Under vigorous stirring, dropwise add water to the reaction solution until the solids are completely dissolved, and supplement 50 mL of tetrahydrofuran. The color of the reaction solution changes from red to yellow until light yellow or even colorless, and the reaction is completed. The whole process lasts about 1 h. Filter to remove insoluble substances, extract the reaction solution with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine, dry, and concentrate under reduced pressure to obtain crude intermediate D, which can be used for the next reaction.

[0129] Example 1: Preparation of Compound 1

[0130]

[0131] Step 1:

[0132]

[0133] Dissolve intermediate D (0.42 mmol, 200 mg) in 3 mL of tetrahydrofuran. Sequentially add 0.5 mL of acetic acid and p-methylbenzaldehyde (0.9 mmol), reflux and react, and detect the reaction by HPLC-MS until the reaction is completed. Concentrate under reduced pressure and purify by column chromatography, eluting with ethyl acetate / petroleum ether to obtain intermediate E (95 mg).

[0134] 1 1H NMR (400 MHz, CDCl3) δ 8.05–7.96 (m, 2H), 7.45 (s, 1H), 7.37 (s, 1H), 7.13 (t, J = 8.3 Hz, 2H), 4.13 (s, 2H), 3.06 (s, 4H), 2.65 (d, J = 41.4 Hz, 4H), 2.43 (s, 3H).

[0135] Step 2:

[0136] Intermediate E (0.28 mmol, 95 mg) and 3,4,5-trimethoxybenzaldehyde (0.336 mmol, 65 mg) were dissolved in 2 mL of dichloromethane. Then sodium triacetoxyborohydride (0.34 mmol, 72 mg) and 0.1 mL of glacial acetic acid were added, and the mixture was refluxed for 3 hours. The reaction was monitored by HPLC-MS until completion. The reaction mixture was concentrated under reduced pressure and purified by column chromatography, eluting with dichloromethane / methanol to obtain the target product, Compound 1.

[0137] Yield: 113 mg, Yield rate: 53%.

[0138] 1 1H NMR (300 MHz, DMSO-d6): 5.68 (1H, t, J = 5.4 Hz, 1-H), 7.67 (1H, s, 2-H), 7.03 (1H, s, 3-H), 2.94 (4H, br.s, 4 and 5-H), 2.58 (4H, br.s, 6 and 7-H), 2.36 (3H, s, 8-H), 7.86 (2H, d, J = 8.4 Hz, 9 and 10-H), 7.32 (2H, d, J = 8.4 Hz, 11 and 12-H), 2.27 (3H, s, 13-H), 4.38 (2H, d, J = 5.4 Hz, 14-H), 6.74 (2H, br.s, 15 and 16-H), 3.75 (6H, br.s, 17 and 19-H), 3.64 (3H, s, 18-H). HR MS (TOF): observed for 519.2438, [M+H]; calcd. for 519.243, C29H35N4O3S.

[0139] Examples 2 - 9:

[0140] The following Compounds 2 - 9 were prepared by referring to the same preparation method as Compound 1 in Example 1:

[0141]

[0142] 11H NMR (300 MHz, DMSO-d6): δ 5.72 (1H, br.s, 1-H), 7.86 (1H, s, 2-H), 7.13 (1H, s, 3-H), 2.91 (4H, br.s, 4 and 5-H), 2.56 (4H, br.s, 6 and 7-H), 2.37 (3H, s, 8-H), 7.87 (2H, d, J = 6.9 Hz, 9 and 10-H), 7.00 (2H, d, J = 6.9 Hz, 11 and 12-H), 2.26 (3H, s, 13-H), 4.64 (2H, d, J = 5.4 Hz, 14-H), 7.33 (3H, m, 15 - 17-H). HR MS (TOF): observed for 435.1645, [M + H]; calcd. for 435.1677, C24H27N4S2.

[0143]

[0144] 1 1H NMR (300 MHz, DMSO-d6): δ 5.71 (1H, t, J = 5.7 Hz, 1-H), 7.65 (1H, s, 2-H), 6.95 (2H, br.s, 3 and 15-H), 2.92 (4H, br.s, 4 and 5-H), 2.57 (4H, br.s, 6 and 7-H), 2.36 (3H, s, 8-H), 7.86 (2H, d, J = 8.4 Hz, 9 and 10-H), 7.31 (2H, d, J = 8.4 Hz, 11 and 12-H), 2.27 (3H, s, 13-H), 4.36 (2H, d, J = 5.7 Hz, 14-H), 6.88 (2H, br.s, 16 and 17-H), 5.98 (2H, s, 18-H). HR MS (TOF): observed for 473.2031, [M + H]; calcd. for 473.2011, C27H29N4O2S.

[0145]

[0146] 11H NMR (400 MHz, DMSO) δ 7.85 (d, J = 7.5 Hz, 2H), 7.67 (d, J = 9.2 Hz, 1H), 7.44 (s, 1H), 7.36 (s, 2H), 7.30 (d, J = 7.4 Hz, 3H), 6.90 (s, 1H), 5.95 (s, 1H), 4.48 (d, J = 5.2 Hz, 2H), 3.00 (s, 4H), 2.82 (s, 4H), 2.42 (s, 3H), 2.35 (s, 3H). HR MS (TOF): observed for 462.1675, [M+H]; calcd. for 462.1645, C26H27ClN4S.

[0147]

[0148] 1 1H NMR (400 MHz, DMSO) δ 8.16 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.74 (s, 1H), 7.45 (s, 1H), 7.37 (d, J = 4.7 Hz, 2H), 7.32–7.24 (m, 1H), 6.95 (s, 1H), 6.02 (t, J = 5.9 Hz, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.01 (s, 4H), 2.83 (s, 4H), 2.42 (s, 3H). HR MS (TOF): observed for: 516.1292, [M+H]; calcd. for: 516.1362, C26H24ClF3N4S.

[0149]

[0150] 1 1H NMR (400 MHz, DMSO) δ 8.18 (d, J = 8.1 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.57–7.48 (m, 1H), 7.38 (dd, J = 5.5, 3.9 Hz, 1H), 7.33–7.25 (m, 2H), 6.89 (s, 1H), 6.10 (t, J = 5.2 Hz, 1H), 4.54 (d, J = 5.8 Hz, 2H), 3.34 (s, 4H), 3.09 (s, 5H), 2.58 (s, 3H). HRMS (TOF): observed for: 516.1311, [M+H]; calcd. for: 516.1362, C26H24ClF3N4S.

[0151]

[0152] 1 1H NMR (300 MHz, DMSO-d6): δ 5.71 (1H, t, J = 5.7 Hz, 1-H), 7.65 (1H, s, 2-H), 6.95 (2H, br.s, 3 and 15-H), 2.92 (4H, br.s, 4 and 5-H), 2.57 (4H, br.s, 6 and 7-H), 2.36 (3H, s, 8-H), 7.86 (2H, d, J = 8.4 Hz, 9 and 10-H), 7.31 (2H, d, J = 8.4 Hz, 11 and 12-H), 2.27 (3H, s, 13-H), 4.36 (2H, d, J = 5.7 Hz, 14-H), 6.88 (2H, br.s, 16 and 17-H), 5.98 (2H, s, 18-H). HR MS (TOF): observed for: 476.1689, [M+H]; calcd. for: 476.1682, C26H25FN4O2S.

[0153]

[0154] 1 1H NMR (300 MHz, DMSO-d6): δ 5.83 (1H, t, J = 5.4 Hz, 1-H), 7.66 (1H, s, 2-H), 7.13 (1H, s, 3-H), 2.87 (4H, br.s, 4 and 5-H), 2.46 (4H, br.s, 6 and 7-H), 2.27 (3H, s, 8-H), 7.86 (2H, d, J = 8.4 Hz, 9 and 10-H), 7.33 (2H, d, J = 8.4 Hz, 11 and 12-H), 2.87 (3H, s, 13-H), 4.59 (2H, d, J = 5.4 Hz, 14-H), 6.68 (1H, d, J = 3.3 Hz, 15-H), 7.59 (1H, d, J = 3.3 Hz, 16-H). HR MS (TOF): observed for 496.1496, [M+H]; calcd. for 496.1477, C24H26N5O3S2.

[0155]

[0156] 11H NMR (300 MHz, DMSO-d6): δ 6.77 (1H, t, J = 5.4 Hz, 1-H), 7.73 (1H, s, 2-H), 6.98 (1H, s, 3-H), 2.95 (4H, br.s, 4 and 5-H), 2.63 (4H, br.s, 6 and 7-H), 2.31 (3H, s, 8-H), 8.18 (1H, d, J = 8.4 Hz, 9-H), 7.57 (1H, br.d, J = 8.4 Hz, 10-H), 7.83 (1H, d, J = 1.5 Hz, 11-H), 4.42 (1H, d, J = 5.4 Hz, 12-H), 7.28 (2H, d, J = 7.5 Hz, 13 and 14-H), 7.15 (2H, d, J = 7.5 Hz, 15 and 16-H), 2.27 (3H, s, 17-H). HR MS (TOF): observed for 497.1335, [M + H]; calcd. for 497.1333, C26H27Cl2N4S.

[0157] Example 10: Preparation of Compound 10

[0158]

[0159] Step 1:

[0160]

[0161] Intermediate D (0.42 mmol, 200 mg) was dissolved in 3 mL of tetrahydrofuran. 0.5 mL of acetic acid and p-methylbenzaldehyde (0.9 mmol) were added successively, and the mixture was refluxed. The reaction was monitored by HPLC-MS until completion. The reaction mixture was concentrated under reduced pressure and purified by column chromatography, eluting with ethyl acetate / petroleum ether to obtain Intermediate E (95 mg).

[0162] Step 2:

[0163] Intermediate E (0.28 mmol, 95 mg) was dissolved in 3 mL of dichloromethane. Triphosgene (0.15 mmol) and Et3N (0.6 mmol) were added successively, and the mixture was reacted at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 3 mL of dichloromethane. 3-Chlorobenzylamine (0.3 mmol) and Et3N (0.7 mmol) were added successively, and the mixture was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography, eluting with dichloromethane / methanol to obtain the target product Compound 10. Yield: 45 mg, Yield rate: 30%.

[0164] 11H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.98 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.88 (m, 2H), 7.41 (m, 2H), 7.34 (m, 4H), 4.37 (d, J = 5.7 Hz, 2H), 2.86 (s, 4H), 2.63 (s, 4H), 2.38 (s, 3H), 2.29 (s, 3H). HR MS (TOF): observed for 505.1751, [M+H]; calcd. for 505.1703, C27H28ClN5OS.

[0165] Examples 11 - 15: Preparation of Compounds 11 - 15

[0166] The following Compounds 11 - 15 were prepared by replacing the corresponding raw materials with the same preparation method as that of Compound 10 in Example 10

[0167]

[0168] 1 1H NMR (300 MHz, DMSO-d6): 8.51 (1H, s, 1-H), 7.84 (1H, s, 2-H), 7.80 (1H, s, 3-H), 2.82 (4H, br.s, 4 and 5-H), 2.59 (4H, br.s, 6 and 7-H), 2.39 (3H, s, 8-H), 7.93 (2H, d, J = 8.1 Hz, 9 and 10-H), 7.36 (2H, d, J = 8.1 Hz, 11 and 12-H), 2.29 (3H, s, 13-H), 7.49 (1H, t, J = 6.0 Hz, 14-H), 4.43 (2H, t, J = 6.0 Hz, 15-H), 3.53 (2H, m, 16-H), 8.05 (1H, s, 17-H), 2.46 (3H, s, 18-H). HR MS (TOF): observed for 535.2249, [M+H]; calcd. for 535.224, C26H31N8O3S.

[0169]

[0170] 11H NMR (300 MHz, DMSO-d6): δ 8.67 (1H, s, 1-H), 8.06 (1H, s, 3-H), 7.84 (1H, s, 6-H), 2.89 (4H, br.s, 8 and 9-H), 2.73 (4H, br.s, 10 and 11-H), 2.38 (3H, s, 12-H), 7.93 (2H, d, J = 7.8 Hz, 15 and 19-H), 7.36 (2H, d, J = 7.8 Hz, 16 and 18-H), 2.38 (3H, s, 20-H), 7.31 (1H, m, 22-H), 4.37 (2H, d, J = 5.4 Hz, 23-H), 7.45 (1H, d, J = 8.7 Hz, 25-H), 7.47 (1H, d, J = 8.7 Hz, 26-H), 7.87 (1H, m, 28-H). HR MS (TOF): observed for 524.1674, [M+H]; calcd. for 524.1687, C27H28ClFN5OS.

[0171]

[0172] 1 1H NMR (300 MHz, DMSO-d6): δ 8.62 (1H, s, 1-H), 7.84 (1H, s, 2-H), 7.83 (1H, s, 3-H), 2.87 (4H, br.s, 4 and 5-H), 2.72 (4H, br.s, 6 and 7-H), 2.39 (3H, s, 8-H), 7.93 (2H, d, J = 7.5 Hz, 9 and 10-H), 7.30 (2H, d, J = 7.5 Hz, 11 and 12-H), 2.39 (3H, s, 13-H), 7.29 (1H, t, J = 7.5 Hz, 14-H), 3.38 (2H, m, 15-H), 2.81 (2H, t, J = 6.9 Hz, 16-H), 7.38 (4H, m, 17 - 20-H). HR MS (TOF): observed for 520.1914, [M+H]; calcd. for 520.1938, C28H31ClN5OS.

[0173]

[0174] 11H NMR (300 MHz, DMSO-d6): 10.29 (1H, s, 1-H), 8.47 (1H, s, 2-H), 7.95 (1H, s, 3-H), 3.16 (4H, br.s, 4 and 5-H), 3.01 (4H, br.s, 6 and 7-H), 2.59 (3H, s, 8-H), 7.93 (2H, m, 9 and 10-H), 7.27 (2H, d, J = 9.3 Hz, 11 and 12-H), 2.38 (3H, s, 13-H), 8.70 (1H, s, 14-H), 7.36 (1H, d, J = 8.4 Hz, 15 and 16-H), 7.31 (1H, d, J = 8.4 Hz, 17 and 18-H). HR MS (TOF): observed for 542.4546, [M+H]; calcd. for 542.1838, C 27 H 27 F3N5O2S.

[0175]

[0176] 1 1H NMR (300 MHz, DMSO-d6): 9.63 (1H, s, 1-H), 8.16 (1H, s, 2-H), 7.93 (1H, s, 3-H), 2.88 (4H, br.s, 4 and 5-H), 2.61 (4H, br.s, 6 and 7-H), 2.29 (3H, s, 8-H), 8.10 (2H, dd, J = 8.7 and 5.7 Hz, 9 and 10-H), 7.39 (2H, t, J = 9.0 Hz, 11 and 12-H), 8.68 (1H, s, 13-H), 7.38 (2H, d, J = 8.4 Hz, 14 and 15-H), 7.25 (2H, d, J = 8.4 Hz, 16 and 17-H), 2.45 (3H, s, 18-H). HR MS (TOF): observed for 491.1795, [M+H]; calcd. for 491.1791, C26H26FN5O2S.

[0177] Example 16: Preparation of Compound 16

[0178]

[0179] Dissolve compound 10 (0.2 mmol, 100 mg) in 2 mL of methanol, then add methanesulfonic acid (0.22 mmol, 21 mg), react at 70 °C for 1 h, then concentrate under reduced pressure to remove methanol, then add 1 mL of absolute ethanol for pulping, and filter to obtain 92 mg of yellow solid compound 16. 1 HNMR (400 MHz, DMSO) δ 9.81 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 7.94 (d, J = 6.5 Hz, 4H), 7.47–7.30 (m, 6H), 4.37 (d, J = 5.6 Hz, 2H), 3.55 (s, 4H), 3.17 (d, J = 12.0 Hz, 2H), 3.05 (t, J = 10.6 Hz, 2H), 2.91 (s, 3H), 2.38 (s, 6H).

[0180] Example 17: Preparation of compound 17

[0181]

[0182] Dissolve compound 10 (0.2 mmol, 100 mg) in 2 mL of methanol, then add 4 M hydrochloric acid in methanol solution (2 mmol, 0.5 mL), react at 70 °C for 1 h, then concentrate under reduced pressure to remove methanol, then add 1 mL of ethyl acetate for pulping, and filter to obtain 98 mg of yellow solid compound 17. 1 H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.96–7.87 (m, 3H), 7.42 (s, 1H), 7.40–7.27 (m, 5H), 4.35 (s, 2H), 3.83 (s, 2H), 3.49 (d, J = 11.2 Hz, 2H), 3.19–3.07 (m, 4H), 2.84 (d, J = 4.5 Hz, 3H), 2.38 (s, 3H).

[0183] Examples 18 - 26

[0184] Compounds 18 - 20, 23 - 26 are prepared by replacing the corresponding raw materials with the same preparation method as in Example 10 above, and compounds 21 - 22 are prepared by replacing the corresponding raw materials with the same preparation method as in Example 1 above.

[0185]

[0186] 11H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.00–7.82 (m, 4H), 7.46–7.28 (m, 6H), 4.38 (d, J = 5.7 Hz, 2H), 2.94 (s, 8H), 2.39 (s, 2H), 2.08 (s, 2H), 1.23 (s, 3H).

[0187]

[0188] 1 1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.37 (m, 6H), 4.78 (t, J = 5.0 Hz, 1H), 4.37 (d, J = 5.7 Hz, 2H), 4.16 (d, J = 5.3 Hz, 2H), 3.85 (s, 2H), 3.72 (s, 2H), 2.82 (s, 4H), 2.37 (s, 3H).

[0189]

[0190] 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.90 (s, 1H), 7.81 (t, J = 5.9 Hz, 1H), 7.45–7.31 (m, 6H), 4.86 (s, 2H), 4.39 (d, J = 5.7 Hz, 2H), 3.70 (d, J = 20.8 Hz, 4H), 2.86 (s, 4H), 2.39 (s, 3H), 2.11 (s, 3H).

[0191]

[0192] 1 1H NMR (400 MHz, DMSO-d6) δ 7.91–7.85 (m, 2H), 7.71 (s, 1H), 7.64 (d, J = 3.8 Hz, 1H), 7.19 (s, 1H), 6.73 (d, J = 3.8 Hz, 1H), 5.87 (dt, J = 12.6, 4.1 Hz, 1H), 4.64 (d, J = 6.3 Hz, 2H), 2.91 (s, 4H), 2.59 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H).

[0193]

[0194] 1 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.30 (dd, J = 11.1, 7.9 Hz, 4H), 7.16 (d, J = 7.8 Hz, 2H), 6.93 (s, 1H), 5.71 (d, J = 6.0 Hz, 1H), 4.41 (d, J = 5.7 Hz, 2H), 2.95 (s, 4H), 2.65 (d, J = 19.3 Hz, 4H), 2.37 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H).

[0195]

[0196] 1 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 11.5 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 6.50 (s, 2H), 5.33 (s, 1H), 2.89 (s, 4H), 2.68 (s, 1H), 2.39 (s, 3H), 1.99 (p, J = 7.0, 6.4 Hz, 3H).

[0197]

[0198] 1 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.28 (s, 1H), 8.19 (t, J = 5.9 Hz, 1H), 7.99–7.92 (m, 2H), 7.91 (s, 1H), 7.45–7.30 (m, 7H), 4.38 (d, J = 5.8 Hz, 2H), 3.43 (t, J = 5.0 Hz, 4H), 3.05 (t, J = 5.0 Hz, 4H), 2.39 (s, 3H).

[0199]

[0200] 11H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 7.97–7.89 (m, 2H), 7.84 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 5.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 4.07 (t, J = 7.0 Hz, 2H), 3.18 (q, J = 6.4 Hz, 2H), 2.85 (t, J = 4.7 Hz, 4H), 2.61 (d, J = 5.8 Hz, 4H), 2.38 (d, J = 2.6 Hz, 6H), 2.29 (s, 3H), 2.03–1.92 (m, 2H). 13 13C NMR (101 MHz, DMSO) δ 166.96, 155.73, 151.28, 145.89, 145.42, 141.40, 140.89, 134.56, 131.05, 130.29 (2C), 127.42, 127.28 (2C), 122.50, 113.62, 112.10, 55.08 (2C), 52.30 (2C), 46.23, 44.70, 36.63, 30.56, 21.47, 13.06.

[0201]

[0202] 1 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.36 (s, 1H), 7.96–7.89 (m, 2H), 7.84 (s, 1H), 7.79 (s, 1H), 7.33 (dd, J = 17.5, 6.8 Hz, 3H), 4.05 (t, J = 7.2 Hz, 2H), 3.18 (q, J = 6.5 Hz, 2H), 2.84 (t, J = 4.7 Hz, 4H), 2.59 (s, 4H), 2.39 (d, J = 2.9 Hz, 6H), 2.28 (s, 3H), 1.79 (p, J = 7.4 Hz, 2H), 1.48 (p, J = 7.1 Hz, 2H). 13 13C NMR (101 MHz, DMSO) δ 166.90, 155.66, 151.27, 145.85, 145.34, 141.38, 140.92, 134.65, 131.06, 130.29 (2C), 127.34, 127.27 (2C), 122.50, 113.56, 112.13, 55.04 (2C), 52.29 (2C), 46.59, 46.22, 38.98, 27.54, 27.10, 21.47, 13.08.

[0203] Examples 27 - 45

[0204] Compounds 27 - 45 were prepared by replacing the corresponding raw materials with the same preparation method as in Example 10 above to prepare the following compounds:

[0205]

[0206]

[0207]

[0208]

[0209] Effect Example 1: Anti - SARS - CoV - 2 effect of the compounds of the present invention

[0210] HEK293T - ACE2 cells were cultured in an incubator at 37°C and 5% CO2, and the culture medium consisted of DMEM + 10% fetal bovine serum + 1% penicillin and streptomycin. Then the cells were seeded into a 96 - well plate (1×10 4 cells per well). After 12 hours, 200 TCID50 SARS - CoV - 2 pseudovirus diluted with serum (the pseudovirus was constructed from two plasmids, pVax - 1 - S - COVID19 and pNL4 - 3Luc_Env_Vpr) and the test compound were added to the 96 - well plate. After incubation for 48 hours, the fluorescence value was measured, and the antiviral IC 50 value of the compound was calculated. The results are shown in Table 1.

[0211] Table 1: Screening results of benzothiazole compounds against SARS - CoV - 2

[0212]

[0213] It can be seen from Table 1 above that the compounds of the present invention all have a certain inhibitory effect on SARS - CoV - 2.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein, Ring A is a saturated or partially unsaturated 4- to 10-membered heterocycle; For Ring C is a 6- to 10-membered aromatic ring; R 1 Each independently is halogen, =O, C 1-4 alkyl, halo-C 1-4 alkyl, 3- to 10-membered cycloalkyl or -C(=O)(CH2) 1-3 -R 1 -1 ; R 1-1 is OH or -OC(O)CH3; R 3 Each independently is halogen, nitro, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, halo-C 1-4 alkyl, halo-C 1-4 alkoxy or halo-C 1-4 alkylthio; m1 and m3 are each independently 0, 1, 2 or 3; X is -(CR b R c )n1-, -C(O)-, -C(O)-NR a (CR b R c )n1- or -S(O)-NR a (CR b R c )n1-; R a , R b and R c Each independently is H or C 1-4 alkyl; n1 is each independently 0, 1, 2, 3 or 4; The number of heteroatoms in the 4- to 10-membered heterocycle is 1, 2 or 3, and each heteroatom is independently N, O or S.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Ring A is a saturated or partially unsaturated 4- to 10-membered heterocycle; Ring C is a 6- to 10-membered aromatic ring; R 1 Each independently is halogen, =O, C 1-4 alkyl, halo-C 1-4 alkyl, 3- to 10-membered cycloalkyl or -C(=O)(CH2) 1-3 -R 1 -1 ; R 1-1 is OH or -OC(O)CH3; R 3 Each independently represents a halogen, nitro group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylthio group, halogenated C 1-4 alkyl group, halogenated C 1-4 alkoxy group or halogenated C 1-4 alkylthio group; m1 and m3 are each independently 0, 1, 2 or 3; X is -(CR b R c )n1-, -C(O)-, -C(O)-NR a (CR b R c )n1- or -S(O)-NR a (CR b R c )n1-; R a , R b and R c Each independently is H or C 1-4 alkyl; n1 is each independently 0, 1 or 2; The number of heteroatoms in the 4- to 10-membered heterocycle is 1, 2 or 3, and each heteroatom is independently N, O or S.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein, In the definition of Ring A, at least one heteroatom in the 4- to 10-membered heterocycle is N; And / or, in the definition of Ring C, the 6- to 10-membered aromatic ring is a benzene ring; and / or, R 1 in the definition of, the halogen is F; and / or, R 1 in the definition of, said C 1-4 alkyl is methyl, ethyl or isopropyl; and / or, R 1 in the definition of, the 3- to 10-membered cycloalkyl group is cyclopropyl; and / or, R 1 In the definition of, said halo C 1-4 alkyl is fluoro C 1-4 alkyl; and / or, R 3 in the definition of, each of the halogens is independently F or Cl; and / or, R 3 in the definition of, said C 1-4 alkyl groups are each independently methyl; and / or, R 3 in the definition of, said C 1-4 alkoxy groups are each independently methoxy; and / or, R 3 in the definition of, said C 1-4 alkylthio groups are each independently methylthio; and / or, R 3 in the definition of, the halo C 1-4 alkyl, halo C 1-4 alkoxy and halo C 1-4 in the alkylthio group, the halo is independently fluorine.

4. The compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 - 3, wherein, Ring A is and / or, ring C is and / or, R 1 each independently is F, =O, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2F, and / or, R 3 each independently is F, Cl, -CH3, -SCH3 or -CF3; and / or, R a , R b and R c each independently is H; And / or, n1 is each independently 1 or 2; And / or, n1 is each independently 3 or 4.

5. The compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, For and / or, is And / or, X is -CH2-, -C(O)-, -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-CH2CH2-, -C(O)-NH-CH2CH2CH2-, -C(O)-NH-CH2CH2CH2CH2- or -S(O)-NH-.

6. The compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, For 7. The compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, It has any one of the following structures:

8. The compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein, It has any one of the following structures:

9. A method for preparing a compound of formula I as described in any one of claims 1 - 8, which comprises Method 1 and Method 2, wherein, The method 1 includes the following steps: In a solvent, reacting the compound shown in formula II with the compound shown in formula III as shown below to obtain the compound shown in formula I. The method 2 includes the following steps: In a solvent, reacting the compound shown in formula II with triphosgene in the presence of a base to obtain an isocyanate product, and reacting the isocyanate product with the compound shown in formula III'' in the presence of a base to obtain the compound shown in formula I.

10. A pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 - 8, and a pharmaceutically acceptable excipient.

11. Use of a compound of formula I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient infected with the SARS-CoV-2 virus.

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