CN116655557A - Benzothiazole compound, preparation method and application thereof - Google Patents

Benzothiazole compound, preparation method and application thereof Download PDF

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Publication number
CN116655557A
CN116655557A CN202310158328.5A CN202310158328A CN116655557A CN 116655557 A CN116655557 A CN 116655557A CN 202310158328 A CN202310158328 A CN 202310158328A CN 116655557 A CN116655557 A CN 116655557A
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ring
independently
compound
formula
alkyl
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刘刚
刘利
陈志伟
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Ningbo Kangbai Ruige Medical Technology Co ltd
Versitech Ltd
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Ningbo Kangbai Ruige Medical Technology Co ltd
Versitech Ltd
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    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
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    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/47Quinolines; Isoquinolines
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    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/64Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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Abstract

The application discloses a benzothiazole compound, a preparation method and application thereof. The compounds have high-efficiency inhibition effect on SARS-CoV-2, and can be used for resisting new coronavirus.

Description

Benzothiazole compound, preparation method and application thereof
Technical Field
The application relates to a benzothiazole compound, a preparation method and application thereof.
Background
Benzothiazole is a two-ring system formed by fusing benzene rings and thiazole rings, and the Hofmann synthesizes the 2-phenylbenzothiazole compound containing the structural fragment for the first time in 1879. In the early 50s of the last century, 2-aminobenzothiazoles were reported as useful as central muscle relaxants. However, such structures have not received widespread attention from pharmaceutical chemists at this time. 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, pharmaceutical chemists did not interest in and began to conduct extensive research on the biological activity of benzothiazole derivatives. Furthermore, it has been increasingly found that some active natural products also contain benzothiazole structural fragments. After that, benzothiazole derivatives or bioisosteres thereof have been used in many fields such as medicines and pesticides due to their wide biological activities. For example, in medicine, for antiviral, anticonvulsant, antibacterial, anti-inflammatory, antitumor, and medical imaging agents, etc.; in agriculture, as herbicides and insecticides.
The following compounds are anti-viral compounds of benzothiazoles reported in recent years, wherein, compound a, compound b and compound c all have the effect of resisting hepatitis C virus; compound d is an inhibitor of HSV-1 virus; the compound e has stronger effect of inhibiting CVB5, ADV7 and EV71 viruses; the compound f has obvious inhibition effect on both Zika virus and dengue virus.
The development of small molecules against new coronaviruses is particularly important. Benzothiazole compounds have important application as dominant skeletons with pharmacological activity all the time, especially in antiviral aspect, however benzothiazole small molecule compounds have not been reported so far in resisting new coronaviruses.
Disclosure of Invention
The application aims to solve the technical problem that no benzothiazole micromolecule medicine is used for resisting new coronavirus at present, so that the application provides a benzothiazole compound, a preparation method and application thereof. The compounds have high-efficiency inhibition effect on SARS-CoV-2, and can be used for resisting new coronavirus.
The application provides a compound shown in a formula I or pharmaceutically acceptable salt thereof,
wherein,,
ring A is a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring C is a 6-10 membered aromatic ring;
R 1 each independently is halogen, = O, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-10 membered cycloalkyl or-C (=o) (CH 2 ) 1-3 -R 1-1
R 1-1 Is OH or-OC (O) CH 3
R 2 And R is 3 Each independently is halogen, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy or halo C 1-4 Alkylthio;
m1, m2 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 ) n 1-or-S (O) -NR a (CR b R c )n1-;
R a 、R b And R is c Each independently is H or C 1-4 An alkyl group;
n1 is each independently 0, 1, 2, 3 or 4;
the number of heteroatoms in the 4-10 membered heterocyclic ring and the 5-10 membered heteroaromatic ring is 1, 2 or 3, each heteroatom being independently N, O or S.
In some embodiments, the method comprises, among other things,
ring A is a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring C is a 6-10 membered aromatic ring;
R 1 each independently is halogen, = O, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-10 membered cycloalkyl or-C (=o) (CH 2 ) 1-3 -R 1-1
R 1-1 Is OH or-OC (O) CH 3
R 2 And R is 3 Each independently is halogen, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy or halo C 1-4 Alkylthio;
m1, m2 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 ) n 1-or-S (O) -NR a (CR b R c )n1-;
R a 、R b And R is c Each independently is H or C 1-4 An alkyl group;
n1 is each independently 0, 1 or 2;
the number of heteroatoms in the 4-10 membered heterocyclic ring and the 5-10 membered heteroaromatic ring is 1, 2 or 3, each heteroatom being independently N, O or S.
In certain preferred embodiments of the present application (hereinafter referred to as "in some embodiments"), certain groups in the compounds of formula I are defined as follows (undefined groups are as described in any of the embodiments of the present application).
In some embodiments, in the definition of ring a, at least one heteroatom in the 4-10 membered heterocyclic ring is N. Ring a is preferably attached to benzothiazole via an N atom.
In some embodiments, ring B is defined as a 6-10 membered aromatic ring that is a benzene ring.
In some embodiments, ring B is defined as having 1 or 2 heteroatoms in the 5-10 membered heteroaromatic ring.
In some embodiments, in the definition of ring B, the heteroatom in the 4-10 membered heterocyclic ring is O.
In some embodiments, in the definition of ring C, the 6-10 membered aromatic ring is a benzene ring.
In some embodiments, R 1 In the definition of (2), the halogen is F.
In some embodiments, R 1 In the definition of (C), said C 1-4 Alkyl is methyl, ethyl or isopropyl.
In some embodiments, R 1 In the definition of (2), the 3-10 membered cycloalkyl is cyclopropyl.
In some embodiments, R 1 In the definition of (C), said halo group 1-4 Alkyl is fluoro C 1-4 An alkyl group.
In some embodiments, R 2 And R is 3 In the definition of (2), each of the halogens is independently F or Cl.
In some embodiments, R 2 And R is 3 In the definition of (C), said C 1-4 Alkyl groups are each independently methyl.
In some embodiments, R 2 And R is 3 In the definition of (C), said C 1-4 Alkoxy groups are each independently methoxy.
In some embodiments, R 2 And R is 3 In the definition of (C), said C 1-4 Alkylthio groups are each independently methylthio.
In some embodiments, R 2 And R is 3 In the definition of (C), said halo group 1-4 Alkyl, halogenated C 1-4 Alkoxy and halo C 1-4 The halo groups in the alkylthio groups are each independently fluoro.
In some embodiments, ring a is Preferably +.>
In some embodiments, ring a is (Represents the position of ring a attached to benzothiazole).
In some embodiments, ring B is
In some embodiments, ring B is(Representing the position where ring B is attached to X).
In some embodiments, ring C is
In some embodiments, R 1 Each independently is F, =O, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 F、
In some embodiments, R 2 Each independently is halogen, nitro, C 1-4 Alkyl, C 1-4 Alkoxy or halo C 1-4 Alkoxy, preferably F, cl, nitro, -CH 3 、-OCH 3 or-OCF 3
In some embodiments, R 3 Each independently is halogen, C 1-4 Alkyl, C 1-4 Alkylthio or halogen C 1-4 Alkyl, preferably F, cl, -CH 3 、-SCH 3 or-CF 3
In some embodiments of the present application, in some embodiments,is->
Preferably is
In some embodiments of the present application, in some embodiments,is->
For example->
In some embodiments of the present application, in some embodiments,is-> Preferably +.>
In some embodiments, R a 、R b And R is c Each independently is H.
In some embodiments, each n1 is independently 1 or 2.
In some embodiments, each n1 is independently 3 or 4.
In some embodiments, X is-CH 2 -、-C(O)-、-C(O)-NH-、-C(O)-NH-CH 2 -、-C(O)-NH-CH 2 CH 2 -or-S (O) -NH-, preferably-CH 2 -or-C (O) -NH-CH 2 -。
In some embodiments, X is-CH 2 -、-C(O)-、-C(O)-NH-、-C(O)-NH-CH 2 -、-C(O)-NH-CH 2 CH 2 -、-C(O)-NH-CH 2 CH 2 CH 2 -、-C(O)-NH-CH 2 CH 2 CH 2 CH 2 -or-S (O) -NH-.
In some embodiments of the present application, in some embodiments,is->
For example->
In some embodiments, the compound of formula I is as shown in formula I-a:
wherein each group is as defined above.
In some embodiments, the compound of formula I is as shown in formula I-b:
wherein each group is as defined above.
In some embodiments, the compound of formula I is as shown in formulas I-c:
wherein each group is as defined above.
In some embodiments, the compound of formula I is as shown in formulas I-d:
wherein each group is as defined above.
In some embodiments, the compound of formula I is as shown in formulas I-e:
wherein each group is defined as above, and m4 is 2 or 3.
In some embodiments, the pharmaceutically acceptable salt of the compound of formula I may be a hydrochloride salt or a mesylate salt. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from any one of the following structures:
in some embodiments, the compound of formula I is selected from any one of the following structures:
the application also provides a preparation method of the compound shown in the formula I, which comprises a method 1 and a method 2, wherein,
the method 1 comprises the following steps: in a solvent (for example, a halogenated hydrocarbon solvent, or for example, dichloromethane), a compound represented by the formula II and a compound represented by the formula III are reacted to obtain a compound represented by the formula I,
wherein X is-CH 2 -, the remaining groups being as defined above;
the method 2 comprises the following steps: in a solvent (such as a halogenated hydrocarbon solvent, for example, dichloromethane) and triphosgene in the presence of alkali (such as triethylamine) to obtain isocyanate product, reacting the isocyanate product with a compound shown in formula III' in the presence of alkali (such as triethylamine) to obtain the compound shown in formula I,
wherein X is-C (O) -NR a (CR b R c ) n 1-and the remaining radicals are as defined above.
In the preparation method of the compound shown in the formula I, the reaction conditions can be conditions conventional in the art for such reactions.
The application also provides a pharmaceutical composition, which comprises the compound shown in the formula I or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials. The compound of formula I or a pharmaceutically acceptable salt thereof may be in a therapeutically effective amount.
The application also provides the use of a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a patient carrying SARS-CoV-2 virus.
Definition description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
In the present application, the term "substitution" or "substituent" is the replacement of a hydrogen atom in a group by the specified group. When no substitution positions are indicated, substitution may be at any position, but only formation of a stable or chemically feasible chemical is allowed. The following are illustrated:the structure represents that the hydrogen atom on the ring A is replaced by m 1R 1 Substituted.
When any variable (e.g., R) occurs 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 with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When the number of a linking group is absent, it means that the linking group is a single bond, e.g., the structure formed when L is absent in A-L-Z is A-Z.
In the present application, the term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon group. C (C) 1-4 Alkyl means an alkyl group having 1 to 4 carbon atoms, which is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In the present application, the term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined above. C (C) 1-4 Alkoxy means-O- (C) 1-4 Alkyl), wherein C 1-4 Alkyl groups are as defined above.
In the present application, the term "alkylthio" refers to-S-alkyl, wherein alkyl is as defined above. C (C) 1-4 Alkylthio means-O- (C) 1-4 Alkyl), wherein C 1-4 Alkyl groups are as defined above.
In the present application, the term "haloalkyl" refers to a group formed by substitution of one or more (e.g., 2, 3,4,5, or 6) hydrogen atoms in an alkyl group with a halogen, wherein each halogen is independently F, cl, br, or I. Halogenated C 1-4 Alkyl means C substituted by one or more halogens 1-4 Alkyl, wherein C 1-4 Alkyl groups are as defined above. In some embodiments, halo C 1-4 Alkyl is fluoro C 1-4 An alkyl group.
In the present application, the term "haloalkoxy" refers to groups in which one or more (e.g., 2, 3,4,5, or 6) hydrogen atoms in the alkoxy group are replaced with halogens, wherein each halogen is independently F, cl, br, or I. Halogenated C 1-4 Alkoxy means C substituted by one or more halogens 1-4 Alkoxy group, wherein C 1-4 Alkoxy groups are as defined above. In some embodiments, halo C 1-4 Alkoxy is fluoro C 1 - 4 An alkoxy group. Wherein alkoxy is as defined above.
In the present application, the term "haloalkylthio" refers to a group formed by substitution of one or more (e.g., 2, 3,4,5, or 6) hydrogen atoms in an alkylthio group with halogen, wherein each halogen is independently F, cl, br, or I. Halogenated C 1-4 Alkylthio means C substituted by one or more halogens 1-4 Alkylthio, wherein C 1-4 Alkylthio groups are as defined above. In some embodiments, halo C 1-4 Alkylthio is fluoro C 1 - 4 Alkylthio groups. Wherein alkylthio is as defined above.
In the present application, the term "heterocycle" refers to a saturated, partially unsaturated or aromatic monocyclic or polycyclic (e.g., fused, spiro or bridged) cyclic group formed from a carbon atom and at least one heteroatom, wherein the heteroatoms are independently selected from N, O and S. In saturated heterocycles, both the carbon and heteroatom of the ring are saturated, examples of saturated heterocycles include, but are not limited to In aromatic heterocycles, each ring is aromatic, examples of aromatic heterocycles include, but are not limited to +.>In partially unsaturated heterocycles, 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 heterocyclic ring may be in particular a 4,5, 6, 7, 8, 9 or 10 membered heterocyclic ring. The 5-10 membered heterocyclic ring may specifically be a 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic ring.
In the present application, the term "aromatic ring" refers to an aromatic carbocyclic ring in which each ring is aromatic. The 6-10 membered aromatic ring may specifically be a benzene ring or a naphthalene ring.
In the present application, the term "heteroaromatic ring" refers to aromatic heterocyclic rings in which each ring is aromatic. Examples of heteroaromatic rings include, but are not limited toThe 5-10 membered heteroaromatic ring may in particular be a 5, 6, 7, 8, 9 or 10 membered heteroaromatic ring.
In the present application, the term "cycloalkyl" refers to a monovalent hydrocarbon group that is monocyclic or polycyclic (e.g., fused, spiro, or bridged), wherein each carbon atom is saturated. The 3-10 membered cycloalkyl group may specifically be a 3,4,5, 6, 7, 8, 9 or 10 membered cycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
In the present application, the term "heterocycloalkyl" means a group formed by substitution of at least one carbon atom in the cycloalkyl group with a heteroatom selected from N, O and S. The 3-to 10-membered heterocycloalkyl group may specifically be a 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group. Examples of heterocycloalkyl groups include, but are not limited to
The compounds of the application and their structures are also meant to include all isomeric (including stereoisomers and tautomers, wherein stereoisomers such as enantiomers, diastereomers, geometric isomers (e.g., cis-trans isomers) and conformational isomers) forms. They can be defined as (R) -/(S) -or (D) -/(L) -or (R, R) -/(R, S) -/(S, S) -, depending on the absolute stereochemistry for the amino acids. The present application includes all such possible isomers, as well as their racemic, enantiomerically enriched, and optionally pure forms. The optical (+) and (-), (R) -and (S) -and (R, R) -/(R, S) -/(S, S) -or (D) -and (L) -isomers can be prepared using chiral starting material synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid phase (HPLC) using chiral columns. When a compound described herein contains an alkenyl double bond or other geometric asymmetric center, unless otherwise specified, the compound includes both E and Z geometric isomers. In chemical structure, bondsThe configuration is not specified, i.e. if there is conformational isomerism in the chemical structure, bond +.>Can be +.>Or alternativelyAt the same time containAnd->Two configurations. Likewise, all tautomeric forms are also included.
In the present application, the term "tautomer" refers to the movement of a proton from one atom of a molecule from the original position to another position of the same molecule. The present application includes tautomers of any of the compounds.
In the present application, the term "pharmaceutically acceptable" refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present application prepared from the compounds of the present application which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present application contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present application contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. The acid addition salts are obtained by contacting the acid of (a) with a neutral form of such a compound.
In the present application, the term "patient" includes any animal, preferably a mammal, more preferably a human.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the application.
The reagents and materials used in the present application are commercially available.
The application has the positive progress effects that: the compound of the present application has high inhibition effect on SARS-CoV-2, obvious effect of inhibiting new coronavirus, high efficiency, low toxicity, high selectivity, high specificity and other advantages.
Detailed Description
The application is further illustrated by means of the following examples, which are not intended to limit the scope of the application. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Preparation of intermediate D
Compound A (10 mmol,2 g) was dissolved in 50mL tetrahydrofuran, methylpiperazine (10 mmol) and DIPEA (10 mmol) were added sequentially, and reacted at room temperature for 30min to give a tetrahydrofuran solution of crude B, which was used for the next reaction. Na at 40 DEG C 2 S·9H 2 O (30 mmol) was dissolved in 40mL of water and NaHCO was added 3 (30 mmol) after the solid had been completely dissolved, 40mL of methanol was added and the reaction temperature was raised to 70 ℃. And (3) dripping the tetrahydrofuran solution of the crude product B into the reaction solution, and continuing to react for 2 hours to obtain a solution of the crude product C. After the temperature of the reaction liquid is reduced to 50 ℃, na is added into the reaction liquid in sequence 2 S 2 O 4 (100 mmol) and K 2 CO 3 (100 mmol). Under vigorous stirring, water was added dropwise to the reaction solution until the solid was completely dissolved, and 50mL of tetrahydrofuran was added. The color of the reaction liquid is changed from red to yellow until the reaction liquid is light yellow or even colorless, and the whole process lasts for about 1h. Insoluble matter was removed by filtration, and the reaction mixture was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine, dried, and concentrated under reduced pressure to give crude intermediate D, which was used in the next reaction.
Example 1: preparation of Compound 1
Step 1:
intermediate D (0.42 mmol,200 mg) was dissolved in 3mL tetrahydrofuran, acetic acid 0.5mL and p-methylbenzaldehyde (0.9 mmol) were added sequentially, the reaction was refluxed, and the reaction was detected by HPLC-MS until the reaction was completed. Concentrating under reduced pressure, separating and purifying by column chromatography, eluting with ethyl acetate/petroleum ether to obtain intermediate E (95 mg).
1 H NMR(400MHz,CDCl3)δ8.05–7.96(m,2H),7.45(s,1H),7.37(s,1H),7.13(t,J=8.3Hz,2H),4.13(s,2H),3.06(s,4H),2.65(d,J=41.4Hz,4H),2.43(s,3H).
Step 2:
intermediate E (0.28 mmol,95 mg) was dissolved in 2mL of methylene chloride and reacted with 3,4, 5-trimethoxybenzaldehyde (0.336 mmol,65 mg) and then added with sodium borohydride acetate (0.34 mmol,72 mg) and 0.1mL of glacial acetic acid under reflux for 3 hours. The reaction was checked by HPLC-MS until the reaction was complete. Concentrating under reduced pressure, separating and purifying by column chromatography, eluting with dichloromethane/methanol to obtain the target product compound 1.
Yield: 113mg, yield: 53%.
1 H NMR(300MHz,DMSO-d6):5.68(1H,t,J=5.4Hz,1-H),7.67(1H,s,2-H),7.03(1H,s,3-H),2.94(4H,br.s,4and 5-H),2.58(4H,br.s,6and 7-H),2.36(3H,s,8-H),7.86(2H,d,J=8.4Hz,9and 10-H),7.32(2H,d,J=8.4Hz,11and 12-H),2.27(3H,s,13-H),4.38(2H,d,J=5.4Hz,14-H),6.74(2H,br.s,15and 16-H),3.75(6H,br.s,17and 19-H),3.64(3H,s,18-H).HR MS(TOF):observed for 519.2438,[M+H];calcd.for 519.243,C29H35N4O3S.
Examples 2 to 9:
the following compounds 2 to 9 were prepared with reference to the same preparation method as that of the compound 1 in example 1:
1 H NMR(300MHz,DMSO-d6):5.72(1H,br.s,1-H),7.86(1H,s,2-H),7.13(1H,s,3-H),2.91(4H,br.s,4and 5-H),2.56(4H,br.s,6and 7-H),2.37(3H,s,8-H),7.87(2H,d,J=6.9Hz,9and 10-H),7.00(2H,d,J=6.9Hz,11and 12-H),2.26(3H,s,13-H),4.64(2H,d,J=5.4Hz,14-H),7.33(3H,m,15-17-H).HR MS(TOF):observed for 435.1645,[M+H];calcd.for 435.1677,C24H27N4S2.
1 H NMR(300 MHz,DMSO-d6):5.71(1H,t,J=5.7 Hz,1-H),7.65(1H,s,2-H),6.95(2H,br.s,3 and15-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,9and 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.for473.2011,C27H29N4O2S.
1 H NMR(400 MHz,DMSO)δ7.85(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.
1 H NMR(400 MHz,DMSO)δ8.16(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.
1 H NMR(400 MHz,DMSO)δ8.18(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).HR MS(TOF):observed for:516.1311,[M+H];calcd.for:516.1362,C26H24ClF3N4S.
1 H NMR(300 MHz,DMSO-d6):5.71(1H,t,J=5.7 Hz,1-H),7.65(1H,s,2-H),6.95(2H,br.s,3 and15-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,9and 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.
1 H NMR(300 MHz,DMSO-d6):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=3.3Hz,15-H),7.59(1H,d,J=3.3Hz,16-H).HR MS(TOF):observed for 496.1496,[M+H];calcd.for496.1477,C24H26N5O3S2.
1 H NMR(300MHz,DMSO-d6):6.77(1H,t,J=5.4Hz,1-H),7.73(1H,s,2-H),6.98(1H,s,3-H),2.95(4H,br.s,4and 5-H),2.63(4H,br.s,6and 7-H),2.31(3H,s,8-H),8.18(1H,d,J=8.4Hz,9-H),7.57(1H,br.d,J=8.4Hz,10-H),7.83(1H,d,J=1.5Hz,11-H),4.42(1H,d,J=5.4Hz,12-H),7.28(2H,d,J=7.5Hz,13and 14-H),7.15(2H,d,J=7.5Hz,15and 16-H),2.27(3H,s,17-H).HR MS(TOF):observed for 497.1335,[M+H];calcd.for 497.1333,C26H27Cl2N4S.
example 10: preparation of Compound 10
Step 1:
intermediate D (0.42 mmol,200 mg) was dissolved in 3mL tetrahydrofuran, acetic acid 0.5mL and p-methylbenzaldehyde (0.9 mmol) were added sequentially, the reaction was refluxed, and the reaction was detected by HPLC-MS until the reaction was completed. Concentrating under reduced pressure, separating and purifying by column chromatography, eluting with ethyl acetate/petroleum ether to obtain intermediate E (95 mg).
Step 2:
intermediate E (0.28 mmol,95 mg) was dissolved in 3mL of dichloromethane and triphosgene (0.15 mmol) and Et were added sequentially 3 N (0.6 mmol) was reacted at room temperature for 30min. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 3mL of methylene chloride, and m-chlorobenzylamine (0.3 mmol) and Et were added in this order 3 N (0.7 mmol) was reacted at room temperature for 1h. Concentrating under reduced pressure, separating and purifying by column chromatography, eluting with dichloromethane/methanol to obtain the target product compound 10. Yield: 45mg, yield: 30%.
1 H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.98(s,1H),7.92(d,J=7.9Hz,2H),7.88(m,2H),7.41(m,2H),7.34(m,4H),4.37(d,J=5.7Hz,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.
Examples 11 to 15: preparation of Compounds 11 to 15
The following compounds 11 to 15 were prepared by replacing the corresponding raw materials by the same preparation method as that of the compound 10 in example 10
1 H NMR(300MHz,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,4and 5-H),2.59(4H,br.s,6and 7-H),2.39(3H,s,8-H),7.93(2H,d,J=8.1Hz,9and 10-H),7.36(2H,d,J=8.1Hz,11and 12-H),2.29(3H,s,13-H),7.49(1H,t,J=6.0Hz,14-H),4.43(2H,t,J=6.0Hz,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.
1 H NMR(300MHz,DMSO-d6):8.67(1H,s,1-H),8.06(1H,s,3-H),7.84(1H,s,6-H),2.89(4H,br.s,8and 9-H),2.73(4H,br.s,10and 11-H),2.38(3H,s,12-H),7.93(2H,d,J=7.8Hz,15and 19-H),7.36(2H,d,J=7.8Hz,16and 18-H),2.38(3H,s,20-H),7.31(1H,m,22-H),4.37(2H,d,J=5.4Hz,23-H),7.45(1H,d,J=8.7Hz,25-H),7.47(1H,d,J=8.7Hz,26-H),7.87(1H,m,28-H).HR MS(TOF):observed for 524.1674,[M+H];calcd.for 524.1687,C27H28ClFN5OS.
1 H NMR(300 MHz,DMSO-d6):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.
1 H NMR(300 MHz,DMSO-d 6 ):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 F 3 N 5 O 2 S.
1 H 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=9.0Hz,11and 12-H),8.68(1H,s,13-H),7.38(2H,d,J=8.4Hz,14and 15-H),7.25(2H,d,J=8.4Hz,16and 17-H),2.45(3H,s,18-H).HR MS(TOF):observed for 491.1795,[M+H];calcd.for 491.1791,C26H26FN5O2S.
Example 16: preparation of Compound 16
Compound 10 (0.2 mmol,100 mg) was dissolved in 2mL of methanol, then methanesulfonic acid (0.22 mmol,21 mg) was added, reacted at 70℃for 1h, then concentrated under reduced pressure to remove methanol, then 1mL of absolute ethanol was added to pulp, and suction filtration was performed to obtain 92mg of yellow solid compound 16. 1 HNMR(400MHz,DMSO)δ9.81(s,1H),8.76(s,1H),8.19(s,1H),7.94(d,J=6.5Hz,4H),7.47–7.30(m,6H),4.37(d,J=5.6Hz,2H),3.55(s,4H),3.17(d,J=12.0Hz,2H),3.05(t,J=10.6Hz,2H),2.91(s,3H),2.38(s,6H).
Example 17: preparation of Compound 17
Compound 10 (0.2 m)mol,100 mg) was dissolved in 2mL of methanol, then 4M methanolic hydrochloric acid (2 mmol,0.5 mL) was added, reacted at 70℃for 1h, then methanol was removed by concentration under reduced pressure, then 1mL of ethyl acetate was added to pulp, and 98mg of yellow solid compound 17 was obtained by suction filtration. 1 H NMR(400MHz,DMSO)δ10.73(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=11.2Hz,2H),3.19–3.07(m,4H),2.84(d,J=4.5Hz,3H),2.38(s,3H).
Examples 18 to 26
The compounds 18 to 20, 23 to 26 were prepared by replacing the corresponding raw materials by the same preparation method as in example 10 above, and the compounds 21 to 22 were prepared by replacing the corresponding raw materials by the same preparation method as in example 1 above.
1 H NMR(400 MHz,DMSO)δ8.69(s,1H),8.00–7.82(m,4H),7.46–7.28(m,6H),4.38(d,J=5.7Hz,2H),2.94(s,8H),2.39(s,2H),2.08(s,2H),1.23(s,3H).
1 H NMR(400 MHz,DMSO)δ8.73(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).
1 H NMR(400 MHz,DMSO-d 6 )δ8.73(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).
1 H NMR(400 MHz,DMSO-d 6 )δ7.91–7.85(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).
1 H NMR(400 MHz,DMSO-d 6 )δ7.86(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).
1 H NMR(400 MHz,DMSO-d 6 )δ8.66(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=7.0,6.4Hz,3H).
1 H NMR(400 MHz,DMSO-d 6 )δ8.76(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).
1 H NMR(400MHz,DMSO-d 6 )δ8.67(s,1H),8.41(s,1H),7.97–7.89(m,2H),7.84(d,J=7.6Hz,2H),7.40(t,J=5.6Hz,1H),7.35(d,J=8.0Hz,2H),4.07(t,J=7.0Hz,2H),3.18(q,J=6.4Hz,2H),2.85(t,J=4.7Hz,4H),2.61(d,J=5.8Hz,4H),2.38(d,J=2.6Hz,6H),2.29(s,3H),2.03–1.92(m,2H). 13 CNMR(101MHz,DMSO)δ166.96,155.73,151.28,145.89,145.42,141.40,140.89,134.56,131.05,130.29(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.
1 H NMR(400MHz,DMSO-d 6 )δ8.65(s,1H),8.36(s,1H),7.96–7.89(m,2H),7.84(s,1H),7.79(s,1H),7.33(dd,J=17.5,6.8Hz,3H),4.05(t,J=7.2Hz,2H),3.18(q,J=6.5Hz,2H),2.84(t,J=4.7Hz,4H),2.59(s,4H),2.39(d,J=2.9Hz,6H),2.28(s,3H),1.79(p,J=7.4Hz,2H),1.48(p,J=7.1Hz,2H). 13 C NMR(101MHz,DMSO)δ166.90,155.66,151.27,145.85,145.34,141.38,140.92,134.65,131.06,130.29(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.
Examples 27 to 45
Compounds 27-45 the following compounds were prepared using the same preparation method as described above in example 10, substituting the corresponding starting materials:
effect example 1: anti-novel coronavirus effects of the compounds of the present application
HEK293T-ACE2 cells were cultured at 37℃with 5% CO 2 The culture medium composition is DMEM+10% foetal calf serum+1% penicillin and streptomycin. Cells were then plated into 96-well plates (1X 10 per well) 4 And then adding 200TCID50SARS-coV-2 pseudovirus (pseudovirus is constructed by two plasmids of pVax-1-S-COVID19 and pNL 4-3Luc_env_Vpr) diluted with serum and the compound to be tested into a 96-well plate after 12 hours, and determining fluorescence value after 48 hours incubation to calculate the compound antiviral IC 50 Values, results are shown in table 1.
Table 1: anti-coronavirus screening result of benzothiazole compounds
As can be seen from table 1 above: the compound has certain inhibition effect on the novel coronavirus.

Claims (11)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein,,
ring A is a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring C is a 6-10 membered aromatic ring;
R 1 each independently is halogen, = O, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-10 membered cycloalkyl or-C (=o) (CH 2 ) 1-3 -R 1 -1
R 1-1 Is OH or-OC (O) CH 3
R 2 And R is 3 Each independently is halogen, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio group,Halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy or halo C 1-4 Alkylthio;
m1, m2 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 ) n 1-or-S (O) -NR a (CR b R c )n1-;
R a 、R b And R is c Each independently is H or C 1-4 An alkyl group;
n1 is each independently 0, 1, 2, 3 or 4;
the number of heteroatoms in the 4-10 membered heterocyclic ring and the 5-10 membered heteroaromatic ring is 1, 2 or 3, each heteroatom being independently N, O or S.
2. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1,
ring A is a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or a saturated or partially unsaturated 4-10 membered heterocyclic ring;
ring C is a 6-10 membered aromatic ring;
R 1 each independently is halogen, = O, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-10 membered cycloalkyl or-C (=o) (CH 2 ) 1-3 -R 1 -1
R 1-1 Is OH or-OC (O) CH 3
R 2 And R is 3 Each independently is halogen, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy or halo C 1-4 Alkylthio;
m1, m2 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 ) n 1-or-S (O) -NR a (CR b R c )n1-;
R a 、R b And R is c Each independently is H or C 1-4 An alkyl group;
n1 is each independently 0, 1 or 2;
the number of heteroatoms in the 4-10 membered heterocyclic ring and the 5-10 membered heteroaromatic ring is 1, 2 or 3, each heteroatom being independently N, O or S.
3. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 2,
in the definition of ring A, at least one heteroatom in the 4-10 membered heterocyclic ring is N;
and/or, in the definition of ring B, the 6-10 membered aromatic ring is a benzene ring;
and/or, in the definition of ring B, the number of heteroatoms in the 5-10 membered heteroaryl ring is 1 or 2;
and/or, in the definition of ring B, the heteroatom in the 4-10 membered heterocyclic ring is O;
and/or, in the definition of ring C, the 6-10 membered aromatic ring is a benzene ring;
and/or R 1 In the definition of (2), the halogen is F;
and/or R 1 In the definition of (C), said C 1-4 Alkyl is methyl, ethyl or isopropyl;
and/or R 1 In the definition of (2), the 3-10 membered cycloalkyl is cyclopropyl;
and/or R 1 In the definition of (C), said halo group 1-4 Alkyl is fluoro C 1-4 An alkyl group; and/or R 2 And R is 3 In the definition of (2), each of said halogens is independently F or Cl;
and/or R 2 And R is 3 In the definition of (C), said C 1-4 Alkyl groups are each independently methyl;
and/or R 2 And R is 3 In the definition of (C), said C 1-4 Alkoxy groups are each independently methoxy;
and/or R 2 And R is 3 In the definition of (C), said C 1-4 Alkylthio groups are each independently methylthio;
and/or R 2 And R is 3 In the definition of (C), said halo group 1-4 Alkyl, halogenated C 1-4 Alkoxy and halo C 1-4 The halo groups in the alkylthio groups are each independently fluoro.
4. A compound of formula I as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ring a is
And/or ring B is
And/or ring C is
And/or R 1 Each independently is F, =O, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 F、
And/or R 2 Each independently is F, cl, nitro, -CH 3 、-OCH 3 or-OCF 3
And/or R 3 Each independently is F, cl, -CH 3 、-SCH 3 or-CF 3
And/or R a 、R b And R is c Each independently is H;
and/or n1 is each independently 1 or 2;
and/or n1 is each independently 3 or 4.
5. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4,is->
And/or the number of the groups of groups,is->
And/or the number of the groups of groups,is->
And/or X is-CH 2 -、-C(O)-、-C(O)-NH-、-C(O)-NH-CH 2 -、-C(O)-NH-CH 2 CH 2 -、-C(O)-NH-CH 2 CH 2 CH 2 -、-C(O)-NH-CH 2 CH 2 CH 2 CH 2 -or-S (O) -NH-.
6. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5,is->
7. A compound of formula I as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, having any one of the following structures:
wherein, ring B, ring C, R 1 、R 2 、R 3 M1, m2 and m3 are as defined in any one of claims 1 to 5, and m4 is 2 or 3.
8. A compound of formula I as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, having any one of the following structures:
9. a process for the preparation of a compound of formula I as claimed in any one of claims 1 to 8, comprising process 1 and process 2, wherein,
the method 1 comprises the following steps: in a solvent, the compound shown in the formula II and the compound shown in the formula III are subjected to the following reaction to obtain the compound shown in the formula I,
wherein X is-CH 2 -,R 1 、R 2 And R is 3 Is as defined in any one of claims 1 to 8;
the method 2 comprises the following steps: in a solvent, reacting a compound shown in a formula II with triphosgene in the presence of alkali to obtain an isocyanate product, reacting the isocyanate product with a compound shown in a formula III' in the presence of alkali to obtain the compound shown in the formula I,
wherein X is-C (O) -NR a (CR b R c )n1-,n1、R a 、R b 、R c 、R 1 、R 2 And R is 3 Is as defined in any one of claims 1 to 8.
10. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
11. Use of a compound of formula I as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a patient carrying SARS-CoV-2 virus.
CN202310158328.5A 2022-02-25 2023-02-23 Benzothiazole compound, preparation method and application thereof Pending CN116655557A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113616642A (en) * 2020-05-06 2021-11-09 上海元熙医药科技有限公司 Use of benzisoselenazole derivatives for preparing anti-coronavirus medicaments
CN115340537A (en) * 2021-05-14 2022-11-15 上海医药集团股份有限公司 Quinazoline compound, preparation method and application thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200740781A (en) * 2005-08-29 2007-11-01 Astrazeneca Ab Novel compounds
US8481547B2 (en) * 2009-12-18 2013-07-09 Janssen Pharmaceutica Nv Substituted benzothiazole and benzoxazole derivatives useful as inhibitors of DPP-1
EP3904354A1 (en) * 2020-04-30 2021-11-03 Perha Pharmaceuticals New imidazolone derivatives as inhibitors of protein kinases in particular dyrk1a, clk1 and/or clk4
CN113620903B (en) * 2020-05-06 2023-08-29 中国科学院上海药物研究所 4- (benzothiazole-2-yl) -N-substituted aniline compound and preparation method and application thereof
WO2022013684A1 (en) * 2020-07-11 2022-01-20 Pfizer Inc. Antiviral heteroaryl ketone derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113616642A (en) * 2020-05-06 2021-11-09 上海元熙医药科技有限公司 Use of benzisoselenazole derivatives for preparing anti-coronavirus medicaments
CN115340537A (en) * 2021-05-14 2022-11-15 上海医药集团股份有限公司 Quinazoline compound, preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XILEI XIE等: "Benzothiazoles exhibit broad-spectrum antitumor activity: Their potency, structureeactivity and structureemetabolism relationships", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 76, 7 February 2014 (2014-02-07), pages 67 - 78 *

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