WO2023160634A1 - 苯并噻唑类化合物、其制备方法及应用 - Google Patents

苯并噻唑类化合物、其制备方法及应用 Download PDF

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WO2023160634A1
WO2023160634A1 PCT/CN2023/077984 CN2023077984W WO2023160634A1 WO 2023160634 A1 WO2023160634 A1 WO 2023160634A1 CN 2023077984 W CN2023077984 W CN 2023077984W WO 2023160634 A1 WO2023160634 A1 WO 2023160634A1
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ring
independently
formula
alkyl
membered
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French (fr)
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刘刚
刘利
陈志伟
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宁波康柏睿格医药科技有限公司
港大科桥有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic 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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/4353—Heterocyclic 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
    • A61K31/437—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to a benzothiazole compound, its preparation method and application.
  • Benzothiazole is a two-ring system formed by the fusion of benzene ring and thiazole ring. Hofmann first synthesized 2-phenylbenzothiazole compounds containing this structural fragment in 1879. As early as the 1950s, there were reports about the use of 2-aminobenzothiazole as a central muscle relaxant. However, such structures did not attract widespread attention from medicinal chemists at the time. Until Riluzole et al.
  • compound a is an inhibitor of HSV-1 virus
  • compound e It has a strong inhibitory effect on CVB5, ADV7 and EV71 viruses
  • compound f has obvious inhibitory effects on Zika virus and dengue fever virus.
  • the technical problem to be solved by the present invention is that there is currently no benzothiazole small-molecule drug used for anti-new coronavirus, so the present invention provides a benzothiazole compound, its preparation method and application.
  • This type of compound has a highly effective inhibitory effect on SARS-CoV-2 and can be used to fight against the new coronavirus.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • 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 1-1 is OH or -OC(O)CH 3 ;
  • R 2 and R 3 are each independently halogen, nitro, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, halogenated C 1-4 alkyl, halo Substituted C 1-4 alkoxy or halogenated C 1-4 alkylthio;
  • n1, 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 )n1- or -S(O)-NR a (CR b R c ) n1-;
  • R a , R b and R c are each independently H or C 1-4 alkyl
  • n1 is each independently 0, 1, 2, 3 or 4;
  • the number of heteroatoms in the 4-10 membered heterocyclic ring and 5-10 membered heteroaromatic ring is 1, 2 or 3, and each heteroatom is independently N, O or S.
  • 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 1-1 is OH or -OC(O)CH 3 ;
  • R 2 and R 3 are each independently halogen, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, halogenated C 1-4 alkyl, halogenated C 1 - 4 alkoxy or halogenated C 1-4 alkylthio;
  • n1, 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 )n1- or -S(O)-NR a (CR b R c ) n1-;
  • R a , R b and R c are each independently H or C 1-4 alkyl
  • each n1 is independently 0, 1 or 2;
  • the number of heteroatoms in the 4-10 membered heterocyclic ring and 5-10 membered heteroaromatic ring is 1, 2 or 3, and each heteroatom is independently N, O or S.
  • At least one heteroatom in the 4-10 membered heterocyclic ring is N.
  • Ring A is preferably attached to the benzothiazole via an N atom.
  • the 6-10 membered aromatic ring is a benzene ring.
  • the number of heteroatoms in the 5-10 membered heteroaromatic ring is 1 or 2.
  • the heteroatom in the 4-10 membered heterocycle is O.
  • the 6-10 membered aromatic ring is a benzene ring.
  • said halogen is F.
  • the C 1-4 alkyl group is methyl, ethyl or isopropyl.
  • the 3-10 membered cycloalkyl is cyclopropyl.
  • the halogenated C 1-4 alkyl is fluoro C 1-4 alkyl.
  • each of said halogens is independently F or Cl.
  • each of the C 1-4 alkyl groups is independently methyl.
  • each of the C 1-4 alkoxy groups is independently a methoxy group.
  • each of the C 1-4 alkylthio groups is independently methylthio.
  • each of the halogenated halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy and halogenated C 1-4 alkylthio are independently fluoro.
  • Ring A is preferably
  • Ring A is ( Indicates the position where ring A is attached to the benzothiazole).
  • Ring B is
  • Ring B is ( Indicates the position where ring B connects to X).
  • Ring C is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each R is independently halogen, nitro, C 1-4 alkyl, C 1-4 alkoxy or haloC 1-4 alkoxy, preferably F, Cl, nitro , -CH 3 , -OCH 3 or -OCF 3 .
  • each R 3 is independently halogen, C 1-4 alkyl, C 1-4 alkylthio or halogenated C 1-4 alkyl, preferably F, Cl, -CH 3 , -SCH 3 or -CF 3 .
  • Ra , Rb , and Rc are each independently H.
  • n1 is each independently 1 or 2.
  • each n1 is independently 3 or 4.
  • X is -CH2- , -C(O)-, -C(O)-NH-, -C(O)-NH- CH2- , -C(O)-NH-CH 2 CH 2 -or -S(O)-NH-, preferably -CH 2 - or -C(O)-NH-CH 2 -.
  • X is -CH2- , -C(O)-, -C(O)-NH-, -C(O)-NH- CH2- , -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-.
  • the compound shown in formula I is shown in formula Ia:
  • the compound shown in formula I is shown in formula Ib:
  • the compound shown in formula I is shown in formula Ic:
  • the compound shown in the formula I is shown in the formula Id:
  • the compound shown in formula I is shown in formula Ie:
  • each group is as defined above, and m4 is 2 or 3.
  • the pharmaceutically acceptable salt of the compound represented by formula I may be hydrochloride or methanesulfonate.
  • the compound represented by the formula I or a pharmaceutically acceptable salt thereof is selected from any of the following structures:
  • the compound represented by the formula I is selected from any of the following structures:
  • the present invention also provides a preparation method of the compound shown in the above formula I, which includes method 1 and method 2, wherein,
  • the method 1 comprises the following steps: in a solvent (such as a halogenated hydrocarbon solvent, such as dichloromethane), the compound shown in the formula II is reacted with the compound shown in the formula III as shown below to obtain the formula
  • a solvent such as a halogenated hydrocarbon solvent, such as dichloromethane
  • X is -CH 2 -, and the definitions of other groups are the same as above;
  • the method 2 comprises the following steps: in a solvent (such as a halogenated hydrocarbon solvent, such as dichloromethane), the compound represented by formula II is reacted with triphosgene in the presence of a base (such as triethylamine) to obtain an isocyanate product , reacting the isocyanate product with the compound shown in the formula III" in the presence of a base (such as triethylamine) to obtain the compound shown in the formula I,
  • a solvent such as a halogenated hydrocarbon solvent, such as dichloromethane
  • a base such as triethylamine
  • X is -C(O)-NR a (CR b R c )n1-, and the definitions of other groups are the same as above.
  • reaction conditions can be conventional conditions for this type of reaction in the art.
  • 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 pharmaceutically acceptable auxiliary materials.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof may be in a therapeutically effective amount.
  • the present invention also provides the use of the compound represented by the formula I described herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating patients carrying the SARS-CoV-2 virus.
  • substituted or "substituent” is a group in which a hydrogen atom is replaced by the designated group.
  • substitutions are at any position, but are permitted only if they result in a stable or chemically viable chemical. Examples are as follows: The structure indicates that the hydrogen atom on ring A is replaced by m1 R1 .
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is absent, it means that the linking group is a single bond, for example, the structure formed when L is absent in A-L-Z is A-Z.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group.
  • C 1-4 alkyl means an alkyl group having 1-4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl base.
  • alkoxy refers to -O-alkyl, wherein the definition of alkyl is as described above.
  • C 1-4 alkoxy refers to -O-(C 1-4 alkyl), wherein the definition of C 1-4 alkyl is as described above.
  • alkylthio refers to -S-alkyl, wherein the definition of alkyl is as described above.
  • C 1-4 alkylthio refers to -O-(C 1-4 alkyl), wherein the definition of C 1-4 alkyl is as described above.
  • haloalkyl refers to a group formed by replacing one or more (for example, 2, 3, 4, 5 or 6) hydrogen atoms in the alkyl group with halogen, wherein each halogen is independently F, Cl, Br or I.
  • Halogenated C 1-4 alkyl refers to C 1-4 alkyl substituted by one or more halogens, wherein C 1-4 alkyl is as defined above.
  • the haloC1-4alkyl is fluoroC1-4alkyl .
  • haloalkoxy refers to a group formed by replacing one or more (for example, 2, 3, 4, 5 or 6) hydrogen atoms in an alkoxy group with a halogen, wherein each halogen is independently Ground is F, Cl, Br or I.
  • Halogenated C 1-4 alkoxy refers to C 1-4 alkoxy substituted by one or more halogens, wherein C 1-4 alkoxy is as defined above.
  • the haloC1-4alkoxy is fluoroC1-4alkoxy . Wherein the definition of alkoxy is as described above.
  • haloalkylthio refers to a group formed by replacing one or more (for example, 2, 3, 4, 5 or 6) hydrogen atoms in an alkylthio group with a halogen, wherein each halogen is independently Ground is F, Cl, Br or I.
  • Halogenated C 1-4 alkylthio refers to C 1-4 alkylthio substituted by one or more halogens, wherein the definition of C 1-4 alkylthio is as described above.
  • the haloC1-4alkylthio is fluoroC1-4alkylthio . Wherein the definition of alkylthio is as described above.
  • heterocycle refers to a saturated, partially unsaturated or aromatic monocyclic ring formed by carbon atoms and at least one heteroatom Cyclic or polycyclic (eg fused, spiro or bridged) cyclic groups wherein the heteroatoms are independently selected from N, O and S.
  • a saturated heterocyclic ring both the carbon atoms and the heteroatoms on the ring are saturated
  • examples of saturated heterocyclic rings include but are not limited to In aromatic heterocycles, each ring is aromatic
  • examples of aromatic heterocycles include but are not limited to In a partially unsaturated heterocyclic ring, at least one atom of the ring is saturated and at least one atom is unsaturated.
  • Examples of partially unsaturated heterocyclic rings include, but are not limited to Specifically, the 4-10 membered heterocycle may be 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.
  • aromatic ring refers to an aromatic carbocyclic ring in which each ring is aromatic.
  • the 6-10 membered aromatic ring may be a benzene ring or a naphthalene ring.
  • heteroaromatic ring refers to an aromatic heterocyclic ring in which each ring is aromatic.
  • heteroaromatic rings include, but are not limited to The 5-10 membered heteroaryl ring can specifically be a 5, 6, 7, 8, 9 or 10 membered heteroaryl ring.
  • cycloalkyl refers to a monocyclic or polycyclic (eg fused, spiro or bridged) monovalent hydrocarbon group in which each carbon atom is saturated.
  • the 3-10 membered cycloalkyl group can specifically be a 3, 4, 5, 6, 7, 8, 9 or 10 membered cycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heterocycloalkyl refers to a group formed by replacing at least one carbon atom in a cycloalkyl group with a heteroatom selected from N, O and S.
  • the 3-10 membered heterocycloalkyl group can specifically be 3, 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group.
  • Examples of heterocycloalkyl include, but are not limited to
  • the compounds of the present invention and their structures also represent all isomers (including stereoisomers and tautomers, wherein stereoisomers such as enantiomers, diastereomers, geometric isomers isomers (such as cis-trans isomers) and conformational isomers) forms. They can be defined according to the absolute stereochemistry for amino acids as (R)-/(S)- or (D)-/(L)- or (R,R)-/(R,S)-/(S,S) -.
  • the present invention includes all such possible isomers, as well as their racemic, enantiomerically enriched and optionally pure forms.
  • Optical rotation (+) and (-), (R)- and (S)- and (R,R)-/(R,S)-/(S,S)- or (D)- and (L)-iso Constructs can be prepared using chiral starting materials synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using chiral columns.
  • HPLC high performance liquid chromatography
  • the compounds described herein contain alkenyl double bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds include both E and Z geometric isomers.
  • chemical structure, bond configuration is not specified, i.e. if there is configurational isomerism in the chemical structure, the bond can be or both Two configurations. Likewise, all tautomeric forms are also included.
  • tautomer refers to the movement of a proton from one atom of a molecule from its original position to another position of the same molecule superior.
  • the present invention includes tautomers of any of said compounds.
  • 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, that is, the substance can be administered to an individual without causing Adverse biological reaction or interaction in an adverse manner with any component contained in the composition.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat 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.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Acid addition salts are obtained by contacting the neutral form of such compounds with the acid.
  • the term "patient” includes any animal, preferably a mammal, more preferably a human.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the compound of the present invention has an efficient inhibitory effect on SARS-CoV-2, has a significant effect on inhibiting the new coronavirus, and also has many advantages such as high efficiency, low toxicity, strong selectivity, and strong specificity. advantage.
  • the tetrahydrofuran solution of the crude product B obtained above was dropped into the above reaction solution, and the reaction was continued for 2 h to obtain a solution of the crude product C.
  • Na 2 S 2 O 4 (100 mmol) and K 2 CO 3 (100 mmol) were sequentially added thereto.
  • water was added dropwise to the reaction solution until the solid was completely dissolved, and 50 mL of tetrahydrofuran was added.
  • the color of the reaction solution turns from red to yellow to light yellow or even colorless, the reaction is complete, and the whole process lasts for about 1 h.
  • Embodiment 1 the preparation of compound 1
  • step 1
  • Embodiment 2 ⁇ embodiment 9:
  • Embodiment 10 the preparation of compound 10
  • step 1
  • Embodiment 11 ⁇ Example 15 Preparation of Compounds 11 ⁇ 15
  • Embodiment 16 the preparation of compound 16
  • Embodiment 17 the preparation of compound 17
  • Dissolve compound 10 (0.2mmol, 100mg) in 2mL of methanol, then add 4M methanolic hydrochloric acid solution (2mmol, 0.5mL), react at 70°C for 1h, then concentrate under reduced pressure to remove methanol, then add 1mL of ethyl acetate for slurry, and filter with suction 98 mg of compound 17 was obtained as a yellow solid.
  • HEK293T-ACE2 cells were cultured at 37°C in an incubator with 5% CO 2 , and the medium composition was DMEM+10% fetal bovine serum+1% penicillin and streptomycin. Then the cells are spread in the 96-well plate (per hole 1 ⁇ 104 ), after 12 hours, the 200TCID50SARS-coV-2 pseudovirus (pseudovirus consists of two plasmids pVax-1-S-COVID19 and pNL4-3Luc_Env_Vpr) diluted with serum constructed) and the compound to be tested were added to a 96-well plate, and the fluorescence value was measured after incubation for 48 hours, and the antiviral IC50 value of the compound was calculated. The results are shown in Table 1.

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Abstract

本发明公开了一种苯并噻唑类化合物、其制备方法及应用。该类化合物对SARS-CoV-2具有高效的抑制作用，可以用于抗新冠病毒。 (I)

Description

苯并噻唑类化合物、其制备方法及应用
本申请要求申请日为2022/2/25的中国专利申请2022101799497的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种苯并噻唑类化合物、其制备方法及应用。
背景技术
苯并噻唑是由苯环和噻唑环稠合而成的两环体系，Hofmann在1879年首次合成了含有这种结构片段的2-苯基苯并噻唑类化合物。早在上世纪50年代，就有关于2-氨基苯并噻唑用于中枢肌肉松弛剂的报道。但当时这类结构并未引起药物化学家的广泛重视。直到Riluzole等人报道了化合物PK-26124(6-三氟甲氧基-2-氨基苯并噻唑)在生物化学、电生理学以及行为学实验中可以干扰谷氨酸能神经传递，药物化学家们才对苯并噻唑类衍生物的生物学活性产生兴趣，并开始对其进行广泛的研究。而且，逐渐发现在一些具有活性的天然产物中，也含有苯并噻唑结构片段。这之后，苯并噻唑类衍生物或者其生物电子等排体因其广泛的生物学活性而被应用于医药和农药等许多领域。例如，在医药学上，用于抗病毒、抗惊厥、抗菌、抗炎、抗肿瘤、以及医学显像剂等；在农业上，用作除草剂和杀虫剂。
以下化合物为近几年报道的苯并噻唑类的抗病毒化合物，其中，化合物a、化合物b、化合物c都具有抗丙型肝炎病毒的作用；化合物d是HSV-1病毒的抑制剂；化合物e具有较强的抑制CVB5、ADV7和EV71病毒的作用；化合物f对寨卡病毒和登革热病毒都有明显抑制作用。
2019年至2021年新冠病毒蔓延至全球，小分子抗新冠病毒的开发显得尤为重要。苯并噻唑类化合物作为一直具有药理活性的优势骨架，特别是在抗病毒方面具有重要的应用，然而到目前为止苯并噻唑类小分子化合物在抗新冠病毒方面还有没报道。
发明内容
本发明所要解决的技术问题是目前尚无苯并噻唑类小分子药物用于抗新冠病毒，从而本发明提供了一种苯并噻唑类化合物、其制备方法及应用。该类化合物对SARS-CoV-2具有高效的抑制作用，可以用于抗新冠病毒。
本发明提供了一种式I所示的化合物或其药学上可接受的盐，
其中，
环A为饱和或部分不饱和的4-10元杂环；
环B为6-10元芳环、5-10元杂芳环、或饱和或部分不饱和的4-10元杂环；
环C为6-10元芳环；
R1各自独立地为卤素、＝O、C1-4烷基、卤代C1-4烷基、3-10元环烷基或-C(＝O)(CH2)1-3-R1-1；
R1-1为OH或-OC(O)CH3；
R2和R3各自独立地为卤素、硝基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤代C1-4烷基、卤代C1-4烷氧基或卤代C1-4烷硫基；
m1、m2和m3各自独立地为0、1、2或3；
X为-(CRbRc)n1-、-C(O)-、-C(O)-NRa(CRbRc)n1-或-S(O)-NRa(CRbRc)n1-；
Ra、Rb和Rc各自独立地为H或C1-4烷基；
n1各自独立地为0、1、2、3或4；
所述4-10元杂环和5-10元杂芳环中的杂原子个数为1、2或3个，每个杂原子独立地为N、O或S。
在一些实施方案中，其中，
环A为饱和或部分不饱和的4-10元杂环；
环B为6-10元芳环、5-10元杂芳环、或饱和或部分不饱和的4-10元杂环；
环C为6-10元芳环；
R1各自独立地为卤素、＝O、C1-4烷基、卤代C1-4烷基、3-10元环烷基或-C(＝O)(CH2)1-3-R1-1；
R1-1为OH或-OC(O)CH3；
R2和R3各自独立地为卤素、硝基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤代C1-4烷基、卤代C1- 4烷氧基或卤代C1-4烷硫基；
m1、m2和m3各自独立地为0、1、2或3；
X为-(CRbRc)n1-、-C(O)-、-C(O)-NRa(CRbRc)n1-或-S(O)-NRa(CRbRc)n1-；
Ra、Rb和Rc各自独立地为H或C1-4烷基；
n1各自独立地为0、1或2；
所述4-10元杂环和5-10元杂芳环中的杂原子个数为1、2或3个，每个杂原子独立地为N、O或S。
在本发明某些优选实施方案中(以下简称“在一些实施方案中”)，所述的如式I所示化合物中的某些基团如下定义(未定义的基团同本申请任一方案所述)。
在一些实施方案中，环A的定义中，所述4-10元杂环中的至少一个杂原子为N。环A优选通过N原子与苯并噻唑相连。
在一些实施方案中，环B的定义中，所述6-10元芳环为苯环。
在一些实施方案中，环B的定义中，所述5-10元杂芳环中的杂原子个数为1或2。
在一些实施方案中，环B的定义中，所述4-10元杂环中的杂原子为O。
在一些实施方案中，环C的定义中，所述6-10元芳环为苯环。
在一些实施方案中，R1的定义中，所述卤素为F。
在一些实施方案中，R1的定义中，所述C1-4烷基为甲基、乙基或异丙基。
在一些实施方案中，R1的定义中，所述3-10元环烷基为环丙基。
在一些实施方案中，R1的定义中，所述卤代C1-4烷基为氟代C1-4烷基。
在一些实施方案中，R2和R3的定义中，所述卤素各自独立地为F或Cl。
在一些实施方案中，R2和R3的定义中，所述C1-4烷基各自独立地为甲基。
在一些实施方案中，R2和R3的定义中，所述C1-4烷氧基各自独立地为甲氧基。
在一些实施方案中，R2和R3的定义中，所述C1-4烷硫基各自独立地为甲硫基。
在一些实施方案中，R2和R3的定义中，所述卤代C1-4烷基、卤代C1-4烷氧基和卤代C1-4烷硫基中的卤代各自独立地为氟代。
在一些实施方案中，环A为 优选为
在一些实施方案中，环A为 (表示环A与苯并噻唑相连的位置)。
在一些实施方案中，环B为
在一些实施方案中，环B为(表示环B与X相连的位置)。
在一些实施方案中，环C为
在一些实施方案中，R1各自独立地为F、＝O、-CH3、-CH2CH3、-CH(CH3)2、-CH2CH2F、
在一些实施方案中，R2各自独立地为卤素、硝基、C1-4烷基、C1-4烷氧基或卤代C1-4烷氧基，优选为F、Cl、硝基、-CH3、-OCH3或-OCF3。
在一些实施方案中，R3各自独立地为卤素、C1-4烷基、C1-4烷硫基或卤代C1-4烷基，优选为F、Cl、-CH3、-SCH3或-CF3。
在一些实施方案中，为 优选为
在一些实施方案中，为 例如
在一些实施方案中，为 优选为
在一些实施方案中，Ra、Rb和Rc各自独立地为H。
在一些实施方案中，n1各自独立地为1或2。
在一些实施方案中，n1各自独立地为3或4。
在一些实施方案中，X为-CH2-、-C(O)-、-C(O)-NH-、-C(O)-NH-CH2-、-C(O)-NH-CH2CH2-或-S(O)-NH-，优选为-CH2-或-C(O)-NH-CH2-。
在一些实施方案中，X为-CH2-、-C(O)-、-C(O)-NH-、-C(O)-NH-CH2-、-C(O)-NH-CH2CH2-、-C(O)-NH-CH2CH2CH2-、-C(O)-NH-CH2CH2CH2CH2-或-S(O)-NH-。
在一些实施方案中，为 例如
在一些实施方案中，所述式I所示的化合物如式I-a所示：
其中，各基团定义同前所述。
在一些实施方案中，所述式I所示的化合物如式I-b所示：
其中，各基团定义同前所述。
在一些实施方案中，所述式I所示的化合物如式I-c所示：
其中，各基团定义同前所述。
在一些实施方案中，所述式I所示的化合物如式I-d所示：
其中，各基团定义同前所述。
在一些实施方案中，所述式I所示的化合物如式I-e所示：
其中，各基团定义同前所述，m4为2或3。
在一些实施方案中，所述式I所示的化合物的药学上可接受的盐可以为盐酸盐或甲磺酸盐。
在一些实施方案中，所述式I所示的化合物或其药学上可接受的盐选自以下任一结构：

在一些实施方案中，所述式I所示的化合物选自以下任一结构：


本发明还提供了一种上述式I所示的化合物的制备方法，其包括方法1和方法2，其中，
所述方法1包括以下步骤：溶剂(例如卤代烃类溶剂，又例如二氯甲烷)中，将式II所示的化合物与式III所示的化合物进行如下所示的反应，得到所述式I所示的化合物即可，
其中，X为-CH2-，其余基团的定义同前所述；
所述方法2包括以下步骤：溶剂(例如卤代烃类溶剂，又例如二氯甲烷)中，将式II所示的化合物在碱(例如三乙胺)存在下与三光气反应，得到异氰酸酯产物，将所述异氰酸酯产物在碱(例如三乙胺)存在下与式III”所示的化合物反应，得到所述式I所示的化合物即可，
其中，X为-C(O)-NRa(CRbRc)n1-，其余基团的定义同前所述。
所述式I所示的化合物的制备方法中，反应条件可为本领域此类反应常规的条件。
本发明还提供了一种药物组合物，其包含本文所述的式I所示的化合物或其药学上可接受的盐、以及药学上可接受的辅料。所述的如式I所示的化合物或其药学上可接受的盐可为治疗有效量。
本发明还提供了本文所述的式I所示的化合物或其药学上可接受的盐在制备用于治疗携带SARS-CoV-2病毒的患者的药物中的应用。
定义说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
在本发明中，术语“取代”或“取代基”是基团中的氢原子被指定的基团所代替。当没有指明取代位置时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。举例说明如下：结构表示环A上的氢原子被m1个R1所取代。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为不存在时，表示该连接基团为单键，例如A-L-Z中L为不存在时形成的结构为A-Z。
在本发明中，术语“烷基”是指饱和的直链或支链的一价烃基。C1-4烷基是指具有1-4个碳原子的烷基，其具体为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在本发明中，术语“烷氧基”是指-O-烷基，其中烷基的定义如前所述。C1-4烷氧基是指-O-(C1-4烷基)，其中C1-4烷基的定义如前所述。
在本发明中，术语“烷硫基”是指-S-烷基，其中烷基的定义如前所述。C1-4烷硫基是指-O-(C1-4烷基)，其中C1-4烷基的定义如前所述。
在本发明中，术语“卤代烷基”是指烷基中的一个或多个(例如2、3、4、5或6)氢原子被卤素所取代形成的基团，其中每个卤素独立地为F、Cl、Br或I。卤代C1-4烷基是指被一个或多个卤素取代的C1-4烷基，其中C1-4烷基的定义如前所述。在一些实施方案中，卤代C1-4烷基为氟代C1-4烷基。
在本发明中，术语“卤代烷氧基”是指烷氧基中的一个或多个(例如2、3、4、5或6)氢原子被卤素所取代形成的基团，其中每个卤素独立地为F、Cl、Br或I。卤代C1-4烷氧基是指被一个或多个卤素取代的C1-4烷氧基，其中C1-4烷氧基的定义如前所述。在一些实施方案中，卤代C1-4烷氧基为氟代C1-4烷氧基。其中烷氧基的定义如前所述。
在本发明中，术语“卤代烷硫基”是指烷硫基中的一个或多个(例如2、3、4、5或6)氢原子被卤素所取代形成的基团，其中每个卤素独立地为F、Cl、Br或I。卤代C1-4烷硫基是指被一个或多个卤素取代的C1-4烷硫基，其中C1-4烷硫基的定义如前所述。在一些实施方案中，卤代C1-4烷硫基为氟代C1-4烷硫基。其中烷硫基的定义如前所述。
在本发明中，术语“杂环”是指由碳原子和至少一个杂原子形成的饱和、部分不饱和或芳香性的单 环或多环(例如并环、螺环或桥环)环状基团，其中杂原子独立地选自N、O和S。在饱和的杂环中，环上的碳原子和杂原子均是饱和的，饱和的杂环的实例包括但不限于 在芳香性的杂环中，每个环均是芳香性的，芳香性的杂环的实例包括但不限于在部分不饱和的杂环中，环上至少有一个原子是饱和的且至少有一个原子是不饱和的，部分不饱和的杂环的实例包括但不限于 4-10元杂环具体可以为4、5、6、7、8、9或10元杂环。5-10元杂环具体可以为5、6、7、8、9或10元杂环。
在本发明中，术语“芳环”是指芳香性的碳环，其中的每个环均是芳香性的。6-10元芳环具体可以为苯环或萘环。
在本发明中，术语“杂芳环”是指芳香性的杂环，其中的每个环均是芳香性的。杂芳环的实例包括但不限于5-10元杂芳环具体可以为5、6、7、8、9或10元杂芳环。
在本发明中，术语“环烷基”是指单环或多环(例如并环、螺环或桥环)的一价烃基，其中的每个碳原子均是饱和的。3-10元环烷基具体可以为3、4、5、6、7、8、9或10元环烷基，包括环丙基、环丁基、环戊基、环己基等。
在本发明中，术语“杂环烷基”是指环烷基中的至少一个碳原子被选自N、O和S的杂原子代替形成的基团。3-10元杂环烷基具体可以为3、4、5、6、7、8、9或10元杂环烷基。杂环烷基的实例包括但不限于
本发明的化合物和它们的结构还表示包括所有异构体(包括立体异构体和互变异构体，其中立体异构体例如对映异构体、非对映异构体、几何异构体(如顺反异构体)和构象异构体)形式。它们可以根据对于氨基酸的绝对立体化学定义为(R)-/(S)-或者(D)-/(L)-或者(R,R)-/(R,S)-/(S,S)-。本发明包括所有这些可能的异构体，以及它们的外消旋的、对映体富集的和任选的纯的形式。旋光(+)和(-)，(R)-和(S)-以及(R,R)-/(R,S)-/(S,S)-或(D)-和(L)-异构体可以使用手性原料合成、手性拆分制备，或者可以使用常规技术例如但不限于使用手性柱的高效液相(HPLC)拆分。当本文所述的化合物包含烯基双键或其他几何不对称中心时，除非另有说明，所述化合物包括E和Z几何异构体两者。化学结构中，键并未指定构型，即如果化学结构中存在构型异构，键可以为或者同时包含 两种构型。同样，还包括所有互变异构体形式。
在本发明中，术语“互变异构体”指质子从分子的一个原子从原位置移动到同一分子的另一个位置 上。本发明包括任何所述化合物的互变异构体。
在本发明中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。的酸与这类化合物的中性形式接触的方式获得酸加成盐。
本发明中，术语“患者”包括任何动物，优选哺乳动物，更优选人。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的化合物对SARS-CoV-2具有高效的抑制作用，具有显著的抑制新冠病毒的效果，同时还具有高效、低毒、选择性强、特异性强等多个优点。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
中间体D的制备
将化合物A(10mmol,2g)溶于50mL四氢呋喃中，依次加入甲基哌嗪(10mmol)和DIPEA(10mmol)，室温下反应30min，得粗品B的四氢呋喃溶液，即可用于下一步反应。40℃条件下，将Na2S·9H2O(30mmol)溶于40mL水中，加NaHCO3(30mmol)，待固体全部溶解后，加40mL甲醇，将反应液温度升至70℃。将前面所得粗品B的四氢呋喃溶液滴入上述反应液中，继续反应2h，得粗品C的溶液。待上述反应液温度降至50℃，依次向其内加入Na2S2O4(100mmol)和K2CO3(100mmol)。剧烈搅拌状态下，向反应液中滴加水，至固体完全溶解，补加50mL四氢呋喃。反应液颜色由红色转为黄色直至淡黄色甚至无色，反应完成，整个过程持续约1h。过滤除去不溶物，将反应液用乙酸乙酯(50mL×3)萃取，合并有机相，饱和食盐水洗涤，干燥，减压浓缩得粗品中间体D，即 可用于下一步反应。
实施例1：化合物1的制备
步骤1：
将中间体D(0.42mmol，200mg)溶于3mL四氢呋喃中，依次加入醋酸0.5mL和对甲基苯甲醛(0.9mmol)，回流反应，HPLC-MS检测反应，至反应完成。减压浓缩，柱色谱分离纯化，乙酸乙酯/石油醚洗脱，得中间体E(95mg)。
1H 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).
步骤2：
将中间体E(0.28mmol，95mg)与3,4,5-三甲氧基苯甲醛(0.336mmol，65mg)溶于2mL二氯甲烷中，在再加入醋酸硼氢化钠(0.34mmol，72mg)和0.1mL冰醋酸回流反应3小时。HPLC-MS检测反应，至反应完成。减压浓缩，柱色谱分离纯化，二氯甲烷/甲醇洗脱，得到目标产物化合物1。产量：113mg，产率：53％。
1H 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.
实施例2～实施例9：
参考与实施例1中化合物1相同的制备方法制备以下化合物2～化合物9：
1H 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,4 and 5-H),2.56(4H,br.s,6 and 7-H),2.37(3H,s,8-H),7.87(2H,d,J＝6.9Hz,9 and 10-H),7.00(2H,d,J＝6.9Hz,11 and 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.
1H NMR(300MHz,DMSO-d6):5.71(1H,t,J＝5.7Hz,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＝8.4Hz,9and 10-H),7.31(2H,d,J＝8.4Hz,11 and 12-H),2.27(3H,s,13-H),4.36(2H,d,J＝5.7Hz,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.
1H NMR(400MHz,DMSO)δ7.85(d,J＝7.5Hz,2H),7.67(d,J＝9.2Hz,1H),7.44(s,1H),7.36(s,2H),7.30(d,J＝7.4Hz,3H),6.90(s,1H),5.95(s,1H),4.48(d,J＝5.2Hz,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.
1H NMR(400MHz,DMSO)δ8.16(d,J＝8.1Hz,2H),7.84(d,J＝8.2Hz,2H),7.74(s,1H),7.45(s,1H),7.37(d,J＝4.7Hz,2H),7.32–7.24(m,1H),6.95(s,1H),6.02(t,J＝5.9Hz,1H),4.49(d,J＝5.9Hz,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.
1H NMR(400MHz,DMSO)δ8.18(d,J＝8.1Hz,2H),7.86(d,J＝8.4Hz,2H),7.80(s,1H),7.57–7.48(m,1H),7.38(dd,J＝5.5,3.9Hz,1H),7.33–7.25(m,2H),6.89(s,1H),6.10(t,J＝5.2Hz,1H),4.54(d,J＝5.8Hz,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.
1H NMR(300MHz,DMSO-d6):5.71(1H,t,J＝5.7Hz,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＝8.4Hz,9 and 10-H),7.31(2H,d,J＝8.4Hz,11 and 12-H),2.27(3H,s,13-H),4.36(2H,d,J＝5.7Hz,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.
1H NMR(300MHz,DMSO-d6):5.83(1H,t,J＝5.4Hz,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＝8.4Hz,9 and 10-H),7.33(2H,d,J＝8.4Hz,11 and 12-H),2.87(3H,s,13-H),4.59(2H,d,J＝5.4Hz,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.
1H 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,4 and 5-H),2.63(4H,br.s,6 and 7-H),2.31(3H,s,8-H),8.18(1H,d,J＝8.4Hz,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,13 and 14-H),7.15(2H,d,J＝7.5Hz,15 and 16-H),2.27(3H,s,17-H).HR MS(TOF):observed for 497.1335,[M+H]；calcd.for 497.1333,C26H27Cl2N4S.
实施例10：化合物10的制备
步骤1：
中间体D(0.42mmol，200mg)溶于3mL四氢呋喃中，依次加入醋酸0.5mL和对甲基苯甲醛(0.9mmol)，回流反应，HPLC-MS检测反应，至反应完成。减压浓缩，柱色谱分离纯化，乙酸乙酯/石油醚洗脱，得中间体E(95mg)。
步骤2：
将中间体E(0.28mmol，95mg)溶于3mL二氯甲烷中，依次加入三光气(0.15mmol)和Et3N(0.6mmol)，室温下反应30min。将反应液减压浓缩，残留物用3mL二氯甲烷溶解，依次加入间氯苄胺(0.3mmol)和Et3N(0.7mmol)，室温下反应1h。减压浓缩，柱色谱分离纯化，二氯甲烷/甲醇洗脱，得到目标产物化合物10。产量：45mg，产率：30％。
1H 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.
实施例11～实施例15：化合物11～15的制备
采用与实施例10中化合物10相同的制备方法替换相应原料制备以下化合物11～15
1H 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,4 and 5-H),2.59(4H,br.s,6 and 7-H),2.39(3H,s,8-H),7.93(2H,d,J＝8.1Hz,9 and 10-H),7.36(2H,d,J＝8.1Hz,11 and 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.
1H 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,8 and 9-H),2.73(4H,br.s,10 and 11-H),2.38(3H,s,12-H),7.93(2H,d,J＝7.8Hz,15 and 19-H),7.36(2H,d,J＝7.8Hz,16 and 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.
1H NMR(300MHz,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＝7.5Hz,9 and 10-H),7.30(2H,d,J＝7.5Hz,11 and 12-H),2.39(3H,s,13-H),7.29(1H,t,J＝7.5Hz,14-H),3.38(2H,m,15-H),2.81(2H,t,J＝6.9Hz,16-H),7.38(4H,m,17-20-H).HR MS(TOF):observed for 520.1914,[M+H]；calcd.for 520.1938,C28H31ClN5OS.
1H NMR(300MHz,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＝9.3Hz, 11 and 12-H),2.38(3H,s,13-H),8.70(1H,s,14-H),7.36(1H,d,J＝8.4Hz,15 and 16-H),7.31(1H,d,J＝8.4Hz,17 and 18-H).HR MS(TOF):observed for 542.4546,[M+H]；calcd.for 542.1838,C27H27F3N5O2S.
1H NMR(300MHz,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 5.7Hz,9 and 10-H),7.39(2H,t,J＝9.0Hz,11 and 12-H),8.68(1H,s,13-H),7.38(2H,d,J＝8.4Hz,14 and 15-H),7.25(2H,d,J＝8.4Hz,16 and 17-H),2.45(3H,s,18-H).HR MS(TOF):observed for 491.1795,[M+H]；calcd.for 491.1791,C26H26FN5O2S.
实施例16：化合物16的制备
将化合物10(0.2mmol，100mg)溶于2mL甲醇，然后加入甲磺酸(0.22mmol，21mg)，70℃反应1h，然后减压浓缩除去甲醇，然后加入1mL无水乙醇打浆，抽滤得92mg黄色固体化合物16。1H NMR(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).
实施例17：化合物17的制备
将化合物10(0.2mmol，100mg)溶于2mL甲醇，然后加入4M的盐酸甲醇溶液(2mmol，0.5mL)，70℃反应1h，然后减压浓缩除去甲醇，然后加入1mL乙酸乙酯打浆，抽滤得98mg黄色固体化合物17。1H 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).
实施例18～26
化合物18～20、23-26采用与上述实施例10相同的制备方法替换相应原料制备得到，化合物21-22采用与上述实施例1相同的制备方法替换相应原料制备得到。
1H NMR(400MHz,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).
1H NMR(400MHz,DMSO)δ8.73(s,1H),8.52(s,1H),8.45(s,1H),7.92(d,J＝8.0Hz,2H),7.85(s,1H),7.37(m,6H),4.78(t,J＝5.0Hz,1H),4.37(d,J＝5.7Hz,2H),4.16(d,J＝5.3Hz,2H),3.85(s,2H),3.72(s,2H),2.82(s,4H),2.37(s,3H).
1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.14(s,1H),7.94(d,J＝8.0Hz,2H),7.90(s,1H),7.81(t,J＝5.9Hz,1H),7.45–7.31(m,6H),4.86(s,2H),4.39(d,J＝5.7Hz,2H),3.70(d,J＝20.8Hz,4H),2.86(s,4H),2.39(s,3H),2.11(s,3H).
1H NMR(400MHz,DMSO-d6)δ7.91–7.85(m,2H),7.71(s,1H),7.64(d,J＝3.8Hz,1H),7.19(s,1H),6.73(d,J＝3.8Hz,1H),5.87(dt,J＝12.6,4.1Hz,1H),4.64(d,J＝6.3Hz,2H),2.91(s,4H),2.59(s,3H),2.38(s,3H),2.29(s,3H).
1H NMR(400MHz,DMSO-d6)δ7.86(d,J＝8.0Hz,2H),7.66(s,1H),7.30(dd,J＝11.1,7.9Hz,4H),7.16(d,J＝7.8Hz,2H),6.93(s,1H),5.71(d,J＝6.0Hz,1H),4.41(d,J＝5.7Hz,2H),2.95(s,4H),2.65(d,J＝19.3Hz,4H),2.37(s,3H),2.32(s,3H),2.28(s,3H).
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.94(d,J＝7.8Hz,2H),7.85(d,J＝11.5Hz,2H),7.37(d,J＝7.9Hz,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.Hz,3H).
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.28(s,1H),8.19(t,J＝5.9Hz,1H),7.99–7.92(m,2H),7.91(s,1H),7.45–7.30(m,7H),4.38(d,J＝5.8Hz,2H),3.43(t,J＝5.0Hz,4H),3.05(t,J＝5.0Hz,4H),2.39(s,3H).
1H NMR(400MHz,DMSO-d6)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).13C NMR(101 MHz,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.
1H NMR(400MHz,DMSO-d6)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).13C 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.
实施例27-45
化合物27-45采用与上述实施例10相同的制备方法替换相应原料制备以下化合物：



效果实施例1：本发明化合物的抗新冠病毒的作用
HEK293T-ACE2细胞培养于37℃，5％CO2的培养箱中，培养基成分为DMEM+10％胎牛血清+1％青霉素和链霉素。然后将细胞铺至96孔板中(每孔1X104个)，12小时后将用血清稀释的200TCID50SARS-coV-2假病毒(假病毒由pVax-1-S-COVID19和pNL4-3Luc_Env_Vpr两个质粒所构建)和待测化合物加入到96孔板中，孵育48小时后测定荧光值，计算化合物抗病毒IC50值，结果如表1所示。
表1：苯并噻唑类化合物抗新冠病毒筛选结果

通过上表1可知：本发明的化合物对新冠病毒均有一定的抑制作用。

Claims (11)

  1. 一种式I所示的化合物或其药学上可接受的盐，
    其中，
    环A为饱和或部分不饱和的4-10元杂环；
    环B为6-10元芳环、5-10元杂芳环、或饱和或部分不饱和的4-10元杂环；
    环C为6-10元芳环；
    R1各自独立地为卤素、＝O、C1-4烷基、卤代C1-4烷基、3-10元环烷基或-C(＝O)(CH2)1-3-R1-1；
    R1-1为OH或-OC(O)CH3；
    R2和R3各自独立地为卤素、硝基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤代C1-4烷基、卤代C1-4烷氧基或卤代C1-4烷硫基；
    m1、m2和m3各自独立地为0、1、2或3；
    X为-(CRbRc)n1-、-C(O)-、-C(O)-NRa(CRbRc)n1-或-S(O)-NRa(CRbRc)n1-；
    Ra、Rb和Rc各自独立地为H或C1-4烷基；
    n1各自独立地为0、1、2、3或4；
    所述4-10元杂环和5-10元杂芳环中的杂原子个数为1、2或3个，每个杂原子独立地为N、O或S。
  2. 如权利要求1所述的式I所示的化合物或其药学上可接受的盐，其特征在于，
    环A为饱和或部分不饱和的4-10元杂环；
    环B为6-10元芳环、5-10元杂芳环、或饱和或部分不饱和的4-10元杂环；
    环C为6-10元芳环；
    R1各自独立地为卤素、＝O、C1-4烷基、卤代C1-4烷基、3-10元环烷基或-C(＝O)(CH2)1-3-R1-1；
    R1-1为OH或-OC(O)CH3；
    R2和R3各自独立地为卤素、硝基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、卤代C1-4烷基、卤代C1- 4烷氧基或卤代C1-4烷硫基；
    m1、m2和m3各自独立地为0、1、2或3；
    X为-(CRbRc)n1-、-C(O)-、-C(O)-NRa(CRbRc)n1-或-S(O)-NRa(CRbRc)n1-；
    Ra、Rb和Rc各自独立地为H或C1-4烷基；
    n1各自独立地为0、1或2；
    所述4-10元杂环和5-10元杂芳环中的杂原子个数为1、2或3个，每个杂原子独立地为N、O或S。
  3. 如权利要求2所述的式I所示的化合物或其药学上可接受的盐，其特征在于，
    环A的定义中，所述4-10元杂环中的至少一个杂原子为N；
    和/或，环B的定义中，所述6-10元芳环为苯环；
    和/或，环B的定义中，所述5-10元杂芳环中的杂原子个数为1或2；
    和/或，环B的定义中，所述4-10元杂环中的杂原子为O；
    和/或，环C的定义中，所述6-10元芳环为苯环；
    和/或，R1的定义中，所述卤素为F；
    和/或，R1的定义中，所述C1-4烷基为甲基、乙基或异丙基；
    和/或，R1的定义中，所述3-10元环烷基为环丙基；
    和/或，R1的定义中，所述卤代C1-4烷基为氟代C1-4烷基；和/或，R2和R3的定义中，所述卤素各自独立地为F或Cl；
    和/或，R2和R3的定义中，所述C1-4烷基各自独立地为甲基；
    和/或，R2和R3的定义中，所述C1-4烷氧基各自独立地为甲氧基；
    和/或，R2和R3的定义中，所述C1-4烷硫基各自独立地为甲硫基；
    和/或，R2和R3的定义中，所述卤代C1-4烷基、卤代C1-4烷氧基和卤代C1-4烷硫基中的卤代各自独立地为氟代。
  4. 如权利要求1-3中任一项所述的式I所示的化合物或其药学上可接受的盐，其特征在于，环A为
    和/或，环B为
    和/或，环C为
    和/或，R1各自独立地为F、＝O、-CH3、-CH2CH3、-CH(CH3)2、-CH2CH2F、
    和/或，R2各自独立地为F、Cl、硝基、-CH3、-OCH3或-OCF3；
    和/或，R3各自独立地为F、Cl、-CH3、-SCH3或-CF3；
    和/或，Ra、Rb和Rc各自独立地为H；
    和/或，n1各自独立地为1或2；
    和/或，n1各自独立地为3或4。
  5. 如权利要求1-4中任一项所述的式I所示的化合物或其药学上可接受的盐，其特征在于，为
    和/或，为
    和/或，为
    和/或，X为-CH2-、-C(O)-、-C(O)-NH-、-C(O)-NH-CH2-、-C(O)-NH-CH2CH2-、-C(O)-NH-CH2CH2CH2-、-C(O)-NH-CH2CH2CH2CH2-或-S(O)-NH-。
  6. 如权利要求1-5中任一项所述的式I所示的化合物或其药学上可接受的盐，其特征在于， 为
  7. 如权利要求1-6中任一项所述的式I所示的化合物或其药学上可接受的盐，其特征在于，其具有以下任一结构：

    其中，环B、环C、R1、R2、R3、m1、m2和m3的定义如权利要求1-5中任一项所述，m4为2或3。
  8. 如权利要求1-6中任一项所述的式I所示的化合物或其药学上可接受的盐，其特征在于，其具有以下任一结构：




  9. 一种如权利要求1-8中任一项所述的式I所示的化合物的制备方法，其包括方法1和方法2，其中，
    所述方法1包括以下步骤：溶剂中，将式II所示的化合物与式III所示的化合物进行如下所示的反应，得到所述式I所示的化合物即可，
    其中，X为-CH2-，R1、R2和R3的定义如权利要求1-8中任一项所述；
    所述方法2包括以下步骤：溶剂中，将式II所示的化合物在碱存在下与三光气反应，得到异氰酸酯产物，将所述异氰酸酯产物在碱存在下与式III”所示的化合物反应，得到所述式I所示的化合物即可，
    其中，X为-C(O)-NRa(CRbRc)n1-，n1、Ra、Rb、Rc、R1、R2和R3的定义如权利要求1-8中任一项所述。
  10. 一种药物组合物，其包含如权利要求1-8中任一项所述的式I所示的化合物或其药学上可接受的盐、以及药学上可接受的辅料。
  11. 一种如权利要求1-8中任一项所述的式I所示的化合物或其药学上可接受的盐在制备用于治疗携带SARS-CoV-2病毒的患者的药物中的应用。
PCT/CN2023/077984 2022-02-25 2023-02-23 苯并噻唑类化合物、其制备方法及应用 WO2023160634A1 (zh)

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