WO2024040497A1 - Antiviral compound, preparation method therefor and use thereof - Google Patents

Antiviral compound, preparation method therefor and use thereof Download PDF

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WO2024040497A1
WO2024040497A1 PCT/CN2022/114690 CN2022114690W WO2024040497A1 WO 2024040497 A1 WO2024040497 A1 WO 2024040497A1 CN 2022114690 W CN2022114690 W CN 2022114690W WO 2024040497 A1 WO2024040497 A1 WO 2024040497A1
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compound
alkyl
independently selected
quinolyl
quinazolinyl
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PCT/CN2022/114690
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French (fr)
Chinese (zh)
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何伟
刘磊
李彬
徐立谦
李昊翔
郑济青
宛世璋
吴彩
王天
王玫景
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清华大学
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Priority to PCT/CN2022/114690 priority Critical patent/WO2024040497A1/en
Publication of WO2024040497A1 publication Critical patent/WO2024040497A1/en

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms

Definitions

  • the present invention relates to the technical field of medicinal chemistry, specifically to an antiviral compound and its preparation method and application, in particular to an anti-coronavirus compound that can be used as a PLPro inhibitor and its preparation method and application.
  • viruses Many important infectious diseases that humans suffer from are caused by viruses. These diseases include rabies, smallpox, polio, hepatitis, pneumonia, yellow fever, immunodeficiency, and various encephalitogenic diseases, many of which are highly contagious and cause acute discomfort and are often fatal. Viruses such as rubella and cytomegalovirus can cause congenital malformations. Coronaviruses are a large family of viruses with the largest genome among currently known positive-strand RNA viruses. Coronaviruses can be divided into four categories based on differences in host, serotype gene sequence and structure: alpha, beta, gamma and delta.
  • the ⁇ coronavirus includes human coronavirus (HCoV-229E, HCoV-NL63), long-winged bat coronavirus (HKU1, HKU8), canine coronavirus (CCoV), feline coronavirus (FCoV), etc.
  • beta coronaviruses include human coronavirus (HCoV-OC43, HCoV-HKU1), novel coronavirus (SARS-CoV-2), SARS coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), murine coronavirus, fruit bat coronavirus HKU9, etc.
  • gamma coronaviruses mainly include avian coronaviruses such as infectious bronchitis virus (IBV) ), Turkish coronavirus (TCoV), etc.
  • delta coronaviruses include nighting
  • Coronavirus mainly damages the respiratory tract, gastrointestinal tract and nervous system, often causing respiratory and intestinal diseases, neurological symptoms and myocarditis.
  • severe upper respiratory tract disease SARS
  • Novel coronavirus SARS-CoV-2
  • COVID-19 novel coronavirus pneumonia
  • COVID-19 novel coronavirus pneumonia
  • Papain-like protease is a hydrolase expressed on nsp3 at the 5' end of the coronavirus genome. Its main function is to cleave polyprotein pp1a specifically between nsp1-2, nsp2-3, and nsp3-4.
  • the sexual tetrapeptide structure LXGG this polyprotein needs to be hydrolyzed to become a mature functional protein, so it is a key protein for the proliferation of coronavirus.
  • PLpro can cleave the ubiquitin unit of the host cell's key immune protein, thereby protecting the coronavirus Viruses evade immune attack by host cells.
  • the PLPro protein that inhibits coronavirus can not only inhibit the proliferation of coronavirus, but also enhance the host cell immune system's monitoring of coronavirus, thereby reducing cytokine storm.
  • PLPro is critical to the life cycle of the virus and can be used as a potential target for anti-coronavirus drug design and screening.
  • PLpro inhibitors with different chemical structures have been developed, but the inhibitory activity still needs to be further improved.
  • the present invention provides a compound having the following structure:
  • Ar is selected from: naphthyl, quinolyl, isoquinolinyl or quinazolinyl, wherein the hydrogen atom in the naphthyl, quinolyl, isoquinolinyl or quinazolinyl may optionally be replaced by C 1 - C 6 alkyl, -NH 2 , -OH, -OC 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -CX 3 substitution;
  • L 1 is selected from: C 1 -C 6 alkylene, -CO-, -SO 2 -;
  • a 1 , A 2 , A 3 , A 4 and A 5 are independently selected from C or N, and when A 1 , A 2 , A 3 , A 4 or A 5 is an N atom, the R 1 , A 5 connected to it are R 2 , R 3 , R 4 or R 5 does not exist;
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from: H, C 1 -C 6 alkyl, -L 2 -NR 9 R 10 , -L 2 -OH, -L 2 -OC 1 -C6 alkyl, -CN, -X, -CH2X , -CHX2 , -CX3 ; or, two of R1 , R2 , R3 , R4 and R5 together with the atom to which they are connected Form heterocyclyl;
  • L 2 is selected from: single bond, C 1 -C 6 alkylene, -CO-, -SO 2 -, -NHCO-, -NH-SO 2 -;
  • R 9 and R 10 are independently selected from: H, C 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -SO 2 (C 1 -C 6 alkyl), -CX 3 , -L 3 - NR 11 R 12 , nitrogen-containing heterocyclic group;
  • L 3 is selected from: C 1 -C 6 alkylene, -CO-, -SO 2 -, -NHCO-, -NH-SO 2 -, phenylene,
  • R 11 and R 12 are independently selected from: H, C 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -SO 2 (C 1 -C 6 alkyl), -CX 3 , -CO(C 1 -C 6 alkyl);
  • X is selected from: F, Cl, Br, I;
  • R 6 is selected from: H, C 1 -C 6 alkyl
  • W 1 and W 2 are independently selected from: C, N, O; and when W 1 or W 2 is O, the corresponding R 7 or R 8 does not exist;
  • the above-mentioned naphthyl group may be 1-naphthyl or 2-naphthyl.
  • the above-mentioned quinolyl group may be 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl. .
  • the above-mentioned isoquinolyl group can be 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl base or 8-isoquinolyl.
  • the above-mentioned quinoxalinyl group may be 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl or 8-quinazoline base.
  • Ar is naphthyl, such as 1-naphthyl or 2-naphthyl, especially 1-naphthyl.
  • R 6 is selected from: H, -CH 3 , -CH 2 CH 3 ; in one embodiment of the invention, R 6 is H.
  • W 1 is C, and W 2 is C; or, W 1 is C, and W 2 is N; or, W 1 is C, and W 2 is O.
  • the above-mentioned compound may have the following structure:
  • the number of N atoms in A 1 , A 2 , A 3 , A 4 and A 5 is 0-2 (for example, 0, 1, 2).
  • a 1 , A 2 , A 3 , A 4 and A 5 are all C.
  • a 1 is N and A 2 , A 3 , A 4 and A 5 are C.
  • a 2 is N and A 1 , A 3 , A 4 and A 5 are C.
  • a 3 is N and A 1 , A 2 , A 4 and A 5 are C.
  • a 4 is N and A 1 , A 2 , A 3 and A 5 are C.
  • a 5 is N and A 1 , A 2 , A 3 and A 4 are C.
  • a 1 and A 2 are N, and A 3 , A 4 and A 5 are C.
  • a 1 and A 3 are N, and A 2 , A 4 and A 5 are C.
  • a 1 and A 4 are N, and A 2 , A 3 and A 5 are C.
  • a 1 and A 5 are N, and A 2 , A 3 and A 4 are C.
  • a 2 and A 3 are N, and A 1 , A 4 and A 5 are C.
  • a 2 and A 4 are N, and A 1 , A 3 and A 5 are C.
  • a 2 and A 5 are N, and A 1 , A 3 and A 4 are C.
  • a 3 and A 4 are N, and A 1 , A 2 and A 5 are C.
  • a 3 and A 5 are N, and A 1 , A 2 and A 4 are C.
  • a 4 and A 5 are N and A 1 , A 2 and A 3 are C.
  • the above-mentioned compound may have the following structure:
  • L 1 is -CO- or -SO 2 -.
  • L 2 is selected from: single bond, -CH 2 -, -SO 2 -, -NHCO-, -NH-SO 2 -.
  • R 9 and R 10 are independently selected from H, -CH 3 , -CH 2 CH 3 , -C(CH 3 ) 3 , -SO 2 CH 3 , -L 3 -NR 9 R 10 , three to five Saturated nitrogen-containing heterocyclyl (e.g. Among them, R 13 is selected from: H, C 1 -C 6 alkyl).
  • L 3 is selected from: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CO-, -SO 2 -,
  • R 11 and R 12 are independently selected from: H, -CH 3 , -CH 2 CH 3 , -COCH 3 , -COCH 2 CH 3 .
  • At least one of R 1 , R 2 , R 3 , R 4 and R 5 is -L 2 -NR 7 R 8 .
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from: H, -CH 3 , -OCH 3 , -CF 3 , -L 2 -NR 7 R 8 ;More specifically, -L 2 -NR 7 R 8 is selected from:
  • two adjacent ones of R 1 , R 2 , R 3 , R 4 and R 5 together with the atoms connected in the middle form a heterocyclic group, such as a five- to seven-membered heteroaryl group (e.g. Five- or six-membered nitrogen-containing heteroaryl), which is the same as Rings form fused rings.
  • a heterocyclic group such as a five- to seven-membered heteroaryl group (e.g. Five- or six-membered nitrogen-containing heteroaryl), which is the same as Rings form fused rings.
  • the heteroaryl group is Parts can be e.g. Wherein R 1 , R 2 and R 5 have the above corresponding definitions of the present invention.
  • the above compound has the following structure: Among them, R 1 , R 3 and R 4 have the above corresponding definitions of the present invention, and at least one of R 1 , R 3 and R 4 is -L 2 -NR 7 R 8 .
  • R 1 is selected from: H, C 1 -C 6 alkyl, -CF 3 , R 3 and R 4 are independently -L 2 -NR 7 R 8 ; more specifically, in formula III , R 1 is selected from: H, -CH 3 , -CF 3 , R 3 and R 4 are independently selected from: in particular
  • the above compound has the following structure: Where, R 2 is -L 2 -NR 7 R 8 .
  • R 2 is selected from: in particular
  • the above compound has the following structure: Among them, R 2 and R 5 have the corresponding definitions mentioned above in the present invention, and at least one of R 2 and R 5 is -L 2 -NR 7 R 8 .
  • R 5 is selected from: H, C 1 -C 6 alkyl, -CF 3 , R 2 is -L 2 -NR 7 R 8 ; more specifically, in Formula V, R 5 is selected from :H, -CH 3 , -CF 3 , R 2 is selected from: in particular
  • the above compounds have the following structures:
  • the present invention also provides pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the above compounds.
  • the present invention also provides a method for the above compound, which may include the following process route:
  • the ethyl Grignard reagent in the above step (1) can be ethylmagnesium bromide.
  • step (1) reaction is carried out in an organic solvent (such as tetrahydrofuran).
  • organic solvent such as tetrahydrofuran
  • reaction temperature in step (1) above is room temperature.
  • the present invention also provides a pharmaceutical composition, which contains the above-mentioned compound of the present invention or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and one or more pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds. Acceptable excipients.
  • the above-mentioned compound of the present invention can be used as the only active ingredient, or can be used in combination with one or more other active ingredients for the same indication or different indications, wherein the above-mentioned compound of the present invention It may be formulated with the other active ingredients for simultaneous, separate or sequential administration.
  • the above-mentioned pharmaceutically acceptable excipients may include sweeteners (specifically, such as sucrose, xylitol, fructooligosaccharides, cyclamate, stevia, aspartame, etc.), aromatics (such as spices, essences, etc.) ), glue agents (specifically such as sodium alginate, gum arabic, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), clarifiers (specifically such as chitosan, gelatin, etc.), preservatives (specifically For example, benzoic acid and its salts, sorbic acid and its salts, paraben series, etc.), disintegrants (specifically, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch carboxyacetate, cross-linked carboxylic acid Sodium methylcellulose, starch, etc.), binders (specifically such as hydroxypropylcellulose, hypromellose, povidone, copovidone, pregelatin
  • suspending agent specifically such as hypromellose, hydroxypropylcellulose, povidone, copovidone, sodium carboxymethylcellulose, methylcellulose, etc.
  • stabilizer specifically such as citric acid , fumaric acid, succinic acid, etc.
  • fillers specifically such as starch, sucrose, lactose, microcrystalline cellulose, etc.
  • binders specifically such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone etc.
  • the above-mentioned pharmaceutical composition can adopt any dosage form or administration form, and those skilled in the art can choose according to the situation, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets) , orally disintegrating tablets, oral tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled release preparations ( For example, instant release preparations, sustained release preparations, sustained release microcapsules), aerosols, films (e.g., orally disintegrating films, oral muco-adhesive film preparations), injections (e.g., subcutaneous injections, intravenous injections, intramuscular injection, intraperitoneal injection), intravenous drip, transdermal absorption preparation, ointment, lotion, adhesive preparation, suppository (for example, rectal suppository, vaginal suppository), small pill, nasal preparation, pulmonary phosphat
  • the present invention also provides the above-mentioned compounds and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the application of the above-mentioned pharmaceutical compositions as PLpro inhibitors, for example, as antiviral drugs. .
  • the present invention also provides the above-mentioned compounds and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds.
  • the above-mentioned pharmaceutical compositions can be prepared to prevent and/or treat viral infections or viral infections. Use of medicines related to diseases or conditions.
  • the compounds and pharmaceutical compositions have the above-mentioned corresponding definitions of the present invention.
  • the above-mentioned virus is a coronavirus, such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2, etc., especially SARS-CoV, MERS-CoV, SARS-CoV-2.
  • a coronavirus such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2, etc., especially SARS-CoV, MERS-CoV, SARS-CoV-2.
  • the above-mentioned diseases or illnesses are those caused by or related to coronavirus infection, such as COVID-19, SARS, MERS, etc.
  • the present invention also provides a method for preventing and/or treating diseases or conditions caused by viral infection or related to viral infection, which includes administering to a subject an effective amount of the above-mentioned compound of the present invention or a pharmaceutically acceptable salt or stereotaxic acid thereof.
  • the compound, pharmaceutical composition, disease or condition has the above corresponding definitions of the present invention.
  • the above-mentioned diseases or illnesses are those caused by or related to coronavirus infection, such as COVID-19, SARS, MERS, etc.
  • the above-mentioned subject is an animal; in one embodiment of the present invention, the above-mentioned subject is a mammal, such as a human, a monkey, a cat, a dog, a rat, a bat, etc.; in another embodiment of the present invention , the subjects mentioned above are birds.
  • the present invention provides a compound with a novel structure, which can be used as a PLPro inhibitor with high activity and can be used for broad-spectrum antivirus, especially coronaviruses (such as SARS-CoV, MERS-CoV, SARS-CoV-2), in The pharmaceutical field has very good application prospects and value.
  • coronaviruses such as SARS-CoV, MERS-CoV, SARS-CoV-2
  • Figure 1 shows the inhibition rate curve of the compound prepared in Example 2.
  • Figure 2 shows the inhibition rate curve of the compound prepared in Example 35.
  • Figure 3 shows the inhibition rate curve of the positive control compound GRL0617.
  • alkyl refers to a straight or branched hydrocarbon chain free radical that does not contain unsaturated bonds and is connected to other parts of the molecule by a single bond.
  • Typical alkyl groups contain 1 to 12 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc.
  • the corresponding "cycloalkylalkyl" free radical such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. .
  • the corresponding radical is an "aralkyl” radical such as benzyl, benzyl, or phenethyl.
  • the corresponding radical is a "heterocyclylalkyl" radical.
  • Alkylene usually refers to an alkanediyl group with two free valence bonds. Typical alkylene groups contain 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene, ethylene, propylene, butylene, etc.
  • alkoxy refers to a substituent formed by replacing the hydrogen in the hydroxyl group with an alkyl group.
  • Typical alkoxy groups contain 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.
  • cycloalkyl refers to a saturated or partially saturated (especially saturated) monocyclic or polycyclic group, which may contain 1 to 4 monocyclic and/or fused rings and 3 to 18 carbon atoms, Preferred are 3-10 (eg 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.
  • aryl refers to monocyclic or polycyclic radicals, including polycyclic radicals containing a monoaryl group and/or a fused aryl group, such as 1-3 monocyclic or fused rings and 6- 18 (such as 6, 8, 10, 12, 14, 16, 18) carbon ring atoms.
  • Typical aryl groups are aryl groups containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, Indenyl et al.
  • “Arylene” refers to a divalent group derived from an aromatic hydrocarbon by removal of two hydrogen atoms.
  • heterocyclyl includes heteroaromatic and heteroalicyclic groups containing from 1 to 3 monocyclic and/or fused rings and from 3 to about 18 ring atoms.
  • Preferred heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms.
  • Suitable heteroaryl groups in the compounds of the invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms.
  • heteroaryl groups include, but are not limited to, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, Pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazole base, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazinyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzo Furyl, benzofurazine, benzothienyl, benzothiazolyl,
  • Suitable heteroalicyclic groups in the compounds of the invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms.
  • heteroalicyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, Oxithiranyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, thietanyl, Azepinyl, oxazepanyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, Indolinyl, 2H-pyranyl, 4H-pyranyl, dio
  • Halogen means bromine, chlorine, iodine or fluorine.
  • Haloalkyl refers to a group in which the hydrogen atom on the alkyl group is replaced by a halogen atom (F, Cl, Br, I), such as -CH 2 Rh, -CHRh 2 , -CRh 3 , where Rh is F, Cl, Br or I; such as -CF 3 .
  • pharmaceutically acceptable salt refers to a salt that is theoretically non-toxic, irritating and allergic, and can achieve or provide clinically acceptable pharmacokinetic properties, absorption, distribution and metabolism properties of the drug molecule, which can achieve Acidic or basic salts for the intended purpose.
  • the salts described in the present invention include pharmaceutically acceptable acidic salts or basic salts of the acidic group, basic group or amphoteric group of the compound. A list of suitable salts can be found in S. M. Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).
  • the pharmaceutically acceptable salts described in the present invention include acid addition salts and base addition salts.
  • the acid addition salts include, but are not limited to, salts from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid and phosphonic acid, and from organic acids such as aliphatic monocarboxylic and dicarboxylic acids. , phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and salts of aliphatic and aromatic sulfonic acids.
  • these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates Salt, hydrochloride, hydrobromide, iodate, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate , Sebacate, fumarate, maleate, amygdalate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalic acid salts, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate and methanesulfonate, and also include salts of amino acids such as arginine salts, Gluconate, galacturonate,
  • Base addition salts refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines.
  • metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium.
  • suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N- Methylglucosamine and procaine.
  • Base addition salts may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid isolated in a conventional manner.
  • solvate is understood to mean any form of a compound according to the invention in which said compound is linked by a non-covalent bond to another molecule (usually a polar solvent), including in particular hydrates and alcoholates, e.g. Methanolates. Preferred solvates are hydrates.
  • prodrug is used in its broadest sense and encompasses derivatives which are converted in vivo to the compounds of the invention.
  • examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable Carbonate esters, biohydrolyzable ureeas, and biohydrolyzable phosphate ester analogs.
  • the prodrug having a carboxyl functional group is a lower alkyl ester of a carboxylic acid.
  • the carboxylic acid esters are readily esterified from any carboxylic acid moiety present in the molecule.
  • Prodrugs can generally be prepared by known methods, as described in Burger “Medicinal Chemistry and Drug Discovery, 6th Edition (Donald J.Abraham ed., 2001, Wiley) and “Design and Applications of Prodrugs” (H.Bundgaard ed., 1985, the method described in Harwood Academic Publishers).
  • any reference to a compound herein is intended to represent such specific compound or some variation or form thereof.
  • the compounds referred to here may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms.
  • any given compound referred to herein represents any one of the racemates, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof.
  • stereoisomers or geometric isomers of double bonds may also exist, whereby in some cases the molecule may exist as the (E)-isomer or the (Z)-isomer (trans and cis isomer).
  • each double bond will have its own stereoisomerism, which may or may not be the same as the stereoisomerism of the other double bonds of the molecule.
  • the compounds referred to herein may exist as atrop isomers. All stereoisomers of the compounds contemplated herein, including enantiomers, diastereoisomers, geometric isomers and atroisomers, and mixtures thereof, are within the scope of the present invention.
  • the specific operation is: place compound 2 (1.0mmol, 1.0e.q.) in a round-bottomed flask, add 10mL THF as solvent, add triethylamine (4.0e.q.), and drop compound 3 (1.0mmol, 1.0e.q.) at 0°C. THF solution, remove the ice bath after the dropwise addition, and stir the reaction at 50°C for 12 hours. After the reaction is completed, spin the solvent to dryness, add ethyl acetate and water to extract, wash once with saturated ammonium chloride solution and once with saturated brine, spin the organic phase to dryness, and purify by silica gel column chromatography to obtain the product THU124.
  • R 1 is one or more independent substituents on the ring, and R 1 , Y 1 , Y 2 , Y 3 and Y 4 are selected according to the specific compound structure.
  • intermediate M1 is Its synthesis route is as follows:
  • R 2 H, -CH 3 , -SO 2 CH 3 or -CH 2 CH 2 N(CH 3 ) 2 ;
  • R 3 -CH 3 , -CONH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 ,
  • the specific operation is: combine 2-methyl-5-bromobenzoic acid methyl ester (5, 10.0mmol, 1.0e.q.), amine compounds (6, 10.0mmol, 1.0e.q.), tris(dibenzylideneacetone) dipalladium (0.2mmol, 0.02e.q.), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.8mmol, 0.08e.q.), and cesium carbonate (20.0mmol, 2.0e.q.) were placed in a sealed tube and added 50 mL of toluene was used as the solvent, and the reaction was continued with stirring at 110°C for 24 hours under argon protection.
  • Reaction buffer 20mM HEPEs, pH 7.5, 100mM NaCl, 1mM TCEP
  • test compound test compound dry powder is dissolved in DMSO to 40mM; diluted to 400 ⁇ M with 50% DMSO; then diluted to 40 ⁇ M with reaction buffer);
  • GRL0617 is a positive reference and is a representative of the class of molecules with the strongest inhibitory activity against PLpro reported in the literature (Ghosh et al., 2009; Ghosh et al., 2010; Ratia et al., 2008).

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Abstract

An antiviral compound, a preparation method therefor and an use thereof; specifically an anti-coronavirus compound that can be used as a PLPro inhibitor, a preparation method therefor and a use thereof. The compound has a structure represented by general formula I. It has high inhibitory activity, can be used as a broad-spectrum antiviral, especially for coronaviruses (such as SARS-CoV, MERS-CoV and SARS-CoV-2), and has very good potential application prospects in the pharmaceutical field.

Description

一种抗病毒化合物及其制备方法和应用An antiviral compound and its preparation method and application 技术领域Technical field
本发明涉及药物化学技术领域，具体涉及一种抗病毒化合物及其制备方法和应用，特别是一种可作为PLPro抑制剂的抗冠状病毒化合物及其制备方法和应用。The present invention relates to the technical field of medicinal chemistry, specifically to an antiviral compound and its preparation method and application, in particular to an anti-coronavirus compound that can be used as a PLPro inhibitor and its preparation method and application.
背景技术Background technique
人类患有的许多重要传染病都是由病毒造成的。这些疾病包括狂犬病、天花、脊髓灰质炎、肝炎、肺炎、黄热病、免疫缺陷和各种脑炎病，它们中的许多是高度传染性的且会产生急性不适，且常常是致命的，其它的例如风疹和巨细胞病毒会造成先天畸形。冠状病毒是一个大型病毒家族，在目前已知的正链RNA病毒中基因组是最大的。根据宿主、血清型基因序列以及结构的不同可将冠状病毒分为四类：α类、β类、γ类和δ类。在这四类中，α类、β类只会感染哺乳动物，γ类和δ类主要感染鸟类；α属冠状病毒包括人冠状病毒(HCoV-229E、HCoV-NL63)、长翼蝠冠状病毒(HKU1、HKU8)、犬冠状病毒(CCoV)和猫冠状病毒(FCoV)等；β属冠状病毒包括人冠状病毒(HCoV-OC43、HCoV-HKU1)、新型冠状病毒(SARS-CoV-2)、SARS冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)、鼠冠状病毒、果蝠冠状病毒HKU9等；γ类冠状病毒主要包括禽冠状病毒如鸡传染性支气管炎病毒(IBV)、土耳其冠状病毒(TCoV)等；δ属冠状病毒包括夜莺冠状病毒(BuCoV HKU11)、绣眼鸟冠状病毒(WECoV)、野鸭冠状病毒(WiCoV)、黑水鸡冠状病毒(CMCoV)等。Many important infectious diseases that humans suffer from are caused by viruses. These diseases include rabies, smallpox, polio, hepatitis, pneumonia, yellow fever, immunodeficiency, and various encephalitogenic diseases, many of which are highly contagious and cause acute discomfort and are often fatal. Viruses such as rubella and cytomegalovirus can cause congenital malformations. Coronaviruses are a large family of viruses with the largest genome among currently known positive-strand RNA viruses. Coronaviruses can be divided into four categories based on differences in host, serotype gene sequence and structure: alpha, beta, gamma and delta. Among these four categories, the α and β categories only infect mammals, and the γ and δ categories mainly infect birds; the α coronavirus includes human coronavirus (HCoV-229E, HCoV-NL63), long-winged bat coronavirus (HKU1, HKU8), canine coronavirus (CCoV), feline coronavirus (FCoV), etc.; beta coronaviruses include human coronavirus (HCoV-OC43, HCoV-HKU1), novel coronavirus (SARS-CoV-2), SARS coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), murine coronavirus, fruit bat coronavirus HKU9, etc.; gamma coronaviruses mainly include avian coronaviruses such as infectious bronchitis virus (IBV) ), Turkish coronavirus (TCoV), etc.; delta coronaviruses include nightingale coronavirus (BuCoV HKU11), white-eye coronavirus (WECoV), wild duck coronavirus (WiCoV), black water chicken coronavirus (CMCoV), etc.
冠状病毒主要侵害呼吸道、胃肠道和神经系统等，往往会造成呼吸道和肠道疾病、神经系统症状和心肌炎。2003年，严重的上呼吸道疾病(SARS)暴发。新型冠状病毒(SARS-CoV-2)是一种以前从未在人类中发现的冠状病毒新毒株，这种新毒株引起了新型冠状病毒肺炎(COVID-19)，有比2003年SARS病毒有更强的感染能力。自从疫情爆发以来至今，全球累计感染人数已经超过三千万，死亡人数多达上百万。这些疾病的感染严重影响了人们的健康。冠状病毒的反复发作，提示人类对于其研究知之甚少，开发治疗冠状病毒的药物迫在眉睫。Coronavirus mainly damages the respiratory tract, gastrointestinal tract and nervous system, often causing respiratory and intestinal diseases, neurological symptoms and myocarditis. In 2003, severe upper respiratory tract disease (SARS) broke out. Novel coronavirus (SARS-CoV-2) is a new strain of coronavirus that has never been found in humans before. This new strain causes novel coronavirus pneumonia (COVID-19), which is more severe than the 2003 SARS virus. Have a stronger ability to infect. Since the outbreak of the epidemic, the cumulative number of infections worldwide has exceeded 30 million, and the number of deaths has exceeded one million. Infections from these diseases seriously affect people's health. The repeated outbreaks of coronavirus suggest that humans know very little about its research, and it is urgent to develop drugs to treat coronavirus.
木瓜样蛋白酶(papain-like protease，PLPro)是表达在冠状病毒5’末端基因组nsp3上的水解酶，主要功能为酶切多聚蛋白pp1a上nsp1-2，nsp2-3，nsp3-4之间特异性四肽结构LXGG，该多聚蛋白需要被水解后成为成熟的功能蛋白，因此是冠状病毒增殖的关键蛋白，同样重要的是，PLpro可以切割宿主细胞关键免疫蛋白的泛素单元，从而保护冠状病毒规避宿主细胞的免疫攻击。因此，抑制冠状病毒的PLPro蛋白不但能够抑制冠状病毒的增殖，也能增强宿主细胞免疫系统对于冠状病毒的监控，从而减少细胞因子风暴。PLPro对于病毒的生命周期至关重要，可以作为抗冠状病毒药物设计筛选的潜在靶点。已经开发了不同化学结构的PLpro抑制剂，但抑制活性仍有待进一步提高。Papain-like protease (PLPro) is a hydrolase expressed on nsp3 at the 5' end of the coronavirus genome. Its main function is to cleave polyprotein pp1a specifically between nsp1-2, nsp2-3, and nsp3-4. The sexual tetrapeptide structure LXGG, this polyprotein needs to be hydrolyzed to become a mature functional protein, so it is a key protein for the proliferation of coronavirus. Equally important, PLpro can cleave the ubiquitin unit of the host cell's key immune protein, thereby protecting the coronavirus Viruses evade immune attack by host cells. Therefore, the PLPro protein that inhibits coronavirus can not only inhibit the proliferation of coronavirus, but also enhance the host cell immune system's monitoring of coronavirus, thereby reducing cytokine storm. PLPro is critical to the life cycle of the virus and can be used as a potential target for anti-coronavirus drug design and screening. PLpro inhibitors with different chemical structures have been developed, but the inhibitory activity still needs to be further improved.
发明内容Contents of the invention
本发明提供一种化合物，其具有以下结构：The present invention provides a compound having the following structure:
Figure PCTCN2022114690-appb-000001
Figure PCTCN2022114690-appb-000001
其中，in,
Ar选自：萘基、喹啉基、异喹啉基或喹唑啉基，其中萘基、喹啉基、异喹啉基或喹唑啉基中的氢原子可以任选地被C 1-C 6烷基、-NH 2、-OH、-OC 1-C 6烷基、-CH 2X、-CHX 2、-CX 3取代； Ar is selected from: naphthyl, quinolyl, isoquinolinyl or quinazolinyl, wherein the hydrogen atom in the naphthyl, quinolyl, isoquinolinyl or quinazolinyl may optionally be replaced by C 1 - C 6 alkyl, -NH 2 , -OH, -OC 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -CX 3 substitution;
L 1选自：C 1-C 6亚烷基、-CO-、-SO 2-； L 1 is selected from: C 1 -C 6 alkylene, -CO-, -SO 2 -;
A 1、A 2、A 3、A 4和A 5独立地选自C或N，且当A 1、A 2、A 3、A 4或A 5为N原子时，与之相连的R 1、R 2、R 3、R 4或R 5不存在； A 1 , A 2 , A 3 , A 4 and A 5 are independently selected from C or N, and when A 1 , A 2 , A 3 , A 4 or A 5 is an N atom, the R 1 , A 5 connected to it are R 2 , R 3 , R 4 or R 5 does not exist;
R 1、R 2、R 3、R 4和R 5独立地选自：H、C 1-C 6烷基、-L 2-NR 9R 10、-L 2-OH、-L 2-OC 1-C 6烷基、-CN、-X、-CH 2X、-CHX 2、-CX 3；或者，R 1、R 2、R 3、R 4和R 5中的两者与其连接的原子一起形成杂环基； R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from: H, C 1 -C 6 alkyl, -L 2 -NR 9 R 10 , -L 2 -OH, -L 2 -OC 1 -C6 alkyl, -CN, -X, -CH2X , -CHX2 , -CX3 ; or, two of R1 , R2 , R3 , R4 and R5 together with the atom to which they are connected Form heterocyclyl;
L 2选自：单键、C 1-C 6亚烷基、-CO-、-SO 2-、-NHCO-、-NH-SO 2-； L 2 is selected from: single bond, C 1 -C 6 alkylene, -CO-, -SO 2 -, -NHCO-, -NH-SO 2 -;
R 9和R 10独立地选自：H、C 1-C 6烷基、-CH 2X、-CHX 2、-SO 2(C 1-C 6烷基)、-CX 3、-L 3-NR 11R 12、含氮杂环基； R 9 and R 10 are independently selected from: H, C 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -SO 2 (C 1 -C 6 alkyl), -CX 3 , -L 3 - NR 11 R 12 , nitrogen-containing heterocyclic group;
L 3选自：C 1-C 6亚烷基、-CO-、-SO 2-、-NHCO-、-NH-SO 2-、亚苯基、
Figure PCTCN2022114690-appb-000002
L 3 is selected from: C 1 -C 6 alkylene, -CO-, -SO 2 -, -NHCO-, -NH-SO 2 -, phenylene,
Figure PCTCN2022114690-appb-000002
R 11和R 12独立地选自：H、C 1-C 6烷基、-CH 2X、-CHX 2、-SO 2(C 1-C 6烷基)、-CX 3、-CO(C 1-C 6烷基)； R 11 and R 12 are independently selected from: H, C 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -SO 2 (C 1 -C 6 alkyl), -CX 3 , -CO(C 1 -C 6 alkyl);
X选自：F、Cl、Br、I；X is selected from: F, Cl, Br, I;
R 6选自：H、C 1-C 6烷基； R 6 is selected from: H, C 1 -C 6 alkyl;
W 1和W 2独立地选自：C、N、O；且当W 1或W 2为O时，相应的R 7或R 8不存在； W 1 and W 2 are independently selected from: C, N, O; and when W 1 or W 2 is O, the corresponding R 7 or R 8 does not exist;
R 7和R 8独立地选自：H、(＝O)、C 1-C 6烷基、-X、-CH 2X、-CHX 2、-CX 3、羟基、-OC 1-C 6烷基。 R 7 and R 8 are independently selected from: H, (=O), C 1 -C 6 alkyl, -X, -CH 2 X, -CHX 2 , -CX 3 , hydroxyl, -OC 1 -C 6 alkyl base.
在本发明的实施例中，上述化合物中
Figure PCTCN2022114690-appb-000003
为
Figure PCTCN2022114690-appb-000004
In embodiments of the present invention, among the above compounds
Figure PCTCN2022114690-appb-000003
for
Figure PCTCN2022114690-appb-000004
具体地，上述萘基可以为1-萘基或2-萘基。Specifically, the above-mentioned naphthyl group may be 1-naphthyl or 2-naphthyl.
具体地，上述喹啉基可以为2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基或8-喹啉基。Specifically, the above-mentioned quinolyl group may be 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl. .
具体地，上述异喹啉基可以为1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基或8-异喹啉基。Specifically, the above-mentioned isoquinolyl group can be 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl base or 8-isoquinolyl.
具体地，上述喹喔啉基可以为2-喹唑啉基、4-喹唑啉基、5-喹唑啉基、6-喹唑啉基、7-喹唑啉基或8-喹唑啉基。Specifically, the above-mentioned quinoxalinyl group may be 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl or 8-quinazoline base.
在本发明的一个实施方式中，上式Ⅰ中，Ar为萘基，例如1-萘基或2-萘基，特别是1-萘基。In one embodiment of the present invention, in the above formula I, Ar is naphthyl, such as 1-naphthyl or 2-naphthyl, especially 1-naphthyl.
具体地，R 6选自：H、-CH 3、-CH 2CH 3；在本发明的一个实施例中，R 6为H。 Specifically, R 6 is selected from: H, -CH 3 , -CH 2 CH 3 ; in one embodiment of the invention, R 6 is H.
具体地，W 1为C，W 2为C；或，W 1为C，W 2为N；或，W 1为C，W 2为O。 Specifically, W 1 is C, and W 2 is C; or, W 1 is C, and W 2 is N; or, W 1 is C, and W 2 is O.
具体地，R 7和R 8独立地选自：H、(＝O)、C1-3烷基、-CF 3、羟基；在本发明的一个实施例中，R 7和R 8均为H。 Specifically, R 7 and R 8 are independently selected from: H, (=O), C1-3 alkyl, -CF 3 , hydroxyl; in one embodiment of the invention, R 7 and R 8 are both H.
具体地，上述化合物可以具有如下结构：Specifically, the above-mentioned compound may have the following structure:
Figure PCTCN2022114690-appb-000005
Figure PCTCN2022114690-appb-000005
具体地，上式Ⅰ中，A 1、A 2、A 3、A 4和A 5中N原子数为0-2(例如0、1、2)个。 Specifically, in the above formula I, the number of N atoms in A 1 , A 2 , A 3 , A 4 and A 5 is 0-2 (for example, 0, 1, 2).
在本发明的一个实施方式中，A 1、A 2、A 3、A 4和A 5均为C。 In one embodiment of the invention, A 1 , A 2 , A 3 , A 4 and A 5 are all C.
在本发明另一个实施方式中，A 1为N，A 2、A 3、A 4和A 5为C。 In another embodiment of the invention, A 1 is N and A 2 , A 3 , A 4 and A 5 are C.
在本发明另一个实施方式中，A 2为N，A 1、A 3、A 4和A 5为C。 In another embodiment of the invention, A 2 is N and A 1 , A 3 , A 4 and A 5 are C.
在本发明另一个实施方式中，A 3为N，A 1、A 2、A 4和A 5为C。 In another embodiment of the invention, A 3 is N and A 1 , A 2 , A 4 and A 5 are C.
在本发明另一个实施方式中，A 4为N，A 1、A 2、A 3和A 5为C。 In another embodiment of the invention, A 4 is N and A 1 , A 2 , A 3 and A 5 are C.
在本发明另一个实施方式中，A 5为N，A 1、A 2、A 3和A 4为C。 In another embodiment of the invention, A 5 is N and A 1 , A 2 , A 3 and A 4 are C.
在本发明另一个实施方式中，A 1和A 2为N，A 3、A 4和A 5为C。 In another embodiment of the invention, A 1 and A 2 are N, and A 3 , A 4 and A 5 are C.
在本发明另一个实施方式中，A 1和A 3为N，A 2、A 4和A 5为C。 In another embodiment of the invention, A 1 and A 3 are N, and A 2 , A 4 and A 5 are C.
在本发明另一个实施方式中，A 1和A 4为N，A 2、A 3和A 5为C。 In another embodiment of the invention, A 1 and A 4 are N, and A 2 , A 3 and A 5 are C.
在本发明另一个实施方式中，A 1和A 5为N，A 2、A 3和A 4为C。 In another embodiment of the invention, A 1 and A 5 are N, and A 2 , A 3 and A 4 are C.
在本发明另一个实施方式中，A 2和A 3为N，A 1、A 4和A 5为C。 In another embodiment of the invention, A 2 and A 3 are N, and A 1 , A 4 and A 5 are C.
在本发明另一个实施方式中，A 2和A 4为N，A 1、A 3和A 5为C。 In another embodiment of the invention, A 2 and A 4 are N, and A 1 , A 3 and A 5 are C.
在本发明另一个实施方式中，A 2和A 5为N，A 1、A 3和A 4为C。 In another embodiment of the invention, A 2 and A 5 are N, and A 1 , A 3 and A 4 are C.
在本发明另一个实施方式中，A 3和A 4为N，A 1、A 2和A 5为C。 In another embodiment of the invention, A 3 and A 4 are N, and A 1 , A 2 and A 5 are C.
在本发明另一个实施方式中，A 3和A 5为N，A 1、A 2和A 4为C。 In another embodiment of the invention, A 3 and A 5 are N, and A 1 , A 2 and A 4 are C.
在本发明另一个实施方式中，A 4和A 5为N，A 1、A 2和A 3为C。 In another embodiment of the invention, A 4 and A 5 are N and A 1 , A 2 and A 3 are C.
具体地，上述化合物可以具有如下结构：Specifically, the above-mentioned compound may have the following structure:
Figure PCTCN2022114690-appb-000006
Figure PCTCN2022114690-appb-000006
在本发明的一个实施例中，L 1为-CO-或-SO 2-。 In one embodiment of the invention, L 1 is -CO- or -SO 2 -.
具体地，L 2选自：单键、-CH 2-、-SO 2-、-NHCO-、-NH-SO 2-。 Specifically, L 2 is selected from: single bond, -CH 2 -, -SO 2 -, -NHCO-, -NH-SO 2 -.
具体地，R 9和R 10独立地选自H、-CH 3、-CH 2CH 3、-C(CH 3) 3、-SO 2CH 3、-L 3-NR 9R 10、三至五元饱和含氮杂环基(例如
Figure PCTCN2022114690-appb-000007
其中，R 13选自：H、C 1-C 6烷基)。 Specifically, R 9 and R 10 are independently selected from H, -CH 3 , -CH 2 CH 3 , -C(CH 3 ) 3 , -SO 2 CH 3 , -L 3 -NR 9 R 10 , three to five Saturated nitrogen-containing heterocyclyl (e.g.
Figure PCTCN2022114690-appb-000007
Among them, R 13 is selected from: H, C 1 -C 6 alkyl).
具体地，L 3选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CO-、-SO 2-、
Figure PCTCN2022114690-appb-000008
Specifically, L 3 is selected from: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CO-, -SO 2 -,
Figure PCTCN2022114690-appb-000008
具体地，R 11和R 12独立地选自：H、-CH 3、-CH 2CH 3、-COCH 3、-COCH 2CH 3。 Specifically, R 11 and R 12 are independently selected from: H, -CH 3 , -CH 2 CH 3 , -COCH 3 , -COCH 2 CH 3 .
具体地，R 1、R 2、R 3、R 4和R 5中的至少一个为-L 2-NR 7R 8。 Specifically, at least one of R 1 , R 2 , R 3 , R 4 and R 5 is -L 2 -NR 7 R 8 .
在本发明的一个实施方式中，R 1、R 2、R 3、R 4和R 5独立地选自：H、-CH 3、-OCH 3、-CF 3、-L 2-NR 7R 8；更具体地，-L 2-NR 7R 8选自：
Figure PCTCN2022114690-appb-000009
In one embodiment of the invention, R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from: H, -CH 3 , -OCH 3 , -CF 3 , -L 2 -NR 7 R 8 ;More specifically, -L 2 -NR 7 R 8 is selected from:
Figure PCTCN2022114690-appb-000009
Figure PCTCN2022114690-appb-000010
Figure PCTCN2022114690-appb-000010
在本发明另一个实施方式中，R 1、R 2、R 3、R 4和R 5中相邻的两者与其中间连接的原子一起形成杂环基，例如五至七元杂芳基(例如五元或六元含氮杂芳基)，其与
Figure PCTCN2022114690-appb-000011
环形成稠合环。 In another embodiment of the present invention, two adjacent ones of R 1 , R 2 , R 3 , R 4 and R 5 together with the atoms connected in the middle form a heterocyclic group, such as a five- to seven-membered heteroaryl group (e.g. Five- or six-membered nitrogen-containing heteroaryl), which is the same as
Figure PCTCN2022114690-appb-000011
Rings form fused rings.
在本发明的一个实施例中，该杂芳基为
Figure PCTCN2022114690-appb-000012
部分可以为例如
Figure PCTCN2022114690-appb-000013
其中R 1、R 2和R 5具有本发明上述相应定义。 In one embodiment of the invention, the heteroaryl group is
Figure PCTCN2022114690-appb-000012
Parts can be e.g.
Figure PCTCN2022114690-appb-000013
Wherein R 1 , R 2 and R 5 have the above corresponding definitions of the present invention.
在本发明的一个实施方式中，上述化合物具有如下结构：
Figure PCTCN2022114690-appb-000014
其中，R 1、R 3、R 4具有本发明上述相应定义，且R 1、R 3、R 4中的至少一个为-L 2-NR 7R 8。 In one embodiment of the invention, the above compound has the following structure:
Figure PCTCN2022114690-appb-000014
Among them, R 1 , R 3 and R 4 have the above corresponding definitions of the present invention, and at least one of R 1 , R 3 and R 4 is -L 2 -NR 7 R 8 .
具体地，式Ⅲ中，R 1选自：H、C 1-C 6烷基、-CF 3，R 3、R 4独立地为-L 2-NR 7R 8；更具体地，式Ⅲ中，R 1选自：H、-CH 3、-CF 3，R 3、R 4独立地选自：
Figure PCTCN2022114690-appb-000015
Figure PCTCN2022114690-appb-000016
Figure PCTCN2022114690-appb-000017
Figure PCTCN2022114690-appb-000018
特别是
Figure PCTCN2022114690-appb-000019
Figure PCTCN2022114690-appb-000020
Specifically, in formula III, R 1 is selected from: H, C 1 -C 6 alkyl, -CF 3 , R 3 and R 4 are independently -L 2 -NR 7 R 8 ; more specifically, in formula III , R 1 is selected from: H, -CH 3 , -CF 3 , R 3 and R 4 are independently selected from:
Figure PCTCN2022114690-appb-000015
Figure PCTCN2022114690-appb-000016
Figure PCTCN2022114690-appb-000017
Figure PCTCN2022114690-appb-000018
in particular
Figure PCTCN2022114690-appb-000019
Figure PCTCN2022114690-appb-000020
在本发明另一个实施方式中，上述化合物具有如下结构：
Figure PCTCN2022114690-appb-000021
其中，R 2为-L 2-NR 7R 8。 In another embodiment of the invention, the above compound has the following structure:
Figure PCTCN2022114690-appb-000021
Where, R 2 is -L 2 -NR 7 R 8 .
具体地，式Ⅳ中，R 2选自：
Figure PCTCN2022114690-appb-000022
Figure PCTCN2022114690-appb-000023
Figure PCTCN2022114690-appb-000024
Figure PCTCN2022114690-appb-000025
特别是
Figure PCTCN2022114690-appb-000026
Specifically, in formula IV, R 2 is selected from:
Figure PCTCN2022114690-appb-000022
Figure PCTCN2022114690-appb-000023
Figure PCTCN2022114690-appb-000024
Figure PCTCN2022114690-appb-000025
in particular
Figure PCTCN2022114690-appb-000026
在本发明另一个实施方式中，上述化合物具有如下结构：
Figure PCTCN2022114690-appb-000027
其中，R 2、R 5具有本发明上述相应定义，且R 2、R 5中的至少一个为-L 2-NR 7R 8。 In another embodiment of the invention, the above compound has the following structure:
Figure PCTCN2022114690-appb-000027
Among them, R 2 and R 5 have the corresponding definitions mentioned above in the present invention, and at least one of R 2 and R 5 is -L 2 -NR 7 R 8 .
具体地，式Ⅴ中，R 5选自：H、C 1-C 6烷基、-CF 3，R 2为-L 2-NR 7R 8；更具体地，式Ⅴ中，R 5选自：H、-CH 3、-CF 3，R 2选自：
Figure PCTCN2022114690-appb-000028
Figure PCTCN2022114690-appb-000029
Figure PCTCN2022114690-appb-000030
特别是
Figure PCTCN2022114690-appb-000031
Specifically, in Formula V, R 5 is selected from: H, C 1 -C 6 alkyl, -CF 3 , R 2 is -L 2 -NR 7 R 8 ; more specifically, in Formula V, R 5 is selected from :H, -CH 3 , -CF 3 , R 2 is selected from:
Figure PCTCN2022114690-appb-000028
Figure PCTCN2022114690-appb-000029
Figure PCTCN2022114690-appb-000030
in particular
Figure PCTCN2022114690-appb-000031
在本发明的一些实施例中，上述化合物具有如下结构：In some embodiments of the invention, the above compounds have the following structures:
Figure PCTCN2022114690-appb-000032
Figure PCTCN2022114690-appb-000032
特别是in particular
Figure PCTCN2022114690-appb-000033
Figure PCTCN2022114690-appb-000033
本发明还提供上述化合物的药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物。The present invention also provides pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the above compounds.
本发明还提供一种上述化合物的方法，其可以包括如下工艺路线：The present invention also provides a method for the above compound, which may include the following process route:
Figure PCTCN2022114690-appb-000034
Figure PCTCN2022114690-appb-000034
具体地，上述步骤(1)中乙基格氏试剂可以为乙基溴化镁。Specifically, the ethyl Grignard reagent in the above step (1) can be ethylmagnesium bromide.
具体地，上述步骤(1)反应在有机溶剂(如四氢呋喃)中进行。Specifically, the above step (1) reaction is carried out in an organic solvent (such as tetrahydrofuran).
具体地，上述步骤(1)反应温度为室温。Specifically, the reaction temperature in step (1) above is room temperature.
本发明还提供一种药物组合物，其包含本发明上述化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物，以及一种或多种药学上可接受的辅料。The present invention also provides a pharmaceutical composition, which contains the above-mentioned compound of the present invention or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and one or more pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds. Acceptable excipients.
具体地，上述药物组合物中，本发明上述化合物可以作为唯一的活性成分，也可与一种或多种其它用于相同适应症或不同适应症的活性成分联用，其中，本发明上述化合物与该其他活性成分可配制用于同时、单独或顺序给药(simultaneous,separate or sequential administration)。Specifically, in the above-mentioned pharmaceutical composition, the above-mentioned compound of the present invention can be used as the only active ingredient, or can be used in combination with one or more other active ingredients for the same indication or different indications, wherein the above-mentioned compound of the present invention It may be formulated with the other active ingredients for simultaneous, separate or sequential administration.
具体地，上述药学上可接受的辅料可以包括甜味剂(具体如，蔗糖、木糖醇、低聚果糖、甜蜜素、甜菊糖、阿斯巴甜等)、芳香剂(如香料、香精等)、胶浆剂(具体如，海藻酸钠、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠等)、澄清剂(具体如，壳聚糖、明胶等)、防腐剂(具体如，苯甲酸及其盐、山梨酸及其盐、尼泊金类系列等)、崩解剂(具体如，低取代羟丙基纤维素、交聚维酮、羧基乙酸淀粉钠、交联羧甲基纤维素钠、淀粉等)、粘结剂(具体如，羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮、预胶凝淀粉等)、润滑剂(具体如，硬脂酸、硬脂酸镁、富马酰硬脂酸钠等)、润湿剂(具体如，聚氧乙烯山梨糖醇酐脂肪酸酯、泊洛沙姆、聚氧乙烯蓖麻油衍生物等)、悬浮剂(具体如，羟丙甲纤维素、羟丙基纤维素、聚维酮、共聚维酮、羧甲基纤维素钠、甲基纤维素等)、稳定剂(具体如，柠檬酸、富马酸、琥珀酸等)、填充剂(具体如，淀粉、蔗糖、乳糖、微晶纤维素等)、粘合剂(具体如，纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮等)等 中的一种或多种。Specifically, the above-mentioned pharmaceutically acceptable excipients may include sweeteners (specifically, such as sucrose, xylitol, fructooligosaccharides, cyclamate, stevia, aspartame, etc.), aromatics (such as spices, essences, etc.) ), glue agents (specifically such as sodium alginate, gum arabic, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), clarifiers (specifically such as chitosan, gelatin, etc.), preservatives (specifically For example, benzoic acid and its salts, sorbic acid and its salts, paraben series, etc.), disintegrants (specifically, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch carboxyacetate, cross-linked carboxylic acid Sodium methylcellulose, starch, etc.), binders (specifically such as hydroxypropylcellulose, hypromellose, povidone, copovidone, pregelatinized starch, etc.), lubricants (specifically such as, Stearic acid, magnesium stearate, sodium fumaryl stearate, etc.), wetting agents (specifically, polyoxyethylene sorbitan fatty acid esters, poloxamer, polyoxyethylene castor oil derivatives, etc. ), suspending agent (specifically such as hypromellose, hydroxypropylcellulose, povidone, copovidone, sodium carboxymethylcellulose, methylcellulose, etc.), stabilizer (specifically such as citric acid , fumaric acid, succinic acid, etc.), fillers (specifically such as starch, sucrose, lactose, microcrystalline cellulose, etc.), binders (specifically such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone etc.), etc. one or more.
具体地，上述药物组合物可以采用任意的剂型或给药形式，本领域技术人员可以根据情况选用，包括，但不限于，片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片、口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊、微胶囊)、锭剂、糖浆剂、溶液剂、乳剂、混悬剂、控制释放制剂(例如，瞬时释放制剂、缓释制剂、缓释微囊)、气雾剂、膜剂(例如，口服崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如，皮下注射、静脉注射、肌内注射、腹膜内注射)、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂(例如，直肠栓剂、阴道栓剂)、小药丸、鼻制剂、肺制剂(吸入剂)、眼睛滴剂等等；给药形式例如，口服给药或胃肠外给药(例如，静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、脑内、直肠内等给药形式)。Specifically, the above-mentioned pharmaceutical composition can adopt any dosage form or administration form, and those skilled in the art can choose according to the situation, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets) , orally disintegrating tablets, oral tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled release preparations ( For example, instant release preparations, sustained release preparations, sustained release microcapsules), aerosols, films (e.g., orally disintegrating films, oral muco-adhesive film preparations), injections (e.g., subcutaneous injections, intravenous injections, intramuscular injection, intraperitoneal injection), intravenous drip, transdermal absorption preparation, ointment, lotion, adhesive preparation, suppository (for example, rectal suppository, vaginal suppository), small pill, nasal preparation, pulmonary preparation (inhalation agents), eye drops, etc.; administration forms, for example, oral administration or parenteral administration (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, infusion, intracerebral, rectal internal administration form).
本发明还提供上述化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物、上述药物组合物作为PLpro抑制剂的应用，例如作为抗病毒药物的应用。The present invention also provides the above-mentioned compounds and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the application of the above-mentioned pharmaceutical compositions as PLpro inhibitors, for example, as antiviral drugs. .
本发明还提供上述化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物、上述药物组合物在制备预防和/或治疗由病毒感染引起或病毒感染相关的疾病或病症的药物中的应用。The present invention also provides the above-mentioned compounds and their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds. The above-mentioned pharmaceutical compositions can be prepared to prevent and/or treat viral infections or viral infections. Use of medicines related to diseases or conditions.
具体地，上述应用中，化合物、药物组合物具有本发明上述相应定义。Specifically, in the above-mentioned applications, the compounds and pharmaceutical compositions have the above-mentioned corresponding definitions of the present invention.
在本发明的一个实施方式中，上述病毒为冠状病毒，例如，HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU、SARS-CoV、MERS-CoV、SARS-CoV-2等，特别是SARS-CoV、MERS-CoV、SARS-CoV-2。In one embodiment of the invention, the above-mentioned virus is a coronavirus, such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2, etc., especially SARS-CoV, MERS-CoV, SARS-CoV-2.
具体地，上述疾病或病症为冠状病毒感染引起或冠状病毒感染相关的疾病或病症，例如COVID-19、SARS、MERS等。Specifically, the above-mentioned diseases or illnesses are those caused by or related to coronavirus infection, such as COVID-19, SARS, MERS, etc.
本发明还提供一种预防和/或治疗由病毒感染引起或病毒感染相关的疾病或病症的方法，其包括对受试者给予有效量的本发明上述化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物，或本发明上述药物组合物的步骤。The present invention also provides a method for preventing and/or treating diseases or conditions caused by viral infection or related to viral infection, which includes administering to a subject an effective amount of the above-mentioned compound of the present invention or a pharmaceutically acceptable salt or stereotaxic acid thereof. Isomers, esters, prodrugs, solvates and deuterated compounds, or steps of the above pharmaceutical compositions of the invention.
具体地，上述方法中，化合物、药物组合物、疾病或病症具有本发明上述相应定义。Specifically, in the above method, the compound, pharmaceutical composition, disease or condition has the above corresponding definitions of the present invention.
特别是，上述疾病或病症为冠状病毒感染引起或冠状病毒感染相关的疾病或病症，例如COVID-19、SARS、MERS等。In particular, the above-mentioned diseases or illnesses are those caused by or related to coronavirus infection, such as COVID-19, SARS, MERS, etc.
具体地，上述受试者为动物；在本发明的一个实施方式中，上述受试者为哺乳动物，如人类、猴、猫、狗、鼠、蝙蝠等；在本发明的另一个实施方式中，上述受试者为鸟类。Specifically, the above-mentioned subject is an animal; in one embodiment of the present invention, the above-mentioned subject is a mammal, such as a human, a monkey, a cat, a dog, a rat, a bat, etc.; in another embodiment of the present invention , the subjects mentioned above are birds.
本发明提供了一种结构新颖的化合物，其可作为PLPro抑制剂，活性高，可用于广谱抗病毒，特别是冠状病毒(例如SARS-CoV、MERS-CoV、SARS-CoV-2)，在药物领域具有非常好的应用前景和价值。The present invention provides a compound with a novel structure, which can be used as a PLPro inhibitor with high activity and can be used for broad-spectrum antivirus, especially coronaviruses (such as SARS-CoV, MERS-CoV, SARS-CoV-2), in The pharmaceutical field has very good application prospects and value.
附图说明Description of drawings
图1所示为实施例2制备的化合物的抑制率曲线。Figure 1 shows the inhibition rate curve of the compound prepared in Example 2.
图2所示为实施例35制备的化合物的抑制率曲线。Figure 2 shows the inhibition rate curve of the compound prepared in Example 35.
图3所示为阳性对照化合物GRL0617的抑制率曲线。Figure 3 shows the inhibition rate curve of the positive control compound GRL0617.
具体实施方式Detailed ways
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。Unless otherwise defined, all scientific and technical terms used in the present invention have the same meaning as commonly understood by a person skilled in the art to which this invention relates.
术语“烷基”是指直链或支链的且不含不饱和键的烃链自由基，且该烃链自由基以单键与分子其它部分连接。典型的烷基基团含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、正己基、异己基等。如果烷基被环烷基取代，其相应为“环烷基烷基”自由基，如环丙基甲基、环丙基乙基、环丁基甲基、环戊基甲基、环己基甲基等。如果烷基被芳基取代，那么其相应为“芳烷基”自由基，如苄基、二苯甲基或苯乙基。如果烷基被杂环基取代，那么其相应为“杂环基烷基”自由基。“亚烷基”通常是指具有两个自由价键的烷二基，典型的亚烷基含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子，如亚甲基、亚乙基、亚丙基、亚丁基等。The term "alkyl" refers to a straight or branched hydrocarbon chain free radical that does not contain unsaturated bonds and is connected to other parts of the molecule by a single bond. Typical alkyl groups contain 1 to 12 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is replaced by a cycloalkyl group, the corresponding "cycloalkylalkyl" free radical, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. . If an alkyl group is substituted by an aryl group, the corresponding radical is an "aralkyl" radical such as benzyl, benzyl, or phenethyl. If an alkyl group is substituted by a heterocyclyl group, the corresponding radical is a "heterocyclylalkyl" radical. "Alkylene" usually refers to an alkanediyl group with two free valence bonds. Typical alkylene groups contain 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene, ethylene, propylene, butylene, etc.
术语“烷氧基”是指羟基中的氢被烷基取代后形成的取代基，典型的烷氧基含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子，如甲氧基、乙氧基、丙氧基、丁氧基等。The term "alkoxy" refers to a substituent formed by replacing the hydrogen in the hydroxyl group with an alkyl group. Typical alkoxy groups contain 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.
术语“环烷基”是指饱和或部分饱和的(特别是饱和的)单环或多环基团，其可以含1至4个单环和/或稠环、含3-18个碳原子，优选3-10(例如3、4、5、6、7、8、9、10)个碳原子，如环丙基、环丁基、环戊基、环己基或金刚烷基等。The term "cycloalkyl" refers to a saturated or partially saturated (especially saturated) monocyclic or polycyclic group, which may contain 1 to 4 monocyclic and/or fused rings and 3 to 18 carbon atoms, Preferred are 3-10 ( eg 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.
术语“芳基”是指单环或多环自由基，包括含单芳基基团和/或稠芳基基团的多环自由基，如包含1-3个单环或稠环及6-18(例如6、8、10、12、14、16、18)个碳环原子，典型的芳基为含有6-12个碳环原子的芳基，如苯基、萘基、联苯基、茚基等。“亚芳基”是指通过移除两个氢原子而衍生自芳族烃的二价基团。The term "aryl" refers to monocyclic or polycyclic radicals, including polycyclic radicals containing a monoaryl group and/or a fused aryl group, such as 1-3 monocyclic or fused rings and 6- 18 (such as 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. Typical aryl groups are aryl groups containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, Indenyl et al. "Arylene" refers to a divalent group derived from an aromatic hydrocarbon by removal of two hydrogen atoms.
术语“杂环基”包括含1至3个单环和/或稠环及3至约18个环原子的杂芳香族基团和杂脂环基团。优选的杂芳香族基团和杂脂环基团含5至约10个环原子。本发明的化合物中的合适的杂芳基含1、2或3种杂原子，所述杂原子选自N、O或S原子。杂芳基的实例，例如，但不限于，香豆素，包括8-香豆素、喹啉基，包括8-喹啉基、异喹啉基、吡啶基、吡嗪基、吡唑基、嘧啶基、呋喃基、吡咯基、噻吩基、噻唑基、异噻唑基、三唑基、四唑基、异恶唑基、恶唑基、咪唑基、吲哚基、异吲哚基、吲唑基、吲嗪基、酞嗪基、蝶啶基、嘌呤基、恶二唑基、噻二唑基、呋吖基、哒嗪基、三嗪基，噌啉基、苯并咪唑基、苯并呋喃基、苯并呋吖基、苯并噻吩基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基，等。本发明的化合物中的合适的杂脂环基团含1、2或3种杂原子，所述杂原子选自N、O或S原子。杂脂环基团的实例，例如，但不限于，吡咯烷基、四氢呋喃基、二氢呋喃、四氢噻吩基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、氧硫杂环己烷基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环丙烷基、硫杂环丙烷基、吖庚因基、氧氮杂环庚基基、二吖庚因基、三吖庚因基、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基，二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、3H-吲哚基和喹嗪基，等。The term "heterocyclyl" includes heteroaromatic and heteroalicyclic groups containing from 1 to 3 monocyclic and/or fused rings and from 3 to about 18 ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms. Suitable heteroaryl groups in the compounds of the invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroaryl groups include, but are not limited to, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, Pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazole base, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazinyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzo Furyl, benzofurazine, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl, etc. Suitable heteroalicyclic groups in the compounds of the invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroalicyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, Oxithiranyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, thietanyl, Azepinyl, oxazepanyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, Indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxanyl, pyrazolinyl, disthianyl, dithiolanyl base, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl , 3H-indolyl and quinolizinyl, etc.
上述基团可以在一个或多个可用的位置被一个或多个合适的基团所取代，所述基团如：OR'、＝O、SR'、SOR'、SO 2R'、OSO 2R'、OSO 3R'、NO 2、NHR'、N(R') 2、＝N-R'、N(R')COR'、N(COR') 2、N(R')SO 2R'、N(R')C(＝NR')N(R')R'、N 3、CN、卤素、COR'、COOR'、OCOR'、OCOOR'、OCONHR'、OCON(R') 2、CONHR'、CON(R') 2、CON(R')OR'、CON(R')SO 2R'、PO(OR') 2、PO(OR')R'、PO(OR')(N(R')R')、C 1-C 12烷基、C 3-C 10环烷基、C 2-C 12烯基、C 2-C 12炔基、芳基和杂环基，其中每个R'基团各自独立地选自：氢、OH、NO 2、NH 2、SH、CN、卤素、COH、CO烷基、COOH、C 1-C 12烷基、C 3-C 10环烷基、C 2-C 12烯基、C 2-C 12炔基、芳基和杂环基。其中，这些基团本身被取代，取代基可选自前述列表。 The above-mentioned groups may be substituted at one or more available positions by one or more suitable groups, such as: OR', =O, SR', SOR', SO 2 R', OSO 2 R ', OSO 3 R', NO 2 , NHR', N(R') 2 , =N-R', N(R')COR', N(COR') 2 , N(R')SO 2 R' , N(R')C(=NR')N(R')R', N 3 , CN, halogen, COR', COOR', OCOR', OCOOR', OCONHR', OCON(R') 2 , CONHR ', CON(R') 2 , CON(R')OR', CON(R')SO 2 R', PO(OR') 2 , PO(OR')R', PO(OR')(N( R')R'), C 1 -C 12 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl and heterocyclyl, where each Each R' group is independently selected from: hydrogen, OH, NO 2 , NH 2 , SH, CN, halogen, COH, CO alkyl, COOH, C 1 -C 12 alkyl, C 3 -C 10 cycloalkyl , C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl and heterocyclyl. Where these groups are themselves substituted, the substituents may be selected from the aforementioned list.
“卤素”是指溴、氯、碘或氟。卤代烷基是指烷基上的氢原子被卤素原子(F、Cl、Br、I)取代的基团，如-CH 2Rh、-CHRh 2、-CRh 3，其中，Rh为F、Cl、Br或I；如-CF 3。 "Halogen" means bromine, chlorine, iodine or fluorine. Haloalkyl refers to a group in which the hydrogen atom on the alkyl group is replaced by a halogen atom (F, Cl, Br, I), such as -CH 2 Rh, -CHRh 2 , -CRh 3 , where Rh is F, Cl, Br or I; such as -CF 3 .
术语“药学上可接受的盐”是指理论上无毒、刺激性及过敏反应的，并且能够实现或提供药物分子临床上可接受的药代动力学性质、吸收、分布及代谢性质，可达到预期目的的酸性盐或碱性盐。本发明所述的盐包括化合物的酸性基团、碱性基团或两性基团药学上可接受的酸性盐或碱性盐。适宜的盐的列表可参见S.M.Birge,et al.，J.Pharm.Sci.,66,1-19(1977)。The term "pharmaceutically acceptable salt" refers to a salt that is theoretically non-toxic, irritating and allergic, and can achieve or provide clinically acceptable pharmacokinetic properties, absorption, distribution and metabolism properties of the drug molecule, which can achieve Acidic or basic salts for the intended purpose. The salts described in the present invention include pharmaceutically acceptable acidic salts or basic salts of the acidic group, basic group or amphoteric group of the compound. A list of suitable salts can be found in S. M. Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).
本发明所述的药学上可接受的盐中包括酸加成盐和碱加成盐。The pharmaceutically acceptable salts described in the present invention include acid addition salts and base addition salts.
所述的酸加成盐包括但不限于来自无机酸诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸和膦酸的盐，以及来自有机酸如脂肪族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳香酸和脂肪族和芳香族磺酸的盐。因此，这些盐包括但不限于硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、氢溴酸盐、碘酸盐、乙酸盐、丙酸盐、辛酸盐、异丁酸盐、乙二酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、苦杏仁酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、酞酸盐、苯磺酸盐、甲苯磺酸盐、苯基乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐和甲磺酸盐，还包含氨基酸的盐如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等。酸加成盐可以通过以常规方式使游离碱形式与足够量的所需酸接触形成盐的方式制备。可通过使盐形式与碱接触重新生成游离碱形式，并且以常规方式分离该游离碱。The acid addition salts include, but are not limited to, salts from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid and phosphonic acid, and from organic acids such as aliphatic monocarboxylic and dicarboxylic acids. , phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and salts of aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates Salt, hydrochloride, hydrobromide, iodate, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate , Sebacate, fumarate, maleate, amygdalate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalic acid salts, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate and methanesulfonate, and also include salts of amino acids such as arginine salts, Gluconate, galacturonate, etc. Acid addition salts may be prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base, and the free base isolated in conventional manner.
本发明所述的碱加成盐是指与金属或者胺形成的盐，诸如碱金属和碱土金属的氢氧化物，或者与有机胺形成。用作阳离子的金属的例子包括但不限于钠、钾、镁、和钙。适当的胺的例子包括但是不限于N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺(乙烷-1,2-二胺)、N-甲基葡糖胺和普鲁卡因。碱加成盐可通过以常规方式使游离酸形式与足够量的所需碱接触形成盐的方式制备。 可通过使盐形式与酸接触重新生成游离酸形式，并且以常规方式分离游离酸。Base addition salts according to the present invention refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N- Methylglucosamine and procaine. Base addition salts may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid isolated in a conventional manner.
术语“溶剂化物”应理解为是指本发明的化合物的任意形式，其中所述化合物通过非共价键与另一个分子相连(通常为极性溶剂)，特别是包括水化物和醇化物，例如甲醇化物。优选的溶剂化物为水化物。The term "solvate" is understood to mean any form of a compound according to the invention in which said compound is linked by a non-covalent bond to another molecule (usually a polar solvent), including in particular hydrates and alcoholates, e.g. Methanolates. Preferred solvates are hydrates.
术语“前体药物”使用其广义含义，并涵盖在体内可转化成本发明化合物的衍生物。前体药物的例子包括但不限于化合物的衍生物和代谢物，包括可生物水解的部分，如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。优选地，具有羧基官能团的前体药物为羧酸的低级烷基酯。所述的羧酸酯易由存在于分子中的任何羧酸部分进行酯化得到。前体药物通常可由已知方法来制备，如在Burger“Medicinal Chemistry and Drug Discovery第六版(Donald J.Abraham ed.，2001，Wiley)和“Design and Applications of Prodrugs”(H.Bundgaard ed.，1985，Harwood Academic Publishers)中描述的方法。The term "prodrug" is used in its broadest sense and encompasses derivatives which are converted in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable Carbonate esters, biohydrolyzable ureeas, and biohydrolyzable phosphate ester analogs. Preferably, the prodrug having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid esters are readily esterified from any carboxylic acid moiety present in the molecule. Prodrugs can generally be prepared by known methods, as described in Burger "Medicinal Chemistry and Drug Discovery, 6th Edition (Donald J.Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H.Bundgaard ed., 1985, the method described in Harwood Academic Publishers).
本文所涉及的任何化合物均旨在代表这样的特定化合物及其某些变形或某些形式。特别地，在这里所涉及的化合物可能具有不对称中心，并因此存在不同的对映体或非对映体形式。由此，本文涉及的任何给定的化合物代表外消旋物的任意一种、一种或多种对映体形式、一种或多种非对映体形式、及其混合物。同样地，也可能存在双键的立体异构体或几何异构体，由此在一些情况中，分子可能存在为(E)-异构体或(Z)-异构体(反式和顺式异构体)。如果分子包含多个双键，那么每个双键将具有其自身的立体异构现象，其可以与所述分子的其它双键的立体异构现象相同或不同。此外，本文中涉及的化合物可存在阿托异构体。本文涉及的化合物的所有立体异构体，包括对映体、非对映异构体、几何异构体和阿托异构体、及其混合物，都在本发明的范围内。Any reference to a compound herein is intended to represent such specific compound or some variation or form thereof. In particular, the compounds referred to here may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Thus, any given compound referred to herein represents any one of the racemates, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomers or geometric isomers of double bonds may also exist, whereby in some cases the molecule may exist as the (E)-isomer or the (Z)-isomer (trans and cis isomer). If a molecule contains multiple double bonds, each double bond will have its own stereoisomerism, which may or may not be the same as the stereoisomerism of the other double bonds of the molecule. In addition, the compounds referred to herein may exist as atrop isomers. All stereoisomers of the compounds contemplated herein, including enantiomers, diastereoisomers, geometric isomers and atroisomers, and mixtures thereof, are within the scope of the present invention.
本文所引用的各种出版物、专利和公开的专利说明书，其公开内容通过引用整体并入本文。The disclosures of the various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present invention.
实施例1：Example 1:
Figure PCTCN2022114690-appb-000035
Figure PCTCN2022114690-appb-000035
THU101: 1H NMR(400MHz,Methanol-d 4)δ8.65(d,J＝8.5Hz,1H),8.00(d,J＝6.0Hz,1H),7.91(d,J＝7.0Hz,1H),7.86(d,J＝8.2Hz,1H),7.79(d,J＝8.3Hz,1H),7.60(t,J＝7.7Hz,1H),7.46(dt,J＝15.3,7.6Hz,2H),7.17(d,J＝2.8Hz,1H),6.52(dd,J＝6.2,2.8Hz,1H),2.92(s,6H),1.51(t,J＝3.5Hz,2H),1.33(t,J＝3.5Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ146.50,138.04,133.97,132.27,131.56,128.95,128.81,128.10,126.15,125.88,125.59,125.51,123.06,113.39,111.21,56.85,55.72,47.13,44.40,43.92,34.64,24.35,18.30,14.51.MS(ESI,m/z):C21H21N3O,[M+H]+332.17. THU101: 1 H NMR (400MHz, Methanol-d 4 ) δ8.65 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H) ,7.86(d,J＝8.2Hz,1H),7.79(d,J＝8.3Hz,1H),7.60(t,J＝7.7Hz,1H),7.46(dt,J＝15.3,7.6Hz,2H) ,7.17(d,J＝2.8Hz,1H),6.52(dd,J＝6.2,2.8Hz,1H),2.92(s,6H),1.51(t,J＝3.5Hz,2H),1.33(t, J=3.5Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 ) δ146.50,138.04,133.97,132.27,131.56,128.95,128.81,128.10,126.15,125.88,125.59,125.51,123.06,11 3.39,111.21,56.85 ,55.72,47.13,44.40,43.92,34.64,24.35,18.30,14.51.MS(ESI,m/z):C21H21N3O,[M+H]+332.17.
实施例2：Example 2:
Figure PCTCN2022114690-appb-000036
Figure PCTCN2022114690-appb-000036
THU102: 1H NMR(400MHz,DMSO-d 6)δ8.98(s,1H),8.68(d,J＝8.3Hz,1H),7.93(d,J＝8.0Hz,1H),7.83(d,J＝7.6Hz,2H),7.52(ddt,J＝29.4,15.2,7.4Hz,3H),6.76(d,J＝8.1Hz,1H),6.45(dd,J＝8.0,2.5Hz,1H),6.29(d,J＝2.5Hz,1H),4.91(s,2H),1.87(s,3H),1.33(d,J＝5.4Hz,2H),1.16(d,J＝5.3Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ170.49,146.47,138.34,138.16,133.91,132.31,131.03,128.92,128.85,128.03,126.19,125.84,125.69,125.49,121.49,115.00,112.79,34.34,18.37,14.68.MS(ESI,m/z):C21H20N2O,[M+H]+317.16. THU102: 1 H NMR (400MHz, DMSO-d 6 ) δ8.98 (s, 1H), 8.68 (d, J = 8.3Hz, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.83 (d, J＝7.6Hz,2H),7.52(ddt,J＝29.4,15.2,7.4Hz,3H),6.76(d,J＝8.1Hz,1H),6.45(dd,J＝8.0,2.5Hz,1H), 6.29(d,J＝2.5Hz,1H),4.91(s,2H),1.87(s,3H),1.33(d,J＝5.4Hz,2H),1.16(d,J＝5.3Hz,2H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.49,146.47,138.34,138.16,133.91,132.31,131.03,128.92,128.85,128.03,126.19,125.84,125.69,125.49,121.49 ,115.00,112.79,34.34,18.37,14.68 .MS(ESI,m/z):C21H20N2O,[M+H]+317.16.
实施例3：Example 3:
Figure PCTCN2022114690-appb-000037
Figure PCTCN2022114690-appb-000037
THU103： 1H NMR(400MHz,Chloroform-d)δ9.00(s,1H),8.61(d,J＝8.5Hz,1H),8.31(dd,J＝4.6,1.6Hz,1H),8.01(dd,J＝7.1,1.3Hz,1H),7.89(d,J＝8.2Hz,1H),7.80(d,J＝8.2Hz,1H),7.64(ddd,J＝8.4,6.8,1.4Hz,1H),7.50(dt,J＝8.0,6.5Hz,3H),7.22(dd,J＝7.8,4.6Hz,1H),2.68(s,3H),1.57(t,J＝3.4Hz,2H),1.44–1.39(m,2H).MS(ESI,m/z):C20H18N2O,[M+H]+303.27. THU103: 1 H NMR (400MHz, Chloroform-d) δ9.00 (s, 1H), 8.61 (d, J = 8.5Hz, 1H), 8.31 (dd, J = 4.6, 1.6Hz, 1H), 8.01 (dd ,J＝7.1,1.3Hz,1H),7.89(d,J＝8.2Hz,1H),7.80(d,J＝8.2Hz,1H),7.64(ddd,J＝8.4,6.8,1.4Hz,1H) ,7.50(dt,J＝8.0,6.5Hz,3H),7.22(dd,J＝7.8,4.6Hz,1H),2.68(s,3H),1.57(t,J＝3.4Hz,2H),1.44– 1.39(m,2H).MS(ESI,m/z):C20H18N2O,[M+H]+303.27.
实施例4：Example 4:
Figure PCTCN2022114690-appb-000038
Figure PCTCN2022114690-appb-000038
THU104： 1H NMR(400MHz,Chloroform-d)δ8.47(d,J＝8.3Hz,1H),8.40–8.32(m,2H),7.94(dd,J＝7.7,4.4Hz,2H),7.84(d,J＝8.2Hz,1H),7.64–7.45(m,3H),7.29(s,1H),6.99(d,J＝4.9Hz,1H),6.75(s,1H),2.16(s,3H),1.60(t,J＝3.6Hz,2H),1.45(t,J＝3.6Hz,2H). 13C NMR(101MHz,Chloroform-d)δ151.82,147.44,129.04,128.69,128.48,126.21,125.50,123.77,120.23,34.93,16.15,14.80,14.71.MS(ESI,m/z):C20H18N2O,[M+H]+303.25. THU104: 1 H NMR (400MHz, Chloroform-d) δ8.47 (d, J＝8.3Hz, 1H), 8.40–8.32 (m, 2H), 7.94 (dd, J＝7.7, 4.4Hz, 2H), 7.84 (d,J＝8.2Hz,1H),7.64–7.45(m,3H),7.29(s,1H),6.99(d,J＝4.9Hz,1H),6.75(s,1H),2.16(s, 3H), 1.60 (t, J = 3.6 Hz, 2H), 1.45 (t, J = 3.6 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 151.82, 147.44, 129.04, 128.69, 128.48, 126.21, 125.50 ,123.77,120.23,34.93,16.15,14.80,14.71.MS(ESI,m/z):C20H18N2O,[M+H]+303.25.
实施例5：Example 5:
Figure PCTCN2022114690-appb-000039
Figure PCTCN2022114690-appb-000039
THU105： 1H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.49–8.38(m,2H),7.96–7.75(m,4H),6.98(s,1H),2.42(s,3H),1.59(t,J＝4.9Hz,2H),1.45(t,J＝4.9Hz,2H). 13C NMR(101MHz,Chloroform-d)δ158.98,158.87,154.47,154.37,136.27,129.87,129.44,129.34,129.21,129.06,128.96,128.85,128.73,126.65,126.43,125.70,125.48,124.01,35.32,15.02,14.93,14.79.MS(ESI,m/z):C19H17N3O,[M+H]+304.34. THU105: 1 H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.49–8.38(m,2H),7.96–7.75(m,4H),6.98(s,1H),2.42(s, 3H), 1.59 (t, J = 4.9 Hz, 2H), 1.45 (t, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 158.98, 158.87, 154.47, 154.37, 136.27, 129.87, 129.44 ,129.34,129.21,129.06,128.96,128.85,128.73,126.65,126.43,125.70,125.48,124.01,35.32,15.02,14.93,14.79.MS(ESI,m/z):C19H17N3O,[ M+H]+304.34.
实施例6：Example 6:
Figure PCTCN2022114690-appb-000040
Figure PCTCN2022114690-appb-000040
THU106： 1H NMR(400MHz,Chloroform-d)δ8.85(s,1H),8.62(d,J＝8.5Hz,1H),8.05(d,J＝5.6Hz,1H),7.97(d,J＝7.0Hz,1H),7.87(d,J＝8.2Hz,1H),7.79(d,J＝8.2Hz,1H),7.62(dd,J＝8.6,6.8Hz,1H),7.48(dt,J＝11.7,7.5Hz,2H),7.36(d,J＝2.4Hz,1H),6.51(dd,J＝5.8,2.4Hz,1H),1.60(t,J＝5.6Hz,2H),1.40(t,J＝5.6Hz,2H). 13C NMR(101MHz,Chloroform-d)δ153.84,137.16,133.96,132.13,128.78,128.67,128.22,126.18,125.45,125.38,124.53,111.00,107.99,53.43,34.17,29.33,14.68.MS(ESI,m/z):C19H17N3O,[M+H]+304.21. THU106: 1 H NMR (400MHz, Chloroform-d) δ8.85 (s, 1H), 8.62 (d, J = 8.5Hz, 1H), 8.05 (d, J = 5.6Hz, 1H), 7.97 (d, J ＝7.0Hz,1H),7.87(d,J＝8.2Hz,1H),7.79(d,J＝8.2Hz,1H),7.62(dd,J＝8.6,6.8Hz,1H),7.48(dt,J ＝11.7,7.5Hz,2H),7.36(d,J＝2.4Hz,1H),6.51(dd,J＝5.8,2.4Hz,1H),1.60(t,J＝5.6Hz,2H),1.40(t , J=5.6Hz, 2H). 13 C NMR (101MHz, Chloroform-d) δ153.84,137.16,133.96,132.13,128.78,128.67,128.22,126.18,125.45,125.38,124.53,111.00,107.99, 53.43,34.17,29.33 ,14.68.MS(ESI,m/z):C19H17N3O,[M+H]+304.21.
实施例7：Example 7:
Figure PCTCN2022114690-appb-000041
Figure PCTCN2022114690-appb-000041
THU107: 1H NMR(400MHz,Chloroform-d)δ8.49(d,J＝8.4Hz,1H),8.45–8.28(m,2H),8.00-7.85(m,2H),7.83(d,J＝8.3Hz,1H),7.65-7.40(m,3H),7.07(d,J＝5.1Hz,1H),6.92(s,1H),2.26(d,J＝1.9Hz,3H),1.61(t,J＝4.5Hz,2H),1.44(t,J＝4.5Hz,2H).MS(ESI,m/z):C20H18N2O,[M+H]+303.25. THU107: 1 H NMR (400MHz, Chloroform-d) δ8.49 (d, J＝8.4Hz, 1H), 8.45–8.28 (m, 2H), 8.00-7.85 (m, 2H), 7.83 (d, J＝ 8.3Hz,1H),7.65-7.40(m,3H),7.07(d,J＝5.1Hz,1H),6.92(s,1H),2.26(d,J＝1.9Hz,3H),1.61(t, J＝4.5Hz,2H),1.44(t,J＝4.5Hz,2H).MS(ESI,m/z):C20H18N2O,[M+H]+303.25.
实施例8：Example 8:
Figure PCTCN2022114690-appb-000042
Figure PCTCN2022114690-appb-000042
THU108： 1H NMR(400MHz,Methanol-d 4)δ8.67(d,J＝8.5Hz,1H),7.90(dd,J＝11.4,8.0Hz,2H),7.80(d,J＝8.3Hz,1H),7.61(t,J＝7.8Hz,1H),7.47(dt,J＝15.8,8.0Hz,3H),7.19(d,J＝7.4Hz,1H),6.63(d,J＝8.3Hz,1H),1.54(t,J＝7.4Hz,2H),1.33(t,J＝7.4Hz,2H). 13C NMR(101MHz,Methanol-d 4)δ166.25, 158.73,137.91,136.91,134.12,132.08,128.36,128.21,127.91,125.74,125.14,124.72,124.28,111.66,110.35,33.83,13.76.MS(ESI,m/z):C19H17N3O,[M+H]+304.39. THU108: 1 H NMR (400MHz, Methanol-d 4 ) δ8.67 (d, J = 8.5Hz, 1H), 7.90 (dd, J = 11.4, 8.0Hz, 2H), 7.80 (d, J = 8.3Hz, 1H),7.61(t,J＝7.8Hz,1H),7.47(dt,J＝15.8,8.0Hz,3H),7.19(d,J＝7.4Hz,1H),6.63(d,J＝8.3Hz, 1H), 1.54 (t, J＝7.4Hz, 2H), 1.33 (t, J＝7.4Hz, 2H). 13 C NMR (101MHz, Methanol-d 4 ) δ 166.25, 158.73, 137.91, 136.91, 134.12, 132.08,128.36,128.21,127.91,125.74,125.14,124.72,124.28,111.66,110.35,33.83,13.76.MS(ESI,m/z):C19H17N3O,[M+H]+304.39.
实施例9：Example 9:
Figure PCTCN2022114690-appb-000043
Figure PCTCN2022114690-appb-000043
THU109： 1H NMR(400MHz,Methanol-d 4)δ8.62–8.55(m,1H),8.00-7.90(m,2H),7.87–7.79(m,2H),7.58(ddd,J＝8.4,6.8,1.4Hz,1H),7.54–7.47(m,1H),7.47–7.41(m,1H),6.81(d,J＝2.8Hz,1H),2.09(s,3H),1.45(t,J＝3.5Hz,2H),1.34–1.28(m,2H). 13C NMR(101MHz,Methanol-d 4)δ170.50,142.54,141.95,136.53,135.59,134.14,132.68,132.06,128.40,127.94,125.72,125.16,124.71,124.34,120.35,34.15,19.00,13.53.MS(ESI,m/z):C20H19N3O,[M+H]+318.18. THU109: 1 H NMR (400MHz, Methanol-d 4 ) δ8.62–8.55(m,1H),8.00-7.90(m,2H),7.87–7.79(m,2H),7.58(ddd,J＝8.4, 6.8,1.4Hz,1H),7.54–7.47(m,1H),7.47–7.41(m,1H),6.81(d,J＝2.8Hz,1H),2.09(s,3H),1.45(t,J =3.5Hz,2H),1.34–1.28(m,2H). 13 C NMR (101MHz, Methanol-d 4 )δ170.50,142.54,141.95,136.53,135.59,134.14,132.68,132.06,128.40,127.94,125.72 ,125.16 ,124.71,124.34,120.35,34.15,19.00,13.53.MS(ESI,m/z):C20H19N3O,[M+H]+318.18.
实施例10：Example 10:
Figure PCTCN2022114690-appb-000044
Figure PCTCN2022114690-appb-000044
THU110： 1H NMR(400MHz,Methanol-d 4)δ8.66(d,J＝8.5Hz,1H),7.93–7.83(m,3H),7.77(d,J＝8.2Hz,1H),7.58(t,J＝7.7Hz,1H),7.48(t,J＝7.5Hz,1H),7.42(t,J＝7.7Hz,1H),6.72(d,J＝4.2Hz,2H),1.44(t,J＝4.4Hz,2H),1.32–1.26(m,2H). 13C NMR(101MHz,Methanol-d 4)δ168.08,159.77,147.04,144.46,136.53,134.11,132.10,128.61,128.39,127.94,125.71,125.12,124.68,124.32,109.64,106.77,34.25,13.66.MS(ESI,m/z):C19H17N3O,[M+H]+304.26. THU110: 1 H NMR (400MHz, Methanol-d 4 ) δ8.66 (d, J = 8.5 Hz, 1H), 7.93–7.83 (m, 3H), 7.77 (d, J = 8.2 Hz, 1H), 7.58 ( t,J＝7.7Hz,1H),7.48(t,J＝7.5Hz,1H),7.42(t,J＝7.7Hz,1H),6.72(d,J＝4.2Hz,2H),1.44(t, J＝4.4Hz,2H),1.32–1.26(m,2H). 13 C NMR (101MHz, Methanol-d 4 )δ168.08,159.77,147.04,144.46,136.53,134.11,132.10,128.61,128.39,127.94,125.71 , 125.12,124.68,124.32,109.64,106.77,34.25,13.66.MS(ESI,m/z):C19H17N3O,[M+H]+304.26.
实施例11：Example 11:
Figure PCTCN2022114690-appb-000045
Figure PCTCN2022114690-appb-000045
THU111： 1H NMR(400MHz,Methanol-d 4)δ8.70(dd,J＝8.5,1.2Hz,1H),7.89(ddd,J＝16.0,7.7,1.3Hz,2H),7.79(d,J＝8.3Hz,1H),7.60(ddd,J＝8.4,6.8,1.4Hz,1H),7.53–7.37(m,2H),7.13–7.02(m,1H),6.99–6.88(m,2H),6.78(ddd,J＝7.9,2.3,1.2Hz,1H),1.49–1.43(m,2H),1.33–1.26(m,2H). 13C NMR(101MHz,Methanol-d 4)δ170.28,147.75,136.96,135.62,134.11,132.17,128.64,128.48,128.32,127.76,125.63,125.05,124.64,124.47,117.77,116.04,113.34,34.22,13.68.MS(ESI,m/z):C20H18N2O,[M+H]+304.17. THU111: 1 H NMR (400MHz, Methanol-d 4 ) δ8.70 (dd, J＝8.5, 1.2Hz, 1H), 7.89 (ddd, J＝16.0, 7.7, 1.3Hz, 2H), 7.79 (d, J ＝8.3Hz,1H),7.60(ddd,J＝8.4,6.8,1.4Hz,1H),7.53–7.37(m,2H),7.13–7.02(m,1H),6.99–6.88(m,2H), 6.78(ddd,J＝7.9,2.3,1.2Hz,1H),1.49–1.43(m,2H),1.33–1.26(m,2H). 13 C NMR (101MHz, Methanol-d 4 )δ170.28,147.75,136.96 ,135.62,134.11,132.17,128.64,128.48,128.32,127.76,125.63,125.05,124.64,124.47,117.77,116.04,113.34,34.22,13.68.MS(ESI,m/z):C2 0H18N2O,[M+H]+ 304.17.
实施例12：Example 12:
Figure PCTCN2022114690-appb-000046
Figure PCTCN2022114690-appb-000046
THU112： 1H NMR(400MHz,Methanol-d 4)δ8.68(d,J＝8.5Hz,1H),8.02(d,J＝4.8Hz,1H),7.90(dd,J＝15.6,7.6Hz,2H),7.80(d,J＝8.3Hz,1H),7.59(s,1H),7.47(d,J＝19.8Hz,2H),6.83(s,1H),6.74(d,J＝5.3Hz,1H),3.04(s,6H),1.48(s,2H),1.33(s,2H). 13C NMR(101MHz,Methanol-d 4)δ168.37,159.32,147.29,143.71,136.58,134.13,132.11,128.64,128.38,127.92,125.65,125.11,124.66,124.34,108.33,104.15,37.06,34.32,13.65.MS(ESI,m/z):C21H21N3O,[M+H]+332.37. THU112: 1 H NMR (400MHz, Methanol-d 4 ) δ8.68 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.90 (dd, J = 15.6, 7.6 Hz, 2H),7.80(d,J＝8.3Hz,1H),7.59(s,1H),7.47(d,J＝19.8Hz,2H),6.83(s,1H),6.74(d,J＝5.3Hz, 1H),3.04(s,6H),1.48(s,2H),1.33(s,2H). 13 C NMR(101MHz,Methanol-d 4 )δ168.37,159.32,147.29,143.71,136.58,134.13,132.11,128.64 ,128.38,127.92,125.65,125.11,124.66,124.34,108.33,104.15,37.06,34.32,13.65.MS(ESI,m/z):C21H21N3O,[M+H]+332.37.
实施例13：Example 13:
Figure PCTCN2022114690-appb-000047
Figure PCTCN2022114690-appb-000047
THU113： 1H NMR(400MHz,Chloroform-d)δ8.83(s,1H),8.59(d,J＝8.5Hz,1H),7.97(d,J＝7.1Hz,1H),7.88(d,J＝8.3Hz,1H),7.79(d,J＝8.3Hz,1H),7.61(t,J＝7.9Hz,1H),7.53–7.42(m,3H),7.37(dd,J＝7.2,2.3Hz,1H),6.56(dd,J＝8.4,2.4Hz,1H),3.07(s,6H),1.61(s,2H),1.41(s,2H). 13C NMR(101MHz,Chloroform-d)δ165.08,157.54,147.80,138.16,137.37,134.05,132.12,128.96, 128.36,128.15,126.03,125.57,125.40,124.20,109.77,108.85,37.99,34.02,14.59,14.55.MS(ESI,m/z):C21H21N3O,[M+H]+332.31. THU113: 1 H NMR (400MHz, Chloroform-d) δ8.83 (s, 1H), 8.59 (d, J = 8.5Hz, 1H), 7.97 (d, J = 7.1Hz, 1H), 7.88 (d, J ＝8.3Hz,1H),7.79(d,J＝8.3Hz,1H),7.61(t,J＝7.9Hz,1H),7.53–7.42(m,3H),7.37(dd,J＝7.2,2.3Hz ,1H),6.56(dd,J＝8.4,2.4Hz,1H),3.07(s,6H),1.61(s,2H),1.41(s,2H). 13 C NMR(101MHz,Chloroform-d)δ165 .08,157.54,147.80,138.16,137.37,134.05,132.12,128.96, 128.36,128.15,126.03,125.57,125.40,124.20,109.77,108.85,37.99,34.02,1 4.59,14.55.MS(ESI,m/z):C21H21N3O, [M+H]+332.31.
实施例14：Example 14:
Figure PCTCN2022114690-appb-000048
Figure PCTCN2022114690-appb-000048
THU114： 1H NMR(400MHz,Methanol-d 4)δ8.60(d,J＝8.4Hz,1H),7.92(dd,J＝7.8,3.4Hz,2H),7.84(d,J＝8.3Hz,1H),7.77(dd,J＝8.0,2.0Hz,1H),7.65-7.56(m,2H),7.54-7.44(m,2H),7.32(d,J＝8.1Hz,1H),2.10(s,3H),1.49(t,J＝5.8Hz,2H),1.34(t,J＝3.6Hz,2H). 13C NMR(100MHz,Methanol-d4)δ168.25,141.87,140.12,134.40,133.27,132.91,132.02,130.37,128.90,127.79,127.72,127.00,126.30,125.96,125.14,124.85,124.50,35.89,20.76,18.80.MS(ESI,m/z):C21H20N2O3S,[M+H]+381.12. THU114: 1 H NMR (400MHz, Methanol-d 4 ) δ8.60 (d, J = 8.4Hz, 1H), 7.92 (dd, J = 7.8, 3.4Hz, 2H), 7.84 (d, J = 8.3Hz, 1H),7.77(dd,J＝8.0,2.0Hz,1H),7.65-7.56(m,2H),7.54-7.44(m,2H),7.32(d,J＝8.1Hz,1H),2.10(s ,3H),1.49(t,J＝5.8Hz,2H),1.34(t,J＝3.6Hz,2H). 13 C NMR(100MHz,Methanol-d4)δ168.25,141.87,140.12,134.40,133.27,132.91, 132.02,130.37,128.90,127.79,127.72,127.00,126.30,125.96,125.14,124.85,124.50,35.89,20.76,18.80.MS(ESI,m/z):C21H20N2O3S,[M+H]+ 381.12.
实施例15：Example 15:
Figure PCTCN2022114690-appb-000049
Figure PCTCN2022114690-appb-000049
THU115： 1H NMR(400MHz,Methanol-d4)δ8.70(d,J＝8.5Hz,1H),7.95(d,J＝7.1Hz,1H),7.89(d,J＝8.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.75(d,J＝9.4Hz,2H),7.66-7.55(m,2H),7.43-7.53(m,3H),4.12(s,2H),1.49(d,J＝6.3Hz,2H),1.36(d,J＝5.5Hz,2H). 13C NMR(100MHz,Methanol-d4)δ169.32,142.50,134.32,133.94,133.27,132.91,130.29,128.76,128.57,127.79,127.72,127.31,126.30,125.96,125.14,124.85,124.50,46.33,35.96,18.80.MS(ESI,m/z):C21H20N2O,[M+H]+317.16. THU115: 1 H NMR (400MHz, Methanol-d4) δ8.70 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 7.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.81(d,J＝8.3Hz,1H),7.75(d,J＝9.4Hz,2H),7.66-7.55(m,2H),7.43-7.53(m,3H),4.12(s,2H),1.49 (d, J＝6.3Hz, 2H), 1.36 (d, J＝5.5Hz, 2H). 13 C NMR (100MHz, Methanol-d4) δ 169.32, 142.50, 134.32, 133.94, 133.27, 132.91, 130.29, 128.76, 128.57 ,127.79,127.72,127.31,126.30,125.96,125.14,124.85,124.50,46.33,35.96,18.80.MS(ESI,m/z):C21H20N2O,[M+H]+317.16.
实施例16：Example 16:
Figure PCTCN2022114690-appb-000050
Figure PCTCN2022114690-appb-000050
THU116： 1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.65(d,J＝8.2Hz,1H),8.43(s,1H),7.94(d,J＝7.9Hz,1H),7.88-7.75(m,2H),7.63-7.50(m,2H),7.48(d,J＝8.0Hz,1H),7.30(d,J＝8.2Hz,1H),7.06(s,1H),6.96(d,J＝8.3Hz,1H),5.77(s,2H),1.94(s,3H),1.34(s,2H),1.17(s,2H). 13C NMR(100MHz,Methanol-d4)δ168.61,156.09,137.72,135.48,135.39,134.40,133.27,132.91,130.48,127.79,127.72,126.30,125.96,125.14,124.85,124.50,121.11,117.46,35.89,20.80,18.80.MS(ESI,m/z):C22H21N3O2,[M+H]+360.16. THU116: 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 8.65 (d, J = 8.2Hz, 1H), 8.43 (s, 1H), 7.94 (d, J = 7.9Hz, 1H ),7.88-7.75(m,2H),7.63-7.50(m,2H),7.48(d,J＝8.0Hz,1H),7.30(d,J＝8.2Hz,1H),7.06(s,1H) ,6.96(d,J＝8.3Hz,1H),5.77(s,2H),1.94(s,3H),1.34(s,2H),1.17(s,2H). 13 C NMR(100MHz,Methanol-d4 )δ168.61,156.09,137.72,135.48,135.39,134.40,133.27,132.91,130.48,127.79,127.72,126.30,125.96,125.14,124.85,124.50,121.11,117 .46,35.89,20.80,18.80.MS(ESI,m/z ):C22H21N3O2,[M+H]+360.16.
实施例17：Example 17:
Figure PCTCN2022114690-appb-000051
Figure PCTCN2022114690-appb-000051
THU117： 1H NMR(400MHz,DMSO-d 6)δ9.27(s,1H),8.65(d,J＝8.2Hz,1H),7.94(d,J＝7.7Hz,1H),7.84(t,J＝7.4Hz,2H),7.63–7.43(m,3H),7.40(dt,J＝8.1,2.1Hz,1H),7.25(d,J＝8.1Hz,1H),7.14(d,J＝2.2Hz,1H),3.50(d,J＝1.7Hz,6H),2.04(d,J＝1.7Hz,3H),1.41(d,J＝5.6Hz,2H),1.24–1.19(m,2H). 13C NMR(101MHz,DMSO-d 6)δ168.45,138.98,137.78,137.74,133.95,132.21,131.93,131.80,131.61,129.37,128.98,128.92,128.25,126.20,125.93,125.54,125.43,43.41,34.64,19.00,14.56,14.52.MS(ESI,m/z):C23H24N2O5S2,[M+H]+473.12. THU117: 1 H NMR (400MHz, DMSO-d 6 ) δ9.27 (s, 1H), 8.65 (d, J = 8.2Hz, 1H), 7.94 (d, J = 7.7Hz, 1H), 7.84 (t, J＝7.4Hz,2H),7.63–7.43(m,3H),7.40(dt,J＝8.1,2.1Hz,1H),7.25(d,J＝8.1Hz,1H),7.14(d,J＝2.2 Hz,1H),3.50(d,J＝1.7Hz,6H),2.04(d,J＝1.7Hz,3H),1.41(d,J＝5.6Hz,2H),1.24–1.19(m,2H). 13 C NMR (101MHz, DMSO-d 6 ) δ168.45,138.98,137.78,137.74,133.95,132.21,131.93,131.80,131.61,129.37,128.98,128.92,128.25,126.20,125.93 ,125.54,125.43,43.41,34.64,19.00 ,14.56,14.52.MS(ESI,m/z):C23H24N2O5S2,[M+H]+473.12.
实施例18：Example 18:
Figure PCTCN2022114690-appb-000052
Figure PCTCN2022114690-appb-000052
THU118: 1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),8.64(d,J＝8.3Hz,1H),8.20(s,1H),7.92 (d,J＝8.0Hz,1H),7.83(d,J＝7.4Hz,2H),7.51(ddd,J＝27.0,15.4,7.1Hz,3H),7.02(t,J＝8.9Hz,1H),6.91(d,J＝8.3Hz,1H),6.80(s,1H),1.86(d,J＝2.3Hz,3H),1.34(s,2H),1.19–1.13(m,2H). 13C NMR(100MHz,DMSO-d 6)δ167.29,138.75,135.89,134.47,133.00,132.69,132.23,129.92,127.69,127.62,126.10,125.79,124.91,124.63,124.31,121.34,117.71,35.89,20.64,18.60.MS(ESI,m/z):C21H21N3O3S,[M+H]+396.13. THU118: 1 H NMR (400MHz, DMSO-d 6 ) δ9.07 (s, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.20 (s, 1H), 7.92 (d, J = 8.0Hz, 1H),7.83(d,J＝7.4Hz,2H),7.51(ddd,J＝27.0,15.4,7.1Hz,3H),7.02(t,J＝8.9Hz,1H),6.91(d,J＝8.3 Hz,1H),6.80(s,1H),1.86(d,J＝2.3Hz,3H),1.34(s,2H),1.19–1.13(m,2H). 13 C NMR(100MHz,DMSO-d 6 )δ167.29,138.75,135.89,134.47,133.00,132.69,132.23,129.92,127.69,127.62,126.10,125.79,124.91,124.63,124.31,121.34,117.71,35. 89,20.64,18.60.MS(ESI,m/z): C21H21N3O3S,[M+H]+396.13.
实施例19：Example 19:
Figure PCTCN2022114690-appb-000053
Figure PCTCN2022114690-appb-000053
THU119: 1H NMR(400MHz,DMSO-d 6)δ9.14(s,1H),8.63(d,J＝8.2Hz,1H),7.95–7.89(m,1H),7.86–7.78(m,2H),7.59–7.42(m,3H),6.86(t,J＝7.7Hz,1H),6.41(d,J＝8.0Hz,1H),6.28(d,J＝7.4Hz,1H),4.54(s,2H),1.74(s,3H),1.38–1.32(m,2H).1.17-1.14(m,2H).MS(ESI,m/z):C21H20N2O,[M+H]+317.16. THU119: 1 H NMR (400MHz, DMSO-d 6 ) δ9.14 (s, 1H), 8.63 (d, J = 8.2Hz, 1H), 7.95–7.89 (m, 1H), 7.86–7.78 (m, 2H ),7.59–7.42(m,3H),6.86(t,J＝7.7Hz,1H),6.41(d,J＝8.0Hz,1H),6.28(d,J＝7.4Hz,1H),4.54(s ,2H),1.74(s,3H),1.38–1.32(m,2H).1.17-1.14(m,2H).MS(ESI,m/z):C21H20N2O,[M+H]+317.16.
实施例20：Example 20:
Figure PCTCN2022114690-appb-000054
Figure PCTCN2022114690-appb-000054
THU120: 1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.63(d,J＝8.3Hz,1H),7.92(dd,J＝8.0,1.5Hz,1H),7.85–7.73(m,2H),7.57(ddd,J＝8.4,6.7,1.6Hz,1H),7.51(ddd,J＝8.0,6.8,1.3Hz,1H),7.44(dd,J＝8.2,7.1Hz,1H),6.85(d,J＝8.3Hz,1H),6.80(d,J＝2.2Hz,1H),6.63(dd,J＝8.3,2.3Hz,1H),5.75(s,2H),1.29(q,J＝4.7,4.3Hz,2H),1.13(q,J＝4.8Hz,2H).MS(ESI,m/z):C21H17F3N2O,[M+H]+371.13. THU120: 1 H NMR (400MHz, DMSO-d 6 ) δ9.03 (s, 1H), 8.63 (d, J = 8.3Hz, 1H), 7.92 (dd, J = 8.0, 1.5Hz, 1H), 7.85– 7.73(m,2H),7.57(ddd,J＝8.4,6.7,1.6Hz,1H),7.51(ddd,J＝8.0,6.8,1.3Hz,1H),7.44(dd,J＝8.2,7.1Hz, 1H),6.85(d,J＝8.3Hz,1H),6.80(d,J＝2.2Hz,1H),6.63(dd,J＝8.3,2.3Hz,1H),5.75(s,2H),1.29( q,J＝4.7,4.3Hz,2H),1.13(q,J＝4.8Hz,2H).MS(ESI,m/z):C21H17F3N2O,[M+H]+371.13.
实施例21：Example 21:
Figure PCTCN2022114690-appb-000055
Figure PCTCN2022114690-appb-000055
THU121: 1H NMR(400MHz,DMSO-d 6)δ8.98(s,1H),8.64(d,J＝8.2Hz,1H),7.92(dd,J＝7.9,1.6Hz,1H),7.86–7.76(m,2H),7.61–7.40(m,3H),6.79(t,J＝7.7Hz,1H),6.57(dd,J＝8.0,1.3Hz,1H),6.21(dd,J＝7.5,1.3Hz,1H),4.87(s,2H),1.69(s,3H),1.32(q,J＝4.6,4.1Hz,2H),1.14(q,J＝4.7Hz,2H).MS(ESI,m/z):C21H20N2O,[M+H]+317.16. THU121: 1 H NMR(400MHz, DMSO-d 6 )δ8.98(s,1H),8.64(d,J＝8.2Hz,1H),7.92(dd,J＝7.9,1.6Hz,1H),7.86– 7.76(m,2H),7.61–7.40(m,3H),6.79(t,J＝7.7Hz,1H),6.57(dd,J＝8.0,1.3Hz,1H),6.21(dd,J＝7.5, 1.3Hz,1H),4.87(s,2H),1.69(s,3H),1.32(q,J＝4.6,4.1Hz,2H),1.14(q,J＝4.7Hz,2H).MS(ESI, m/z):C21H20N2O,[M+H]+317.16.
实施例22：Example 22:
Figure PCTCN2022114690-appb-000056
Figure PCTCN2022114690-appb-000056
THU122: 1H NMR(400MHz,DMSO-d 6)δ8.69(d,J＝9.1Hz,2H),7.91(d,J＝8.1Hz,1H),7.80(d,J＝7.6Hz,2H),7.57(t,J＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.44(t,J＝7.7Hz,1H),6.94–6.85(m,1H),6.26(d,J＝7.4Hz,2H),5.25(s,2H),2.05(s,3H),1.30(d,J＝6.0Hz,2H),1.12(s,2H).MS(ESI,m/z):C21H20N2O,[M+H]+317.16. THU122: 1 H NMR (400MHz, DMSO-d 6 ) δ8.69(d,J＝9.1Hz,2H),7.91(d,J＝8.1Hz,1H),7.80(d,J＝7.6Hz,2H) ,7.57(t,J＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.44(t,J＝7.7Hz,1H),6.94–6.85(m,1H),6.26(d, J＝7.4Hz,2H),5.25(s,2H),2.05(s,3H),1.30(d,J＝6.0Hz,2H),1.12(s,2H).MS(ESI,m/z): C21H20N2O,[M+H]+317.16.
实施例23：Example 23:
Figure PCTCN2022114690-appb-000057
Figure PCTCN2022114690-appb-000057
THU123: 1H NMR(400MHz,DMSO-d 6)δ9.19(s,1H),8.62(d,J＝8.4Hz,1H),7.93(d,J＝8.0Hz,1H),7.81(dd,J＝12.6,7.9Hz,2H),7.65–7.49(m,2H),7.46(t,J＝7.6Hz,1H),7.25(d,J＝8.6Hz,1H),6.56(d,J ＝8.6Hz,1H),6.22(s,1H),5.85(s,2H),1.29(s,3H),1.13(s,2H).MS(ESI,m/z):C21H17F3N2O,[M+H]+371.13. THU123: 1 H NMR (400MHz, DMSO-d 6 ) δ9.19 (s, 1H), 8.62 (d, J = 8.4Hz, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.81 (dd, J＝12.6,7.9Hz,2H),7.65–7.49(m,2H),7.46(t,J＝7.6Hz,1H),7.25(d,J＝8.6Hz,1H),6.56(d,J＝8.6 Hz,1H),6.22(s,1H),5.85(s,2H),1.29(s,3H),1.13(s,2H).MS(ESI,m/z):C21H17F3N2O,[M+H]+ 371.13.
实施例24：Example 24:
Figure PCTCN2022114690-appb-000058
Figure PCTCN2022114690-appb-000058
THU124: 1H NMR(400MHz,Chloroform-d)δ8.23(d,J＝8.4Hz,1H),7.79(d,J＝8.1Hz,1H),7.64–7.53(m,2H),7.49(t,J＝7.5Hz,1H),7.18–7.01(m,3H),6.45(d,J＝2.1Hz,2H),5.57(s,1H),3.57(s,2H),1.79(d,J＝1.9Hz,3H),1.69(s,2H),1.20(s,2H). 13C NMR(101MHz,Chloroform-d)δ144.07,138.46,134.30,133.72,132.54,131.28,129.04,128.30,127.50,126.45,125.59,125.57,124.56,123.09,118.52,116.19,36.85,18.27.MS(ESI,m/z):C20H20N2O2S,[M+H]+353.13. THU124: 1 H NMR(400MHz,Chloroform-d)δ8.23(d,J＝8.4Hz,1H),7.79(d,J＝8.1Hz,1H),7.64–7.53(m,2H),7.49(t ,J＝7.5Hz,1H),7.18–7.01(m,3H),6.45(d,J＝2.1Hz,2H),5.57(s,1H),3.57(s,2H),1.79(d,J＝ 1.9Hz,3H),1.69(s,2H),1.20(s,2H). 13 C NMR(101MHz,Chloroform-d)δ144.07,138.46,134.30,133.72,132.54,131.28,129.04,128.30,127.50,126.45, 125.59,125.57,124.56,123.09,118.52,116.19,36.85,18.27.MS(ESI,m/z):C20H20N2O2S,[M+H]+353.13.
实施例25：Example 25:
Figure PCTCN2022114690-appb-000059
Figure PCTCN2022114690-appb-000059
THU125: 1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),8.69(d,J＝8.0Hz,1H),8.23–7.96(m,3H),7.93(d,J＝7.6Hz,1H),7.81(t,J＝7.9Hz,2H),7.62–7.42(m,3H),6.96(d,J＝7.9Hz,1H),6.75(d,J＝7.9Hz,1H),6.52(s,1H),3.50–3.41(m,2H),2.86(s,2H),2.80(s,3H),1.90(s,3H),1.37(s,2H),1.17(s,2H). 13C NMR(101MHz,DMSO-d 6)δ170.12,138.35,138.08,133.93,132.28,131.44,128.90,128.85,128.09,126.13,125.89,125.70,125.51,50.08,36.15,34.58,18.36,14.57.MS(ESI,m/z):C24H27N3O,[M+H]+374.22. THU125: 1 H NMR (400MHz, DMSO-d 6 ) δ9.07 (s, 1H), 8.69 (d, J = 8.0Hz, 1H), 8.23–7.96 (m, 3H), 7.93 (d, J = 7.6 Hz,1H),7.81(t,J＝7.9Hz,2H),7.62–7.42(m,3H),6.96(d,J＝7.9Hz,1H),6.75(d,J＝7.9Hz,1H), 6.52(s,1H),3.50–3.41(m,2H),2.86(s,2H),2.80(s,3H),1.90(s,3H),1.37(s,2H),1.17(s,2H) . 13 C NMR (101MHz, DMSO-d 6 ) δ170.12,138.35,138.08,133.93,132.28,131.44,128.90,128.85,128.09,126.13,125.89,125.70,125.51,50.08,36.15 ,34.58,18.36,14.57.MS( ESI,m/z):C24H27N3O,[M+H]+374.22.
实施例26：Example 26:
Figure PCTCN2022114690-appb-000060
Figure PCTCN2022114690-appb-000060
THU126: 1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),8.69(d,J＝8.4Hz,3H),7.98–7.90(m,1H),7.82(t,J＝8.3Hz,2H),7.64–7.43(m,3H),6.96(d,J＝8.5Hz,1H),6.74(dd,J＝8.5,2.8Hz,1H),6.49(d,J＝2.8Hz,1H),3.49(t,J＝6.9Hz,2H),2.96(q,J＝6.6Hz,2H),2.79(s,3H),2.54(d,J＝5.3Hz,3H),1.92(s,3H),1.37(q,J＝4.4Hz,2H),1.18(t,J＝3.3Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ170.18,138.08,133.93,132.28,131.43,128.91,128.10,126.15,125.89,125.68,125.52,48.85,45.51,34.58,33.09,18.36,14.57.MS(ESI,m/z):C25H29N3O,[M+H]+424.20. THU126: 1 H NMR (400MHz, DMSO-d 6 ) δ9.05 (s, 1H), 8.69 (d, J = 8.4Hz, 3H), 7.98–7.90 (m, 1H), 7.82 (t, J = 8.3 Hz,2H),7.64–7.43(m,3H),6.96(d,J＝8.5Hz,1H),6.74(dd,J＝8.5,2.8Hz,1H),6.49(d,J＝2.8Hz,1H ),3.49(t,J＝6.9Hz,2H),2.96(q,J＝6.6Hz,2H),2.79(s,3H),2.54(d,J＝5.3Hz,3H),1.92(s,3H ),1.37(q,J＝4.4Hz,2H),1.18(t,J＝3.3Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ170.18,138.08,133.93,132.28,131.43,128.91,128.10 ,126.15,125.89,125.68,125.52,48.85,45.51,34.58,33.09,18.36,14.57.MS(ESI,m/z):C25H29N3O,[M+H]+424.20.
实施例27：Example 27:
Figure PCTCN2022114690-appb-000061
Figure PCTCN2022114690-appb-000061
THU127: 1H NMR(400MHz,Methanol-d 4)δ8.61(d,J＝8.4Hz,1H),7.91(dd,J＝7.2,1.4Hz,2H),7.82(d,J＝8.2Hz,1H),7.61–7.55(m,1H),7.51(td,J＝7.4,6.7,1.2Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H),7.00(d,J＝8.5Hz,1H),6.69(dd,J＝8.6,2.8Hz,1H),6.40(d,J＝2.8Hz,1H),3.40(t,J＝6.9Hz,4H),2.54(s,4H),2.32(s,12H),2.00(s,3H),1.46(t,J＝3.5Hz,2H),1.32(q,J＝4.7Hz,2H).MS(ESI,m/z):C29H38N4O,[M+H]+459.31. THU127: 1 H NMR (400MHz, Methanol-d 4 ) δ8.61 (d, J = 8.4Hz, 1H), 7.91 (dd, J = 7.2, 1.4Hz, 2H), 7.82 (d, J = 8.2Hz, 1H),7.61–7.55(m,1H),7.51(td,J＝7.4,6.7,1.2Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H),7.00(d,J＝8.5Hz ,1H),6.69(dd,J＝8.6,2.8Hz,1H),6.40(d,J＝2.8Hz,1H),3.40(t,J＝6.9Hz,4H),2.54(s,4H),2.32 (s,12H),2.00(s,3H),1.46(t,J＝3.5Hz,2H),1.32(q,J＝4.7Hz,2H).MS(ESI,m/z):C29H38N4O,[M +H]+459.31.
实施例28：Example 28:
Figure PCTCN2022114690-appb-000062
Figure PCTCN2022114690-appb-000062
THU128: 1H NMR(400MHz,Methanol-d 4)δ8.64(d,J＝8.5Hz,1H),8.33(d,J＝21.6Hz,1H),7.96–7.87(m,2H),7.82(dd,J＝7.9,4.5Hz,1H),7.60(dddd,J＝8.4,6.8,2.9,1.4Hz,1H),7.55–7.45 (m,2H),7.38(d,J＝1.8Hz,1H),2.20(d,J＝17.9Hz,3H),1.49(td,J＝7.8,7.3,2.9Hz,2H),1.33(dt,J＝11.6,5.6Hz,2H). 13C NMR(101MHz,Methanol-d 4)δ172.29,141.94,136.76,134.18,132.62,132.12,130.74,128.40,128.34,127.87,125.66,125.11,124.70,115.31,113.93,34.27,18.31,13.52.MS(ESI,m/z):C22H19N3O,[M+H]+342.41. THU128: 1 H NMR (400MHz, Methanol-d 4 ) δ8.64 (d, J＝8.5Hz, 1H), 8.33 (d, J＝21.6Hz, 1H), 7.96–7.87 (m, 2H), 7.82 ( dd,J＝7.9,4.5Hz,1H),7.60(dddd,J＝8.4,6.8,2.9,1.4Hz,1H),7.55–7.45 (m,2H),7.38(d,J＝1.8Hz,1H) ,2.20(d,J＝17.9Hz,3H),1.49(td,J＝7.8,7.3,2.9Hz,2H),1.33(dt,J＝11.6,5.6Hz,2H). 13 C NMR (101MHz, Methanol -d 4 )δ172.29,141.94,136.76,134.18,132.62,132.12,130.74,128.40,128.34,127.87,125.66,125.11,124.70,115.31,113.93,34.27,18.31,1 3.52.MS(ESI,m/z):C22H19N3O ,[M+H]+342.41.
实施例29：Example 29:
Figure PCTCN2022114690-appb-000063
Figure PCTCN2022114690-appb-000063
THU129: 1H NMR(400MHz,Methanol-d 4)δ8.61(d,J＝8.5Hz,1H),7.91(dt,J＝7.0,2.7Hz,2H),7.83(d,J＝8.3Hz,1H),7.62(t,J＝7.8Hz,1H),7.57–7.41(m,2H),7.09(d,J＝8.1Hz,1H),6.90(dd,J＝8.2,2.7Hz,1H),6.67(d,J＝2.5Hz,1H),4.53(q,J＝6.9,6.5Hz,1H),4.31(t,J＝9.6Hz,2H),4.14(dd,J＝10.9,6.5Hz,2H),1.99(d,J＝2.4Hz,3H),1.50(s,2H),1.32(d,J＝7.8Hz,2H). 13C NMR(101MHz,Methanol-d 4)δ171.86,139.27,137.44,136.49,134.16,132.07,131.62,129.01,128.42,128.00,125.81,125.22,124.70,124.43,117.64,114.42,51.80,47.30,34.38,16.97,13.54.MS(ESI,m/z):C24H25N3O,[M+H]+372.46. THU129: 1 H NMR (400MHz, Methanol-d 4 ) δ8.61 (d, J＝8.5Hz, 1H), 7.91 (dt, J＝7.0, 2.7Hz, 2H), 7.83 (d, J＝8.3Hz, 1H),7.62(t,J＝7.8Hz,1H),7.57–7.41(m,2H),7.09(d,J＝8.1Hz,1H),6.90(dd,J＝8.2,2.7Hz,1H), 6.67(d,J＝2.5Hz,1H),4.53(q,J＝6.9,6.5Hz,1H),4.31(t,J＝9.6Hz,2H),4.14(dd,J＝10.9,6.5Hz,2H ), 1.99 (d, J = 2.4Hz, 3H), 1.50 (s, 2H), 1.32 (d, J = 7.8Hz, 2H). 13 C NMR (101MHz, Methanol-d 4 ) δ 171.86, 139.27, 137.44, 136.49,134.16,132.07,131.62,129.01,128.42,128.00,125.81,125.22,124.70,124.43,117.64,114.42,51.80,47.30,34.38,16.97,13.54.MS( ESI,m/z):C24H25N3O,[M+ H]+372.46.
实施例30：Example 30:
Figure PCTCN2022114690-appb-000064
Figure PCTCN2022114690-appb-000064
THU130: 1H NMR(400MHz,Methanol-d 4)δ8.60(d,J＝8.4Hz,1H),7.90(d,J＝7.6Hz,2H),7.81(d,J＝8.2Hz,1H),7.59(t,J＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.44(t,J＝7.7Hz,1H),6.89(d,J＝8.3Hz,1H),6.59(d,J＝8.3Hz,1H),6.38(s,1H),3.41(d,J＝18.7Hz,3H),3.15–3.06(m,1H),2.83(s,3H),2.10(d,J＝13.8Hz,2H),1.94(s,3H),1.57(d,J＝21.0Hz,2H),1.46(d,J＝5.6Hz,2H),1.30(d,J＝5.4Hz,2H).MS(ESI,m/z):C27H31N3O,[M+H]+414.36. THU130: 1 H NMR (400MHz, Methanol-d 4 ) δ8.60 (d, J = 8.4Hz, 1H), 7.90 (d, J = 7.6Hz, 2H), 7.81 (d, J = 8.2Hz, 1H) ,7.59(t,J＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.44(t,J＝7.7Hz,1H),6.89(d,J＝8.3Hz,1H),6.59 (d,J＝8.3Hz,1H),6.38(s,1H),3.41(d,J＝18.7Hz,3H),3.15–3.06(m,1H),2.83(s,3H),2.10(d, J＝13.8Hz,2H),1.94(s,3H),1.57(d,J＝21.0Hz,2H),1.46(d,J＝5.6Hz,2H),1.30(d,J＝5.4Hz,2H) .MS(ESI,m/z):C27H31N3O,[M+H]+414.36.
实施例31：Example 31:
Figure PCTCN2022114690-appb-000065
Figure PCTCN2022114690-appb-000065
THU131: 1H NMR(400MHz,MeOD)δ8.61(d,J＝8.5Hz,1H),7.94–7.86(m,2H),7.81(d,J＝8.2Hz,1H),7.58(t,J＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.48–7.41(m,1H),6.88(d,J＝8.1Hz,1H),6.58(dd,J＝8.2,2.6Hz,1H),6.35(d,J＝2.5Hz,1H),3.35–3.31(m,2H),3.26(d,J＝10.9Hz,1H),3.11(d,J＝12.8Hz,2H),2.71(t,J＝12.2Hz,2H),1.96(d,J＝2.1Hz,5H),1.44(d,J＝5.7Hz,2H),1.30(s,2H). 13C NMR(101MHz,MeOD)δ172.88,145.07,137.40,136.86,134.16,132.12,130.80,128.37,128.27,127.81,125.60,125.09,124.71,124.52,114.76,111.47,48.91,46.97,43.91,34.11,31.18,16.72,13.49.MS(ESI,m/z):C26H29N3O,[M+H]+400.23. THU131: 1 H NMR(400MHz,MeOD)δ8.61(d,J＝8.5Hz,1H),7.94–7.86(m,2H),7.81(d,J＝8.2Hz,1H),7.58(t,J ＝7.7Hz,1H),7.51(t,J＝7.5Hz,1H),7.48–7.41(m,1H),6.88(d,J＝8.1Hz,1H),6.58(dd,J＝8.2,2.6Hz ,1H),6.35(d,J＝2.5Hz,1H),3.35–3.31(m,2H),3.26(d,J＝10.9Hz,1H),3.11(d,J＝12.8Hz,2H),2.71 (t, J＝12.2Hz, 2H), 1.96 (d, J＝2.1Hz, 5H), 1.44 (d, J＝5.7Hz, 2H), 1.30 (s, 2H). 13 C NMR (101MHz, MeOD) δ172.88,145.07,137.40,136.86,134.16,132.12,130.80,128.37,128.27,127.81,125.60,125.09,124.71,124.52,114.76,111.47,48.91,46.9 7,43.91,34.11,31.18,16.72,13.49.MS(ESI, m/z):C26H29N3O,[M+H]+400.23.
实施例32：Example 32:
Figure PCTCN2022114690-appb-000066
Figure PCTCN2022114690-appb-000066
THU132: 1H NMR(400MHz,MeOD)δ8.61(d,J＝8.5Hz,1H),7.95–7.89(m,2H),7.84(d,J＝8.2Hz,1H),7.60(ddd,J＝8.4,6.9,1.3Hz,1H),7.49(ddd,J＝21.5,8.0,6.8Hz,2H),7.24(s,2H),7.01(s,1H),4.41–4.31(m,1H),3.59(ddd,J＝27.7,12.4,7.3Hz,2H),3.48–3.36(m,2H),2.38(dq,J＝14.6,7.4Hz,1H),2.21(dq,J＝13.7,7.1Hz,1H),2.06(s,3H),1.50(q,J＝4.8Hz,2H),1.36–1.31(m,2H). 13C NMR(101MHz,MeOD)δ170.80,138.39,136.57,134.16,132.07,131.91,128.44,128.40,127.96,125.76,125.17,124.71,124.41,120.56,117.66,57.00,44.37,34.25,28.18,17.17,13.57.MS(ESI,m/z):C25H27N3O,[M+H]+386.22. THU132: 1 H NMR(400MHz,MeOD)δ8.61(d,J＝8.5Hz,1H),7.95–7.89(m,2H),7.84(d,J＝8.2Hz,1H),7.60(ddd,J ＝8.4,6.9,1.3Hz,1H),7.49(ddd,J＝21.5,8.0,6.8Hz,2H),7.24(s,2H),7.01(s,1H),4.41–4.31(m,1H), 3.59(ddd,J＝27.7,12.4,7.3Hz,2H),3.48–3.36(m,2H),2.38(dq,J＝14.6,7.4Hz,1H),2.21(dq,J＝13.7,7.1Hz, 1H), 2.06 (s, 3H), 1.50 (q, J = 4.8Hz, 2H), 1.36–1.31 (m, 2H). 13 C NMR (101MHz, MeOD) δ 170.80, 138.39, 136.57, 134.16, 132.07, 131.91 ,128.44,128.40,127.96,125.76,125.17,124.71,124.41,120.56,117.66,57.00,44.37,34.25,28.18,17.17,13.57.MS(ESI,m/z):C25H27N3O,[M+ H]+386.22.
实施例33：Example 33:
Figure PCTCN2022114690-appb-000067
Figure PCTCN2022114690-appb-000067
THU133: 1H NMR(400MHz,MeOD)δ8.60(d,J＝8.4Hz,1H),7.94–7.89(m,2H),7.83(d,J＝8.3Hz,1H),7.58(t,J＝7.6Hz,1H),7.47(ddd,J＝25.3,12.5,5.0Hz,3H),7.25(d,J＝2.4Hz,1H),7.12(d,J＝8.3Hz,1H),2.05(s,3H),1.66(d,J＝7.2Hz,2H),1.50–1.40(m,4H),1.33(d,J＝5.8Hz,2H). 13C NMR(101MHz,MeOD)δ171.60,167.98,137.12,136.68,134.84,134.13,132.08,131.53,130.51,128.38(d,J＝5.5Hz),127.90,125.69,125.14,124.70,124.43,122.30,119.54,35.50,34.15,17.21,13.64,12.05.MS(ESI,m/z):C25H25N3O2,[M+H]+400.19. THU133: 1 H NMR(400MHz,MeOD)δ8.60(d,J＝8.4Hz,1H),7.94–7.89(m,2H),7.83(d,J＝8.3Hz,1H),7.58(t,J ＝7.6Hz,1H),7.47(ddd,J＝25.3,12.5,5.0Hz,3H),7.25(d,J＝2.4Hz,1H),7.12(d,J＝8.3Hz,1H),2.05(s ,3H),1.66(d,J＝7.2Hz,2H),1.50–1.40(m,4H),1.33(d,J＝5.8Hz,2H). 13 C NMR(101MHz,MeOD)δ171.60,167.98,137.12 ,136.68,134.84,134.13,132.08,131.53,130.51,128.38(d,J＝5.5Hz),127.90,125.69,125.14,124.70,124.43,122.30,119.54,35.50,34.15,17 .21,13.64,12.05.MS(ESI ,m/z):C25H25N3O2,[M+H]+400.19.
实施例34：Example 34:
Figure PCTCN2022114690-appb-000068
Figure PCTCN2022114690-appb-000068
THU134: 1H NMR(400MHz,CDCl 3)δ8.46(d,J＝8.0Hz,1H),7.95(d,J＝6.5Hz,1H),7.91(d,J＝7.5Hz,1H),7.82(d,J＝8.0Hz,1H),7.59–7.43(m,3H),7.08–6.93(m,3H),6.83(s,1H),6.54(s,1H),6.34(d,J＝7.4Hz,1H),6.29–6.20(m,2H),2.12(s,3H),1.60–1.51(m,2H),1.43–1.35(m,2H). 13C NMR(101MHz,CDCl 3)δ169.77,147.52,144.20,140.67,137.30,136.86,133.99,131.91,131.68,130.22,129.01,128.74,128.33,128.09,126.19,125.51,125.49,124.08,119.83,116.88,108.06,107.92,103.66,34.81,18.69,14.83.MS(ESI,m/z):C27H25N3O,[M+H]+408.20. THU134: 1 H NMR (400MHz, CDCl 3 ) δ8.46 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 6.5 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.82 (d,J＝8.0Hz,1H),7.59–7.43(m,3H),7.08–6.93(m,3H),6.83(s,1H),6.54(s,1H),6.34(d,J＝7.4 Hz,1H),6.29–6.20(m,2H),2.12(s,3H),1.60–1.51(m,2H),1.43–1.35(m,2H). 13 C NMR (101MHz, CDCl 3 )δ169. 77,147.52,144.20,140.67,137.30,136.86,133.99,131.91,131.68,130.22,129.01,128.74,128.33,128.09,126.19,125.51,125.49,124.08,1 19.83,116.88,108.06,107.92,103.66,34.81,18.69,14.83. MS(ESI,m/z):C27H25N3O,[M+H]+408.20.
实施例35：Example 35:
Figure PCTCN2022114690-appb-000069
Figure PCTCN2022114690-appb-000069
THU135: 1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),9.01(s,1H),8.65(d,J＝8.1Hz,1H),8.07(s,1H),7.93(d,J＝7.2Hz,1H),7.82(d,J＝6.2Hz,2H),7.57–7.37(m,4H),7.07(t,J＝8.0Hz,1H),6.94(d,J＝7.9Hz,1H),6.78(s,1H),6.64(d,J＝8.0Hz,1H),2.02(s,3H),1.98(s,3H),1.40–1.29(m,2H),1.20–1.14(m,2H). 13C NMR(101MHz,CDCl 3)δ170.09,168.50,144.07,139.60,138.59,137.19,136.41,133.96,132.04,129.90,129.74,128.88,128.77,128.04,125.69,125.38,125.25,124.65,120.82,117.74,112.87,110.75,107.47,34.83,24.82,19.10,14.58.MS(ESI,m/z):C29H27N3O2,[M+H]+450.21. THU135: 1 H NMR (400MHz, DMSO-d 6 ) δ9.79 (s, 1H), 9.01 (s, 1H), 8.65 (d, J = 8.1Hz, 1H), 8.07 (s, 1H), 7.93 ( d,J＝7.2Hz,1H),7.82(d,J＝6.2Hz,2H),7.57–7.37(m,4H),7.07(t,J＝8.0Hz,1H),6.94(d,J＝7.9 Hz,1H),6.78(s,1H),6.64(d,J＝8.0Hz,1H),2.02(s,3H),1.98(s,3H),1.40–1.29(m,2H),1.20–1.14 (m,2H). 13 C NMR (101MHz, CDCl 3 ) δ170.09,168.50,144.07,139.60,138.59,137.19,136.41,133.96,132.04,129.90,129.74,128.88,128.77,128.04,1 25.69,125.38,125.25,124.65 ,120.82,117.74,112.87,110.75,107.47,34.83,24.82,19.10,14.58.MS(ESI,m/z):C29H27N3O2,[M+H]+450.21.
上述实施例化合物的制备：Preparation of the compounds of the above examples:
(1)环丙基胺中间体(1-(萘-1-基)环丙胺)的制备，合成路线如下：(1) Preparation of cyclopropylamine intermediate (1-(naphthyl-1-yl)cyclopropylamine), the synthesis route is as follows:
Figure PCTCN2022114690-appb-000070
Figure PCTCN2022114690-appb-000070
具体操作如下所示：The specific operations are as follows:
将1-萘甲腈(1，5mmol，1.0e.q.)置于圆底烧瓶中，加入10mL干燥的四氢呋喃作为溶剂，随后加入钛酸四异丙酯(5.5mmol，1.0e.q.)，将反应体系降温至-78℃，然后向反应体系中缓慢滴加乙基格氏试剂(11mmol，2.2e.q.)。滴加完成后，将反应体系升温至室温反应1.5小时。随后向反应体系中滴加三氟化硼乙醚(10mmol，2.0e.q.)，滴加完成后常温下搅拌反应三小时。反应结束后向反应体系中滴加2N盐酸20mL，搅拌淬灭20分钟，随后加入过量的饱和氢氧化钠溶液。加入乙酸乙酯萃取，收集有机相并旋干后通过硅胶柱层析分离，既可获得环丙基胺中间体2。Place 1-naphthylcarbonitrile (1,5mmol, 1.0e.q.) in a round-bottomed flask, add 10 mL of dry tetrahydrofuran as the solvent, then add tetraisopropyl titanate (5.5mmol, 1.0e.q.), and cool the reaction system to -78°C, and then slowly add ethyl Grignard reagent (11 mmol, 2.2e.q.) into the reaction system dropwise. After the dropwise addition was completed, the reaction system was heated to room temperature and reacted for 1.5 hours. Then, boron trifluoride ether (10 mmol, 2.0 e.q.) was added dropwise to the reaction system. After the dropwise addition was completed, the reaction was stirred at room temperature for three hours. After the reaction, 20 mL of 2N hydrochloric acid was added dropwise to the reaction system, stirred to quench for 20 minutes, and then excess saturated sodium hydroxide solution was added. Add ethyl acetate for extraction, collect the organic phase, spin it to dryness, and then separate it through silica gel column chromatography to obtain cyclopropylamine intermediate 2.
(2)实施例24的化合物的制备，合成路线如下：(2) Preparation of the compound of Example 24, the synthesis route is as follows:
Figure PCTCN2022114690-appb-000071
Figure PCTCN2022114690-appb-000071
具体操作为：将化合物2(1.0mmol，1.0e.q.)置于圆底烧瓶内，加入10mL THF作溶剂，加入三乙胺(4.0e.q.)，0℃下滴加化合物3(1.0mmol，1.0e.q.)的THF溶液，滴加完毕后撤去冰浴，50℃搅拌反应12h。待反应结束后，旋干溶剂，加入乙酸乙酯和水萃取，用饱和氯化铵溶液洗涤一次，饱和食盐水洗涤一次，有机相旋干，硅胶柱层析纯化得到产物THU124。The specific operation is: place compound 2 (1.0mmol, 1.0e.q.) in a round-bottomed flask, add 10mL THF as solvent, add triethylamine (4.0e.q.), and drop compound 3 (1.0mmol, 1.0e.q.) at 0°C. THF solution, remove the ice bath after the dropwise addition, and stir the reaction at 50°C for 12 hours. After the reaction is completed, spin the solvent to dryness, add ethyl acetate and water to extract, wash once with saturated ammonium chloride solution and once with saturated brine, spin the organic phase to dryness, and purify by silica gel column chromatography to obtain the product THU124.
(3)实施例28的化合物的制备，合成路线如下：(3) Preparation of the compound of Example 28, the synthesis route is as follows:
Figure PCTCN2022114690-appb-000072
Figure PCTCN2022114690-appb-000072
将中间体4与先前得到的三元环胺中间体2按照一比一当量加入DMF溶剂，加入HATU(1.5e.q.)和DIPEA(2.0e.q.)，70℃下反应12h，乙酸乙酯萃取反应液，用饱和氯化铵溶液洗涤三次，有机相旋干后，硅胶柱层析纯化得到产物THU128。Add intermediate 4 and the previously obtained three-membered cyclic amine intermediate 2 to DMF solvent at a ratio of one to one equivalent, add HATU (1.5e.q.) and DIPEA (2.0e.q.), react at 70°C for 12 hours, and extract the reaction solution with ethyl acetate. It was washed three times with saturated ammonium chloride solution, and the organic phase was spin-dried and purified by silica gel column chromatography to obtain the product THU128.
(4)其他实施例化合物的制备，合成路线如下：(4) Preparation of other example compounds, the synthesis route is as follows:
Figure PCTCN2022114690-appb-000073
Figure PCTCN2022114690-appb-000073
具体操作为：The specific operations are:
将中间体M1(1.0e.q.)置于圆底烧瓶，加入四氢呋喃：水＝2:1作为溶剂，随后向反应体系中加入氢氧化锂(4.0e.q.)，60℃搅拌反应6小时后将反应体系用2N盐酸酸化，加入乙酸乙酯后既析出白色固体，抽滤出固体并干燥后既得到中间体M2。Place intermediate M1 (1.0e.q.) in a round-bottomed flask, add tetrahydrofuran: water = 2:1 as the solvent, then add lithium hydroxide (4.0e.q.) to the reaction system, stir the reaction at 60°C for 6 hours, and then use Acidify with 2N hydrochloric acid. After adding ethyl acetate, a white solid precipitates. The solid is filtered out and dried to obtain intermediate M2.
将中间体M2与先前得到的三元环胺中间体2按照一比一当量加入DMF溶剂，加入HATU(1.5e.q.)和DIPEA(2.0e.q.)，70℃下反应12h，乙酸乙酯萃取反应液，用饱和氯化铵溶液洗涤三次，有机相旋干后，硅胶柱层析纯化得到产物P。Add intermediate M2 and the previously obtained three-membered cyclic amine intermediate 2 to the DMF solvent at a ratio of one to one equivalent, add HATU (1.5e.q.) and DIPEA (2.0e.q.), react at 70°C for 12 hours, and extract the reaction solution with ethyl acetate. It was washed three times with saturated ammonium chloride solution, and the organic phase was spin-dried and purified by silica gel column chromatography to obtain product P.
上中R 1为环上一个或多个独立的取代基，R 1、Y 1、Y 2、Y 3、Y 4根据具体化合物结构选择。 In the above, R 1 is one or more independent substituents on the ring, and R 1 , Y 1 , Y 2 , Y 3 and Y 4 are selected according to the specific compound structure.
例如对于化合物THU116、THU117、THU118、THU125、THU126、THU127、THU129、THU130、THU131、THU132、THU134、THU135，中间体M1为
Figure PCTCN2022114690-appb-000074
其合成路线如下： For example, for compounds THU116, THU117, THU118, THU125, THU126, THU127, THU129, THU130, THU131, THU132, THU134, THU135, intermediate M1 is
Figure PCTCN2022114690-appb-000074
Its synthesis route is as follows:
Figure PCTCN2022114690-appb-000075
Figure PCTCN2022114690-appb-000075
其中，R 2＝H、-CH 3、-SO 2CH 3或-CH 2CH 2N(CH 3) 2； Among them, R 2 =H, -CH 3 , -SO 2 CH 3 or -CH 2 CH 2 N(CH 3 ) 2 ;
R 3＝-CH 3、-CONH 2、-SO 2CH 3、-SO 2NH 2、-CH 2CH 2NH 2、-CH 2CH 2NH(CH 3)、-CH 2CH 2N(CH 3) 2、 R 3 =-CH 3 , -CONH 2 , -SO 2 CH 3 , -SO 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NH(CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 ,
Figure PCTCN2022114690-appb-000076
Figure PCTCN2022114690-appb-000076
具体操作为：将2-甲基-5-溴苯甲酸甲酯(5，10.0mmol，1.0e.q.)、胺类化合物(6，10.0mmol，1.0e.q.)、三(二亚苄基丙酮)二钯(0.2mmol，0.02e.q.)、2-二环己基磷-2,4,6-三异丙基联苯(0.8mmol，0.08e.q.)、碳酸铯(20.0mmol，2.0e.q.)置于密封管内，加入50mL甲苯作为溶剂，在氩气保护下110℃持续搅拌反应24h。反应结束后将反应液移至圆底烧瓶内，旋干溶剂，加入乙酸乙酯和水萃取，有机相用饱和氯化铵溶液、饱和食盐水各洗涤一次，旋干有机相，硅胶柱层析纯化得到中间体M1。The specific operation is: combine 2-methyl-5-bromobenzoic acid methyl ester (5, 10.0mmol, 1.0e.q.), amine compounds (6, 10.0mmol, 1.0e.q.), tris(dibenzylideneacetone) dipalladium (0.2mmol, 0.02e.q.), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.8mmol, 0.08e.q.), and cesium carbonate (20.0mmol, 2.0e.q.) were placed in a sealed tube and added 50 mL of toluene was used as the solvent, and the reaction was continued with stirring at 110°C for 24 hours under argon protection. After the reaction is completed, move the reaction solution to a round-bottomed flask, spin the solvent dry, add ethyl acetate and water for extraction, wash the organic phase once each with saturated ammonium chloride solution and saturated brine, spin the organic phase to dryness, and perform silica gel column chromatography. Purification gave intermediate M1.
实验实施例1：检测上述实施例制备的化合物的PLpro抑制活性Experimental Example 1: Detection of PLpro inhibitory activity of compounds prepared in the above examples
生物测试条件：Biological test conditions:
1、Reaction buffer:20mM HEPEs,pH 7.5,100mM NaCl,1mM TCEP1. Reaction buffer: 20mM HEPEs, pH 7.5, 100mM NaCl, 1mM TCEP
2、母液配制：2. Preparation of mother liquor:
(1)20μM Ub-AMC(Ub-AMC干粉直接用reaction buffer溶解，离心去除沉淀后使用)；(1) 20μM Ub-AMC (Ub-AMC dry powder is directly dissolved in reaction buffer, and centrifuged to remove the precipitate before use);
(2)400nM PLpro(分子筛纯化后冻存至-80℃，用前冰上融化，用reaction buffer稀释)；(2) 400nM PLpro (purified by molecular sieve and stored at -80°C, thawed on ice before use, diluted with reaction buffer);
(3)40μM试验化合物(试验化合物干粉用DMSO溶解至40mM；用50％DMSO稀释至400μM；再用reaction buffer稀释至40μM)；(3) 40μM test compound (test compound dry powder is dissolved in DMSO to 40mM; diluted to 400μM with 50% DMSO; then diluted to 40μM with reaction buffer);
3、对于单点抑制试验反应体系：10μM Ub-AMC,100nM PLpro,1μM试验化合物,总体积20μL，384孔板内反应；3. For single-point inhibition test reaction system: 10μM Ub-AMC, 100nM PLpro, 1μM test compound, total volume 20μL, reaction in 384-well plate;
将5μL PLpro母液+5μL试验化合物母液，加入384孔板后，4℃孵育30min；Add 5 μL PLpro stock solution + 5 μL test compound stock solution to the 384-well plate and incubate at 4°C for 30 minutes;
将10μL Ub-AMC母液加入384孔板，37℃反应30min后测AMC荧光强度(excitation:360nm；emission:460nm)；Add 10 μL Ub-AMC stock solution to the 384-well plate, react at 37°C for 30 minutes, and then measure the AMC fluorescence intensity (excitation: 360nm; emission: 460nm);
4、+Control:对应稀释倍数的DMSO代替试验化合物；4. +Control: DMSO corresponding to the dilution ratio replaces the test compound;
Blank:Reaction buffer替代PLpro；Blank: Reaction buffer replaces PLpro;
5、数据处理：将测得数值减去Blank值，以DMSO数值为基准做归一化；5. Data processing: Subtract the Blank value from the measured value and normalize it based on the DMSO value;
6、IC 50测定： 6. IC 50 determination:
试验化合物浓度梯度(nM)：10000，5000，1000，500，250，125，62.5，31.25，15.625,10，5，2，1，0.5，0.1，0.01Test compound concentration gradient (nM): 10000, 5000, 1000, 500, 250, 125, 62.5, 31.25, 15.625, 10, 5, 2, 1, 0.5, 0.1, 0.01
反应15min测荧光值(15min左右酶反应速率处于线性区间，30min非线性区间)；Measure the fluorescence value after 15 minutes of reaction (the enzyme reaction rate is in the linear interval around 15 minutes and in the non-linear interval at 30 minutes);
7、数据拟合：数据归一化后用Sigmaplot处理(拟合方程：Logistic,3Parameter)。7. Data fitting: After data normalization, use Sigmaplot to process (fitting equation: Logistic, 3Parameter).
结果如下表所示。The results are shown in the table below.
表1 实验结果Table 1 Experimental results
Figure PCTCN2022114690-appb-000077
Figure PCTCN2022114690-appb-000077
Figure PCTCN2022114690-appb-000078
Figure PCTCN2022114690-appb-000078
Figure PCTCN2022114690-appb-000079
Figure PCTCN2022114690-appb-000079
Figure PCTCN2022114690-appb-000080
Figure PCTCN2022114690-appb-000080
Figure PCTCN2022114690-appb-000081
Figure PCTCN2022114690-appb-000081
其中GRL0617为阳性参照，是文献中报道的对PLpro抑制活性最强的一类分子代表(Ghosh et al.,2009；Ghosh et al.,2010；Ratia et al.,2008)。Among them, GRL0617 is a positive reference and is a representative of the class of molecules with the strongest inhibitory activity against PLpro reported in the literature (Ghosh et al., 2009; Ghosh et al., 2010; Ratia et al., 2008).
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention. within.
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。The foregoing embodiments and methods described in the present invention may vary based on the abilities, experience and preferences of those skilled in the art.
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。In the present invention, only listing the steps of the method in a certain order does not constitute any restriction on the order of the steps of the method.

Claims (16)

  1. 一种化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物，所述化合物具有以下结构：A compound, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, having the following structure:
    Figure PCTCN2022114690-appb-100001
    Figure PCTCN2022114690-appb-100001
    其中，in,
    Ar选自：萘基、喹啉基、异喹啉基和喹唑啉基，其中萘基、喹啉基、异喹啉基或喹唑啉基中的氢原子可以任选地被C 1-C 6烷基、-NH 2、-OH、-OC 1-C 6烷基、-CH 2X、-CHX 2、-CX 3取代； Ar is selected from: naphthyl, quinolinyl, isoquinolinyl and quinazolinyl, wherein the hydrogen atom in the naphthyl, quinolinyl, isoquinolinyl or quinazolinyl group may optionally be replaced by C 1 - C 6 alkyl, -NH 2 , -OH, -OC 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -CX 3 substitution;
    L 1选自：C 1-C 6亚烷基、-CO-、-SO 2-； L 1 is selected from: C 1 -C 6 alkylene, -CO-, -SO 2 -;
    A 1、A 2、A 3、A 4和A 5独立地选自C或N，且当A 1、A 2、A 3、A 4或A 5为N原子时，与之相连的R 1、R 2、R 3、R 4或R 5不存在； A 1 , A 2 , A 3 , A 4 and A 5 are independently selected from C or N, and when A 1 , A 2 , A 3 , A 4 or A 5 is an N atom, the R 1 , A 5 connected to it are R 2 , R 3 , R 4 or R 5 does not exist;
    R 1、R 2、R 3、R 4和R 5独立地选自：H、C 1-C 6烷基、-L 2-NR 9R 10、-L 2-OH、-L 2-OC 1-C 6烷基、-CN、-X、-CH 2X、-CHX 2、-CX 3；或者，R 1、R 2、R 3、R 4和R 5中的两者与其连接的原子一起形成杂环基； R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from: H, C 1 -C 6 alkyl, -L 2 -NR 9 R 10 , -L 2 -OH, -L 2 -OC 1 -C6 alkyl, -CN, -X, -CH2X , -CHX2 , -CX3 ; or, two of R1 , R2 , R3 , R4 and R5 together with the atom to which they are connected Form heterocyclyl;
    L 2选自：单键、C 1-C 6亚烷基、-CO-、-SO 2-、-NHCO-、-NH-SO 2-； L 2 is selected from: single bond, C 1 -C 6 alkylene, -CO-, -SO 2 -, -NHCO-, -NH-SO 2 -;
    R 9和R 10独立地选自：H、C 1-C 6烷基、-CH 2X、-CHX 2、-SO 2(C 1-C 6烷基)、-CX 3、-L 3-NR 11R 12、含氮杂环基； R 9 and R 10 are independently selected from: H, C 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -SO 2 (C 1 -C 6 alkyl), -CX 3 , -L 3 - NR 11 R 12 , nitrogen-containing heterocyclic group;
    L 3选自：C 1-C 6亚烷基、-CO-、-SO 2-、-NHCO-、-NH-SO 2-、亚苯基、
    Figure PCTCN2022114690-appb-100002
    L 3 is selected from: C 1 -C 6 alkylene, -CO-, -SO 2 -, -NHCO-, -NH-SO 2 -, phenylene,
    Figure PCTCN2022114690-appb-100002
    R 11和R 12独立地选自：H、C 1-C 6烷基、-CH 2X、-CHX 2、-SO 2(C 1-C 6烷基)、-CX 3、-CO(C 1-C 6烷基)； R 11 and R 12 are independently selected from: H, C 1 -C 6 alkyl, -CH 2 X, -CHX 2 , -SO 2 (C 1 -C 6 alkyl), -CX 3 , -CO(C 1 -C 6 alkyl);
    X选自：F、Cl、Br、I；X is selected from: F, Cl, Br, I;
    R 6选自：H、C 1-C 6烷基； R 6 is selected from: H, C 1 -C 6 alkyl;
    W 1和W 2独立地选自：C、N、O；且当W 1或W 2为O时，相应的R 7或R 8不存在； W 1 and W 2 are independently selected from: C, N, O; and when W 1 or W 2 is O, the corresponding R 7 or R 8 does not exist;
    R 7和R 8独立地选自：H、(＝O)、C 1-C 6烷基、-X、-CH 2X、-CHX 2、-CX 3、羟基、-OC 1-C 6烷基。 R 7 and R 8 are independently selected from: H, (=O), C 1 -C 6 alkyl, -X, -CH 2 X, -CHX 2 , -CX 3 , hydroxyl, -OC 1 -C 6 alkyl base.
  2. 如权利要求1所述的化合物，其特征在于，Ar选自：1-萘基、2-萘基、2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基、1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基、8-异喹啉基、2-喹唑啉基、4-喹唑啉基、5-喹唑啉基、6-喹唑啉基、7-喹唑啉基、8-喹唑啉基；The compound of claim 1, wherein Ar is selected from: 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl , 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl Quinolinyl, 7-isoquinolinyl, 8-isoquinolinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazole Phyllinyl, 8-quinazolinyl;
    优选地，Ar为1-萘基或2-萘基。Preferably, Ar is 1-naphthyl or 2-naphthyl.
  3. 如权利要求1或2所述的化合物，其特征在于，A 1、A 2、A 3、A 4和A 5均为C；或， The compound of claim 1 or 2, wherein A 1 , A 2 , A 3 , A 4 and A 5 are all C; or,
    A 1为N，A 2、A 3、A 4和A 5为C；或， A 1 is N, A 2 , A 3 , A 4 and A 5 are C; or,
    A 2为N，A 1、A 3、A 4和A 5为C；或， A 2 is N, A 1 , A 3 , A 4 and A 5 are C; or,
    A 3为N，A 1、A 2、A 4和A 5为C；或， A 3 is N, A 1 , A 2 , A 4 and A 5 are C; or,
    A 4为N，A 1、A 2、A 3和A 5为C；或， A 4 is N, A 1 , A 2 , A 3 and A 5 are C; or,
    A 5为N，A 1、A 2、A 3和A 4为C；或， A 5 is N, A 1 , A 2 , A 3 and A 4 are C; or,
    A 1和A 2为N，A 3、A 4和A 5为C；或， A 1 and A 2 are N, A 3 , A 4 and A 5 are C; or,
    A 1和A 3为N，A 2、A 4和A 5为C；或， A 1 and A 3 are N, A 2 , A 4 and A 5 are C; or,
    A 1和A 4为N，A 2、A 3和A 5为C；或， A 1 and A 4 are N, A 2 , A 3 and A 5 are C; or,
    A 1和A 5为N，A 2、A 3和A 4为C；或， A 1 and A 5 are N, A 2 , A 3 and A 4 are C; or,
    A 2和A 3为N，A 1、A 4和A 5为C；或， A 2 and A 3 are N, A 1 , A 4 and A 5 are C; or,
    A 2和A 4为N，A 1、A 3和A 5为C；或， A 2 and A 4 are N, A 1 , A 3 and A 5 are C; or,
    A 2和A 5为N，A 1、A 3和A 4为C；或， A 2 and A 5 are N, A 1 , A 3 and A 4 are C; or,
    A 3和A 4为N，A 1、A 2和A 5为C；或， A 3 and A 4 are N, A 1 , A 2 and A 5 are C; or,
    A 3和A 5为N，A 1、A 2和A 4为C；或， A 3 and A 5 are N, A 1 , A 2 and A 4 are C; or,
    A 4和A 5为N，A 1、A 2和A 3为C。 A 4 and A 5 are N, and A 1 , A 2 and A 3 are C.
  4. 如权利要求1-3任一项所述的化合物，其特征在于，W 1为C，W 2为C；或，W 1为C，W 2为N；或，W 1为C，W 2为O。 The compound according to any one of claims 1 to 3, characterized in that, W 1 is C, W 2 is C; or, W 1 is C, W 2 is N; or, W 1 is C, W 2 is O.
  5. 如权利要求1-4任一项所述的化合物，其特征在于，R 7和R 8独立地选自：H、(＝O)、C1-3烷基、-CF 3、羟基；优选地，R 7和R 8均为H。 The compound according to any one of claims 1 to 4, wherein R 7 and R 8 are independently selected from: H, (=O), C1-3 alkyl, -CF 3 , hydroxyl; preferably, R 7 and R 8 are both H.
  6. 如权利要求1所述的化合物，其特征在于，所述化合物具有如下结构：The compound of claim 1, wherein the compound has the following structure:
    Figure PCTCN2022114690-appb-100003
    Figure PCTCN2022114690-appb-100003
  7. 如权利要求1-6任一项所述的化合物，其特征在于，L 1为-CO-或-SO 2-。 The compound according to any one of claims 1 to 6, wherein L 1 is -CO- or -SO 2 -.
  8. 如权利要求1-7任一项所述的化合物，其特征在于，R 6选自：H、-CH 3、-CH 2CH 3。 The compound according to any one of claims 1 to 7, wherein R 6 is selected from: H, -CH 3 , -CH 2 CH 3 .
  9. 如权利要求1-8任一项所述的化合物，其特征在于，L 2选自：单键、-CH 2-、-SO 2-、-NHCO-、-NH-SO 2-；和/或， The compound according to any one of claims 1 to 8, wherein L 2 is selected from: single bond, -CH 2 -, -SO 2 -, -NHCO-, -NH-SO 2 -; and/or ,
    R 9和R 10独立地选自H、-CH 3、-CH 2CH 3、-C(CH 3) 3、-SO 2CH 3、-L 3-NR 9R 10、三至五元饱和含氮杂环基； R 9 and R 10 are independently selected from H, -CH 3 , -CH 2 CH 3 , -C(CH 3 ) 3 , -SO 2 CH 3 , -L 3 -NR 9 R 10 , three- to five-membered saturated nitrogen heterocyclyl;
    优选地，所述三至五元饱和含氮杂环基选自：
    Figure PCTCN2022114690-appb-100004
    其中，R 13选自：H、C 1-C 6烷基。     Preferably, the three- to five-membered saturated nitrogen-containing heterocyclic group is selected from:
    Figure PCTCN2022114690-appb-100004
    Among them, R 13 is selected from: H, C 1 -C 6 alkyl.
  10. 如权利要求1-9任一项所述的化合物，其特征在于，L 3选自：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CO-、-SO 2-、
    Figure PCTCN2022114690-appb-100005
    和/或，     The compound according to any one of claims 1 to 9, wherein L 3 is selected from: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CO-, -SO 2 -,
    Figure PCTCN2022114690-appb-100005
    and / or,
    R 11和R 12独立地选自：H、-CH 3、-CH 2CH 3、-COCH 3、-COCH 2CH 3。 R 11 and R 12 are independently selected from: H, -CH 3 , -CH 2 CH 3 , -COCH 3 , -COCH 2 CH 3 .
  11. 如权利要求1-10任一项所述的化合物，其特征在于，R 1、R 2、R 3、R 4和R 5独立地选自：H、-CH 3、-OCH 3、-CF 3、-L 2-NR 7R 8； The compound according to any one of claims 1 to 10, wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from: H, -CH 3 , -OCH 3 , -CF 3 , -L 2 -NR 7 R 8 ;
    优选地，-L 2-NR 7R 8选自：
    Figure PCTCN2022114690-appb-100006
    Preferably, -L 2 -NR 7 R 8 is selected from:
    Figure PCTCN2022114690-appb-100006
    Figure PCTCN2022114690-appb-100007
    Figure PCTCN2022114690-appb-100007
  12. 如权利要求1所述的化合物，其特征在于，所述化合物具有如下结构：The compound of claim 1, wherein the compound has the following structure:
    Figure PCTCN2022114690-appb-100008
    Figure PCTCN2022114690-appb-100008
    Figure PCTCN2022114690-appb-100009
    Figure PCTCN2022114690-appb-100009
  13. 一种药物组合物，其包含权利要求1-12任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物，以及一种或多种药学上可接受的辅料。A pharmaceutical composition comprising the compound of any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or A variety of pharmaceutically acceptable excipients.
  14. 权利要求1-12任一项所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物、权利要求13所述的药物组合物在制备预防和/或治疗由病毒感染引起或病毒感染相关的疾病或病症的药物中的应用。The compound according to any one of claims 1 to 12 or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, and the pharmaceutical composition according to claim 13 in the preparation of prophylactic and/or use in medicines for the treatment of diseases or conditions caused by or associated with viral infections.
  15. 如权利要求14所述的应用，其特征在于，所述病毒为冠状病毒，例如，HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU、SARS-CoV、MERS-CoV、SARS-CoV-2。The application according to claim 14, wherein the virus is a coronavirus, such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV- 2.
  16. 如权利要求14所述的应用，其特征在于，所述疾病或病症为COVID-19、SARS或MERS。The application of claim 14, wherein the disease or condition is COVID-19, SARS or MERS.
PCT/CN2022/114690 2022-08-25 2022-08-25 Antiviral compound, preparation method therefor and use thereof WO2024040497A1 (en)

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