WO2023283831A1 - 病毒主蛋白酶抑制剂及其制备方法和用途 - Google Patents

病毒主蛋白酶抑制剂及其制备方法和用途 Download PDF

Info

Publication number
WO2023283831A1
WO2023283831A1 PCT/CN2021/106302 CN2021106302W WO2023283831A1 WO 2023283831 A1 WO2023283831 A1 WO 2023283831A1 CN 2021106302 W CN2021106302 W CN 2021106302W WO 2023283831 A1 WO2023283831 A1 WO 2023283831A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
straight chain
branched
heterocyclic group
compound
Prior art date
Application number
PCT/CN2021/106302
Other languages
English (en)
French (fr)
Inventor
沈祖源
李岳
朱坚
黄琴琴
殷健
徐艳芬
吴阿亮
苏文姬
蒯乐天
Original Assignee
上海药明康德新药开发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海药明康德新药开发有限公司 filed Critical 上海药明康德新药开发有限公司
Priority to PCT/CN2021/106302 priority Critical patent/WO2023283831A1/zh
Publication of WO2023283831A1 publication Critical patent/WO2023283831A1/zh

Links

Images

Classifications

    • 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
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the fields of medicinal chemistry and pharmacotherapeutics. It specifically relates to a compound of general formula (I) capable of inhibiting viral main protease (3CL protease, M pro ), its preparation method, pharmaceutical composition containing the compound and its use.
  • a compound of general formula (I) capable of inhibiting viral main protease (3CL protease, M pro ), its preparation method, pharmaceutical composition containing the compound and its use.
  • SARS-Cov-2 SARS coronavirus
  • MERS coronavirus MERS coronavirus
  • the 3CL protease (also known as M pro ) in coronavirus is a type of cysteine hydrolase, which can cleave polyproteins at 11 different sites in the virus and generate multiple active proteases.
  • M pro structure of SARS-CoV-2 is basically the same as that of SARS-CoV, with a homology of >96%.
  • SARS-Cov2M pro has a unique recognition sequence and cleavage site [Leu-Gln (Ser, Ala, Gly)], and similar structures do not exist in human proteases.
  • the catalytic residues Cys145 and His41 in Mpro are buried in the active site cavity on the surface of the protein.
  • M pro has now become one of the key targets for anti-coronavirus, and the development of its inhibitor can block the replication process of coronavirus, which is of great value and significance for the prevention and treatment of coronavirus infection.
  • the purpose of the present invention is to provide a novel and effective inhibitor of virus main protease M pro .
  • Another object of the present invention is to provide an effective antiviral drug.
  • the first aspect of the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, diastereoisomer or racemate Spin body:
  • Ring A is a benzene ring or an aromatic heterocyclic group, W 1 , W 2 , W 3 , W 4 and W 5 are independently CH or N;
  • Ring Ar is the following groups that are unsubstituted or substituted by 1-2 substituents: phenyl, 5-6 membered aromatic heterocyclic group, benzo 5-6 membered aromatic heterocyclic group, benzo 5-6 membered heterocyclic group Cyclic group, 1 to 3 azaphenyl and 5 to 6 membered aromatic heterocyclic groups, 1 to 3 azaphenyl and 5 to 6 membered heterocyclic groups, and each of the heterocyclic and aromatic heterocyclic groups contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the following group: halogen, C 1 to C 4 straight chain or branched chain alkyl, C 2 to C 4 straight chain or Branched alkenyl, C 2 ⁇ C 4 straight or branched alkynyl, C 1 ⁇ C 4 straight or branched alkoxy, C 1 ⁇ C 4 straight or branched alkylcarbonyloxy, cyano , nitro, hydroxyl, amino, amino
  • X is empty, or -OR a -linking group
  • R a is empty, or C 1 ⁇ C 4 straight chain or branched chain alkyl
  • R 1 is hydrogen, the following groups that are unsubstituted or substituted by 1-2 substituents: C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 5 -C 7 aryl ring, C 5 ⁇ C 7 aromatic heterocyclic group, benzo 5-6 membered aromatic heterocyclic group, 5-6 membered heterocyclic group, benzo 5-6 membered heterocyclic group, C 2 ⁇ C 7 alkynyl, C 2 ⁇ C 7 Alkenyl, the heterocyclic group and aromatic heterocyclic group each contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; the substituents are each independently selected from the following group: halogen, C 1 to C 4 straight Chain or branched chain alkyl, C 2 ⁇ C 4 straight chain or branched chain alkenyl, C 2 ⁇ C 4 straight chain or branched chain alkynyl, C 1 ⁇ C 4 straight chain or branched chain alkoxy, C 1 ⁇ C 4 straight or
  • R 2 is hydrogen, and the following groups are unsubstituted or substituted by 1-3 substituents: C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 5 -C 7 aromatic ring, C 5 ⁇ C 7 aromatic heterocyclic group, benzo 5-6 membered aromatic heterocyclic group, 5-6 membered heterocyclic group, benzo 5-6 membered heterocyclic group, C 2 ⁇ C 7 alkynyl, C 2 ⁇ C 7 Alkenyl, the heterocyclic group and aromatic heterocyclic group each contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; the substituents are each independently selected from the following group: halogen, C 1 to C 4 straight Chain or branched chain alkyl, C 2 ⁇ C 4 straight chain or branched chain alkenyl, C 2 ⁇ C 4 straight chain or branched chain alkynyl, C 1 ⁇ C 4 straight chain or branched chain alkoxy, C 1 ⁇ C 4 straight or branched
  • R 3 is hydrogen, the following groups that are unsubstituted or substituted by 1-2 substituents: C 3 ⁇ C 7 cycloalkyl, C 1 ⁇ C 6 alkyl, C 5 ⁇ C 7 aryl ring, C 5 ⁇ C 7 -membered aromatic heterocyclic group, 5-6 membered heterocyclic group, C 2 ⁇ C 7 alkynyl, C 2 ⁇ C 7 alkenyl, the heterocyclic group and aromatic heterocyclic group each contain 1 to 3 optional Heteroatoms from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the following group: halogen, C 1 ⁇ C 4 straight chain or branched chain alkyl, C 2 ⁇ C 4 straight chain or branched chain alkenyl, C 2 ⁇ C 4 straight chain or branched alkynyl, C 1 ⁇ C 4 straight chain or branched alkoxy, C 1 ⁇ C 4 straight chain or branched alkylcarbonyloxy, C 1 ⁇ C 4 straight
  • R 4 is a covalent reactive or reversible covalent reactive group, including unsubstituted or 1-2 substituents substituted aldehyde, cyano, boronic acid, carboxylic acid, ⁇ -carbonyl alcohol, ⁇ -carbonyl aldehyde, ⁇ - Carbonyl amide, ⁇ -carbonyltrifluoromethyl, acryloyl, ⁇ -haloacetyl, 1-(oxirane-2-yl) acetyl, 2-butynoyl, the substituents are each independently selected from From the following group: halogen, C 1 ⁇ C 4 straight chain or branched chain alkyl, C 2 ⁇ C 4 straight chain or branched chain alkenyl, C 2 ⁇ C 4 straight chain or branched chain alkynyl, C 1 ⁇ C 4 Straight chain or branched alkoxy, C 1 ⁇ C 4 straight chain or branched alkylcarbonyloxy, C 1 ⁇ C 4 straight chain or branched
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3, 4 or 5.
  • the compound of formula (I) is selected from the compounds shown in Table 1.
  • the condensing agent is 1-hydroxybenzotriazole (HOBT) and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
  • the base is N,N-diisopropylethylamine (DIEA);
  • the catalyst is methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Pd G3)
  • base is phosphoric acid Potassium (K 3 PO 4 ).
  • a pharmaceutical composition which comprises: a therapeutically effective amount of one or more compounds represented by general formula (I) in the first aspect of the present invention, or Its pharmaceutically acceptable salt, and optional pharmaceutically acceptable carrier.
  • the pharmaceutical composition of general formula (I) described in the first aspect of the present invention in the preparation of a drug for inhibiting viral replication, preferably, the pharmaceutical composition is used To inhibit the main protease M pro of coronavirus.
  • the compound of the present invention has excellent inhibitory activity to the main protease Mpro of coronavirus, the compound of the present invention and its pharmaceutically acceptable salt, and the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used for treatment, prevention and alleviation Products for diseases mediated by coronaviruses are covered by this patent.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral administration, intratumoral administration, parenteral administration (intravenous, intramuscular) and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium salt compounds; (g) wetting agents such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 20-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the advantages of the present invention mainly include: the present invention provides a compound with the structure shown in formula I, which has excellent inhibitory activity against coronavirus M pro .
  • the compound of the present invention has a simple preparation process and low production cost, and has shown good positive results in experiments closely related to the occurrence and development of viruses, so it is expected to be developed into antiviral drugs targeting M pro .
  • aryl ring group refers to an aromatic group, preferably an aromatic ring group with 5-12 members, for example, selected from the following group (but not limited to): phenyl, naphthyl.
  • 5-6 membered aromatic heterocyclic group refers to a 5-membered or 6-membered aromatic group having one or more heteroatoms selected from nitrogen, oxygen or sulfur, which may be selected from the following group (but not limited to): pyridyl , pyrimidinyl, thiazolyl, isothiazolyl, furyl, thienyl, pyrrolyl.
  • benzo 5-6 membered aromatic heterocyclic group refers to a 5-membered or 6-membered aromatic group with one or more heteroatoms selected from nitrogen, oxygen or sulfur fused with a benzene ring, which can be selected from The following group (but not limited to): benzopyridyl, benzopyrimidinyl, benzothiazolyl, benzisothiazolyl, benzopyrrolyl, benzofuryl, benzothienyl, benzimidazolyl, ind Indolyl, Indazolyl.
  • 5-6 membered heterocyclic group refers to a 5-membered or 6-membered ring group with one or more heteroatoms selected from nitrogen, oxygen or sulfur, which can be selected from the following group (but not limited to): Linyl, Tetrahydrofuranyl, Tetrahydrothiazolyl, Dioxanyl, Dioxanyl.
  • benzo 5-6 membered heterocyclic group refers to a 5-membered or 6-membered cyclic group with one or more heteroatoms selected from nitrogen, oxygen or sulfur, which is fused with a benzene ring. selected from the group consisting of (but not limited to): benzodioxane, benzodioxane.
  • C 1 ⁇ C 6 alkyl refers to a straight or branched alkyl group with 1 to 6 carbon atoms, which can be selected from the following group (but not limited to): methyl, ethyl, n-propyl Base, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
  • C 3 -C 6 cycloalkyl refers to a cyclic group with 3 to 6 carbon atoms, which can be selected from the following group (but not limited to): cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl.
  • C 5 -C 7 cycloalkyl refers to a cyclic group with 5 to 7 carbon atoms, which can be selected from the following group (but not limited to): cyclopentyl, cyclohexyl, cycloheptyl.
  • C 1 ⁇ C 3 alkoxy refers to a straight or branched alkoxy group with 1 to 3 carbon atoms, which can be selected from the following group (but not limited to): methoxy, ethoxy , n-propoxy, isopropoxy.
  • halogen refers to fluorine, chlorine, bromine, iodine.
  • halo refers to fluoro, chloro, bromo, iodo.
  • Each group in the present invention may be unsubstituted or substituted, and the substituted means being substituted by a substituent selected from the following group: hydroxyl, halogen, C 1 ⁇ C 6 alkyl, halogenated C 1 ⁇ C 6 alkane radical, C 1 ⁇ C 3 alkoxy, halogenated C 1 ⁇ C 3 alkoxy, cyano, tert-butylamino, -O-(CH 2 ) n -O-; wherein, n is between 1 and 3 Integer between.
  • the substituents may be substituted at various positions of each group.
  • Dissolve compound 1.1 (82.0mg, 208umol) in 10mL of acetonitrile solvent, weigh N,N-diethylaniline (DEA, 78.1mg, 208umol) into the reaction bottle, react at room temperature for 30 minutes, and check whether the reaction is Completely, the reaction was terminated, and the reaction solution was concentrated to obtain the crude product 1.2 (70 mg) in the form of yellow gum, which was directly used in the next reaction.
  • DEA N,N-diethylaniline
  • Test method GC376, a known covalent inhibitor of broad-spectrum coronavirus M pro cysteine protease, was used as a positive control for the enzyme activity assay.
  • the specific test steps are: first, pre-incubate the compound to be tested with SARS-CoV-2 M pro at room temperature for 60 minutes; after incubation, add the substrate to the mixture, and incubate at 37°C Cleavage of the substrate is initiated; the fluorescent signal is recorded in a time-dependent manner to assess the inhibitory effect of the compound.
  • the ability of three of the compounds to inhibit coronavirus Mpro is analyzed as shown in Table 2
  • IC 50 (++++) ⁇ 0.2 ⁇ M; 0.2 ⁇ M ⁇ (+++) ⁇ 1 ⁇ M;1 ⁇ M ⁇ (++) ⁇ 10 ⁇ M;
  • the compound of the present invention has a certain selective inhibitory effect on coronavirus M pro , and has the highest inhibitory activity on SARS and SARS-2 coronaviruses.
  • the inhibitory activity of the activity of I-1 to SARS and SARS-2 coronaviruses is less than 200nM, and the potential therapeutic index is high.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种对病毒主蛋白酶(3CL蛋白酶，Mpro)有抑制作用的化合物，同时对SARS冠状病毒(SARS-CoV)和新型冠状病毒(SARS-Cov-2)的Mpro有显著抑制活性。本发明还公开含此类化合物的药用组合物或其药学上可接受的盐在制备、预防和/或治疗病毒Mpro相关疾病的应用，例如用于治疗对新型冠状病毒(SARS-Cov-2)的疾病。

Description

病毒主蛋白酶抑制剂及其制备方法和用途 技术领域
本发明涉及药物化学和药物治疗学领域。具体涉及一种对病毒主蛋白酶(3CL蛋白酶，M pro)有抑制作用的通式(I)化合物、其制备方法、含此类化合物的药用组合物及用途。
背景技术
从2019年12月开始的由新型冠状病毒(SARS-Cov-2)引起的二型非典型性肺炎迅速席卷全球，给人类健康和社会发展带来前所未有的的挑战。SARS-CoV-2是继SARS冠状病毒(SARS-CoV)、MERS冠状病毒(MERS-CoV)之后发现的一种新型冠状病毒。
在病毒感染宿主的过程中，冠状病毒中的3CL蛋白酶(又称为M pro)是一类半胱氨酸水解酶，能够在病毒中11个不同的位点裂解多蛋白，生成多个有活性的功能蛋白，研究结果表明SARS-CoV-2与SARS-CoV的M pro结构基本一致，同源性>96％。而且SARS-Cov2M pro具有独特的识别序列和切割位点[Leu-Gln(Ser，Ala，Gly)]，在人类蛋白酶中类似结构不存在。M pro中的催化残基Cys145和His41埋在位于蛋白质表面的活性位点腔中，以上结构和活性位点特征为其作为成药靶点奠定了理论基础。因此，M pro目前已经成为抗冠状病毒的关键靶标之一，可通过开发其抑制剂，阻断冠状病毒复制过程，对于冠状病毒感染的防治具有重要价值与意义。
发明内容
本发明的目的是提供一种结构新颖且有效的病毒主蛋白酶M pro的抑制剂。
本发明的另一个目的在于，提供一种有效的抗病毒药物。
本发明的第一方面，提供一种如式(I)所示的化合物或其在药学上可接受的盐、溶剂合物、水合物、对映异构体、非对应异构体或外消旋体：
Figure PCTCN2021106302-appb-000001
式(Ⅰ)中：
环A为苯环或者芳杂环基，W 1,W 2,W 3,W 4和W 5独立自为CH或者N；
环Ar为未被取代或被1-2个取代基取代的以下基团：苯基、5～6元芳杂环基、苯并5～6元芳杂环基、苯并5～6元杂环基，1～3个氮杂苯基并5～6元芳杂环基、1～3个氮杂苯基并5～6元杂环基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
X为空,或为-OR a-连接基团；
R a为空，或C 1～C 4直链或支链烷基；
R 1为氢、未被取代或被1-2个取代基取代的以下基团：C 3～C 7环烷基、C 1～C 6烷基、C 5～C 7芳环基、C 5～C 7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6元杂环基、C 2～C 7炔基、C 2～C 7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R 2为氢，未被取代或被1-3个取代基取代的以下基团：C 3～C 7环烷基、C 1～C 6烷基、C 5～C 7芳环基、C 5～C 7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6元杂环基、C 2～C 7炔基、C 2～C 7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、甲巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R 3为氢、未被取代或被1-2个取代基取代的以下基团：C 3～C 7环烷基、C 1～C 6烷基、C 5～C 7芳环基、C 5～C 7元芳杂环基、5～6元杂环基、C 2～C 7炔基、C 2～C 7烯基， 所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、C 1～C 4直链或支链烷硫基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R 4为共价反应或可逆共价反应基团，包括未取代或1-2个取代基取代的醛基、氰基、硼酸、羧酸基、α-羰基醇、α-羰基醛、α-羰基酰胺、α-羰基三氟甲基、丙烯酰基、α-卤代乙酰基、1-(环氧乙烷-2-基)乙酰基、2-丁炔酰基，所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、C 1～C 4直链或支链烷硫基、C 3～C 7环烷基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
m是0，1，2或3；
n是0，1，2，3，4或5。
优选例中，所述的(I)式化合物选自表1所示的化合物。
在本发明第二方面中，提供了一种如本发明第一方面所述通式(I)所示的化合物的制备方法，包括步骤：
通式(Ib)化合物的合成方法：
Figure PCTCN2021106302-appb-000002
在惰性溶剂中，在缩合剂和碱存在下，用化合物II和化合物Ia反应，得到化合物Ib；优选地，所述的缩合剂为1-羟基苯并三唑(HOBT)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，碱为N,N-二异丙基乙胺(DIEA)；
通式(I)化合物的合成方法：
Figure PCTCN2021106302-appb-000003
在惰性溶剂中，在催化剂和碱存在下，用化合物Ib和化合物III反应，得到式I化合物；优选地，所述的催化剂为甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(XPhos Pd G3)，碱为磷酸钾(K 3PO 4)。
在本发明第三方面中，提供了一种药物组合物，所述的药物组合物包括：治疗有效量的一种或多种本发明第一方面所述通式(I)所示化合物，或其药学上可接受的盐，以及任选的药学上可接受的载体。
在本发明第四方面中，提供了一种本发明第一方面所述通式(I)的药物组合物在用于制备抑制病毒复制的药物的用途，优选地，所述的药物组合物用于抑制冠状病毒主蛋白酶M pro。
药物施用方法
由于本发明化合物对冠状病毒主蛋白酶M pro具有优异的抑制活性，因此本发明化合物及其药学上可接受的盐，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由冠状病毒介导的疾病的产品均包含在本专利中。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2021106302-appb-000004
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、肠胃外(静脉内、肌肉内)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺盐化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物 (如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的优点主要包括：本发明提供一种式I所示结构的化合物，该化合物对冠状病毒M pro具有优异的抑制活性。
本发明化合物制备工艺简单、生产成本低，在和病毒发生、发展密切相关的实验中均显示出良好的阳性结果，因此有望开发成靶向M pro抗病毒药物。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
具体实施方式
下面将对本发明的技术方案进行清楚、完整的描述，显然，所描述的实施例是本发明的一部分实施例，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做出创造性劳动的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。
术语
术语“芳环基”是指具有芳香性的基团，优选为具有5元至12元的芳环基，例如选自下组(但不限于)：苯基、萘基。
术语“5～6元芳杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6元的芳香基，可选自下组(但不限于)：吡啶基、嘧啶基、噻唑基、异噻唑基、呋喃基、噻吩基、吡咯基。
术语“苯并5～6元芳杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6元的芳香基与苯环稠合的基团，可选自下组(但不限于)：苯并吡啶基、苯并嘧啶基、苯并噻唑基、苯并异噻唑基、苯并吡咯基、苯并呋喃基、苯并噻吩基、苯并咪唑基、吲哚基、吲唑基。
术语“5～6元杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6元的环状基团，可选自下组(但不限于)：吗啉基、四氢呋喃基、四氢噻唑基、二氧六环基、二氧五环基。
述语“苯并5～6元杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6 元的环状基团与苯环稠合的基团，可选自下组(但不限于)：苯并二氧六环、苯并二氧五环。
述语“C 1～C 6烷基”是指具有1个至6个碳原子的直连或支链的烷基，可选自下组(但不限于)：甲基、乙基、正丙基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基。
述语“C 3～C 6环烷基”是指具有3个至6个碳原子的环状基团，可选自下组(但不限于)：环丙基、环丁基、环戊基、环己基。
述语“C 5～C 7环烷基”是指具有5个至7个碳原子的环状基团，可选自下组(但不限于)：环戊基、环己基、环庚基。
术语“C 1～C 3烷氧基”是指具有1个至3个碳原子的直连或支链的烷氧基，可选自下组(但不限于)：甲氧基、乙氧基、正丙氧基、异丙氧基。
术语“卤素”是指氟、氯、溴、碘。术语“卤代的”是指氟代的、氯代的、溴代的、碘代的。
本发明的各个基团可以未取代或取代的，所述取代的是指被选自下组的取代基所取代：羟基、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、C 1～C 3烷氧基、卤代的C 1～C 3烷氧基、氰基、叔丁氨基、-O-(CH 2) n-O-；其中，n为1～3之间的整数。所述取代基可取代在各基团的各个位置上。
实施案例1
(R)-4-(2-(2-甲酰基-4-(1H-吲唑-4-基)苯酚)乙酰胺-N,6-二甲基庚酰胺(I-1)的合成路线
Figure PCTCN2021106302-appb-000005
步骤1.(6-甲基-1-(甲基氨基)-1-氧代庚-4-基)氨基甲酸叔丁酯(1.1)的合成
Figure PCTCN2021106302-appb-000006
称取甲胺盐酸盐(21.2mg,315umol)和(4R)-4-(9H-芴-9-基甲氧基羰基氨基)-6-甲基-庚酸(100mg,262umol)于2mL CH 2CL 2溶液中，然后依次加入HOBT(53.1mg,393umol)和DIEA(102mg,786umol,137uL)，室温下反应1小时，TLC检测反应完全，结束反应。加入6mL CH 2Cl 2于反应液中萃取，用柠檬酸(5mL x 2)洗，收集有机相溶液再用碳酸氢钠饱和溶液洗(5mL x 2)和饱和食盐水(5mL x 2)洗，并用无水Na 2SO 4干燥，过滤，旋除溶剂，经柱层析(CH 2Cl 2/MeOH＝80/1到20/1)分离，得白色固体物1.1(82.0mg，产率为79.29％)。
步骤2.(R)-4-氨基-N,6-二甲基庚酰胺(1.2)合成
Figure PCTCN2021106302-appb-000007
将化合物1.1(82.0mg,208umol)溶于10mL乙腈溶剂中，称取N,N-二乙基苯胺(DEA,78.1mg,208umol)加入反应瓶中，在室温下反应30分钟，TLC检测反应是否完全，结束反应，浓缩反应液得黄色胶状粗品1.2(70mg)，直接用于下一步反应。
步骤3.(4R)-4-[[2-(4-溴-2-甲酰苯氧基)乙酰基]氨基]-N,6-二甲基-庚酰胺(1.3)合成
Figure PCTCN2021106302-appb-000008
称取化合物1.2(85.0mg,493umol)和2-(4-溴-2-甲酰苯氧基)乙酸(89.5mg,345umol)溶于3mL CH 2Cl 2中，然后在氮气保护下加入HOBT(100mg,740umol),EDCI(142mg,740umol)和DIEA(191mg,1.48mmol)，混合体系室温反应2小时。LCMS监测显示反应完全，结束反应。加入6mL CH 2Cl 2于反应液中萃取，用柠檬酸(5mL x 2)洗，收集有机相溶液再用碳酸氢钠饱和溶液洗(5mL x 2)和饱和食盐水(5mL x 2)洗，并用无水Na 2SO 4干燥，过滤，旋除溶剂，经柱层析(CH 2Cl 2/MeOH＝80/1到20/1)分离，得无色胶状物1.3(82.0mg，产率为40.21％)。
步骤4.(R)-4-(2-(4-bromo-2-formylphenoxy)acetamido)-N,6-二甲基庚酰胺(I-1)合 成
Figure PCTCN2021106302-appb-000009
称取化合物1.3(82.0mg,198umol)溶于3mL二氧六环和1mL水中，然后在氮气保护下加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(48.4mg,198umol),K 3PO 4(126mg,595umol)和Xphos Pd G3(16.8mg,19.8umol)，混合体系95℃反应10小时。LCMS监测显示反应完全，结束反应。加入5mL水，用EtOAc(5mL x 2)萃取，有机相溶液再用饱和食盐水(5mL x 2)洗，并用无水Na 2SO 4干燥，过滤，旋除溶剂，经HPLC([water(0.05％HCl)-ACN]；B％:35％-65％,8min)分离，得黄色固体产物I-1(20.0mg，纯度为99.8％，产率为22.3％)。
1HNMR:EB3098-19-P1M2(400MHz,DMSO-d 6)
δ10.47-10.51(m,1H),8.11(s,1H),8.00-8.07(m,2H),7.93(d,J＝9.2Hz,1H),7.71(brs,1H),7.56(d,J＝8.4Hz,1H),7.41-7.47(m,1H),7.20-7.29(m,2H),4.75(s,2H),3.85-3.90(m,1H),2.51-2.54(m,3H),2.05(t,J＝7.8Hz,2H),1.62-1.73(m,1H),1.56-1.60(m,1H),1.45-1.54(m,1H),1.23-1.26(m,1H),1.20-1.22(m,1H),0.82(d,J＝6.8Hz,6H)
LCMS:m/z＝451.4(M+H) +,Rt＝1.420min
实施案例2.
3-(2-氰基苯基)-N-[(1R)-1-环戊基-2-(甲氨基)-2-氧代-乙基]-5-甲酰基-苯甲酰胺(I-2)的合成路线
Figure PCTCN2021106302-appb-000010
步骤1. 3-溴-5-甲酰基-苯甲酸(2.3)的合成
Figure PCTCN2021106302-appb-000011
称取3-甲酰基苯甲酸(400mg,2.66mmol)于室温下加入4mL浓硫酸中，而后升温至60℃，向反应液中分三次加入NBS(500mg,2.81mmol)，每次间隔反应15分钟，加毕继续在该温度下反应2小时。TLC检测反应完全，结束反应。加入5g冰于反应液中，过滤其中的固体，滤液用10mL水洗，无水Na 2SO 4干燥，过滤，旋除溶剂，经柱层析(CH 2Cl 2/MeOH＝80/1到20/1)分离，得黄色固体物2.3(660mg，产率为98.33％)。
合成路线中剩余步骤，化合物2.1，化合物2.2,化合物2.4和化合物I-2分别替换实施案例1中的化合物1.1，化合物1.2，化合物1.3和化合物I-1的合成方法。最终得到5.01mg白色固体产物I-2，纯度为98.74％。
1HNMR:EB3098-23-P1N1(400MHz,CDCl 3)
δ10.47-10.51(m,1H),8.36(s,1H),8.25(s,1H),8.21(s,1H),7.82(d,J＝7.6Hz,1H),7.71-7.74(m,1H),7.53-7.59(m,2H),6.95-6.97(m,1H),5.99-6.01(m,1H),4.41-4.52(m,1H),2.86(s,3H),2.41-2.45(m,1H),1.86-1.89(m,2H),1.83-1.85(m,2H),1.25-1.49(m,4H)
LCMS:m/z＝390.0(M+H) +,Rt＝1.819min
实施案例3.
(S)-3-(2-((2'-氰基-3-甲酰基-[1,1'-联苯]-4-基)氧基)乙酰氨基)-N,5-二甲基己酰胺(I-4)的合成路线
Figure PCTCN2021106302-appb-000012
化合物4.2合成步骤：
Figure PCTCN2021106302-appb-000013
称取化合物4.1(100mg,387umol)溶于1.5mL CH 2Cl 2溶剂中，室温下逐滴加入盐酸/二氧六环溶液(4M,0.5mL)，室温下反应2小时，TLC检测反应是否完全，结束反应，浓缩反应液得白色固体粗品4.2，110mg，直接用于下一步反应。
合成路线中剩余步骤，化合物4.1，化合物4.3和化合物I-4分别替换实施案例1中的化合物1.1，化合物1.3和化合物I-1的合成方法。最终得到10.78mg白色固体产物I-4，纯度为99.4％。
1HNMR:EB3098-13-P1N1(400MHz,CDCl 3)
δ10.41(s,1H),8.02-8.13(m,1H),8.01(s,1H),7.80-7.81(m,2H),7.69(s,1H),7.46-7.56(m,2H),7.04-7.13(m,1H),6.04(br s,1H),4.67(br s,2H),4.35-4.47(m,1H),2.80(br s,3H),2.38-2.57(m,2H),1.65-1.73(m,2H),1.37-1.48(m,1H),0.95(t,J＝6.0Hz,6H)
LCMS:m/z＝422.4(M+H) +,Rt＝1.465min
实施案例4.
按照实施案例1-3的化合物I-1,I-2和I-4的合成方法，进一步制备得到化合物I-3，I-5，I-6，I-7，I-8，I-9，I-10，I-11，I-12，I-13，I-14，I-15，I-16，I-17，I-18，I-19，I-20，I-21，I-22，I-23，I-24，I-25。
Figure PCTCN2021106302-appb-000014
实施案例5.
体外化合物对靶点蛋白M pro的抑制活性测试研究
Figure PCTCN2021106302-appb-000015
测试方法：已知的广谱冠状病毒M pro半胱氨酸蛋白酶共价抑制剂GC376被用作酶活性测定的阳性对照。对化合物进行对于酶促测定，具体测试步骤为：首先将待测试化合物与SARS-CoV-2 M pro在室温下预孵育60分钟；温育后，将底物加入混合物中，并在37℃下开始底物的裂解；以时间依赖性方式记录荧光信号以评估化合物的抑制作用。分析得到其中三个化合物抑制冠状病毒M pro的能力如表2所示
表2:化合物抑制冠状病毒M pro的IC 50
Figure PCTCN2021106302-appb-000016
IC 50:(++++)≤0.2μM；0.2μM<(+++)≤1μM；1μM<(++)≤10μM；
10μM<(+)≤100μM；100μM<(-)。
实验结论：从以上实验结果可以看出，本发明的化合物对冠状病毒M pro有一定的选择性抑制，对SARS和SARS-2冠状病毒抑制活性最高。其中I-1的活性对SARS和SARS-2冠状病毒的抑制活性均小于200nM,潜在治疗指数高。
实施案例6.
结构生物学研究
为了探索本文公开的化合物与冠状病毒M pro结合并抑制其酶活性的机理，将某些抑制剂与SARS-CoV-2 M pro共同结晶。培养共结晶的最优条件是0.1M MES pH 6.0,11％PEG4000，形成晶体后，以SARS-CoV-2 M pro的晶体结构被作为初始模型，通过分子 置换确定了SARS-CoV-2 M pro/化合物I-1复合物的晶体结构，并将其细化到
Figure PCTCN2021106302-appb-000017
化合物I-1与SARS-CoV-2 M pro形成1:1的复合物。在晶体结构中，化合物I-1结合到M pro的催化口袋，从而竞争性地抑制了M pro底物的结合(图1A)。化合物I-1与M pro底物的主要结合相互作用如附图(图1B)所示：化合物I-1苯环上醛基靶向SARS-CoV-2 M pro活性口袋中的Cys145，和Cys145形成共价键，同时共价连接后形成的羟基和这周围的Gly143在水分子的介导下形成氢键；化合物I-1吡唑环上的氮原子和His163和Glu166的侧链形成两个氢键，化合物I-1酰胺键的羰基和氨基基团分别与Glu166的氨基和羧基基团形成两个氢键。化合物与SARS-CoV-2 M pro的可逆共价作用和多个氢键相互作用增加了二者的结合作用力。
综上所述，上述各实施例仅为本发明的较佳实施例而已，并不用以限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，皆应包含在本发明的保护范围内。

Claims (6)

  1. 一种通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对应异构体或外消旋体：
    Figure PCTCN2021106302-appb-100001
    式(Ⅰ)中：
    环A为苯环或者芳杂环基，W 1,W 2,W 3,W 4和W 5独立自为CH或者N；
    环Ar为未被取代或被1-2个取代基取代的以下基团：苯基、5～6元芳杂环基、苯并5～6元芳杂环基、苯并5～6元杂环基，1～3个氮杂苯基并5～6元芳杂环基、1～3个氮杂苯基并5～6元杂环基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
    X为空,或为-OR a-连接基团；
    R a为空，或C 1～C 4直链或支链烷基；
    R 1为氢、未被取代或被1-2个取代基取代的以下基团：C 3～C 7环烷基、C 1～C 6烷基、C 5～C 7芳环基、C 5～C 7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6元杂环基、C 2～C 7炔基、C 2～C 7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
    R 2为氢，未被取代或被1-3个取代基取代的以下基团：C 3～C 7环烷基、C 1～C 6烷基、C 5～C 7芳环基、C 5～C 7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6元杂环基、C 2～C 7炔基、C 2～C 7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、甲巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
    R 3为氢、未被取代或被1-2个取代基取代的以下基团：C 3～C 7环烷基、C 1～C 6烷基、C 5～C 7芳环基、C 5～C 7元芳杂环基、5～6元杂环基、C 2～C 7炔基、C 2～C 7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、C 1～C 4直链或支链烷硫基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
    R 4为共价反应或可逆共价反应基团，包括未取代或1-2个取代基取代的醛基、氰基、硼酸、羧酸基、α-羰基醇、α-羰基醛、α-羰基酰胺、α-羰基三氟甲基、丙烯酰基、α-卤代乙酰基、1-(环氧乙烷-2-基)乙酰基、2-丁炔酰基，所述取代基各自独立地选自下组：卤素、C 1～C 4直链或支链烷基、C 2～C 4直链或支链烯基、C 2～C 4直链或支链炔基、C 1～C 4直链或支链烷氧基、C 1～C 4直链或支链烷基羰氧基、C 1～C 4直链或支链烷硫基、C 3～C 7环烷基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C 1～C 4酰基、酰胺基、氨基磺酰基、C 1～C 4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
    m是0，1，2或3；
    n是0，1，2，3，4或5。
  2. 根据权利要求1要求所述的化合物或其药学上可接受的盐、对映异构体、非对应异构体或外消旋体，其中，所述化合物选自以下表1所示的化合物：
    表1：代表化合物I-1～I-25
    Figure PCTCN2021106302-appb-100002
  3. 一种如权利要求1所述通式(I)所示的化合物的制备方法，包括步骤：
    Figure PCTCN2021106302-appb-100003
    (1)在惰性溶剂中，在缩合剂和碱存在下，用化合物II和化合物Ia反应，得到式化合物Ib；优选地，所述的缩合剂为1-羟基苯并三唑(HOBT)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，碱为N,N-二异丙基乙胺(DIEA)；
    Figure PCTCN2021106302-appb-100004
    (2)在惰性溶剂中，在催化剂和碱存在下，用化合物Ib和化合物III反应，得到化合物I；优选地，所述的催化剂为甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(XPhos Pd G3)，碱为磷酸钾(K 3PO 4)；
    上述各反应通式中，各基团的定义如权利要求1所述。
  4. 一种药物组合物，所述的药物组合物包括：治疗有效量的一种或多种权利要求1所述通式(I)所示化合物，其药学上可接受的盐，以及任选的药学上可接受的载体。
  5. 如权利要求1要求的通式(I)的药物组合物在以病毒关键药物靶点M pro为作用靶点中的应用。
  6. 如权利要求1要求的通式(I)的药物组合物在预防或抗病毒的药物中的应用，其特征在于，所述冠状病毒包括人冠状病毒OC43、人冠状病毒229E、人冠状病毒NL63、人冠状病毒HKU1、重症急性呼吸综合征冠状病毒(SARS-Cov-1)、中东呼吸综合征冠状病毒(MERS)和新型冠状病毒(SARS-Cov-2)。
PCT/CN2021/106302 2021-07-14 2021-07-14 病毒主蛋白酶抑制剂及其制备方法和用途 WO2023283831A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/106302 WO2023283831A1 (zh) 2021-07-14 2021-07-14 病毒主蛋白酶抑制剂及其制备方法和用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/106302 WO2023283831A1 (zh) 2021-07-14 2021-07-14 病毒主蛋白酶抑制剂及其制备方法和用途

Publications (1)

Publication Number Publication Date
WO2023283831A1 true WO2023283831A1 (zh) 2023-01-19

Family

ID=84919831

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/106302 WO2023283831A1 (zh) 2021-07-14 2021-07-14 病毒主蛋白酶抑制剂及其制备方法和用途

Country Status (1)

Country Link
WO (1) WO2023283831A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200424175A (en) * 2003-04-21 2004-11-16 Pfizer Inhibitors of severe acute respiratory syndrome (SARS) 3c-like proteinase
US20050267071A1 (en) * 2003-10-31 2005-12-01 Fulcrum Pharmaceuticals, Inc. Inhibitors of coronavirus protease and methods of use thereof
CN103159665A (zh) * 2011-12-09 2013-06-19 天津市国际生物医药联合研究院 对sars冠状病毒主蛋白酶具有抑制作用的靛红-5-酰胺类抑制剂
CN105837487A (zh) * 2016-03-17 2016-08-10 天津国际生物医药联合研究院 MERS-CoV主蛋白酶小分子抑制剂及其制备方法和用途
CN106928206A (zh) * 2015-12-31 2017-07-07 中国科学院上海药物研究所 醛基类化合物及其制法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200424175A (en) * 2003-04-21 2004-11-16 Pfizer Inhibitors of severe acute respiratory syndrome (SARS) 3c-like proteinase
US20050267071A1 (en) * 2003-10-31 2005-12-01 Fulcrum Pharmaceuticals, Inc. Inhibitors of coronavirus protease and methods of use thereof
CN103159665A (zh) * 2011-12-09 2013-06-19 天津市国际生物医药联合研究院 对sars冠状病毒主蛋白酶具有抑制作用的靛红-5-酰胺类抑制剂
CN106928206A (zh) * 2015-12-31 2017-07-07 中国科学院上海药物研究所 醛基类化合物及其制法和用途
CN105837487A (zh) * 2016-03-17 2016-08-10 天津国际生物医药联合研究院 MERS-CoV主蛋白酶小分子抑制剂及其制备方法和用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

Similar Documents

Publication Publication Date Title
WO2017114509A1 (zh) 醛基类化合物及其制法和用途
WO2021206876A1 (en) Inhibitors of norovirus and coronavirus replication
KR20210043617A (ko) 케토아미드계 화합물 및 이의 제조 방법, 약학 조성물과 용도
JP5372751B2 (ja) Ａｚａ−ペプチドプロテアーゼ阻害剤
JPWO2010110231A1 (ja) 置換された３−ヒドロキシ−４−ピリドン誘導体
KR20010101675A (ko) 2ｈ-프탈라진-1-온 유도체 및 그 유도체를 유효 성분으로하는 약제
CN102838523A (zh) 抗肠病毒71(ev71)戊内酰胺类化合物及其制备方法和用途
RU2299202C2 (ru) N-фениларилсульфонамид, фармацевтическая композиция, содержащая указанное соединение в качестве активного ингредиента, соединение, являющееся промежуточным в синтезе указанного соединения, и способ его получения
CA3210873A1 (en) Compounds, compositions, and methods of using the same
KR102145649B1 (ko) 구아니디노벤조산 에스테르 화합물
CN110105348A (zh) 新型迈克尔受体类肠病毒71型抑制剂的制备及用途
CN112920136B (zh) 一类化合物及其用于新型冠状病毒肺炎的医药用途
WO2023283831A1 (zh) 病毒主蛋白酶抑制剂及其制备方法和用途
ES2355421T3 (es) Agente preventivo o terapéutico para enfermedades asociadas con el virus herpes.
CN107459511B (zh) 抗肠病毒71(ev71)4-亚氨基恶唑烷-2-酮类化合物及其制备方法和用途
JPWO2003011812A1 (ja) ヒト−β−トリプターゼ阻害活性を有する新規アミン誘導体およびそれを含有する医薬
WO2023165334A1 (zh) 酮酰胺类衍生物及其制药用途
CN106866648B (zh) 邻苯二甲酰亚胺类吲哚胺-2,3-双加氧酶1抑制剂及其用途
EP1844775B1 (en) Therapeutic agent for the treatment of herpes progenitalis after development of lesions
CN113773259A (zh) 病毒主蛋白酶抑制剂及其制备方法和用途
JPH06128227A (ja) ロイコトリエン拮抗薬としてのインドールカルバミン酸類
CN112010774A (zh) FXIa凝血因子抑制剂、其药物组合物和用途
CN113698383B (zh) 一种哌嗪类化合物及其应用
WO2022156693A1 (zh) 含有n-(取代磺酰基)乙酰胺结构的病毒蛋白酶抑制剂，及其在抗病毒药物中的应用
EP1844776B1 (en) Agent for prevention/treatment of disease caused by acyclovir-resistant herpesvirus

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21949623

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE