CN113773259A - Virus main protease inhibitor and preparation method and application thereof - Google Patents

Virus main protease inhibitor and preparation method and application thereof Download PDF

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CN113773259A
CN113773259A CN202110795720.1A CN202110795720A CN113773259A CN 113773259 A CN113773259 A CN 113773259A CN 202110795720 A CN202110795720 A CN 202110795720A CN 113773259 A CN113773259 A CN 113773259A
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沈祖源
李岳
朱坚
黄琴琴
殷健
徐艳芬
吴阿亮
苏文姬
蒯乐天
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Wuxi Apptec Co Ltd
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Abstract

The invention discloses a virus-targeting main protease (3CL protease, M)pro) Compounds with inhibitory effect on M of SARS coronavirus (SARS-CoV) and novel coronavirus (SARS-Cov-2)proHas obvious inhibiting activity. The invention also relates to a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof for preparing, preventing and/or treating the virus MproUse of the related diseases, for example for the treatment of diseases against the novel coronavirus (SARS-Cov-2).

Description

Virus main protease inhibitor and preparation method and application thereof
Technical Field
The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics. In particular to a virus-targeting main protease (3CL protease, M)pro) Compounds of general formula (I) having inhibitory action, processes for their preparation, pharmaceutical compositions containing them and their use.
Background
Atypical pneumonia of type II caused by the novel coronavirus (SARS-Cov-2) rapidly rolls around the world, presenting an unprecedented challenge to human health and social development. SARS-CoV-2 is a novel coronavirus discovered following SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV).
The 3CL protease (also known as M) in coronaviruses during viral infection of a hostpro) It is a kind of cysteine hydrolase, can cleave polyprotein at 11 different sites in virus to generate multiple active functional proteins, and the research result shows that SARS-CoV-2 and M of SARS-CoVproSubstantial structural identity, homology>96 percent. And SARS-Cov 2MproHas unique recognition sequence and cleavage site [ Leu-Gln (Ser, Ala, Gly)]Similar structures are not present in human proteases. MproThe catalytic residues Cys145 and His41 in the protein are buried in the active site cavity on the surface of the protein, and the structure and the active site characteristics lay the theoretical foundation for the use of the protein as a drug target. Thus, MproThe inhibitor can block the replication process of the coronavirus by developing the inhibitor, and has important value and significance for preventing and treating coronavirus infection.
Disclosure of Invention
The purpose of the present invention is to provide a virus master protease M which has a novel and effective structureproThe inhibitor of (1).
It is another object of the present invention to provide an effective antiviral drug.
In a first aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, diastereomer or racemate thereof:
Figure RE-GDA0003342091240000011
in formula (I):
ring A is a benzene ring or an aromatic heterocyclic group, W1,W2,W3,W4And W5Independently is CH or N;
ring Ar is the following group unsubstituted or substituted with 1-2 substituents: phenyl, 5-to 6-membered aromatic heterocyclic group, benzo 5-to 6-membered heterocyclic group, 1-3 azaphenyl groups and 5-to 6-membered aromatic heterocyclic groupThe heterocyclic group and the aromatic heterocyclic group respectively contain 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, cyano, nitro, hydroxy, amino, aminomethyl, dimethylamino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
x is null, OR is-ORa-a linking group;
Rais empty, or C1～C4A linear or branched alkyl group;
R1is hydrogen, the following groups unsubstituted or substituted with 1 to 2 substituents: c3～C7Cycloalkyl radical, C1～C6Alkyl radical, C5～C7Aromatic ring radical, C5～C7Aromatic heterocyclic group, benzo-5-6 membered heterocyclic group, C2～C7Alkynyl, C2～C7An alkenyl group, the heterocyclic group and the aromatic heterocyclic group each containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～ C4Straight or branched chain alkylcarbonyloxy, cyano, nitro, hydroxy, amino, aminomethyl, dimethylamino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl substitutedSulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
R2hydrogen, the following groups unsubstituted or substituted with 1 to 3 substituents: c3～C7Cycloalkyl radical, C1～C6Alkyl radical, C5～C7Aromatic ring radical, C5～C7Aromatic heterocyclic group, benzo-5-6 membered heterocyclic group, C2～C7Alkynyl, C2～C7An alkenyl group, the heterocyclic group and the aromatic heterocyclic group each containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～ C4Straight or branched chain alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, methylmercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
R3is hydrogen, the following groups unsubstituted or substituted with 1 to 2 substituents: c3～C7Cycloalkyl radical, C1～C6Alkyl radical, C5～C7Aromatic ring radical, C5～C7Aromatic heterocyclic group, 5-6 membered heterocyclic group, C2～C7Alkynyl, C2～C7An alkenyl group, the heterocyclic group and the aromatic heterocyclic group each containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, C1～C4Straight or branched alkylthio, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
R4is a covalently reactive or reversibly covalently reactive group comprising an aldehyde group, cyano group, boronic acid, carboxylic acid group, α -carbonyl alcohol, α -carbonyl aldehyde, α -carbonyl amide, α -carbonyl trifluoromethyl, acryloyl group, α -haloacetyl group, 1- (oxido-2-yl) acetyl group, 2-butynoyl group, unsubstituted or substituted with 1-2 substituents each independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, C1～C4Straight-chain or branched alkylthio, C3～C7Cycloalkyl, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
m is 0,1, 2 or 3;
n is 0,1, 2, 3, 4 or 5.
In a preferred embodiment, the compound of formula (I) is selected from the compounds shown in Table 1.
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) as described in the first aspect of the present invention, comprising the steps of:
a method of synthesizing a compound of formula (Ib):
Figure RE-GDA0003342091240000031
reacting a compound II with a compound Ia in an inert solvent in the presence of a condensing agent and a base to obtain a compound Ib; preferably, the condensing agent is 1-Hydroxybenzotriazole (HOBT) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), and the base is N, N-Diisopropylethylamine (DIEA);
a method of synthesizing a compound of formula (I):
Figure RE-GDA0003342091240000032
reacting a compound Ib with a compound III in an inert solvent in the presence of a catalyst and alkali to obtain a compound of a formula I; preferably, the catalyst is methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (XPhos Pd G3), and the base is potassium phosphate (K)3PO4)。
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: a therapeutically effective amount of one or more compounds of formula (I) according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, there is provided a use of a pharmaceutical composition of formula (I) according to the first aspect of the present invention for the preparation of a medicament for inhibiting viral replication, preferably for inhibiting coronavirus main protease Mpro。
Method of drug administration
The compound of the invention is used for treating coronavirus main protease MproThe compounds of the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the compounds as the main active ingredient are included in the present patent as products for treating, preventing and alleviating diseases mediated by coronavirus.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the 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 be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)
Figure RE-GDA0003342091240000041
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, parenteral (intravenous, intramuscular) and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium salt compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain 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 as, 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 nonaqueous 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.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The advantages of the invention mainly include: the invention provides a compound with a structure shown in formula I, which is used for treating coronavirus MproHas excellent inhibitory activity.
The compound of the invention has simple preparation process and low production cost, shows good positive results in experiments closely related to virus generation and development, and is expected to be developed into target MproAn antiviral drug.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Drawings
FIG. 1 shows SARS-CoV-2MproCrystal structure of Compound I-1 Complex, wherein FIG. 1A shows Compound I-1 Complex bound to MproThereby competitively inhibiting MproBinding of the substrate, FIG. 1B shows Compounds I-1 and MproThe primary binding interaction of the substrate.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Term(s) for
The term "aromatic ring group" refers to a group having aromatic character, preferably an aromatic ring group having 5 to 12 members, for example selected from the group (but not limited to): phenyl, naphthyl.
The term "5-6 membered arylheterocyclyl" refers to a 5-or 6-membered aromatic group having one or more heteroatoms selected from nitrogen, oxygen, or sulfur, and may be selected from the group (but is not limited to): pyridyl, pyrimidyl, thiazolyl, isothiazolyl, furyl, thienyl, pyrrolyl.
The term "benzo 5-6 membered arylheterocyclyl" refers to a group having one or more heteroatoms selected from nitrogen, oxygen or sulfur, a 5-or 6-membered aromatic group fused to a benzene ring, and may be selected from the group consisting of (but not limited to): benzopyridyl, benzopyrimidinyl, benzothiazolyl, benzisothiazolyl, benzopyrolyl, benzofuranyl, benzothienyl, benzimidazolyl, indolyl, indazolyl.
The term "5-6 membered heterocyclyl" refers to a 5-or 6-membered cyclic group having one or more heteroatoms selected from nitrogen, oxygen or sulfur, and may be selected from the group (but is not limited to): morpholinyl, tetrahydrofuryl, tetrahydrothiazolyl, dioxanyl, dioxolanyl.
The term "benzo 5-to 6-membered heterocyclic group" refers to a group in which a 5-or 6-membered cyclic group having one or more heteroatoms selected from nitrogen, oxygen or sulfur is fused with a benzene ring, and may be selected from the following group (but is not limited to): benzodioxan, benzodioxole.
The term "C1～C6Alkyl "refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, which may be selected from the group (but is not limited to): methyl, ethyl, n-propyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
The term "C3～C6Cycloalkyl "refers to a cyclic group having 3 to 6 carbon atoms, and may be selected from the group (but is not limited to): cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "C5～C7Cycloalkyl "refers to a cyclic group having 5 to 7 carbon atoms, and may be selected from the group (but is not limited to): cyclopentyl, cyclohexyl, cycloheptyl.
The term "C1～C3Alkoxy "refers to a straight or branched chain alkoxy group having 1 to 3 carbon atoms, which may be selected from the group (but is not limited to): methoxy, ethoxy, n-propoxy, isopropoxy.
The term "halogen" refers to fluorine, chlorine, bromine, iodine. The term "halogenated" refers to fluorinated, chlorinated, brominated, and iodinated.
Each group of the present invention may be unsubstituted or substituted, said substituted being substituted with a substituent selected from the group consisting of: hydroxy, halogen, C1～C6Alkyl, halo C1～C6Alkyl radical, C1～C3Alkoxy, halogenated C1～C3Alkoxy, cyano, tert-butylamino, -O- (CH)2)n-O-; wherein n is an integer between 1 and 3. The substituents may be substituted at each position of each group.
Example 1
Synthetic route of (R) -4- (2- (2-formyl-4- (1H-indazol-4-yl) phenol) acetamide-N, 6-dimethylheptanoamide (I-1)
Figure RE-GDA0003342091240000071
Step 1 Synthesis of tert-butyl (6-methyl-1- (methylamino) -1-oxohept-4-yl) carbamate (1.1)
Figure RE-GDA0003342091240000072
Weighing methylamineHydrochloride (21.2mg,315umol) and (4R) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -6-methyl-heptanoic acid (100mg,262umol) in 2mL CH2CL2To the solution, HOBT (53.1mg,393 umol) and DIEA (102mg,786umol,137uL) were added in this order, and the reaction was terminated after completion of the TLC detection at room temperature for 1 hour. 6mL of CH was added2Cl2Extracting in reaction solution, washing with citric acid (5mL x 2), collecting organic phase solution, washing with saturated solution of sodium bicarbonate (5mL x 2) and saturated brine (5mL x 2), and washing with anhydrous Na2SO4Drying, filtering, removing solvent, and performing column Chromatography (CH)2Cl2Separation in MeOH 80/1 to 20/1) gave 1.1 as a white solid (82.0mg, 79.29% yield).
Step 2 Synthesis of (R) -4-amino-N, 6-dimethylheptanamide (1.2)
Figure RE-GDA0003342091240000081
Dissolving the compound 1.1(82.0mg,208umol) in 10mL acetonitrile solvent, weighing N, N-diethylaniline (DEA,78.1mg,208umol) and adding into a reaction bottle, reacting for 30 minutes at room temperature, detecting whether the reaction is complete by TLC, finishing the reaction, and concentrating the reaction solution to obtain yellow colloidal crude product 1.2(70mg), which is directly used for the next reaction.
Step 3 Synthesis of (4R) -4- [ [2- (4-bromo-2-formylphenoxy) acetyl ] amino ] -N, 6-dimethyl-heptanamide (1.3)
Figure RE-GDA0003342091240000082
Compound 1.2(85.0mg,493umol) and 2- (4-bromo-2-formylphenoxy) acetic acid (89.5mg,345 umol) were weighed out and dissolved in 3mL CH2Cl2Then, HOBT (100mg, 740. mu. mol), EDCI (142mg, 740. mu. mol) and DIEA (191mg,1.48mmol) were added under nitrogen, and the mixture was reacted at room temperature for 2 hours. LCMS monitoring indicated complete reaction, ending the reaction. 6mL of CH was added2Cl2Extracting in reaction solution, washing with citric acid (5mL x 2), collecting organic phase solution, and adding carbonWashed with saturated sodium hydrogen carbonate solution (5 mL. times.2) and saturated brine (5 mL. times.2), and washed with anhydrous Na2SO4Drying, filtering, removing solvent, and performing column Chromatography (CH)2Cl2Separation in MeOH 80/1 to 20/1) gave 1.3 as a colourless gum (82.0mg, 40.21% yield).
Step 4, (R) -4- (2- (4-bromo-2-formolphenoxy) acetamido) -N, 6-dimethyl heptanamide (I-1) synthesis
Figure RE-GDA0003342091240000083
Compound 1.3(82.0mg,198umol) was weighed out and dissolved in 3mL dioxane and 1mL water, then 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (48.4mg,198 umol), K, was added under nitrogen protection3PO4(126mg,595umol) and Xphos Pd G3(16.8mg,19.8umol) were reacted in a mixed system at 95 ℃ for 10 hours. LCMS monitoring indicated complete reaction, ending the reaction. 5mL of water was added, extracted with EtOAc (5mL x 2), and the organic phase was washed with brine (5mL x 2) and dried over anhydrous Na2SO4Drying, filtering, removing solvent by rotary evaporation, and HPLC ([ water (0.05% HCl) -ACN)](ii) a 35 percent to 65 percent for 8min to obtain a yellow solid product I-1(20.0mg, the purity is 99.8 percent, and the yield is 22.3 percent).
1HNMR:EB3098-19-P1M2(400MHz,DMSO-d6)
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
Example 2 was carried out.
Synthetic route to 3- (2-cyanophenyl) -N- [ (1R) -1-cyclopentyl-2- (methylamino) -2-oxo-ethyl ] -5-formyl-benzamide (I-2)
Figure RE-GDA0003342091240000091
Step 1.3 Synthesis of bromo-5-formyl-benzoic acid (2.3)
Figure RE-GDA0003342091240000092
3-formylbenzoic acid (400mg,2.66mmol) was weighed out and added to 4mL of concentrated sulfuric acid at room temperature, then heated to 60 ℃ and NBS (500mg,2.81mmol) was added to the reaction solution three times, each time with 15 minutes intervals, and the reaction was continued at this temperature for 2 hours after the addition. The reaction was complete by TLC detection and was complete. 5g of ice was added to the reaction solution, the solid was filtered, and the filtrate was washed with 10mL of water and anhydrous Na2SO4Drying, filtering, removing solvent, and performing column Chromatography (CH)2Cl2Isolated as a yellow solid 2.3(660mg, 98.33% yield) with MeOH 80/1 to 20/1.
The remaining steps in the synthetic route, compound 2.1, compound 2.2, compound 2.4 and compound I-2, replace the synthetic methods of compound 1.1, compound 1.2, compound 1.3 and compound I-1, respectively, in example 1. 5.01mg of white solid product I-2 with a purity of 98.74% are finally obtained.
1HNMR:EB3098-23-P1N1(400MHz,CDCl3)
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
Example 3 was carried out.
Synthetic route for (S) -3- (2- ((2 '-cyano-3-formyl- [1,1' -biphenyl ] -4-yl) oxy) acetamido) -N, 5-dimethylhexanamide (I-4)
Figure RE-GDA0003342091240000101
Compound 4.2 synthetic procedure:
Figure RE-GDA0003342091240000102
weighing Compound 4.1(100mg,387umol) dissolved in 1.5mL CH2Cl2Adding hydrochloric acid/dioxane solution (4M,0.5mL) into a solvent at room temperature, reacting at room temperature for 2 hours, detecting whether the reaction is complete by TLC, finishing the reaction, concentrating the reaction solution to obtain a white solid crude product 4.2, 110mg, and directly using the white solid crude product in the next reaction.
The remaining steps in the synthetic route, compound 4.1, compound 4.3 and compound I-4, replace the synthetic methods of compound 1.1, compound 1.3 and compound I-1, respectively, in example 1. 10.78mg of white solid product I-4 with a purity of 99.4% are finally obtained.
1HNMR:EB3098-13-P1N1(400MHz,CDCl3)
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
Example 4 was carried out.
According to the synthetic methods of the compounds I-1, I-2 and I-4 of examples 1 to 3, the compounds 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 and I-25 were further prepared.
Figure RE-GDA0003342091240000121
Example 5 was carried out.
In vitro compound on target protein MproStudy on inhibitory Activity
Figure RE-GDA0003342091240000131
The test method comprises the following steps: known broad spectrum coronavirus MproThe cysteine protease covalent inhibitor GC376 was used as a positive control for the enzyme activity assay. Compounds were tested for enzymatic assays using the following specific test procedures: the test compound is first contacted with SARS-CoV-2MproPre-incubation for 60 min at room temperature; after incubation, the substrate was added to the mixture and cleavage of the substrate was started at 37 ℃; the fluorescent signal was recorded in a time-dependent manner to assess the inhibitory effect of the compound. Analyzing to obtain three compounds for inhibiting coronavirus MproThe ability of (A) is shown in Table 2
TABLE 2 inhibition of coronavirus M by compoundsproIC of50
Figure RE-GDA0003342091240000132
IC50:(++++)≤0.2μM；0.2μM<(+++)≤1μM；1μM<(++)≤10μM；
10μM<(+)≤100μM；100μM<(-)。
And (4) experimental conclusion: as can be seen from the above experimental results, the compounds of the present invention are effective against coronavirus MproHas certain selective inhibition, and has the highest SARS and SARS-2 coronavirus inhibition activity. Wherein the activity of I-1 is less than 200nM for inhibiting SARS and SARS-2 coronavirus, and the potential therapeutic index is high.
Example 6 was carried out.
Study of structural biology
In order to explore the compounds disclosed herein and coronavirus MproCombining and inhibiting the enzyme activity mechanism of the inhibitor, and combining the inhibitor with SARS-CoV-2MproAnd (4) co-crystallizing. The optimal conditions for culturing the cocrystallization are 0.1M MES pH 6.0, 11% PEG4000, after forming crystals, SARS-CoV-2MproIs used as an initial model to determine SAR by molecular replacementS-CoV-2 MproThe crystal structure of the Compound I-1, and refining it to
Figure RE-GDA0003342091240000133
Compound I-1 and SARS-CoV-2MproA 1:1 complex is formed. In the crystal structure, Compound I-1 binds to MproThereby competitively inhibiting MproBinding of substrate (FIG. 1A). Compounds I-1 and MproThe main binding interactions of the substrates are shown in the attached figure (FIG. 1B): aldehyde group on benzene ring of compound I-1 targeting SARS-CoV-2MproCys145 in the active pocket and Cys145 form a covalent bond, and a hydroxyl group formed after the covalent bond and the surrounding Gly143 form a hydrogen bond under the mediation of water molecules; the nitrogen atom on the pyrazole ring of the compound I-1 and the side chains of His163 and Glu166 form two hydrogen bonds, and the carbonyl group and the amino group of the amide bond of the compound I-1 form two hydrogen bonds with the amino group and the carboxyl group of Glu166, respectively. Compounds and SARS-CoV-2MproThe reversible covalent interactions and multiple hydrogen bonding interactions increase the binding forces of the two.
In summary, the above embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (6)

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof:
Figure FDA0003162667680000011
in formula (I):
ring A is a benzene ring or an aromatic heterocyclic group, W1,W2,W3,W4And W5Independently is CH or N;
ring Ar is unsubstituted or substituted by 1-2 substituentsThe following groups: phenyl, 5-6-membered aromatic heterocyclic group, 5-6-membered heterocyclic group, 1-3 azaphenyl-5-6-membered aromatic heterocyclic group, 1-3 azaphenyl-5-6-membered heterocyclic group, each of the heterocyclic group and the aromatic heterocyclic group containing 1-3 hetero atoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, cyano, nitro, hydroxy, amino, aminomethyl, dimethylamino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
x is null, OR is-ORa-a linking group;
Rais empty, or C1～C4A linear or branched alkyl group;
R1is hydrogen, the following groups unsubstituted or substituted with 1 to 2 substituents: c3～C7Cycloalkyl radical, C1～C6Alkyl radical, C5～C7Aromatic ring radical, C5～C7Aromatic heterocyclic group, benzo-5-6 membered heterocyclic group, C2～C7Alkynyl, C2～C7An alkenyl group, the heterocyclic group and the aromatic heterocyclic group each containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, cyano, nitro, hydroxy, amino, aminomethyl, dimethylamino, hydroxymethyl, trifluoromethylCarboxyl, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
R2hydrogen, the following groups unsubstituted or substituted with 1 to 3 substituents: c3～C7Cycloalkyl radical, C1～C6Alkyl radical, C5～C7Aromatic ring radical, C5～C7Aromatic heterocyclic group, benzo-5-6 membered heterocyclic group, C2～C7Alkynyl, C2～C7An alkenyl group, the heterocyclic group and the aromatic heterocyclic group each containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, methylmercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
R3is hydrogen, the following groups unsubstituted or substituted with 1 to 2 substituents: c3～C7Cycloalkyl radical, C1～C6Alkyl radical, C5～C7Aromatic ring radical, C5～C7Aromatic heterocyclic group, 5-6 membered heterocyclic group, C2～C7Alkynyl, C2～C7An alkenyl group, the heterocyclic group and the aromatic heterocyclic group each containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen; each of the substituents is independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, C1～C4Straight or branched alkylthio, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
R4is a covalently reactive or reversibly covalently reactive group comprising an aldehyde group, cyano group, boronic acid, carboxylic acid group, α -carbonyl alcohol, α -carbonyl aldehyde, α -carbonyl amide, α -carbonyl trifluoromethyl, acryloyl group, α -haloacetyl group, 1- (oxido-2-yl) acetyl group, 2-butynoyl group, unsubstituted or substituted with 1-2 substituents each independently selected from the group consisting of: halogen, C1～C4Straight or branched alkyl, C2～C4Straight-chain or branched alkenyl, C2～C4Straight-chain or branched alkynyl, C1～C4Straight or branched alkoxy, C1～C4Straight or branched chain alkylcarbonyloxy, C1～C4Straight-chain or branched alkylthio, C3～C7Cycloalkyl, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, carboxy, mercapto, C1～C4Acyl, amido, aminosulfonyl, C1～C4Alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring;
m is 0,1, 2 or 3;
n is 0,1, 2, 3, 4 or 5.
2. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds shown in table 1 below, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof:
table 1: represent compounds I-1 to I-25
Figure FDA0003162667680000031
3. A process for the preparation of a compound of formula (I) as claimed in claim 1, comprising the steps of:
Figure FDA0003162667680000041
(1) reacting a compound II with a compound Ia in an inert solvent in the presence of a condensing agent and a base to obtain a compound Ib; preferably, the condensing agent is 1-Hydroxybenzotriazole (HOBT) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), and the base is N, N-Diisopropylethylamine (DIEA);
Figure FDA0003162667680000042
(2) reacting a compound Ib with a compound III in an inert solvent in the presence of a catalyst and alkali to obtain a compound I; preferably, the catalyst is methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (XPhos Pd G3), and the base is potassium phosphate (K)3PO4)；
In each of the above reaction formulae, each group is as defined in claim 1.
4. A pharmaceutical composition, said pharmaceutical composition comprising: a therapeutically effective amount of one or more compounds of formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
5. The use of a pharmaceutical composition of formula (I) as claimed in claim 1 for targeting a viral-critical drug target MproIs applied in acting target.
6. Use of a pharmaceutical composition of general formula (I) as claimed in claim 1 in a prophylactic or antiviral medicament, wherein the coronavirus comprises human coronavirus OC43, human coronavirus 229E, human coronavirus NL63, human coronavirus HKU1, severe acute respiratory syndrome coronavirus (SARS-Cov-1), middle east respiratory syndrome coronavirus (MERS) and novel coronavirus (SARS-Cov-2).
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