A 4-quinoline aniline main protease inhibitor and its preparation method and medical use

Abstract

The present invention discloses a 4-quinoline aniline main protease inhibitor, its preparation method, and medical use. The 4-quinoline aniline main protease inhibitor comprises a compound represented by Formula I or a pharmaceutically acceptable salt or isomer thereof, and the structural formula of the compound represented by Formula I is: #imgabs0# The present invention also specifically discloses a preparation method of the 4-quinoline aniline main protease inhibitor and its medical use against coronaviruses. The present invention synthesizes a series of main protease inhibitors for the first time, and the main protease inhibitors can be used to treat viral infectious diseases such as SARS-CoV-2, SARS-CoV, and MERS-CoV.

Description

Technical Field

[0001] The present invention belongs to the technical field of 4-quinoline aniline compounds and their anti-coronavirus applications, and particularly relates to a 4-quinoline aniline main protease inhibitor, a preparation method thereof, and medical applications thereof. Background Art

[0002] The new coronavirus infection (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seriously threatens people's health and economic development (Wu et al, Nature 2020, 579, 265-269.). Although effective vaccines have been administered globally, some highly contagious SARS-CoV-2 strains can evade therapeutic antibodies and vaccines (Cao et al, Nature 2022, 602, 657-663; Grant et al, Lancet Reg. Health Eur. 2022, 13, 100278.). In addition, the vaccine is ineffective for people with weakened immunity and is not recommended for allergic people. Therefore, the development of direct-acting antiviral drugs (DAAs) for SARS-CoV-2 and other coronaviruses that may appear in the future is still urgently needed.

[0003] SARS-CoV-2 is an enveloped, single-stranded, positive-strand RNA virus. After entering the host cell, it is cleaved by human tissue proteases and other proteins to release the S-protein, which is then translated into polyproteins pp1a and pp1ab. pro , also known as 3CL pro ) and papain (PL pro ) These two cysteine ​​proteases can be released from the polyprotein and further hydrolyze the polyprotein into a variety of non-structural proteins nsp1-16 that play an essential role in the viral replication-translation process (Gioia et al, Biochem. Pharmacol. 2020, 182, 114225; Luan et al, J. Proteome Res. 2020, 19, 4316-4326.). Therefore, M pro and PL pro It is an important target for developing DAAs against SARS-CoV-2. pro With a broader substrate range, its inhibitors are expected to have better therapeutic effects.

[0004] M proThe active site of M. pyogenes contains a catalytic dyad consisting of cysteine ​​Cys145 and histidine His41, which preferentially hydrolyzes substrates with the following consensus sequences: P2 (leucine / phenylalanine / methionine / valine), P1 (glutamine), and P1' (serine / alanine) residues. There are few human proteases with similar substrate selectivity. With the outbreak of the COVID-19 pandemic, M. pro Inhibitors have been reported one after another, most of which are covalent inhibitors that use α-ketoamide, α, β-unsaturated ketone, aldehyde, dihaloamide and vinyl sulfone to interact with Cys145 (Jin et al, Nature 2020, 582, 289-293; Zhang et al, Science 2020, 368, 409-412; Dai et al, Science 2020, 368, 1331-1335; Ma et al, J. Am. Chem. Soc. 2021, 143, 20697-20709.). Recently, Pfizer's Paxlovid was approved by the U.S. Food and Drug Administration for the treatment of new coronavirus infection. It is produced by M pro The drug is composed of the inhibitor Nematevir and the HIV protease inhibitor Ritonavir. Ritonavir is mainly used to inhibit the rapid metabolism of Nematevir caused by CYP3A (Owen et al, Science 2021, 374, 1586-1593.). Its excellent efficacy further illustrates the efficacy of M pro Inhibitors have great potential as anti-coronavirus drugs. However, this treatment regimen has serious drug-drug interactions, is not recommended for patients with severe renal or liver damage, and has drug resistance. pro The development of inhibitors is urgently needed. Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a 4-quinoline aniline main protease inhibitor and a preparation method thereof. The 4-quinoline aniline main protease inhibitor prepared by the method can be used to prepare drugs for preventing or treating viral infectious diseases such as SARS-CoV-2, SARS-CoV and / or MERS-CoV.

[0006] The present invention adopts the following technical solutions to solve the above technical problems:

[0007] A 4-quinolinylaniline main protease inhibitor, characterized in that the 4-quinolinylaniline main protease inhibitor comprises a compound represented by Formula I or a pharmaceutically acceptable salt or isomer thereof, wherein the structural formula of the compound represented by Formula I is:

[0008]

[0009] R1 C 1-6 Alkyl or halogen substituted C 1-6 Alkyl; R3 is H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0010] R 2 for:

[0011]

[0012] R4 is H, halogen, C 1-6 Alkyl or halogen substituted C 1-6 Alkyl; R5 is halogen or cyano.

[0013] Preferably, R 1 is methyl, ethyl or cyclopropyl; R 2 for R 3 is H, methyl, methoxy or halogen.

[0014] Preferably, the 4-quinoline aniline main protease inhibitor includes a compound with the following specific structure:

[0015]

[0016] A method for preparing a 4-quinoline aniline main protease inhibitor, characterized in that the synthesis route is:

[0017]

[0018] Reagents and conditions: (i) KOH, EtOH, 100°C; (ii) concentrated H2SO4, MeOH, 75°C; (iii) acylating agent, Et3N, DCM, rt; (iv) NaBH4, MeOH, 80°C; (v) acyl chloride / anhydride, Et3N, DCM, rt or carboxylic acid, DCC, 4-DMAP, DCM, rt;

[0019]

[0020] Reagents and conditions: (vi) Dess-Martin reagent, Na2CO3, THF, rt; (vii) CF3-BHA, TFA, DME, 80°C.

[0021] A pharmaceutical composition characterized by comprising the above-mentioned 4-quinoline aniline main protease inhibitor and a pharmaceutically acceptable carrier.

[0022] The 4-quinoline aniline main protease inhibitor or pharmaceutical composition of the present invention is used in the preparation of a drug for inhibiting M pro Use in active pharmaceutical ingredients.

[0023] The use of the 4-quinolineaniline main protease inhibitor or pharmaceutical composition described in the present invention in the preparation of drugs for treating new coronavirus infectious diseases.

[0024] The present invention relates to the use of the 4-quinoline aniline main protease inhibitor or pharmaceutical composition in the preparation of a drug for preventing or treating SARS-CoV-2, SARS-CoV or / and MERS-CoV viral infectious diseases.

[0025] The present invention has the following advantages and beneficial effects: the present invention synthesizes a series of main protease inhibitors for the first time, and the main protease inhibitors can be used to treat viral infectious diseases such as SARS-CoV-2, SARS-CoV, and MERS-CoV. DETAILED DESCRIPTION

[0026] Some chemical terms

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0028] It should be understood that the above overview and the detailed description below are exemplary and for explanation only and do not limit the subject matter of the present invention in any way. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It should also be noted that, unless the context clearly dictates otherwise, as used in the specification and claims, the singular forms "a", "an", "the", or "said" include plural referents. It should also be noted that, unless otherwise stated, the use of "or" or "alternatively" means "and / or". In addition, the use of the term "including" and other forms is not restrictive. Similarly, the use of the term "comprising" and other forms is not restrictive.

[0029] The following can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY4 THDefinitions of standard chemical terms can be found in "Chemicals of the Present Invention," ed." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, HPLC, IR and UV / Vis spectroscopy and pharmacological methods, are employed. Unless specific definitions are provided, the nomenclature employed in connection with analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry described herein, as well as the experimental procedures and techniques thereof, are those known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kits can be utilized, or the reactions and purification techniques can be performed in a manner known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.

[0030] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the structure were written from right to left. For example, CH2O is equivalent to OCH2.

[0031] Unless otherwise indicated, general chemical terms such as, but not limited to, "alkyl" and "aryl" are equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.

[0032] As used herein, a group referred to as "C1-C6" refers to a group having from 1 to 6 carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. Thus, by way of example only, "C1-C6 alkyl" means that there are from 1 to 6 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isomers thereof.

[0033] The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent saturated hydrocarbon having 1 to about 18 carbon atoms, or 1 to about 10 carbon atoms, or 1 to about 6 carbon atoms. "Lower alkyl" as used herein, alone or in combination, refers to an alkyl group having a relatively small number of carbon atoms, for example, 1 to about 8 carbon atoms, preferably 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like.

[0034] The "alkyl group" used in combination includes, but is not limited to, the "alkyl group" included in the "alkoxy group".

[0035] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical (O-alkyl). Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0036]

[0046] The terms "halogen," "halo," or "halide," as used herein, alone or in combination, refer to fluoro, chloro, bromo, and iodo.

[0037] Cyano refers to the –CN group.

[0038] A substituent herein refers to one substituent or multiple substituents.

[0039] The present invention also includes isotope-labeled compounds. Common isotope atoms include but are not limited to 2 H. 3 H. 13 C. 14 C. 17 O. 18 O. 15 N, etc. These atoms are identical to their most abundant atoms in nature but have different mass numbers. The application of isotope labeling in drug discovery has been reported (Elmore, Charles S., Annual Report of Medicinal Chemistry, 2009, 44, 515-534).

[0040] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds described herein and is relatively non-toxic, i.e., the substance can be administered to a subject without causing adverse biological effects or interacting in a deleterious manner with any components included in the composition.

[0041] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound and has no adverse biological or other effects. The compounds described herein may have acidic or basic groups and can therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the purified compound in its free base form with a suitable organic or inorganic acid separately and isolating the salt thus formed. Examples of pharmaceutically acceptable salts include those prepared by reactions between the compounds described herein and inorganic or organic acids or inorganic or organic bases.

[0043] The term "isomers" as used herein refers to isomers that are readily interconvertible from the compounds of the present invention by, for example, hydrogen atom migration or proton migration.

[0044] IC 50 It refers to the concentration of a particular compound that inhibits a specific measured activity by 50%.

[0045] General synthetic method of the compound of the present invention:

[0046] The compounds of the present invention can generally be synthesized by the chemical synthesis routes shown in Scheme 1 and Scheme 2. All related compounds can be prepared similarly according to the general methods shown in Scheme 1 and Scheme 2, and the synthesis of specific compounds will be provided in the compound examples described below.

[0047] Isatin and 4-aminoacetophenone undergo a Pfitzinger reaction to yield quinoline-4-carboxylic acid compound B-3 (Scheme 1). This is then esterified with methanol in the presence of concentrated sulfuric acid to yield intermediate compound B-4. Compound B-4 reacts with the corresponding acyl chloride or anhydride to yield intermediate B-5, which is then reduced with sodium borohydride to alcohol B-6, which then reacts with the corresponding acyl chloride, anhydride, or carboxylic acid to yield the desired product.

[0048] Plan-1

[0049]

[0050] Reagents and conditions: (i) KOH, EtOH, 100 ° C; (ii) concentrated H2SO4, MeOH, 75 ° C; (iii) acylating agent acetic anhydride, Et3N, DCM, rt; (iv) NaBH4, MeOH, 80 ° C; (v) acid chloride / anhydride, Et3N, DCM, rt or carboxylic acid, DCC, 4-DMAP, DCM, rt;

[0051] B-6 is used as an intermediate for oxidation reaction to generate an aldehyde compound (Scheme-2). The aldehyde compound reacts with CF3-BHA under acidic conditions to generate a cyano compound.

[0052]

[0053] Reagents and conditions: (vi) Dess-Martin reagent, Na2CO3, THF, rt; (vii) CF3-BHA, TFA, DME, 80°C.

[0054] Example 1

[0055] Synthesis of (2-(4-acetamidophenyl)quinolin-4-yl) methacrylate

[0056]

[0057] Synthesis of intermediate B-3

[0058]

[0059] At room temperature, a 10 mL ethanol solution of 4-aminoacetophenone (2.74 g, 20.3 mmol) was added to a 6 M KOH aqueous solution (10 mL) of isatin (2.00 g, 13.6 mmol), and the mixture was heated to 100 ° C and reacted for 24 h. After the reaction was completed, it was cooled to room temperature, the ethanol was removed under reduced pressure, and a 1 M HCl solution was added to adjust the pH of the mixture to 5. The mixture was filtered, and the filter cake was washed with water and ethanol, respectively, to obtain a red solid compound B-3 (2.50 g, yield 47%).

[0060] Synthesis of compound B-4

[0061]

[0062] At room temperature, compound B-3 (5.67 mmol, 1.50 g, 1.0 eq.) was dissolved in methanol (20 mL), cooled to 0°C, and concentrated sulfuric acid (1 mL) was added dropwise to the reaction system. The temperature was then raised to 75°C and stirred for 12 h. After the reaction was completed, it was cooled to room temperature and 20 mL of water was added to quench the reaction. Saturated aqueous sodium carbonate solution was added to the reaction system to adjust the mixed system to be weakly alkaline, and then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 150 / 1) to obtain compound B-4 (1.21 g, yellow solid) with a yield of 77%.

[0063] Synthesis of compound B-5

[0064]

[0065] At room temperature, compound B-4 (4.35 mmol, 1.21 g, 1.0 eq.) was dissolved in dichloromethane (10 mL), cooled to 0°C, and triethylamine (12.93 mmol, 2.15 mL, 3.0 eq.) and acetic anhydride (8.62 mmol, 880 mg, 2.0 eq.) were added in sequence. The mixture was then heated to room temperature and stirred for 3 h. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 200 / 1) to obtain compound B-5 (1.04 g, yellow solid) with a yield of 75%.

[0066] Synthesis of compound B-6

[0067]

[0068] At room temperature, compound B-5 (3.25 mmol, 1.04 g, 1.0 eq.) was dissolved in anhydrous ethanol (10 mL), and sodium borohydride (9.75 mmol, 369 mg, 3.0 eq.) was added. The temperature was raised to 80°C and stirred for 3 h. After the reaction was completed, the mixture was cooled to room temperature and about 50 mL of ice water was added to quench the reaction. A white insoluble solid was produced, which was vacuum filtered and dried to obtain compound B-6 (651 mg, white solid) with a yield of 69%.

[0069] Synthesis of compound 1

[0070]

[0071] At room temperature, compound B-6 (0.51 mmol, 150 mg, 1.0 eq.) was dissolved in dichloromethane (10 mL), cooled to 0°C, and triethylamine (1.53 mmol, 155 mg, 3.0 eq.) and acryloyl chloride (1.02 mmol, 92 mg, 2.0 eq.) were added in sequence. The mixture was then heated to room temperature and stirred for 3 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 90 / 1) to obtain compound 1 (111 mg, white solid) with a yield of 60%.

[0072] White solid, mp130-131℃; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.23(d,J=8.4Hz,2H),8.13-8.06(m,3H),7.82-7.77(m,3H),7.64-7.61( m,1H),6.44(d,J=17.2Hz,1H),6.33(dd,J=17.2,10.0Hz,1H),6.02(d,J=10.0Hz,1H),5.75(s,2H),2.09(s,3H). 13 CNMR(100MHz,DMSO-d6)δ168.6,165.2,155.4,147.7,142.0,140.9,132.8,132.5 ,129.9,129.6,127.9,127.7,126.6,124.6,123.6,119.0,117.4,62.9,24.1.HRMS Calcd forC 21 H 19 N2O3[M+H] + :m / z 347.1390Found:347.1391.

[0073] Example 2

[0074] Synthesis of (2-(4-acetamidophenyl)quinolin-4-yl)methyl (E)-4,4,4-trifluoro-2-butenoate

[0075]

[0076] Prepared according to the method of Example 1. Yield 49%; white solid, mp 192-193°C; 1H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.26(d,J=8.8Hz,2H),8.19(s,1H),8.09(d,J=8.4Hz,2H),7. 82-7.77(m,3H),7.65-7.61(m,1H),7.24-7.15(m,1H),6.94-6.89(m,1H),5.82(s,2H),2.10(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.6,163.5,155.4,147.7,141.3,140.9,132.8,130.9(q,J=34.0Hz),129.9,1 29.6,129.5(q,J=6.0Hz),127.8,126.6,124.5,123.7,122.4(q,J=268.0Hz),,118.9,117.5,63.9,24.1. 19 F NMR(376MHz,DMSO-d6)δ-63.9.HRMS Calcd for C 22 H 18 F3N2O3[M+H] + :m / z 415.1264,Found:415.1262.

[0077] Example 3

[0078] Synthesis of (2-(4-acetamidophenyl)quinolin-4-yl)methylbutynoate

[0079]

[0080] Prepared according to the method of Example 1. Yield 47%; white solid, mp 110-111°C; 1 H NMR (400MHz, CDCl3) δ8.19-8.14 (m, 3H), 7.91 (d, J = 8.4Hz, 1H), 7.89 (s, 1H), 7.75-7.68(m,3H),7.58-7.55(m,2H),5.69(s,2H),2.21(s,3H),2.02(s,3H). 13 C NMR (100MHz, CDCl3) δ168.6,156.5,153.4,148.5,140.7,139.4,135.2,130.5,12 9.9,128.5,126.9,124.9,122.8,119.9,117.9,87.4,72.1,64.1,24.9,4.1.HRMS Calcd for C 22H 19 N2O3[M+H] + :m / z359.1390,Found:359.1391.

[0081] Example 4

[0082] Synthesis of (2-(4-acetamidophenyl)quinolin-4-yl)methylpropiolate

[0083]

[0084] Prepared according to the method of Example 1. Yield 55%; white solid, mp 109-110°C; 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.23(d,J=8.4Hz,2H),8.15(s,1H),8.11-8.07 (m,2H),7.83-7.77(m,3H),7.66-7.62(m,1H),5.79(s,2H),4.67(s,1H),2.10(s,3H). 13 C NMR(150MHz,DMSO-d6)δ168.6,155.5,151.9,147.8,141.0,140.7,132.7,130.0 ,129.7,127.7,126.7,124.7,123.8,119.0,118.4,79.9,74.4,64.7,24.1.HRMS Calcd for C 21 H 17 N2O3[M+H] + :m / z 345.1234,Found:345.1230.

[0085] Example 5

[0086] Synthesis of (2-(4-acetamidophenyl)quinolin-4-yl)methyl chloroacetate

[0087]

[0088] Prepared according to the method of Example 1. Yield 60%; White solid, mp 210-211°C; 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.25(d,J=8.8Hz,2H),8.13(s,1H),8.10-8.07 (m,2H),7.82-7.77(m,3H),7.64-7.60(m,1H),5.78(s,2H),4.60(s,2H),2.10(s,3H).13 C NMR (100MHz, DMSO-d6) δ168.6,167.3,155.4,147.7,141.5,140.9,132.7,130.0,129.6,127.7,126.6,124.4,123.7,118.9,117.1,64.0,24.1.HRMS Calcd for C 20 H 18 ClN2O3[M+H] + :m / z369.1000,Found:369.1002.

[0089] Example 6

[0090] Synthesis of (2-(4-acetamidophenyl)quinolin-4-yl)methyl bromoacetate

[0091]

[0092] Prepared according to the method of Example 1. Yield 50%; White solid, mp 199-200℃; 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.25(d,J=8.8Hz,2H),8.13(s,1H),8.10-8.06 (m,2H),7.82-7.77(m,3H),7.64-7.60(m,1H),5.77(s,2H),4.35(s,2H),2.10(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.6,167.1,155.4,147.6,141.6,140.9,132.7,12 9.9,129.6,127.7,126.5,124.4,123.7,119.0,116.9,64.0,27.1,24.1.HRMS Calcd for C 20 H 18 BrN2O3[M+H] + :m / z 413.0495,Found:413.0485.

[0093] Example 7

[0094] Synthesis of (2-(4-acetamidophenyl)quinolin-4-yl)methyl cyanoacetate

[0095]

[0096] Prepared according to the method of Example 1. Yield 30%; White solid, mp 184-185°C; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.25(d,J=8.8Hz,2H),8.14(s,1H),8.09(dd,J=8.0 ,3.2Hz,2H),7.83-7.77(m,3H),7.65-7.61(m,1H),5.77(s,2H),4.22(s,2H),2.10(s,3H). 13 CNMR(100MHz,DMSO-d6)δ168.6,164.3,155.4,147.7,141.3,141.0,132.7,130.0 ,129.6,127.7,126.6,124.4,123.7,118.9,117.1,115.1,64.2,24.7,24.1.HRMS Calcd forC 21 H 18 N3O3[M+H] + :m / z 360.1343,Found:360.1344.

[0097] Example 8

[0098] Synthesis of N-((2-(4-acetamidophenyl)quinolin-4-yl)methyl)acrylate

[0099]

[0100] Prepared according to the method of Example 1. Yield 36%; White solid, mp 220-221°C; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.78(t,J=5.6Hz,1H),8.19(d,J=8.8Hz,2H),8.10(dd,J=20.0,8.0Hz,2H),7.98(s,1H),7.80-7.76(m,2H) ,7.62-7.58(m,1H),6.34(dd,J=17.2,10.0Hz,1H),6.19(dd,J=17.2,2.4Hz,1H),5.67(dd,J=10.02.4Hz,1H),4.91(d,J=5.6Hz,2H),2.09(s,3H). 13C NMR(150MHz,DMSO-d6)δ168.6,164.8,155.3,147.8,145.1,140.8,133.0,131 .4,129.7,129.7,127.6,126.3,126.0,125.1,123.6,119.0,117.0,24.1.HRMS Calcd for C 21 H 20 N3O2[M+H] + :m / z 346.1550,Found:346.1550.

[0101] Example 9

[0102] Synthesis of N-(4-(4-formyl)quinolin-2-yl)phenyl)acetamide

[0103]

[0104] Compound B-6 (0.51 mmol, 150 mg, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL) at room temperature. Dess-Martin periodinane (1.02 mmol, 433 mg, 2.0 eq.) and sodium carbonate (1.28 mmol, 135 mg, 2.5 eq.) were added sequentially and stirred for 6 h. After completion, the reaction was quenched with water and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to afford N-(4-(4-formyl)quinolin-2-yl)phenyl)acetamide (65 mg, yellow solid) in a 44% yield. mp 172-173°C. 1 HNMR (400MHz, DMSO-d6) δ10.54(s,1H),10.21(s,1H),8.92(d,J=8.4Hz,1H),8.64(s,1H),8.29(d,J=8.8 Hz,2H),8.15(d,J=8.4Hz,1H),7.87-7.83(m,1H),7.80(d,J=8.4Hz,2H),7.73-7.70(m,1H),2.10(s,3H). 13 C NMR(100MHz,DMSO-d6)δ195.4,169.2,156.55,149.0,141.7,138.1,132.6,130.9,130.0,129.0,128.3,124.7,124.7,122.5,119.5,24.60.HRMSCalcd for C 18 H 15N2O2[M+H] + :m / z 291.1128,Found:291.1131.

[0105] Example 10

[0106] Synthesis of N-(4-(4-cyano)quinolin-2-yl)phenyl)acetamide

[0107]

[0108] N-(4-(4-Formyl)quinolin-2-yl)phenyl)acetamide (0.63 mmol, 183 mg, 1.0 eq.) was dissolved in ethylene glycol dimethyl ether (10 mL) at room temperature. TFA (0.19 mmol, 22 mg, 0.3 eq.) and CF3-BHA (0.94 mmol, 193 mg, 1.5 eq.) were then added sequentially. The mixture was heated to 80°C and stirred for 12 h. After completion, the reaction was cooled to room temperature. Water was added to the reaction system and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to afford N-(4-(4-cyano)quinolin-2-yl)phenyl)acetamide (60 mg, yellow solid) in a 33% yield. mp 142-143°C. 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.76(s,1H),8.30(d,J=8.8Hz,2H),8.18(d,J= 8.4Hz,1H),8.10(d,J=8.0Hz,1H),7.96-7.92(m,1H),7.83-7.77(m,3H),2.10(s,3H). 13 C NMR (100MHz, DMSO-d6) δ168.7,155.5,147.3,141.5,131.6,131.4,129.9,128.8,128.0,124.2,123.7,123.4,119.0,118.6,115.8,24.15.HRMS Calcd for C 18 H 14 N2O[M+H] + :m / z288.1131,Found:288.1132.

[0109] Example 11

[0110] Synthesis of N-(4-(4-ethynyl)quinolin-2-yl)phenyl)acetamide

[0111]

[0112] Prepared according to the method of Example 1. Yield 52%; White solid, mp 202-203°C; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.28-8.25(m,3H),8.20(d,J=8.4Hz,1H),8.09(d,J=8.4 Hz,1H),7.85-7.81(m,1H),7.77(d,J=8.4Hz,2H),7.70-7.66(m,1H),5.05(s,1H),2.09(s,3H). 13 C NMR (100MHz, DMSO-d6) δ168.6,155.3,147.4,141.1,132.2,130.6,129.6,128.8,127.8,127.3,125.8,125.1,121.5,118.9,90.0,79.3,24.1.HRMS Calcd forC 19 H 15 N2O[M+H] + :m / z 287.1179,Found:287.1172.

[0113] Example 12

[0114] Synthesis of (2-(4-propionamidophenyl)quinolin-4-yl) methacrylate

[0115]

[0116] Prepared according to the method of Example 1. Yield 45%; White solid, mp 170-171°C; 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.23(d,J=8.8Hz,2H),8.14(s,1H),8.10-8.06(m,2H),7.81-7.78(m,3H),7.65-7.60(m,1H),6.44(dd ,J=17.2,1.6Hz,1H),6.33(dd,J=17.2,10.0Hz,1H),6.02(dd,J=10.0,1.6Hz,1H),5.75(s,2H),2.37(q,J=7.6Hz,2H),1.11(t,J=7.6Hz,3H). 13C NMR(100MHz,DMSO-d6)δ172.3,165.2,155.4,147.7,142.0,141.0,132.7,132.5,12 9.9,129.6,127.9,127.7,126.6,124.6,123.6,119.0,117.5,62.9,29.6,9.60.HRMS Calcd for C 22 H 21 N2O3[M+H] + :m / z 361.1547,Found:361.1546.

[0117] Example 13

[0118] Synthesis of (2-(4-cyclopropanamidephenyl)quinolin-4-yl) methacrylate

[0119]

[0120] Prepared according to the method of Example 1. Yield 56%; white solid, mp 180-181°C; 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.24(d,J=8.8Hz,2H),8.14(s,1H),8.10-8.06(m,2H),7.81-7.78(m,3H),7.64-7.60(m,1H),6.43 (dd,J=17.2,1.6Hz,1H),6.33(dd,J=17.2,10.0Hz,1H),6.02(dd,J=10.0,1.6Hz,1H),5.75(s,2H),1.87-1.80(m,1H),0.87-0.80(m,4H). 13 C NMR (150MHz, DMSO-d6) δ171.9,165.2,155.4,147.7,142.0,140.9,132.7,132.5,129. 9,129.6,127.9,127.7,126.6,124.6,123.6,119.0,117.5,62.9,14.7,7.4.HRMSCalcd for C 23 H 21 N2O3[M+H] + :m / z 373.1547,Found:373.1552.

[0121] Example 14

[0122] Synthesis of (2-(4-tert-Butylamidophenyl)quinolin-4-yl) methacrylate

[0123]

[0124] Prepared according to the method of Example 1. Yield 52%; white solid, mp 139-140°C; 1 H NMR(400MHz, DMSO-d6)δ9.42(s,1H),8.24(d,J=8.4Hz,2H),8.16(s,1H),8.11-8.06(m,2H),7.87(d,J=8.8Hz,2H),7.82-7.78(m,1H),7 .64-7.61(m,1H),6.43(dd,J=17.2,1.6Hz,1H),6.32(dd,J=17.2,10.0Hz,1H),6.02(dd,J=10.0,1.6Hz,1H),5.75(s,2H),1.26(s,9H). 13 C NMR(100MHz,DMSO-d6)δ176.7,165.2,155.4,147.7,141.9,141.1,132.8,132.4, 129.9,129.6,127.9,127.4,126.6,124.7,123.7,120.1,117.6,62.9,27.2.HRMS Calcdfor C 24 H 25 N2O3[M+H] + :m / z 389.1860,Found:389.1864.

[0125] Example 15

[0126] Synthesis of (2-(4-tert-Butylamidophenyl)quinolin-4-yl) methacrylate

[0127]

[0128] Prepared according to the method of Example 1. Yield 38%; white solid, mp 165-166°C; 1H NMR (400MHz, DMSO-d6) δ11.47(s,1H),8.34(d,J=8.8Hz,2H),8.19(s,1H),8.14-8.09(m,2H),7.89(d,J=8.8Hz,2H),7.85-7.81(m ,1H),7.68-7.64(m,1H),6.44(dd,J=17.2,1.6Hz,1H),6.33(dd,J=17.2,10.0Hz,1H),6.03(dd,J=10.0,1.6Hz,1H),5.77(s,2H). 13 C NMR (150MHz, DMSO-d6) δ165.2, 155.0, 154.6 (q, J = 36.0Hz), 147.7, 142.2, 137.8, 135.4, 132.5 ,130.1,129.8,127.9,127.9,126.9,124.8,123.7,121.1,117.6,115.7(q,J=288.0Hz),62.9. 19 F NMR(376MHz,DMSO-d6)δ-73.8.HRMS Calcd for C 21 H 16 F3N2O3[M+H] + :m / z401.1108,Found:401.1109.

[0129] Example 16

[0130] Synthesis of (2-(4-(2-chloroacetamido)phenyl)quinolin-4-yl)methacrylate

[0131]

[0132] Prepared according to the method of Example 1. Yield 42%; white solid, mp 183-184°C; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.28(d,J=8.4Hz,2H),8.15(s,1H),8.12-8.08(m,2H),7.81-7.79(m,3H),7.66-7.62( m,1H),6.44(dd,J=17.2,1.6Hz,1H),6.33(dd,J=17.2,10.0Hz,1H),6.03(dd,J=10.0,1.6Hz,1H),5.76(s,2H),4.31(s,2H). 13C NMR(100MHz,DMSO-d6)δ165.2,164.9,155.2,147.7,142.1,140.0,133.6,132.5, 130.0,129.7,127.9,127.8,126.7,124.7,123.7,119.4,117.5,62.9,43.6.HRMS Calcd for C 21 H 18 ClN2O3[M+H] + :m / z 381.1000,Found:381.0999.

[0133] Example 17

[0134] Synthesis of N-(4-(4-formylquinolin-2-yl)phenyl)propionamide

[0135]

[0136] Prepared according to the method of Example 9. Yield 48%; yellow solid, mp 182-183°C; 1 H NMR (600MHz, DMSO-d6) δ10.56(s,1H),10.13(s,1H),8.94(d,J=8.4Hz,1H),8.69(s,1H),8.32(d,J=8.4Hz,2H ),8.17(d,J=8.4Hz,1H),7.88-7.83(m,3H),7.75-7.72(m,1H),2.38(q,J=7.8Hz,2H),1.12(t,J=7.8Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ194.9,172.4,156.1,148.5,141.4,137.7,132.0,130.4,129.5,128.5,127.8,124.3,124.2,122.1,119.1,29.6,9.6.HRMS Calcd for C 19 H 17 N2O2[M+H] + :m / z 305.1285,Found:305.1286.

[0137] Example 18

[0138] Synthesis of N-(4-(4-Formylquinolin-2-yl)phenyl)trimethylacetamide

[0139]

[0140] Prepared according to the method of Example 9. Yield 45%; yellow solid, mp 172-173°C; 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),9.46(s,1H),8.95(d,J=8.4Hz,1H),8.72(s,1H),8.33 (d,J=8.8Hz,2H),8.18(d,J=8.0Hz,1H),7.93-7.85(m,3H),7.76-7.70(m,1H),1.27(s,9H). 13 C NMR (100MHz, DMSO-d6) δ195.0,176.8,156.1,148.5,141.5,137.7,132.1,130.4,129.5,128.5,127.5,124.3,124.2,122.1,120.1,27.1.HRMS Calcd for C 21 H 21 N2O2[M+H] + :m / z 333.1598,Found:333.1599.

[0141] Example 19

[0142] Synthesis of (2-(4-cyclopropionamido)phenyl)quinolin-4-yl)methyl-2-bromoacetate

[0143]

[0144] Prepared according to the method of Example 1. Yield 35%; white solid, mp 214-215℃; 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.25 (d, J = 8.8Hz, 2H), 8.14 (s, 1H), 8.10-8.08 (m, 2H), 7.81 -7.78(m,3H),7.65-7.60(m,1H),5.78(s,2H),4.60(s,2H),1.86-1.80(m,1H),0.85-0.81(m,4H). 13 C NMR(100MHz,DMSO-d6)δ171.9,167.3,155.4,147.7,141.5,140.9,132.6,13 0.0,129.6,127.8,126.6,124.5,123.7,119.0,117.1,64.0,14.7,7.4.HRMS Calcd forC 22 H 20 BrN2O3[M+H]+ :m / z 439.0652,Found:439.0646.

[0145] Example 20

[0146] Synthesis of (2-(4-acetamido)phenyl)-6-methylquinolin-4-yl)methyl-2-bromoacetate

[0147]

[0148] Prepared according to the method of Example 1. Yield 41%; white solid, mp 204-205°C; 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.21(d,J=8.8Hz,2H),8.08(s,1H),7.98(d,J=8.8Hz,1H),7.84(s,1 H),7.77(d,J=8.8Hz,2H),7.63(dd,J=8.8,1.6Hz,1H),5.73(s,2H),4.35(s,2H),2.53(s,3H),2.09(s,3H). 13 C NMR(150MHz,DMSO-d6)δ168.6,167.2,154.5,146.2,140.9,140.7,136.2,132.9 ,132.0,129.4,127.5,124.3,122.5,119.0,116.8,64.0,27.1,24.1,21.4.HRMS Calcd for C 21 H 20 BrN2O3[M+H] + :m / z 427.0652,Found:427.0652.

[0149] Example 21

[0150] Synthesis of (2-(4-acetamido)phenyl)-6-fluoroquinolin-4-yl)methyl-2-bromoacetate

[0151]

[0152] Prepared according to the method of Example 1. Yield 42%; white solid, mp 213-214°C; 1H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.23(d,J=8.8Hz,2H),8.17-8.13(m,2H),7.87(dd,J=10. 0, 2.4Hz, 1H), 7.78 (d, J = 8.8Hz, 2H), 7.74-7.69 (m, 1H), 5.72 (s, 2H), 4.35 (s, 2H), 2.09 (s, 3H). 13 C NMR (150MHz, DMSO-d6) δ168.6,167.1,159.7(d,J=244.5Hz),155.0,144.9,141.5(d,J=6.0Hz),141.0,132.5,132.3 (d,J=9.0Hz),127.7,125.2(d,J=9.0Hz),119.9(d,J=10.5Hz),119.0,117.8,107.8(d,J=7.5Hz),64.0,27.1,24.1. 19 F NMR(376MHz,DMSO-d6)δ-112.5.HRMS Calcd for C 20 H 17 BrFN2O3[M+H] + :m / z 431.0401,Found:431.0408.

[0153] Example 22

[0154] Synthesis of (2-(4-acetamido)phenyl)-7-methoxyquinolin-4-yl)methyl-2-bromoacetate

[0155]

[0156] Prepared according to the method of Example 1. Yield 39%; white solid, mp 188-189°C; 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.22(d,J=8.8Hz,2H),7.98(d,J=9.2Hz,2H),7.77(d,J=8.8Hz,2H) ,7.47(d,J=2.4Hz,1H),7.26(dd,J=9.2,2.4Hz,1H),5.72(s,2H),4.34(s,2H),3.95(s,3H),2.09(s,3H). 13C NMR(150MHz,DMSO-d6)δ168.6,167.1,160.5,155.7,149.6,141.5,140.9,132.8 ,127.7,124.9,119.4,119.0,118.9,114.8,108.0,64.0,55.5,27.1,24.1.HRMS Calcd for C 21 H 20 BrN2O4[M+H] + :m / z 443.0601,Found:443.0603.

[0157] Example 23

[0158] Synthesis of (2-(4-acetamido)phenyl)-7-chloroquinolin-4-yl)methyl-2-bromoacetate

[0159]

[0160] Prepared according to the method of Example 1. Yield 45%; white solid, mp 211-212°C; 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 8.23 ​​(d, J = 8.8Hz, 2H), 8.15-8.09 (m, 3H), 7.78 (d,J=8.8Hz,2H),7.64(dd,J=9.2,2.0Hz,1H),5.74(s,2H),4.34(s,2H),2.10(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.6,167.1,156.6,148.2,142.0,141.3,134.5,132 .2,128.1,127.9,126.9,125.9,123.1,118.9,117.4,63.9,27.05,24.13.HRMS Calcd for C 20 H 17 BrClN2O3[M+H] + :m / z 447.0106,Found:447.0107.

[0161] Example 24

[0162] Synthesis of (2-(4-acetamido)phenyl)-7-bromoquinolin-4-yl)methyl-2-bromoacetate

[0163]

[0164] Prepared according to the method of Example 1. Yield 54%; white solid, mp 223-224°C; 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),8.28(d,J=2.0Hz,1H),8.24(d,J=8.8Hz,2H),8.18 (s,1H),8.04(d,J=8.9Hz,1H),7.79-7.74(m,3H),5.75(s,2H),4.34(s,2H),2.10(s,3H). 13 CNMR(100MHz,DMSO-d6)δ168.6,167.1,156.6,148.5,142.1,141.3,132.2,13 1.3,129.5,127.9,126.0,123.3,123.2,118.9,117.5,63.8,27.1,24.1.HRMS Calcd for C 20 H 17 Br2N2O3[M+H] + :m / z 490.9600,Found:490.9590.

[0165] Example 25

[0166] Synthesis of (2-(4-acetamido)phenyl)-8-bromoquinolin-4-yl)methyl-2-bromoacetate

[0167]

[0168] Compound 25

[0169] Prepared according to the method of Example 1. Yield 40%; white solid, mp 209-210℃; 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.34(d,J=8.8Hz,2H),8.24(s,1H),8.18(d,J=7.6Hz,1H),8.1 0(d,J=8.4Hz,1H),7.80(d,J=8.4Hz,2H),7.54-7.50(m,1H),5.78(s,2H),4.36(s,2H),2.10(s,3H). 13C NMR(150MHz,DMSO-d6)δ172.5,168.7,155.9,144.3,143.2,141.4,133.5,132.2 ,128.0,127.2,125.9,124.9,123.8,119.0,117.6,62.3,59.7,24.2.HRMSCalcd for C 20 H 17 Br2N2O3[M+H] + :m / z 490.9600,Found:490.9590.

[0170] Example 26

[0171] Synthesis of (7-bromo-2-(4-propionamidophenyl)quinolin-4-yl)methyl-2-bromoacetate

[0172]

[0173] Prepared according to the method of Example 1. Yield 45%; white solid, mp 187-188°C; 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.29(d,J=2.0Hz,1H),8.25(d,J=8.8Hz,2H),8.18(s,1H),8.04(d,J=8.8Hz,1H),7 .80(d,J=8.8Hz,2H),7.76(dd,J=8.8,2.0Hz,1H),5.75(s,2H),4.34(s,2H),2.38(q,J=7.6Hz,2H),1.11(t,J=7.6Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ172.3,167.1,156.6,148.5,142.1,141.3,132.1,131. 3,129.5,127.9,126.0,123.3,123.2,119.0,117.5,63.9,29.6,27.1,9.6.HRMS Calcd for C 21 H 19 Br2N2O3[M+H] + :m / z504.9757,Found:504.9750.

[0174] Example 27

[0175] Synthesis of (2-(4-acetamidophenyl)-6-methylquinolin-4-yl) methacrylate

[0176]

[0177] Prepared according to the method of Example 1. Yield 48%; white solid, mp 186-187°C; 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.20(d,J=8.8Hz,2H),8.06(s,1H),7.99(d,J=8.4Hz,1H),7.84(s,1H),7.76(d,J=8.8Hz,2H),7.63(dd,J=8 .4,1.6Hz,1H),6.45(dd,J=17.2,1.6Hz,1H),6.34(dd,J=17.2,10.0Hz,1H),6.03(dd,J=10.0,1.6Hz,1H),5.72(s,2H),2.53(s,3H),2.09(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.6,165.3,154.5,146.3,141.2,140.7,136.2,132.9,13 2.4,132.0,129.4,128.0,127.5,124.5,122.4,119.0,117.2,62.8,24.1,21.4.HRMS Calcd for C 22 H 21 N2O3[M+H] + :m / z 361.1547,Found:361.1547.

[0178] Example 28

[0179] Synthesis of (2-(4-acetamidophenyl)-6-methoxyquinolin-4-yl) methacrylate

[0180]

[0181] Prepared according to the method of Example 1. Yield 43%; white solid, mp 194-195°C; 1H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.17(d,J=8.8Hz,2H),8.07(s,1H),8.01(d,J=9.2Hz,1H),7.75(d,J=8.8Hz,2H),7.45(dd,J=9.2,2.4Hz,1H),7. 35(d,J=2.8Hz,1H),6.45(dd,J=17.2,1.6Hz,1H),6.35(dd,J=17.2,10.0Hz ,1H),6.03(dd,J=10.0,1.6Hz,1H),5.74(s,2H),3.92(s,3H),2.09(s,3H). 13 C NMR(150MHz,DMSO-d6)δ168.5,165.3,157.3,153.0,143.7,140.7,140.5,133.0,13 2.4,131.2,128.0,127.3,125.6,122.0,119.0,117.5,102.1,63.1,55.6,24.1.HRMS Calcd for C 22 H 21 N2O4[M+H] + :m / z 377.1496,Found:377.1499.

[0182] Example 29

[0183] Synthesis of (2-(4-acetamidophenyl)-7-methoxyquinolin-4-yl) methacrylate

[0184]

[0185] Prepared according to the method of Example 1. Yield 49%; white solid, mp 177-178°C; 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.21(d,J=8.4Hz,2H),7.99-7.96(m,2H),7.77(d,J=8.8Hz,2H),7.47(d,J=2.8Hz,1H),7.27(dd,J=9.2, 2.4Hz,1H),6.43(dd,J=17.2,1.6Hz,1H),6.32(dd,J=17.2,10.0Hz,1H),6.02(dd,J=10.0,1.6Hz,1H),5.71(s,2H),3.95(s,3H),2.09(s,3H). 13C NMR(150MHz,DMSO-d6)δ168.6,165.2,160.4,155.7,149.7,141.8,140.8,132.9,13 2.4,127.9,127.6,124.9,119.6,119.0,118.9,115.3,108.1,62.9,55.5,24.1.HRMS Calcd for C 22 H 21 N2O4[M+H] + :m / z 377.1496,Found:377.1491.

[0186] Example 30

[0187] Synthesis of (2-(4-acetamidophenyl)-6-fluoroquinolin-4-yl) methacrylate

[0188]

[0189] Prepared according to the method of Example 1. Yield 44%; white solid, mp 177-178°C; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.21(d,J=8.8Hz,2H),8.17-8.13(m,2H),7.86(dd,J=10.0,2.8Hz,1H),7.77(d,J=8.8Hz,2H),7 .74-7.69(m,1H),6.44(dd,J=17.2,1.6Hz,1H),6.33(dd,J=17.2,10.0Hz,1H),6.03(dd,J=10.0,1.6Hz,1H),5.71(s,2H),2.09(s,3H). 13 CNMR(150MHz,DMSO-d6)δ168.6,165.2,160.6,158.9,155.0,145.0,141.9,140.9,132.5(d,J=9.0Hz),132.4(d,J=9 .0Hz),127.92,127.65,125.4(d,J=9.0Hz),119.9(d,J=25.5Hz),118.98,118.22,107.7(d,J=22.5Hz),62.9,24.1. 19 F NMR(376MHz,DMSO-d6)δ-112.5.HRMS Calcd for C 21 H 18 FN2O3[M+H] +:m / z 365.1296,Found:365.1300.

[0190] Example 31

[0191] Synthesis of (2-(4-acetamidophenyl)-6-chloroquinolin-4-yl) methacrylate

[0192]

[0193] Prepared according to the method of Example 1. Yield 47%; white solid, mp 183-184°C; 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.22(d,J=8.4Hz,2H),8.18(s,1H),8.15(d,J=2.0Hz,1H),8.10(d,J=8.8Hz,1H),7.81(dd,J=9.2,2.4Hz, 1H),7.77(d,J=8.8Hz,2H),6.44(dd,J=17.2,1.6Hz,1H),6.34(dd,J=17.2,10.0Hz,1H),6.03(dd,J=10.0,1.6Hz,1H),5.74(s,2H),2.09(s,3H). 13 C NMR(150MHz,DMSO-d6)δ168.6,165.2,155.9,146.2,141.7,141.1,132.5,132.4, 131.7,131.0,130.5,127.9,127.8,125.4,122.9,119.0,118.4,62.7,24.1.HRMS Calcd for C 21 H 18 ClN2O3[M+H] + :m / z 381.1000,Found:381.1004.

[0194] Example 32

[0195] Synthesis of (2-(4-acetamidophenyl)-7-bromoquinolin-4-yl) methacrylate

[0196]

[0197] Prepared according to the method of Example 1. Yield 55%; white solid, mp 180-181°C; 1H NMR (400MHz, DMSO-d6) δ10.19(s,1H),8.28(d,J=2.0Hz,1H),8.23(d,J=8.4Hz,2H),8.18(s,1H),8.04(d,J=8.8Hz,1H),7.79-7. 75(m,3H),6.43(dd,J=17.2,1.6Hz,1H),6.32(dd,J=17.2,10.0Hz,1H),6.03(dd,J=10.0,1.6Hz,1H),5.73(s,2H),2.09(s,3H). 13 C NMR(150MHz,DMSO-d6)δ168.6,165.2,156.6,148.5,142.5,141.2,132.5,132.3, 131.4,129.5,127.9,127.9,125.9,123.5,123.2,119.0,118.0,62.8,24.1.HRMS Calcd for C 21 H 18 BrN2O3[M+H] + :m / z 425.0495,Found:425.0489.

[0198] Example 33

[0199] Synthesis of N-(4-(4-formyl-6-methylquinolin-2-yl)phenyl)acetamide

[0200]

[0201] Prepared according to the method of Example 9. Yield 46%; yellow solid mp 251-252°C; 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),10.19(s,1H),8.75(s,1H),8.65(s,1H),8.29(d,J=8.8Hz,2H) ,8.07(d,J=8.4Hz,1H),7.80(d,J=8.8Hz,2H),7.72(dd,J=8.4,1.6Hz,1H),2.56(s,3H),2.10(s,3H). 13 C NMR(100MHz,DMSO-d6)δ195.0,168.6,155.2,147.2,141.1,138.5,137.1,13 2.4,132.2,129.3,127.6,124.2,123.0,122.1,119.0,24.1,21.7.HRMSCalcd for C 19 H17 N2O2[M+H] + :m / z 305.1285,Found:305.1281.

[0202] Example 34

[0203] Synthesis of N-(4-(4-formyl-6-methoxyquinolin-2-yl)phenyl)acetamide

[0204]

[0205] Prepared according to the method of Example 9. Yield 52%; yellow solid, mp 200-201°C; 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),10.18(s,1H),8.64(s,1H),8.38(d,J=2.8Hz,1H),8.26(d,J=8.4Hz ,2H),8.08(d,J=9.2Hz,1H),7.79(d,J=8.8Hz,2H),7.52(dd,J=9.2,2.8Hz,1H),3.94(s,3H),2.10(s,3H). 13 C NMR (151MHz, DMSO-d6) δ195.2,168.6,159.3,153.5,144.8,140.9,136.3,132.3,131.1,127.4,124.8,123.4,122.5,119.1,102.6,55.6,24.HRMS Calcd for C 19 H 17 N2O3[M+H] + :m / z 321.1234,Found:321.1233.

[0206] Example 35

[0207] Synthesis of N-(4-(4-formyl-7-methoxyquinolin-2-yl)phenyl)acetamide

[0208]

[0209] Prepared according to the method of Example 9. Yield 40%; yellow solid, mp 200-201°C; 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.20(s,1H),8.83(d,J=9.2Hz,1H),8.50(s,1H),8.30(d,J=8.8Hz ,2H),7.80(d,J=8.8Hz,2H),7.54(d,J=2.8Hz,1H),7.38(dd,J=9.2,2.8Hz,1H),3.97(s,3H),2.10(s,3H). 13 C NMR(150MHz,DMSO-d6)δ195.0,168.6,160.6,156.4,150.6,141.2,137.6,132.2,127.7,125.3,121.6,121.0,119.0,117.1,108.0,55.5,24.1.HRMS Calcd for C 19 H 17 N2O3[M+H] + :m / z 321.1234,Found:321.1235.

[0210] Example 36

[0211] Synthesis of N-(4-(6-fluoro-4-formylquinolin-2-yl)phenyl)acetamide

[0212]

[0213] Prepared according to the method of Example 9. Yield 48%; yellow solid, mp 192-193°C; 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.21(s,1H),8.74(s,1H),8.64(dd,J=10.8,2.8Hz, 1H), 8.29 (d, J=8.8Hz, 2H), 8.23 ​​(dd, J=9.6, 6.0Hz, 1H), 7.81 (d, J=8.8Hz, 3H), 2.10 (s, 3H). 13 C NMR (150MHz, DMSO-d6) δ194.7,168.7,161.3(d,J=247.5Hz),155.7,145.8,141.4,137.3(d,J=6.0Hz),132.4(d ,J=9.0Hz),131.8,127.7,125.2,122.7(d,J=10.5Hz),120.4(d,J=25.5Hz),119.0,108.2(d,J=24.0Hz),24.2. 19F NMR(376MHz,DMSO-d6)δ-110.34.HRMS Calcd for C 18 H 14 FN2O2[M+H] + :m / z 309.1034,Found:309.1027.

[0214] Example 37

[0215] Synthesis of N-(4-(6-chloro-4-formylquinolin-2-yl)phenyl)acetamide

[0216]

[0217] Prepared according to the method of Example 9. Yield 52%; yellow solid, mp 155-156°C; 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),10.23(s,1H),8.96(d,J=2.4Hz,1H),8.74(s,1H),8.31(d,J= 8.8Hz,2H),8.16(d,J=8.8Hz,1H),7.88(dd,J=9.2,2.4Hz,1H),7.81(d,J=8.8Hz,2H),2.11(s,3H). 13 C NMR (100MHz, DMSO-d6) δ194.6,168.7,156.6,146.9,141.5,136.9,133.2,131.7,131.5,130.9,127.9,125.3,123.3,122.6,119.0,24.2.HRMS Calcd forC 18 H 14 ClN2O2[M+H] + :m / z 325.0738,Found:325.0728.

[0218] Example 38

[0219] Synthesis of N-(4-(7-bromo-4-formylquinolin-2-yl)phenyl)acetamide

[0220]

[0221] Prepared according to the method of Example 9. Yield 38%; yellow solid, mp 192-193°C; 1H NMR (400MHz, DMSO-d6) δ10.50(s,1H),10.23(s,1H),8.85(d,J=8.8Hz,1H),8.73(s,1H),8.35(d,J= 2.0Hz, 1H), 8.30 (d, J=8.4Hz, 2H), 7.87 (dd, J=9.2, 2.0Hz, 1H), 7.81 (d, J=8.8Hz, 2H), 2.10 (s, 3H). 13 C NMR (150MHz, DMSO-d6) δ194.6,168.7,157.3,149.2,141.7,137.9,131.6,131.4,131.3,128.0,126.3,124.8,123.8,120.9,119.0,24.2.HRMS Calcd forC 18 H 14 BrN2O2[M+H] + :m / z 369.0233,Found:369.0223.

[0222] SARS CoV-2 main protease inhibitory activity test:

[0223] The purpose of this test is to detect the target compound's effect on SARS CoV-2M pro inhibitory activity.

[0224] The inhibitory activity of the target compound on the SARS CoV-2 main protease was determined using the FRET method. pro The inhibitory activity was evaluated by the ability to cleave the fluorescent substrate peptide. The fluorescent peptide sequence Dabcyl-KNSTLQSGLRKE-Edans was obtained from GLBiochem. pro The drug at different concentrations was added to a 96-well black plate in sequence, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 30 minutes. The reaction was then initiated by adding a substrate peptide at a final concentration of 20 μM to each well. The reaction was incubated at room temperature for 10 minutes, and the fluorescence signal was measured using a SpectraMax iD5 multi-function microplate reader at an excitation wavelength of 340 nm and an emission wavelength of 460 nm. The log value of the compound concentration was used as the horizontal axis, and the corresponding percentage inhibition rate was used as the vertical axis. The log (inhibitor) vs. response-variable slope of GraphPad Prism 9 was used to fit the dose-effect curve to obtain the IC value of each compound for enzyme inhibition. 50 value.

[0225] Table 1 SARS CoV-2 main protease inhibitory activity of some target compounds

[0226]

[0227] Anti-new coronavirus activity test:

[0228] The anti-SARS-CoV-2 activity of the target compounds was evaluated using a cytopathic effect (CPE) inhibition assay. Vero E6 cells were added to a 96-well plate and inoculated with 100 TCID50 of the novel coronavirus at 37°C for 2 hours. After removing the inoculum, different concentrations of the test compounds were added and incubated for 72 hours. The CPE effect was observed under a microscope, and the 50% effective concentration (EC 50 ).

[0229] Table 2 Anti-COVID-19 activity of representative compounds

[0230]

[0231] The basic principles, main features and advantages of the present invention are shown and described above. Without departing from the spirit and scope of the present invention, the present invention may also be subject to various changes and improvements, which fall within the scope of the present invention to be protected.

Claims

1. A 4-quinoline aniline main protease inhibitor, characterized in that The 4-quinoline aniline main protease inhibitor is selected from the following compounds or pharmaceutically acceptable salts thereof:

2. A method for preparing the 4-quinoline aniline main protease inhibitor according to claim 1, characterized in that The synthetic route is: Reagents and conditions: (i) KOH, EtOH, 100°C; (ii) concentrated H2SO4, MeOH, 75°C; (iii) acylating agent, Et3N, DCM, rt; (iv) NaBH4, MeOH, 80°C; (v) acid chloride / anhydride, Et3N, DCM, rt or carboxylic acid, DCC, 4-DMAP, DCM, rt.

3. A pharmaceutical composition, characterized in that The invention comprises the 4-quinoline aniline main protease inhibitor according to claim 1 and a pharmaceutically acceptable carrier thereof.

4. Use of the 4-quinoline aniline main protease inhibitor according to claim 1 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for inhibiting Mpro activity.

5. Use of the 4-quinolineaniline main protease inhibitor according to claim 1 or the pharmaceutical composition according to claim 3 in the preparation of drugs for treating novel coronavirus infectious diseases.

6. Use of the 4-quinolinaniline main protease inhibitor according to claim 1 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for preventing or treating SARS-CoV-2, SARS-CoV or / and MERS-CoV viral infectious diseases.

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