Tertiary amide compounds and their medical uses

Abstract

The present application discloses an amide compound as shown in the following formula 1 and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates, as well as pharmaceutical compositions containing them, and their use as 3CL pro The invention relates to the use of the inhibitor and the method for using the same. The tertiary amide derivatives have good antiviral activity, especially anti-new coronavirus activity.

Description

Technical Field

[0001] The present invention belongs to the field of pharmacy, and in particular, relates to a class of tertiary amide derivatives and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof, as well as pharmaceutical compositions containing them, and their use as 3CL pro The invention relates to the use of the inhibitor and the method for using the same. The tertiary amide derivatives have good antiviral activity, especially anti-new coronavirus activity. Background Art

[0002] Novel coronavirus pneumonia is a highly contagious disease caused by SARS-CoV-2. There are two cysteine ​​proteases as potential antiviral therapeutic targets for SARS-CoV-2, the main protease (3CL pro or M pro ) and papain-like protease (PL pro )(J.Med.Chem.2022,65,2940-2955). 3CLpro (main protease) is a crucial protein in the replication and maturation of the new coronavirus, responsible for processing at 11 different cleavage sites of the coronavirus polyprotein, PL pro Responsible for cleavage at three other unique sites. Without these essential proteases, replication is impaired and the viral life cycle is shut down (J Biomol Struct Dyn 2021, 39, 7, 2607-2616). In the human novel coronavirus, 3CL pro The protease has the highest sequence homology, which exists between SARS-CoV-1 and SARS-CoV-2, with an overall sequence homology of 96% and an active site homology of 100%, resulting in similar substrate specificity, and the human body lacks a homologous protease (Nature, 26 (2022)). pro It has become one of the ideal targets for the development of new broad-spectrum anti-coronavirus drugs, thus providing a new target for SARS-CoV-2 3CL pro The development of inhibitors provides an advanced starting point.

[0003] In short, 3CL pro Targeted inhibitors play a crucial role in the replication and maturation of SARS-CoV-2, targeting 3CL pro The discovery of ligands will help to identify new treatments for diseases such as SARS-CoV-2 and possible future coronaviruses.

[0004] Artificially synthesized 3CL is disclosed in U.S. patent application WO 2022 / 226203 Al proTargeted inhibitor CCF0058981

[0005]

[0006] CCF0058981 is a 3CL-targeted pro ligand, with potential to fight the new coronavirus (J.Med.Chem.2022,65,2880-2904). CCF0058981 has low nanomolar biochemical inhibition, and its potency in cell models is comparable to that of the FDA-approved RNA polymerase inhibitor remdesivir. CCF0058981 still needs to be improved in drug metabolism and pharmacokinetics, and its activity against a wider spectrum of coronaviruses needs to be studied. Summary of the invention

[0007] After extensive and in-depth research, the inventors of the application designed and synthesized a series of small molecule compounds with novel structures, which are potent 3CL pro Inhibitor with good antiviral activity, especially anti-new coronavirus activity.

[0008] According to one aspect of the present invention, an object of the present invention is to provide an amide compound as shown in the following formula 1 and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates:

[0009]

[0010] Among them, R 1 Selected from substituted C 6-14 Aryl, substituted five to ten membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to the C 6-14 The aryl group, the five- to ten-membered heteroaromatic ring group, has a radical selected from H, halogen, hydroxyl, carbonyl, amino, cyano, -COORa, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 1 to 5 substituents of the cycloalkoxy group, wherein R a Select from H or C 1-6 alkyl;

[0011] L is the connecting key, C 1-3 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene;

[0012] R 2 and R 17 Each independently selected from H, C 1-10Alkoxy, -CONRbRc, a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein Rb and Rc are each independently selected from H or C 1-6 alkyl;

[0013] R 3 , R 4 , R 5 and R 6 Each is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 6-14 Aryl, -COORd, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein Rd is selected from H or C 1-6 alkyl.

[0014] Preferably, R 1 Selected from substituted C 6-10 Aryl, substituted five to ten membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N and O, wherein the "substituted" refers to the C 6-10 The aryl group, the five- to ten-membered heteroaromatic ring group, has a radical selected from H, halogen, hydroxyl, carbonyl, amino, cyano, -COORa, C 1-6 Alkyl, C 1-6 1 to 5 substituents of the alkoxy group, wherein R a Select from H or C 1-3 alkyl;

[0015] Preferably, L is a linker, methylene, ethylene, propylene, isopropylene, vinylene, propenylene, butenylene, ethynylene, propynylene, butynylene;

[0016] Preferably, R 2 and R 17 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, -CONR a R b , a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein R a and R b Each independently selected from H or C 1-3 alkyl;

[0017] More preferably, R 2 Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, imidazole, -CONR aR b , a five- to six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and O, wherein R a and R b Each independently selected from H or C 1-3 alkyl;

[0018] More preferably, R 2 and R 17 Each is independently selected from H, methoxy, ethoxy, -CONH methyl, -CONH ethyl, -CONH propyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, wherein R a and R b Each is independently selected from H, methyl, ethyl, propyl, isopropyl;

[0019] Preferably, R 3 , R 4 , R 5 and R 6 Each is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -COOR c , where R c Select from H or C 1-6 alkyl.

[0020] More preferably, R 3 , R 4 , R 5 and R 6 Each is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, -COOR c , where R c Select from H or C 1-3 alkyl.

[0021] More preferably, R 3 , R 4 , R 5 and R 6 are each independently selected from H, halogen, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -COOR c , where R c Selected from H, methyl, ethyl, propyl, isopropyl.

[0022] Preferably, the amide compounds and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof according to the present invention are represented by the following formulas 1-1, 1-2, 1-3 and 1-4:

[0023]

[0024] Wherein the definitions of R1 to R6 are the same as those in Formula 1;

[0025] Wherein, X1, X2, X3, X4 and X5 are each independently selected from C, O and N;

[0026] R7 and R8 are each independently selected from H, halogen, hydroxy, amino, cyano, C 1-10 Alkyl, C 1-10 Alkoxy;

[0027] R9 and R10 are each independently selected from H, halogen, hydroxy, carbonyl, amino, cyano, C 1-10 Alkyl, C 1-10 Alkoxy;

[0028] R11 and R12 are each independently selected from H, halogen, hydroxyl, amino, cyano, -COOC 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy;

[0029] R13 is selected from H, halogen, hydroxy, carbonyl, amino, cyano, C 1-10 Alkyl, C 1-10 Alkoxy;

[0030] R14, R15 and R16 are each independently selected from H, halogen, hydroxy, carbonyl, amino, cyano, C 1-10 Alkyl, C 1-10 Alkoxy;

[0031] When X1, X2, and X3 are all N and R2 is When R3, R4, R5 and R16 are not halogen atoms.

[0032] Preferably, in Formula 1-1, the structure Selected from The substituents R7 to R10 are the same as defined in Formula 1-1.

[0033] Preferably, R7 and R8 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy;

[0034] Preferably, R9 and R10 are each independently selected from H, carbonyl, C 1-6 alkyl;

[0035] More preferably, R7 and R8 are each independently selected from H, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;

[0036] More preferably, R9 and R10 are each independently selected from H, carbonyl, methyl, ethyl, propyl, isopropyl;

[0037] Preferably, R11 and R12 are each independently selected from H, halogen, hydroxyl, -COOC 1-3 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy;

[0038] More preferably, R11 and R12 are each independently selected from H, halogen, hydroxyl, -COOCH 3 ,-COOC 2 H 5 ,-COOC 3 H 7 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;

[0039] Preferably, R13 is selected from H, halogen, hydroxyl, carbonyl, C 1-4 Alkyl, C 1-4 Alkoxy;

[0040] More preferably, R13 is a carbonyl group;

[0041] Preferably, R14, R15 and R16 are each independently selected from H, halogen, hydroxyl, carbonyl, C 1-4 Alkyl, C 1-4 Alkoxy;

[0042] More preferably, R14, R15 and R16 are each independently selected from H or hydroxyl.

[0043] Preferably, the amide compound represented by the following formula 1 according to the present invention and its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, tautomer and solvate are selected from the following compounds:

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058] According to another aspect of the present invention, another object of the present invention is to provide a method for preparing an amide compound as shown in Formula 1 and a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, tautomer and solvate thereof, the method being carried out according to the following reaction formula:

[0059]

[0060] i) Benzaldehyde compound 2 With aniline compound 1 Compound 1a is produced by a nucleophilic addition reaction at room temperature in the presence of a catalyst and a reductive amination reaction at room temperature in the presence of a reducing agent;

[0061] ii) Compound 1a and aldehyde compound 3 The compound shown in formula 1 is produced by an acyl chloride method through an amide condensation reaction;

[0062] In the above reaction formula, the definitions of substituents R1 to R6 and L are the same as those in Formula 1.

[0063] Wherein, in step i), the catalyst is p-toluenesulfonic acid, and the reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0064] In step ii), the organic base is an acid-binding agent, and the amide condensation reaction is carried out at room temperature. The acid-binding agent is selected from triethylamine, N,N-diisopropylethylamine and pyridine.

[0065] According to another aspect of the present invention, another object of the present invention is to provide an amide compound as shown in Formula 1 and a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, tautomer and solvate thereof as 3CL pro Use of inhibitors of 3CL pro Inhibitors can be used for, but are not limited to, antiviral purposes.

[0066] Preferably, the virus is a coronavirus, including severe acute respiratory syndrome virus (SARS-COV), novel severe acute respiratory syndrome virus (SARS-COV-2), Middle East respiratory syndrome virus (MERS-CoV), etc.

[0067] More preferably, the virus subtype of the novel coronavirus (SARS-COV-2) is Omicron or Delta.

[0068] According to another aspect of the present invention, the present invention provides a pharmaceutical composition, comprising a therapeutically effective amount of an amide compound as shown in Formula 1 according to the present invention and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof as active ingredients, and pharmaceutically acceptable excipients.

[0069] According to another aspect of the present invention, another object of the present invention is to provide a 3CL pro A method for treating related diseases or conditions, the method comprising administering to a patient in need thereof a therapeutically effective amount of an amide compound represented by Formula 1 according to the present invention and a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, tautomer and solvate thereof, or the pharmaceutical composition according to the present invention.

[0070] Preferably, the 3CL pro The related diseases or conditions are viral infectious diseases or conditions, and the viruses are severe acute respiratory syndrome virus (SARS-COV), new severe acute respiratory syndrome virus (SARS-COV-2), Middle East respiratory syndrome virus (MERS-CoV), etc.

[0071] More preferably, the virus subtype of the novel coronavirus is Omicron or Delta.

[0072] Beneficial Effects

[0073] The present invention discloses a class of novel amide compounds. Pharmacological experiments have shown that the compounds of the present invention have very good 3CL pro It has good inhibitory activity and is effective in treating viral infections, especially novel coronavirus infections. Therefore, it can be widely used in combination with 3CL pro Treatment of related diseases. DETAILED DESCRIPTION

[0074] Hereinafter, the present invention will be described in detail. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that the inventor is allowed to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are only preferred examples for illustrative purposes and are not intended to limit the scope of the present invention, so that it should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0075] As used herein, the terms "include", "comprising", "having", "containing" or any other similar terms are open-ended transitional phrases, which are intended to cover non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or article. In addition, unless otherwise expressly stated, the term "or" refers to an inclusive "or" rather than an exclusive "or". For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "include", "comprising", "having", and "containing" should be interpreted as having been specifically disclosed and simultaneously covering closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of".

[0076] In this article, all features or conditions defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values ​​within the range, especially integer values. For example, the range description of "1 to 8" should be deemed to have specifically disclosed all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., especially secondary ranges defined by all integer values, and should be deemed to have specifically disclosed individual values ​​such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. Unless otherwise specified, the above interpretation method applies to all contents of the entire present invention, regardless of whether the range is broad or not.

[0077] If the quantity or other numerical value or parameter is expressed as a range, a preferred range or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and the lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, if a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0078] In this document, under the premise of achieving the purpose of the invention, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0079] In this article, for the use of Markush groups or optional terms to describe the features or examples of the present invention, those skilled in the art should understand that all subgroups of elements in the Markush group or option list or any individual element can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2 and X3", it also means that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, for the use of Markush groups or optional terms to describe the features or examples of the present invention, those skilled in the art should understand that any combination of all subgroups of elements in the Markush group or option list or individual elements can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2 and X3", and Y is described as "selected from the group consisting of Y1, Y2 and Y3", it means that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0080] definition

[0081] The expression "compound of the present invention" used herein refers to the amide compound represented by Formula 1 and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof.

[0082] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-05 In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 In some embodiments, an alkyl group has 1 carbon atom (“C 1 In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 C 1-6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g. n-propyl, isopropyl), butyl (C 4 ) (e.g. n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C 6 ) (e.g., n-hexyl). Other examples of alkyl groups include n-heptyl (C 7 )wait.

[0083] "Alkoxy" refers to a monovalent -O-alkyl group, wherein the alkyl portion has the specified number of carbon atoms. In the present disclosure, alkoxy groups generally contain 1 to 10 carbon atoms ("C 1-10 "alkoxy"), for example, includes methoxy, ethoxy, isopropoxy, tert-butyloxy and the like.

[0084] "Alkenylene" refers to a straight or branched chain alkylene radical having 2 to 4 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C 2-4 In some embodiments, an alkenylene group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenylene group has 2 carbon atoms (“C 2 The one or more carbon-carbon double bonds may be internal (such as in 2-butenylene) or terminal (such as in 1-butenylene). 2-4 Examples of alkenylene groups include vinylene (C 2 ), 1-propylene (C 3 ), 2-propylene (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadiene (C 4 ) etc. In certain embodiments, in alkenyl groups, a C=C double bond of unspecified stereochemistry may be an (E)- or (Z)-double bond.

[0085] "Alkyne" refers to a straight or branched chain hydrocarbon radical having 2 to 4 carbon atoms, one or more carbon-carbon triple bonds and optionally one or more double bonds ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 In some embodiments, an alkynylene group has 2 carbon atoms (“C 2 The one or more carbon-carbon triple bonds may be internal (such as in 2-butynylene) or terminal (such as in 1-butynylene). 2-4 Examples of alkynylene groups include, but are not limited to, ethynylene (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 )wait.

[0086] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 cycloalkyl”) and zero heteroatom non-aromatic cycloalkyl groups. Exemplary C 3-6 Cycloalkyl includes, but is not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like. As shown in the foregoing examples, in certain embodiments, the cycloalkyl is a monocyclic ring ("monocyclic cycloalkyl") or contains a fused ring, a bridged ring or a spirocyclic ring system, such as a bicyclic ring system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes a ring system in which the point of attachment of the cycloalkyl as defined above to one or more aryl or heteroaryl groups is fused to a carbocyclic ring, and in this case, the carbon number continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise indicated, each instance of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted or substituted with one or more substituents.

[0087] "Heterocycloalkyl" refers to a group of a four to eight-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("four to eight-membered heterocyclyl"). In a heterocyclyl containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as the valence permits. Heterocycloalkyl may be a monocyclic ("monocyclic heterocycloalkyl") or a condensed ring, a bridged ring or a spirocyclic system, such as a bicyclic system ("bicyclic heterocycloalkyl"), and may be saturated or may be partially unsaturated. The heterocycloalkyl bicyclic system may contain one or more heteroatoms in one or both rings. "Heterocycloalkyl" also includes a ring system in which the heterocycle as defined above is fused to one or more carbocyclyl groups at a point of attachment on a carbocyclyl or heterocycle, or a ring system in which the heterocycle as defined above is fused to one or more aryl or heteroaryl groups at a point of attachment on a heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocycle system.

[0088] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in the cyclic array) ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms (“C 6 In some embodiments, an aryl group has 10 ring carbon atoms (“C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system.

[0089] "Heteroaryl" refers to a group of a five to eight-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("five to eight-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups wherein the point of attachment is on the aryl or heteroaryl ring, and in this case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0090] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0091] The invention includes all possible geometric isomers of the compounds within its scope, such as Z and E isomers (cis and trans isomers), and all possible optical isomers of the compounds of the invention, such as diastereomers and enantiomers. In addition, the invention includes individual isomers within its scope and any mixtures thereof, such as racemic mixtures. Individual isomers can be obtained using the corresponding isomeric form of the starting material, or they can be separated after the final compound preparation according to conventional separation methods. For separating optical isomers, such as enantiomers, from their mixtures, conventional resolution methods can be applied, such as fractional crystallization or preparative chiral chromatography.

[0092] The invention includes all possible solvates of the compounds within its scope. The solvents in the "solvates" herein include the third class solvents specified in the pharmacopoeia and mixed solvents of the third class solvents and water: pentane, formic acid, acetic acid, ether, acetone, anisole, 1-propanol, 2-propanol, 1-butanol, 2-butanol, amyl alcohol, butyl acetate, tributyl methyl ether, isopropyl acetate, methyl ethyl ketone, dimethyl sulfoxide, isopropyl benzene, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, propyl acetate. The compounds of the present invention or their pharmaceutically acceptable salts may exist in the form of their hydrates, solvates or prodrugs. Therefore, hydrates, solvates or prodrugs of the compounds of the present invention or their pharmaceutically acceptable salts are also included in the scope of the present invention.

[0093] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0094] The term "pharmaceutically acceptable excipient" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For other information about the carrier, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0095] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared by a compound with a specific substituent discovered by the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt (i.e., a pharmaceutically acceptable salt) can be obtained by contacting the neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; the organic acid includes, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid , propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, fumaric acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptose, gluconic acid, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, phosphorous acid, etc.; acetic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0096] A typical formulation is prepared by mixing the compound represented by formula (I) of the present invention and auxiliary materials, diluents or excipients. Suitable carriers, diluents or excipients are well known to those skilled in the art, and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc.

[0097] The specific adjuvant, diluent or excipient used will be determined according to the mode and purpose of use of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives to make the drug in an acceptable form for manufacture or use.

[0098] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0099] The term "treatment" refers to reversing, alleviating, delaying the onset of a disease described herein, or inhibiting the development of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to pathogens) to delay or prevent the onset of the disease. Treatment may also be continued after symptoms subside, for example, to delay or prevent recurrence.

[0100] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0101] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0102] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0103] The following examples are only listed as examples of embodiments of the present invention, and do not constitute any limitation to the present invention. It will be appreciated by those skilled in the art that modifications within the scope of the spirit and concept of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products. Suitable starting materials can be used by a variety of synthetic routes similar to or according to known methods in the literature.

[0104] Example

[0105] Example 1: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(2,3-dioxoindolin-1-yl)acetamide hydrochloride

[0106]

[0107] (Z)-N-(4-(1H-imidazol-4-yl)phenyl)-1-(3-chlorophenyl)methanimine

[0108]

[0109] Slowly add 3-chlorobenzaldehyde (562.28 mg, 4 mmol) to a solution of 4-(1H-imidazol-4-yl)aniline (636.76 mg, 4 mmol) in anhydrous ethanol and stir for 3 h. Protect with nitrogen to precipitate an off-white solid, which is filtered and dried to obtain a yellow solid.

[0110] (Z)-tert-Butyl 4-(4-((3-chlorobenzylidene)amino)phenyl)-1H-imidazole-1-carboxylate

[0111]

[0112] Slowly add di-tert-butyl dicarbonate (750 mg, 3.44 mmol) into anhydrous ethanol solution of compound (Z)-N-(4-(1H-imidazol-4-yl)phenyl)-1-(3-chlorophenyl)methanimine (1056 mg, 3.44 mmol) and stir for 3 h. Protect with nitrogen to precipitate an off-white solid. Filter and dry to obtain a yellow solid.

[0113] tert-Butyl 4-(4-((3-chlorobenzyl)amino)phenyl)-1H-imidazole-1-carboxylate

[0114]

[0115] (Z)-4-(4-((3-chlorobenzylidene)amino)phenyl)-1H-imidazole-1-carboxylic acid tert-butyl ester was added to a 1,2-dichloroethane solution, and under nitrogen protection, sodium triacetoxyborohydride was added to the reaction system in four batches. After stirring at room temperature for 24 hours, the reaction was quenched with a saturated sodium bicarbonate solution (10 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (15 ml*3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography with a mobile phase of petroleum ether / ethyl acetate (1:3). After elution, 2a was obtained by spin drying. The compound was an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.16(d,J=1.3Hz,1H),7.70(d,J=1.3Hz,1H),7.59–7.51(m,2H),7.41(t,J=1.8Hz,1H),7.37–7.31(m,2H) ,7.28(dt,J=7.2,2.1Hz,1H),6.65–6.52(m,2H),6.48(t,J=6.2Hz,1H),4.31(d,J=6.1Hz,2H),1.58(s,9H).

[0116] tert-Butyl 4-(4-(N-(3-chlorobenzyl)-2-(2,3-dioxoindole-1-yl)acetylamino)phenyl)-1H-imidazole-1-carboxylate

[0117]

[0118] Add isotonic acid (102.59, 0.5mmol) to DCM under ice bath, add one drop of N,N-dimethylformamide, add oxalyl chloride (126.93, 1mmol), stir in ice bath for 1h, stir at room temperature for 2h, remove dichloromethane to obtain 2-(1-benzotriazole)acetyl chloride. Add compound 2a (102.5mg, 0.25mmol) to dichloromethane with ice bath to 0°C, add the above-mentioned dichloromethane solvent of 2-(1-benzotriazole)acetyl chloride, stir in ice bath for 1h, stir at 25 degrees for 24h. The crude compound is purified by silica gel column chromatography, using petroleum ether / ethyl acetate (1:2) as the mobile phase, and eluted and spin-dried to obtain 2b as a yellow solid product.

[0119] N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(2,3-dioxoindolin-1-yl)acetamide hydrochloride

[0120]

[0121] A solution of hydrochloric acid in ethyl acetate (4 M) was added to the solution of compound 2b in ethyl acetate, and the mixture was stirred overnight at 15° C. Filtration was performed to obtain a yellow powder, 113 mg, and a yield of 96.35%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.24(s,1H),8.24(s,1H),8.02(d,J=8.0Hz,2H),7.79–7.67(m,1H),7.60(dd,J=12. 2,7.7Hz,3H),7.48–7.25(m,4H),7.25–7.05(m,3H),4.96(s,2H),4.40(s,2H).ESI-MS m / z:[M+H] + :470.11.

[0122] Example 2: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3,5-dimethoxybenzyl)-2-(2,3-dioxoindolin-1-yl)acetamide hydrochloride

[0123]

[0124] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was a yellow powder, 102 mg, with a yield of 87.94%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.24(s,1H),8.23(s,1H),8.01(d,J=8.1Hz,2H),7.70(td,J=7.8,1.3Hz,1H),7.66–7.52(m ,3H),7.17(q,J=8.1,7.5Hz,2H),6.38(s,3H),4.87(s,2H),4.40(s,2H),3.70(s,6H).ESI-MS m / z:[M+H] + :497.17.

[0125] Example 3: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(5-methyl-2,3-dioxoindol-1-yl)acetamide hydrochloride

[0126]

[0127] Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1, orange powder, 112 mg, yield 76.83%. 1H NMR (400 MHz, DMSO-d 6 )δ9.23(d,J=1.3Hz,1H),8.22(s,1H),8.02(d,J=8.1Hz,2H),7.59(d,J=8.1Hz,2H),7.52(dd,J=8.3,1.8Hz,1H),7.40(d,J= 1.7Hz,1H),7.36–7.28(m,3H),7.20(d,J=6.7Hz,1H),7.09(d,J=8.1Hz,1H),4.95(s,2H),4.37(s,2H),2.29(s,3H).ESI-MS m / z:[M+H] + :485.1374.

[0128] Example 4: N-(4-(1H-imidazol-4-yl)phenyl)-2-(7-bromo-2,3-dioxoindolyl-1-yl)-N-(3-chlorobenzyl)acetamide hydrochloride

[0129]

[0130] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 103 mg, yield 75.38%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.26(s,1H),8.25(s,1H),8.02(d,J=8.1Hz,2H),7.86(d,J=8.1Hz,1H),7.63(dd,J=13. 3,7.7Hz,3H),7.33(d,J=7.4Hz,3H),7.25–7.02(m,2H),4.95(s,2H),4.61(s,2H).ESI-MS m / z:[M+H] + :551.0304.

[0131] Example 5: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(6-fluoro-2,3-dioxoindol-1-yl)acetamide hydrochloride

[0132]

[0133] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was a light yellow powder (132 mg), with a yield of 93.45%. 1 H NMR (400 MHz, DMSO-d 6)δ9.19(s,1H),8.17(s,1H),7.96(d,J=8.1Hz,2H),7.63(dd,J=8.3,5.7Hz,1H),7.55(d,J=8.1Hz,2H),7. 31–7.18(m,4H),7.14(d,J=6.9Hz,1H),6.90(td,J=9.0,8.5,2.1Hz,1H),4.89(s,2H),4.32(s,2H).ESI-MS m / z:[M+H] + :489.1124.

[0134] Example 6: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(5-fluoro-2,3-dioxoindolin-1-yl)acetamide hydrochloride

[0135]

[0136] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, light orange powder, 78 mg, yield 95.64%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.23(s,1H),8.23(s,1H),8.01(d,J=8.0Hz,2H),7.61(ddt,J=9.0,5.8,2.9Hz,3H),7.50(dd,J=7.0,2.8Hz,1H), 7.36–7.29(m,3H),7.26(dd,J=8.7,3.7Hz,1H),7.20(d,J=7.0Hz,1H),4.96(s,2H),4.41(s,2H).ESI-MSm / z:[M+H] + :489.1124.

[0137] Example 7: N-(4-(1H-imidazol-4-yl)phenyl)-2-(7-chloro-2,3-dioxoindolin-1-yl)-N-(3-chlorobenzyl)acetamide hydrochloride

[0138]

[0139] Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1 as a yellow powder with a yield of 83.16%. 1 H NMR (400 MHz, DMSO-d 6)δ9.19(s,1H),8.17(s,1H),7.97(d,J=8.1Hz,2H),7.65(d,J=8.1Hz,1H),7.52(dd,J=25.1,7.6 Hz,3H),7.25(d,J=6.4Hz,3H),7.12(t,J=7.7Hz,2H),4.89(s,2H),4.51(d,J=8.5Hz,2H).ESI-MS m / z:[M+H] + :505.0827.

[0140] Example 8: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(7-fluoro-2,3-dioxoindolin-1-yl)acetamide hydrochloride

[0141]

[0142] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was yellow powder, 56 mg, and the yield was 98.73%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.24(s,1H),8.23(s,1H),8.05(d,J=8.1Hz,2H),7.63(dd,J=11.8,8.3Hz,1H),7.55–7.45(m,3H ),7.33(dq,J=9.8,7.4,6.8Hz,4H),7.19(dq,J=7.8,4.1Hz,2H),4.96(s,2H),4.44(s,2H).ESI-MS m / z:[M+H] + :489.1123.

[0143] Example 9: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(5,6-difluoro-2,3-dioxoindol-1-yl)acetamide hydrochloride

[0144]

[0145] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, light yellow powder, 104 mg, yield 92.36%. 1 H NMR (400 MHz, DMSO-d 6)δ9.35–9.08(m,1H),8.24(s,1H),8.02(d,J=8.0Hz,2H),7.84(t,J=8.3Hz,1H),7. 69–7.52(m,3H),7.42–7.28(m,3H),7.22(s,1H),4.96(s,2H),4.38(s,2H).ESI-MS m / z:[M+H] + :507.1030.

[0146] Example 10: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(4,7-dimethyl-2,3-dioxoindol-1-yl)acetamide hydrochloride

[0147]

[0148] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 154 mg, yield 99.01%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.24(s,1H),8.25(s,1H),8.04(d,J=8.1Hz,2H),7.52(d,J=8.2Hz,2H),7.36–7.25(m,4H),7.2 2–7.14(m,1H),6.87(d,J=7.9Hz,1H),4.95(s,2H),4.52(s,2H),2.44(s,3H),2.29(s,3H).ESI-MS m / z:[M+H] + :499.1531.

[0149] Example 11: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(5,7-dimethyl-2,3-dioxoindole-1-yl)acetamide hydrochloride

[0150]

[0151] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 78 mg, yield 96.81%. 1 H NMR (400 MHz, DMSO-d 6)δ9.30–9.03(m,1H),8.17(s,1H),7.97(d,J=8.1Hz,2H),7.45(d,J=8.1Hz,2H),7.35–7.15(m,5 H),7.11(d,J=6.5Hz,1H),4.88(s,2H),4.44(s,2H),2.23(s,3H),2.16(s,3H).ESI-MSm / z:[M+H] + :499.15.

[0152] Example 12: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(7-methyl-2,3-dioxoindole-1-yl)acetamide hydrochloride

[0153]

[0154] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 134 mg, yield 95.11%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.24(s,1H),8.25(s,1H),8.05(d,J=8.1Hz,2H),7.53(d,J=8.1Hz,2H),7.46(t,J=7.1Hz,2H),7.34(d,J=6.4Hz,2H ),7.28(s,1H),7.18(d,J=6.5Hz,1H),7.07(t,J=7.5Hz,1H),4.96(s,2H),4.54(s,2H),2.35(s,3H).ESI-MSm / z:[M+H] + :485.13.

[0155] Example 13: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(7-methoxy-2,3-dioxoindole-1-yl)acetamide hydrochloride

[0156]

[0157] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 86 mg, yield 98.68%. 1 H NMR (400 MHz, DMSO-d 6)δ9.20(d,J=1.3Hz,1H),8.21(s,1H),8.03(d,J=8.1Hz,2H),7.53(d,J=8.1Hz,2H),7.45(dd,J=8.4,1.1Hz,1H),7. 39–7.27(m,3H),7.25–7.17(m,2H),7.13(t,J=7.9Hz,1H),4.95(s,2H),4.46(s,2H),3.86(s,3H).ESI-MSm / z:[M+H] + :501.13.

[0158] Example 14: N-(4-(1H-imidazol-4-yl)phenyl)-2-(5-bromo-2,3-dioxoindole-1-yl)-N-(3-chlorobenzyl)acetamide hydrochloride

[0159]

[0160] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was yellow powder, 113 mg, and the yield was 96.35%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.25(d,J=1.3Hz,1H),8.23(s,1H),8.01(d,J=8.1Hz,2H),7.89(dd,J=8.4,2.1Hz,1H),7.75(d,J=2.1Hz,1H),7.60( d,J=8.1Hz,2H),7.33(tt,J=8.6,5.1Hz,3H),7.21(dd,J=10.4,7.2Hz,2H),4.95(s,2H),4.41(s,2H).ESI-MSm / z:[M+H] + :549.03.

[0161] Example 15: N-(4-(1H-imidazol-4-yl)phenyl)-2-(5-chloro-2,3-dioxoindole-1-yl)-N-(3-chlorobenzyl)acetamide hydrochloride

[0162]

[0163] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was a yellow powder, 108 mg, with a yield of 94.61%. 1 H NMR (400 MHz, DMSO-d 6)δ9.17(d,J=1.3Hz,1H),8.16(s,1H),7.93(d,J=8.1Hz,2H),7.70(dd,J=8.4,2.3Hz,1H),7.58(d,J=2.2Hz,1H),7.53(d, J=8.0Hz,2H),7.31–7.18(m,5H),7.13(d,J=6.9Hz,1H),4.87(d,J=14.5Hz,2H),4.33(d,J=8.1Hz,2H).ESI-MSm / z:[M+H] + :505.08.

[0164] Example 16: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(5,7-dibromo-2,3-dioxoindole-1-yl)acetamide hydrochloride

[0165]

[0166] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was a yellow powder, 108 mg, with a yield of 94.61%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.20(d,J=1.3Hz,1H),8.22(s,1H),8.14(t,J=2.8Hz,1H),7.98(dd,J=12.4,8.3Hz,2H),7.83(d,J=2.0Hz,1H),7. 62(d,J=8.1Hz,2H),7.33(t,J=6.1Hz,4H),7.24–7.15(m,1H),4.93(d,J=13.2Hz,2H),4.59(s,2H).ESI-MSm / z:[M+H] + :628.93.

[0167] Example 17: 4-(N-(3-chlorobenzyl)-2-(2,3-dioxoindolin-1-yl)acetylamino)-N-methylbenzamide

[0168]

[0169] (Z)-4-((3-Chlorobenzylidene)amino)-N-methylbenzamide

[0170]

[0171] 4-Amino-N-methylbenzamide (1500mg, 10mmol) was slowly added to a solution of (3-chlorophenyl)formaldehyde (1400mg, 10mmol) in 1,2-dichloroethane (25ml) with stirring at room temperature. Sodium triacetoxyborohydride (2968mg, 14mmol) was added to the reaction system in four batches. After stirring at room temperature for 24h, the reaction was quenched with a saturated sodium bicarbonate solution (10ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (15ml*3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (1:3) as the mobile phase, and compound 3a was obtained by spin drying after elution as a light yellow product solid (, 1639mg, 59.80%). 1 H NMR (400 MHz, DMSO-d 6 )δ8.00(q,J=4.5Hz,1H),7.58(d,J=8.5Hz,2H),7.47–7.18(m,4H),6.83(t,J =6.2Hz,1H),6.67–6.45(m,2H),4.34(d,J=6.2Hz,2H),2.72(d,J=4.5Hz,3H).

[0172] 4-(N-(3-chlorobenzyl)-2-(2,3-dioxoindolin-1-yl)acetylamino)-N-methylbenzamide

[0173]

[0174] 2-(1-benzotriazole)acetic acid (2mmol) was added to DCM under ice bath, and a drop of N,N-dimethylformamide was added, and oxalyl chloride (4mmol) was added, and stirred in ice bath for 1h, and stirred at room temperature for 2h, and dichloromethane was removed to obtain 2-(1-benzotriazole)acetyl chloride. Compound 3a (1mmol) was added to dichloromethane with ice bath to 0°C, and the above-mentioned dichloromethane solvent of 2-(1-benzotriazole)acetyl chloride was added dropwise, and stirred in ice bath for 1h, and stirred at 25°C for 24h. The crude compound was purified by silica gel column chromatography, and petroleum ether / ethyl acetate (1:2) was used as the mobile phase. After elution, the target compound 4-(N-(3-chlorobenzyl)-2-(2,3-dioxoindolin-1-yl)acetylamino)-N-methylbenzamide was obtained by spin drying as a white powder, 105mg, and a yield of 45.57%. 1 H NMR (400 MHz, DMSO-d 6)δ8.50(d,J=4.9Hz,1H),7.89(d,J=8.1Hz,2H),7.70(td,J=7.8,1.4Hz,1H),7.61–7.49(m,3H) ,7.41–7.26(m,3H),7.22–7.09(m,3H),4.94(s,2H),4.35(s,2H),2.78(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :462.1215.

[0175] Example 18: 4-(N-(3-chlorobenzyl)-2-(5-methoxy-2,3-dioxoindolin-1-yl)acetylamino)-N-methylbenzamide

[0176]

[0177] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 116.92 mg, yield 51.43%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.49(d,J=4.9Hz,1H),7.88(d,J=8.1Hz,2H),7.52(d,J=8.0Hz,2H),7.37–6. 78(m,7H),4.94(s,2H),4.33(s,2H),3.78(s,3H),2.78(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :492.1318.

[0178] Example 19: N-(4-carbamoylphenyl)-N-(3,5-dimethoxybenzyl)-2-oxo-2H-chromene-3-carboxamide

[0179]

[0180] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 120 mg, yield 26.2%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.36(s,1H),7.91(s,1H),7.78–7.56(m,4H),7.44–7.18(m,4H),6.63–6.44( m,3H),6.37(dt,J=9.0,2.3Hz,1H),5.06(s,2H),3.71(d,J=3.4Hz,6H).ESI-MS m / z:[M+H] +:459.15

[0181] Example 20: N-(3-chlorobenzyl)-N-(4-(methylcarbamoyl)phenyl)-2-oxo-2H-chromene-3-carboxamide

[0182]

[0183] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 110 mg, yield 69.51%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.39(d,J=9.6Hz,2H),7.67(td,J=22.8,19.7,7.9Hz,4H),7.50–7.06(m,8H),5.14(s,2H),2.25(s,3H).ESI-MS m / z:[M+H] + :447.11

[0184] Example 21: N-(3,5-dimethoxybenzyl)-N-(4-(methylcarbamoyl)phenyl)-2-oxo-2H-chromene-3-carboxamide

[0185]

[0186] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 107 mg, yield 66.52%.

[0187] 1 H NMR (400 MHz, DMSO-d 6 )δ8.37(d,J=6.5Hz,2H),7.81–7.49(m,4H),7.43–7.14(m,4H),6.53(s,2H),6 .39(s,1H),5.06(s,2H),3.72(s,6H),2.70(d,J=4.5Hz,3H).ESI-MSm / z:[M+H] + :473.17

[0188] Example 22: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3,5-dimethoxybenzyl)-3,4,5-trihydroxybenzamide hydrochloride

[0189]

[0190] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 35 mg, yield 56.8%. 1H NMR (500 MHz, DMSO-d 6 )δ10.75(s,2H),9.20(d,J=1.3Hz,1H),8.14(d,J=1.3Hz,1H),7.87–7.64(m,2H),7.18(d, J=8.3Hz,2H),6.54(s,2H),6.40(dd,J=20.4,2.3Hz,3H),5.04(s,2H),3.70(s,7H).ESI-MS m / z:[M+H] + :461.18.

[0191] Example 23: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-oxo-2H-chromene-3-carboxamide hydrochloride

[0192]

[0193] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, with 86 mg of white powder and a yield of 61.23%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.03(s,1H),8.43(s,1H),8.04(s,1H),7.83–7.70(m,3H),7.67–7.54(m,1H),7.51–7.25(m,8H),5.14(s,2H).ESI-MS m / z:[M+H] + :456.11.

[0194] Example 24: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3,5-dimethoxybenzyl)-2-oxo-2H-chromene-3-carboxamide hydrochloride

[0195]

[0196] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, with 180 mg of white powder and a yield of 80.88%. 1 H NMR (400 MHz, DMSO-d 6)δ8.91(s,1H),8.38(s,1H),7.99(s,1H),7.73(td,J=6.3,5.7,3.0Hz,3H),7.62(t,J=7.9Hz,1H), 7.35(dt,J=15.1,7.6Hz,4H),6.54(d,J=2.3Hz,2H),6.39(s,1H),5.05(s,2H),3.72(s,6H).ESI-MS m / z:[M+H] + :482.17.

[0197] Example 25: (E)-4-(N-(3,5-dimethoxybenzyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide)-N-methylbenzamide

[0198]

[0199] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 85 mg, yield 40.12%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.47(q,J=4.5Hz,1H),7.89–7.79(m,2H),7.55(d,J=15.4Hz,1H),7.36–7.28(m,2H),7.02(d,J=2.1Hz,1H),6.89(d,J=7. 7Hz,1H),6.74(d,J=8.2Hz,1H),6.36(q,J=2.1Hz,3H),5.00(s,2H),3.73(s,3H),3.68(s,6H),2.78(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :477.19.

[0200] Example 26: (E)-4-(N-(3-chlorobenzyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide)-N-methylbenzamide

[0201]

[0202] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 175 mg, yield 83.32%. 1 H NMR (400 MHz, DMSO-d 6)δ9.54(s,1H),8.50(q,J=4.4Hz,1H),7.96–7.79(m,2H),7.58(d,J=15.4Hz,1H),7.43–7.28(m,5H),7.21(dt,J=7.2,1.8Hz,1H),7.04(d,J=2 .0Hz,1H),6.91(dd,J=8.2,2.0Hz,1H),6.76(d,J=8.2Hz,1H),6.30(d,J=15.4Hz,1H),5.09(s,2H),3.75(s,3H),2.80(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :451.14.

[0203] Example 27: (E)-4-(N-(4-hydroxy-3-methoxybenzyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide)-N-methylbenzamide

[0204]

[0205] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 78 mg, yield 33.14%. 1 H NMR (500 MHz, DMSO-d 6 )δ9.47(s,1H),8.87(s,1H),8.46(t,J=4.5Hz,1H),7.83(d,J=8.2Hz,2H),7.54(d,J=15.4Hz,1H),7.27(d,J=8.2Hz,2H),7.00(s ,1H),6.86(d,J=8.2Hz,1H),6.77–6.48(m,4H),6.25(s,1H),4.95(s,2H),3.70(d,J=26.2Hz,6H),2.78(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :463.1864.

[0206] Example 28: (E)-4-(3-((4-acetoxy-3-methoxybenzyl)(4-(methylcarbamoyl)phenyl)amino)-3-oxoprop-1-en-1-yl)-2-methoxyphenyl acetate

[0207]

[0208] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials. The product was a yellow powder (409 mg). The yield was 74.89%. 1H NMR (500 MHz, DMSO-d 6 )δ8.47(d,J=5.2Hz,1H),7.89–7.79(m,2H),7.63(d,J=15.4Hz,1H),7.41–7.34(m,2H),7.25(s,1H),7.08–6.91(m,4H),6.80( dd,J=8.1,1.9Hz,1H),5.08(s,2H),3.85(d,J=6.1Hz,1H),3.78–3.68(m,6H),2.78(d,J=4.6Hz,3H),2.31–2.21(m,6H).ESI-MS m / z:[M+H] + :547.20.

[0209] Example 29: (E)-4-(3-(3,4-dihydroxyphenyl)-N-(3,5-dimethoxybenzyl)acrylamide)-N-methylbenzamide

[0210]

[0211] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials. The product was a yellow powder, 56 mg, with a yield of 56.02%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.49(q,J=4.5Hz,1H),7.96–7.76(m,2H),7.46(d,J=15.3Hz,1H),7.36–7.26(m,2H),6.81–6.61( m,3H),6.35(s,3H),6.15(d,J=15.1Hz,1H),4.98(s,2H),3.67(s,6H),2.79(d,J=4.3Hz,3H).ESI-MS m / z:[M+H] + :463.18.

[0212] Example 30: (E)-4-(N-(3-chlorobenzyl)-3-(3,4-dihydroxyphenyl)acrylamide)-N-methylbenzamide

[0213]

[0214] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 26 mg, yield 61.45%. 1 H NMR (400 MHz, DMSO-d 6)δ9.27(d,J=92.6Hz,2H),8.50(q,J=4.6Hz,1H),7.86(d,J=8.1Hz,2H),7.47(d,J=15.4Hz,1H),7.31(dt,J=13.6,4.9 Hz,5H),7.18(d,J=7.0Hz,1H),6.96–6.37(m,3H),6.12(d,J=15.4Hz,1H),5.05(s,2H),2.78(d,J=4.4Hz,3H).ESI-MS m / z:[M+H] + :437.12.

[0215] Example 31: (E)-N-(4-(1H-imidazol-4-yl)phenyl)-N-(3,5-dimethoxybenzyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide hydrochloride

[0216]

[0217] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was yellow powder, 35 mg, and the yield was 32.39%. 1 H NMR (500 MHz, DMSO-d 6 )δ9.55(s,1H),9.21(d,J=1.3Hz,1H),8.18(d,J=1.4Hz,1H),7.99–7.90(m,2H),7.56(d,J=15.4Hz,1H),7.43–7.30(m,2H),7.13–6. 98(m,1H),6.90(d,J=8.3Hz,1H),6.76(d,J=8.2Hz,1H),6.37(dd,J=11.9,2.3Hz,4H),5.02(s,2H),3.72(s,3H),3.68(s,6H).ESI-MS m / z:[M+H] + :486.20.

[0218] Example 32: (E)-N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-3-(3-hydroxy-4-methoxyphenyl)acrylamide hydrochloride

[0219]

[0220] Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1, off-white powder, 40 mg, yield 60.8%. 1 H NMR (500 MHz, DMSO-d 6)δ9.39–9.09(m,2H),8.20(d,J=1.3Hz,1H),8.06–7.83(m,2H),7.51(d,J=15.4Hz,1H),7.43–7.36(m,2H),7.35–7.27(m,3H ),7.21(dt,J=7.3,1.6Hz,1H),6.90(d,J=2.1Hz,2H),6.82(s,1H),6.23(d,J=15.4Hz,1H),5.07(s,2H),3.76(s,4H).ESI-MS m / z:[M+H] + :460.14.

[0221] Example 33: (E)-N-(4-(1H-imidazol-4-yl)phenyl)-N-(3,5-dimethoxybenzyl)-3-(3-hydroxy-4-methoxyphenyl)acrylamide hydrochloride

[0222]

[0223] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, white powder, 25 mg, yield 87.35%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.19(d,J=8.8Hz,2H),8.25–8.17(m,1H),7.95(d,J=8.2Hz,2H),7.50(d,J=15.4Hz,1H),7.39(d,J=8.5Hz,2H), 6.89(s,2H),6.82(s,1H),6.37(dd,J=7.4,2.2Hz,3H),6.27(s,1H),5.00(s,2H),3.75(s,3H),3.68(s,6H).ESI-MS m / z:[M+H] + :486.28.

[0224] Example 34: (E)-N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-3-(3,4-dihydroxyphenyl)acrylamide hydrochloride

[0225]

[0226] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was yellow powder, 78 mg, and the yield was 87.25%. 1 H NMR (400 MHz, DMSO-d 6)δ9.26(d,J=1.4Hz,1H),8.22(d,J=1.3Hz,1H),7.98(d,J=8.4Hz,2H),7.59– 7.14(m,7H),6.85–6.60(m,3H),6.18(d,J=15.4Hz,1H),5.07(s,2H).ESI-MS m / z:[M+H] + :446.13.

[0227] Example 35: (E)-N-(4-(1H-imidazol-4-yl)phenyl)-3-(3,4-dihydroxyphenyl)-N-(3,5-dimethoxybenzyl)acrylamide hydrochloride

[0228]

[0229] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, with a yellow powder of 60 mg and a yield of 95%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.51(s,1H),9.24(d,J=1.3Hz,1H),9.13(s,1H),8.21(d,J=1.4Hz,1H),7.96(d,J=8.4Hz,2H),7.47(d,J=15.3Hz,1H),7.3 9(d,J=8.5Hz,2H),6.87–6.67(m,3H),6.37(dd,J=7.3,2.2Hz,3H),6.20(d,J=15.7Hz,1H),5.00(s,2H),3.68(s,6H).ESI-MS m / z:[M+H] + :472.19.

[0230] Example 36: (E)-N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide hydrochloride

[0231]

[0232] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, with 100 mg of white powder and a yield of 80.37%. 1 H NMR (400 MHz, DMSO-d 6)δ8.86–8.69(m,1H),8.03(d,J=1.2Hz,1H),7.96–7.81(m,2H),7.56(d,J=15.4Hz,1H),7.40–7.25(m,5H),7.20(dt,J=7.2,1.7Hz,1H ),7.02(d,J=2.1Hz,1H),6.88(dd,J=8.2,1.9Hz,1H),6.76(d,J=8.2Hz,1H),6.31(d,J=15.5Hz,1H),5.07(s,2H),3.72(s,3H).ESI-MS m / z:[M+H] + :460.14.

[0233] Example 37: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)cinnamamide hydrochloride

[0234]

[0235] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, white powder, 40 mg, yield 51.3%. 1 H NMR (500 MHz, DMSO-d 6 )δ9.23(d,J=1.3Hz,1H),8.21(d,J=1.3Hz,1H),8.06–7.88(m,2H),7.65(d,J=15.5Hz,1H),7.52–7.13(m,11H),6.50(s,1H),5.10(s,2H).ESI-MS m / z:[M+H] + :414.14.

[0236] Example 38: (E)-4-(3-((4-acetoxy-3,5-dimethoxybenzyl)(4-(methylcarbamoyl)phenyl)amino)-3-oxoprop-1-en-1-yl)-2-methoxyphenyl acetate

[0237]

[0238] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 218 mg, yield 68.33%. 1 H NMR (500 MHz, DMSO-d 6)δ8.48(q,J=4.4Hz,1H),7.91–7.84(m,2H),7.64(d,J=15.5Hz,1H),7.47–7.38(m,2H),7.26(s,1H),7.04(d,J=4.4Hz,2H),6.59 (d,J=4.5Hz,2H),6.42(s,1H),5.08(s,2H),3.75(s,3H),3.69(d,J=3.3Hz,6H),2.78(d,J=4.5Hz,3H),2.30–2.19(m,6H).ESI-MS m / z:[M+H] + :577.2182.

[0239] Example 39: (E)-N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-3-(3-hydroxy-4-methoxyphenyl)acrylamide hydrochloride

[0240]

[0241] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, with a white powder of 42 mg and a yield of 85.3%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.20(s,1H),9.12(s,1H),8.17(d,J=1.3Hz,1H),8.02–7.90(m,2H),7.50(d,J=15.4Hz,1H),7.37(dd,J=8.7,6.7Hz,2H),7.3 4–7.27(m,3H),7.20(dt,J=7.1,1.7Hz,1H),6.89(s,2H),6.81(s,1H),6.22(d,J=15.5Hz,1H),5.07(s,2H),3.75(s,3H).ESI-MS m / z:[M+H] + :460.10.

[0242] Example 40: 4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(3-chlorobenzyl)acetamide)-N-methylbenzamide

[0243]

[0244] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, and the product was a yellow solid (301 mg) with a yield of 65.57%. 1 H NMR (400 MHz, DMSO-d 6)δ8.53(q,J=4.8,4.4Hz,1H),8.05(dd,J=8.4,1.0Hz,1H),7.93(d,J=8.0Hz ,2H),7.85–7.79(m,1H),7.62(d,J=8.1Hz,2H),7.57(ddd,J=8.2,6.9,1.0Hz ,1H),7.41(ddd,J=8.0,6.9,1.0Hz,1H),7.33(dq,J=6.3,4.2,3.5Hz,3H),7. 21(d,J=7.2Hz,1H),5.51(s,2H),4.97(s,2H),2.80(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :434.13.

[0245] Example 41: 4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(3,5-dimethoxybenzyl)acetamide)-N-methylbenzamide

[0246]

[0247] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 213 mg, yield 98.01%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.51(d,J=5.1Hz,1H),8.04(d,J=8.3Hz,1H),7.90(d,J=8.1Hz,2H),7.80(d,J=8.3Hz,1H),7.65–7.52(m,3H),7. 40(ddd,J=8.0,6.9,0.9Hz,1H),6.38(s,3H),5.50(s,2H),4.88(s,2H),3.69(s,6H),2.79(d,J=4.4Hz,3H).ESI-MS m / z:[M+H] + :460.20

[0248] Example 42: 4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(3,5-dimethoxybenzyl)acetamide)benzamide

[0249]

[0250] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials. The compound was white powder, 103 mg, yield 23.1%. 1 H NMR (400 MHz, DMSO-d 6)δ8.12–8.00(m,2H),7.96(d,J=8.0Hz,2H),7.80(dt,J=8.3,1.0Hz,1H),7.67–7.47(m,4H),7 .41(ddd,J=8.2,7.0,1.0Hz,1H),6.38(s,3H),5.52(s,2H),4.89(s,2H),3.70(s,7H).ESI-MS m / z:[M+H] + :446.18

[0251] Example 43: 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

[0252]

[0253] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, light yellow powder, 80 mg, yield 63.95%. 1 H NMR (500 MHz, DMSO-d 6 )δ8.94(s,1H),8.47(s,1H),8.04(d,J=8.4Hz,1H),7.74(dd,J=24.3,8.3Hz,2H),7.64–7.50(m,2H),7.45–7.35(m, 1H),7.21(s,1H),7.11–7.00(m,1H),6.84–6.57(m,3H),5.52(s,2H),4.84(s,2H),3.95(s,3H),3.70(s,3H).ESI-MS m / z:[M+H] + :486.17

[0254] Example 44: 4-(2-(1H-benzo[d]imidazol-1-yl)-N-(3-chlorobenzyl)acetamido)-N-methylbenzamide

[0255]

[0256] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, yellow powder, 100 mg, yield 23.21%. 1 H NMR (500 MHz, DMSO-d 6)δ8.51(d,J=4.6Hz,1H),8.07(s,1H),7.91(d,J=8.1Hz,2H),7.64(dd,J=7.5,1.2Hz,1H),7.55(d,J=8.1Hz,2H) ,7.49–7.44(m,1H),7.37–7.29(m,3H),7.27–7.17(m,3H),4.97(d,J=24.1Hz,4H),2.79(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :433.1426.

[0257] Example 45: 4-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamido)-N-methylbenzamide

[0258]

[0259] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, white powder, 56 mg, yield 26.73%. 1 H NMR (500 MHz, DMSO-d 6 )δ8.94(s,1H),8.52–8.48(m,1H),8.04(d,J=8.3Hz,1H),7.90(d,J=8.1Hz,2H),7.79(d,J=8.3Hz,1H),7.59–7.49(m,3H),7.41(d dd,J=8.1,6.8,1.0Hz,1H),6.74–6.65(m,2H),6.58(s,1H),5.44(s,2H),4.83(s,2H),3.69(s,3H),2.79(d,J=4.5Hz,3H).ESI-MS m / z:[M+H] + :446.18

[0260] Example 46: 4-((2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(4-(methylcarbamoyl)phenyl)acetamido)methyl)-2-methoxyphenyl acetate

[0261]

[0262] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials. The product was a yellow powder (386 mg). The yield was 77.01%. 1 H NMR (500 MHz, DMSO-d 6)δ8.51(s,1H),8.04(dt,J=8.3,0.9Hz,1H),7.91(d,J=8.0Hz,2H),7.80(dt,J=8.4,0.9Hz,1H),7.72–7.48(m,3H),7.41(ddd, J=8.2,6.9,1.0Hz,1H),7.11–6.69(m,3H),5.50(s,2H),4.95(s,2H),3.71(s,3H),2.79(d,J=4.5Hz,3H),2.24(s,3H).ESI-MS m / z:[M+H] + :488.1928.

[0263] Example 47: N-(4-(1H-imidazol-4-yl)phenyl)-2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(3,5-dimethoxybenzyl)acetamide hydrochloride

[0264]

[0265] Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1 to obtain a white solid. 68 mg, yield 75.03%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.39–9.15(m,1H),8.25(s,1H),8.04(t,J=8.4Hz,3H),7.82(d,J=8.4Hz,1H),7.66(d,J=8.1Hz,2H ),7.55(t,J=7.6Hz,1H),7.39(t,J=7.6Hz,1H),6.46–6.33(m,3H),5.55(s,2H),4.89(s,2H).ESI-MS m / z:[M+H] + :469.19.

[0266] Example 48: 4-((2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(4-(methylcarbamoyl)phenyl)acetamido)methyl)-2,6-dimethoxyphenyl acetate

[0267]

[0268] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials. The product was a yellow powder (181 mg). The yield was 63.17%. 1 H NMR (500 MHz, DMSO-d 6)δ8.51(d,J=5.0Hz,1H),8.04(d,J=8.3Hz,1H),7.93(d,J=8.0Hz,2H),7.80(d,J=8.3Hz,1H),7.64(d,J=8.0Hz,2H),7.58–7. 52(m,1H),7.48–7.32(m,1H),6.59(s,2H),5.53(s,2H),4.94(s,2H),3.71(s,6H),2.80(d,J=4.5Hz,3H),2.23(s,3H).ESI-MS m / z:[M+H] + :518.2034.

[0269] Example 49: 4-((N-(4-(1H-imidazol-4-yl)phenyl)-2-(1H-benzo[d][1,2,3]triazol-1-yl)acetamido)methyl)-2-methoxyphenyl acetate hydrochloride

[0270]

[0271] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced. The product was white powder, 50 mg, and the yield was 56.3%. 1 H NMR (500 MHz, DMSO-d 6 )δ9.21(s,1H),8.23(s,1H),8.03(t,J=8.9Hz,3H),7.83(d,J=8.3Hz,1H),7.68(d,J=8.0Hz,2H),7.56(t,J=7.6Hz,1H),7. 40(t,J=7.6Hz,1H),7.08–6.92(m,2H),6.84(d,J=8.1Hz,1H),5.54(s,2H),4.96(s,2H),3.73(s,3H),2.24(s,3H).ESI-MS m / z:[M+H] + :497.1932.

[0272] Example 50: 2-methoxy-4-((N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamido)methyl)phenyl acetate

[0273]

[0274] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials, light yellow powder, 245 mg, yield 54.16%. 1H NMR (500 MHz, DMSO-d 6 )δ8.46(s,1H),7.73(d,J=8.2Hz,1H),7.58(s,1H),7.17(d,J=1.9Hz,1H),7.15–7.05(m,5H),7.01(d,J=8.0Hz,1H),6 .98(s,1H),6.90–6.75(m,1H),4.92(s,2H),4.57(s,2H),3.92(s,3H),3.73(s,3H),3.30(s,3H),2.24(s,3H).ESI-MS m / z:[M+H] + :557.2031.

[0275] Example 51: N-(4-hydroxy-3-methoxybenzyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide

[0276]

[0277] The target compound was prepared according to the method of Example 17 except replacing the corresponding reaction raw materials. The product was a light yellow powder (178 mg). The yield was 80.64%. 1 H NMR (500 MHz, DMSO-d 6 )δ8.92(s,1H),8.46(s,1H),7.71(d,J=8.2Hz,1H),7.58(s,1H),7.17–7.13(m,2H),7.11–7.04(m,3H),6.99(dd,J=8.3,1.9Hz,1H), 6.77(s,1H),6.68(d,J=8.0Hz,1H),6.60(d,J=8.0Hz,1H),4.81(s,2H),4.52(s,2H),3.93(s,3H),3.70(s,3H),3.30(s,3H).ESI-MS m / z:[M+H] + :515.19

[0278] Example 52: N-(4-(1H-imidazol-4-yl)phenyl)-2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamide hydrochloride

[0279]

[0280] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, white powder, 34 mg, yield 74.56%.1 H NMR (400 MHz, DMSO-d 6 )δ12.25(s,1H),8.92(s,1H),8.04(d,J=8.3Hz,1H),7.84(d,J=8.0Hz,2H),7.79(d,J=8.4Hz,1H),7.73(s,1H),7.66(s,1H),7. 59–7.51(m,1H),7.48–7.32(m,3H),6.79–6.53(m,3H),5.43(s,2H),4.79(s,2H),3.68(s,3H),1.91(s,1H),1.75(s,0H).ESI-MS m / z:[M+H] + :455.18.

[0281] Example 53: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide hydrochloride

[0282]

[0283] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, white powder, 20 mg, yield 60.60%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.14(s,1H),8.17(s,1H),7.92(d,J=8.1Hz,2H),7.56(d,J=8.0Hz,2H),7.39 –7.27(m,4H),7.23–7.02(m,6H),4.94(s,2H),4.52(s,2H),3.31(s,3H).ESI-MS m / z:[M+H] + :472.15.

[0284] Example 54: 4-((N-(4-(1H-imidazol-4-yl)phenyl)-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamido)methyl)-2-methoxyphenyl acetate hydrochloride

[0285]

[0286] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, white powder, 60 mg, yield 57.2%. 1 H NMR (500 MHz, DMSO-d 6)δ9.29–9.12(m,1H),8.22(s,1H),8.00(d,J=8.1Hz,2H),7.59(d,J=8.0Hz,2H),7.21–6.90(m,7H ),6.81(d,J=8.1Hz,1H),4.93(s,2H),4.53(s,2H),3.73(s,3H),3.32(s,4H),2.24(s,3H).ESI-MS m / z:[M+H] + :526.2086.

[0287] Example 55: N-(4-(1H-imidazol-4-yl)phenyl)-2-(5-bromo-2,3-dioxoindole-1-yl)-N-(3-chlorobenzyl)acetamide hydrochloride dioxane

[0288]

[0289] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 103 mg, yield 75.80%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.25(d,J=1.3Hz,1H),8.23(s,1H),8.01(d,J=8.1Hz,2H),7.89(dd,J=8.4,2.1Hz,1H),7.75(d,J=2.1Hz,1H),7.6 0(d,J=8.1Hz,2H),7.33(tt,J=8.6,5.1Hz,3H),7.21(dd,J=10.4,7.2Hz,2H),4.95(s,2H),4.41(s,2H),3.57(s,4H).

[0290] Example 56: N-(4-(1H-imidazol-4-yl)phenyl)-N-(3-chlorobenzyl)-2-(5,7-dimethyl-2,3-dioxoindole-1-yl)acetamide hydrochloride dioxane

[0291]

[0292] The target compound was prepared according to the method of Example 1 except that the corresponding reaction raw materials were replaced, orange powder, 82 mg, yield 93.01%. 1 H NMR (400 MHz, DMSO-d 6)δ9.28–9.14(m,1H),8.17(s,1H),7.97(d,J=8.1Hz,2H),7.45(d,J=8.1Hz,2H), 7.27–7.16(m,5H),7.11(d,J=6.5Hz,1H),4.88(s,2H),4.44(s,2H),3.50(s,4H).

[0293] Test Example 1: 3CL pro Screening of protein level enzyme inhibitory activity

[0294] Test Materials and Methods:

[0295] Test kit: Novel Coronavirus M pro / 3CL pro Inhibitor screening kit, Biotechnology Biotech Co., Ltd. (Product No.: P0312M).

[0296] Positive control drug: Ebselen, Biotime Biotech Co., Ltd. (Product No.: P0312M).

[0297] Sample treatment: DMSO was used to prepare the stock solution before use.

[0298] Test method: 3CL configuration pro / Assay Buffer (1:92) solution, add DMSO solution containing different concentrations of samples and positive control drugs (the sample gradient is set to 25μM, 6.25μM, 1.56μM, 0.39μM, 0.097μM, and the positive drug concentration is 1μM), and set up Ebselen control wells and blank control wells. Quickly add 2μL of Substrate to each well, incubate at 37℃ in the dark for 5 minutes, and use a multifunctional enzyme label for fluorescence determination. The excitation wavelength is 340nm and the emission wavelength is 490nm.

[0299] Record the average fluorescence value of each sample well and blank control well, which can be recorded as RFU. 空白对照 、RFU 100％酶活性对照 、RFU 阳性对照 and RFU 样品 RFU, Relative Fluorescence Unit. Inhibition rate (%) = (RFU100% 酶活性对照 -RFU 样品 ) / (RFU100% 酶活性对照 -RFU 空白对照 )×100% to calculate and obtain the half maximal inhibition concentration (IC50) of the sample. The test results are shown in Table 1 below.

[0300] Test Example 2: Compound Cytotoxicity Experiment

[0301] Test cells: Vero (African green monkey kidney epithelial cells), purchased from ATCC.

[0302] Test method: Digest and resuspend the cells in high-glucose MEM medium (I1522M1, MACGENE) containing 10% fetal bovine serum (10091148, Gibco), and plate them in a 96-well plate, 20,000 cells / well, and culture them in an incubator at 37°C and 5% CO2 for 12 hours. After the cells adhere to the wall, discard the old medium, add 200μL of the corresponding 100μM, 80μM, 60μM, 40μM, 20μM drug-containing medium to each well, set up 3 replicates, and set up a solvent control group. After 72 hours of culture at 37°C, discard the supernatant, add 10μL of the newly prepared medium per 100μL to each well, and set up a background control group. Place the 96-well plate in an incubator for 1 hour and take it out. Use an enzyme reader to measure the OD value at 450nm. The value measured by the enzyme reader is the value after automatically subtracting the background value. Cell viability (%) = (OD value of drug experimental group / OD value of solvent control group) × 100%. Inhibition rate (%) = 100% - cell viability (%). The test results are shown in Table 1 below.

[0303] Table 1:

[0304]

[0305]

[0306] Note:

[0307] (1) “-” in the table means that the sample has no cytotoxicity or no antiviral activity at the maximum dose

[0308] (2)CC 50 : The half-toxic concentration of a drug; IC 50 : Half inhibitory concentration of the drug on the virus; SI: Selective index, SI = CC 50 / IC 50 .

[0309] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. An amide compound as shown in the following formula 1-1 and its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer: R2 is selected from pyrazolyl, oxazolyl, isoxazolyl, imidazolyl; R3, R4, R5 and R6 are each independently selected from H, halogen, hydroxyl, C 1-6 Alkoxy, -COOR d , where R d Select from H or C 1-6 alkyl; In formula 1-1, the structure for Wherein R7 and R8 are each independently selected from H, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy.

2. The amide compound and its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer according to claim 1, characterized in that: R3, R4, R5 and R6 are each independently selected from H, Cl, hydroxy, methoxy, ethoxy, -COOR d , where R d Selected from H, methyl, ethyl.

3. The amide compound and its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer according to claim 1, characterized in that: The amide compound and its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer are selected from the following compounds:

4. The amide compound of formula 1-1 and its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer in the preparation of antiviral 3CL according to any one of claims 1 to 3 pro Use in inhibitors.

5. The use according to claim 4, characterized in that: The virus is a coronavirus selected from severe acute respiratory syndrome virus SARS-COV, new severe acute respiratory syndrome virus SARS-COV-2, and Middle East respiratory syndrome virus MERS-CoV.

6. The use according to claim 5, characterized in that: The virus subtype of the new severe acute respiratory syndrome virus SARS-COV-2 is Omicron or Delta.

7. A pharmaceutical composition comprising a therapeutically effective amount of an amide compound represented by formula 1-1 according to any one of claims 1 to 3 and a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer thereof as an active ingredient, and a pharmaceutically acceptable excipient.

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