Compound containing aromatic ring pyridone amide

Abstract

The invention provides a compound containing aromatic ring pyridone amide, and particularly provides an aromatic ring pyridone amide compound with a structure as shown in a general formula I, and a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture of the racemate, the R-isomer, the S-isomer and the pharmaceutically acceptable salt thereof. The compound provided by the invention can be used as a 3CL protease (also known as main protease) inhibitor, and is especially used for treating viral diseases with 3CL protease, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, norovirus and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry and pharmacotherapy, and in particular to a class of aromatic ring-containing pyridone amide compounds as coronavirus 3CL protease inhibitors, preparation methods thereof, pharmaceutical compositions containing such compounds, and 3CL protease (also known as main protease) inhibitors, especially for treating viral diseases in which 3CL protease is present, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, norovirus, etc. Background Art

[0003] The pathogen causing the novel coronavirus is SARS-CoV-2, a new type of coronavirus. The coronavirus is about 80 to 120 nm in diameter and consists of an envelope and a single-stranded positive RNA coated therein. The 5′ end of the RNA chain has a methylated cap-like structure and the 3′ end has a poly(A) tail. The total length of the genome is about 27-32 kb. One-third of the RNA in its genome is used to encode structural and auxiliary proteins, including membrane M protein (membrance, M), spike S protein (spike, S), envelope E protein (envelope, E), and nucleocapsid N protein (nucleocapsid, N). The remaining two-thirds of the genome consists of two open reading frames (ORFs), called ORF 1a and ORF 1b. ORF 1a encodes a polyprotein of about 450 kDa, called pp1a, and ORF 1a and ORF 1b together encode a polyprotein of about 750 kDa, called pp1ab. Under the action of viral proteases, these two polyproteins release a variety of non-structural proteins (nsps) to execute viral replication.

[0004] 3CL protease is one of the key enzymes of coronavirus and plays an important role in regulating the replication of the virus. pro ) can hydrolyze the original polyproteins of pp1a and pp1ab from at least 11 conserved cleavage sites to help them form the replicase complex. On January 26, 2020, Yang Haitao, Rao Zihe and their team announced the crystal structure of the SARS-CoV-2 coronavirus 3CL protease binding compound N3, with a resolution of (PDB ID 6LU7). The active form of SARS-CoV-2 3CLpro is a homodimer consisting of two monomers. Each monomer consists of three domains with a total of 306 residues. Domain I (residues 8-101) and domain II (residues 102-184) have an inverted β-sheet structure. Domain III (residues 201-303) contains five α-helical structures and is connected to domain II by a long loop region (residues 185-200).

[0005] 3CL protease is one of the key enzymes of coronavirus and norovirus, playing an important role in regulating viral replication, and 3CL protease has no human homolog. At the same time, further sequence comparison shows that the 3CL proteases of the three coronaviruses SARS-CoV, SARS-CoV-2 and MERS-CoV show high structural similarity and conservation. These characteristics make 3CL protease an attractive drug target for inhibiting SARS-CoV-2 and other types of viruses.

[0006] Researchers have done a lot of work on inhibitors of 3CL proteases. These inhibitors can be roughly divided into two categories according to their structural characteristics: peptidomimetic inhibitors and non-peptidomimetic small molecule inhibitors. Peptidomimetic inhibitors mainly use electrophilic "warhead" groups to covalently bind to the cysteine ​​residues of 3CL proteases, thereby achieving irreversible inhibition. Non-peptidomimetic small molecule inhibitors mainly achieve inhibition by forming hydrogen bonds, hydrophobic bonds, and van der Waals interactions with amino acid residues in the binding pocket.

[0007] At present, a number of peptidomimetic 3CL protease inhibitors have entered clinical research, among which Pfizer's Nirmatrelvir (PF-07321332) has been approved for marketing by the FDA, but it must be used in combination with ritonavir to improve its poor pharmacokinetic properties. The first oral non-peptide 3CL protease small molecule inhibitor S-217622 reported by Shionogi Co., Ltd. in Japan to enter clinical research showed good pharmacokinetic properties and has been approved for marketing in Japan. In view of the possible development trend of the virus, the development of new small molecule inhibitors targeting 3CL protease still has great clinical value. Summary of the invention

[0008] The purpose of the present invention is to provide a small molecule inhibitor targeting 3CL protease target.

[0009] The first aspect of the present invention provides an aromatic ring pyridone amide compound having a structure shown in general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:

[0010]

[0011] Among them, X, X 1 , X 2 can be selected from CH or N, and when X is CH, the hydrogen atoms on the CH can be independently replaced by R 1 replace;

[0012] R 1 is one or more substituents located on the ring, and each R 1 Each is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonyl C1-C3 alkyl (i.e., S(O)2C1-C3 alkyl), imino C1-C3 alkyl, 3-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl, and 3-12 membered heteroaryloxy; and when R 1 When there are multiple substituents, each R 1 Can be the same or different;

[0013] R 2 Selected from the group consisting of hydrogen, hydroxymethyl, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonyl C1-C3 alkyl, imino C1-C3 alkyl, 3-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy;

[0014] It has the following structure:

[0015] -L 1 -L 2 -L 3 -;

[0016] Among them, L 1 and L 3 Each independently selected from the group consisting of: chemical bonds (i.e., when L 1 or L 3 not present), C1-C6 alkyl, NH, O or S; L 2Selected from the following group: C1-C6 alkyl, C3-C8 cycloalkyl, 4-7 membered heterocyclic ring, or 7-20 membered polycyclic ring (including fused ring, bridged ring or spiro ring, wherein the fused ring can be selected from the following group: saturated ring and saturated ring, saturated ring and aromatic ring);

[0017] The may be substituted by 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, imino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonylC1-C3 alkyl, iminoC1-C3 alkyl, 5-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy;

[0018] The A is selected from the following groups: -NH-R, 4-7 membered heteromonocyclic ring, or 7-20 membered heteropolycyclic ring (including cyclic, bridged or spirocyclic ring); the R is selected from the following groups: C1-C6 alkyl, C3-C9 cycloalkyl (including monocyclic or polycyclic), or 4-10 membered heterocyclic group (including monocyclic or polycyclic); and A may be optionally substituted by 1, 2, 3 or 4 substituents selected from the following groups: hydrogen, halogen, cyano, nitro, amino, hydroxyl, carbonyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C 1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonyl C1-C3 alkyl, imino C1-C3 alkyl, 3-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy;

[0019] Wherein, each of the heterocycles (including heteroaromatic rings, heterocyclic rings or heterocyclic groups) independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclic group, aryl and heteroaryl are independently substituted by 1 to 3 substituents selected from the following group: halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, oxo (=O), C1-C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group, and the halogen is F, Cl, Br or I;

[0020] Unless otherwise specified, the aryl or heteroaryl groups may include a single ring or a condensed ring; the cycloalkyl, cycloalkenyl, heterocyclic group may include a single ring, a fused ring, a spiro ring or a bridged ring; the heterocyclic group may be saturated or partially unsaturated, but not aromatic.

[0021] In another preferred embodiment, the A has a structure selected from the following group:

[0022] Where n = 0, 1, 2 or 3, Y = O or NR 5 ; R 5 It may be independently selected from the following groups: hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy substituted with halogen, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, imino C1-C3 alkyl, 3-12 membered heteroaryl, 3-12 membered heterocyclyl.

[0023] In another preferred embodiment, the A group is selected from the following group: Where n=0, 1, 2 or 3.

[0024] In another preferred embodiment, the Having a structure selected from the group consisting of:

[0025] Where n = 0, 1 or 2;

[0026] R 6It is one or more substituents selected from the following group: hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, imino C1-C3 alkyl, 3-12 membered heteroaryl, 3-12 membered heterocyclyl.

[0027] In another preferred embodiment, the Select from the following group: Where n = 0, 1 or 2, R 6 It is one or more substituents selected from the following group: hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C10 aryl, 3-12 membered heteroaryl, 3-12 membered heterocyclyl.

[0028] In another preferred embodiment, the R 3 and R 4 Selected from the following group: H, halogen, cyano, nitro, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered heteroaryl.

[0029] In another preferred embodiment, the R 3 and R 4 Selected from the following group: halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl.

[0030] In another preferred embodiment, the R 1 is one or more substituents located on the ring, and each R 1 Each is independently selected from the following group: hydrogen, halogen, cyano, trifluoromethyl, methyl, methoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonyl C1-C3 alkyl (i.e. S(O)2C1-C3 alkyl), imino C1-C3 alkyl, 3-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy.

[0031] In another preferred embodiment, the R 3Selected from the following group: H, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl.

[0032] In another preferred embodiment, the R 4 Selected from the group consisting of halogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] In another preferred embodiment, the compound is the compound described in each embodiment.

[0034] The second aspect of the present invention provides a pharmaceutical composition, which comprises: one or more of the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0035] The third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, and the use of its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof for preparing a pharmaceutical composition for treating or preventing diseases associated with 3CL protease activity.

[0036] In another preferred embodiment, the disease is a disease caused by a virus containing 3CL protease. Preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, or a combination thereof.

[0037] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0038] After long-term and in-depth research, the inventors have designed and synthesized a class of novel aromatic ring pyridone amide compounds, which have excellent inhibitory activity against 3CL proteases and can be used to treat, prevent and alleviate diseases related to 3CL proteases, especially for treating viral diseases with 3CL proteases, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, norovirus, etc. Based on the above findings, the inventors have completed the present invention.

[0039] Preparation of compounds of formula I

[0040] The present invention also provides a method for preparing a compound represented by general formula I. There are no specifically defined variables in this scheme. According to the definition of formula I in the present disclosure, the preparation method is carried out according to the following scheme:

[0041]

[0042] Step a: dissolving the raw material in an organic solvent, adding DIPEA at room temperature, and reacting to obtain a product; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof;

[0043] Step b: dissolving the raw material in an organic solvent and slowly adding acid under stirring at 0°C, stirring the reaction solution at room temperature for 1 hour, and concentrating the reaction solution after completion of the reaction. The residue is dissolved in 100 mL of ethyl acetate and washed with a saturated sodium carbonate solution and the pH is adjusted to 8-9, followed by washing with a saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain the product. The organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; the acid is trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.

[0044] Step c: dissolving the raw material in an organic solvent, adding a certain amount of alkali and a condensing agent, and reacting at room temperature to obtain a product; the condensing agent is HATU or CMPI; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; the alkali is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.

[0045] Step d: dissolve the raw material in an appropriate amount of a mixed solvent of THF / H2O, add potassium hydroxide, and react under reflux with stirring for two hours. After the reaction is completed, the solvent is dried and the pH is adjusted to acidic using hydrochloric acid. Solid precipitation is observed and the solid is collected by suction filtration to obtain the product.

[0046] Step e: dissolving the raw material in an organic solvent, adding a certain amount of alkali and condensing agent, and reacting at room temperature to obtain the product. The condensing agent is HATU or CMPI; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; the alkali is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.

[0047] Pharmaceutical compositions and methods of administration

[0048] Since the compounds of the present invention have excellent 3CL protease inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to 3CL protease, especially for the treatment of viral diseases in which 3CL protease is present, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, norovirus, etc.

[0049] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-3000 (active dose range 3-30 mg / kg) mg of the compound of the present invention / dose, more preferably, 10-2000 mg of the compound of the present invention / dose. Preferably, the "one dose" is a capsule or tablet.

[0050] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0051] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0052] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0053] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0054] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0055] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0056] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0057] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0058] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0059] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0060] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 6 to 600 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0061] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0062] Example 1 N-((1S, 2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (1)

[0063] Methyl 5-bromo-2-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-3-nitrobenzoate

[0064] Methyl 5-bromo-2-fluoro-3-nitrobenzoate (1 g, 3.6 mmol) and tert-butyl ((1S, 2R)-2-aminocyclohexyl)carbamate (0.77 g, 3.6 mmol) were dissolved in an appropriate amount of DMF, followed by addition of DIPEA (1.4 g, 10.8 mmol), stirred at 80°C, and reacted overnight. After the reaction was completed, excess water was added, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brown-yellow oil (1.7 g, yield 100%), which was directly used in the next step.

[0065] Methyl 2-(((1R,2S)-2-aminocyclohexyl)amino)-5-bromo-3-nitrobenzoate

[0066] 5-bromo-2-(((1R, 2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-3-nitrobenzoic acid methyl ester (1.7 g, 3.6 mmol) was dissolved in an appropriate amount of dichloromethane and 15 mL of trifluoroacetic acid was slowly added under stirring at 0°C, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, washed with a saturated sodium carbonate solution and the pH was adjusted to 8-9, then extracted three times with ethyl acetate, the organic phases were combined, washed with a saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily substance, namely 2-(((1R, 2S)-2-aminocyclohexyl)amino)-5-bromo-3-nitrobenzoic acid methyl ester (1.34 g, yield 100%).

[0067] Methyl 5-bromo-3-nitro-2-(((1R,2S)-2-(2-oxo-1,2-dihydroquinoline-4-carboxamido)cyclohexyl)amino)benzoate

[0068] Dissolve methyl 2-(((1R, 2S)-2-aminocyclohexyl)amino)-5-bromo-3-nitrobenzoate (1.34 g, 3.6 mmol) in an appropriate amount of DMF, add 2-hydroxyquinoline-4-carboxylic acid (0.68 g, 3.6 mmol), HATU (1.37 g, 3.6 mmol), DIPEA (1.4 g, 10.8 mmol), stir at room temperature for one hour, add excess water after the reaction is complete, and then add acetic acid. The mixture was extracted with ethyl ester three times, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brown-yellow oil. The oil was separated by column chromatography using dichloromethane / methanol = 20:1 as eluent to obtain a brown-red solid, which was the compound 5-bromo-3-nitro-2-(((1R, 2S)-2-(2-oxo-1,2-dihydroquinoline-4-carboxamido)cyclohexyl)amino)benzoic acid methyl ester (0.978 g, yield 50%).

[0069] 5-Bromo-3-nitro-2-(((1R,2S)-2-(2-oxo-1,2-dihydroquinoline-4-carboxamido)cyclohexyl)amino)benzoic acid

[0070] Methyl 5-bromo-3-nitro-2-(((1R, 2S)-2-(2-oxo-1,2-dihydroquinoline-4-carboxamido)cyclohexyl)amino)benzoate (0.978 g, 1.8 mmol) was dissolved in a proper amount of a mixed solvent of THF / H2O, potassium hydroxide (0.404 g, 7.2 mmol) was added, and the mixture was stirred and reacted under reflux for two hours. After the reaction was completed, the solvent was dried by spin drying, and the pH was adjusted to acidic with hydrochloric acid. Solid precipitation was observed, and the solid was collected by filtration to obtain compound 5-bromo-3-nitro-2-(((1R, 2S)-2-(2-oxo-1,2-dihydroquinoline-4-carboxamido)cyclohexyl)amino)benzoic acid (0.858 g, yield 90%).

[0071] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (1)

[0072] Dissolve 5-bromo-3-nitro-2-(((1R, 2S)-2-(2-oxo-1,2-dihydroquinoline-4-carboxamido)cyclohexyl)amino)benzoic acid (0.858 g, 1.62 mmol) in an appropriate amount of DMF, add methylamine hydrochloride (0.11 g, 1.62 mmol), HATU (0.616 g, 1.62 mmol), DIPEA (0.63 g, 4.86 mmol), stir at room temperature for one hour, and after the reaction is completed, add excess of water, extracted three times with ethyl acetate, combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brown oil, which was separated by column chromatography using dichloromethane / methanol = 20:1 as the eluent to obtain a red solid, namely the compound N-((1S, 2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (0.439 g, yield 50%). LRMS (ESI) m / z 542 [M+H] + .

[0073] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (2)

[0074] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 2, LRMS (ESI) m / z 560 [M+H] + .

[0075] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (3)

[0076] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 3, LRMS (ESI) m / z 572 [M+H] + .

[0077] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide (4)

[0078] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 4, LRMS (ESI) m / z 556 [M+H] + .

[0079] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (5)

[0080] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 5, LRMS (ESI) m / z 560 [M+H] + .

[0081] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (6)

[0082] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 6, LRMS (ESI) m / z 572 [M+H] + .

[0083] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-cyano-2-oxo-1,2-dihydroquinoline-4-carboxamide (7)

[0084] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 7, LRMS (ESI) m / z 567 [M+H] + .

[0085] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide (8)

[0086] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 8, LRMS (ESI) m / z 556 [M+H] + .

[0087] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (9)

[0088] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 9, LRMS (ESI) m / z 560 [M+H] + .

[0089] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (10)

[0090] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 10, LRMS (ESI) m / z 572 [M+H] + .

[0091] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-7-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide (11)

[0092] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 11, LRMS (ESI) m / z 556 [M+H] + .

[0093] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (12)

[0094] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 12, LRMS (ESI) m / z 560 [M+H] + .

[0095] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-8-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (13)

[0096] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 13, LRMS (ESI) m / z 572 [M+H] + .

[0097] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-8-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide (14)

[0098] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 14, LRMS (ESI) m / z 556 [M+H] + .

[0099] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-4-carboxamide (15)

[0100] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 15, LRMS (ESI) m / z 543 [M+H] + .

[0101] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclopentyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (16)

[0102] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 16, LRMS (ESI) m / z 584 [M+H] + .

[0103] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclopentyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (17)

[0104] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 17, LRMS (ESI) m / z 602 [M+H] + .

[0105] N-((1S,2R)-2-((4-cyclopropyl-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclopentyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (18)

[0106] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 18, LRMS (ESI) m / z 559 [M+H] + .

[0107] N-((1S,2R)-2-((4-cyclopropyl-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclopentyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (19)

[0108] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 19, LRMS (ESI) m / z 589 [M+H] + .

[0109] N-((1S,2R)-2-((4-cyclopropyl-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclopentyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (20)

[0110] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 20, LRMS (ESI) m / z 577 [M+H] + .

[0111] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclopentyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (21)

[0112] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 21, LRMS (ESI) m / z 598 [M+H] + .

[0113] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclopentyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (22)

[0114] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 22, LRMS (ESI) m / z 616 [M+H] + .

[0115] 5-Bromo-N-methyl-3-nitro-2-(4-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazin-1-yl)benzamide (23)

[0116] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 23, LRMS (ESI) m / z 514 [M+H] + .

[0117] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)-1,2,4-tetrahydro-1,4-ethylnaphthyl-2-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (24)

[0118] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 24, LRMS (ESI) m / z 616 [M+H] + .

[0119] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)-1,2,4-tetrahydro-1,4-naphth-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (25)

[0120] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 25, LRMS (ESI) m / z 634 [M+H] + .

[0121] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)-1,2,4-tetrahydro-1,4-naphth-2-yl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (26)

[0122] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 26, LRMS (ESI) m / z 646 [M+H] + .

[0123] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)-1,2,4-tetrahydro-1,4-naphth-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (27)

[0124] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 27, LRMS (ESI) m / z 634 [M+H] + .

[0125] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)-1,2,4-tetrahydro-1,4-naphth-2-yl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (28)

[0126] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 28, LRMS (ESI) m / z 646 [M+H] + .

[0127] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)-1,2,4-tetrahydro-1,4-naphth-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (29)

[0128] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 29, LRMS (ESI) m / z 634 [M+H] + .

[0129] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)-1,2,4-tetrahydro-1,4-naphth-2-yl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (30)

[0130] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 30, LRMS (ESI) m / z 634 [M+H] + .

[0131] N-((1S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (31)

[0132] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 31, LRMS (ESI) m / z 542 [M+H] + .

[0133] N-((1S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (32)

[0134] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 32, LRMS (ESI) m / z 560 [M+H] + .

[0135] N-((1S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (33)

[0136] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 33, LRMS (ESI) m / z 572 [M+H] + .

[0137] N-((1S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (34)

[0138] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 34, LRMS (ESI) m / z 560 [M+H] + .

[0139] N-((1S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (35)

[0140] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 35, LRMS (ESI) m / z 572 [M+H] + .

[0141] N-((1S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (36)

[0142] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 36, LRMS (ESI) m / z 560 [M+H] + .

[0143] N-((1S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (37)

[0144] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 37, LRMS (ESI) m / z 560 [M+H] + .

[0145] N-(1-(4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)piperidin-4-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (38)

[0146] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 38, LRMS (ESI) m / z 528 [M+H] + .

[0147] N-(2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (39)

[0148] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 39, LRMS (ESI) m / z 488 [M+H] + .

[0149] 5-Bromo-N-methyl-3-nitro-2-(3-(2-oxo-1,2-dihydroquinoline-4-carbonyl)tetrahydropyrimidin-1(2H)-yl)benzamide (40)

[0150] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 40, LRMS (ESI) m / z 514 [M+H] + .

[0151] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (41)

[0152] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 41, LRMS (ESI) m / z 598 [M+H] + .

[0153] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (42)

[0154] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 42, LRMS (ESI) m / z 616 [M+H] + .

[0155] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (43)

[0156] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 43, LRMS (ESI) m / z 628 [M+H] + .

[0157] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (44)

[0158] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 44, LRMS (ESI) m / z 616 [M+H] + .

[0159] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (45)

[0160] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 45, LRMS (ESI) m / z 628 [M+H] + .

[0161] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (46)

[0162] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 46, LRMS (ESI) m / z 616 [M+H] + .

[0163] N-((1S,2R)-2-((4-bromo-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (47)

[0164] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 47, LRMS (ESI) m / z 616 [M+H] + .

[0165] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (48)

[0166] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 48, LRMS (ESI) m / z 611 [M+H] + .

[0167] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (49)

[0168] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 49, LRMS (ESI) m / z 629 [M+H] + .

[0169] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (50)

[0170] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 50, LRMS (ESI) m / z 641 [M+H] + .

[0171] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (51)

[0172] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 51, LRMS (ESI) m / z 629 [M+H] + .

[0173] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (52)

[0174] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 52, LRMS (ESI) m / z 641 [M+H] + .

[0175] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (53)

[0176] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 53, LRMS (ESI) m / z 629 [M+H] + .

[0177] N-((1S,2R)-2-((4-bromo-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (54)

[0178] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 54, LRMS (ESI) m / z 629 [M+H] + .

[0179] N-((1S,2R)-2-((4-bromo-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (55)

[0180] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 55, LRMS (ESI) m / z 610 [M+H] + .

[0181] N-((1S,2R)-2-((4-bromo-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (56)

[0182] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 56, LRMS (ESI) m / z 628 [M+H] + .

[0183] N-((1S,2R)-2-((4-bromo-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (57)

[0184] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 57, LRMS (ESI) m / z 640 [M+H] + .

[0185] N-((1S,2R)-2-((4-bromo-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (58)

[0186] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 58, LRMS (ESI) m / z 628 [M+H] + .

[0187] N-((1S,2R)-2-((4-bromo-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (59)

[0188] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 59, LRMS (ESI) m / z 640 [M+H] + .

[0189] N-((1S,2R)-2-((4-bromo-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (60)

[0190] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 60, LRMS (ESI) m / z 628 [M+H] + .

[0191] N-((1S,2R)-2-((4-bromo-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (61)

[0192] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 61, LRMS (ESI) m / z 628 [M+H] + .

[0193] N-((1S,2R)-2-((4-bromo-2-nitro-6-(3-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (62)

[0194] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 62, LRMS (ESI) m / z 666 [M+H] + .

[0195] N-((1S,2R)-2-((4-bromo-2-nitro-6-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (63)

[0196] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 63, LRMS (ESI) m / z 638 [M+H] + .

[0197] N-((1S,2R)-2-((2-(3-oxo-6-azabicyclo[3.1.1]heptane-6-carbonyl)-4-bromo-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (64)

[0198] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 64, LRMS (ESI) m / z 610 [M+H] + .

[0199] N-((1S,2R)-2-((4-bromo-2-(3-methylmorpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (65)

[0200] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 65, LRMS (ESI) m / z 612 [M+H] + .

[0201] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (66)

[0202] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 66, LRMS (ESI) m / z 504 [M+H] + .

[0203] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (67)

[0204] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 67, LRMS (ESI) m / z 522 [M+H] + .

[0205] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (68)

[0206] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 68, LRMS (ESI) m / z 534 [M+H] + .

[0207] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (69)

[0208] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 69, LRMS (ESI) m / z 522 [M+H] + .

[0209] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (70)

[0210] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 70, LRMS (ESI) m / z 534 [M+H] + .

[0211] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (71)

[0212] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 71, LRMS (ESI) m / z 522 [M+H] + .

[0213] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (72)

[0214] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 72, LRMS (ESI) m / z 522 [M+H] + .

[0215] N-((1S,2R)-2-((4-methyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (73)

[0216] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 73, LRMS (ESI) m / z 478 [M+H] + .

[0217] N-((1S,2R)-2-((4-ethyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (74)

[0218] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 74, LRMS (ESI) m / z 492 [M+H] + .

[0219] N-((1S,2R)-2-((4-isopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (75)

[0220] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 75, LRMS (ESI) m / z 506 [M+H] + .

[0221] N-((1S,2R)-2-((4-cyclobutyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (76)

[0222] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 76, LRMS (ESI) m / z 518 [M+H] + .

[0223] N-((1S,2R)-2-((4-cyclopentyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (77)

[0224] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 77, LRMS (ESI) m / z 532 [M+H] + .

[0225] N-((1S,2R)-2-((4-cyclohexyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (78)

[0226] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 78, LRMS (ESI) m / z 546 [M+H] + .

[0227] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (79)

[0228] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 79, LRMS (ESI) m / z 560 [M+H] + .

[0229] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (80)

[0230] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 80, LRMS (ESI) m / z 578 [M+H] + .

[0231] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-5-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (81)

[0232] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 81, LRMS (ESI) m / z 590 [M+H] + .

[0233] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-6-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (82)

[0234] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 82, LRMS (ESI) m / z 578 [M+H] + .

[0235] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxamide (83)

[0236] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 83, LRMS (ESI) m / z 590 [M+H] + .

[0237] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (84)

[0238] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 84, LRMS (ESI) m / z 578 [M+H] + .

[0239] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-8-fluoro-2-oxo-1,2-dihydroquinoline-4-carboxamide (85)

[0240] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 85, LRMS (ESI) m / z 578 [M+H] + .

[0241] N-((1S,2R)-2-((4-cyclopropyl-2-nitro-6-(4-oxopiperidin-1-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (86)

[0242] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 86, LRMS (ESI) m / z 572 [M+H] + .

[0243] N-((1S,2R)-2-((4-cyclopropyl-2-(4-methylpiperazine-1-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (87)

[0244] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 87, LRMS (ESI) m / z 573 [M+H] + .

[0245] N-((1S,2R)-2-((4-cyclopropyl-2-(3-methylmorpholine-4-carbonyl)-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (88)

[0246] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 88, LRMS (ESI) m / z 574 [M+H] + .

[0247] N-((1S,2R)-2-((4-cyclopropyl-2-nitro-6-(3-oxa-9-azaspiro[5.5]undecane-9-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (89)

[0248] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 89, LRMS (ESI) m / z 628 [M+H] + .

[0249] N-((1S,2R)-2-((4-cyclopropyl-2-nitro-6-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (90)

[0250] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 90, LRMS (ESI) m / z 600 [M+H] + .

[0251] N-((1S,2R)-2-((2-(3-oxo-6-azabicyclo[3.1.1]heptane-6-carbonyl)-4-cyclopropyl-6-nitrophenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (91)

[0252] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 91, LRMS (ESI) m / z 572 [M+H] + .

[0253] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (92)

[0254] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 92, LRMS (ESI) m / z 497 [M+H] + .

[0255] N-((1S,2R)-2-((4-bromo-2-cyano-6-(methylcarbamoyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (93)

[0256] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 93, LRMS (ESI) m / z 522 [M+H] + .

[0257] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-(trifluoromethyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (94)

[0258] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 94, LRMS (ESI) m / z 565 [M+H] + .

[0259] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-((trifluoromethyl)sulfonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (95)

[0260] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 95, LRMS (ESI) m / z 629 [M+H] + .

[0261] N-((1S,2R)-2-((2-cyano-4-cyclopropyl-6-(methylcarbamoyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (96)

[0262] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 96, LRMS (ESI) m / z 484 [M+H] + .

[0263] N-((1S,2R)-2-((2-cyano-4-cyclopropyl-6-(morpholine-4-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (97)

[0264] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 97, LRMS (ESI) m / z 540 [M+H] + .

[0265] N-((1S,2R)-2-((2-cyano-4-cyclopropyl-6-(4-methylpiperazine-1-carbonyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (98)

[0266] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 98, LRMS (ESI) m / z 553 [M+H] + .

[0267] N-((1S,2R)-2-((4-cyclopropyl-2-(methylcarbamoyl)-6-(trifluoromethyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (99)

[0268] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 99, LRMS (ESI) m / z 527 [M+H] + .

[0269] N-((1S,2R)-2-((4-cyclopropyl-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (100)

[0270] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 100, LRMS (ESI) m / z 583 [M+H] + .

[0271] N-((1S,2R)-2-((4-cyclopropyl-2-(4-methylpiperazine-1-carbonyl)-6-(trifluoromethyl)phenyl)amino)cyclohexyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (101)

[0272] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 101, LRMS (ESI) m / z 596 [M+H] + .

[0273] N-((5S,6R)-6-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)octahydro-1H-inden-5-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (102)

[0274] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 102, LRMS (ESI) m / z 582 [M+H] + .

[0275] N-((5S,6R)-6-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)octahydro-1H-inden-5-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (103)

[0276] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 103, LRMS (ESI) m / z 544 [M+H] + .

[0277] N-((3S,4R)-4-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)bicyclo[4.1.0]heptane-3-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (104)

[0278] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 104, LRMS (ESI) m / z 554 [M+H] + .

[0279] N-((3S,4R)-4-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)bicyclo[4.1.0]heptane-3-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (105)

[0280] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 105, LRMS (ESI) m / z 516 [M+H] + .

[0281] N-((2S,3R)-3-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)decahydronaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (106)

[0282] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 106, LRMS (ESI) m / z 596 [M+H] + .

[0283] N-((2S,3R)-3-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)decahydronaphthalen-2-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (107)

[0284] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 107, LRMS (ESI) m / z 558 [M+H] + .

[0285] N-((5S,6R)-6-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)spiro[2.5]octan-5-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (108)

[0286] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 108, LRMS (ESI) m / z 568 [M+H] + .

[0287] N-((5S,6R)-6-((4-cyclopropyl-2-(methylcarbamoyl)-6-nitrophenyl)amino)spiro[2.5]octan-5-yl)-2-oxo-1,2-dihydroquinoline-4-carboxamide (109)

[0288] Different compounds were used as reaction raw materials and the preparation method was the same as in Example 1 to obtain compound 109, LRMS (ESI) m / z 530 [M+H] + .

[0289] N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide (WU-04)

[0290] WU-04 was synthesized according to the literature as one of the reference compounds.

[0291]

[0292] Pharmacological Activity Test Example

[0293] Pharmacological Example 1. Molecular level inhibitory activity test of compounds on 3CL protease

[0294] Experimental principle: Based on the basic characteristics of SARS-CoV-2 3CLpro protein as a proteolytic enzyme, a screening system for detecting the activity of SARS-CoV-2 3CLpro protein by fluorescence method was established. SARS-CoV-2 3CLpro protein can specifically cleave substrates with Gln (Q) at the P1 position, and its activity detection can use fluorescent peptides as substrates, and the generation of fluorescent signals can be used to reflect the activity of its proteolytic enzyme.

[0295] Table 1: Inhibition rate and IC of some compounds 50 data

[0296]

[0297]

[0298] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. An aromatic ring pyridone amide compound having a structure shown in general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof: in, X, X 1 , X 2 can be selected from CH or N, and when X is CH, the hydrogen atoms on the CH can be independently replaced by R 1 replace; R 1 is one or more substituents located on the ring, and each R 1 , R 3 and R 4 R may be independently selected from the following group: hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonyl C1-C3 alkyl (i.e. S(O)2C1-C3 alkyl), imino C1-C3 alkyl, 3-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy; and when R 1 When there are multiple substituents, each R 1 Can be the same or different; R 2 Selected from the group consisting of hydrogen, hydroxymethyl, cyano, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonyl C1-C3 alkyl, imino C1-C3 alkyl, 3-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy; It has the following structure: -L 1 -L 2 -L 3 -; Among them, L 1 and L 3 Each independently selected from the group consisting of: chemical bonds (i.e., when L 1 or L 3 not present), C1-C6 alkyl, NH, O or S; L 2 Selected from the following group: C1-C6 alkyl, C3-C8 cycloalkyl, 4-7 membered heterocyclic ring, or 7-20 membered polycyclic ring (including fused ring, bridged ring or spiro ring, wherein the fused ring can be selected from the following group: saturated ring and saturated ring, saturated ring and aromatic ring); The may be substituted by 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, imino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonylC1-C3 alkyl, iminoC1-C3 alkyl, 5-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy; The A is selected from the following groups: -NH-R, -OR, 4-7 membered heteromonocyclic ring, or 7-20 membered heteropolycyclic ring (including cyclic, bridged or spirocyclic ring); the R is selected from the following groups: C1-C6 alkyl, C3-C9 cycloalkyl (including monocyclic or polycyclic), or 4-10 membered heterocyclic group (including monocyclic or polycyclic); and A can be optionally substituted by 1, 2, 3 or 4 substituents selected from the following groups: hydrogen, halogen, cyano, nitro, amino, hydroxyl, carbonyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl. , C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, C6-C10 aryl, C3-C10 cycloalkenyl, C2-C10 alkoxycarbonyl, sulfonyl C1-C3 alkyl, imino C1-C3 alkyl, 3-12 membered heteroaryl, C6-C12 aryloxy, 3-12 membered heterocyclyl and 3-12 membered heteroaryloxy; Wherein, each of the heterocyclic rings (including heteroaromatic rings, heterocyclic rings or heterocyclic groups) independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; Unless otherwise specified, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclic group, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, oxo (=O), C1-C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group, wherein the halogen is F, Cl, Br or I; Unless otherwise specified, the aryl or heteroaryl groups may include a single ring or a condensed ring; the cycloalkyl, cycloalkenyl, heterocyclic group may include a single ring, a fused ring, a spiro ring or a bridged ring; the heterocyclic group may be saturated or partially unsaturated, but not aromatic.

2. The aromatic ring pyridone amide compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The A has a structure selected from the following group: Where n = 0, 1, 2 or 3, Y = O or NR 5 ; R 5 It may be independently selected from the following groups: hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy substituted with halogen, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, imino C1-C3 alkyl, 3-12 membered heteroaryl, 3-12 membered heterocyclyl.

3. The aromatic ring pyridone amide compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The A group is selected from the following group: Where n=0, 1, 2 or 3.

4. The aromatic ring pyridone amide compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: Said Having a structure selected from the group consisting of: Where n = 0, 1 or 2; R 6 It is one or more substituents selected from the following group: hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, imino C1-C3 alkyl, 3-12 membered heteroaryl, 3-12 membered heterocyclyl.

5. The aromatic ring pyridone amide compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The Select from the following group: Where n = 0, 1 or 2, R 6 It is one or more substituents selected from the following group: hydrogen, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, sulfinyl, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C10 aryl, 3-12 membered heteroaryl, 3-12 membered heterocyclyl.

6. The aromatic ring pyridone amide compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The R 3 and R 4 Selected from the following group: H, halogen, cyano, nitro, trifluoromethyl, trifluoromethanesulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered heteroaryl.

7. The aromatic ring pyridone amide compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The R 3 and R 4 Selected from the following group: halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl.

8. The aromatic ring pyridone amide compound according to claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, characterized in that: The compound is selected from the following group:

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: one or more of the compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

10. The use of the compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: For preparing a pharmaceutical composition for treating or preventing a disease associated with 3CL protease activity; preferably, the disease is a disease caused by a virus in which 3CL protease is present, preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, norovirus, or a combination thereof.

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