WO2020098710A1 - Substituted bis-aryl amide compound and preparation method and application therefor - Google Patents

Substituted bis-aryl amide compound and preparation method and application therefor Download PDF

Info

Publication number
WO2020098710A1
WO2020098710A1 PCT/CN2019/118109 CN2019118109W WO2020098710A1 WO 2020098710 A1 WO2020098710 A1 WO 2020098710A1 CN 2019118109 W CN2019118109 W CN 2019118109W WO 2020098710 A1 WO2020098710 A1 WO 2020098710A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
compound represented
substituted
methylene
Prior art date
Application number
PCT/CN2019/118109
Other languages
French (fr)
Chinese (zh)
Inventor
胡来兴
刘永华
彭宗根
李健蕊
谭佳丽
武燕彬
Original Assignee
中国医学科学院医药生物技术研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国医学科学院医药生物技术研究所 filed Critical 中国医学科学院医药生物技术研究所
Publication of WO2020098710A1 publication Critical patent/WO2020098710A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Definitions

  • the present application relates to a compound, in particular to a substituted bis-aryl amide compound and its preparation method and application.
  • Hepatitis C is a liver disease caused by Hepatitis C virus (abbreviation: HCV).
  • HCV Hepatitis C virus
  • the virus can cause acute or chronic hepatitis, ranging in severity from a mild illness lasting a few weeks to a serious lifelong illness.
  • Acute hepatitis C virus infection is usually asymptomatic and only causes life-threatening diseases in very rare cases.
  • About 15% to 45% of infected people can clear the virus themselves within 6 months of infection without any treatment. The remaining 55% –85% of infected people will develop chronic hepatitis C virus infection.
  • the risk of developing cirrhosis within 20 years is 15% –30%.
  • the APOBEC3G (hA3G) enzyme is a member of the apolipoprotein B messenger RNA editing enzyme catalyzing polypeptide-like protein family and has an anti-retroviral effect.
  • the protein it encodes has an inhibitory effect on VIF gene-deficient HIV-1.
  • IFN- ⁇ can up-regulate hA3G expression. It is speculated that hA3G can participate in the host defense system and resist HCV infection.
  • hA3G is a limiting factor for antagonizing HCV replication in the host cell, increasing the content of hA3G in the cell, or adding a stabilizer of hA3G can inhibit HCV infection. Therefore, the host antiviral mechanism mediated by hA3G can be used as a new strategy.
  • a broad-spectrum anti-HCV or HCV / HIV-1 coinfection drug was found.
  • the present application provides a substituted bisarylamide compound or a pharmaceutically acceptable salt thereof, which has activity against hepatitis C virus.
  • the present application also provides a method for preparing the substituted bisarylamide compound or a pharmaceutically acceptable salt thereof.
  • the synthetic route is simple and the cost is low.
  • the present application also provides an application of the above substituted bisarylamide compound or a pharmaceutically acceptable salt thereof in the preparation of anti-hepatitis C drugs, which has strong anti-hepatitis C activity.
  • the present application also provides an anti-hepatitis C pharmaceutical composition
  • an anti-hepatitis C pharmaceutical composition comprising the above-mentioned substituted bisarylamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is independently selected from hydrogen, substituted or unsubstituted C 1-12 linear alkyl, C 3-12 branched alkyl or C 3-12 cycloalkyl;
  • R 2 is independently selected from -NO 2 , -NH 2 , -NHCOR 5 , -CF 3 , -NHSO 2 NH 2 ;
  • R 3 is independently selected from hydrogen, halogen, -CF 3 , -F, -CN, -NO 2 , -NH 2 ;
  • R 4 is independently selected from hydrogen, substituted or unsubstituted heterocyclyl
  • R 5 is independently selected from substituted or unsubstituted C 1-12 linear alkyl or C 3-12 branched alkyl;
  • X is independently selected from a hydrogen atom or a nitrogen atom.
  • R 1 when R 1 is a substituted C 1-12 linear alkyl group, C 3-12 branched alkyl group or C 3-12 cycloalkyl group, the substituent may be selected from a halogen atom or a secondary amine (-NR c R d ).
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom;
  • R c and R d may be independently selected from lower alkyl groups substituted or unsubstituted by halogen, hydroxy group, wherein, “lower alkyl group "Is a linear alkyl group, a branched alkyl group or a cycloalkyl group having 1 to 6 carbon atoms.
  • R 3 When R 3 is halogen, it may be selected from -F, -Cl, -Br, and -I.
  • R 4 is a substituted heterocyclic group
  • the substituent may be a lower alkyl group or a lower alkoxy group substituted or unsubstituted by a halogen or a hydroxy group, wherein “lower alkoxy group” has 1 to 1 carbon atoms 6 alkoxy groups, such as methoxy, ethoxy, etc .
  • the heterocyclic group may be a cycloalkyl group having 4-8 ring atoms and the ring atoms include hetero atoms, wherein the hetero atom may be oxygen , Sulfur, nitrogen atoms.
  • R 5 is a substituted C 1-12 linear alkyl group or C 3-12 branched alkyl group
  • the substituent may be independently selected from a halogen atom (-F, -Cl, -Br, -I), a secondary amine Group (-NR c R d , R c and R d are the same as above), sulfonamide group, heterocyclic group (cycloalkyl group with 4-8 ring atoms and ring atoms including hetero atoms).
  • R 1 is independently selected from hydrogen, substituted or unsubstituted C 1-6 linear alkyl, C 3-6 branched alkane Group or C 3-6 cycloalkyl.
  • C 1-6 linear alkyl groups include methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, and n-heptyl groups;
  • C 3-6 branched alkyl groups include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and isohexyl;
  • C 3-6 cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 4 is independently selected from hydrogen or the following formula [a] -formula [e] Groups shown:
  • R a and R b are independently selected from hydrogen, C 1-6 linear alkyl or C 3-6 branched alkyl.
  • substituted bisarylamide compounds provided in this application may be, for example, compounds numbered 1-32:
  • the pharmaceutically acceptable salt of the bisarylamide compound having the structure of formula [1] provided by the present application is a product of a salt-forming reaction between the bisarylamide compound and an acid.
  • the acid may be a conventional acid in the pharmaceutical field, and may be an inorganic acid such as hydrochloric acid, phosphoric acid, hydrobromic acid, or sulfuric acid; or an organic acid such as oxalic acid, maleic acid, lactic acid, succinic acid, methanesulfonic acid, or Benzoic acid, fumaric acid, malic acid, tartaric acid, benzoic acid or citric acid.
  • the present application also provides a method for preparing the substituted bisarylamide compound or a pharmaceutically acceptable salt thereof, including the following steps:
  • the compound represented by formula [2] and the compound represented by formula [3] undergo a condensation reaction in the presence of a condensing agent to produce a compound represented by formula [1a];
  • Rc is independently selected from -NO 2 and -CF 3 .
  • reaction process is completed in an appropriate condensation system, which can be controlled using conventional condensation agents and corresponding conditions to obtain the desired product.
  • the above synthetic route process a specifically includes: adding the compound represented by formula [2] and the compound represented by formula [3] as reactants to a solvent of dichloromethane, and at zero degrees, sequentially to the reactants Add amide coupling agent, such as 4-dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), after stirring for 30min, After warming to room temperature for 5-12 h, the compound represented by formula [3] disappeared by TLC detection.
  • amide coupling agent such as 4-dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI)
  • the reaction solution was diluted with ethyl acetate, it was washed sequentially with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the concentrate was purified by flash column chromatography to obtain the compound represented by formula [1a].
  • the molar ratio of the compound represented by the formula [2], the compound represented by the formula [3], DMAP and EDCI is 1.1: 1.0: 0.2: 2.0.
  • the amide coupling reagent used in the above synthetic route may also be HOBt / EDCI / DIPEA, HATU / DIPEA, or the like.
  • the process a is the same as described above.
  • the compound represented by formula [2a] can be obtained by hydrolyzing the carboxylic acid ester of formula [2a] (commercially available).
  • the process e is specifically: dissolving the compound represented by formula [1e] in anhydrous DMF, adding substituted or unsubstituted haloalkanes, such as brominated alkanes, and sequentially adding sodium iodide, Anhydrous potassium carbonate or anhydrous sodium carbonate, the reaction solution was heated to 60 ° C through an oil bath and the reaction was stirred for 3-15 h until the compound represented by formula [1e] disappeared by TLC monitoring.
  • the reaction solution was diluted with a certain amount of ethyl acetate, it was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound represented by formula [1a].
  • the molar ratio of the compound represented by formula [1e], haloalkane, sodium iodide, and anhydrous potassium carbonate or anhydrous sodium carbonate is 1.0: (1.5-2.0): 1.0: (1.5-2.0).
  • the compound represented by formula [1a] obtained by the above production method is a bisarylamide compound having the structure of formula [1] in which R 2 is -NO 2 and -CF 3 .
  • the compound represented by the formula [1a] can also be reduced to represent Rc -NO 2 is reduced to -NH 2 to obtain a compound represented by [1b], that is, a bisarylamide compound having the structure of formula [1] where R 2 is -NH 2 .
  • reaction process is completed in an appropriate reduction system, which can be controlled using conventional reducing agents and corresponding conditions to obtain the desired product.
  • the above synthetic route process b specifically includes: placing the compound represented by formula [1a] in a reaction kettle, such as a hydrogenation reaction flask, dissolved in a mixed solution of methanol and tetrahydrofuran, and adding Pd / C (The loading amount is 5%), the reaction is carried out under a pressure of 40 Psi or 1 atm for 2-3 hours, the reaction solution is filtered through celite, and the filtrate is concentrated to obtain the compound represented by formula [1] b.
  • a reaction kettle such as a hydrogenation reaction flask
  • Pd / C The loading amount is 5%
  • process b may also be specifically: dissolving the compound represented by formula [1a] in tetrahydrofuran, adding activated zinc powder, and adding acetic acid dropwise at around zero degrees until the compound represented by formula [1a] is monitored by TLC disappear.
  • the reaction solution was filtered, and the filtrate was diluted with a certain amount of ethyl acetate, washed sequentially with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound represented by formula [1] b.
  • the molar ratio of the compound represented by formula [1a], zinc powder and acetic acid is 1.0: 10: (1.5-3).
  • the compound represented by the formula [1b] obtained by the above production method is a bisarylamide compound having the structure of the formula [1] in which R 2 is -NH 2 .
  • reaction process is completed in an appropriate amidation system, which can be controlled using conventional catalysts and corresponding conditions to obtain the desired product.
  • the above synthetic route process c specifically includes: controlling the reaction temperature below zero (-10 ° C to 0 ° C), adding the acid chloride represented by R 5 COCl to methylene chloride or the compound represented by formula [1b] In the DMF solution, under basic conditions, such as triethylamine or pyridine catalysis, after stirring the reaction for 30 min, the reaction solution was raised to room temperature to continue stirring the reaction until the compound represented by formula [1b] disappeared by TLC monitoring.
  • the reaction solution was diluted with a certain amount of ethyl acetate, it was sequentially washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound represented by formula [1] c.
  • the molar ratio of the compound represented by formula [1b], acid chloride and triethylamine or pyridine is 1.0: 1.1: (1.5-2.0).
  • reaction process is completed in an appropriate sulfamidation system, which can be controlled using conventional catalysts and corresponding conditions to obtain the desired product.
  • the above-mentioned synthetic route process d is specifically: controlling the reaction temperature below zero, adding H 2 NSO 2 Cl to the methylene chloride or DMF solution of the compound represented by formula [1b], under alkaline conditions, For example, under the catalysis of triethylamine or pyridine, after stirring the reaction for 30 min, the reaction solution was raised to room temperature to continue stirring the reaction until the compound represented by formula [1b] disappeared by TLC monitoring. After the reaction solution was diluted with a certain amount of ethyl acetate, it was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound represented by formula [1d]. Among them, the molar ratio of the compound represented by the formula [1b], sulfamoyl chloride and triethylamine or pyridine is 1.2: 1.1: (1.5-2.0).
  • the corresponding pharmaceutically acceptable salt can be obtained by further salt formation reaction.
  • X 1 is a halogen atom.
  • reaction process is completed in an appropriate system, which can be controlled with corresponding conditions to obtain the desired product.
  • the above synthetic route process f specifically includes: adding the compound represented by formula [4] to the carbon tetrachloride solution, controlling the concentration of the compound represented by formula [4] to 2M, and adding N-brominated Succinimide (NBS) and azobisisobutyronitrile (AIBN) were refluxed overnight until the compound represented by formula [4] disappeared by TLC monitoring.
  • NBS N-brominated Succinimide
  • AIBN azobisisobutyronitrile
  • Process g is specifically: dissolving the compound represented by formula [5] obtained through process f in DMF, controlling the concentration of the reaction solution to 2.5M, adding potassium carbonate and a secondary amine R 4 H, and stirring the reaction at 50 ° C. 3- 5h until the disappearance of the compound represented by formula [5] was monitored by TLC. After the reaction solution was concentrated under reduced pressure, it was separated and purified by silica gel column chromatography to obtain the compound represented by formula [6]. Among them, the molar ratio of the compound represented by the formula [5], potassium carbonate, and secondary amine is 1.0: 1.5: 0.2.
  • Process h can be specifically referred to process b, as long as the reactants in process b are replaced with compounds represented by formula [6].
  • process i can be specifically referred to process e, and only the compound represented by formula [1e] in process e should be replaced with the compound represented by formula [7]. Among them, the compound represented by formula [7] is commercially available.
  • reaction process j is completed in an appropriate hydrolysis system (for example, acidic hydrolysis or basic hydrolysis), which can be controlled by conventional corresponding conditions to obtain the desired product.
  • an appropriate hydrolysis system for example, acidic hydrolysis or basic hydrolysis
  • the above synthetic route process j is specifically: dissolving the compound represented by formula [8] in an aqueous solution of tetrahydrofuran (the volume ratio of tetrahydrofuran to water is 1: 1), and controlling the compound represented by formula [8]
  • concentration is 0.3M
  • lithium hydroxide is added around zero and the reaction is stirred until the compound shown by TLC monitoring formula [8] disappears.
  • pH of the reaction solution was adjusted to 7 with hydrochloric acid, ethyl acetate was added for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the compound represented by formula [2].
  • the molar ratio of the compound represented by formula [8] and lithium hydroxide is 1.0: 1.5.
  • the present application also provides the use of any of the above-mentioned substituted bisarylamide compounds or pharmaceutically acceptable salts thereof in the preparation of anti-hepatitis C drugs.
  • the present application also provides an anti-hepatitis C pharmaceutical composition, which includes as an effective anti-hepatitis C component any of the above-mentioned substituted bisarylamide compounds or pharmaceutically acceptable salts thereof, and also includes pharmaceutically acceptable drugs Accessories.
  • the above substituted bisarylamide compound or its pharmaceutically acceptable salt itself or a mixture with pharmaceutically acceptable excipients, diluents, etc. can be made into the form of tablets, capsules, granules, powders or syrups .
  • the above formulations can be prepared by conventional pharmaceutical methods.
  • excipients can be used in conventional pharmaceutical methods.
  • useful pharmaceutical excipients include excipients (for example, sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; cellulose Derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium aluminum silicate; Phosphate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (such as gelatin, polyvinylpyrrolidone, and polyethylene glycol), disintegrating agents (such as cellulose derivatives such as carboxymethyl cellulose Sodium, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate,
  • the substituted bisarylamide compound in the anti-hepatitis C pharmaceutical composition of the present application is a unit preparation.
  • the unit preparation is a preparation that satisfies the active ingredients required for one-time administration, such as a unit (needle) injection.
  • the amount of medicine required for a patient to administer at one time can be conveniently obtained by calculating the product of the patient's body weight and the unit body weight dose required for the patient's one-time administration. For example, in the process of preparing medicines, it is generally considered that the adult body weight is 50-70 kg, and the dosage can be determined by the equivalent dose conversion relationship between the unit weight doses of laboratory animals and humans.
  • the human and mouse doses can be converted using a conversion factor of 0.0026 according to the body surface area of humans and mice.
  • the administration method of the anti-hepatitis C pharmaceutical composition provided by the present application is, for example, intravenous injection, intraperitoneal injection, or intragastric administration or oral administration.
  • the present application also provides a method for treating hepatitis C, that is, administering the above anti-hepatitis C pharmaceutical composition to a patient according to a clinically effective dose.
  • the substituted bisarylamide compound or its pharmaceutically acceptable salt provided in this application has good antiviral efficacy, especially strong anti-hepatitis C virus activity, which provides the possibility of developing new anti-hepatitis C drugs;
  • the preparation method of the substituted bisarylamide compound or its pharmaceutically acceptable salt provided in this application has a simple synthetic route and low cost, which is beneficial to industrial implementation.
  • reaction solution was concentrated under reduced pressure, ethyl acetate and saturated sodium bicarbonate solution were added for extraction 2-4 times, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with petroleum ether / ethyl acetate (20: 1-15: 1) As an eluent, it is separated and purified by silica gel column chromatography to obtain 3-trifluoromethyl-4-bromomethyl-nitrobenzene.
  • reaction solution was concentrated under reduced pressure, and separated and purified by silica gel column chromatography using dichloromethane / methanol (15: 1) as an eluent to obtain 3-trifluoromethyl-4-((4-methylpiperazine-1 -Yl) -methylene) nitrobenzene.
  • Compound 1 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • step 2) Referring to the method of step 2) in Embodiment 1, replacing 3-nitro-4-hydroxybenzoate with 3-nitro-4-methoxybenzoate to prepare 3-nitro-4 -Methoxybenzoic acid.
  • step 3) in Example 1 replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4-methoxybenzoic acid, and finally use the volume ratio of petroleum ether: tetrahydrofuran: ammonia water Silica gel column chromatography was carried out for separation and purification at 1: 1.5: 0.01 to obtain compound 2.
  • Compound 2 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • Example 2 Using compound 1 and isopropyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the silica gel column chromatography was finally performed with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Isolation and purification gave compound 3.
  • Compound 3 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • Example 2 Using compound 1 and 2-fluoroethyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, a silica gel column was finally carried out with a volume ratio of methylene chloride: methanol: ammonia water of 15: 1: 0.01 Chromatographic separation and purification gave compound 4.
  • Compound 4 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 2 Using compound 1 and 3-fluoro-propyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 5.
  • Compound 5 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 2 Using compound 1 and 2-chloro-ethyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 6.
  • Compound 6 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 2 Using compound 1 and 3-chloro-propyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 7.
  • Compound 7 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • Example 2 Using compound 1 and 4-chloro-butyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of methylene chloride: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 8.
  • Compound 8 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) as follows:
  • Example 2 Using Compound 1 and 5-chloro-pentyloxy bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 9.
  • Compound 9 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • step 4) Referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro-propoxy) -benzoic acid, and replace Fluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline was replaced with 3-trifluoromethyl-4-methylaniline, and finally the volume of petroleum ether: tetrahydrofuran: ammonia A ratio of 1: 1.5: 0.01 was separated and purified by silica gel column chromatography to obtain compound 10.
  • Compound 10 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • step 1) in Example 1 replacing 4-methylpiperazine with 3-N, N-dimethylamino-tetrahydropyrrole to prepare 3-trifluoromethyl-4-((3-N , N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) nitrobenzene intermediate product, continue to reduce to give 3-trifluoromethyl-4-((3-N, N-di Methylamino-tetrahydropyrrol-1-yl) -methylene) aniline.
  • Compound 11 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • step 1) in Example 1 replacing 4-methylpiperazine with 3-N, N-dimethylamino-azetidine to prepare 3-trifluoromethyl-4-((3 -N, N-dimethylamino-azetidin-1-yl) -methylene) nitrobenzene intermediate product, continue the reduction to obtain 3-trifluoromethyl-4-((3-N , N-dimethylamino-azetidin-1-yl) -methylene) aniline.
  • Example 10 3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) aniline and 3-nitro- in Example 10 4- (3-chloro-propoxy) -benzoic acid as the raw material, referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3 -Chloro-propoxy) -benzoic acid, replacing 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 3-trifluoromethyl-4 -((3-N, N-dimethylamino-azetidin-1-yl) -methylene) aniline, finally with dichloromethane: methanol: ammonia volume ratio of 30: 1: 0.01 Silica gel column chromatography separated and purified to obtain compound 12.
  • Compound 12 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • step 1) in Example 1 replacing 4-methylpiperazine with morpholine to prepare 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) nitrobenzene
  • step 2) in Example 1 replacing 4-methylpiperazine with morpholine to prepare 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) nitrobenzene
  • step 2) in Example 1 replacing 4-methylpiperazine with morpholine to prepare 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) nitrobenzene
  • the reduction is continued to obtain 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) aniline.
  • Example 10 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) aniline and 3-nitro-4- (3-chloro-propoxy) -benzoic acid in Example 10
  • As a raw material referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro-propoxy) -benzoic acid, replace 3- Replace trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 3-trifluoromethyl-4-((morpholin-1-yl) -methylene )
  • Aniline is finally separated and purified by silica gel column chromatography with a volume ratio of petroleum ether: ethyl acetate of 2: 1 to obtain compound 13.
  • Compound 13 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • step 1) in Example 1 replacing 4-methylpiperazine with 3,6-dimethyl-morpholine to prepare 3-trifluoromethyl-4-((3,6-dimethyl -Morpholin-1-yl) -methylene) nitrobenzene intermediate product, continue to reduce to give 3-trifluoromethyl-4-((3,6-dimethyl-morpholin-1-yl) -Methylene) aniline.
  • Compound 14 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • step 1) in Example 1 replace 3-trifluoromethyl-4-methylnitrobenzene with 2-methyl-4-nitropyridine and 4-methylpiperazine with N-methyl Piperazine, to prepare 2- (N-methylpiperazin-1-yl-methylene) -4-nitro-pyridine intermediate product, continue palladium hydrocarbon reduction to obtain 2- (N-methylpiper Azin-1-yl-methylene) -4-amino-pyridine was directly dropped into the next reaction.
  • Example 10 With 2- (N-methylpiperazin-1-yl-methylene) -4-amino-pyridine and 3-nitro-4- (3-chloro-propoxy) -benzene in Example 10
  • Formic acid is used as the raw material, referring to the method of step 3) in Example 1, replacing 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro-propoxy) -benzoic acid, replacing 3 -Trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline is replaced by 2- (N-methylpiperazin-1-yl-methylene) -4-
  • the amino-pyridine is finally separated and purified by silica gel column chromatography with a volume ratio of dichloromethane: methanol: ammonia water of 20: 1: 0.3 to obtain compound 15.
  • Compound 15 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 10 Using the compound 10 in Example 10 as the raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of petroleum ether: ethyl acetate was 5: 1 as the eluent. Column chromatography separated and purified to obtain compound 16.
  • Compound 16 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 7 Using compound 7 in Example 7 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of dichloromethane: methanol: ammonia water was 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 17.
  • Compound 17 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 12 Using compound 12 in Example 12 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol: ammonia water was 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 18.
  • Compound 18 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 14 Using compound 14 in Example 14 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of petroleum ether: ethyl acetate was 5: 1 as the eluent. Column chromatography separated and purified to obtain compound 19.
  • Compound 19 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 15 Using compound 15 in Example 15 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol: ammonia was 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 20.
  • Compound 20 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 3 Using compound 3 in Example 3 as a raw material, referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol: ammonia water is 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 21.
  • Compound 21 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Compound 22 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Example 8 Using compound 8 in Example 8 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol was 15: 1 as the eluent. Chromatographic separation and purification gave compound 23.
  • Compound 23 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • propionyl chloride (1.1 eq) is added to a solution of compound 22 (1.0 eq) in methylene chloride or DMF, under basic conditions, such as triethylamine or pyridine (1.5-2.0 eq), After stirring the reaction for 30 min, the reaction solution was raised to room temperature to continue stirring the reaction until TLC monitored the disappearance of compound 22 to stop the reaction. After the reaction solution was diluted with a certain amount of ethyl acetate, it was washed with saturated sodium bicarbonate solution and brine successively, dried over anhydrous sodium sulfate, filtered and concentrated. Finally, the volume ratio of dichloromethane: methanol was 20: 1 as the elution The concentrated solution was separated and purified by silica gel column chromatography to obtain compound 24.
  • Compound 24 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • propionyl chloride (1.1 eq) is added to a solution of 3-amino-4-methoxybenzoic acid (1.0 eq) in methylene chloride or DMF.
  • basic conditions such as triethylamine or pyridine ( Under the catalysis of 1.5-2.0eq)
  • the reaction solution was raised to room temperature to continue stirring the reaction until TLC monitored the disappearance of 3-amino-4-methoxybenzoic acid to stop the reaction.
  • reaction solution was diluted with a certain amount of ethyl acetate, it was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3-propionamido-4-methoxybenzoic acid.
  • step 3) in Example 1 replace 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 4-((4-methylpiper Aziridine-1-yl) -methylene) aniline, replacing 3-nitro-4-hydroxybenzoic acid with 3-propionamido-4-methoxybenzoic acid, and finally dichloromethane: methanol: ammonia
  • a volume ratio of 20: 1: 0.1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 25.
  • Compound 25 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
  • step 1) in Example 25 replace 3-amino-4-methoxybenzoic acid with N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl)- Methylene) phenyl) -3-amino-4-methoxybenzamide, the final dichloromethane: methanol volume ratio is 20: 1 as the eluent, the concentrated liquid was separated and purified by silica gel column chromatography To give compound 26.
  • Compound 26 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) as follows:
  • Example 21 Using compound 21 in Example 21 as a raw material and referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 21, and finally the volume ratio of dichloromethane: methanol was 20 : 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 27.
  • Compound 27 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • Example 21 Using compound 21 in Example 21 as a raw material, referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 21, and propionyl chloride was replaced with 2-bromo-propionyl chloride, Finally, the dichloromethane: methanol volume ratio of 20: 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 28.
  • Compound 28 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) as follows:
  • Example 17 Using compound 17 in Example 17 as a raw material and referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 17, and finally the volume ratio of methylene chloride: methanol: ammonia water The concentrated solution was separated and purified by silica gel column chromatography using 20: 1: 0.1 as the eluent to obtain compound 29.
  • Compound 29 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • Example 23 Using compound 23 in Example 23 as the raw material and referring to the method in Example 24, the compound was replaced with compound 23, and finally the volume ratio of dichloromethane: methanol was 20: 1 as the eluent. The concentrated solution was subjected to silica gel column layer Separation and purification gave compound 30.
  • Compound 30 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • Example 18 Using compound 18 in Example 18 as a raw material and referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 18, and finally the volume ratio of methylene chloride to methanol was 20 : 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 31.
  • Compound 31 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
  • Example 20 Using compound 18 in Example 20 as a raw material, referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 20, and finally the volume ratio of methylene chloride: methanol was 10 : 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 32.
  • Compound 32 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
  • Huh7.5 cells were seeded into 96-well plates at a density of 3 ⁇ 10 4 cells / cm 2 , and after 24 hours of culture, the cells adhered, and the prepared HCV virus supernatant was used at 45IU The unit of / cell is infected with Huh7.5 cells, and the positive control drugs Simeprevir (Simeprevir) and Trapivir (VX950, Telaprevir) and the test compounds 1-32 are added to the control and experimental groups, respectively.
  • Simeprevir Simeprevir
  • Trapivir VX950, Telaprevir
  • RNeasy Mini Kit was used to extract intracellular RNA, and CytoBuster protein extract (Novagen) and 1 mM protein inhibitor were used to treat the total intracellular protein.
  • Real-time quantitative RT-PCR was used to detect the expression level of HCV-RNA.
  • EC50 is calculated by Reed & Muench method.
  • CC50 Huh7.5 cells were seeded into 96-well plates at a density of 3 ⁇ 10 4 cells / cm 2. After culturing for 24 hours, the cells adhered to the cells, added test samples of different concentrations, and used MTT Method cultured for 72 hours. The CC50 value is calculated using the Reed & Muench method.
  • Table 1 is the test data of anti-HCV activity of compound 1-32 and positive control.

Abstract

Provided in the present application are a substituted bis-aryl amide compound and a preparation method and an application therefor, the substituted bis-aryl amide compound or a pharmaceutically acceptable salt thereof having the structure of formula [1], R1 being independently selected from hydrogen or substituted or unsubstituted C1-12 linear alkyl, C3-12 branched alkyl, or C3-12 cycloalkyl, R2 being independently selected from -NO2, -NH2, -NHCOR5, -CF3, or -NHSO2NH2; R3 being independently selected from hydrogen, -CF3, -F, -CN, or -NH2; R4 being independently selected from hydrogen or substituted or unsubstituted heterocyclyl; and X being independently selected from hydrogen or nitrogen atoms. The substituted bis-aryl amide compound or pharmaceutically acceptable salt thereof provided in the present application have high anti-hepatitus C virus activity.

Description

一种取代的双芳香基酰胺化合物及其制备方法和应用Substituted bis-aromatic amide compound, and preparation method and application thereof
本申请要求于2018年11月15日提交中国专利局、申请号为201811361076.1、申请名称为“一种取代的双芳香基酰胺化合物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application requires the priority of the Chinese patent application submitted to the Chinese Patent Office on November 15, 2018, with the application number 201811361076.1 and the application name as "a substituted bisarylamide compound and its preparation method and application" The content is incorporated into this application by reference.
技术领域Technical field
本申请涉及一种化合物，尤其涉及一种取代的双芳香基酰胺化合物及其制备方法和应用。The present application relates to a compound, in particular to a substituted bis-aryl amide compound and its preparation method and application.
背景技术Background technique
丙型肝炎(丙肝)是由丙型肝炎病毒(Hepatitis C Virus，简称：HCV)引起的一种肝脏疾病。该病毒可造成急性或慢性肝炎，其严重程度从持续几周的轻微病症到终身严重疾病不等。急性丙肝病毒感染通常没有症状，且仅在十分罕见情况下才会导致危及生命的疾病，约有15％-45％的感染者不经任何治疗即可在感染6个月之内自行清除病毒，其余55％–85％的感染者会发生慢性丙肝病毒感染。在这些慢性丙肝病毒感染者中，20年内出现肝硬化的危险为15％–30％。截止2015年，全球统计约有7100万人受到丙肝感染。聚乙二醇干扰素ɑ和利巴韦林联合用药是目前传统的治疗丙肝感染的药物，但对于HCV-基因-1型感染的治愈率只有20-40％，同时伴随贫血，中性粒细胞减少，抑郁等副作用。特拉匹韦(Telaprevir,VX-950)和波普瑞韦(boceprevir)是近几年疗效较好的针对基因1型NS3/4A蛋白酶的抗HCV药物，但也出现了耐药的问题。因此，仍然需要进行具有新作用靶点和新化学实体的抗HCV药物的研究。Hepatitis C (Hepatitis C) is a liver disease caused by Hepatitis C virus (abbreviation: HCV). The virus can cause acute or chronic hepatitis, ranging in severity from a mild illness lasting a few weeks to a serious lifelong illness. Acute hepatitis C virus infection is usually asymptomatic and only causes life-threatening diseases in very rare cases. About 15% to 45% of infected people can clear the virus themselves within 6 months of infection without any treatment. The remaining 55% –85% of infected people will develop chronic hepatitis C virus infection. Among those with chronic hepatitis C virus infection, the risk of developing cirrhosis within 20 years is 15% –30%. As of 2015, approximately 71 million people worldwide have been infected with hepatitis C. The combination of peginterferon ɑ and ribavirin is currently the traditional drug for the treatment of hepatitis C infection, but the cure rate for HCV-genotype-1 infection is only 20-40%, accompanied by anemia and neutrophils Reduce side effects such as depression. Telaprevir (VX-950) and boceprevir (boceprevir) are good anti-HCV drugs against the genotype 1 NS3 / 4A protease in recent years, but the problem of drug resistance has also appeared. Therefore, research on anti-HCV drugs with new targets and new chemical entities is still needed.
APOBEC3G(hA3G)酶为载脂蛋白B信使RNA编辑酶催化多肽样蛋白家族的一员，具有抗逆转录酶病毒的作用，其编码产生的蛋白对VIF基因缺陷型HIV-1具有抑制作用。近年来发现感染HCV或HBV/HCV共感染患者较非感染者体内有较高的hA3G表达，并且IFN-α能够上调hA3G的表达量，推测hA3G能够参与宿主防御***，抵抗HCV的感染，随后研究证实hA3G是宿主细胞内拮抗HCV复制的限制性因子，提高细胞内hA3G的含量，或加入hA3G的稳定剂均可抑制HCV的感染，因此，hA3G介导的宿主抗病毒机制可以作为一个新策略去发现广谱的抗HCV或HCV/HIV-1共感染的药物。The APOBEC3G (hA3G) enzyme is a member of the apolipoprotein B messenger RNA editing enzyme catalyzing polypeptide-like protein family and has an anti-retroviral effect. The protein it encodes has an inhibitory effect on VIF gene-deficient HIV-1. In recent years, it has been found that patients infected with HCV or HBV / HCV co-infection have higher hA3G expression than non-infected patients, and IFN-α can up-regulate hA3G expression. It is speculated that hA3G can participate in the host defense system and resist HCV infection. It is confirmed that hA3G is a limiting factor for antagonizing HCV replication in the host cell, increasing the content of hA3G in the cell, or adding a stabilizer of hA3G can inhibit HCV infection. Therefore, the host antiviral mechanism mediated by hA3G can be used as a new strategy. A broad-spectrum anti-HCV or HCV / HIV-1 coinfection drug was found.
因此，研究一种针对新靶点hA3G的抗HCV的化合物，对治疗HCV具有十分重要的意义，能够为临床提供更加有效的新型抗HCV药物。Therefore, the study of an anti-HCV compound targeting the new target hA3G is very important for the treatment of HCV, and can provide more effective new anti-HCV drugs for the clinic.
发明内容Summary of the invention
本申请提供一种取代的双芳香基酰胺化合物或其药用可接受的盐，其具有抗丙肝病毒的活性。The present application provides a substituted bisarylamide compound or a pharmaceutically acceptable salt thereof, which has activity against hepatitis C virus.
本申请还提供一种上述取代的双芳香基酰胺化合物或其药用可接受的盐的制备 方法，合成路线简单，成本较低。The present application also provides a method for preparing the substituted bisarylamide compound or a pharmaceutically acceptable salt thereof. The synthetic route is simple and the cost is low.
本申请还提供一种上述取代的双芳香基酰胺化合物或其药用可接受的盐在制备抗丙肝药物中的应用，具有较强的抗丙肝活性。The present application also provides an application of the above substituted bisarylamide compound or a pharmaceutically acceptable salt thereof in the preparation of anti-hepatitis C drugs, which has strong anti-hepatitis C activity.
本申请还提供一种抗丙肝药物组合物，包含上述取代的双芳香基酰胺化合物或其药用可接受的盐作为活性成分。The present application also provides an anti-hepatitis C pharmaceutical composition comprising the above-mentioned substituted bisarylamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
本申请提供一种取代的双芳香基酰胺化合物或其药用可接受的盐，其具有式[1]的结构：This application provides a substituted bisarylamide compound or a pharmaceutically acceptable salt thereof, which has the structure of formula [1]:
Figure PCTCN2019118109-appb-000001
Figure PCTCN2019118109-appb-000001
其中，among them,
R 1独立地选自氢、取代或未取代的C 1－12直链烷基、C 3－12支链烷基或C 3－12环烷基； R 1 is independently selected from hydrogen, substituted or unsubstituted C 1-12 linear alkyl, C 3-12 branched alkyl or C 3-12 cycloalkyl;
R 2独立地选自-NO 2、-NH 2、-NHCOR 5、-CF 3、-NHSO 2NH 2； R 2 is independently selected from -NO 2 , -NH 2 , -NHCOR 5 , -CF 3 , -NHSO 2 NH 2 ;
R 3独立地选自氢、卤素、-CF 3、-F、-CN、-NO 2、-NH 2； R 3 is independently selected from hydrogen, halogen, -CF 3 , -F, -CN, -NO 2 , -NH 2 ;
R 4独立地选自氢、取代或未取代的杂环基； R 4 is independently selected from hydrogen, substituted or unsubstituted heterocyclyl;
R 5独立地选自取代或未取代的C 1－12直链烷基或C 3－12支链烷基； R 5 is independently selected from substituted or unsubstituted C 1-12 linear alkyl or C 3-12 branched alkyl;
X独立地选自氢原子或氮原子。X is independently selected from a hydrogen atom or a nitrogen atom.
其中，当R 1为取代的C 1－12直链烷基、C 3－12支链烷基或C 3－12环烷基时，取代基可以选自卤素原子或者二级胺(-NR cR d)。具体地，卤素原子可以为氟原子、氯原子、溴原子、碘原子；R c、R d可以独立的选自被卤素、羟基取代的或未被取代的低级烷基，其中，“低级烷基”为碳原子个数为1-6的直链烷基、支链烷基或环烷基。 Wherein, when R 1 is a substituted C 1-12 linear alkyl group, C 3-12 branched alkyl group or C 3-12 cycloalkyl group, the substituent may be selected from a halogen atom or a secondary amine (-NR c R d ). Specifically, the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; R c and R d may be independently selected from lower alkyl groups substituted or unsubstituted by halogen, hydroxy group, wherein, “lower alkyl group "Is a linear alkyl group, a branched alkyl group or a cycloalkyl group having 1 to 6 carbon atoms.
当R 3为卤素时，可以选自-F、-Cl、-Br、-I。 When R 3 is halogen, it may be selected from -F, -Cl, -Br, and -I.
当R 4为取代的杂环基时，取代基可以为被卤素、羟基取代或未被取代的低级烷基和低级烷氧基，其中，“低级烷氧基”为碳原子个数为1-6的烷氧基，例如甲氧基、乙氧基等；杂环基可以是成环原子个数为4-8个且成环原子包括杂原子的环烷基，其中，杂原子可以为氧、硫、氮原子。 When R 4 is a substituted heterocyclic group, the substituent may be a lower alkyl group or a lower alkoxy group substituted or unsubstituted by a halogen or a hydroxy group, wherein “lower alkoxy group” has 1 to 1 carbon atoms 6 alkoxy groups, such as methoxy, ethoxy, etc .; the heterocyclic group may be a cycloalkyl group having 4-8 ring atoms and the ring atoms include hetero atoms, wherein the hetero atom may be oxygen , Sulfur, nitrogen atoms.
当R 5为取代的C 1－12直链烷基或C 3－12支链烷基时，取代基可以独立选自卤素原子(-F、-Cl、-Br、-I)、二级胺基(-NR cR d，R c、R d同上)、磺酰胺基、杂环基(成环原子个数为4-8个且成环原子包括杂原子的环烷基)。 When R 5 is a substituted C 1-12 linear alkyl group or C 3-12 branched alkyl group, the substituent may be independently selected from a halogen atom (-F, -Cl, -Br, -I), a secondary amine Group (-NR c R d , R c and R d are the same as above), sulfonamide group, heterocyclic group (cycloalkyl group with 4-8 ring atoms and ring atoms including hetero atoms).
根据本申请提供的取代的双芳香基酰胺化合物或其药用可接受的盐，R 1独立地选自氢、取代或未取代的C 1－6直链烷基、C 3－6支链烷基或C 3－6环烷基。 According to the substituted bisarylamide compound provided herein or a pharmaceutically acceptable salt thereof, R 1 is independently selected from hydrogen, substituted or unsubstituted C 1-6 linear alkyl, C 3-6 branched alkane Group or C 3-6 cycloalkyl.
C 1－6直链烷基例如可列举甲基、乙基、丙基、烯丙基、正丁基、正戊基、正己基、正庚基等； Examples of C 1-6 linear alkyl groups include methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, and n-heptyl groups;
C 3－6支链烷基例如可列举异丙基、异丁基、仲丁基、叔丁基、异戊基、异己基等； Examples of C 3-6 branched alkyl groups include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and isohexyl;
C 3－6环烷基例如可列举环丙基、环丁基、环戊基、环己基等。 Examples of C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
根据本申请提供的双芳香基酰胺化合物或其药用可接受的盐的制备方法，或其药用可接受的盐，R 4独立地选自氢、或以下式[a]-式[e]所示的基团： According to the preparation method of the bisarylamide compound or the pharmaceutically acceptable salt thereof provided in the present application, or the pharmaceutically acceptable salt thereof, R 4 is independently selected from hydrogen or the following formula [a] -formula [e] Groups shown:
Figure PCTCN2019118109-appb-000002
Figure PCTCN2019118109-appb-000002
R a和R b独立地选自氢、C 1－6直链烷基或C 3－6支链烷基。 R a and R b are independently selected from hydrogen, C 1-6 linear alkyl or C 3-6 branched alkyl.
其中，“*”表示键结。Among them, "*" means bonding.
作为非限定性的示例，本申请提供的取代的双芳香基酰胺化合物可以例如编号为1-32的化合物：As a non-limiting example, the substituted bisarylamide compounds provided in this application may be, for example, compounds numbered 1-32:
1：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-羟基苯甲酰胺；1: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4-hydroxybenzamide;
2：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-甲氧基苯甲酰胺；2: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4-methoxybenzamide;
3：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-异丙氧基-苯甲酰胺；3: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4-isopropoxy-benzyl Amide
4：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(2-氟-乙氧基)-苯甲酰胺；4: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (2-fluoro-ethoxy Radical) -benzamide;
5：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(3-氟-丙氧基)-苯甲酰胺；5: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (3-fluoro-propoxy Radical) -benzamide;
6：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(2-氯-乙氧基)-苯甲酰胺；6: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (2-chloro-ethoxy Radical) -benzamide;
7：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺；7: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (3-chloro-propoxy Radical) -benzamide;
8：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(4-氯-丁氧基)-苯甲酰胺；8: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (4-chloro-butoxy Radical) -benzamide;
9：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(5-氯-戊氧基)-苯甲酰胺；9: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (5-chloro-pentyloxy Radical) -benzamide;
10：N-(3-三氟甲基-4-甲基苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺；10: N- (3-trifluoromethyl-4-methylphenyl) -3-nitro-4- (3-chloro-propoxy) -benzamide;
11：N-(3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺；11: N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) phenyl) -3-nitro-4 -(3-chloro-propoxy) -benzamide;
12：N-(3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺；12: N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) phenyl) -3-nitro -4- (3-chloro-propoxy) -benzamide;
13：N-(3-三氟甲基-4-((吗啉-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺；13: N- (3-trifluoromethyl-4-((morpholin-1-yl) -methylene) phenyl) -3-nitro-4- (3-chloro-propoxy) -benzene Formamide
14：N-(3-三氟甲基-4-((3,5-二甲基-吗啉-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺；14: N- (3-trifluoromethyl-4-((3,5-dimethyl-morpholin-1-yl) -methylene) phenyl) -3-nitro-4- (3- Chloro-propoxy) -benzamide;
15：N-(2-(N-甲基哌嗪-1-基-亚甲基)吡啶-5-基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺；15: N- (2- (N-methylpiperazin-1-yl-methylene) pyridin-5-yl) -3-nitro-4- (3-chloro-propoxy) -benzamide ;
16：N-(3-三氟甲基-4-甲基苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺；16: N- (3-trifluoromethyl-4-methylphenyl) -3-amino-4- (3-chloro-propoxy) -benzamide;
17：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺；17: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-amino-4- (3-chloro-propoxy Radical) -benzamide;
18：N-(3-三氟甲基-4-((3-N，N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺；18: N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) phenyl) -3-amino -4- (3-chloro-propoxy) -benzamide;
19：N-(3-三氟甲基-4-((3,5-二甲基-吗啉-1-基)-亚甲基)苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺；19: N- (3-trifluoromethyl-4-((3,5-dimethyl-morpholin-1-yl) -methylene) phenyl) -3-amino-4- (3- Chloro-propoxy) -benzamide;
20：N-(2-(N-甲基哌嗪-1-基-亚甲基)吡啶-5-基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺；20: N- (2- (N-methylpiperazin-1-yl-methylene) pyridin-5-yl) -3-amino-4- (3-chloro-propoxy) -benzamide ;
21：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-异丙氧基-苯甲酰胺；21: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-amino-4-isopropoxy-benzyl Amide
22：N-(3-三氟甲基-4-甲基苯基)-3-胺基-4-丙氧基-苯甲酰胺；22: N- (3-trifluoromethyl-4-methylphenyl) -3-amino-4-propoxy-benzamide;
23：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-(5-氯-戊氧基)-苯甲酰胺；23: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-amino-4- (5-chloro-pentyloxy Radical) -benzamide;
24：N-(3-三氟甲基-4-甲基苯基)-3-丙酰胺基-4-丙氧基-苯甲酰胺；24: N- (3-trifluoromethyl-4-methylphenyl) -3-propionamido-4-propoxy-benzamide;
25：N-(4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-甲氧基苯甲酰胺；25: N- (4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4-methoxybenzamide;
26：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-甲氧基苯甲酰胺；26: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4-methoxybenzamide ;
27：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-异丙氧基苯甲酰胺；27: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4-isopropoxybenzyl Amide
28：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-(2-溴-丙酰胺基)-4-异丙氧基苯甲酰胺；28: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3- (2-bromo-propionamido) -4- Isopropoxybenzamide;
29：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-(3-氯-丙氧基)苯甲酰胺；29: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4- (3-chloro-propane Oxy) benzamide;
30：N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-(5-氯-戊氧基)-苯甲酰胺；30: N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4- (5-chloro-pentane Oxy) -benzamide;
31：N-(3-三氟甲基-4-((3-N，N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯基)-3-丙酰胺基-4-(3-氯-丙氧基)-苯甲酰胺；31: N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) phenyl) -3-propanamide Yl-4- (3-chloro-propoxy) -benzamide;
32：N-(2-(N-甲基哌嗪-1-基-亚甲基)吡啶-5-基)-3-丙酰胺基-4-(3-氯-丙氧基)-苯甲酰胺。32: N- (2- (N-methylpiperazin-1-yl-methylene) pyridin-5-yl) -3-propionamido-4- (3-chloro-propoxy) -benzoyl Amide.
本申请提供的具有式[1]结构的双芳香基酰胺化合物药用可接受的盐，为该双芳香基酰胺化合物与酸发生成盐反应的产物。所述酸可以为制药领域常规的酸，可以是无机酸，例如盐酸、磷酸、氢溴酸或硫酸等；或者为有机酸，例如草酸、马来酸、乳酸、琥珀酸、甲磺酸、对苯甲酸、富马酸、苹果酸、酒石酸、苯甲酸或柠檬酸等。The pharmaceutically acceptable salt of the bisarylamide compound having the structure of formula [1] provided by the present application is a product of a salt-forming reaction between the bisarylamide compound and an acid. The acid may be a conventional acid in the pharmaceutical field, and may be an inorganic acid such as hydrochloric acid, phosphoric acid, hydrobromic acid, or sulfuric acid; or an organic acid such as oxalic acid, maleic acid, lactic acid, succinic acid, methanesulfonic acid, or Benzoic acid, fumaric acid, malic acid, tartaric acid, benzoic acid or citric acid.
本申请还提供一种上述取代的双芳香基酰胺化合物或其药用可接受的盐的制备方法，包括以下步骤：The present application also provides a method for preparing the substituted bisarylamide compound or a pharmaceutically acceptable salt thereof, including the following steps:
式[2]所示的化合物和式[3]所示的化合物在缩合剂的存在下发生缩合反应，生成式[1a]所示的化合物；The compound represented by formula [2] and the compound represented by formula [3] undergo a condensation reaction in the presence of a condensing agent to produce a compound represented by formula [1a];
Figure PCTCN2019118109-appb-000003
Figure PCTCN2019118109-appb-000003
其中，Rc独立的选自-NO 2、-CF 3。 Among them, Rc is independently selected from -NO 2 and -CF 3 .
具体合成过程可以描述如下：The specific synthesis process can be described as follows:
Figure PCTCN2019118109-appb-000004
Figure PCTCN2019118109-appb-000004
该反应过程在一个适当的缩合体系中完成，可以采用常规的缩合剂及相应的条件控制，得到预期产物。The reaction process is completed in an appropriate condensation system, which can be controlled using conventional condensation agents and corresponding conditions to obtain the desired product.
本申请的实施中，上述合成路线过程a具体为：将式[2]所示的化合物和式[3]所示的化合物作为反应物加入二氯甲烷的溶剂中，零度下，依次向反应物中加入酰胺偶联剂，例如4-二甲氨基吡啶(DMAP)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，搅拌反应30min后，再升至室温反应5-12h，直至通过TLC检测式[3]所示的化合物消失。反应液用乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，浓缩物利用快速柱层析纯化，得到式[1a]所示的化合物。其中，式[2]所示的化合物、式[3]所示的化合物、DMAP和EDCI的摩尔比为1.1:1.0:0.2:2.0。上述合成路线中所用酰胺偶联试剂还可以为HOBt/EDCI/DIPEA,或HATU/DIPEA等。In the implementation of the present application, the above synthetic route process a specifically includes: adding the compound represented by formula [2] and the compound represented by formula [3] as reactants to a solvent of dichloromethane, and at zero degrees, sequentially to the reactants Add amide coupling agent, such as 4-dimethylaminopyridine (DMAP) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), after stirring for 30min, After warming to room temperature for 5-12 h, the compound represented by formula [3] disappeared by TLC detection. After the reaction solution was diluted with ethyl acetate, it was washed sequentially with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash column chromatography to obtain the compound represented by formula [1a]. Among them, the molar ratio of the compound represented by the formula [2], the compound represented by the formula [3], DMAP and EDCI is 1.1: 1.0: 0.2: 2.0. The amide coupling reagent used in the above synthetic route may also be HOBt / EDCI / DIPEA, HATU / DIPEA, or the like.
除了上述方法外，还可以通过下述步骤制备式[1a]所示的化合物，具体合成路线为：In addition to the above method, the compound represented by formula [1a] can also be prepared by the following steps, the specific synthetic route is:
Figure PCTCN2019118109-appb-000005
Figure PCTCN2019118109-appb-000005
其中，过程a与前述相同。式[2a]所示的化合物可以通过式[2a]的羧酸酯(市售获得) 水解得到。Among them, the process a is the same as described above. The compound represented by formula [2a] can be obtained by hydrolyzing the carboxylic acid ester of formula [2a] (commercially available).
本申请实施例中，过程e具体为：将式[1e]所示的化合物溶于无水DMF中，加入被取代或未被取代的卤代烷烃后，例如溴代烷烃，依次加入碘化钠、无水碳酸钾或无水碳酸钠，通过油浴将反应液加热至60℃并搅拌反应3-15h，直至TLC监测式[1e]所示的化合物消失。反应液用一定量的乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，得到式[1a]所示的化合物。其中，式[1e]所示的化合物、卤代烷、碘化钠和无水碳酸钾或无水碳酸钠的摩尔比为1.0:(1.5-2.0):1.0:(1.5-2.0)。In the embodiment of the present application, the process e is specifically: dissolving the compound represented by formula [1e] in anhydrous DMF, adding substituted or unsubstituted haloalkanes, such as brominated alkanes, and sequentially adding sodium iodide, Anhydrous potassium carbonate or anhydrous sodium carbonate, the reaction solution was heated to 60 ° C through an oil bath and the reaction was stirred for 3-15 h until the compound represented by formula [1e] disappeared by TLC monitoring. After the reaction solution was diluted with a certain amount of ethyl acetate, it was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound represented by formula [1a]. Wherein, the molar ratio of the compound represented by formula [1e], haloalkane, sodium iodide, and anhydrous potassium carbonate or anhydrous sodium carbonate is 1.0: (1.5-2.0): 1.0: (1.5-2.0).
能够理解的是，当欲制备R 1为-OH的具有式[1]结构的化合物时，上述制备过程则无需进行过程e。 It can be understood that when the compound having the structure of formula [1] wherein R 1 is -OH is to be prepared, the above-mentioned preparation process does not need to perform process e.
通过上述制备方法得到的式[1a]所示的化合物，即为R 2为-NO 2、-CF 3的具有式[1]结构的双芳香基酰胺化合物。 The compound represented by formula [1a] obtained by the above production method is a bisarylamide compound having the structure of formula [1] in which R 2 is -NO 2 and -CF 3 .
当需要制备R 2为-NH 2的具有式[1]结构的双芳香基酰胺化合物，在上述制备方法的基础上，还可以通过对式[1a]所示的化合物进行还原，将Rc所示的-NO 2还原为-NH 2，从而得到[1b]所示的化合物，即R 2为-NH 2的具有式[1]结构的双芳香基酰胺化合物。 When it is necessary to prepare a bisarylamide compound having the structure [1] where R 2 is -NH 2 , on the basis of the above preparation method, the compound represented by the formula [1a] can also be reduced to represent Rc -NO 2 is reduced to -NH 2 to obtain a compound represented by [1b], that is, a bisarylamide compound having the structure of formula [1] where R 2 is -NH 2 .
具体地，该合成过程可描述如下：Specifically, the synthesis process can be described as follows:
Figure PCTCN2019118109-appb-000006
Figure PCTCN2019118109-appb-000006
该反应过程在一个适当的还原体系中完成，可以采用常规的还原剂及相应的条件控制，得到预期产物。The reaction process is completed in an appropriate reduction system, which can be controlled using conventional reducing agents and corresponding conditions to obtain the desired product.
本申请的实施例中，上述合成路线过程b具体为：将式[1a]所示的化合物置于反应釜中，例如氢化反应瓶中，溶于甲醇和四氢呋喃的混合溶液中，加入Pd/C(负载量为5％)，在40Psi或1atm的压力下反应2-3h，利用硅藻土过滤反应液，浓缩滤液得到式[1]b所示的化合物。In the embodiment of the present application, the above synthetic route process b specifically includes: placing the compound represented by formula [1a] in a reaction kettle, such as a hydrogenation reaction flask, dissolved in a mixed solution of methanol and tetrahydrofuran, and adding Pd / C (The loading amount is 5%), the reaction is carried out under a pressure of 40 Psi or 1 atm for 2-3 hours, the reaction solution is filtered through celite, and the filtrate is concentrated to obtain the compound represented by formula [1] b.
或者，过程b还可以具体为：将式[1a]所示的化合物溶于四氢呋喃中，加入活化的锌粉，在零度左右逐滴加入乙酸，直至利用TLC监测到式[1a]所示的化合物消失。过滤反应液，滤液用一定量的乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，得到式[1]b所示的化合物。其中，式[1a]所示的化合物、锌粉和乙酸的摩尔比为1.0:10:(1.5-3)。Alternatively, process b may also be specifically: dissolving the compound represented by formula [1a] in tetrahydrofuran, adding activated zinc powder, and adding acetic acid dropwise at around zero degrees until the compound represented by formula [1a] is monitored by TLC disappear. The reaction solution was filtered, and the filtrate was diluted with a certain amount of ethyl acetate, washed sequentially with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound represented by formula [1] b. Among them, the molar ratio of the compound represented by formula [1a], zinc powder and acetic acid is 1.0: 10: (1.5-3).
通过上述制备方法得到的式[1b]所示的化合物，即为R 2为-NH 2的具有式[1]结构的双芳香基酰胺化合物。 The compound represented by the formula [1b] obtained by the above production method is a bisarylamide compound having the structure of the formula [1] in which R 2 is -NH 2 .
以式[1b]所示的化合物为原料还可以进一步制备当R 2为-NHCOR 5、-NHSO 2NH 2的化合物，以下进行具体说明。 Using the compound represented by formula [1b] as a raw material, a compound in which R 2 is -NHCOR 5 or -NHSO 2 NH 2 can be further prepared, which will be described in detail below.
当需要制备R 2为-NHCOR 5的具有式[1]结构的化合物，在上述制备方法的基础上，还可以通过对式[1b]所示的化合物进行酰胺化反应来实现，即式[1c]所示的化合物。 When it is necessary to prepare a compound having the structure of formula [1] where R 2 is -NHCOR 5 , on the basis of the above preparation method, it can also be achieved by amidation reaction of the compound represented by formula [1b], that is, formula [1c ] The compound shown.
具体地，该合成过程可描述如下：Specifically, the synthesis process can be described as follows:
Figure PCTCN2019118109-appb-000007
Figure PCTCN2019118109-appb-000007
该反应过程在一个适当的酰胺化体系中完成，可以采用常规的催化剂及相应的条件控制，得到预期产物。The reaction process is completed in an appropriate amidation system, which can be controlled using conventional catalysts and corresponding conditions to obtain the desired product.
本申请实施中，上述合成路线过程c具体为：控制反应温度零度以下(-10℃-0℃)，将R 5COCl所示的酰氯加入到式[1b]所示的化合物的二氯甲烷或DMF溶液中，在碱性条件下，例如三乙胺或吡啶的催化下，搅拌反应30min后，将反应液升至室温继续搅拌反应，直至TLC监测式[1b]所示的化合物消失。反应液用一定量的乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，得到式[1]c所示的化合物。其中，式[1b]所示的化合物、酰氯和三乙胺或吡啶的摩尔比为1.0:1.1:(1.5-2.0)。 In the practice of the present application, the above synthetic route process c specifically includes: controlling the reaction temperature below zero (-10 ° C to 0 ° C), adding the acid chloride represented by R 5 COCl to methylene chloride or the compound represented by formula [1b] In the DMF solution, under basic conditions, such as triethylamine or pyridine catalysis, after stirring the reaction for 30 min, the reaction solution was raised to room temperature to continue stirring the reaction until the compound represented by formula [1b] disappeared by TLC monitoring. After the reaction solution was diluted with a certain amount of ethyl acetate, it was sequentially washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound represented by formula [1] c. Wherein, the molar ratio of the compound represented by formula [1b], acid chloride and triethylamine or pyridine is 1.0: 1.1: (1.5-2.0).
当需要制备R 2为-NHSO 2NH 2的具有式[1]结构的化合物，还可以通过对式[1b]所示的化合物进行磺酰胺化反应，从而得到R 2为-NHSO 2NH 2的具有式[1]结构的双芳香基酰胺化合物，即式[1d]所示的化合物。 When it is necessary to prepare a compound having the structure of formula [1] where R 2 is -NHSO 2 NH 2 , the compound represented by formula [1b] can also be subjected to a sulfonamide reaction to obtain a compound wherein R 2 is -NHSO 2 NH 2 The bisarylamide compound having the structure of formula [1], that is, the compound represented by formula [1d].
具体地，该合成过程可描述如下：Specifically, the synthesis process can be described as follows:
Figure PCTCN2019118109-appb-000008
Figure PCTCN2019118109-appb-000008
该反应过程在一个适当的磺酰胺化体系中完成，可以采用常规的催化剂剂及相应的条件控制，得到预期产物。The reaction process is completed in an appropriate sulfamidation system, which can be controlled using conventional catalysts and corresponding conditions to obtain the desired product.
本申请实施中，上述合成路线过程d具体为：控制反应温度零度以下，将H 2NSO 2Cl加入到式[1b]所示的化合物的二氯甲烷或DMF溶液中，在碱性条件下，例如三乙胺或吡啶的催化下，搅拌反应30min后，将反应液升至室温继续搅拌反应，直至TLC监测式[1b]所示的化合物消失。反应液用一定量的乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，得到式[1d]所示的化合物。其中，式[1b]所示的化合物、氨基磺酰氯和三乙胺或吡啶的摩尔比为1.2:1.1:(1.5-2.0)。 In the implementation of this application, the above-mentioned synthetic route process d is specifically: controlling the reaction temperature below zero, adding H 2 NSO 2 Cl to the methylene chloride or DMF solution of the compound represented by formula [1b], under alkaline conditions, For example, under the catalysis of triethylamine or pyridine, after stirring the reaction for 30 min, the reaction solution was raised to room temperature to continue stirring the reaction until the compound represented by formula [1b] disappeared by TLC monitoring. After the reaction solution was diluted with a certain amount of ethyl acetate, it was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound represented by formula [1d]. Among them, the molar ratio of the compound represented by the formula [1b], sulfamoyl chloride and triethylamine or pyridine is 1.2: 1.1: (1.5-2.0).
根据设计需要，在上述方法基础上进一步经成盐反应即得到相应的药用可接受盐。例如，将式[1]所示的化合物溶于干燥的二氯甲烷或乙酸乙酯中，零度以下，加入二个等当 量的二氯甲烷/HCl或乙酸乙酯/HCl溶液，浓缩溶剂析晶，得到相应的盐酸盐。According to the design requirements, on the basis of the above method, the corresponding pharmaceutically acceptable salt can be obtained by further salt formation reaction. For example, dissolve the compound represented by formula [1] in dry methylene chloride or ethyl acetate, below zero, add two equivalents of methylene chloride / HCl or ethyl acetate / HCl solution, and concentrate the solvent to crystallize To obtain the corresponding hydrochloride salt.
本发明人经过研究和实验，设计合成了一系列含双芳香酰胺化合物，并且惊奇的发现，该类化合物可以稳定细胞内的hA3G，同时具有显著的抗HCV的生理活性，如编号为6、7，9，11，12，15，30的化合物，其抗HCV的EC50值均小于0.1μmol,化合物6和12的抗HCV病毒活性与临床用药西咪匹韦和/或特拉匹韦(VEX950)相当。After research and experiment, the inventor designed and synthesized a series of bis-aromatic amide-containing compounds, and was surprised to find that these compounds can stabilize hA3G in cells and have significant anti-HCV physiological activities, such as number 6, 7 , The compounds of 9,11,12,15,30, the EC50 value of anti-HCV are less than 0.1μmol, the anti-HCV activity of compounds 6 and 12 and the clinical use of cimipirvir and / or tramavir (VEX950) quite.
进一步地，当R 4选自式[a]-式[e]所示的基团时，式[3]所示的化合物可以按照如下方法制备： Further, when R 4 is selected from the groups represented by formula [a] -formula [e], the compound represented by formula [3] can be prepared as follows:
式[4]所示的化合物发生卤代反应，生成式[5]所示的化合物；The compound represented by formula [4] undergoes a halogenation reaction to produce the compound represented by formula [5];
式[5]所示的化合物与R 4H发生取代反应，生成式[6]所示的化合物； The compound represented by formula [5] undergoes substitution reaction with R 4 H to produce the compound represented by formula [6];
式[6]所示的化合物经加氢还原，生成式[3]所示的化合物；The compound represented by formula [6] is reduced by hydrogenation to produce the compound represented by formula [3];
Figure PCTCN2019118109-appb-000009
Figure PCTCN2019118109-appb-000009
其中，X 1为卤素原子。 Among them, X 1 is a halogen atom.
具体合成过程可以描述如下：The specific synthesis process can be described as follows:
Figure PCTCN2019118109-appb-000010
Figure PCTCN2019118109-appb-000010
该反应过程在一个适当的体系中完成，可以采用相应的条件控制，得到预期产物。The reaction process is completed in an appropriate system, which can be controlled with corresponding conditions to obtain the desired product.
本申请实施中，上述合成路线过程f具体为：将式[4]所示的化合物加入四氯化碳溶液中，控制式[4]所示的化合物的浓度为2M，分别加入N-溴代丁二酰亚胺(NBS)和偶氮二异丁腈(AIBN)，回流过夜直至TLC监测式[4]所示的化合物消失。反应液减压除去溶剂，加入乙酸乙酯和饱和碳酸氢钠溶液萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱层析分离纯化，得到式[5]所示的化合物。其中，式[4]所示的化合物、NBS、AIBN的摩尔比为1.0:1.2:0.5。In the implementation of this application, the above synthetic route process f specifically includes: adding the compound represented by formula [4] to the carbon tetrachloride solution, controlling the concentration of the compound represented by formula [4] to 2M, and adding N-brominated Succinimide (NBS) and azobisisobutyronitrile (AIBN) were refluxed overnight until the compound represented by formula [4] disappeared by TLC monitoring. The solvent of the reaction solution was removed under reduced pressure, ethyl acetate and saturated sodium bicarbonate solution were added for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the formula [5]. The compound shown. However, the molar ratio of the compound represented by formula [4], NBS, and AIBN is 1.0: 1.2: 0.5.
过程g具体为：将经由过程f得到的式[5]所示的化合物溶于DMF中，控制反应液浓度为2.5M，加入碳酸钾和二级胺R 4H，在50℃搅拌反应3-5h，直至通过TLC监测式[5]所示的化合物消失。反应液减压浓缩后，通过硅胶柱层析分离纯化得到式[6]所示的化合物。其中，式[5]所示的化合物、碳酸钾、二级胺的摩尔比为1.0:1.5:0.2。 Process g is specifically: dissolving the compound represented by formula [5] obtained through process f in DMF, controlling the concentration of the reaction solution to 2.5M, adding potassium carbonate and a secondary amine R 4 H, and stirring the reaction at 50 ° C. 3- 5h until the disappearance of the compound represented by formula [5] was monitored by TLC. After the reaction solution was concentrated under reduced pressure, it was separated and purified by silica gel column chromatography to obtain the compound represented by formula [6]. Among them, the molar ratio of the compound represented by the formula [5], potassium carbonate, and secondary amine is 1.0: 1.5: 0.2.
过程h具体可以参照过程b进行，只需将过程b中的反应物相应替换为式[6]所示的化合物即可。Process h can be specifically referred to process b, as long as the reactants in process b are replaced with compounds represented by formula [6].
此外，通过上述制备方法可以想到，当欲制备R 4为-H的具有式[3]所示的化合物时，可以以式[4]所示的化合物为原料直接通过过程h进行还原即可。 In addition, it is conceivable from the above-mentioned preparation method that when R 4 is -H and the compound represented by formula [3] is to be prepared, the compound represented by formula [4] can be directly reduced through process h.
进一步地，式[2]所示的化合物按照如下方法制备：Further, the compound represented by formula [2] is prepared according to the following method:
式[7]所示的化合物发生取代反应，生成式[8]所示的化合物；The compound represented by formula [7] undergoes a substitution reaction to produce the compound represented by formula [8];
式[8]所示的化合物发生水解反应生成式[2]所示的化合物；The compound represented by formula [8] undergoes a hydrolysis reaction to form the compound represented by formula [2];
Figure PCTCN2019118109-appb-000011
Figure PCTCN2019118109-appb-000011
具体合成过程可以描述如下：The specific synthesis process can be described as follows:
上述合成路线中，过程i具体可以参照过程e进行，只需将过程e中式[1e]所示的化合物应替换为式[7]所示的化合物即可。其中，式[7]所示的化合物可以通过市售获得。In the above synthetic route, process i can be specifically referred to process e, and only the compound represented by formula [1e] in process e should be replaced with the compound represented by formula [7]. Among them, the compound represented by formula [7] is commercially available.
反应过程j在一个适当的水解体系中完成(例如酸性水解或碱性水解)，可以采用常规相应条件控制，得到预期产物。The reaction process j is completed in an appropriate hydrolysis system (for example, acidic hydrolysis or basic hydrolysis), which can be controlled by conventional corresponding conditions to obtain the desired product.
本申请实施中，上述合成路线过程j具体为：将式[8]所示的化合物溶于四氢呋喃的水溶液中(四氢呋喃与水的体积比为1:1)，控制式[8]所示的化合物的浓度为0.3M，零度左右加入氢氧化锂并搅拌反应，直至TLC监测式[8]所示的化合物消失。用盐酸将反应液的pH调至7后，加入乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液浓缩后得到式[2]所示的化合物。其中，式[8]所示的化合物和氢氧化锂的摩尔比为1.0:1.5。In the implementation of the present application, the above synthetic route process j is specifically: dissolving the compound represented by formula [8] in an aqueous solution of tetrahydrofuran (the volume ratio of tetrahydrofuran to water is 1: 1), and controlling the compound represented by formula [8] The concentration is 0.3M, lithium hydroxide is added around zero and the reaction is stirred until the compound shown by TLC monitoring formula [8] disappears. After the pH of the reaction solution was adjusted to 7 with hydrochloric acid, ethyl acetate was added for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the compound represented by formula [2]. However, the molar ratio of the compound represented by formula [8] and lithium hydroxide is 1.0: 1.5.
通过上述式[2]所示的化合物的制备方法可以发现，当欲制备R 1为H的式[2]所示的化合物时，可以以式[7]所示的化合物为原料，通过过程j直接反应。 Through the preparation method of the compound represented by the above formula [2], it can be found that when the compound represented by the formula [2] wherein R 1 is H is to be prepared, the compound represented by the formula [7] can be used as a raw material through the process j Direct response.
本申请还提供一种上述任一所述的取代的双芳香基酰胺化合物或其药用可接受的盐在制备抗丙肝药物中的应用。The present application also provides the use of any of the above-mentioned substituted bisarylamide compounds or pharmaceutically acceptable salts thereof in the preparation of anti-hepatitis C drugs.
本申请还提供一种抗丙肝药物组合物，包括作为抗丙肝有效成分的上述任一所述的取代的双芳香基酰胺化合物或其药用可接受的盐，还包括药剂学上可接受的药物辅料。The present application also provides an anti-hepatitis C pharmaceutical composition, which includes as an effective anti-hepatitis C component any of the above-mentioned substituted bisarylamide compounds or pharmaceutically acceptable salts thereof, and also includes pharmaceutically acceptable drugs Accessories.
可将上述取代的双芳香基酰胺化合物或其药用可接受的盐本身或其与可药用赋形剂、稀释剂等的混合物制成片剂、胶囊、颗粒剂、散剂或糖浆剂的形式。上述制剂可通过常规制药方法制备。The above substituted bisarylamide compound or its pharmaceutically acceptable salt itself or a mixture with pharmaceutically acceptable excipients, diluents, etc. can be made into the form of tablets, capsules, granules, powders or syrups . The above formulations can be prepared by conventional pharmaceutical methods.
药物辅料可使用在常规制药方法中的物质。可用的药物辅料的例子包括赋形剂(例如糖类衍生物诸如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物诸如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠；***胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝；磷酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)、稀释剂和注射液用溶剂(例如水。乙醇和甘油等)。Pharmaceutical excipients can be used in conventional pharmaceutical methods. Examples of useful pharmaceutical excipients include excipients (for example, sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; cellulose Derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium aluminum silicate; Phosphate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (such as gelatin, polyvinylpyrrolidone, and polyethylene glycol), disintegrating agents (such as cellulose derivatives such as carboxymethyl cellulose Sodium, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl paraben, paraben) Propyl ester, etc.), flavoring agents (such as commonly used sweeteners, sour agents and flavors, etc.), diluents and solvents for injections (such as water, ethanol, glycerin, etc.).
本申请的所述抗丙肝药物组合物中的取代的双芳香基酰胺化合物为单位制剂。所述单位制剂为满足一次给药所需有效成分的制剂，如一单位(针)针剂等。患者一次施用所需的药物的量可以方便地通过计算患者的体重和该患者一次用药所需单位体 重剂量的乘积得到。例如，在制备药物的过程中，一般认为成人体重为50-70kg，可以通过实验动物与人的单位体重剂量之间的等效剂量换算关系来确定用药量。例如，可以根据FDA、SFDA等药品管理机构提出的指导意见，也可参考(黄继汉等，“药理试验中动物间和动物与人体间的等效剂量换算”，《中国临床药理学与治疗学》,2004 Sep；9(9):1069-1072)来确定。在本申请的实施方式中，可以使用按照人和小鼠的体表面积折算系数0.0026来换算人和小鼠的剂量。The substituted bisarylamide compound in the anti-hepatitis C pharmaceutical composition of the present application is a unit preparation. The unit preparation is a preparation that satisfies the active ingredients required for one-time administration, such as a unit (needle) injection. The amount of medicine required for a patient to administer at one time can be conveniently obtained by calculating the product of the patient's body weight and the unit body weight dose required for the patient's one-time administration. For example, in the process of preparing medicines, it is generally considered that the adult body weight is 50-70 kg, and the dosage can be determined by the equivalent dose conversion relationship between the unit weight doses of laboratory animals and humans. For example, it can be based on the guidance provided by FDA, SFDA and other drug regulatory agencies, and can also be referred to (Huang Jihan et al., "Equivalent dose conversion between animals and animals and humans in pharmacological trials", "Chinese Journal of Clinical Pharmacology and Therapeutics" , 2004 Sep; 9 (9): 1069-1072) to determine. In the embodiment of the present application, the human and mouse doses can be converted using a conversion factor of 0.0026 according to the body surface area of humans and mice.
本申请提供的抗丙肝药物组合物的给药方式例如为：静脉、腹腔内注射，或者灌胃、口服等。The administration method of the anti-hepatitis C pharmaceutical composition provided by the present application is, for example, intravenous injection, intraperitoneal injection, or intragastric administration or oral administration.
本申请还提供了治疗丙型肝炎的方法，即，按照临床有效剂量给患者施用上述抗丙肝药物组合物。The present application also provides a method for treating hepatitis C, that is, administering the above anti-hepatitis C pharmaceutical composition to a patient according to a clinically effective dose.
本申请方案的实施，至少具有以下优势：The implementation of this application plan has at least the following advantages:
1、本申请提供的取代的双芳香基酰胺化合物或其药用可接受的盐，具有良好抗病毒功效，尤其具有强的抗丙肝病毒的活性，为开发新型抗丙肝药物提供了可能；1. The substituted bisarylamide compound or its pharmaceutically acceptable salt provided in this application has good antiviral efficacy, especially strong anti-hepatitis C virus activity, which provides the possibility of developing new anti-hepatitis C drugs;
2、本申请提供的取代的双芳香基酰胺化合物或其药用可接受的盐的制备方法，合成路线简单，成本较低，利于工业化实施。2. The preparation method of the substituted bisarylamide compound or its pharmaceutically acceptable salt provided in this application has a simple synthetic route and low cost, which is beneficial to industrial implementation.
具体实施方式detailed description
为使本申请的目的、技术方案和优点更加清楚，下面将结合本申请的实施例，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。In order to make the purpose, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely in conjunction with the embodiments of the present application. Obviously, the described embodiments are part of the implementation of the present application Example, not all examples. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application.
实施例1Example 1
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-羟基苯甲酰胺(1)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4-hydroxybenzamide (1)
Figure PCTCN2019118109-appb-000012
Figure PCTCN2019118109-appb-000012
1)3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺的制备1) Preparation of 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline
将3-三氟甲基-4-甲基硝基苯(1.0eq，市售获得)加入四氯化碳溶液中，并控制3-三氟甲基-4-甲基硝基苯在其四氯化碳的溶液中的浓度为2.0M，分别向上述溶液中加入NBS(1.20eq)和AIBN(0.5eq)后，加热回流并搅拌反应过夜，当通过TLC监测3-三氟甲基-3-甲基硝基苯消失后停止反应。将反应液减压浓缩，加入乙酸乙酯和饱和碳酸氢钠溶液萃取2-4次，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩，以石油醚/乙酸乙酯(20:1-15:1)作为洗脱液利用硅胶柱层析分离纯化，得到3-三氟甲基-4-溴甲基-硝基苯。Add 3-trifluoromethyl-4-methylnitrobenzene (1.0eq, commercially available) to the carbon tetrachloride solution, and control 3-trifluoromethyl-4-methylnitrobenzene in its four The concentration of the carbon chloride solution is 2.0M. After adding NBS (1.20eq) and AIBN (0.5eq) to the above solution, heat to reflux and stir the reaction overnight. When monitoring 3-trifluoromethyl-3 by TLC -Stop the reaction after methyl nitrobenzene disappears. The reaction solution was concentrated under reduced pressure, ethyl acetate and saturated sodium bicarbonate solution were added for extraction 2-4 times, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with petroleum ether / ethyl acetate (20: 1-15: 1) As an eluent, it is separated and purified by silica gel column chromatography to obtain 3-trifluoromethyl-4-bromomethyl-nitrobenzene.
将3-三氟甲基-4-溴甲基-硝基苯溶于DMF溶液中，控制3-三氟甲基-4-溴甲基-硝 基苯在DMF溶液中的浓度为2.5M，再加入碳酸钾(1.5eq)和4-甲基哌嗪(1.2eq)，在50℃加热反应3-5h，直至TLC监测到3-三氟甲基-4-溴甲基-硝基苯消失后停止反应。将反应液减压浓缩，以二氯甲烷/甲醇(15:1)作为洗脱液利用硅胶柱层析分离纯化，得到3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)硝基苯。Dissolve 3-trifluoromethyl-4-bromomethyl-nitrobenzene in DMF solution and control the concentration of 3-trifluoromethyl-4-bromomethyl-nitrobenzene in DMF solution to 2.5M. Potassium carbonate (1.5eq) and 4-methylpiperazine (1.2eq) were added, and the reaction was heated at 50 ° C for 3-5h until TLC detected the disappearance of 3-trifluoromethyl-4-bromomethyl-nitrobenzene Then stop the reaction. The reaction solution was concentrated under reduced pressure, and separated and purified by silica gel column chromatography using dichloromethane / methanol (15: 1) as an eluent to obtain 3-trifluoromethyl-4-((4-methylpiperazine-1 -Yl) -methylene) nitrobenzene.
将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)硝基苯(1.0eq)置于氢化反应瓶中并溶于甲醇和四氢呋喃的混合溶液，加入Pd/C(5％)，在40Psi或1atm下反应2-3h，利用硅藻土过滤反应液，浓缩滤液得到3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺。Place 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) nitrobenzene (1.0 eq) in a hydrogenation reaction flask and dissolve in a mixed solution of methanol and tetrahydrofuran , Add Pd / C (5%), react at 40Psi or 1atm for 2-3h, filter the reaction solution using celite, and concentrate the filtrate to obtain 3-trifluoromethyl-4-((4-methylpiperazine-1 -Yl) -methylene) aniline.
2)3-硝基-4-羟基苯甲酸的制备2) Preparation of 3-nitro-4-hydroxybenzoic acid
将3-硝基-4-羟基苯甲酸酯(1.0eq，市售获得)溶于四氢呋喃和水的混合液中(四氢呋喃与水的体积比为1:1)，并控制3-硝基-4-羟基苯甲酸酯在混合溶液中的浓度为0.3M，在0℃左右向上述溶液中加入氢氧化锂(1.5eq)，搅拌反应直至TLC监测3-硝基-4-羟基苯甲酸酯消失后停止反应。用稀盐酸将反应液的pH值调制7后，加入乙酸乙酯萃取2-4次，合并有机相并用无水硫酸钠干燥，过滤，减压浓缩得到3-硝基-4-羟基苯甲酸。Dissolve 3-nitro-4-hydroxybenzoate (1.0eq, commercially available) in a mixture of tetrahydrofuran and water (the volume ratio of tetrahydrofuran to water is 1: 1), and control 3-nitro- The concentration of 4-hydroxybenzoate in the mixed solution is 0.3M, lithium hydroxide (1.5eq) is added to the above solution at about 0 ° C, and the reaction is stirred until TLC monitors 3-nitro-4-hydroxybenzoic acid After the ester disappears, the reaction stops. After the pH value of the reaction solution was adjusted to 7 with dilute hydrochloric acid, ethyl acetate was added for extraction 2-4 times, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-nitro-4-hydroxybenzoic acid.
3)化合物1的制备3) Preparation of Compound 1
将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺(1.0eq)和3-硝基-4-羟基苯甲酸(1.1eq)加入二氯甲烷中，在0℃依次再加入DMAP(0.2eq)和EDCI(2.0eq)，搅拌30min后，升至室温反应5-12h，直至TLC监测3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺消失后停止反应。反应液用乙酸乙酯稀释，依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥、过滤、浓缩，利用硅胶柱层析分离纯化(石油醚：四氢呋喃：甲胺(体积比)＝1:1:0.01洗脱)，得到化合物1。Add 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline (1.0 eq) and 3-nitro-4-hydroxybenzoic acid (1.1 eq) to di To methyl chloride, add DMAP (0.2eq) and EDCI (2.0eq) sequentially at 0 ° C. After stirring for 30min, warm to room temperature and react for 5-12h until TLC monitors 3-trifluoromethyl-4-((4- Methylpiperazin-1-yl) -methylene) aniline disappeared and the reaction stopped. The reaction solution was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: tetrahydrofuran: methylamine (volume ratio) = 1: 1: 0.01 elution) to obtain compound 1.
化合物1通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 1 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(DMSO-d 6,500MHz,δppm)2.41(s,3H),2.48(m,4H),2.68(m,4H),3.59(s,2H),6.94(d,J＝7.5Hz,1H),7.67(d,J＝7.5Hz,1H),7.96(d,J＝7.5Hz,1H),8.04(d,J＝7.5Hz,1H),8.17(s,1H),8.54(s,1H),10.34(s,1H)； 1 HNMR (DMSO-d 6 , 500 MHz, δ ppm) 2.41 (s, 3H), 2.48 (m, 4H), 2.68 (m, 4H), 3.59 (s, 2H), 6.94 (d, J = 7.5 Hz, 1H ), 7.67 (d, J = 7.5Hz, 1H), 7.96 (d, J = 7.5Hz, 1H), 8.04 (d, J = 7.5Hz, 1H), 8.17 (s, 1H), 8.54 (s, 1H) ), 10.34 (s, 1H);
13CNMR(DMSO-d 6,125Hz，δppm)44.3,51.4,54.0,57.1,117.1,117.2,119.8,121.9,125.7,131.1,133.5,136.6,138.6,160.5,164.1. 13 CNMR (DMSO-d 6 , 125 Hz, δ ppm) 44.3, 51.4, 54.0, 57.1, 117.1, 117.2, 119.8, 121.9, 125.7, 131.1, 133.5, 136.6, 138.6, 160.5, 164.1.
实施例2Example 2
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-甲氧基苯甲酰胺(2)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4-methoxybenzamide (2 )
Figure PCTCN2019118109-appb-000013
Figure PCTCN2019118109-appb-000013
1)3-硝基-4-甲氧基苯甲酸酯的制备1) Preparation of 3-nitro-4-methoxybenzoate
将3-硝基-4-羟基苯甲酸酯(1.0eq，市售获得)溶于无水DMF中，加入1-溴甲烷后(1.5-2.0eq)，依次加入碘化钠(1.0eq)、无水碳酸钾或无水碳酸钠(1.5-2.0eq)，通过油浴将反应液加热至60℃并搅拌反应3-15h，直至TLC监测3-硝基-4-羟基苯甲酸酯消 失。反应液用一定量的乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，得到3-硝基-4-甲氧基苯甲酸酯。Dissolve 3-nitro-4-hydroxybenzoate (1.0eq, commercially available) in anhydrous DMF, add 1-bromomethane (1.5-2.0eq), then add sodium iodide (1.0eq), Anhydrous potassium carbonate or anhydrous sodium carbonate (1.5-2.0eq), the reaction solution was heated to 60 ° C through an oil bath and stirred for 3-15h until TLC monitored the disappearance of 3-nitro-4-hydroxybenzoate. After the reaction solution was diluted with a certain amount of ethyl acetate, it was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3-nitro-4-methoxybenzoate.
2)参照实施1中步骤2)的方法，将3-硝基-4-羟基苯甲酸酯替换为3-硝基-4-甲氧基苯甲酸酯，制备得到3-硝基-4-甲氧基苯甲酸。2) Referring to the method of step 2) in Embodiment 1, replacing 3-nitro-4-hydroxybenzoate with 3-nitro-4-methoxybenzoate to prepare 3-nitro-4 -Methoxybenzoic acid.
3)参照实施例1中步骤3)的方法，将3-硝基-4-羟基苯甲酸替换为3-硝基-4-甲氧基苯甲酸，最终以石油醚：四氢呋喃：氨水的体积比为1:1.5:0.01进行硅胶柱层析分离纯化，得到化合物2。3) Referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4-methoxybenzoic acid, and finally use the volume ratio of petroleum ether: tetrahydrofuran: ammonia water Silica gel column chromatography was carried out for separation and purification at 1: 1.5: 0.01 to obtain compound 2.
化合物2通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 2 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(DMSO-d 6,500MHz，δppm)2.15(s,3H),2.38(m,8H),3.55(s,2H),4.02(s,3H),7.53(d,J＝8.0Hz,1H),7.70(d,J＝7.5Hz,1H),8.03(d,J＝7.5Hz,1H),8.16(s,1H),8.29(d,J＝7.5Hz,1H),8.55(s,1H)； 1 HNMR (DMSO-d 6 , 500 MHz, δ ppm) 2.15 (s, 3H), 2.38 (m, 8H), 3.55 (s, 2H), 4.02 (s, 3H), 7.53 (d, J = 8.0 Hz, 1H ), 7.70 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 8.16 (s, 1H), 8.29 (d, J = 7.5 Hz, 1H), 8.55 (s, 1H );
13CNMR(DMSO-d 6,125Hz，δppm)30.3,45.6,52.6,54.7,57.1,57.4,117.2(q,J＝5.9Hz),123.5,124.3(q,J＝273.2),124.5,124.9,126.1,127.2,127.5(q,J＝7.0Hz),131.2,132.2,133.9,137.9,138.6,154.5,163.1. 13 CNMR (DMSO-d 6 , 125 Hz, δ ppm) 30.3, 45.6, 52.6, 54.7, 57.1, 57.4, 117.2 (q, J = 5.9 Hz), 123.5, 124.3 (q, J = 273.2), 124.5, 124.9, 126.1 , 127.2, 127.5 (q, J = 7.0 Hz), 131.2, 132.2, 133.9, 137.9, 138.6, 154.5, 163.1.
实施例3Example 3
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-异丙氧基-苯甲酰胺(3)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4-isopropoxy-benzamide (3)
Figure PCTCN2019118109-appb-000014
Figure PCTCN2019118109-appb-000014
以实施例1中的化合物1和异丙基溴为原料，参照实施例2的步骤1)的方法，最终以二氯甲烷：甲醇：氨水的体积比为15:1:0.01进行硅胶柱层析分离纯化，得到化合物3。Using compound 1 and isopropyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the silica gel column chromatography was finally performed with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Isolation and purification gave compound 3.
化合物3通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 3 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)1.47(s,3H),1.48(s,3H),2.36(s,3H),2.56(m,8H),3.67(s,2H),4.82(m,1H),7.18(dd,J＝7.5,3.0Hz,1H),7.75(m,1H),7.86(m,2H),8.10(d,J＝7.5Hz,1H),8.32(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 1.47 (s, 3H), 1.48 (s, 3H), 2.36 (s, 3H), 2.56 (m, 8H), 3.67 (s, 2H), 4.82 (m, 1H ), 7.18 (dd, J = 7.5, 3.0 Hz, 1H), 7.75 (m, 1H), 7.86 (m, 2H), 8.10 (d, J = 7.5 Hz, 1H), 8.32 (s, 1H);
13CNMR(CDCl 3,125Hz，δppm)21.8,45.9,52.9,55.2,57.8,73.3,115.6,118.1(d，J＝6.0Hz),123.7,124.1(q,J＝272.6Hz),124.5,125.9,129.3(q,J＝30Hz),131.4,136.6,137.8,140.0,154.1,163.6. 13 CNMR (CDCl 3 , 125 Hz, δ ppm) 21.8, 45.9, 52.9, 55.2, 57.8, 73.3, 115.6, 118.1 (d, J = 6.0 Hz), 123.7, 124.1 (q, J = 272.6 Hz), 124.5, 125.9, 129.3 (q, J = 30Hz), 131.4, 136.6, 137.8, 140.0, 154.1, 163.6.
实施例4Example 4
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(2-氟-乙氧基)-苯甲酰胺(4)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (2-fluoro-ethoxy ) -Benzamide (4)
以实施例1中的化合物1和2-氟乙基溴为原料，参照实施例2的步骤1)的方法，最终以二氯甲烷：甲醇：氨水的体积比为15:1:0.01进行硅胶柱层析分离纯化，得到化 合物4。Using compound 1 and 2-fluoroethyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, a silica gel column was finally carried out with a volume ratio of methylene chloride: methanol: ammonia water of 15: 1: 0.01 Chromatographic separation and purification gave compound 4.
Figure PCTCN2019118109-appb-000015
Figure PCTCN2019118109-appb-000015
化合物4通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 4 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.29(s,3H),2.50(m,8H),3.61(s,2H),4.42(d,J＝27Hz,2H),4.80(d,J＝47Hz,2H),7.16(d,J＝8.5Hz,1H),7.75(d,J＝8.5Hz,1H),7.86(d,J＝8.5Hz,1H),7.88(s,1H),8.13(d,J＝8.5Hz,1H),8.37(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.29 (s, 3H), 2.50 (m, 8H), 3.61 (s, 2H), 4.42 (d, J = 27 Hz, 2H), 4.80 (d, J = 47 Hz, 2H), 7.16 (d, J = 8.5Hz, 1H), 7.75 (d, J = 8.5Hz, 1H), 7.86 (d, J = 8.5Hz, 1H), 7.88 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H);
13CNMR(CDCl 3,125Hz，δppm)29.7,46.0,53.1,55.2,57.8,69.1,69.2,80.5,81.9,114.9,118.0,123.6,124.6,125.2,127.2,129.3,130.2,131.3,134.2,136.3,139.4,154.4,163.3； 13 CNMR (CDCl 3 , 125 Hz, δ ppm) 29.7, 46.0, 53.1, 55.2, 57.8, 69.1, 69.2, 80.5, 81.9, 114.9, 118.0, 123.6, 124.6, 125.2, 127.2, 129.3, 130.2, 131.3, 134.2, 136.3, 139.4, 154.4, 163.3;
HRMS(ESI)m/z calcd for C 22H 25F 4N 4O 4(M+H) +485.18064；found,485.1799. HRMS (ESI) m / z calcd for C 22 H 25 F 4 N 4 O 4 (M + H) + 485.18064; found, 485.1799.
实施例5Example 5
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(3-氟-丙氧基)-苯甲酰胺(5)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (3-fluoro-propoxy ) -Benzamide (5)
Figure PCTCN2019118109-appb-000016
Figure PCTCN2019118109-appb-000016
以实施例1中的化合物1和3-氟-丙基溴为原料，参照实施例2的步骤1)的方法，最终以二氯甲烷：甲醇：氨水的体积比为15:1:0.01进行硅胶柱层析分离纯化，得到化合物5。Using compound 1 and 3-fluoro-propyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 5.
化合物5通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 5 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.23(m,2H),2.30(s,3H),2.51(m,8H),3.63(s,2H),4.32(t,J＝5.5Hz,2H),4.65(t,J＝5.0Hz,1H),4.74(t,J＝5.0Hz,1H),7.19(d,J＝9.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.85(d,J＝9.0Hz,1H),7.86(s,1H),8.14(d,J＝8.5Hz,1H),8.21(br s,1H),8.37(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.23 (m, 2H), 2.30 (s, 3H), 2.51 (m, 8H), 3.63 (s, 2H), 4.32 (t, J = 5.5 Hz, 2H), 4.65 (t, J = 5.0 Hz, 1H), 4.74 (t, J = 5.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.85 ( d, J = 9.0 Hz, 1H), 7.86 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.21 (br s, 1H), 8.37 (s, 1H);
13CNMR(CDCl 3,125Hz，δppm)29.7,29.9,30.0,46.0,53.1,55.2,57.8,65.5,79.3,80.6,114.5,117.9,123.5,124.5,126.6,129.2,129.7,133.6,136.2,139.1,154.8,163.2； 13 CNMR (CDCl 3 , 125 Hz, δ ppm) 29.7, 29.9, 30.0, 46.0, 53.1, 55.2, 57.8, 65.5, 79.3, 80.6, 114.5, 117.9, 123.5, 124.5, 126.6, 129.2, 129.7, 133.6, 136.2, 139.1, 154.8, 163.2;
HRMS(ESI)m/z calcd for C 23H 27F 4N 4O 4(M+H) +499.19629；found,499.19510. HRMS (ESI) m / z calcd for C 23 H 27 F 4 N 4 O 4 (M + H) + 499.19629; found, 499.19510.
实施例6Example 6
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(2-氯-乙氧基)-苯甲酰胺(6)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (2-chloro-ethoxy ) -Benzamide (6)
Figure PCTCN2019118109-appb-000017
Figure PCTCN2019118109-appb-000017
以实施例1中的化合物1和2-氯-乙基溴为原料，参照实施例2的步骤1)的方法，最终以二氯甲烷：甲醇：氨水的体积比为15:1:0.01进行硅胶柱层析分离纯化，得到化合物6。Using compound 1 and 2-chloro-ethyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 6.
化合物6通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 6 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.28(s,3H),2.50(m,8H),3.61(s,2H),3.87(t,J＝5.5Hz,2H),4.42(t,J＝5.0Hz,1H),7.15(d,J＝9.0Hz,1H),7.76(d,J＝8.5Hz,1H),7.85(d,J＝9.0Hz,1H),7.85(s,1H),8.12(d,J＝8.5Hz,1H),8.36(d,J＝1.0Hz,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.28 (s, 3H), 2.50 (m, 8H), 3.61 (s, 2H), 3.87 (t, J = 5.5 Hz, 2H), 4.42 (t, J = 5.0 Hz, 1H), 7.15 (d, J = 9.0Hz, 1H), 7.76 (d, J = 8.5Hz, 1H), 7.85 (d, J = 9.0Hz, 1H), 7.85 (s, 1H), 8.12 ( d, J = 8.5 Hz, 1H), 8.36 (d, J = 1.0 Hz, 1H);
13CNMR(CDCl 3,100Hz，δppm)40.9,46.1,53.2,55.2,57.8,69.9,77.3,114.9,118.0(q,J＝6.0Hz),123.7,124.0(q,J＝272.7Hz),124.69,127.3,129.2(q,J＝30Hz),131.4,133.7,134.3,136.2,139.3,154.2,163.3； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 40.9, 46.1, 53.2, 55.2, 57.8, 69.9, 77.3, 114.9, 118.0 (q, J = 6.0 Hz), 123.7, 124.0 (q, J = 272.7 Hz), 124.69, 127.3, 129.2 (q, J = 30Hz), 131.4, 133.7, 134.3, 136.2, 139.3, 154.2, 163.3;
HRMS(ESI)m/z calcd for C 22H 25ClF 3N 4O 4(M+H) +501.15109；found,501.15028. HRMS (ESI) m / z calcd for C 22 H 25 ClF 3 N 4 O 4 (M + H) + 501.15109; found, 501.15028.
实施例7Example 7
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺(7)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (3-chloro-propoxy ) -Benzamide (7)
Figure PCTCN2019118109-appb-000018
Figure PCTCN2019118109-appb-000018
以实施例1中的化合物1和3-氯-丙基溴为原料，参照实施例2的步骤1)的方法，最终以二氯甲烷：甲醇：氨水的体积比为15:1:0.01进行硅胶柱层析分离纯化，得到化合物7。Using compound 1 and 3-chloro-propyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 7.
化合物7通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 7 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(CDCl 3,500MHz,δppm)2.32(m,2H),2.32(s,3H),2.52(m,8H),3.63(s,2H),3.81(t,J＝5.5Hz,2H),4.35(t,J＝5.0Hz,2H),7.20(d,J＝9.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.85(d,J＝9.0Hz,1H),7.87(s,1H),8.16(d,J＝9.0Hz,1H),8.18(s,1H),8.40(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.32 (m, 2H), 2.32 (s, 3H), 2.52 (m, 8H), 3.63 (s, 2H), 3.81 (t, J = 5.5 Hz, 2H), 4.35 (t, J = 5.0 Hz, 2H), 7.20 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.87 ( s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.18 (s, 1H), 8.40 (s, 1H);
13CNMR(CDCl 3,125Hzδ,ppm)31.6,40.9,45.8,52.8,55.1,57.7,66.1,114.5,117.9(d,J＝5.7Hz),123.6,124.7(q,J＝272Hz),126.5,129.2(q,J＝30Hz),131.3,133.8,133.9,136.4,138.9,154.7,163.4. 13 CNMR (CDCl 3 , 125 Hz δ, ppm) 31.6, 40.9, 45.8, 52.8, 55.1, 57.7, 66.1, 114.5, 117.9 (d, J = 5.7 Hz), 123.6, 124.7 (q, J = 272 Hz), 126.5, 129.2 (q, J = 30Hz), 131.3, 133.8, 133.9, 136.4, 138.9, 154.7, 163.4.
实施例8Example 8
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(4-氯-丁氧基)-苯 甲酰胺(8)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (4-chloro-butoxy ) -Benzamide (8)
Figure PCTCN2019118109-appb-000019
Figure PCTCN2019118109-appb-000019
以实施例1中的化合物1和4-氯-丁基溴为原料，参照实施例2的步骤1)的方法，最终以二氯甲烷：甲醇：氨水的体积比为15:1:0.01进行硅胶柱层析分离纯化，得到化合物8。Using compound 1 and 4-chloro-butyl bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of methylene chloride: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 8.
化合物8通过核磁共振氢谱( 1HNMR)表征如下： Compound 8 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.04(m,2H),2.30(m,2H),2.30(s,3H),2.51(m,8H),3.63(s,4H),4.24(s,2H),7.17(d,J＝8.5Hz,1H),7.77(d,J＝8.5Hz,1H),7.85(d,J＝9.0Hz,1H),7.87(s,1H),8.12(s,1H),8.13(d,J＝9.0Hz,1H),8.37(s,1H). 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.04 (m, 2H), 2.30 (m, 2H), 2.30 (s, 3H), 2.51 (m, 8H), 3.63 (s, 4H), 4.24 (s, 2H ), 7.17 (d, J = 8.5Hz, 1H), 7.77 (d, J = 8.5Hz, 1H), 7.85 (d, J = 9.0Hz, 1H), 7.87 (s, 1H), 8.12 (s, 1H) ), 8.13 (d, J = 9.0 Hz, 1H), 8.37 (s, 1H).
实施例9Example 9
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-硝基-4-(5-氯-戊氧基)-苯甲酰胺(9)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-nitro-4- (5-chloro-pentyloxy ) -Benzamide (9)
Figure PCTCN2019118109-appb-000020
Figure PCTCN2019118109-appb-000020
以实施例1中的化合物1和5-氯-戊氧基溴为原料，参照实施例2步骤1)的方法，最终以二氯甲烷：甲醇：氨水的体积比为15:1:0.01进行硅胶柱层析分离纯化，得到化合物9。Using Compound 1 and 5-chloro-pentyloxy bromide in Example 1 as raw materials, referring to the method of step 1) in Example 2, the final silica gel was carried out with a volume ratio of dichloromethane: methanol: ammonia water of 15: 1: 0.01 Column chromatography separated and purified to obtain compound 9.
化合物9通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下： Compound 9 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)1.69(m,3H),1.89(m,5H),2.32(s,3H),2.52(m,8H),3.58(s,2H),3.64(s,2H),4.21(s,2H),7.18(d,J＝6.0Hz,1H),7.78(d,J＝9.0Hz,1H),7.85(d,J＝9.0Hz,1H),7.87(s,1H),7.98(s,1H),8.13(d,J＝8.5Hz,1H),8.36(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 1.69 (m, 3H), 1.89 (m, 5H), 2.32 (s, 3H), 2.52 (m, 8H), 3.58 (s, 2H), 3.64 (s, 2H ), 4.21 (s, 2H), 7.18 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.87 (s, 1H ), 7.98 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H);
HRMS(ESI)m/z calcd for C 25H 31ClF 3N 4O 4(M+H) +543.19804；found,543.19696. HRMS (ESI) m / z calcd for C 25 H 31 ClF 3 N 4 O 4 (M + H) + 543.19804; found, 543.19696.
实施例10Example 10
制备N-(3-三氟甲基-4-甲基苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺(10)Preparation of N- (3-trifluoromethyl-4-methylphenyl) -3-nitro-4- (3-chloro-propoxy) -benzamide (10)
Figure PCTCN2019118109-appb-000021
Figure PCTCN2019118109-appb-000021
1)3-硝基-4-(3-氯-丙氧基)-苯甲酸甲酯的制备1) Preparation of 3-nitro-4- (3-chloro-propoxy) -benzoic acid methyl ester
以3-硝基-4-羟基苯甲酸甲酯和3-氯-丙氧基溴为原料，参照实施例2的步骤1)的方 法，最终以石油醚：乙酸乙酯的体积比为5:1进行硅胶柱层析分离纯化，得到3-硝基-4-(3-氯-丙氧基)-苯甲酸甲酯；Using 3-nitro-4-hydroxybenzoic acid methyl ester and 3-chloro-propoxy bromide as raw materials, referring to the method of step 1) in Example 2, the final volume ratio of petroleum ether: ethyl acetate is 5: 1. Separate and purify by silica gel column chromatography to obtain methyl 3-nitro-4- (3-chloro-propoxy) -benzoate;
3-硝基-4-(3-氯-丙氧基)-苯甲酸甲酯通过核磁共振氢谱( 1HNMR)表征如下： The 3-nitro-4- (3-chloro-propoxy) -benzoic acid methyl ester is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.36(m,2H),3.78(m,2H),3.93(s,3H),4.34(m,2H),7.14(m,1H),8.21(m,1H),8.52(m,1H). 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.36 (m, 2H), 3.78 (m, 2H), 3.93 (s, 3H), 4.34 (m, 2H), 7.14 (m, 1H), 8.21 (m, 1H ), 8.52 (m, 1H).
2)3-硝基-4-(3-氯-丙氧基)-苯甲酸的制备2) Preparation of 3-nitro-4- (3-chloro-propoxy) -benzoic acid
以3-硝基-4-(3-氯-丙氧基)-苯甲酸甲酯为原料，参照实施例1中步骤2)的方法，得到3-硝基-4-(3-氯-丙氧基)-苯甲酸；Using 3-nitro-4- (3-chloro-propoxy) -benzoic acid methyl ester as the raw material and referring to the method of step 2) in Example 1, 3-nitro-4- (3-chloro-propane) was obtained Oxy) -benzoic acid;
得到3-硝基-4-(3-氯-丙氧基)-苯甲酸通过核磁共振氢谱( 1HNMR)表征如下： The obtained 3-nitro-4- (3-chloro-propoxy) -benzoic acid was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.36(m,2H),3.80(m,2H),4.37(m,2H),7.20(m,1H),8.27(m,1H),8.58(m,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.36 (m, 2H), 3.80 (m, 2H), 4.37 (m, 2H), 7.20 (m, 1H), 8.27 (m, 1H), 8.58 (m, 1H );
3)3-三氟甲基-4-甲基苯胺的制备3) Preparation of 3-trifluoromethyl-4-methylaniline
将3-三氟甲基-4-甲基硝基苯(1.0eq，市售获得)置于氢化反应瓶中，溶于甲醇和四氢呋喃的混合溶液中，加入Pd/C(5％)，在40Psi或1atm的压力下反应2-3h，利用硅藻土过滤反应液，浓缩滤液得到3-三氟甲基-4-甲基苯胺。Place 3-trifluoromethyl-4-methylnitrobenzene (1.0 eq, commercially available) in a hydrogenation reaction flask, dissolve in a mixed solution of methanol and tetrahydrofuran, add Pd / C (5%), The reaction was carried out at a pressure of 40 Psi or 1 atm for 2-3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain 3-trifluoromethyl-4-methylaniline.
4)参照实施例1中步骤3)的方法，将3-硝基-4-羟基苯甲酸替换为3-硝基-4-(3-氯-丙氧基)-苯甲酸，将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺替换为3-三氟甲基-4-甲基苯胺，最终以石油醚：四氢呋喃：氨水的体积比为1:1.5:0.01进行硅胶柱层析分离纯化，得到化合物10。4) Referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro-propoxy) -benzoic acid, and replace Fluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline was replaced with 3-trifluoromethyl-4-methylaniline, and finally the volume of petroleum ether: tetrahydrofuran: ammonia A ratio of 1: 1.5: 0.01 was separated and purified by silica gel column chromatography to obtain compound 10.
化合物10通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 10 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(DMSO-d 6,500MHz，δppm)2.20-2.25(m,3H),2.41(s,3H),3.66-3.82(m,3H),4.38(m,2H),7.43(d,J＝7.5Hz,1H),7.57(d,J＝8.0Hz,1H),7.95(d,J＝9.0Hz,1H),8.14,(s,1H),8.28(d,J＝7.5Hz,1H),8.55(s,1H),10.53(s,1H)； 1 HNMR (DMSO-d 6 , 500 MHz, δ ppm) 2.20-2.25 (m, 3H), 2.41 (s, 3H), 3.66-3.82 (m, 3H), 4.38 (m, 2H), 7.43 (d, J = 7.5Hz, 1H), 7.57 (d, J = 8.0Hz, 1H), 7.95 (d, J = 9.0Hz, 1H), 8.14, (s, 1H), 8.28 (d, J = 7.5Hz, 1H), 8.55 (s, 1H), 10.53 (s, 1H);
13CNMR(DMSO-d 6,125MHz，δppm)18.1,31.2,41.5,66.5,115.0,117.3,123.6,124.7,126.3,127.2,130.9,132.6,134.0,134.3,137.1,138.7,153.5,163.0. 13 CNMR (DMSO-d 6 , 125 MHz, δ ppm) 18.1, 31.2, 41.5, 66.5, 115.0, 117.3, 123.6, 124.7, 126.3, 127.2, 130.9, 132.6, 134.0, 134.3, 137.1, 138.7, 153.5, 163.0.
实施例11Example 11
制备N-(3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺(11)Preparation of N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) phenyl) -3-nitro-4- (3-chloro-propoxy) -benzamide (11)
Figure PCTCN2019118109-appb-000022
Figure PCTCN2019118109-appb-000022
1)3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)苯胺的制备1) Preparation of 3-trifluoromethyl-4-((3-N, N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) aniline
参照实施例1步骤1)的方法，将4-甲基哌嗪替换为3-N,N-二甲基氨基-四氢吡咯，制备得到3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)硝基苯中间产物后，继续还原，得到3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)苯胺。Referring to the method of step 1) in Example 1, replacing 4-methylpiperazine with 3-N, N-dimethylamino-tetrahydropyrrole to prepare 3-trifluoromethyl-4-((3-N , N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) nitrobenzene intermediate product, continue to reduce to give 3-trifluoromethyl-4-((3-N, N-di Methylamino-tetrahydropyrrol-1-yl) -methylene) aniline.
3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)硝基苯通过核磁共振氢谱 ( 1HNMR)表征如下： 3-Trifluoromethyl-4-((3-N, N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) nitrobenzene is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)1.78(m,1H),2.02(m,1H),2.21(s,6H),2.52(m,1H),2.70(m,3H),2.82(m,1H),3.87(q,J＝16Hz,2H),8.06(d,J＝8.5Hz,1H),8.26(d,J＝8.5Hz,1H),8.49(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 1.78 (m, 1H), 2.02 (m, 1H), 2.21 (s, 6H), 2.52 (m, 1H), 2.70 (m, 3H), 2.82 (m, 1H ), 3.87 (q, J = 16 Hz, 2H), 8.06 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.49 (s, 1H);
3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)苯胺通过核磁共振氢谱( 1HNMR)表征如下： 3-Trifluoromethyl-4-((3-N, N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) aniline is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)1.74(m,1H),1.97(m,1H),2.22(s,6H),2.46(m,1H),2.55(s,1H),2.62(m,1H),2.72(m,1H),2.85(m,1H),3.60(s,2H),3.62(br s,2H),6.76(d,J＝7.5Hz,1H),6.88(s,1H),7.42(d,J＝6.0Hz,1H). 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 1.74 (m, 1H), 1.97 (m, 1H), 2.22 (s, 6H), 2.46 (m, 1H), 2.55 (s, 1H), 2.62 (m, 1H ), 2.72 (m, 1H), 2.85 (m, 1H), 3.60 (s, 2H), 3.62 (br s, 2H), 6.76 (d, J = 7.5Hz, 1H), 6.88 (s, 1H), 7.42 (d, J = 6.0 Hz, 1H).
2)化合物11的制备2) Preparation of compound 11
以3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)苯胺和实施例10中的3-硝基-4-(3-氯-丙氧基)-苯甲酸为原料，参照实施例1中步骤3)的方法，将3-硝基-4-羟基苯甲酸替换为3-硝基-4-(3-氯-丙氧基)-苯甲酸，将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺替换为3-三氟甲基-4-((3-N,N-二甲基氨基-四氢吡咯-1-基)-亚甲基)苯胺，最终以石油醚：四氢呋喃：氨水的体积比为1:1:0.01进行硅胶柱层析分离纯化，得到化合物11。3-trifluoromethyl-4-((3-N, N-dimethylamino-tetrahydropyrrol-1-yl) -methylene) aniline and 3-nitro-4- in Example 10 (3-chloro-propoxy) -benzoic acid as raw material, referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro -Propoxy) -benzoic acid, replacing 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 3-trifluoromethyl-4- ( (3-N, N-Dimethylamino-tetrahydropyrrol-1-yl) -methylene) aniline, finally separated by silica gel column chromatography with petroleum ether: tetrahydrofuran: ammonia volume ratio of 1: 1: 0.01 Purify to give compound 11.
化合物11通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 11 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)1.70(m,1H),1.96(m,1H),2.17(s,6H),2.25(m,2H),2.41(m,1H),2.53(m 1H),2.62(m,1H),2.73(m 2H),3.65(m,2H),3.75(t,J＝5.5Hz,2H),4.28(t,J＝5.5Hz,2H),7.10(d,J＝8.5Hz,1H),7.67(d,J＝8.5Hz,1H),7.82(d,J＝9.0Hz,1H),7.88(s,1H),8.12(d,J＝9.0Hz,1H),8.39(s,1H),9.12(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 1.70 (m, 1H), 1.96 (m, 1H), 2.17 (s, 6H), 2.25 (m, 2H), 2.41 (m, 1H), 2.53 (m 1H) , 2.62 (m, 1H), 2.73 (m 2H), 3.65 (m, 2H), 3.75 (t, J = 5.5 Hz, 2H), 4.28 (t, J = 5.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.88 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.39 (s, 1H), 9.12 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)29.3,31.7,41.0,43.8,53.5,55.5,58.4,65.5,66.1,106.8,114.3,118.0(d,J＝6.0Hz),123.9,124.1(q,J＝272Hz),124.9,126.7,128.4(q,J＝30.3Hz),131.0,133.9,134.6,136.4,138.8,148.9,154.6,163.7； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 29.3, 31.7, 41.0, 43.8, 53.5, 55.5, 58.4, 65.5, 66.1, 106.8, 114.3, 118.0 (d, J = 6.0 Hz), 123.9, 124.1 (q, J = 272Hz), 124.9, 126.7, 128.4 (q, J = 30.3Hz), 131.0, 133.9, 134.6, 136.4, 138.8, 148.9, 154.6, 163.7;
HRMS(ESI)m/z calcd for C 24H 29ClF 3N 4O 4(M+H) +529.18239；found,529.18120. HRMS (ESI) m / z calcd for C 24 H 29 ClF 3 N 4 O 4 (M + H) + 529.18239; found, 529.18120.
实施例12Example 12
制备N-(3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺(12)Preparation of N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) phenyl) -3-nitro- 4- (3-chloro-propoxy) -benzamide (12)
Figure PCTCN2019118109-appb-000023
Figure PCTCN2019118109-appb-000023
1)3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯胺的制备1) Preparation of 3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) aniline
参照实施例1步骤1)的方法，将4-甲基哌嗪替换为3-N,N-二甲基氨基-氮杂环丁烷，制备得到3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)硝基苯中间产物后，继续还原，得到3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯胺。Referring to the method of step 1) in Example 1, replacing 4-methylpiperazine with 3-N, N-dimethylamino-azetidine to prepare 3-trifluoromethyl-4-((3 -N, N-dimethylamino-azetidin-1-yl) -methylene) nitrobenzene intermediate product, continue the reduction to obtain 3-trifluoromethyl-4-((3-N , N-dimethylamino-azetidin-1-yl) -methylene) aniline.
3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)硝基苯通过核磁共振氢谱( 1HNMR)表征如下： 3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) nitrobenzene characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.11(s,6H),2.92(m,1H),2.99(t,J＝6.0Hz,2H),3.55(t,J＝6.0Hz,2H),3.88(s,2H),7.94(d,J＝7.0Hz,1H),8.33(dd,J＝7.0,2.0Hz,1H),8.44(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.11 (s, 6H), 2.92 (m, 1H), 2.99 (t, J = 6.0 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.88 ( s, 2H), 7.94 (d, J = 7.0 Hz, 1H), 8.33 (dd, J = 7.0, 2.0 Hz, 1H), 8.44 (s, 1H);
3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯胺通过核磁共振氢谱( 1HNMR)表征如下： 3-Trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) aniline is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.06(s,6H),2.87(m,3H),3.47(t,J＝5.0Hz,2H),3.64(s,2H),3.79(br s,2H),6.72(dd,J＝6.0,1.5Hz,1H),6.85(d,J＝1.5Hz,1H),7.34(d,J＝6.0Hz,1H). 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.06 (s, 6H), 2.87 (m, 3H), 3.47 (t, J = 5.0 Hz, 2H), 3.64 (s, 2H), 3.79 (br s, 2H) , 6.72 (dd, J = 6.0, 1.5Hz, 1H), 6.85 (d, J = 1.5Hz, 1H), 7.34 (d, J = 6.0Hz, 1H).
2)化合物12的制备2) Preparation of compound 12
以3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯胺和实施例10中的3-硝基-4-(3-氯-丙氧基)-苯甲酸为原料，参照实施例1中步骤3)的方法，将3-硝基-4-羟基苯甲酸替换为3-硝基-4-(3-氯-丙氧基)-苯甲酸，将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺替换为3-三氟甲基-4-((3-N,N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯胺，最终以二氯甲烷：甲醇：氨水的体积比为30:1:0.01进行硅胶柱层析分离纯化，得到化合物12。3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) aniline and 3-nitro- in Example 10 4- (3-chloro-propoxy) -benzoic acid as the raw material, referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3 -Chloro-propoxy) -benzoic acid, replacing 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 3-trifluoromethyl-4 -((3-N, N-dimethylamino-azetidin-1-yl) -methylene) aniline, finally with dichloromethane: methanol: ammonia volume ratio of 30: 1: 0.01 Silica gel column chromatography separated and purified to obtain compound 12.
化合物12通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 12 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.12(s,6H),2.26(m,3H),2.92(m,1H),2.96(m,2H),3.55(t,J＝5.5Hz,2H),3.75(m,4H),4.35(t,J＝5.5Hz,2H),7.19(d,J＝8.5Hz,1H),7.66(d,J＝8.5Hz,1H),7.83(d,J＝9.0Hz,1H),7.89(s,1H),8.14(d,J＝9.0Hz,1H),8.19(s,1H),8.39(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.12 (s, 6H), 2.26 (m, 3H), 2.92 (m, 1H), 2.96 (m, 2H), 3.55 (t, J = 5.5 Hz, 2H), 3.75 (m, 4H), 4.35 (t, J = 5.5Hz, 2H), 7.19 (d, J = 8.5Hz, 1H), 7.66 (d, J = 8.5Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.89 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 8.19 (s, 1H), 8.39 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)31.8,41.1,42.2,57.0,59.1,60.0,66.3,114.4,118.0,123.6,124.7,126.7,130.6,133.8,136.3,139.2,154.9,163.2； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 31.8, 41.1, 42.2, 57.0, 59.1, 60.0, 66.3, 114.4, 118.0, 123.6, 124.7, 126.7, 130.6, 133.8, 136.3, 139.2, 154.9, 163.2;
HRMS(ESI)m/z calcd for C 23H 27ClF 3N 4O 4(M+H) +515.16674；found,515.16648. HRMS (ESI) m / z calcd for C 23 H 27 ClF 3 N 4 O 4 (M + H) + 515.16674; found, 515.16648.
实施例13Example 13
制备N-(3-三氟甲基-4-((吗啉-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺(13)Preparation of N- (3-trifluoromethyl-4-((morpholin-1-yl) -methylene) phenyl) -3-nitro-4- (3-chloro-propoxy) -benzoyl Amide (13)
Figure PCTCN2019118109-appb-000024
Figure PCTCN2019118109-appb-000024
1)3-三氟甲基-4-((吗啉-1-基)-亚甲基)苯胺的制备1) Preparation of 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) aniline
参照实施例1步骤1)的方法，将4-甲基哌嗪替换为吗啉，制备得到3-三氟甲基-4-((吗啉-1-基)-亚甲基)硝基苯中间产物后，继续还原，得到3-三氟甲基-4-((吗啉-1-基)-亚甲基)苯胺。Referring to the method of step 1) in Example 1, replacing 4-methylpiperazine with morpholine to prepare 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) nitrobenzene After the intermediate product, the reduction is continued to obtain 3-trifluoromethyl-4-((morpholin-1-yl) -methylene) aniline.
3-三氟甲基-4-((吗啉-1-基)-亚甲基)硝基苯通过核磁共振氢谱( 1HNMR)表征如下： 3-Trifluoromethyl-4-((morpholin-1-yl) -methylene) nitrobenzene is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.50(m,4H),3.74(m,6H),8.12(d,J＝6.0Hz,1H),8.37(d,J＝6.0Hz,1H),8.51(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.50 (m, 4H), 3.74 (m, 6H), 8.12 (d, J = 6.0 Hz, 1H), 8.37 (d, J = 6.0 Hz, 1H), 8.51 ( s, 1H);
3-三氟甲基-4-((吗啉-1-基)-亚甲基)苯胺通过核磁共振氢谱( 1HNMR)表征如下： 3-Trifluoromethyl-4-((morpholin-1-yl) -methylene) aniline is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.44(m,4H),3.52(m,2H),3.70(m,4H),3.78(br s,2H),6.79(dd,J＝6.0,1.5Hz,1H),6.92(d,J＝1.5Hz,1H),7.48(d,J＝6.0Hz,1H). 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.44 (m, 4H), 3.52 (m, 2H), 3.70 (m, 4H), 3.78 (br s, 2H), 6.79 (dd, J = 6.0, 1.5 Hz, 1H), 6.92 (d, J = 1.5Hz, 1H), 7.48 (d, J = 6.0Hz, 1H).
2)化合物13的制备2) Preparation of compound 13
以3-三氟甲基-4-((吗啉-1-基)-亚甲基)苯胺和实施例10中的3-硝基-4-(3-氯-丙氧基)-苯甲酸为原料，参照实施例1中步骤3)的方法，将3-硝基-4-羟基苯甲酸替换为3-硝基-4-(3-氯-丙氧基)-苯甲酸，将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺替换为3-三氟甲基-4-((吗啉-1-基)-亚甲基)苯胺，最终以石油醚：乙酸乙酯的体积比为2:1进行硅胶柱层析分离纯化，得到化合物13。3-trifluoromethyl-4-((morpholin-1-yl) -methylene) aniline and 3-nitro-4- (3-chloro-propoxy) -benzoic acid in Example 10 As a raw material, referring to the method of step 3) in Example 1, replace 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro-propoxy) -benzoic acid, replace 3- Replace trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 3-trifluoromethyl-4-((morpholin-1-yl) -methylene ) Aniline is finally separated and purified by silica gel column chromatography with a volume ratio of petroleum ether: ethyl acetate of 2: 1 to obtain compound 13.
化合物13通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 13 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.33(m,2H),2.43(m,4H),3.63(s,2H),3.72(m,4H),3.82(t,J＝5.5Hz,2H),4.37(t,J＝5.5Hz,2H),7.22(d,J＝8.5Hz,1H),7.80(d,J＝8.5Hz,1H),7.86(d,J＝9.0Hz,1H),7.87(s,1H),8.03(s,1H),8.14(d,J＝9.0Hz,1H),8.39(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.33 (m, 2H), 2.43 (m, 4H), 3.63 (s, 2H), 3.72 (m, 4H), 3.82 (t, J = 5.5 Hz, 2H), 4.37 (t, J = 5.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.87 ( s, 1H), 8.03 (s, 1H), 8.14 (d, J = 9.0Hz, 1H), 8.39 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)31.8,41.1,53.8,58.4,66.4,67.2,114.8,118.0(d,J＝6.0Hz),123.6,124.6,129.5,133.8,136.4,139.2,155.0,163.2； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 31.8, 41.1, 53.8, 58.4, 66.4, 67.2, 114.8, 118.0 (d, J = 6.0 Hz), 123.6, 124.6, 129.5, 133.8, 136.4, 139.2, 155.0, 163.2;
HRMS(ESI)m/z calcd for C 22H 24ClF 3N 3O 5(M+H) +502.13511；found,502.13484. HRMS (ESI) m / z calcd for C 22 H 24 ClF 3 N 3 O 5 (M + H) + 502.13511; found, 502.13484.
实施例14Example 14
制备N-(3-三氟甲基-4-((3,5-二甲基-吗啉-1-基)-亚甲基)苯基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺(14)Preparation of N- (3-trifluoromethyl-4-((3,5-dimethyl-morpholin-1-yl) -methylene) phenyl) -3-nitro-4- (3-chloro -Propoxy) -benzamide (14)
Figure PCTCN2019118109-appb-000025
Figure PCTCN2019118109-appb-000025
1)3-三氟甲基-4-((3,6-二甲基-吗啉-1-基)-亚甲基)苯胺的制备1) Preparation of 3-trifluoromethyl-4-((3,6-dimethyl-morpholin-1-yl) -methylene) aniline
参照实施例1步骤1)的方法，将4-甲基哌嗪替换为3,6-二甲基-吗啉，制备得到3-三氟甲基-4-((3,6-二甲基-吗啉-1-基)-亚甲基)硝基苯中间产物后，继续还原，得到3-三氟甲基-4-((3,6-二甲基-吗啉-1-基)-亚甲基)苯胺。Referring to the method of step 1) in Example 1, replacing 4-methylpiperazine with 3,6-dimethyl-morpholine to prepare 3-trifluoromethyl-4-((3,6-dimethyl -Morpholin-1-yl) -methylene) nitrobenzene intermediate product, continue to reduce to give 3-trifluoromethyl-4-((3,6-dimethyl-morpholin-1-yl) -Methylene) aniline.
3-三氟甲基-4-((3,6-二甲基-吗啉-1-基)-亚甲基)硝基苯通过核磁共振氢谱( 1HNMR)表征如下： 3-Trifluoromethyl-4-((3,6-dimethyl-morpholin-1-yl) -methylene) nitrobenzene is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CDCl 3,500MHz，δppm)1.13(d,J＝5.5Hz,6H),1.88(t,J＝9.0Hz,2H),2.62(d,J＝9.5Hz,2H),3.71(m,2H),8.09(d,J＝7.5Hz,1H),8.34(d,J＝7.5Hz,1H),8.46(s,1H) 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 1.13 (d, J = 5.5 Hz, 6H), 1.88 (t, J = 9.0 Hz, 2H), 2.62 (d, J = 9.5 Hz, 2H), 3.71 (m, 2H), 8.09 (d, J = 7.5Hz, 1H), 8.34 (d, J = 7.5Hz, 1H), 8.46 (s, 1H)
3-三氟甲基-4-((3,6-二甲基-吗啉-1-基)-亚甲基)苯胺通过高分辨质谱(HRMS)表征如下：3-Trifluoromethyl-4-((3,6-dimethyl-morpholin-1-yl) -methylene) aniline is characterized by high resolution mass spectrometry (HRMS) as follows:
HRMS(ESI+)288.1449Calcd for C 14H 19F 3N 2O 288.1522[M+H]+. HRMS (ESI +) 288.1449Calcd for C 14 H 19 F 3 N 2 O 288.1522 [M + H] +.
2)化合物14的制备2) Preparation of compound 14
以3-三氟甲基-4-((3,6-二甲基-吗啉-1-基)-亚甲基)苯胺和实施例10中的3-硝基-4-(3-氯-丙氧基)-苯甲酸为原料，参照实施例1中步骤3)的方法，将3-硝基-4-羟基苯甲酸替换为3-硝基-4-(3-氯-丙氧基)-苯甲酸，将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺替换为3-三氟甲基-4-((3,6-二甲基-吗啉-1-基)-亚甲基)苯胺，最终以石油醚：乙酸乙酯的体积比为2:1进行硅胶柱层析分离纯化，得到化合物14。3-trifluoromethyl-4-((3,6-dimethyl-morpholin-1-yl) -methylene) aniline and 3-nitro-4- (3-chloro in Example 10 -Propoxy) -benzoic acid as raw material, referring to the method of step 3) in Example 1, replacing 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro-propoxy ) -Benzoic acid, replacing 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 3-trifluoromethyl-4-((3,6 -Dimethyl-morpholin-1-yl) -methylene) aniline, finally separated and purified by silica gel column chromatography with a petroleum ether: ethyl acetate volume ratio of 2: 1 to obtain compound 14.
化合物14通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 14 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)1.14(s,6H),1.84(m,2H),2.33(m,2H),2.66(m.2H),3.60(s,3H),3.75(m,2H),3.82(t,J＝5.5Hz,2H),4.37(t,J＝5.5Hz,2H),7.22(d,J＝8.5Hz,1H),7.79(d,J＝8.5Hz,1H),7.86(d,J＝9.0Hz,1H),7.87(s,1H),8.03(s,1H),8.14(d,J＝9.0Hz,1H),8.39(s,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 1.14 (s, 6H), 1.84 (m, 2H), 2.33 (m, 2H), 2.66 (m. 2H), 3.60 (s, 3H), 3.75 (m, 2H ), 3.82 (t, J = 5.5 Hz, 2H), 4.37 (t, J = 5.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.87 (s, 1H), 8.03 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 8.39 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)19.2,31.8,41.1,57.9,59.6,66.4,71.9,114.8,118.0(d,J＝6.0Hz),123.6,124.6,126.7,131.6,133.8,136.4,139.2,155.0,163.3； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 19.2, 31.8, 41.1, 57.9, 59.6, 66.4, 71.9, 114.8, 118.0 (d, J = 6.0 Hz), 123.6, 124.6, 126.7, 131.6, 133.8, 136.4, 139.2, 155.0, 163.3;
HRMS(ESI)m/z calcd for C 24H 28ClF 3N 3O 5(M+H) +530.16641；found,530.16623. HRMS (ESI) m / z calcd for C 24 H 28 ClF 3 N 3 O 5 (M + H) + 530.16641; found, 530.16623.
实施例15Example 15
制备N-(2-(N-甲基哌嗪-1-基-亚甲基)吡啶-5-基)-3-硝基-4-(3-氯-丙氧基)-苯甲酰胺(15)Preparation of N- (2- (N-methylpiperazin-1-yl-methylene) pyridin-5-yl) -3-nitro-4- (3-chloro-propoxy) -benzamide ( 15)
Figure PCTCN2019118109-appb-000026
Figure PCTCN2019118109-appb-000026
1)2-(N-甲基哌嗪-1-基-亚甲基)-4-胺基-吡啶的制备1) Preparation of 2- (N-methylpiperazin-1-yl-methylene) -4-amino-pyridine
参照实施例1步骤1)的方法，将3-三氟甲基-4-甲基硝基苯替换为2-甲基-4-硝基吡啶，将4-甲基哌嗪替换为N-甲基哌嗪，制备得到2-(N-甲基哌嗪-1-基-亚甲基)-4-硝基-吡啶中间产物后，继续钯碳氢化还原，得到2-(N-甲基哌嗪-1-基-亚甲基)-4-胺基-吡啶直接投到下一步反应。Referring to the method of step 1) in Example 1, replace 3-trifluoromethyl-4-methylnitrobenzene with 2-methyl-4-nitropyridine and 4-methylpiperazine with N-methyl Piperazine, to prepare 2- (N-methylpiperazin-1-yl-methylene) -4-nitro-pyridine intermediate product, continue palladium hydrocarbon reduction to obtain 2- (N-methylpiper Azin-1-yl-methylene) -4-amino-pyridine was directly dropped into the next reaction.
2-(N-甲基哌嗪-1-基-亚甲基)-4-硝基-吡啶通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下： 2- (N-Methylpiperazin-1-yl-methylene) -4-nitro-pyridine was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.31(s,3H),2.51(m,4H),2.58(m,4H),7.69(d,J＝7.5Hz,1H),8.44(dd,J＝7.5,2.0Hz,1H),9.37(d,J＝2.0Hz,1H)； 13CNMR(CDCl 3,125MHz)δppm 46.1,53.4,55.2,64.0,123.0,131.5,143.4,144.8,166.1； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.31 (s, 3H), 2.51 (m, 4H), 2.58 (m, 4H), 7.69 (d, J = 7.5 Hz, 1H), 8.44 (dd, J = 7.5 , 2.0Hz, 1H), 9.37 ( d, J = 2.0Hz, 1H); 13 CNMR (CDCl 3, 125MHz) δppm 46.1,53.4,55.2,64.0,123.0,131.5,143.4,144.8,166.1;
HRMS(ESI)m/z calcd for C 11H 17N 4O 2(M+H) +237.13460；found,237.13455. HRMS (ESI) m / z calcd for C 11 H 17 N 4 O 2 (M + H) + 237.13460; found, 237.13455.
2)化合物15的制备2) Preparation of compound 15
以2-(N-甲基哌嗪-1-基-亚甲基)-4-胺基-吡啶和实施例10中的3-硝基-4-(3-氯-丙氧基)-苯甲酸为原料，参照实施例1中步骤3)的方法，将3-硝基-4-羟基苯甲酸替换为3-硝基-4-(3-氯-丙氧基)-苯甲酸，将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺替换为2-(N-甲基哌嗪-1-基-亚甲基)-4-胺基-吡啶，最终以二氯甲烷：甲醇：氨水的 体积比为20:1:0.3进行硅胶柱层析分离纯化，得到化合物15。With 2- (N-methylpiperazin-1-yl-methylene) -4-amino-pyridine and 3-nitro-4- (3-chloro-propoxy) -benzene in Example 10 Formic acid is used as the raw material, referring to the method of step 3) in Example 1, replacing 3-nitro-4-hydroxybenzoic acid with 3-nitro-4- (3-chloro-propoxy) -benzoic acid, replacing 3 -Trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline is replaced by 2- (N-methylpiperazin-1-yl-methylene) -4- The amino-pyridine is finally separated and purified by silica gel column chromatography with a volume ratio of dichloromethane: methanol: ammonia water of 20: 1: 0.3 to obtain compound 15.
化合物15通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 15 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CDCl 3,500MHz，δppm)2.28(s,3H),2.32(m,2H),2.46(m,8H),3.64(s,3H),3.81(t,J＝5.5Hz,2H),4.37(t,J＝5.5Hz,2H),7.22(d,J＝7.5Hz,1H),7.43(d,J＝7.0Hz,1H),8.18(dd,J＝7.5,2.0Hz,1H),8.22(dd,J＝7.5,2.0Hz,1H),8.35(s,1H),8.43(d,J＝1.5Hz,1H),8.66(d,J＝1.5Hz,1H)； 1 HNMR (CDCl 3 , 500 MHz, δ ppm) 2.28 (s, 3H), 2.32 (m, 2H), 2.46 (m, 8H), 3.64 (s, 3H), 3.81 (t, J = 5.5 Hz, 2H), 4.37 (t, J = 5.5 Hz, 2H), 7.22 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 7.0 Hz, 1H), 8.18 (dd, J = 7.5, 2.0 Hz, 1H), 8.22 (dd, J = 7.5, 2.0 Hz, 1H), 8.35 (s, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.66 (d, J = 1.5 Hz, 1H);
13CNMR(CDCl 3,100Hz，δppm)31.8,41.1,46.2,53.4,55.2,64.1,66.3,114.7,123.6,124.9,126.6,128.6,133.2,133.9,139.1,141.4,154.9,155.0,163.6； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 31.8, 41.1, 46.2, 53.4, 55.2, 64.1, 66.3, 114.7, 123.6, 124.9, 126.6, 128.6, 133.2, 133.9, 139.1, 141.4, 154.9, 155.0, 163.6;
HRMS(ESI)m/z calcd for C 21H 27ClN 4O 5(M+H) +448.17461；found,448.17444. HRMS (ESI) m / z calcd for C 21 H 27 ClN 4 O 5 (M + H) + 448.17461; found, 448.17444.
实施例16Example 16
制备N-(3-三氟甲基-4-甲基苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺(16)Preparation of N- (3-trifluoromethyl-4-methylphenyl) -3-amino-4- (3-chloro-propoxy) -benzamide (16)
Figure PCTCN2019118109-appb-000027
Figure PCTCN2019118109-appb-000027
以实施例10中的化合物10为原料，参照实施例1步骤1)中的Pd/C还原法，最终将石油醚：乙酸乙酯的体积比为5:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物16。Using the compound 10 in Example 10 as the raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of petroleum ether: ethyl acetate was 5: 1 as the eluent. Column chromatography separated and purified to obtain compound 16.
化合物16通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 16 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3OD,600MHz，δppm)2.29(t,J＝6Hz,2H),2.44(s,3H),3.82(t,J＝6Hz,2H),4.24(t,J＝6Hz,2H),6.94(d,J＝8.4Hz,1H),7.32(m,3H),7.79(dd,J＝8.4,1.8Hz,1H),8.04(d,J＝1.8Hz,1H)； 1 HNMR (CD 3 OD, 600 MHz, δ ppm) 2.29 (t, J = 6 Hz, 2H), 2.44 (s, 3H), 3.82 (t, J = 6 Hz, 2H), 4.24 (t, J = 6 Hz, 2H) , 6.94 (d, J = 8.4 Hz, 1H), 7.32 (m, 3H), 7.79 (dd, J = 8.4, 1.8 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H);
13CNMR(CD 3OD,100MHz，δppm)18.8,33.4,42.3,66.3,111.9,115.3,119.2,119.3,125.1,125.2,126.9,128.6,133.0,133.5,138.4,138.4,150.9,169.1； 13 CNMR (CD 3 OD, 100 MHz, δ ppm) 18.8, 33.4, 42.3, 66.3, 111.9, 115.3, 119.2, 119.3, 125.1, 125.2, 126.9, 128.6, 133.0, 133.5, 138.4, 138.4, 150.9, 169.1;
MS(ESI)m/z calcd for C 18H 19ClF 3N 2O 2(M+H) +387.11；found,387.10. MS (ESI) m / z calcd for C 18 H 19 ClF 3 N 2 O 2 (M + H) + 387.11; found, 387.10.
实施例17Example 17
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺(17)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-amino-4- (3-chloro-propoxy ) -Benzamide (17)
Figure PCTCN2019118109-appb-000028
Figure PCTCN2019118109-appb-000028
以实施例7中的化合物7为原料，参照实施例1步骤1)中的Pd/C还原法，最终将二氯甲烷：甲醇：氨水的体积比为15:1:0.1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物17。Using compound 7 in Example 7 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of dichloromethane: methanol: ammonia water was 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 17.
化合物17通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下： Compound 17 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3Cl,600MHz，δppm)2.31(m,2H),2.32(s,3H),2.52(m,8H),3.62(s,3H),3.75(t,J＝6Hz,2H),3.95(brs,2H),4.23(t,J＝6Hz,2H),6.84(d,J＝8.4Hz,1H),7.22(dd,J＝8.4,1.8Hz,1H),7.29(d,J＝1.8Hz,1H),7.74(d,J＝8.4Hz,1H),7.86(m,3H)； 1 HNMR (CD 3 Cl, 600 MHz, δ ppm) 2.31 (m, 2H), 2.32 (s, 3H), 2.52 (m, 8H), 3.62 (s, 3H), 3.75 (t, J = 6 Hz, 2H), 3.95 (brs, 2H), 4.23 (t, J = 6 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.29 (d, J = 1.8Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.86 (m, 3H);
HRMS(ESI)m/z calcd for C 23H 29ClF 3N 4O 2(M+H) +485.19256；found,485.19230. HRMS (ESI) m / z calcd for C 23 H 29 ClF 3 N 4 O 2 (M + H) + 485.19256; found, 485.19230.
实施例18Example 18
制备N-(3-三氟甲基-4-((3-N，N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺(18)Preparation of N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) phenyl) -3-amino- 4- (3-chloro-propoxy) -benzamide (18)
Figure PCTCN2019118109-appb-000029
Figure PCTCN2019118109-appb-000029
以实施例12中的化合物12为原料，参照实施例1步骤1)中的Pd/C还原法，最终将二氯甲烷：甲醇：氨水的体积比为15:1:0.1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物18。Using compound 12 in Example 12 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol: ammonia water was 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 18.
化合物18通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 18 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3Cl,600MHz，δppm)2.11(s,6H),2.29(t,J＝6Hz,2H),2.96(t,J＝7.2Hz,2H),3.54(t,J＝6Hz,2H),3.74(t,J＝6Hz,2H),3.78(s,2H),4.20(t,J＝6Hz,2H),6.80(d,J＝8.4Hz,1H),7.20(dd,J＝8.4,2.4Hz,1H),7.24(d,J＝2.4Hz,1H),7.61(d,J＝8.4Hz,1H),7.81(dd,J＝8.4,1.8Hz,1H),7.84(m,1H),7.99(s,1H)； 1 HNMR (CD 3 Cl, 600 MHz, δ ppm) 2.11 (s, 6H), 2.29 (t, J = 6 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 3.54 (t, J = 6 Hz, 2H) ), 3.74 (t, J = 6 Hz, 2H), 3.78 (s, 2H), 4.20 (t, J = 6 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4 , 2.4Hz, 1H), 7.24 (d, J = 2.4Hz, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.81 (dd, J = 8.4, 1.8Hz, 1H), 7.84 (m, 1H ), 7.99 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)32.2,41.5,42.2,56.9,58.9,59.8,65.1,110.7,113.8,117.5(d,J＝6.4Hz),123.3,124.2(q,J＝272.6Hz),127.4,128.6(q,J＝30.3Hz),130.5,132.8,136.7,137.1,149.2,165.9； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 32.2, 41.5, 42.2, 56.9, 58.9, 59.8, 65.1, 110.7, 113.8, 117.5 (d, J = 6.4 Hz), 123.3, 124.2 (q, J = 272.6 Hz), 127.4, 128.6 (q, J = 30.3 Hz), 130.5, 132.8, 136.7, 137.1, 149.2, 165.9;
HRMS(ESI)m/z calcd for C 23H 29ClF 3N 4O 2(M+H) +485.19256；found,485.19228. HRMS (ESI) m / z calcd for C 23 H 29 ClF 3 N 4 O 2 (M + H) + 485.19256; found, 485.19228.
实施例19Example 19
制备N-(3-三氟甲基-4-((3,5-二甲基-吗啉-1-基)-亚甲基)苯基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺(19)Preparation of N- (3-trifluoromethyl-4-((3,5-dimethyl-morpholin-1-yl) -methylene) phenyl) -3-amino-4- (3-chloro -Propoxy) -benzamide (19)
Figure PCTCN2019118109-appb-000030
Figure PCTCN2019118109-appb-000030
以实施例14中的化合物14为原料，参照实施例1步骤1)中的Pd/C还原法，最终将石油醚：乙酸乙酯的体积比为5:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物19。Using compound 14 in Example 14 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of petroleum ether: ethyl acetate was 5: 1 as the eluent. Column chromatography separated and purified to obtain compound 19.
化合物19通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 19 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3OD,500MHz，δppm)2.30(q,J＝6.0Hz,2H),2.53(s,3H),2.67(m,4H),2.84(m 4H),3.69(s,2H),3.82(t,J＝6.6Hz,2H),4.24(t,J＝6.0Hz,2H),6.95(d,J＝7.8Hz,1H),7.32(dd,J＝8.4,2.4Hz,1H),7.34(s,1H),7.50(d,J＝8.4Hz,1H),8.19(dd,J＝8.4,2.4Hz,1H),8.83(d,J＝2.4Hz,1H)； 1 HNMR (CD 3 OD, 500 MHz, δ ppm) 2.30 (q, J = 6.0 Hz, 2H), 2.53 (s, 3H), 2.67 (m, 4H), 2.84 (m 4H), 3.69 (s, 2H), 3.82 (t, J = 6.6 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 6.95 (d, J = 7.8 Hz, 1H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.34 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 8.19 (dd, J = 8.4, 2.4 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H);
13CNMR(CDCl 3,100Hz，δppm)19.07,32.0,41.3,57.8,59.4,64.9,71.7,110.6,113.6,117.4(d,J＝6.4Hz),123.1,124.2(q,J＝272.6Hz),127.35,131.4,136.6,165.7； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 19.07, 32.0, 41.3, 57.8, 59.4, 64.9, 71.7, 110.6, 113.6, 117.4 (d, J = 6.4 Hz), 123.1, 124.2 (q, J = 272.6 Hz), 127.35, 131.4, 136.6, 165.7;
HRMS(ESI)m/z calcd for C 21H 29ClN 5O 2(M+H) +418.20043；found,418.20044. HRMS (ESI) m / z calcd for C 21 H 29 ClN 5 O 2 (M + H) + 418.20043; found, 418.20044.
实施例20Example 20
制备N-(2-(N-甲基哌嗪-1-基-亚甲基)吡啶-5-基)-3-胺基-4-(3-氯-丙氧基)-苯甲酰胺(20)Preparation of N- (2- (N-methylpiperazin-1-yl-methylene) pyridin-5-yl) -3-amino-4- (3-chloro-propoxy) -benzamide ( 20)
Figure PCTCN2019118109-appb-000031
Figure PCTCN2019118109-appb-000031
以实施例15中的化合物15为原料，参照实施例1步骤1)中的Pd/C还原法，最终将二氯甲烷：甲醇：氨水的体积比为15:1:0.1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得化合物20。Using compound 15 in Example 15 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol: ammonia was 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 20.
化合物20通过核磁共振氢谱( 1HNMR)和高分辨质谱(HRMS)表征如下： Compound 20 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3Cl,600MHz，δppm)1.18(t,J＝6.0Hz,3H),1.40(s,6H),1.84(t,J＝6.0Hz,2H),2.25(s,6H),2.37(t,J＝6.0Hz,2H),3.24(dd,2H),4.23(t,J＝6.0Hz,2H),6.83(d,J＝8.4Hz,1H),7.20(dd,J＝8.4,2.4Hz,1H),7.27(d,J＝2.4Hz,1H),7.74(d,J＝8.4Hz,1H),7.83(m,1H),7.86(d,J＝8.4Hz,1H),7.87(s,1H)； 1 HNMR (CD 3 Cl, 600 MHz, δ ppm) 1.18 (t, J = 6.0 Hz, 3H), 1.40 (s, 6H), 1.84 (t, J = 6.0 Hz, 2H), 2.25 (s, 6H), 2.37 (t, J = 6.0 Hz, 2H), 3.24 (dd, 2H), 4.23 (t, J = 6.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.4, 2.4Hz, 1H), 7.27 (d, J = 2.4Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.83 (m, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.87 (s, 1H);
HRMS(ESI)m/z calcd for C 24H 30ClF 3N 3O 3(M+H) +500.19223；found,500.19229. HRMS (ESI) m / z calcd for C 24 H 30 ClF 3 N 3 O 3 (M + H) + 500.19223; found, 500.19229.
实施例21Example 21
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-异丙氧基-苯甲酰胺(21)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-amino-4-isopropoxy-benzamide (twenty one)
Figure PCTCN2019118109-appb-000032
Figure PCTCN2019118109-appb-000032
以实施例3中的化合物3为原料，参照实施例1步骤1)中的Pd/C还原法，最终将二氯甲烷：甲醇：氨水的体积比为15:1:0.1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到 化合物21。Using compound 3 in Example 3 as a raw material, referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol: ammonia water is 15: 1: 0.1 as the eluent to concentrate The liquid was separated and purified by silica gel column chromatography to obtain compound 21.
化合物21通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 21 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.39(d,J＝6.0Hz,6H),2.31(s,3H),2.52(m,8H),3.63(s,2H),3.95(br s,2H),4.64(m 1H),6.82(d,J＝8.5Hz,1H),7.20(d,J＝8.5,1H),7.74(d,J＝8.5Hz,1H),7.84(m,3H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.39 (d, J = 6.0 Hz, 6H), 2.31 (s, 3H), 2.52 (m, 8H), 3.63 (s, 2H), 3.95 (br s, 2H ), 4.64 (m 1H), 6.82 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.84 (m, 3H);
13CNMR(CDCl 3,100Hz，δppm)22.2,46.0,53.0,55.2,57.9,70.8,111.9,113.8,117.6(d,J＝7.8Hz),123.3,124.2(q,J＝272.7Hz),126.8,129.3(q,J＝30.0Hz),131.3,133.1,137.2,137.4,148.5,166.1； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 22.2, 46.0, 53.0, 55.2, 57.9, 70.8, 111.9, 113.8, 117.6 (d, J = 7.8 Hz), 123.3, 124.2 (q, J = 272.7 Hz), 126.8, 129.3 (q, J = 30.0Hz), 131.3, 133.1, 137.2, 137.4, 148.5, 166.1;
HRMS(ESI)m/z calcd for C 22H 25ClF 3N 4O 4(M+H) +501.15109；found,501.15028. HRMS (ESI) m / z calcd for C 22 H 25 ClF 3 N 4 O 4 (M + H) + 501.15109; found, 501.15028.
实施例22Example 22
制备N-(3-三氟甲基-4-甲基苯基)-3-胺基-4-丙氧基-苯甲酰胺(22)Preparation of N- (3-trifluoromethyl-4-methylphenyl) -3-amino-4-propoxy-benzamide (22)
Figure PCTCN2019118109-appb-000033
Figure PCTCN2019118109-appb-000033
以4-羟基-3-硝基苯甲酸为和4-甲基-3-三氟甲基-苯胺为原料，参照实施例1中步骤3的方法反应，柱层析石油醚/乙酸乙酯(5:1)洗脱，得到N-(3-三氟甲基-4-甲基苯基)-3-硝基-4–羟基-苯甲酰胺，此化合物用实施例2中步骤1的方法与溴丙烷反应得到N-(3-三氟甲基-4-甲基苯基)-3-硝基-4–丙氧基-苯甲酰胺，再经实施例1步骤1中的催化氢化还原得到化合物22。Using 4-hydroxy-3-nitrobenzoic acid as the raw material and 4-methyl-3-trifluoromethyl-aniline as the raw material, referring to the method of step 3 in Example 1, the reaction was performed by column chromatography petroleum ether / ethyl acetate ( 5: 1) elution to obtain N- (3-trifluoromethyl-4-methylphenyl) -3-nitro-4-hydroxy-benzamide, this compound was used in the method of step 1 in Example 2 Reaction with bromopropane yields N- (3-trifluoromethyl-4-methylphenyl) -3-nitro-4-propoxy-benzamide, which is then reduced by catalytic hydrogenation in step 1 of Example 1 Compound 22 is obtained.
化合物22通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 22 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.06(t,J＝6.0Hz,3H),1.83(br s,2H),1.87(m,2H),2.44(s,3H),4.01(t,J＝5.5Hz,3H),6.82(d,J＝7.0Hz,1H),7.23(m,1H),7.26(m,2H),7.79(d,J＝7.0Hz,1H),7.81(s,1H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.06 (t, J = 6.0 Hz, 3H), 1.83 (br s, 2H), 1.87 (m, 2H), 2.44 (s, 3H), 4.01 (t, J = 5.5 Hz, 3H), 6.82 (d, J = 7.0 Hz, 1H), 7.23 (m, 1H), 7.26 (m, 2H), 7.79 (d, J = 7.0 Hz, 1H), 7.81 (s, 1H );
MS(ESI)m/z calcd for C 18H 20F 3N 2O 2(M+H) +353.15；found,353.20. MS (ESI) m / z calcd for C 18 H 20 F 3 N 2 O 2 (M + H) + 353.15; found, 353.20.
实施例23Example 23
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-(5-氯-戊氧基)-苯甲酰胺(23)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-amino-4- (5-chloro-pentyloxy ) -Benzamide (23)
Figure PCTCN2019118109-appb-000034
Figure PCTCN2019118109-appb-000034
以实施例8中的化合物8为原料，参照实施例1步骤1)中的Pd/C还原法，最终将二氯甲烷：甲醇的体积比为15:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物23。Using compound 8 in Example 8 as a raw material and referring to the Pd / C reduction method in Step 1) of Example 1, the final volume ratio of methylene chloride: methanol was 15: 1 as the eluent. Chromatographic separation and purification gave compound 23.
化合物23通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 23 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3OD,600MHz，δppm)1.1.43(m,1H),1.48(m,1H),1.65(m,1H),1.85(m,3H),2.50(s,3H),2.62(m,4H),2.79(m,4H),3.59(t,J＝6.0Hz,2H),3.67(s,2H),4.07(m,2H),6.89(dd,J＝8.4,3.0Hz,1H),7.32(m,2H),7.71(d,J＝8.4Hz,1H),7.90(dd,J＝8.4,3.0Hz,1H),8.10(d,J＝1.8Hz,1H)； 1 HNMR (CD 3 OD, 600 MHz, δ ppm) 1.1.43 (m, 1H), 1.48 (m, 1H), 1.65 (m, 1H), 1.85 (m, 3H), 2.50 (s, 3H), 2.62 ( m, 4H), 2.79 (m, 4H), 3.59 (t, J = 6.0 Hz, 2H), 3.67 (s, 2H), 4.07 (m, 2H), 6.89 (dd, J = 8.4, 3.0 Hz, 1H ), 7.32 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.4, 3.0 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H);
13CNMR(CD 3OD,150Hz)δppm 23.5,24.5,29.3,29.5,33.4,45.0,45.6,52.6,55.5,58.6,69.2,69.5,111.5,115.1,119.3,124.9,125.7(q,J＝271.8Hz),127.9,128.0,130.1(q,J＝30.1Hz),132.5,133.0,133.4,138.1,139.6,151.3,169.1； 13 CNMR (CD 3 OD, 150 Hz) δ ppm 23.5, 24.5, 29.3, 29.5, 33.4, 45.0, 45.6, 52.6, 55.5, 58.6, 69.2, 69.5, 111.5, 115.1, 119.3, 124.9, 125.7 (q, J = 271.8Hz ), 127.9, 128.0, 130.1 (q, J = 30.1Hz), 132.5, 133.0, 133.4, 138.1, 139.6, 151.3, 169.1;
HRMS(ESI)m/z calcd for C 25H 33ClF 3N 4O 2(M+H) +513.22387；found,513.22375. HRMS (ESI) m / z calcd for C 25 H 33 ClF 3 N 4 O 2 (M + H) + 513.22387; found, 513.22375.
实施例24Example 24
制备N-(3-三氟甲基-4-甲基苯基)-3-丙酰胺基-4-丙氧基-苯甲酰胺(24)Preparation of N- (3-trifluoromethyl-4-methylphenyl) -3-propionamido-4-propoxy-benzamide (24)
Figure PCTCN2019118109-appb-000035
Figure PCTCN2019118109-appb-000035
0℃下，将丙酰氯(1.1eq)加入到化合物22(1.0eq)的二氯甲烷或DMF溶液中，在碱性条件下，例如三乙胺或吡啶(1.5-2.0eq)的催化下，搅拌反应30min后，将反应液升至室温继续搅拌反应，直至TLC监测化合物22消失停止反应。反应液用一定量的乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，最终将二氯甲烷：甲醇的体积比为20:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物24。At 0 ° C, propionyl chloride (1.1 eq) is added to a solution of compound 22 (1.0 eq) in methylene chloride or DMF, under basic conditions, such as triethylamine or pyridine (1.5-2.0 eq), After stirring the reaction for 30 min, the reaction solution was raised to room temperature to continue stirring the reaction until TLC monitored the disappearance of compound 22 to stop the reaction. After the reaction solution was diluted with a certain amount of ethyl acetate, it was washed with saturated sodium bicarbonate solution and brine successively, dried over anhydrous sodium sulfate, filtered and concentrated. Finally, the volume ratio of dichloromethane: methanol was 20: 1 as the elution The concentrated solution was separated and purified by silica gel column chromatography to obtain compound 24.
化合物24通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 24 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.08(t,J＝7.0Hz,3H),1.26(t,J＝7.5Hz,3H),1.89(q,J＝7.0Hz,2H),2.44(s,3H),2.46(m,2H),4.06(t,J＝6.5Hz,2H),6.94(d,J＝8.5Hz,1H),7.24(d,J＝8.5Hz,1H),7.75(m,2H),7.86(d,J＝8.5Hz,1H),7.87(s,1H),8.16(s,1H),8.89(s,1H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.08 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H), 1.89 (q, J = 7.0 Hz, 2H), 2.44 (s , 3H), 2.46 (m, 2H), 4.06 (t, J = 6.5Hz, 2H), 6.94 (d, J = 8.5Hz, 1H), 7.24 (d, J = 8.5Hz, 1H), 7.75 (m , 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 8.16 (s, 1H), 8.89 (s, 1H);
13CNMR(CD 3Cl,100Hz，δppm)9.6,10.5,18.8,22.5,31.2,70.5,111.1,117.0,118.0(d,J＝6.0Hz),123.4,124.9,126.8,127.5,132.2,132.5,136.2,150.0,165.3,172.4； 13 CNMR (CD 3 Cl, 100 Hz, δ ppm) 9.6, 10.5, 18.8, 22.5, 31.2, 70.5, 111.1, 117.0, 118.0 (d, J = 6.0 Hz), 123.4, 124.9, 126.8, 127.5, 132.2, 132.5, 136.2 , 150.0,165.3,172.4;
HRMS(ESI)m/z calcd for C 21H 21F 7N 3O(M+H) +464.15674；found,464.15592. HRMS (ESI) m / z calcd for C 21 H 21 F 7 N 3 O (M + H) + 464.15674; found, 464.15592.
实施例25Example 25
制备N-(4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-甲氧基苯甲酰胺(25)Preparation of N- (4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4-methoxybenzamide (25)
Figure PCTCN2019118109-appb-000036
Figure PCTCN2019118109-appb-000036
1)3-丙酰胺基-4-甲氧基苯甲酸的制备1) Preparation of 3-propionamido-4-methoxybenzoic acid
0℃下，将丙酰氯(1.1eq)加入到3-氨基-4-甲氧基苯甲酸(1.0eq)的二氯甲烷或DMF溶液中，在碱性条件下，例如三乙胺或吡啶(1.5-2.0eq)的催化下，搅拌反应30min后，将反应液升至室温继续搅拌反应，直至TLC监测3-氨基-4-甲氧基苯甲酸消失停止反应。反应液用一定量的乙酸乙酯稀释后，依次用饱和碳酸氢钠溶液和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，得到3-丙酰胺基-4-甲氧基苯甲酸。At 0 ° C, propionyl chloride (1.1 eq) is added to a solution of 3-amino-4-methoxybenzoic acid (1.0 eq) in methylene chloride or DMF. Under basic conditions, such as triethylamine or pyridine ( Under the catalysis of 1.5-2.0eq), after stirring the reaction for 30min, the reaction solution was raised to room temperature to continue stirring the reaction until TLC monitored the disappearance of 3-amino-4-methoxybenzoic acid to stop the reaction. After the reaction solution was diluted with a certain amount of ethyl acetate, it was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3-propionamido-4-methoxybenzoic acid.
3-丙酰胺基-4-甲氧基苯甲酸通过核磁共振氢谱( 1HNMR)表征如下： The 3-propionamido-4-methoxybenzoic acid was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(DMSO-d 6,400MHz，δppm)1.07(t,J＝7.2Hz,3H),2.40(q,J＝7.2Hz,2H),3.89(s,3H),7.11(d,J＝8.8Hz,1H),7.68(dd,J＝8.8,2.0Hz,1H),8.57(s,1H),9.13(s,1H),12.59(s,1H). 1 HNMR (DMSO-d 6 , 400 MHz, δ ppm) 1.07 (t, J = 7.2 Hz, 3H), 2.40 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 7.11 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.8, 2.0 Hz, 1H), 8.57 (s, 1H), 9.13 (s, 1H), 12.59 (s, 1H).
2)化合物25的制备2) Preparation of compound 25
参照实施例1步骤3)的方法，将3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯胺替换为4-((4-甲基哌嗪-1-基)-亚甲基)苯胺，将3-硝基-4-羟基苯甲酸替换为3-丙酰胺基-4-甲氧基苯甲酸，最终将二氯甲烷：甲醇：氨水的体积比为20:1:0.1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物25。Referring to the method of step 3) in Example 1, replace 3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) aniline with 4-((4-methylpiper Aziridine-1-yl) -methylene) aniline, replacing 3-nitro-4-hydroxybenzoic acid with 3-propionamido-4-methoxybenzoic acid, and finally dichloromethane: methanol: ammonia A volume ratio of 20: 1: 0.1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 25.
化合物25通过核磁共振氢谱( 1HNMR)表征如下： Compound 25 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) as follows:
1HNMR(CD 3Cl,400MHz，δppm)1.27(t,J＝8.0Hz,3H),2.30(s,3H),2.47(m,8H),3.48(s,2H),3.95(s,3H),6.98(d,J＝8.8Hz,1H),7.30(d,J＝8.8Hz,1H),7.59(m,2H),7.79(dd,J＝8.8,2.6Hz,1H),7.82(br s,1H),7.94(s,1H),8.89(s,1H). 1 HNMR (CD 3 Cl, 400 MHz, δ ppm) 1.27 (t, J = 8.0 Hz, 3H), 2.30 (s, 3H), 2.47 (m, 8H), 3.48 (s, 2H), 3.95 (s, 3H) , 6.98 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.59 (m, 2H), 7.79 (dd, J = 8.8, 2.6 Hz, 1H), 7.82 (br s , 1H), 7.94 (s, 1H), 8.89 (s, 1H).
实施例26Example 26
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-甲氧基苯甲酰胺(26)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4-methoxybenzamide ( 26)
Figure PCTCN2019118109-appb-000037
Figure PCTCN2019118109-appb-000037
以实施例2中的化合物2为原料，参照实施例10步骤3)的方法，得到N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-甲氧基苯甲酰胺；Using Compound 2 in Example 2 as a raw material and referring to the method of Step 3) in Example 10, N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene Group) phenyl) -3-amino-4-methoxybenzamide;
参照实施例25步骤1)的方法，将3-氨基-4-甲氧基苯甲酸替换为N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-胺基-4-甲氧基苯甲酰胺，最终将二氯甲烷：甲醇的体积比 为20:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物26。Referring to the method of step 1) in Example 25, replace 3-amino-4-methoxybenzoic acid with N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl)- Methylene) phenyl) -3-amino-4-methoxybenzamide, the final dichloromethane: methanol volume ratio is 20: 1 as the eluent, the concentrated liquid was separated and purified by silica gel column chromatography To give compound 26.
化合物26通过核磁共振氢谱( 1HNMR)表征如下： Compound 26 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) as follows:
1HNMR(CD 3Cl,400MHz，δppm)1.28(t,J＝8.0Hz,3H),2.32(s,3H),2.47(m,10H),3.63(s,2H),3.96(s,3H),7.00(d,J＝8.8Hz,1H),7.74(d,J＝8.8Hz,1H),7.81(dd,J＝8.8,2.4Hz,1H),7.85(m,2H),7.91(d,J＝2.4Hz,1H),8.19(s,1H),8.89(s,1H). 1 HNMR (CD 3 Cl, 400 MHz, δ ppm) 1.28 (t, J = 8.0 Hz, 3H), 2.32 (s, 3H), 2.47 (m, 10H), 3.63 (s, 2H), 3.96 (s, 3H) , 7.00 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.81 (dd, J = 8.8, 2.4 Hz, 1H), 7.85 (m, 2H), 7.91 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.89 (s, 1H).
实施例27Example 27
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-异丙氧基苯甲酰胺(27)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4-isopropoxybenzamide (27)
Figure PCTCN2019118109-appb-000038
Figure PCTCN2019118109-appb-000038
以实施例21中的化合物21为原料，参照实施例25步骤1)的方法，将3-氨基-4-甲氧基苯甲酸替换为化合物21，最终将二氯甲烷：甲醇的体积比为20:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物27。Using compound 21 in Example 21 as a raw material and referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 21, and finally the volume ratio of dichloromethane: methanol was 20 : 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 27.
化合物27通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 27 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.27(t,J＝7.5Hz,3H),1.42(d,J＝6.0Hz,6H),2.47(m,5H),2.70(m,8H),3.66(s,2H),4.71(m,1H),6.98(d,J＝8.5Hz,1H),7.65(d,J＝8.5Hz,1H),7.77(d,J＝8.5Hz,1H),7.86(m,2H),7.91(s,1H),8.22(s,1H),8.91(s,1H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.27 (t, J = 7.5 Hz, 3H), 1.42 (d, J = 6.0 Hz, 6H), 2.47 (m, 5H), 2.70 (m, 8H), 3.66 (s, 2H), 4.71 (m, 1H), 6.98 (d, J = 8.5Hz, 1H), 7.65 (d, J = 8.5Hz, 1H), 7.77 (d, J = 8.5Hz, 1H), 7.86 (m, 2H), 7.91 (s, 1H), 8.22 (s, 1H), 8.91 (s, 1H);
13CNMR(CDCl 3,125Hz，δppm)9.6,18.7,22.1,31.1,44.8,45.9,51.5,54.6,57.7,71.7,112.2,117.7,118.1(d，J＝6.4Hz),123.5,124.2(q,J＝272.6Hz),124.9,126.5 127.8,129.2(q,J＝30Hz),131.4,132.1,137.8,149.0,165.6,172.4. 13 CNMR (CDCl 3 , 125 Hz, δ ppm) 9.6, 18.7, 22.1, 31.1, 44.8, 45.9, 51.5, 54.6, 57.7, 71.7, 112.2, 117.7, 118.1 (d, J = 6.4 Hz), 123.5, 124.2 (q, J = 272.6 Hz), 124.9, 126.5 127.8, 129.2 (q, J = 30 Hz), 131.4, 132.1, 137.8, 149.0, 165.6, 172.4.
实施例28Example 28
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-(2-溴-丙酰胺基)-4-异丙氧基苯甲酰胺(28)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3- (2-bromo-propionamido) -4-iso Propoxybenzamide (28)
Figure PCTCN2019118109-appb-000039
Figure PCTCN2019118109-appb-000039
以实施例21中的化合物21为原料，参照实施例25步骤1)的方法，将3-氨基-4-甲氧基苯甲酸替换为化合物21，将丙酰氯替换为2-溴-丙酰氯，最终将二氯甲烷：甲醇的体积比为20:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物28。Using compound 21 in Example 21 as a raw material, referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 21, and propionyl chloride was replaced with 2-bromo-propionyl chloride, Finally, the dichloromethane: methanol volume ratio of 20: 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 28.
化合物28通过核磁共振氢谱( 1HNMR)表征如下： Compound 28 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.43(d,J＝5.0Hz,6H),1.99(d,J＝6.0Hz,3H),2.28 (s,3H),2.49(m,8H),3.62(s,2H),4.60(m,1H),4.73(m,1H),7.00(d,J＝8.5Hz,1H),7.74(m,2H),7.79(dd,J＝8.5,2.5Hz,1H),7.85(d,J＝8.5Hz,1H),7.88(s,1H),8.16(s,1H),8.81(s,1H),8.95(s,1H). 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.43 (d, J = 5.0 Hz, 6H), 1.99 (d, J = 6.0 Hz, 3H), 2.28 (s, 3H), 2.49 (m, 8H), 3.62 (s, 2H), 4.60 (m, 1H), 4.73 (m, 1H), 7.00 (d, J = 8.5Hz, 1H), 7.74 (m, 2H), 7.79 (dd, J = 8.5, 2.5Hz, 1H), 7.85 (d, J = 8.5Hz, 1H), 7.88 (s, 1H), 8.16 (s, 1H), 8.81 (s, 1H), 8.95 (s, 1H).
化合物29Compound 29
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-(3-氯-丙氧基)苯甲酰胺(29)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4- (3-chloro-propoxy Group) benzamide (29)
Figure PCTCN2019118109-appb-000040
Figure PCTCN2019118109-appb-000040
以实施例17中的化合物17为原料，参照实施例25步骤1)的方法，将3-氨基-4-甲氧基苯甲酸替换为化合物17，最终将二氯甲烷：甲醇：氨水的体积比为20:1：0.1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物29。Using compound 17 in Example 17 as a raw material and referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 17, and finally the volume ratio of methylene chloride: methanol: ammonia water The concentrated solution was separated and purified by silica gel column chromatography using 20: 1: 0.1 as the eluent to obtain compound 29.
化合物29通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 29 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.24(t,J＝7.2Hz,3H),2.32(m,5H),2.52(m,8H),3.61(s,2H),3.74(t,J＝6.0Hz,2H),4.27(t,J＝6.0Hz,1H),6.97(d,J＝9.0Hz,1H),7.69(d,J＝8.4Hz,1H),7.75(d,J＝8.4Hz,1H),7.84(s,1H),7.86(d,J＝8.4Hz,1H),7.91(s,1H),8.53(s,1H),8.83(s,1H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.24 (t, J = 7.2 Hz, 3H), 2.32 (m, 5H), 2.52 (m, 8H), 3.61 (s, 2H), 3.74 (t, J = 6.0Hz, 2H), 4.27 (t, J = 6.0Hz, 1H), 6.97 (d, J = 9.0Hz, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.75 (d, J = 8.4Hz , 1H), 7.84 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.91 (s, 1H), 8.53 (s, 1H), 8.83 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)9.6,31.1,31.8,41.5,45.7,52.7,55.1,57.9,66.2,111.2,117.7,117.9(q,J＝5.8Hz),123.5,124.1(q,J＝272.5Hz),127.3,127.4,129.2(q,J＝30.1Hz),131.3,133.0,137.2,149.7,165.3,172.5. 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 9.6, 31.1, 31.8, 41.5, 45.7, 52.7, 55.1, 57.9, 66.2, 111.2, 117.7, 117.9 (q, J = 5.8 Hz), 123.5, 124.1 (q, J = 272.5Hz), 127.3, 127.4, 129.2 (q, J = 30.1Hz), 131.3, 133.0, 137.2, 149.7, 165.3, 172.5.
化合物30Compound 30
制备N-(3-三氟甲基-4-((4-甲基哌嗪-1-基)-亚甲基)苯基)-3-丙酰胺基-4-(5-氯-戊氧基)-苯甲酰胺(30)Preparation of N- (3-trifluoromethyl-4-((4-methylpiperazin-1-yl) -methylene) phenyl) -3-propionamido-4- (5-chloro-pentyloxy Base) -benzamide (30)
Figure PCTCN2019118109-appb-000041
Figure PCTCN2019118109-appb-000041
以实施例23中的化合物23为原料，参照实施例24的方法，将化合物替换为化合物23，最终将二氯甲烷：甲醇的体积比为20:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物30。Using compound 23 in Example 23 as the raw material and referring to the method in Example 24, the compound was replaced with compound 23, and finally the volume ratio of dichloromethane: methanol was 20: 1 as the eluent. The concentrated solution was subjected to silica gel column layer Separation and purification gave compound 30.
化合物30通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 30 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.64(m,2H),1.84(m,4H),2.28(s,3H),2.49(m,8H),3.58(m,4H),3.93(s,2H),4.03(t,J＝6.0Hz,2H),6.77(d,J＝9.0Hz,1H),7.20(d,J＝8.4Hz,1H),7.25(d,J＝8.4Hz,1H),7.71(d,J＝8.4Hz,1H),7.81(m,2H),8.02(s, 1H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.64 (m, 2H), 1.84 (m, 4H), 2.28 (s, 3H), 2.49 (m, 8H), 3.58 (m, 4H), 3.93 (s, 2H), 4.03 (t, J = 6.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H) , 7.71 (d, J = 8.4 Hz, 1H), 7.81 (m, 2H), 8.02 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)9.5,14.0,22.3,23.2,28.1,28.2,28.6,29.6,31.0,44.7,45.4,52.3,54.9,57.7,68.5,69.0,110.9,116.8,117.0,117.7(q,J＝5.8Hz),123.3,124.8,126.7,127.3,129.2(q,J＝30.1Hz),131.3,132.8,137.0,149.8,149.9,165.1,172.3. 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 9.5, 14.0, 22.3, 23.2, 28.1,28.2, 28.6, 29.6, 31.0, 44.7, 45.4, 52.3, 54.9, 57.7, 68.5, 69.0, 110.9, 116.8, 117.0, 117.7 ( q, J = 5.8Hz), 123.3, 124.8, 126.7, 127.3, 129.2 (q, J = 30.1Hz), 131.3, 132.8, 137.0, 149.8, 149.9, 165.1, 172.3.
实施例31Example 31
制备N-(3-三氟甲基-4-((3-N，N-二甲基氨基-氮杂环丁烷-1-基)-亚甲基)苯基)-3-丙酰胺基-4-(3-氯-丙氧基)-苯甲酰胺(31)Preparation of N- (3-trifluoromethyl-4-((3-N, N-dimethylamino-azetidin-1-yl) -methylene) phenyl) -3-propionamide -4- (3-chloro-propoxy) -benzamide (31)
Figure PCTCN2019118109-appb-000042
Figure PCTCN2019118109-appb-000042
以实施例18中的化合物18为原料，参照实施例25步骤1)的方法，将3-氨基-4-甲氧基苯甲酸替换为化合物18，最终将二氯甲烷：甲醇的体积比为20:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物31。Using compound 18 in Example 18 as a raw material and referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 18, and finally the volume ratio of methylene chloride to methanol was 20 : 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 31.
化合物31通过核磁共振氢谱( 1HNMR)和核磁共振碳谱( 13CNMR)表征如下： Compound 31 is characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR) and nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.27(t,J＝8.0Hz,3H),2.12(s,6H),2.35(m,2H),2.47(m,2H),2.95(m,3H),3.56(t,J＝6.0Hz,2H),3.75(t,J＝7.2Hz,2H),3.79(s,2H),4.30(t,J＝7.2Hz,2H),7.01(d,J＝9.6Hz,1H),7.63(d,J＝9.6Hz,1H),7.78(d,J＝9.6Hz,1H),7.85(m,1H),7.92(s,1H),8.10(s,1H),8.88(s,1H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.27 (t, J = 8.0 Hz, 3H), 2.12 (s, 6H), 2.35 (m, 2H), 2.47 (m, 2H), 2.95 (m, 3H) , 3.56 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 7.2 Hz, 2H), 3.79 (s, 2H), 4.30 (t, J = 7.2 Hz, 2H), 7.01 (d, J = 9.6Hz, 1H), 7.63 (d, J = 9.6Hz, 1H), 7.78 (d, J = 9.6Hz, 1H), 7.85 (m, 1H), 7.92 (s, 1H), 8.10 (s, 1H) , 8.88 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)9.6,31.1,31.8,41.5,42.2,57.0,59.1,59.9,66.2,111.3,117.2,117.8(q,J＝6.0Hz),123.4,124.2(q,J＝272.5Hz),127.3,127.6,128.7(q,J＝30.1Hz),130.4,133.0,136.9,149.6,165.2,172.5. 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 9.6, 31.1, 31.8, 41.5, 42.2, 57.0, 59.1, 59.9, 66.2, 111.3, 117.2, 117.8 (q, J = 6.0 Hz), 123.4, 124.2 (q, J = 272.5Hz), 127.3, 127.6, 128.7 (q, J = 30.1Hz), 130.4, 133.0, 136.9, 149.6, 165.2, 172.5.
实施例32Example 32
制备N-(2-(N-甲基哌嗪-1-基-亚甲基)吡啶-5-基)-3-丙酰胺基-4-(3-氯-丙氧基)-苯甲酰胺(32)Preparation of N- (2- (N-methylpiperazin-1-yl-methylene) pyridin-5-yl) -3-propionamido-4- (3-chloro-propoxy) -benzamide (32)
Figure PCTCN2019118109-appb-000043
Figure PCTCN2019118109-appb-000043
以实施例20中的化合物18为原料，参照实施例25步骤1)的方法，将3-氨基-4-甲氧基苯甲酸替换为化合物20，最终将二氯甲烷：甲醇的体积比为10:1作为洗脱液对浓缩液进行硅胶柱层析分离纯化，得到化合物32。Using compound 18 in Example 20 as a raw material, referring to the method of step 1) in Example 25, 3-amino-4-methoxybenzoic acid was replaced with compound 20, and finally the volume ratio of methylene chloride: methanol was 10 : 1 was used as the eluent to separate and purify the concentrated solution by silica gel column chromatography to obtain compound 32.
化合物32通过核磁共振氢谱( 1HNMR)、核磁共振碳谱( 13CNMR)和高分辨质谱(HRMS)表征如下： Compound 32 was characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 HNMR), nuclear magnetic resonance carbon spectroscopy ( 13 CNMR) and high resolution mass spectrometry (HRMS) as follows:
1HNMR(CD 3Cl,500MHz，δppm)1.17(t,J＝7.5Hz,3H),2.24(s,3H),2.29(m,2H), 2.47(m,10H),3.57(s,2H),3.71(t,J＝6.0Hz,2H),4.23(t,J＝6.0Hz,2H),6.92(d,J＝7.5Hz,1H),7.33(d,J＝7.5Hz,1H),7.71(d,J＝7.5Hz,1H),8.17(d,J＝7.5Hz,1H),8.65(d,J＝1.5Hz,1H),8.76(s,1H),8.84(s,1H)； 1 HNMR (CD 3 Cl, 500 MHz, δ ppm) 1.17 (t, J = 7.5 Hz, 3H), 2.24 (s, 3H), 2.29 (m, 2H), 2.47 (m, 10H), 3.57 (s, 2H) , 3.71 (t, J = 6.0 Hz, 2H), 4.23 (t, J = 6.0 Hz, 2H), 6.92 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 8.65 (d, J = 1.5 Hz, 1H), 8.76 (s, 1H), 8.84 (s, 1H);
13CNMR(CDCl 3,100Hz，δppm)9.6,30.9,31.7,41.4,46.0,53.2,55.0,64.0,66.0,111.0,118.0,123.2,124.9,127.2,128.2,133.9,141.3,149.7,153.7,165.7,172.4； 13 CNMR (CDCl 3 , 100 Hz, δ ppm) 9.6, 30.9, 31.7, 41.4, 46.0, 53.2, 55.0, 64.0, 66.0, 111.0, 118.0, 123.2, 124.9, 127.2, 128.2, 133.9, 141.3, 149.7, 153.7, 165.7, 172.4;
HRMS(ESI)m/z calcd for C 24H 33ClN 5O 3(M+H) +474.22664；found,474.22678. HRMS (ESI) m / z calcd for C 24 H 33 ClN 5 O 3 (M + H) + 474.22664; found, 474.22678.
抗HCV活性测试Anti-HCV activity test
将实施例1-32制备的化合物1-32进行下述抗菌实验。The compounds 1-32 prepared in Examples 1-32 were subjected to the following antibacterial experiments.
1、试剂和材料1. Reagents and materials
实验样品：实施例1-32制备的化合物1-32。Experimental sample: Compound 1-32 prepared in Examples 1-32.
阳性对照：西咪匹韦(Simeprevir)和特拉匹韦(VX950，Telaprevir)，购自上海乐琛国际贸易有限公司；Positive controls: Simeprevir and Trapavi (VX950, Telaprevir), purchased from Shanghai Lechen International Trade Co., Ltd .;
实验细胞：Huh7.细胞，购自Vertex Pharmaceuticals,Boston MA。Experimental cells: Huh7. Cells, purchased from Vertex Pharmaceuticals, Boston, MA.
2、试验方法2. Test method
半最大效应浓度(EC50)的测定：Huh7.5细胞以3×10 4cells/cm 2的密度接种到96孔板中，培养24小时细胞贴壁后，用制备的HCV病毒上清液以45IU/cell的单位感染Huh7.5细胞，分别加入阳性对照药西咪匹韦(Simeprevir)和特拉匹韦(VX950，Telaprevir)和待测化合物1-32处理，成为对照组和实验组。 Determination of half-maximum effect concentration (EC50): Huh7.5 cells were seeded into 96-well plates at a density of 3 × 10 4 cells / cm 2 , and after 24 hours of culture, the cells adhered, and the prepared HCV virus supernatant was used at 45IU The unit of / cell is infected with Huh7.5 cells, and the positive control drugs Simeprevir (Simeprevir) and Trapivir (VX950, Telaprevir) and the test compounds 1-32 are added to the control and experimental groups, respectively.
MTT方法培养72小时后，用RNeasy Mini Kit提取细胞内RNA，用CytoBuster蛋白提取剂(Novagen)和1mM蛋白抑制剂处理细胞内总蛋白。用实时定量的RT-PCR检测HCV-RNA表达水平。EC50用Reed&Muench法计算。After 72 hours of incubation with the MTT method, RNeasy Mini Kit was used to extract intracellular RNA, and CytoBuster protein extract (Novagen) and 1 mM protein inhibitor were used to treat the total intracellular protein. Real-time quantitative RT-PCR was used to detect the expression level of HCV-RNA. EC50 is calculated by Reed & Muench method.
半数毒性浓度(CC50):Huh7.5细胞以3×10 4cells/cm 2的密度接种到96孔板中，培养24小时细胞贴壁后，加入配制的不同浓度的受试样品，用MTT方法培养72小时。CC50值用Reed&Muench法计算。 CC50: Huh7.5 cells were seeded into 96-well plates at a density of 3 × 10 4 cells / cm 2. After culturing for 24 hours, the cells adhered to the cells, added test samples of different concentrations, and used MTT Method cultured for 72 hours. The CC50 value is calculated using the Reed & Muench method.
3、试验结果3. Test results
上述试验结果如表1所示。表1为化合物1-32和阳性对照的抗HCV活性试验数据。The above test results are shown in Table 1. Table 1 is the test data of anti-HCV activity of compound 1-32 and positive control.
其中，EC 50越低表示药物活性越高，CC 50越高表示药物毒性越低。 Among them, the lower the EC 50, the higher the drug activity, and the higher the CC 50, the lower the drug toxicity.
化合物Chemical compound EC 50(μM) EC 50 (μM) CC 50(μM) CC 50 (μM) SI(CC50/EC50)SI (CC50 / EC50)
11 >4> 4 94.06±5.0694.06 ± 5.06 ＜23＜ 23
22 0.100.10 25.025.0 250250
33 〈0.09<0.09 3.473.47 >39> 39
44 0.2180.218 13.1513.15 60.360.3
55 0.2750.275 8.058.05 29.329.3
66 0.0260.026 10.8310.83 416.5416.5
77 0.0440.044 6.786.78 154.1154.1
88 0.1000.100 3.743.74 37.437.4
99 0.0600.060 2.142.14 35.735.7
1010 0.350.35 50.050.0 142.0142.0
1111 0.0510.051 5.785.78 113.3113.3
1212 0.0210.021 7.797.79 370.9370.9
1313 0.3150.315 6.096.09 19.319.3
1414 0.1740.174 2.322.32 13.313.3
1515 0.0830.083 12.5712.57 151.4151.4
1616 >4> 4 >100> 100  A
1717 1.1771.177 12.8612.86 10.910.9
1818 0.7810.781 14.3614.36 18.418.4
1919 0.3460.346 8.328.32 24.024.0
2020 0.6350.635 45.4745.47 71.671.6
21twenty one 0.2070.207 8.808.80 42.542.5
22twenty two >4> 4 >100> 100  A
23twenty three 1.1251.125 2.742.74 2.42.4
24twenty four 0.1700.170 55.3455.34 325.5325.5
2525 23.0223.02 >200> 200 8.78.7
2626 1.841.84 23.3023.30 1313
2727 0.300.30 15.3315.33 5151
2828 0.320.32 8.668.66 2727
2929 0.2170.217 7.877.87 36.336.3
3030 0.0590.059 5.255.25 89.089.0
3131 0.2610.261 9.939.93 38.238.2
3232 0.2530.253 65.6665.66 259.5259.5
SimeprevirSimeprevir 0.0080.008 38.0438.04 47554755
VX950VX950 0.0220.022 23.7323.73 1078.61078.6
通过表1可以看出，EC50和CC50的结果与阳性对照药相比，显示本申请的化合物1-32对于HCV病毒都具有明显的抗丙肝病毒效果，尤其是多数化合物的EC 50值在nMol级，此外，化合物6、12的EC 50值更是接近阳性对照药VX950，且SI值达到350以上，具有较强的抑制HCV病毒的效果，因此可作为先导化合物进行进一步研究。 It can be seen from Table 1 that the results of EC50 and CC50 show that the compounds 1-32 of the present application have a significant anti-hepatitis C virus effect against HCV virus, especially the EC 50 value of most compounds is in the nMol level. In addition, the EC 50 values of compounds 6 and 12 are close to the positive control drug VX950, and the SI value reaches 350 or more, which has a strong effect of inhibiting HCV virus, so it can be used as a lead compound for further research.
最后应说明的是：以上各实施例仅用以说明本申请的技术方案，而非对其限制；尽管参照前述各实施例对本申请进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本申请各实施例技术方案的范围。Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, not to limit them; although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: The technical solutions described in the foregoing embodiments can still be modified, or some or all of the technical features can be equivalently replaced; and these modifications or replacements do not deviate from the essence of the corresponding technical solutions of the technical solutions of the embodiments of the present application. range.

Claims (11)

  1. 一种取代的双芳香基酰胺化合物或其药用可接受的盐，其具有式[1]的结构：A substituted bisarylamide compound or a pharmaceutically acceptable salt thereof, which has the structure of formula [1]:
    Figure PCTCN2019118109-appb-100001
    Figure PCTCN2019118109-appb-100001
    其中，R 1独立地选自氢、取代或未取代的C 1－12直链烷基、C 3－12支链烷基或C 3－ 12环烷基；R 2独立地选自-NO 2、-NH 2、-NHCOR 5、-CF 3、-NHSO 2NH 2；R 3独立地选自氢、卤素、-CF 3、-F、-CN、-NO 2、-NH 2；R 4独立地选自氢、取代或未取代的杂环基；R 5独立地选自取代或未取代的C 1－12直链烷基或C 3－12支链烷基； Wherein, R 1 is independently selected from hydrogen, a substituted or unsubstituted C 1-12 straight chain alkyl, C 3-12 branched alkyl or C 3- 12 cycloalkyl; R 2 is independently selected from -NO 2 , -NH 2 , -NHCOR 5 , -CF 3 , -NHSO 2 NH 2 ; R 3 is independently selected from hydrogen, halogen, -CF 3 , -F, -CN, -NO 2 , -NH 2 ; R 4 is independently Selected from hydrogen, substituted or unsubstituted heterocyclic groups; R 5 is independently selected from substituted or unsubstituted C 1-12 straight-chain alkyl or C 3-12 branched-chain alkyl;
    X独立地选自氢原子或氮原子。X is independently selected from a hydrogen atom or a nitrogen atom.
  2. 根据权利要求1所述的取代的双芳香基酰胺化合物或其药用可接受的盐，其中，R 1独立地选自氢、取代或未取代的C 1－6直链烷基、C 3－6支链烷基或C 3－6环烷基。 The substituted bisarylamide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is independently selected from hydrogen, substituted or unsubstituted C 1-6 linear alkyl group, C 3- 6 branched chain alkyl or C 3-6 cycloalkyl.
  3. 根据权利要求1所述的取代的双芳香基酰胺化合物或其药用可接受的盐，其中，R 4独立地选自氢、或式[a]-式[e]所示的基团： The substituted bisarylamide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 is independently selected from hydrogen or a group represented by formula [a] -formula [e]:
    Figure PCTCN2019118109-appb-100002
    Figure PCTCN2019118109-appb-100002
    R a和R b独立地选自氢、C 1－6直链烷基或C 3－6支链烷基。 R a and R b are independently selected from hydrogen, C 1-6 linear alkyl or C 3-6 branched alkyl.
  4. 权利要求1-3任一所述的取代的双芳香基酰胺化合物或其药用可接受的盐的制备方法，包括以下步骤：The method for preparing the substituted bisarylamide compound or its pharmaceutically acceptable salt according to any one of claims 1-3, comprising the following steps
    式[2]所示的化合物和式[3]所示的化合物发生缩合反应，生成式[1a]所示的化合物，
    Figure PCTCN2019118109-appb-100003
    The compound represented by formula [2] and the compound represented by formula [3] undergo a condensation reaction to produce the compound represented by formula [1a],
    Figure PCTCN2019118109-appb-100003
    其中，Rc独立的选自-NO 2、-CF 3。 Among them, Rc is independently selected from -NO 2 and -CF 3 .
  5. 根据权利要求4所述的取代的双芳香基酰胺化合物或其药用可接受的盐的制备方法，还包括以下步骤：The method for preparing the substituted bisarylamide compound or the pharmaceutically acceptable salt thereof according to claim 4, further comprising the following steps:
    式[1a]所示的化合物发生还原反应生成式[1b]所示的化合物，The compound represented by formula [1a] undergoes a reduction reaction to produce the compound represented by formula [1b],
    Figure PCTCN2019118109-appb-100004
    Figure PCTCN2019118109-appb-100004
  6. 根据权利要求4所述的取代的双芳香基酰胺化合物或其药用可接受的盐的制备方法，其中，R 4选自式[a]-式[e]所示的基团，还包括按照如下方法制备式[3]所示的化合物： The method for preparing a substituted bisarylamide compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein R 4 is selected from the group represented by formula [a] -formula [e], further including The compound represented by formula [3] is prepared as follows:
    式[4]所示的化合物经卤代反应得到式[5]所示的化合物；The compound represented by formula [4] is halogenated to obtain the compound represented by formula [5];
    式[5]所示的化合物与R 4H发生取代反应，生成式[6]所示的化合物； The compound represented by formula [5] undergoes substitution reaction with R 4 H to produce the compound represented by formula [6];
    式[6]所示的化合物经加氢还原，生成式[3]所示的化合物；The compound represented by formula [6] is reduced by hydrogenation to produce the compound represented by formula [3];
    Figure PCTCN2019118109-appb-100005
    Figure PCTCN2019118109-appb-100005
    其中，X 1为卤素原子。 Among them, X 1 is a halogen atom.
  7. 根据权利要求4所述的取代的双芳香基酰胺化合物或其药用可接受的盐的制备方法，其中，还包括制备式[2]所示的化合物的步骤：The method for preparing a substituted bisarylamide compound or a pharmaceutically acceptable salt thereof according to claim 4, further comprising the step of preparing the compound represented by formula [2]:
    式[7]所示的化合物发生取代反应，生成式[8]所示的化合物；The compound represented by formula [7] undergoes a substitution reaction to produce the compound represented by formula [8];
    式[8]所示的化合物发生水解反应生成式[2]所示的化合物；The compound represented by formula [8] undergoes a hydrolysis reaction to form the compound represented by formula [2];
    Figure PCTCN2019118109-appb-100006
    Figure PCTCN2019118109-appb-100006
  8. 根据权利要求4所述的取代的双芳香基酰胺化合物或其药用可接受的盐的制备方法，其中，所述缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和4-二甲氨基吡啶。The method for preparing a substituted bisarylamide compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein the condensing agent is 1- (3-dimethylaminopropyl) -3-ethyl carbon Diimine hydrochloride and 4-dimethylaminopyridine.
  9. 权要要求1-3任一所述的取代的双芳香基酰胺化合物或其药用可接受的盐在制备抗丙肝药物中的应用。The use of the substituted bis-arylamide compound described in any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of anti-hepatitis C drugs.
  10. 一种抗丙肝药物组合物，其包括作为抗丙肝有效成分的权利要求1-3任一项所述的取代的双芳香基酰胺化合物或其药用可接受的盐，还包括药剂学上可接受的药物辅料。An anti-hepatitis C pharmaceutical composition, which comprises as an anti-hepatitis C active ingredient the substituted bisarylamide compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and further includes a pharmaceutically acceptable Pharmaceutical excipients.
  11. 一种治疗丙型肝炎的方法，包括给患者适用权利要求10所述的药物组合物。A method for treating hepatitis C, comprising applying the pharmaceutical composition of claim 10 to a patient.
PCT/CN2019/118109 2018-11-15 2019-11-13 Substituted bis-aryl amide compound and preparation method and application therefor WO2020098710A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811361076.1A CN109503518B (en) 2018-11-15 2018-11-15 Substituted biaryl amide compound and preparation method and application thereof
CN201811361076.1 2018-11-15

Publications (1)

Publication Number Publication Date
WO2020098710A1 true WO2020098710A1 (en) 2020-05-22

Family

ID=65748731

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/118109 WO2020098710A1 (en) 2018-11-15 2019-11-13 Substituted bis-aryl amide compound and preparation method and application therefor

Country Status (2)

Country Link
CN (1) CN109503518B (en)
WO (1) WO2020098710A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022226182A1 (en) 2021-04-22 2022-10-27 Halia Therapeutics, Inc. Nek7 inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111943889B (en) * 2020-07-24 2022-07-22 中国医学科学院医药生物技术研究所 Bis-aryl amine compound and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101309902A (en) * 2005-09-16 2008-11-19 阿罗治疗有限公司 Biphenyl derivatives and their use in treating hepatitis c
CN102206172A (en) * 2010-03-30 2011-10-05 中国医学科学院医药生物技术研究所 Substituted diaryl compound and preparation method and antiviral application thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2622175A (en) * 1950-05-16 1952-12-16 Ciba Ltd Trisazo-dyestuffs
AU1529799A (en) * 1997-12-23 1999-07-12 Warner-Lambert Company Thiourea and benzamide compounds, compositions and methods of treating or preventing inflammatory diseases and atherosclerosis
GB0524436D0 (en) * 2005-11-30 2006-01-11 Novartis Ag Organic compounds
CN101553468A (en) * 2006-10-18 2009-10-07 诺瓦提斯公司 Organic compounds
CN101367749B (en) * 2008-09-28 2013-04-24 中国医学科学院医药生物技术研究所 A set of mesidino mesitoyl derivant, preparation and application thereof
WO2016029136A1 (en) * 2014-08-21 2016-02-25 Northwestern University 3-amidobenzamides and uses thereof for increasing cellular levels of a3g
CN105837575B (en) * 2015-01-13 2019-01-15 四川大学 3- acetenyl Pyrazolopyrimidine derivative and its preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101309902A (en) * 2005-09-16 2008-11-19 阿罗治疗有限公司 Biphenyl derivatives and their use in treating hepatitis c
CN102206172A (en) * 2010-03-30 2011-10-05 中国医学科学院医药生物技术研究所 Substituted diaryl compound and preparation method and antiviral application thereof

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DATABASE 0 15 January 2004 (2004-01-15), retrieved from STN Database accession no. 637728-72-4 *
DATABASE 0 15 January 2004 (2004-01-15), retrieved from STN Database accession no. 637728-73-5 *
DATABASE 0 15 January 2004 (2004-01-15), retrieved from STN Database accession no. 637730-54-2 *
DATABASE 0 15 January 2004 (2004-01-15), retrieved from STN Database accession no. 637730-56-4 *
DATABASE 0 16 January 2004 (2004-01-16), retrieved from STN Database accession no. 638153-92-1 *
DATABASE 0 16 January 2004 (2004-01-16), retrieved from STN Database accession no. 638153-96-5 *
DATABASE 0 9 August 2012 (2012-08-09), retrieved from STN Database accession no. 1388542-13-9 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022226182A1 (en) 2021-04-22 2022-10-27 Halia Therapeutics, Inc. Nek7 inhibitors

Also Published As

Publication number Publication date
CN109503518B (en) 2021-03-30
CN109503518A (en) 2019-03-22

Similar Documents

Publication Publication Date Title
CN109311851B (en) Dihydro pyrimidinyl benzazepine carboxamide compounds
CA2835229C (en) Quinazoline derivatives for the treatment of viral infections and further diseases
JP6134338B2 (en) Inhibitors of hepatitis B virus covalently closed circular DNA formation and methods for their use
JP5206405B2 (en) Imidazo [1,2-a] pyridine derivatives: production and pharmaceutical use
CN112341450B (en) Immunomodulator
JP6266639B2 (en) Alkylamide-substituted pyrimidine compounds useful for the modulation of IL-12, IL-23 and / or IFNα
CN101166726A (en) Quinoline and quinoxaline derivatives as inhibitors of kinase enzymatic activity
RU2522578C2 (en) Phenylpyrimidone derivatives, pharmaceutical compositions, methods for preparing and using them
ES2743199T3 (en) Indanone derivatives, pharmaceutically acceptable salts or optical isomers thereof, method of preparation thereof and pharmaceutical compositions containing them as active ingredient to prevent or treat viral diseases
EP2975023B1 (en) Guanidinobenzoic acid ester compound
JP2023537402A (en) Functionalized peptides as antiviral agents
WO2022161274A1 (en) Pyrimidine-2,4-diamine compound, preparation method therefor and use thereof
WO2020098710A1 (en) Substituted bis-aryl amide compound and preparation method and application therefor
WO2015070713A1 (en) Limonin oxime ether derivatives, preparation method and medicinal use thereof
WO2020125673A1 (en) Influenza virus replication inhibitor, intermediate and use thereof
EP1445250A1 (en) Novel amine derivative having human beta-tryptase inhibitory activity and drugs containing the same
WO2023025319A1 (en) Novel cytidine derivative and pharmaceutical composition and use thereof
ES2621901T3 (en) Piperazinyl pyrimidine derivatives, preparation method and its use
AU2013237073A1 (en) Crystalline form of a succinate salt
TW201031402A (en) New retinoid derivatives endowed with cytotoxic and/or antiangiogenic properties
WO2015109925A1 (en) Crystalline form of hepatitis c drug and preparation method, pharmaceutical composition and use thereof
JPH08198876A (en) A trans-n-(1h-pyrazolo(3,4-b)pyridine-4-yl)-4-guanidinomethyl cyclohexane carboxamide-1 methane sulfonic acid salt-1 hydrate
WO2016107542A1 (en) Pyrrole amide compound, preparation method therefor, and use thereof
WO2023055580A1 (en) Benzylthiophene derivatives
CN113979936A (en) 2-aryl ureido-N- [3- (4-morpholinyl) propyl ] nicotinamide compound and application thereof

Legal Events

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

Ref document number: 19885779

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19885779

Country of ref document: EP

Kind code of ref document: A1